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Sample records for early axon loss

  1. Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease.

    PubMed

    Caminiti, Silvia Paola; Presotto, Luca; Baroncini, Damiano; Garibotto, Valentina; Moresco, Rosa Maria; Gianolli, Luigi; Volonté, Maria Antonietta; Antonini, Angelo; Perani, Daniela

    2017-01-01

    A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinson's disease (PD). Recent neuropathological evidence however suggests that the axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to in vivo PD, and also to the mesolimbic system has not been investigated yet. We used [ 11 C]FeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21.8 ± 10.7) and 14 healthy controls similar for age. We also performed anatomically-driven partial correlation analysis to evaluate possible changes in the connectivity within both the dopamine networks at an early clinical phase. In the nigrostriatal system, we found a severe DAT reduction in the afferents to the dorsal putamen (DPU) (η 2  = 0.84), whereas the SN was the less affected region (η 2  = 0.31). DAT activity in the ventral tegmental area (VTA) and the ventral striatum (VST) were also reduced in the patient group, but to a lesser degree (VST η 2  = 0.71 and VTA η 2  = 0.31). In the PD patients compared to the controls, there was a marked decrease in dopamine network connectivity between SN and DPU nodes, supporting the significant derangement in the nigrostriatal pathway. These results suggest that neurodegeneration in the dopamine pathways is initially more prominent in the afferent axons and more severe in the nigrostriatal system. Considering PD as a disconnection syndrome starting from the axons, it would justify neuroprotective interventions even if patients have already manifested clinical symptoms.

  2. Axonal loss in the multiple sclerosis spinal cord revisited.

    PubMed

    Petrova, Natalia; Carassiti, Daniele; Altmann, Daniel R; Baker, David; Schmierer, Klaus

    2018-05-01

    Preventing chronic disease deterioration is an unmet need in people with multiple sclerosis, where axonal loss is considered a key substrate of disability. Clinically, chronic multiple sclerosis often presents as progressive myelopathy. Spinal cord cross-sectional area (CSA) assessed using MRI predicts increasing disability and has, by inference, been proposed as an indirect index of axonal degeneration. However, the association between CSA and axonal loss, and their correlation with demyelination, have never been systematically investigated using human post mortem tissue. We extensively sampled spinal cords of seven women and six men with multiple sclerosis (mean disease duration= 29 years) and five healthy controls to quantify axonal density and its association with demyelination and CSA. 396 tissue blocks were embedded in paraffin and immuno-stained for myelin basic protein and phosphorylated neurofilaments. Measurements included total CSA, areas of (i) lateral cortico-spinal tracts, (ii) gray matter, (iii) white matter, (iv) demyelination, and the number of axons within the lateral cortico-spinal tracts. Linear mixed models were used to analyze relationships. In multiple sclerosis CSA reduction at cervical, thoracic and lumbar levels ranged between 19 and 24% with white (19-24%) and gray (17-21%) matter atrophy contributing equally across levels. Axonal density in multiple sclerosis was lower by 57-62% across all levels and affected all fibers regardless of diameter. Demyelination affected 24-48% of the gray matter, most extensively at the thoracic level, and 11-13% of the white matter, with no significant differences across levels. Disease duration was associated with reduced axonal density, however not with any area index. Significant association was detected between focal demyelination and decreased axonal density. In conclusion, over nearly 30 years multiple sclerosis reduces axonal density by 60% throughout the spinal cord. Spinal cord cross sectional area

  3. Premyelinated central axons express neurotoxic NMDA receptors: relevance to early developing white-matter injury

    PubMed Central

    Huria, Tahani; Beeraka, Narasimha Murthy; Al-Ghamdi, Badrah; Fern, Robert

    2015-01-01

    Ischemic-type injury to developing white matter is associated with the significant clinical condition cerebral palsy and with the cognitive deficits associated with premature birth. Premyelinated axons are the major cellular component of fetal white matter and loss of axon function underlies the disability, but the cellular mechanisms producing ischemic injury to premyelinated axons have not previously been described. Injury was found to require longer periods of modelled ischemia than at latter developmental points. Ischemia produced initial hyperexcitability in axons followed by loss of function after Na+ and Ca2+ influx. N-methyl-D-aspartate- (NMDA) type glutamate receptor (GluR) agonists potentiated axon injury while antagonists were protective. The NMDA GluR obligatory Nr1 subunit colocalized with markers of small premyelinated axons and expression was found at focal regions of axon injury. Ischemic injury of glial cells present in early developing white matter was NMDA GluR independent. Axons in human postconception week 18 to 23 white matter had a uniform prediameter expansion phenotype and postembedded immuno-gold labelling showed Nr1 subunit expression on the membrane of these axons, demonstrating a shared key neuropathologic feature with the rodent model. Premyelinated central axons therefore express high levels of functional NMDA GluRs that confer sensitivity to ischemic injury. PMID:25515212

  4. Early Pregnancy Loss

    MedlinePlus

    ... known pregnancies. What causes early pregnancy loss? About one half of cases of early pregnancy loss are caused by a ... do not show any signs of an infection, one option is to wait and let the ... may take longer in some cases. Another option is to take medication that helps ...

  5. Regional Retinal Ganglion Cell Axon Loss in a Murine Glaucoma Model

    PubMed Central

    Schaub, Julie A.; Kimball, Elizabeth C.; Steinhart, Matthew R.; Nguyen, Cathy; Pease, Mary E.; Oglesby, Ericka N.; Jefferys, Joan L.; Quigley, Harry A.

    2017-01-01

    Purpose To determine if retinal ganglion cell (RGC) axon loss in experimental mouse glaucoma is uniform in the optic nerve. Methods Experimental glaucoma was induced for 6 weeks with a microbead injection model in CD1 (n = 78) and C57BL/6 (B6, n = 68) mice. From epoxy-embedded sections of optic nerve 1 to 2 mm posterior to the globe, total nerve area and regional axon density (axons/1600 μm2) were measured in superior, inferior, nasal, and temporal zones. Results Control eyes of CD1 mice have higher axon density and more total RGCs than control B6 mice eyes. There were no significant differences in control regional axon density in all mice or by strain (all P > 0.2, mixed model). Exposure to elevated IOP caused loss of RGC in both strains. In CD1 mice, axon density declined without significant loss of nerve area, while B6 mice had less density loss, but greater decrease in nerve area. Axon density loss in glaucoma eyes was not significantly greater in any region in either mouse strain (both P > 0.2, mixed model). In moderately damaged CD1 glaucoma eyes, and CD1 eyes with the greatest IOP elevation exposure, density loss differed by region (P = 0.05, P = 0.03, mixed model) with the greatest loss in the temporal and superior regions, while in severely injured B6 nerves superior loss was greater than inferior loss (P = 0.01, mixed model, Bonferroni corrected). Conclusions There was selectively greater loss of superior and temporal optic nerve axons of RGCs in mouse glaucoma at certain stages of damage. Differences in nerve area change suggest non-RGC responses differ between mouse strains. PMID:28549091

  6. Ectopic vesicular glutamate release at the optic nerve head and axon loss in mouse experimental glaucoma.

    PubMed

    Fu, Christine T; Sretavan, David W

    2012-11-07

    Although clinical and experimental observations indicate that the optic nerve head (ONH) is a major site of axon degeneration in glaucoma, the mechanisms by which local retinal ganglion cell (RGC) axons are injured and damage spreads among axons remain poorly defined. Using a laser-induced ocular hypertension (LIOH) mouse model of glaucoma, we found that within 48 h of intraocular pressure elevation, RGC axon segments within the ONH exhibited ectopic accumulation and colocalization of multiple components of the glutamatergic presynaptic machinery including the vesicular glutamate transporter VGLUT2, several synaptic vesicle marker proteins, glutamate, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex and active zone cytomatrix components, as well as ultrastructurally identified, synaptophysin-containing vesicles. Ectopic vesicle exocytosis and glutamate release were detected in acute preparations of the LIOH ONH. Immunolocalization and analysis using the ionotropic receptor channel-permeant cation agmatine indicated that ONH axon segments and glia expressed glutamate receptors, and these receptors were more active after LIOH compared with controls. Pharmacological antagonism of glutamate receptors and neuronal activity resulted in increased RGC axon sparing in vivo. Furthermore, in vivo RGC-specific genetic disruption of the vesicular glutamate transporter VGLUT2 or the obligatory NMDA receptor subunit NR1 promoted axon survival in experimental glaucoma. As the inhibition of ectopic glutamate vesicular release or glutamate receptivity can independently modify the severity of RGC axon loss, synaptic release mechanisms may provide useful therapeutic entry points into glaucomatous axon degeneration.

  7. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.

    PubMed

    Mei, Feng; Lehmann-Horn, Klaus; Shen, Yun-An A; Rankin, Kelsey A; Stebbins, Karin J; Lorrain, Daniel S; Pekarek, Kara; A Sagan, Sharon; Xiao, Lan; Teuscher, Cory; von Büdingen, H-Christian; Wess, Jürgen; Lawrence, J Josh; Green, Ari J; Fancy, Stephen Pj; Zamvil, Scott S; Chan, Jonah R

    2016-09-27

    Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.

  8. CD8+ T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis

    PubMed Central

    Schmalstieg, William F.; Sauer, Brian M.; Wang, Huan; German, Christopher L.; Windebank, Anthony J.; Rodriguez, Moses; Howe, Charles L.

    2010-01-01

    Background The objective of this study was to test the hypothesis that CD8+ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8+ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice. Methodology/Principal Findings To determine if CD8+ T cells are necessary and sufficient to directly injure demyelinated axons, we adoptively transferred purified perforin-competent CD8+ spinal cord-infiltrating T cells into profoundly demyelinated but functionally preserved perforin-deficient host mice. Transfer of CD8+ spinal cord-infiltrating T cells rapidly and irreversibly impaired motor function, disrupted spinal cord motor conduction, and reduced the number of medium- and large-caliber spinal axons. Likewise, immunodepletion of CD8+ T cells from chronically demyelinated wildtype mice preserved motor function and limited axon loss without altering other disease parameters. Conclusions/Significance In multiple sclerosis patients, CD8+ T cells outnumber CD4+ T cells in active lesions and the number of CD8+ T cells correlates with the extent of ongoing axon injury and functional disability. Our findings suggest that CD8+ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis. PMID:20814579

  9. Age related optic nerve axonal loss in adult Brown Norway rats.

    PubMed

    Cepurna, William O; Kayton, Robert J; Johnson, Elaine C; Morrison, John C

    2005-06-01

    The effect of age on the number and morphology of optic nerve axons in adult Brown Norway rats (5-31 months old) (n=29) was examined using transmission electron microscopy (TEM). By manually counting every axon in areas representing 60% of the optic nerve cross-section, we found a significant negative correlation between age and axon count (R(2)=0.18, P<0.05). However, when the oldest animals were omitted, the relationship was no longer statistically significant. Simultaneously, the proportion of spontaneously degenerating axons increased at an exponential rate (R(2)=0.79, P<0.05), with significantly more degeneration in the 31-month group than in 5-month-old animals (ANOVA, P<0.05). This study demonstrates, using quantitative TEM methods, that optic nerve axonal numbers are relatively constant throughout the majority of the adult life of the Brown Norway rat, an increasingly popular strain for glaucoma research. Total axonal loss with aging is substantially less than that reported for other strains. The reduction in axonal numbers and the rate of axonal degeneration do not appear significantly altered until the last few months of life, failing to support some studies that have concluded that optic nerve axon loss in adult rats is linear. However, they do agree with other studies in the rat, and a similar study performed in non-human primate eyes, that concluded that aging changes in the optic nerve and retina follow a complex pattern. Therefore, the impact of animal age must be considered when modeling the course and pathophysiology of experimental glaucomatous optic nerve damage in rats.

  10. c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy

    PubMed Central

    Hantke, Janina; Carty, Lucy; Wagstaff, Laura J.; Turmaine, Mark; Wilton, Daniel K.; Quintes, Susanne; Koltzenburg, Martin; Baas, Frank; Mirsky, Rhona

    2014-01-01

    Charcot–Marie–Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot–Marie–Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot–Marie–Tooth disease type 1A. In line with our previous findings in humans with Charcot–Marie–Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun−/− mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot–Marie–Tooth disease type 1A: on the one hand they are the genetic source of

  11. Early development of the circumferential axonal pathway in mouse and chick spinal cord.

    PubMed

    Holley, J A

    1982-03-10

    The early development of the circumferential axonal pathway in the brachial and lumbar spinal cord of mouse and chick embryos was studied by scanning and transmission electron microscopy. The cellular processes which comprise this pathway grow in the transverse plane and along the lateral margin of the marginal zone (i.e., circumferentially oriented), as typified by the early embryonic commissural axons. The first formative event observed was in the ventrolateral margin of the primitive spinal cord ventricular zone. Cellular processes were found near the external limiting membrane that appeared to grow a variable distance either dorsally or ventrally. Later in development, presumptive motor column neurons migrated into the ventrolateral region, distal to these early circumferentially oriented processes. Concurrently, other circumferentially oriented perikarya and processes appeared along the dorsolateral margin. Due to their aligned sites of origin and parallel growth, the circumferential processes formed a more or less continuous line or pathway, which in about 10% of the scanned specimens could be followed along the entire lateral margin of the embryonic spinal cord. Several specimens later in development had two sets of aligned circumferential processes in the ventral region. Large numbers of circumferential axons were then found to follow the preformed pathway by fasciculation, after the primitive motor column had become established. Since the earliest circumferential processes appeared to differentiate into axons and were found nearly 24 hours prior to growth of most circumferential axons, their role in guidance as pioneering axons was suggested.

  12. Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons

    PubMed Central

    Berthet, Amandine; Margolis, Elyssa B.; Zhang, Jue; Hsieh, Ivy; Zhang, Jiasheng; Hnasko, Thomas S.; Ahmad, Jawad; Edwards, Robert H.; Sesaki, Hiromi; Huang, Eric J.

    2014-01-01

    Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics—mitochondrial fission—in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate–putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons. PMID:25339743

  13. Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons.

    PubMed

    Berthet, Amandine; Margolis, Elyssa B; Zhang, Jue; Hsieh, Ivy; Zhang, Jiasheng; Hnasko, Thomas S; Ahmad, Jawad; Edwards, Robert H; Sesaki, Hiromi; Huang, Eric J; Nakamura, Ken

    2014-10-22

    Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics-mitochondrial fission-in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate-putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons. Copyright © 2014 the authors 0270-6474/14/3414304-14$15.00/0.

  14. The "waiting period" of sensory and motor axons in early chick hindlimb: its role in axon pathfinding and neuronal maturation.

    PubMed

    Wang, G; Scott, S A

    2000-07-15

    During embryonic development motor axons in the chick hindlimb grow out slightly before sensory axons and wait in the plexus region at the base of the limb for approximately 24 hr before invading the limb itself (Tosney and Landmesser, 1985a). We have investigated the role of this waiting period by asking, Is the arrest of growth cones in the plexus region a general property of both sensory and motor axons? Why do axons wait? Does eliminating the waiting period affect the further development of motor and sensory neurons? Here we show that sensory axons, like motor axons, pause in the plexus region and that neither sensory nor motor axons require cues from the other population to wait in or exit from the plexus region. By transplanting older or younger donor limbs to host embryos, we show that host axons innervate donor limbs on a schedule consistent with the age of the grafted limbs. Thus, axons wait in the plexus region for maturational changes to occur in the limb rather than in the neurons themselves. Both sensory and motor axons innervate their appropriate peripheral targets when the waiting period is eliminated by grafting older donor limbs. Therefore, axons do not require a prolonged period in the plexus region to sort out and project appropriately. Eliminating the waiting period does, however, accelerate the onset of naturally occurring cell death, but it does not enhance the development of central projections or the biochemical maturation of sensory neurons.

  15. Mice with GFAP-targeted loss of neurofibromin demonstrate increased axonal MET expression with aging.

    PubMed

    Su, Weiping; Xing, Rubing; Guha, Abhijit; Gutmann, David H; Sherman, Larry S

    2007-05-01

    Neurofibromatosis 1 (NF1) is a common genetic disease that predisposes patients to peripheral nerve tumors and central nervous system (CNS) abnormalities including low-grade astrocytomas and cognitive disabilities. Using mice with glial fibrillary acidic protein (GFAP)-targeted Nf1 loss (Nf1(GFAP)CKO mice), we found that Nf1(-/-) astrocytes proliferate faster and are more invasive than wild-type astrocytes. In light of our previous finding that aberrant expression of the MET receptor tyrosine kinase contributes to the invasiveness of human NF1-associated malignant peripheral nerve sheath tumors, we sought to determine whether MET expression is aberrant in the brains of Nf1 mutant mice. We found that Nf1(-/-) astrocytes express slightly more MET than wild-type cells in vitro, but do not express elevated MET in situ. However, fiber tracts containing myelinated axons in the hippocampus, midbrain, cerebral cortex, and cerebellum express higher than normal levels of MET in older (> or =6 months) Nf1(GFAP)CKO mice. Both Nf1(GFAP)CKO and wild-type astrocytes induced MET expression in neurites of wild-type hippocampal neurons in vitro, suggesting that astrocyte-derived signals may induce MET in Nf1 mutant mice. Because the Nf1 gene product functions as a RAS GTPase, we examined MET expression in the brains of mice with GFAP-targeted constitutively active forms of RAS. MET was elevated in axonal fiber tracts in mice with active K-RAS but not H-RAS. Collectively, these data suggest that loss of Nf1 in either astrocytes or GFAP(+) neural progenitor cells results in increased axonal MET expression, which may contribute to the CNS abnormalities in children and adults with NF1. (c) 2007 Wiley-Liss, Inc.

  16. Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice.

    PubMed

    Martin, Nellie A; Molnar, Viktor; Szilagyi, Gabor T; Elkjaer, Maria L; Nawrocki, Arkadiusz; Okarmus, Justyna; Wlodarczyk, Agnieszka; Thygesen, Eva K; Palkovits, Miklos; Gallyas, Ferenc; Larsen, Martin R; Lassmann, Hans; Benedikz, Eirikur; Owens, Trevor; Svenningsen, Asa F; Illes, Zsolt

    2018-01-01

    The cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes differentiation of oligodendrocyte precursor cells (OPCs) during remyelination, but its role has not been examined during demyelination. MicroRNAs were examined by Agilent Mouse miRNA Microarray in the corpus callosum during CPZ-induced demyelination and remyelination. Demyelination, axonal loss, changes in number of oligodendrocytes, OPCs, and macrophages/microglia was compared by histology/immunohistochemistry between KO and WT mice. Differential expression of target genes and proteins of miR-146a was analyzed in the transcriptome (4 × 44K Agilent Whole Mouse Genome Microarray) and proteome (liquid chromatography tandem mass spectrometry) of CPZ-induced de- and remyelination in WT mice. Levels of proinflammatory molecules in the corpus callosum were compared in WT versus KO mice by Meso Scale Discovery multiplex protein analysis. miR-146a was increasingly upregulated during CPZ-induced de- and remyelination. The absence of miR-146a in KO mice protected against demyelination, axonal loss, body weight loss, and atrophy of thymus and spleen. The number of CNP + oligodendrocytes was increased during demyelination in the miR-146a KO mice, while there was a trend of increased number of NG2 + OPCs in the WT mice. miR-146a target genes, SNAP25 and SMAD4, were downregulated in the proteome of demyelinating corpus callosum in WT mice. Higher levels of SNAP25 were measured by ELISA in the corpus callosum of miR-146a KO mice, but there was no difference between KO and WT mice during demyelination. Multiplex protein analysis of the corpus callosum lysate revealed upregulated TNF-RI, TNF-RII, and CCL2 in the WT mice in contrast to KO mice. The number of Mac3 + and Iba1 + macrophages/microglia was

  17. [Total brain T2-hyperintense lesion-volume and the axonal damage in the normal-appearing white matter of brainstem in early lapsing-remitting multiple sclerosis].

    PubMed

    Pascual-Lozano, A M; Martínez-Bisbal, M C; Boscá-Blasco, I; Valero-Merino, C; Coret-Ferrer, F; Martí-Bonmatí, L; Martínez-Granados, B; Celda, B; Casanova-Estruch, B

    To evaluate the relationship between the total brain T2-hyperintense lesion volume (TBT2LV) and the axonal damage in the normal-appearing white matter of brainstem measured by 1H-MRS in a group of early relapsing-remitting multiple sclerosis patients. 40 relapsing-remitting multiple sclerosis patients and ten sex- and age-matched healthy subjects were prospectively studied for two years. T2-weighted MR and 1H-MRS imaging were acquired at time of recruitment and at year two. The TBT2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) resonances areas were integrated with jMRUI program and the ratios were calculated for four volume elements that represented the brainstem. At basal study we obtained an axonal loss (as a decrement of NAA/ Cho ratio) in the group of patients compared with controls (p = 0.017); this axonal loss increased at the second year of the follow-up for patients (NAA/Cho decrease, p = 0.004, and NAA/Cr decrease, p = 0.002) meanwhile control subjects had no significant metabolic changes. Higher lesion load was correlated with a poor clinical outcome, being the correlation between the basal TBT2LV and the Expanded Disability Status Scale at second year (r = 0.299; p = 0.05). Besides, axonal loss was not homogeneous for all multiple sclerosis patients, being stronger in the subgroup of patients with high basal TBT2LV (p = 0.043; ANOVA). Our data suggest that axonal damage is early in multiple sclerosis and higher in patients high basal TBT2LV, suggesting a possible relationship between these two phenomena.

  18. Axonal loss in patients with inflammatory demyelinating polyneuropathy as determined by motor unit number estimation and MUNIX.

    PubMed

    Paramanathan, Sansuthan; Tankisi, Hatice; Andersen, Henning; Fuglsang-Frederiksen, Anders

    2016-01-01

    This study quantifies functioning axons and reinnervation by applying two methods multiple point stimulation (MPS) MUNE, and motor unit number index (MUNIX), in patients with acute- and chronic inflammatory demyelinating polyneuropathy (AIDP, CIDP). Nineteen patients with inflammatory demyelinating polyneuropathy (eleven AIDP and eight CIDP) were prospectively included. MPS MUNE and MUNIX examinations on the thenar muscle group by stimulating the median nerve were applied on all patients. Motor unit size was calculated as single motor unit potential (sMUP) and motor unit size index (MUSIX). The results were compared with twenty healthy subjects. In AIDP patients mean MPS MUNE (106) and MUNIX (80) were lower than control MPS MUNE (329) and MUNIX (215) (p<0.001). In CIDP patients both MPS MUNE (88) and MUNIX (67) were lower than controls (p<0.001). In CIDP patients sMUP (63) and MUSIX (90) were higher than control sMUP (35) and MUSIX (58) (p<0.05 and p<0.01). When AIDP and CIDP groups were combined the sensitivity for MPS MUNE and MUNIX were 89.5% and 68.4%, respectively. Decreased MPS MUNE and MUNIX suggest presence of axonal loss or loss of functioning axons in AIDP and CIDP. Increased motor unit size in CIDP patients indicates compensatory reinnervation. Moreover, both MPS MUNE and MUNIX can discriminate between disease versus non-disease. Estimation of the number and the average size of motor units may have clinical value for the assessment of axonal loss or loss of functioning axons in patients with AIDP and CIDP. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  19. ApoE influences regional white-matter axonal density loss in Alzheimer's disease.

    PubMed

    Slattery, Catherine F; Zhang, Jiaying; Paterson, Ross W; Foulkes, Alexander J M; Carton, Amelia; Macpherson, Kirsty; Mancini, Laura; Thomas, David L; Modat, Marc; Toussaint, Nicolas; Cash, David M; Thornton, John S; Henley, Susie M D; Crutch, Sebastian J; Alexander, Daniel C; Ourselin, Sebastien; Fox, Nick C; Zhang, Hui; Schott, Jonathan M

    2017-09-01

    Mechanisms underlying phenotypic heterogeneity in young onset Alzheimer disease (YOAD) are poorly understood. We used diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI) with tract-based spatial statistics to investigate apolipoprotein (APOE) ε4 modulation of white-matter damage in 37 patients with YOAD (22, 59% APOE ε4 positive) and 23 age-matched controls. Correlation between neurite density index (NDI) and neuropsychological performance was assessed in 4 white-matter regions of interest. White-matter disruption was more widespread in ε4+ individuals but more focal (posterior predominant) in the absence of an ε4 allele. NODDI metrics indicate fractional anisotropy changes are underpinned by combinations of axonal loss and morphological change. Regional NDI in parieto-occipital white matter correlated with visual object and spatial perception battery performance (right and left, both p = 0.02), and performance (nonverbal) intelligence (WASI matrices, right, p = 0.04). NODDI provides tissue-specific microstructural metrics of white-matter tract damage in YOAD, including NDI which correlates with focal cognitive deficits, and APOEε4 status is associated with different patterns of white-matter neurodegeneration. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Myelin Loss and Axonal Ion Channel Adaptations Associated with Gray Matter Neuronal Hyperexcitability

    PubMed Central

    Hamada, Mustafa S.

    2015-01-01

    Myelination and voltage-gated ion channel clustering at the nodes of Ranvier are essential for the rapid saltatory conduction of action potentials. Whether myelination influences the structural organization of the axon initial segment (AIS) and action potential initiation is poorly understood. Using the cuprizone mouse model, we combined electrophysiological recordings with immunofluorescence of the voltage-gated Nav1.6 and Kv7.3 subunits and anchoring proteins to analyze the functional and structural properties of single demyelinated neocortical L5 axons. Whole-cell recordings demonstrated that neurons with demyelinated axons were intrinsically more excitable, characterized by increased spontaneous suprathreshold depolarizations as well as antidromically propagating action potentials ectopically generated in distal parts of the axon. Immunofluorescence examination of demyelinated axons showed that βIV-spectrin, Nav1.6, and the Kv7.3 channels in nodes of Ranvier either dissolved or extended into the paranodal domains. In contrast, while the AIS in demyelinated axons started more closely to the soma, ankyrin G, βIV-spectrin, and the ion channel expression were maintained. Structure–function analysis and computational modeling, constrained by the AIS location and realistic dendritic and axonal morphologies, confirmed that a more proximal onset of the AIS slightly reduced the efficacy of action potential generation, suggesting a compensatory role. These results suggest that oligodendroglial myelination is not only important for maximizing conduction velocity, but also for limiting hyperexcitability of pyramidal neurons. PMID:25948275

  1. Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease–Related Tau Phosphorylation Via PAR-1

    PubMed Central

    Iijima-Ando, Kanae; Sekiya, Michiko; Suzuki, Emiko; Lu, Bingwei; Iijima, Koichi M.

    2012-01-01

    Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In this study, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity in vivo. Using transgenic Drosophila expressing human tau, we found that RNAi–mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD–related site Ser262 increased with knockdown of milton or Miro; and partitioning defective-1 (PAR-1), the Drosophila homolog of mammalian microtubule affinity-regulating kinase, mediated this increase of tau phosphorylation. Tau phosphorylation at Ser262 has been reported to promote tau detachment from microtubules, and we found that the levels of microtubule-unbound free tau increased by milton knockdown. Blocking tau phosphorylation at Ser262 site by PAR-1 knockdown or by mutating the Ser262 site to unphosphorylatable alanine suppressed the enhancement of tau-induced neurodegeneration caused by milton knockdown. Furthermore, knockdown of milton or Miro increased the levels of active PAR-1. These results suggest that an increase in tau phosphorylation at Ser262 through PAR-1 contributes to tau-mediated neurodegeneration under a pathological condition in which axonal mitochondria is depleted. Intriguingly, we found that knockdown of milton or Miro alone caused late-onset neurodegeneration in the fly brain, and this neurodegeneration could be suppressed by knockdown of Drosophila tau or PAR-1. Our results suggest that loss of axonal mitochondria may play an important role in tau phosphorylation and toxicity in the pathogenesis of AD. PMID:22952452

  2. Decreased Axon Caliber Underlies Loss of Fiber Tract Integrity, Disproportional Reductions in White Matter Volume, and Microcephaly in Angelman Syndrome Model Mice

    PubMed Central

    Judson, Matthew C.; Burette, Alain C.; Shen, Mark D.; Rumple, Ashley M.; Del Cid, Wilmer A.; Paniagua, Beatriz

    2017-01-01

    Angelman syndrome (AS) is a debilitating neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A allele. It is currently unclear how the consequences of this genetic insult unfold to impair neurodevelopment. We reasoned that by elucidating the basis of microcephaly in AS, a highly penetrant syndromic feature with early postnatal onset, we would gain new insights into the mechanisms by which maternal UBE3A loss derails neurotypical brain growth and function. Detailed anatomical analysis of both male and female maternal Ube3a-null mice reveals that microcephaly in the AS mouse model is primarily driven by deficits in the growth of white matter tracts, which by adulthood are characterized by densely packed axons of disproportionately small caliber. Our results implicate impaired axon growth in the pathogenesis of AS and identify noninvasive structural neuroimaging as a potentially valuable tool for gauging therapeutic efficacy in the disorder. SIGNIFICANCE STATEMENT People who maternally inherit a deletion or nonfunctional copy of the UBE3A gene develop Angelman syndrome (AS), a severe neurodevelopmental disorder. To better understand how loss of maternal UBE3A function derails brain development, we analyzed brain structure in a maternal Ube3a knock-out mouse model of AS. We report that the volume of white matter (WM) is disproportionately reduced in AS mice, indicating that deficits in WM development are a major factor underlying impaired brain growth and microcephaly in the disorder. Notably, we find that axons within the WM pathways of AS model mice are abnormally small in caliber. This defect is associated with slowed nerve conduction, which could contribute to behavioral deficits in AS, including motor dysfunction. PMID:28663201

  3. The effects of voluntary running exercise coincidence with social isolation after early weaning on monoaminergic axonal development.

    PubMed

    Ishikawa, J; Ishikawa, A

    2013-01-29

    The axonal development of serotonin (5-HT)-, noradrenaline (NA)-, or tyrosine hydroxylase (TH)-containing monoaminergic neurons is affected by rearing conditions during the juvenile period. Impaired monoaminergic axonal development is implicated in the pathophysiology of emotional and cognitive dysfunction. On the other hand, exercise may have beneficial effects on emotional and learning performance in adults. We have examined whether voluntary running exercise during social isolation after early weaning (early weaning/social isolation; EI) from postnatal day (PD) 14-28 could prevent the impaired monoaminergic axonal development associated with EI. Compared with control animals reared with their dam and siblings until PD28, the EI animals showed lower density of 5-HT and NA axons in the dorsal-medial prefrontal cortex (mPFC) and basolateral nucleus of the amygdala and of NA- and TH-containing axons in the ventral-mPFC. These adverse effects of EI were not observed in rats taking part in voluntary running (EI+R) when these animals were compared to controls. The 5-HT axon density in the ventral-mPFC was significantly higher in the EI+R rats than that in the EI rats, although both these values were significantly lower than those in the control rats. The density of monoaminergic axons in the dentate gyrus and CA3 of the hippocampus was not affected by either EI or EI+R. These results suggest that the beneficial effects of voluntary running may be because of the modulation of monoaminergic axonal morphology. Our findings will hopefully provide the basis for future research into the beneficial effects of voluntary exercise during the juvenile period on brain development and emotional and cognitive performance. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Progressive Chronic Retinal Axonal Loss Following Acute Methanol-Induced Optic Neuropathy: Four-Year Prospective Cohort Study.

    PubMed

    Nurieva, Olga; Diblik, Pavel; Kuthan, Pavel; Sklenka, Petr; Meliska, Martin; Bydzovsky, Jan; Heissigerova, Jarmila; Urban, Pavel; Kotikova, Katerina; Navratil, Tomas; Komarc, Martin; Seidl, Zdenek; Vaneckova, Manuela; Pelclova, Daniela; Zakharov, Sergey

    2018-04-27

    To study the dynamics and clinical determinants of chronic retinal nerve fiber layer thickness (RNFL) loss after methanol-induced optic neuropathy. Prospective cohort study. All patients underwent complete ophthalmic evaluation including SD-OCT three times during four years of observation:4.9[±0.6], 25.0[±0.6], and 49.9[±0.5] months after discharge. Eighty-four eyes of 42 survivors of methanol poisoning; mean age (standard deviation) of 45.7[±4.4] years, and 82 eyes of 41 controls; mean age 44.0[±4.2] years. global and temporal RNFL loss. Abnormal RNFL thickness was registered in 13/42(31%) survivors of methanol poisoning and chronic axonal loss in 10/42(24%) patients. Significant decrease of global/temporal RNFL thickness during the observation period was found in the study population compared to the controls (p<0.001). The risk estimate of chronic global RNFL loss for arterial blood pH<7.3 at admission was: 11.65(1.91-71.12;95%CI) after adjusting for age and sex. The patients with chronic axonal degeneration demonstrated progressive visual loss in 7/10 cases. The patients with abnormal RNFL thickness had magnetic resonance signs of brain damage in 10/13 versus 8/29 cases with normal RNFL thickness (p=0.003). Signs of brain hemorrhages were present in 7/13 patients with abnormal RNFL thickness versus 5/29 cases with normal RNFL thickness (p=0.015). Methanol-induced optic neuropathy may lead to chronic retinal axonal loss during the following years. Arterial blood pH on admission is the strongest predictor of chronic RNFL thickness decrease. Chronic retinal neurodegeneration is associated with the progressive loss of visual functions and necrotic brain lesions. Copyright © 2018. Published by Elsevier Inc.

  5. Xanthine Oxidase Mediates Axonal and Myelin Loss in a Murine Model of Multiple Sclerosis

    PubMed Central

    Okuno, Tatsusada; Takata, Kazushiro; Koda, Toru; Tada, Satoru; Shirakura, Takashi; Fujimura, Harutoshi; Mochizuki, Hideki; Sakoda, Saburo; Nakatsuji, Yuji

    2013-01-01

    Objectives Oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS). Though reactive oxygen species (ROS) are produced by various mechanisms, xanthine oxidase (XO) is a major enzyme generating ROS in the context of inflammation. The objectives of this study were to investigate the involvement of XO in the pathogenesis of MS and to develop a potent new therapy for MS based on the inhibition of ROS. Methods XO were assessed in a model of MS: experimental autoimmune encephalomyelitis (EAE). The contribution of XO-generated ROS to the pathogenesis of EAE was assessed by treating EAE mice with a novel XO inhibitor, febuxostat. The efficacy of febuxostat was also examined in in vitro studies. Results We showed for the first time that the expression and the activity of XO were increased dramatically within the central nervous system of EAE mice as compared to naïve mice. Furthermore, prophylactic administration of febuxostat, a XO inhibitor, markedly reduced the clinical signs of EAE. Both in vivo and in vitro studies showed infiltrating macrophages and microglia as the major sources of excess XO production, and febuxostat significantly suppressed ROS generation from these cells. Inflammatory cellular infiltration and glial activation in the spinal cord of EAE mice were inhibited by the treatment with febuxostat. Importantly, therapeutic efficacy was observed not only in mice with relapsing-remitting EAE but also in mice with secondary progressive EAE by preventing axonal loss and demyelination. Conclusion These results highlight the implication of XO in EAE pathogenesis and suggest XO as a target for MS treatment and febuxostat as a promising therapeutic option for MS neuropathology. PMID:23951137

  6. The effect of hyperbaric oxygen treatment on early regeneration of sensory axons after nerve crush in the rat.

    PubMed

    Bajrović, Fajko F; Sketelj, Janez; Jug, Marko; Gril, Iztok; Mekjavić, Igor B

    2002-09-01

    Abstract The effect of hyperbaric oxygen treatment (HBO) on sensory axon regeneration was examined in the rat. The sciatic nerve was crushed in both legs. In addition, the distal stump of the sural nerve on one side was made acellular and its blood perfusion was compromised by freezing and thawing. Two experimental groups received hyperbaric exposures (2.5 ATA) to either compressed air (pO2 = 0.5 ATA) or 100% oxygen (pO2 = 2.5 ATA) 90 minutes per day for 6 days. Sensory axon regeneration in the sural nerve was thereafter assessed by the nerve pinch test and immunohistochemical reaction to neurofilament. HBO treatment increased the distances reached by the fastest regenerating sensory axons by about 15% in the distal nerve segments with preserved and with compromised blood perfusion. There was no significant difference between the rats treated with different oxygen tensions. The total number of regenerated axons in the distal sural nerve segments after a simple crush injury was not affected, whereas in the nerve segments with compromised blood perfusion treated by the higher pO2, the axon number was about 30% lower than that in the control group. It is concluded that the beneficial effect of HBO on sensory axon regeneration is not dose-dependent between 0.5 and 2.5 ATA pO2. Although the exposure to 2.5 ATA of pO2 moderately enhanced early regeneration of the fastest sensory axons, it decreased the number of regenerating axons in the injured nerves with compromised blood perfusion of the distal nerve stump.

  7. Treadmill Training Enhances Axon Regeneration In Injured Mouse Peripheral Nerves Without Increased Loss of Topographic Specificity

    PubMed Central

    English, Arthur W.; Cucoranu, Delia; Mulligan, Amanda; Sabatier, Manning

    2009-01-01

    We investigated the extent of misdirection of regenerating axons when that regeneration was enhanced using treadmill training. Retrograde fluorescent tracers were applied to the cut proximal stumps of the tibial and common fibular nerves two or four weeks after transection and surgical repair of the mouse sciatic nerve. The spatial locations of retrogradely labeled motoneurons were studied in untreated control mice and in mice receiving two weeks of treadmill training, either according to a continuous protocol (10 m/min, one hour/day, five day/week) or an interval protocol (20 m/min for two minutes, followed by a five minute rest, repeated 4 times, five days/week). More retrogradely labeled motoneurons were found in both treadmill trained groups. The magnitude of this increase was as great as or greater than that found after using other enhancement strategies. In both treadmill trained groups, the proportions of motoneurons labeled from tracer applied to the common fibular nerve that were found in spinal cord locations reserved for tibial motoneurons in intact mice was no greater than in untreated control mice and significantly less than found after electrical stimulation or chondroitinase treatment. Treadmill training in the first two weeks following peripheral nerve injury produces a marked enhancement of motor axon regeneration without increasing the propensity of those axons to choose pathways leading to functionally inappropriate targets. PMID:19731339

  8. Axonal loss from acute optic neuropathy documented by scanning laser polarimetry

    PubMed Central

    Meier, F M; Bernasconi, P; Stürmer, J; Caubergh, M-J; Landau, K

    2002-01-01

    Background/aims: Retinal nerve fibre layer analysis by scanning laser polarimetry has been shown to facilitate diagnosis of glaucoma while its role in glaucoma follow up is still unclear. A major difficulty is the slow reduction of retinal nerve fibre layer thickness in glaucomatous optic neuropathy. Eyes of patients were studied after acute retrobulbar optic nerve lesion in order to evaluate the usefulness of scanning laser polarimetry in documenting retinal nerve fibre layer loss over time. Methods: Five patients who suffered severe retrobulbar optic neuropathy have had repeated measurements of the retinal nerve fibre layer using scanning laser polarimetry at various intervals, the first examination being within 1 week of injury. Results: All eyes showed a marked decrease in peripapillary retinal nerve fibre layer thickness, which followed an exponential curve and occurred predominantly within 8 weeks of injury. Compared to a previous study using red-free photographs, scanning laser polarimetry showed retinal nerve fibre layer loss earlier in the course of descending atrophy. Conclusion: Scanning laser polarimetry is useful for early detection and documentation of retinal nerve fibre layer loss following acute injury to the retrobulbar optic nerve. It seems to be a promising tool for follow up of individual glaucoma patients. PMID:11864884

  9. Early and Selective Impairments in Axonal Transport Kinetics of Synaptic Cargoes Induced by Soluble Amyloid β-Protein Oligomers

    PubMed Central

    Tang, Yong; Scott, David A.; Das, Utpal; Edland, Steven D.; Radomski, Kryslaine; Koo, Edward H.; Roy, Subhojit

    2013-01-01

    The downstream targets of amyloid β (Aβ)-oligomers remain elusive. One hypothesis is that Aβ-oligomers interrupt axonal transport. Although previous studies have demonstrated Aβ-induced transport blockade, early effects of low-n soluble Aβ-oligomers on axonal transport remain unclear. Furthermore, the cargo selectivity for such deficits (if any) or the specific effects of Aβ on the motility kinetics of transported cargoes are also unknown. Toward this, we visualized axonal transport of vesicles in cultured hippocampal neurons treated with picomolar (pm) levels of cell-derived soluble Aβ-oligomers. We examined select cargoes thought to move as distinct organelles and established imaging parameters that allow organelle tracking with consistency and high fidelity – analyzing all data in a blinded fashion. Aβ-oligomers induced early and selective diminutions in velocities of synaptic cargoes but had no effect on mitochondrial motility, contrary to previous reports. These changes were N-methyl d-aspartate receptor/glycogen synthase kinase-3β dependent and reversible upon washout of the oligomers. Cluster-mode analyses reveal selective attenuations in faster-moving synaptic vesicles, suggesting possible decreases in cargo/motor associations, and biochemical experiments implicate tau phosphorylation in the process. Collectively, the data provide a biological basis for Aβ-induced axonal transport deficits. PMID:22309053

  10. Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia

    PubMed Central

    Denton, Kyle R.; Lei, Ling; Grenier, Jeremy; Rodionov, Vladimir; Blackstone, Craig; Li, Xue-Jun

    2013-01-01

    Human neuronal models of hereditary spastic paraplegias (HSP) that recapitulate disease-specific axonal pathology hold the key to understanding why certain axons degenerate in patients and to developing therapies. SPG4, the most common form of HSP, is caused by autosomal dominant mutations in the SPAST gene, which encodes the microtubule-severing ATPase spastin. Here, we have generated a human neuronal model of SPG4 by establishing induced pluripotent stem cells (iPSCs) from an SPG4 patient and differentiating these cells into telencephalic glutamatergic neurons. The SPG4 neurons displayed a significant increase in axonal swellings, which stained strongly for mitochondria and tau, indicating the accumulation of axonal transport cargoes. In addition, mitochondrial transport was decreased in SPG4 neurons, revealing that these patient iPSC-derived neurons recapitulate disease-specific axonal phenotypes. Interestingly, spastin protein levels were significantly decreased in SPG4 neurons, supporting a haploinsufficiency mechanism. Furthermore, cortical neurons derived from spastin-knockdown human embryonic stem cells (hESCs) exhibited similar axonal swellings, confirming that the axonal defects can be caused by loss of spastin function. These spastin-knockdown hESCs serve as an additional model for studying HSP. Finally, levels of stabilized acetylated-tubulin were significantly increased in SPG4 neurons. Vinblastine, a microtubule-destabilizing drug, rescued this axonal swelling phenotype in neurons derived from both SPG4 iPSCs and spastin-knockdown hESCs. Thus, this study demonstrates the successful establishment of human pluripotent stem cell-based neuronal models of SPG4, which will be valuable for dissecting the pathogenic cellular mechanisms and screening compounds to rescue the axonal degeneration in HSP. PMID:24123785

  11. Noninvasive Detection and Differentiation of Axonal Injury/Loss, Demyelination, and Inflammation

    DTIC Science & Technology

    2015-10-01

    and Inflammation 5b. GRANT NUMBER W81XWH-12-1-0457 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Sheng-Kwei Song, William M. Spees...Std. Z39.18 34 - 3 - Table of Contents Page 1. Introduction…………………………………………………………. 4 2. Keywords……………………………………………………………. 4 3. Overall Project ...neuritis Overall project Summary Our work during this funding period focused on (1) quantitatively validating in vivo DBSI derived axon volume

  12. Noninvasive Detection and Differentiation of Axonal Injury/Loss, Demyelination, and Inflammation

    DTIC Science & Technology

    2014-10-01

    PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Sheng-Kwei Song, William M. Spees, Peng Sun, Yong Wang, Anne Cross 5e. TASK NUMBER E-Mail...Page 1. Introduction…………………………………………………………. 4 2. Keywords……………………………………………………………. 4 3. Overall Project Summary…………………………………………... 4 – 8 4. Key...diffusion basis spectrum imaging, diffusion tensor imaging, EAE, inflammation, axonal injury, curizone, demyelination Overall project Summary The primary

  13. Signs and Symptoms of Early Pregnancy Loss

    PubMed Central

    Sapra, Katherine J.; Joseph, K.S.; Galea, Sandro; Bates, Lisa M.; Louis, Germaine M. Buck; Ananth, Cande V.

    2016-01-01

    Approximately one-third of pregnancies end in loss; however, the natural history of early pregnancy loss, including signs and symptoms preceding loss, has yet to be fully described and its underlying mechanisms fully understood. We searched PubMed/MEDLINE and Embase to identify articles with prospective ascertainment of signs and symptoms, including vaginal bleeding, nausea, and vomiting, of pregnancy loss < 20 weeks gestation in spontaneous conceptions to ascertain existing literature on symptomatology of pregnancy loss. Two preconception and 16 pregnancy cohort studies that ascertained information on bleeding and/or nausea/vomiting prior to pregnancy loss ascertainment were included. Data from these studies indicated increased risk of loss with vaginal bleeding and decreased risk of loss with nausea/vomiting, though these studies were mostly comprised of pregnancies surviving into late first trimester. While such associations are biologically plausible, these study designs are subject to bias, given recruitment of women at later gestational ages and reliance on women presenting to care. Reporting symptoms to clinicians and over long periods may introduce reporting error. Data gaps remain regarding (1) relationships between signs and symptoms and losses occurring very early, prior to care entry; (2) empirical testing of whether relationships between signs and symptoms and loss differ across gestational age; (3) whether similar relationships between signs and symptoms and loss are observed in populations using assisted reproductive technologies; (4) the patterning of multiple signs and symptoms in relation to loss; and (5) how hormonal and physiologic adaptions to early pregnancy relate to symptomatology and pregnancy loss. PMID:27342274

  14. Signs and Symptoms of Early Pregnancy Loss.

    PubMed

    Sapra, Katherine J; Joseph, K S; Galea, Sandro; Bates, Lisa M; Louis, Germaine M Buck; Ananth, Cande V

    2017-04-01

    Approximately one-third of pregnancies end in loss; however, the natural history of early pregnancy loss, including signs and symptoms preceding loss, has yet to be fully described and its underlying mechanisms fully understood. We searched PubMed/MEDLINE and Embase to identify articles with prospective ascertainment of signs and symptoms, including vaginal bleeding, nausea, and vomiting, of pregnancy loss < 20 weeks gestation in spontaneous conceptions to ascertain existing literature on symptomatology of pregnancy loss. Two preconception and 16 pregnancy cohort studies that ascertained information on bleeding and/or nausea/vomiting prior to pregnancy loss ascertainment were included. Data from these studies indicated increased risk of loss with vaginal bleeding and decreased risk of loss with nausea/vomiting, though these studies were mostly comprised of pregnancies surviving into late first trimester. While such associations are biologically plausible, these study designs are subject to bias, given recruitment of women at later gestational ages and reliance on women presenting to care. Reporting symptoms to clinicians and over long periods may introduce reporting error. Data gaps remain regarding (1) relationships between signs and symptoms and losses occurring very early, prior to care entry; (2) empirical testing of whether relationships between signs and symptoms and loss differ across gestational age; (3) whether similar relationships between signs and symptoms and loss are observed in populations using assisted reproductive technologies; (4) the patterning of multiple signs and symptoms in relation to loss; and (5) how hormonal and physiologic adaptions to early pregnancy relate to symptomatology and pregnancy loss.

  15. JUN regulates early transcriptional responses to axonal injury in retinal ganglion cells.

    PubMed

    Fernandes, Kimberly A; Harder, Jeffrey M; Kim, Jessica; Libby, Richard T

    2013-07-01

    The AP1 family transcription factor JUN is an important molecule in the neuronal response to injury. In retinal ganglion cells (RGCs), JUN is upregulated soon after axonal injury and disrupting JUN activity delays RGC death. JUN is known to participate in the control of many different injury response pathways in neurons, including pathways controlling cell death and axonal regeneration. The role of JUN in regulating genes involved in cell death, ER stress, and regeneration was tested to determine the overall importance of JUN in regulating RGC response to axonal injury. Genes from each of these pathways were transcriptionally controlled following axonal injury and Jun deficiency altered the expression of many of these genes. The differentially expressed genes included, Atf3, Ddit3, Ecel1, Gadd45α, Gal, Hrk, Pten, Socs3, and Sprr1a. Two of these genes, Hrk and Atf3, were tested for importance in RGC death using null alleles of each gene. Disruption of the prodeath Bcl2 family member Hrk did not affect the rate or amount of RGC death after axonal trauma. Deficiency in the ATF/CREB family transcription factor Atf3 did lessen the amount of RGC death after injury, though it did not provide long term protection to RGCs. Since JUN's dimerization partner determines its transcriptional targets, the expression of several candidate AP1 family members were examined. Multiple AP1 family members were induced by axonal injury and had a different expression profile in Jun deficient retinas compared to wildtype retinas (Fosl1, Fosl2 and Jund). Overall, JUN appears to play a multifaceted role in regulating RGC response to axonal injury. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Loss of Autophagy in Proopiomelanocortin Neurons Perturbs Axon Growth and Causes Metabolic Dysregulation

    PubMed Central

    Coupé, Bérengère; Ishii, Yuko; Dietrich, Marcelo O; Komatsu, Masaaki; Horvath, Tamas L.; Bouret, Sebastien G.

    2012-01-01

    Summary The hypothalamic melanocortin system, which includes neurons that produce proopiomelanocortin (POMC)-derived peptides, is a major negative regulator of energy balance. POMC neurons begin to acquire their unique properties during neonatal life. The formation of functional neural systems requires massive cytoplasmic remodeling that may involve autophagy, an important intracellular mechanism for the degradation of damaged proteins and organelles. Here we investigated the functional and structural effects of the deletion of an essential autophagy gene, Atg7, in POMC neurons. Lack of Atg7 in POMC neurons caused higher post-weaning body weight, increased adiposity, and glucose intolerance. These metabolic impairments were associated with an age-dependant accumulation of ubiquitin/p62-positive aggregates in the hypothalamus and a disruption in the maturation of POMC-containing axonal projections. Together, these data provide direct genetic evidence that Atg7 in POMC neurons is required for normal metabolic regulation and neural development, and they implicate hypothalamic autophagy deficiency in the pathogenesis of obesity. PMID:22285542

  17. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation.

    PubMed

    Coupé, Bérengère; Ishii, Yuko; Dietrich, Marcelo O; Komatsu, Masaaki; Horvath, Tamas L; Bouret, Sebastien G

    2012-02-08

    The hypothalamic melanocortin system, which includes neurons that produce pro-opiomelanocortin (POMC)-derived peptides, is a major negative regulator of energy balance. POMC neurons begin to acquire their unique properties during neonatal life. The formation of functional neural systems requires massive cytoplasmic remodeling that may involve autophagy, an important intracellular mechanism for the degradation of damaged proteins and organelles. Here we investigated the functional and structural effects of the deletion of an essential autophagy gene, Atg7, in POMC neurons. Lack of Atg7 in POMC neurons caused higher postweaning body weight, increased adiposity, and glucose intolerance. These metabolic impairments were associated with an age-dependent accumulation of ubiquitin/p62-positive aggregates in the hypothalamus and a disruption in the maturation of POMC-containing axonal projections. Together, these data provide direct genetic evidence that Atg7 in POMC neurons is required for normal metabolic regulation and neural development, and they implicate hypothalamic autophagy deficiency in the pathogenesis of obesity. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Axonal Degeneration Is Mediated by the Mitochondrial Permeability Transition Pore

    PubMed Central

    Barrientos, Sebastian A.; Martinez, Nicolas W.; Yoo, Soonmoon; Jara, Juan S.; Zamorano, Sebastian; Hetz, Claudio; Twiss, Jeffery L.; Alvarez, Jaime; Court, Felipe A.

    2011-01-01

    Axonal degeneration is an active process that has been associated with neurodegenerative conditions triggered by mechanical, metabolic, infectious, toxic, hereditary and inflammatory stimuli. This degenerative process can cause permanent loss of function, so it represents a focus for neuroprotective strategies. Several signaling pathways are implicated in axonal degeneration, but identification of an integrative mechanism for this self-destructive process has remained elusive. Here, we show that rapid axonal degeneration triggered by distinct mechanical and toxic insults is dependent on the activation of the mitochondrial permeability transition pore (mPTP). Both pharmacological and genetic targeting of cyclophilin D, a functional component of the mPTP, protects severed axons and vincristine-treated neurons from axonal degeneration in ex vivo and in vitro mouse and rat model systems. These effects were observed in axons from both the peripheral and central nervous system. Our results suggest that the mPTP is a key effector of axonal degeneration, upon which several independent signaling pathways converge. Since axonal and synapse degeneration are increasingly considered early pathological events in neurodegeneration, our work identifies a potential target for therapeutic intervention in a wide variety of conditions that lead to loss of axons and subsequent functional impairment. PMID:21248121

  19. Loss of Optineurin In Vivo Results in Elevated Cell Death and Alters Axonal Trafficking Dynamics

    PubMed Central

    Paulus, Jeremiah D.; Link, Brian A.

    2014-01-01

    Mutations in Optineurin have been associated with ALS, glaucoma, and Paget’s disease of bone in humans, but little is known about how these mutations contribute to disease. Most of the cellular consequences of Optineurin loss have come from in vitro studies, and it remains unclear whether these same defects would be seen in vivo. To answer this question, we assessed the cellular consequences of Optineurin loss in zebrafish embryos to determine if they showed the same defects as have been described in the in vitro studies. We found that loss of Optineurin resulted in increased cell death, as well as subtle cell morphology, cell migration and vesicle trafficking defects. However, unlike experiments on cells in culture, we found no indication that the Golgi apparatus was disrupted or that NF-κB target genes were upregulated. Therefore, we conclude that in vivo loss of Optineurin shows some, but not all, of the defects seen in in vitro work. PMID:25329564

  20. Early axonal damage and progressive myelin pathology define the kinetics of CNS histopathology in a mouse model of multiple sclerosis.

    PubMed

    Recks, Mascha S; Stormanns, Eva R; Bader, Jonas; Arnhold, Stefan; Addicks, Klaus; Kuerten, Stefanie

    2013-10-01

    Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. LIMITED RECOVERY OF PINEAL FUNCTION AFTER REGENERATION OF PREGANGLIONIC SYMPATHETIC AXONS: EVIDENCE FOR LOSS OF GANGLIONIC SYNAPTIC SPECIFICITY

    PubMed Central

    Lingappa, Jaisri R.; Zigmond, Richard E.

    2013-01-01

    The cervical sympathetic trunks (CST) contain axons of preganglionic neurons that innervate the superior cervical ganglia (SCG). Since, regeneration of CST fibers can be extensive and can reestablish certain specific patterns of SCG connections, restoration of end organ function would be expected. This expectation was examined with respect to the pineal gland, an organ innervated by the two SCG. The activity of pineal serotonin N-acetyltransferase (NAT) exhibits a large circadian rhythm, with activity high at night, which is dependent on the gland’s sympathetic input. Thirty six hours after the CST were crushed bilaterally, nocturnal NAT was decreased by 99%. Three months later, enzyme activity had recovered only to 15% of control values, a recovery dependent on regeneration of CST fibers. Nevertheless, a small day-night rhythm was present in lesioned animals. Neither the density of the gland’s adrenergic innervation nor the ability of an adrenergic agonist to stimulate NAT activity was reduced in rats with regenerated CST. In addition, stimulation of the regenerated CST at a variety of frequencies was at least as effective in increasing NAT activity as seen with control nerves. These data suggest that the failure of pineal function to recover is not due to a quantitative deficit in the extent of reinnervation or in synaptic efficacy. Rather, we suggest that there is some loss of specificity in the synaptic connections made in the SCG during reinnervation, resulting in a loss of the central neuronal information necessary for directing a normal NAT rhythm and thus normal pineal function. PMID:23486957

  2. Acute nutritional axonal neuropathy.

    PubMed

    Hamel, Johanna; Logigian, Eric L

    2018-01-01

    This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018. © 2017 Wiley Periodicals, Inc.

  3. Pathfinding in a large vertebrate axon tract: isotypic interactions guide retinotectal axons at multiple choice points

    PubMed Central

    Pittman, Andrew J.; Law, Mei-Yee; Chien, Chi-Bin

    2008-01-01

    Summary Navigating axons respond to environmental guidance signals, but can also follow axons that have gone before—pioneer axons. Pioneers have been studied extensively in simple systems, but the role of axon-axon interactions remains largely unexplored in large vertebrate axon tracts, where cohorts of identical axons could potentially use isotypic interactions to guide each other through multiple choice points. Furthermore, the relative importance of axon-axon interactions compared to axon-autonomous receptor function has not been assessed. Here we test the role of axon-axon interactions in retinotectal development, by devising a technique to selectively remove or replace early-born retinal ganglion cells (RGCs). We find that early RGCs are both necessary and sufficient for later axons to exit the eye. Furthermore, introducing misrouted axons by transplantation reveals that guidance from eye to tectum relies heavily on interactions between axons, including both pioneer-follower and community effects. We conclude that axon-axon interactions and ligand-receptor signaling have coequal roles, cooperating to ensure the fidelity of axon guidance in developing vertebrate tracts. PMID:18653554

  4. Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro.

    PubMed

    Sobieski, Courtney; Jiang, Xiaoping; Crawford, Devon C; Mennerick, Steven

    2015-08-05

    Neuron-astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (-astrocyte) within the same culture dish. -Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. Certain glial cell types (oligodendrocytes, Schwann cells) facilitate the propagation of neuronal electrical signals, but a role for astrocytes has not been identified despite many other functions of astrocytes in supporting and modulating neuronal signaling. Under identical global conditions, we cultured neurons with or without local astrocyte support. Without local astrocytes, glutamate transmission was desynchronized by an alteration of the waveform and arrival time of axonal

  5. Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro

    PubMed Central

    Sobieski, Courtney; Jiang, Xiaoping; Crawford, Devon C.

    2015-01-01

    Neuron–astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (−astrocyte) within the same culture dish. −Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. SIGNIFICANCE STATEMENT Certain glial cell types (oligodendrocytes, Schwann cells) facilitate the propagation of neuronal electrical signals, but a role for astrocytes has not been identified despite many other functions of astrocytes in supporting and modulating neuronal signaling. Under identical global conditions, we cultured neurons with or without local astrocyte support. Without local astrocytes, glutamate transmission was desynchronized by an alteration of the waveform

  6. Hematopoietic Stem Cell Transplantation in Late-Onset Krabbe Disease: No Evidence of Worsening Demyelination and Axonal Loss 4 Years Post-allograft.

    PubMed

    Laule, Cornelia; Vavasour, Irene M; Shahinfard, Elham; Mädler, Burkhard; Zhang, Jing; Li, David K B; MacKay, Alex L; Sirrs, Sandra M

    2018-05-01

    Late-onset adult Krabbe disease is a very rare demyelinating leukodystrophy, affecting less than 1 in a million people. Hematopoietic stem cell transplantation (HSCT) strategies can stop the accumulation of toxic metabolites that damage myelin-producing cells. We used quantitative advanced imaging metrics to longitudinally assess the impact of HSCT on brain abnormalities in adult-onset Krabbe disease. A 42-year-old female with late-onset Krabbe disease and an age/sex-matched healthy control underwent annual 3T MRI (baseline was immediately prior to HSCT for the Krabbe subject). Imaging included conventional scans, myelin water imaging, diffusion tensor imaging, and magnetic resonance spectroscopy. Brain abnormalities far beyond those visible on conventional imaging were detected, suggesting a global pathological process occurs in Krabbe disease with adult-onset etiology, with myelin being more affected than axons, and evidence of wide-spread gliosis. After HSCT, our patient showed clinical stability in all measures, as well as improvement in gait, dysarthria, and pseudobulbar affect at 7.5 years post-transplant. No MRI evidence of worsening demyelination and axonal loss was observed up to 4 years post-allograft. Clinical evidence and stability of advanced MR measures related to myelin and axons supports HSCT as an effective treatment strategy for stopping progression associated with late-onset Krabbe disease. Copyright © 2018 by the American Society of Neuroimaging.

  7. Will PEDF Therapy Reverse Chronic Demyelination and Prevent Axon Loss in a Murine Model of Progressive Multiple Sclerosis

    DTIC Science & Technology

    2015-12-01

    Multiple Sclerosis ? PRINCIPAL INVESTIGATOR: David Pleasure MD CONTRACTING ORGANIZATION: University of California Davis, CA 95618 REPORT DATE...Murine Model of Progressive Multiple Sclerosis ? 5b. GRANT NUMBER W81XWH-12-1-0566 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David Pleasure MD 5d...enhance central nervous system (CNS) remyelination and preserve CNS axons in mouse models of multiple sclerosis models. After determining the dosage of

  8. Normal development of spinal axons in early embryo stages and posterior locomotor function is independent of GAL-1.

    PubMed

    Pasquini, Juana M; Barrantes, Francisco J; Quintá, Héctor R

    2017-09-01

    It was recently described that Galectin-1 (Gal-1) promotes axonal growth after spinal cord injury. This effect depends on protein dimerization, since monomeric Gal-1 fails to stimulate axonal re-growth. Gal-1 is expressed in vivo at concentrations that favor the monomeric species. The aim of the present study is to investigate whether endogenous Gal-1 is required for spinal axon development and normal locomotor behavior in mice. In order to characterize axonal development, we used a novel combination of 3-DISCO technique with 1-photon microscopy and epifluorescence microscopy under high power LED illumination, followed by serial image section deconvolution and 3-D reconstruction. Cleared whole lgals-1 -/- embryos were used to analyze the 3-D cytoarchitecture of motor, commissural, and sensory axons. This approach allowed us to evaluate axonal development, including the number of fibers, fluorescence density of the fiber tracts, fiber length as well as the morphology of axonal sprouting, deep within the tissue. Gal-1 deficient embryos did not show morphological/anatomical alterations in any of the axonal populations and parameters analyzed. In addition, specific guidance receptor PlexinA4 did not change its axonal localization in the absence of Gal-1. Finally, Gal-1 deficiency did not change normal locomotor activity in post-natal animals. Taken together, our results show that development of spinal axons as well as the locomotor abilities observed in adult mice are independent of Gal-1. Supporting our previous observations, the present study further validates the use of lgals-1 -/- mice to develop spinal cord- or traumatic brain injury models for the evaluation of the regenerative action of Gal-1. © 2017 Wiley Periodicals, Inc.

  9. Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis.

    PubMed

    Singh, Shailender; Dallenga, Tobias; Winkler, Anne; Roemer, Shanu; Maruschak, Brigitte; Siebert, Heike; Brück, Wolfgang; Stadelmann, Christine

    2017-03-17

    Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination. Wallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions. Furthermore, we studied the effects of Wallerian degeneration blockage on clinical severity, inflammatory pathology, acute axonal damage, and long-term axonal loss in experimental autoimmune encephalomyelitis using Wallerian degeneration slow (Wld S ) mutant mice. The highest numbers of axons undergoing Wallerian degeneration were found in the perilesional white matter of multiple sclerosis patients early in the disease course and with actively demyelinating lesions. Furthermore, Wallerian degeneration was more abundant in patients harboring chronic active as compared to chronic inactive lesions. No co-localization of neuropeptide Y-Y1 receptor, a bona fide immunohistochemical marker of Wallerian degeneration, with amyloid precursor protein, frequently used as an indicator of acute axonal transport disturbance, was observed in human and mouse tissue, indicating distinct axon-degenerative processes. Experimentally, a delay of Wallerian degeneration, as observed in Wld S mice, did not result in a reduction of clinical disability or acute axonal damage in experimental autoimmune encephalomyelitis, further supporting that acute axonal damage as reflected by axonal transport disturbances does not share common molecular mechanisms with Wallerian degeneration. Furthermore, delaying Wallerian degeneration

  10. Differential effects of myostatin deficiency on motor and sensory axons.

    PubMed

    Jones, Maria R; Villalón, Eric; Northcutt, Adam J; Calcutt, Nigel A; Garcia, Michael L

    2017-12-01

    Deletion of myostatin in mice (MSTN -/- ) alters structural properties of peripheral axons. However, properties like axon diameter and myelin thickness were analyzed in mixed nerves, so it is unclear whether loss of myostatin affects motor, sensory, or both types of axons. Using the MSTN -/- mouse model, we analyzed the effects of increasing the number of muscle fibers on axon diameter, myelin thickness, and internode length in motor and sensory axons. Axon diameter and myelin thickness were increased in motor axons of MSTN -/- mice without affecting internode length or axon number. The number of sensory axons was increased without affecting their structural properties. These results suggest that motor and sensory axons establish structural properties by independent mechanisms. Moreover, in motor axons, instructive cues from the neuromuscular junction may play a role in co-regulating axon diameter and myelin thickness, whereas internode length is established independently. Muscle Nerve 56: E100-E107, 2017. © 2017 Wiley Periodicals, Inc.

  11. A morphological study of diffuse axonal injury in a rat model by lateral head rotation trauma.

    PubMed

    Xiaoshengi, He; Guitao, Yang; Xiang, Zhang; Zhou, Fei

    2010-03-01

    Morphology in diffuse axonal injury (DAI) by lateral head rotation was investigated. SD rats were divided into injury (n=9) and sham (n=3) groups. A device was used to produce lateral rotational acceleration of the rats' heads. At different survival times three rats were killed for light and electron microscopic examination of the brain tissue. Sagittal sections were made from medulla oblongata and immunolabelled for NF68. At post-traumatic 30 min, NF68 immunolabelling showed a small number ofswollen and irregular axons. Ultrastructurally slightly-separated myelin lamellae and disorderly arranged neurofilaments occurred. At 2 and 24 h axonal damage became more severe. Increases in immunolabelled axonal swellings, disconnected axons and axonal retraction bulbs appeared. EM provided evidence of myelin separation, peri-axonal spaces, blank areas in axoplasm, loss of microtubules, peripheral accumulation of mitochondria and clumped neurofilaments for DAI. A tendency was noted for greater labelling with NF68 as axonal damage increased. The disorderly arrangement of NFs occurred at early stage of post-traumatic axonal changes.

  12. Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins.

    PubMed

    Yalçın, Belgin; Zhao, Lu; Stofanko, Martin; O'Sullivan, Niamh C; Kang, Zi Han; Roost, Annika; Thomas, Matthew R; Zaessinger, Sophie; Blard, Olivier; Patto, Alex L; Sohail, Anood; Baena, Valentina; Terasaki, Mark; O'Kane, Cahir J

    2017-07-25

    Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.

  13. Differential screening of mutated SOD1 transgenic mice reveals early up-regulation of a fast axonal transport component in spinal cord motor neurons.

    PubMed

    Dupuis, L; de Tapia, M; René, F; Lutz-Bucher, B; Gordon, J W; Mercken, L; Pradier, L; Loeffler, J P

    2000-08-01

    In the present study we analyze the molecular mechanisms underlying motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS). For this, we used a transgenic mouse model expressing the Cu/Zn superoxide dismutase (SOD1) gene with a Gly(86) to Arg (G86R) mutation equivalent to that found in a subset of human FALS. Using an optimized suppression subtractive hybridization method, a cDNA specifically up-regulated during the asymptomatic phase in the lumbar spinal cord of G86R mice was identified by sequence analysis as the KIF3-associated protein (KAP3), a regulator of fast axonal transport. RT-PCR analysis revealed that KAP3 induction was an early event arising long before axonal degeneration. Immunohistochemical studies further revealed that KAP3 protein predominantly accumulates in large motor neurons of the ventral spinal cord. We further demonstrated that KAP3 up-regulation occurs independent of any change in the other components of the kinesin II complex. However, since the ubiquitous KIF1A motor is up-regulated, our results show an early and complex rearrangement of the fast axonal transport machinery in the course of FALS pathology. Copyright 2000 Academic Press.

  14. Preterit Loss in Early Modern Nuremberg

    ERIC Educational Resources Information Center

    Bagwell, Angela Catania

    2013-01-01

    This study investigates "Prateritumschwund," one of the most salient developments in the Upper German dialect area during the Early Modern period. Drawing on a wide range of text types originating in Nuremberg and its surrounding areas from the 13th to the 17th centuries, this study tests various hypotheses put forward as alleged causes…

  15. Mild and Unilateral Hearing Loss: Implications for Early Intervention

    ERIC Educational Resources Information Center

    Holstrum, W. June; Biernath, Krista; McKay, Sarah; Ross, Danielle S.

    2009-01-01

    Newborn hearing screening has become a standard practice in most birthing hospitals in the United States. Historically, the primary target for the identification of hearing loss has been infants with permanent bilateral loss of moderate degree or greater (i.e., greater than 40 dB). However, research indicates that without early identification and…

  16. Early investigational drugs for hearing loss

    PubMed Central

    Mukherjea, Debashree; Ghosh, Sumana; Bhatta, Puspanjali; Sheth, Sandeep; Tupal, Srinivasan; Borse, Vikrant; Brozoski, Thomas; Sheehan, Kelly E; Rybak, Leonard P; Ramkumar, Vickram

    2017-01-01

    Introduction Sensorineural hearing loss (HL) is becoming a global phenomenon at an alarming rate. Nearly 600 million people have been estimated to have significant HL in at least one ear. There are several different causes of sensorineural HL included in this review of new investigational drugs for HL. They are noise-induced, drug-induced, sudden sensorineural HL, presbycusis and HL due to cytomegalovirus infections. Areas covered This review presents trends in research for new investigational drugs encompassing a variety of causes of HL. The studies presented here are the latest developments either in the research laboratories or in preclinical, Phase 0, Phase I or Phase II clinical trials for drugs targeting HL. Expert opinion While it is important that prophylactic measures are developed, it is extremely crucial that rescue strategies for unexpected or unavoidable cochlear insult be established. To achieve this goal for the development of drugs for HL, innovative strategies and extensive testing are required for progress from the bench to bedside. However, although a great deal of research needs to be done to achieve the ultimate goal of protecting the ear against acquired sensorineural HL, we are likely to see exciting breakthroughs in the near future. PMID:25243609

  17. Neuronal loss is an early component of subacute sclerosing panencephalitis.

    PubMed

    Yüksel, Deniz; Diren, Barış; Ulubay, Hakan; Altunbaşak, Sakir; Anlar, Banu

    2014-09-02

    We performed diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) studies in a group of patients with subacute sclerosing panencephalitis (SSPE) in order to estimate the pathologic process underlying the phenotypic variability. Patients with SSPE who had MRI including DTI and MRS examinations were evaluated according to their clinical status as determined by the SSPE Scoring System and their mental age as determined by tests appropriate for age and developmental level. Comparisons of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups. Control (n = 18) and SSPE (n = 39) groups differed in all DTI and MRS parameters except FA, choline (Cho), and Cho/creatine (Cr). SSPE cases had higher ADC and lower N-acetylaspartate (NAA), NAA/Cho, and NAA/Cr in all regions of interest, suggesting cell loss. Disease progression rate and neurologic deficit appeared to be associated with the degree of ADC elevation and NAA reduction: the group with severe global deterioration had the lowest NAA (230.75 ± 197.97 in forceps minor), and rapid progression was associated with acute reduction in NAA. The combination of MRS and diffusion MRI findings suggests neuronal loss can be a primary target in rapidly or subacutely progressing SSPE, and preservation or regeneration of axonal structure may be beneficial in chronic cases. © 2014 American Academy of Neurology.

  18. Prevalence and impact of diffuse axonal injury in patients with moderate and severe head injury: a cohort study of early magnetic resonance imaging findings and 1-year outcome.

    PubMed

    Skandsen, Toril; Kvistad, Kjell Arne; Solheim, Ole; Strand, Ingrid Haavde; Folvik, Mari; Vik, Anne

    2010-09-01

    In this prospective cohort study the authors examined patients with moderate to severe head injuries using MR imaging in the early phase. The objective was to explore the occurrence of diffuse axonal injury (DAI) and determine whether DAI was related to level of consciousness and patient outcome. One hundred and fifty-nine patients (age range 5-65 years) with traumatic brain injury, who survived the acute phase, and who had a Glasgow Coma Scale (GCS) score of 3-13 were admitted between October 2004 and August 2008. Of these 159 patients, 106 were examined using MR imaging within 4 weeks postinjury. Patients were classified into 1 of 3 stages of DAI: Stage 1, in which lesions were confined to the lobar white matter; Stage 2, in which there were callosal lesions; and Stage 3, in which lesions occurred in the dorsolateral brainstem. The outcome measure used 12 months postinjury was the Glasgow Outcome Scale-Extended (GOSE). Diffuse axonal injury was detected in 72% of the patients and a combination of DAI and contusions or hematomas was found in 50%. The GCS score was significantly lower in patients with "pure DAI" (median GCS Score 9) than in patients without DAI (median GCS Score 12; p < 0.001). The GCS score was related to outcome only in those patients with DAI (r = 0.47; p = 0.001). Patients with DAI had a median GOSE score of 7, and patients without DAI had a median GOSE score of 8 (p = 0.10). Outcome was better in patients with DAI Stage 1 (median GOSE Score 8) and DAI Stage 2 (median GOSE Score 7.5) than in patients with DAI Stage 3 (median GOSE Score 4; p < 0.001). Thus, in patients without any brainstem injury, there was no difference in good recovery between patients with DAI (67%) and patients without DAI (66%). Diffuse axonal injury was found in almost three-quarters of the patients with moderate and severe head injury who survived the acute phase. Diffuse axonal injury influenced the level of consciousness, and only in patients with DAI was GCS score

  19. Sensory Temporal Processing in Adults with Early Hearing Loss

    ERIC Educational Resources Information Center

    Heming, Joanne E.; Brown, Lenora N.

    2005-01-01

    This study examined tactile and visual temporal processing in adults with early loss of hearing. The tactile task consisted of punctate stimulations that were delivered to one or both hands by a mechanical tactile stimulator. Pairs of light emitting diodes were presented on a display for visual stimulation. Responses consisted of YES or NO…

  20. Auditory Deprivation and Early Conductive Hearing Loss from Otitis Media.

    ERIC Educational Resources Information Center

    Gunnarson, Adele D.; And Others

    1990-01-01

    This article reviews auditory deprivation effects on anatomy, physiology, and behavior in animals and discusses the sequelae of otitis media with effusion (OME) in children. Focused on are central auditory processing disorders associated with early fluctuating hearing loss from OME. (DB)

  1. On the nature and consequences of early loss.

    PubMed

    Hofer, M A

    1996-01-01

    To describe how an animal model system can be used to explore basic questions about the nature of loss and the effects of early loss on later vulnerability to disease. The physiological and behavioral responses of infant rats to separation from their mothers are first described and then analyzed experimentally into component mechanisms. These studies have revealed an extensive layer of processes underlying the psychological constructs generally used to understand the response to loss. Hidden within the observable interactions of parent and offspring, we found a number of discrete sensorimotor, thermal, and nutrient-based events that have unexpected long-term regulatory effects on specific components of infant physiology and behavior. Release from all of these inhibitory and excitatory regulators together during maternal separation constitutes a novel mechanism by which the experience of loss can be translated into a complex patterned response. Evidence for early regulatory processes has also been found in monkey and human mother-infant interactions. Here they may well constitute the building blocks from which attachment and object representations develop. We and others have found long-term effects of loss, and of selective replacement of regulators, on behavioral development and on later vulnerability to disease. The results give us a new understanding of early attachment as a developmental force and of human grief as a risk to health.

  2. Axonal abnormalities in vanishing white matter.

    PubMed

    Klok, Melanie D; Bugiani, Marianna; de Vries, Sharon I; Gerritsen, Wouter; Breur, Marjolein; van der Sluis, Sophie; Heine, Vivi M; Kole, Maarten H P; Baron, Wia; van der Knaap, Marjo S

    2018-04-01

    We aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. Axons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed. In the corpus callosum of Eif2b5- mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5- mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5 -mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal. In vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

  3. Atmospheric Loss and Warming Of The Early Mars

    NASA Astrophysics Data System (ADS)

    Airapetian, V.; Gronoff, G.; Grocer, A.; Khazanov, G. V.; Hébrard, E.

    2016-12-01

    Today Mars represents an inhospitable world with a thin 6-mbar atmosphere that cannot support surface water. Current evidence suggests that the early Mars was a wet and at least somewhat warmer world that could support life. How hospitable Mars was for life? The atmospheric evolution of Mars over the last 4 billion years was affected by the rate of atmospheric loss and the chemical changes induced by space weather events from the evolving Sun and the planet's early outgassing history. We apply our atmospheric model enhanced with chemistry that describes photo-collisional dissociation and ionization of molecular nitrogen and carbon dioxide rich atmosphere of the early Mars due to XUV emission and penetration of energetic protons accelerated in extended shock waves driven by super Carrington events from the young Sun. We calculate the rate of atmospheric loss of oxygen ions from the atmosphere of early Mars to be 200 kg/s. This suggests that the early Martian atmosphere was subject to significant erosion, which implies the large rate of outgassing due to tectonic and volcanic activity. We also show that energetic protons produce multiple generations of secondary electrons that contribute to the destruction of N2 into reactive nitrogen, and the subsequent destruction of CO2 and CH4 efficiently producing N2O, a powerful greenhouse gas. The efficient production of nitrous oxide in the Martian troposphere can explain the longstanding problem of the Faint Young Sun paradox for Mars.

  4. Work instability and financial loss in early inflammatory arthritis.

    PubMed

    Looper, Karl J; Mustafa, Sally S; Zelkowitz, Phyllis; Purden, Margaret; Baron, Murray

    2012-12-01

    Inflammatory arthritis is associated with a high degree of work instability and financial burden. In this study, we examine the extent of work instability and financial loss as well as their association with disease characteristics during the first 18 months of inflammatory arthritis. One hundred and four patients in the early phase (more than 6 weeks, < 18 months) of inflammatory arthritis were recruited from a larger early inflammatory arthritis registry. Questionnaires recorded sociodemographic data and disease characteristics, including pain assessed using the Short Form McGill Pain Questionnaire (MPQ) and physical functioning measured with the Medical Outcomes Study Short Form 36 (SF-36) physical functioning score. The Rheumatoid Arthritis Work Instability Scale (RA-WIS) was used to measure patient-perceived functioning in the workplace and the Financial Loss Questionnaire (FLQ) measured the impact on family finances. Participants' mean age was 56 years, 70.2% were female and 49.0% were working. Average yearly household income was < 60 000 Canadian dollars (CAD) for 38.5% of the sample. Of our working patients, 43% had a medium or high risk of work loss as measured by the RA-WIS and 35% reported a financial loss. On multivariate analysis, MPQ and SF-36 contributed to the dependent variable work instability, while age and SF-36 contributed to financial loss. This study identifies pain and physical dysfunction as potential modifiable risk factors for negative socioeconomic repercussions of illness in early inflammatory arthritis. © 2012 The Authors International Journal of Rheumatic Diseases © 2012 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  5. Hearing loss and risk of early retirement. The HUNT study

    PubMed Central

    Krokstad, Steinar; Tambs, Kristian

    2013-01-01

    Background: We explore the possible consequences of measured hearing impairment (HI) and perceived hearing difficulties for early retirement in a large population-based study. Furthermore, we study whether having a part-time position was associated with measured HI and perceived hearing difficulties in the same population. Methods: This study included 25 740 persons from the Nord-Trøndelag Health Study (HUNT) aged 20–54 years at baseline in HUNT1 (1984–1986) who also participated in the follow up, HUNT2, including a hearing examination 11 years later. Logistic regression analysis was conducted for men and women separately and in two age strata. Effects of low-, middle- and high-frequency hearing levels were explored, adjusting for each other. Further adjustment was made for socio-economic class and general health in HUNT1. Results: The risk of early retirement increased with degree of loss of low-frequency hearing in young and middle-aged men and middle-aged women. The middle-aged men and women experiencing hearing disability had an increased risk of early retirement. Degree of hearing level was not associated with part-time work, but in middle-aged men, awareness of having a hearing loss was associated with part-time employment. Conclusions: Degree of low-frequency hearing loss was associated with early retirement but not with part-time work. Perceived hearing disability increased the risk of early retirement in middle-aged men and women and also the risk of part-time work in middle-aged men. PMID:22930741

  6. Hearing loss and risk of early retirement. The HUNT study.

    PubMed

    Helvik, Anne-Sofie; Krokstad, Steinar; Tambs, Kristian

    2013-08-01

    We explore the possible consequences of measured hearing impairment (HI) and perceived hearing difficulties for early retirement in a large population-based study. Furthermore, we study whether having a part-time position was associated with measured HI and perceived hearing difficulties in the same population. This study included 25,740 persons from the Nord-Trøndelag Health Study (HUNT) aged 20-54 years at baseline in HUNT1 (1984-1986) who also participated in the follow up, HUNT2, including a hearing examination 11 years later. Logistic regression analysis was conducted for men and women separately and in two age strata. Effects of low-, middle- and high-frequency hearing levels were explored, adjusting for each other. Further adjustment was made for socio-economic class and general health in HUNT1. The risk of early retirement increased with degree of loss of low-frequency hearing in young and middle-aged men and middle-aged women. The middle-aged men and women experiencing hearing disability had an increased risk of early retirement. Degree of hearing level was not associated with part-time work, but in middle-aged men, awareness of having a hearing loss was associated with part-time employment. Degree of low-frequency hearing loss was associated with early retirement but not with part-time work. Perceived hearing disability increased the risk of early retirement in middle-aged men and women and also the risk of part-time work in middle-aged men.

  7. Creatine pretreatment protects cortical axons from energy depletion in vitro

    PubMed Central

    Shen, Hua; Goldberg, Mark P.

    2012-01-01

    Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6 mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24 h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2 h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency. PMID:22521466

  8. Method for early detection of cooling-loss events

    DOEpatents

    Bermudez, Sergio A.; Hamann, Hendrik; Marianno, Fernando J.

    2015-06-30

    A method of detecting cooling-loss event early is provided. The method includes defining a relative humidity limit and change threshold for a given space, measuring relative humidity in the given space, determining, with a processing unit, whether the measured relative humidity is within the defined relative humidity limit, generating a warning in an event the measured relative humidity is outside the defined relative humidity limit and determining whether a change in the measured relative humidity is less than the defined change threshold for the given space and generating an alarm in an event the change is greater than the defined change threshold.

  9. Method for early detection of cooling-loss events

    DOEpatents

    Bermudez, Sergio A.; Hamann, Hendrik F.; Marianno, Fernando J.

    2015-12-22

    A method of detecting cooling-loss event early is provided. The method includes defining a relative humidity limit and change threshold for a given space, measuring relative humidity in the given space, determining, with a processing unit, whether the measured relative humidity is within the defined relative humidity limit, generating a warning in an event the measured relative humidity is outside the defined relative humidity limit and determining whether a change in the measured relative humidity is less than the defined change threshold for the given space and generating an alarm in an event the change is greater than the defined change threshold.

  10. Axonal interferon responses and alphaherpesvirus neuroinvasion

    NASA Astrophysics Data System (ADS)

    Song, Ren

    , unlike treatment with IFNgamma, IFNbeta induces a non-canonical, local antiviral response in axons. The activation of a local IFNbeta response in axons represents a new paradigm for early cytokine control of neuroinvasion. And the two response modes induced by the two distinct types of IFN erect an efficient and appropriate barrier against PNS infection.

  11. Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease.

    PubMed

    Bogdanik, Laurent P; Sleigh, James N; Tian, Cong; Samuels, Mark E; Bedard, Karen; Seburn, Kevin L; Burgess, Robert W

    2013-05-01

    Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous condition characterized by peripheral axon degeneration with subsequent motor and sensory deficits. Several CMT gene products function in endosomal sorting and trafficking to the lysosome, suggesting that defects in this cellular pathway might present a common pathogenic mechanism for these conditions. LRSAM1 is an E3 ubiquitin ligase that is implicated in this process, and mutations in LRSAM1 have recently been shown to cause CMT. We have generated mouse mutations in Lrsam1 to create an animal model of this form of CMT (CMT2P). Mouse Lrsam1 is abundantly expressed in the motor and sensory neurons of the peripheral nervous system. Both homozygous and heterozygous mice have largely normal neuromuscular performance and only a very mild neuropathy phenotype with age. However, Lrsam1 mutant mice are more sensitive to challenge with acrylamide, a neurotoxic agent that causes axon degeneration, indicating that the axons in the mutant mice are indeed compromised. In transfected cells, LRSAM1 primarily localizes in a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome to lysosome trafficking pathway, suggesting that other cellular mechanisms also merit consideration.

  12. Diffusion tensor imaging of normal-appearing white matter in mild cognitive impairment and early Alzheimer disease: preliminary evidence of axonal degeneration in the temporal lobe.

    PubMed

    Huang, J; Friedland, R P; Auchus, A P

    2007-01-01

    Diffusion tensor imaging (DTI) is a sensitive technique for studying cerebral white matter. We used DTI to characterize microstructural white matter changes and their associations with cognitive dysfunction in Alzheimer disease (AD) and mild cognitive impairment (MCI). We studied elderly subjects with mild AD (n = 6), MCI (n = 11), or normal cognition (n = 8). A standardized clinical and neuropsychological evaluation was conducted on each subject. DTI images were acquired, and fractional anisotropy (FA), axial diffusivity (DA), and radial diffusivity (DR) of normal-appearing white matter (NAWM) in frontal, temporal, parietal, and occipital lobes were determined. These diffusion measurements were compared across the 3 groups, and significant differences were further examined for correlations with tests of cognitive function. Compared with normal controls, AD subjects demonstrated decreased FA and increased DR in the temporal, parietal, and frontal NAWM and decreased DA in temporal NAWM. MCI subjects also showed decreased FA and decreased DA in temporal NAWM, with decreased FA and increased DR in parietal NAWM. Diffusion measurements showed no differences in occipital NAWM. Across all subjects, temporal lobe FA and DR correlated with episodic memory, frontal FA and DR correlated with executive function, and parietal DR significantly correlated with visuospatial ability. We found evidence for functionally relevant microstructural changes in the NAWM of patients with AD and MCI. These changes were present in brain regions serving higher cortical functions, but not in regions serving primary functions, and are consistent with a hypothesized loss of axonal processes in the temporal lobe.

  13. Axonal Degeneration Is Regulated by a Transcriptional Program that Coordinates Expression of Pro- and Anti-degenerative Factors.

    PubMed

    Maor-Nof, Maya; Romi, Erez; Sar Shalom, Hadas; Ulisse, Valeria; Raanan, Calanit; Nof, Aviv; Leshkowitz, Dena; Lang, Roland; Yaron, Avraham

    2016-12-07

    Developmental neuronal cell death and axonal elimination are controlled by transcriptional programs, of which their nature and the function of their components remain elusive. Here, we identified the dual specificity phosphatase Dusp16 as part of trophic deprivation-induced transcriptome in sensory neurons. Ablation of Dusp16 enhanced axonal degeneration in response to trophic withdrawal, suggesting that it has a protective function. Moreover, axonal skin innervation was severely reduced while neuronal elimination was increased in the Dusp16 knockout. Mechanistically, Dusp16 negatively regulates the transcription factor p53 and antagonizes the expression of the pro-degenerative factor, Puma (p53 upregulated modulator of apoptosis). Co-ablation of Puma with Dusp16 protected axons from rapid degeneration and specifically reversed axonal innervation loss early in development with no effect on neuronal deficits. Overall, these results reveal that physiological axonal elimination is regulated by a transcriptional program that integrates regressive and progressive elements and identify Dusp16 as a new axonal preserving factor. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration

    PubMed Central

    Misko, Albert; Sasaki, Yo; Tuck, Elizabeth; Milbrandt, Jeffrey; Baloh, Robert H.

    2012-01-01

    Summary Alterations in mitochondrial dynamics (fission, fusion and movement) are implicated in many neurodegenerative diseases, from rare genetic disorders such as Charcot-Marie-Tooth disease, to common conditions including Alzheimer’s disease. However, the relationship between altered mitochondrial dynamics and neurodegeneration is incompletely understood. Here we show that disease associated MFN2 proteins suppressed both mitochondrial fusion and transport, and produced classic features of segmental axonal degeneration without cell body death, including neurofilament filled swellings, loss of calcium homeostasis, and accumulation of reactive oxygen species. By contrast, depletion of Opa1 suppressed mitochondrial fusion while sparing transport, and did not induce axonal degeneration. Axon degeneration induced by mutant MFN2 proteins correlated with the disruption of the proper mitochondrial positioning within axons, rather than loss of overall mitochondrial movement, or global mitochondrial dysfunction. We also found that augmenting expression of MFN1 rescued the axonal degeneration caused by MFN2 mutants, suggesting a possible therapeutic strategy for Charcot-Marie-Tooth disease. These experiments provide evidence that the ability of mitochondria to sense energy requirements and localize properly within axons is key to maintaining axonal integrity, and may be a common pathway by which disruptions in axonal transport contribute to neurodegeneration. PMID:22442078

  15. Early retirement and income loss in patients with early and advanced Parkinson's disease.

    PubMed

    Johnson, Scott; Davis, Matthew; Kaltenboeck, Anna; Birnbaum, Howard; Grubb, Elizabeth; Tarrants, Marcy; Siderowf, Andrew

    2011-11-01

    The indirect costs of Parkinson's disease (PD) may be larger than direct healthcare costs, and the largest component of indirect costs is income loss related to early retirement. No recent retrospective analysis details PD-related early retirement and income loss in the US. We used an observational, matched cohort to study wages and labour force participation over 4 years and to simulate lifetime income losses conditional on being newly diagnosed with PD (naive) or having evidence of increasing disability. Actively employed primary beneficiaries of private insurance policies aged 18-64 years with more than two PD diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 332.x) or one diagnosis and a prescription of an antiparkinsonian drug were selected from a privately insured claims database. Continuous health coverage during analysis periods was required. Naive patients were defined as having no claims history indicative of PD during the year prior to first diagnosis or prescription use. A PD with ambulatory assistance devices (PDAAD) cohort was also followed from the date of first evidence of a wheelchair or walker. Controls without PD were matched on age, sex and region. Survival analysis and Wilcoxon rank sum tests were used to compare rates of early retirement and income loss. A simulation of projected economic loss was conducted for PD cohorts diagnosed at different ages using Bureau of Labor Statistics labour force participation and income data. Naive PD patients (n = 278) and PDAAD patients (n = 28) were on average aged 53 years and had significantly higher rates of co-morbidities at baseline versus controls. Conditional on being employed, there was no statistical difference in earnings. However, the hazard of early retirement associated with PD was 2.08 (p < 0.001) for the naive cohort and 5.01 (p < 0.001) for the PDAAD cohort. From age 40 to 79 years, earnings losses in year 2009 values were

  16. Infant hearing loss: the necessity for early identification.

    PubMed

    Harney, C L

    2000-01-01

    There has been controversy in the health professions about the necessity for newborn infant hearing screening. It is well accepted that patient history or a birth that places the infant in the high-risk registry (HHR) can identify 50% of all infants born with permanent bilateral hearing loss. Two major factors which have been cited as reasons for not screening the well-baby nursery have been poor cost effectiveness and the lack of documentation as to the benefits derived from early identification and intervention. Recent technological developments and published data are presented which indicate that economical well-baby hearing screening can be done in any setting, and that the language acquisition of the infant is permanently affected if the intervention is not done in the first six months after birth.

  17. Factors Associated With Early Loss of Hallux Valgus Correction.

    PubMed

    Shibuya, Naohiro; Kyprios, Evangelos M; Panchani, Prakash N; Martin, Lanster R; Thorud, Jakob C; Jupiter, Daniel C

    Recurrence is common after hallux valgus corrective surgery. Although many investigators have studied the risk factors associated with a suboptimal hallux position at the end of long-term follow-up, few have evaluated the factors associated with actual early loss of correction. We conducted a retrospective cohort study to identify the predictors of lateral deviation of the hallux during the postoperative period. We evaluated the demographic data, preoperative severity of the hallux valgus, other angular measurements characterizing underlying deformities, amount of hallux valgus correction, and postoperative alignment of the corrected hallux valgus for associations with recurrence. After adjusting for the covariates, the only factor associated with recurrence was the postoperative tibial sesamoid position. The recurrence rate was ~50% and ~60% when the postoperative tibial sesamoid position was >4 and >5 on the 7-point scale, respectively. Published by Elsevier Inc.

  18. Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

    PubMed Central

    Yalçın, Belgin; Zhao, Lu; Stofanko, Martin; O'Sullivan, Niamh C; Kang, Zi Han; Roost, Annika; Thomas, Matthew R; Zaessinger, Sophie; Blard, Olivier; Patto, Alex L; Sohail, Anood; Baena, Valentina; Terasaki, Mark; O'Kane, Cahir J

    2017-01-01

    Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function. DOI: http://dx.doi.org/10.7554/eLife.23882.001 PMID:28742022

  19. Loss of Nfkb1 leads to early onset aging.

    PubMed

    Bernal, Giovanna M; Wahlstrom, Joshua S; Crawley, Clayton D; Cahill, Kirk E; Pytel, Peter; Liang, Hua; Kang, Shijun; Weichselbaum, Ralph R; Yamini, Bakhtiar

    2014-11-01

    NF-κB is a major regulator of age-dependent gene expression and the p50/NF-κB1 subunit is an integral modulator of NF-κB signaling. Here, we examined Nfkb1-/- mice to investigate the relationship between this subunit and aging. Although Nfkb1-/- mice appear similar to littermates at six months of age, by 12 months they have a higher incidence of several observable age-related phenotypes. In addition, aged Nfkb1-/- animals have increased kyphosis, decreased cortical bone, increased brain GFAP staining and a decrease in overall lifespan compared to Nfkb1+/+. In vitro, serially passaged primary Nfkb1-/- MEFs have more senescent cells than comparable Nfkb1+/+ MEFs. Also, Nfkb1-/- MEFs have greater amounts of phospho-H2AX foci and lower levels of spontaneous apoptosis than Nfkb1+/+, findings that are mirrored in the brains of Nfkb1-/- animals compared to Nfkb1+/+. Finally, in wildtype animals a substantial decrease in p50 DNA binding is seen in aged tissue compared to young. Together, these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. These findings support the strong link between the NF-κB pathway and mammalian aging.

  20. Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus

    PubMed Central

    2012-01-01

    Background Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer’s patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Results Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. Conclusion A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor

  1. Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus.

    PubMed

    Torres, Manuel; Jimenez, Sebastian; Sanchez-Varo, Raquel; Navarro, Victoria; Trujillo-Estrada, Laura; Sanchez-Mejias, Elisabeth; Carmona, Irene; Davila, Jose Carlos; Vizuete, Marisa; Gutierrez, Antonia; Vitorica, Javier

    2012-11-22

    Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer's patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be

  2. Advances in early fetal loss research: importance for risk assessment.

    PubMed Central

    Sweeney, A M; LaPorte, R E

    1991-01-01

    The assessment of early fetal losses (EFLs) in relationship to environmental agents offers unique advantages compared to other end points for hazard assessment. There is a high incidence (greater than 20% of all pregnancies end in an EFL), and the interval between exposure and end point is the short duration between conception and event, i.e., approximately 12 weeks. In contrast, cancer, which is the primary end point evaluated in risk assessment models, occurs with much lower frequency, and the latency period is measured in years or decades. EFLs have not been used effectively for risk assessment because most of the events are not detected. Prospective studies provide the only approach whereby it is possible to link exposure to EFLs. Recent methodologic advancements have demonstrated that it is now possible to conduct population-based studies of EFLs. It is likely that EFLs could serve as sentinels to monitor adverse health effects of many potential environmental hazards. The methodology will be demonstrated using lead exposure in utero as an example. PMID:2050056

  3. Whole exome sequencing in recurrent early pregnancy loss

    PubMed Central

    Qiao, Ying; Wen, Jiadi; Tang, Flamingo; Martell, Sally; Shomer, Naomi; Leung, Peter C.K.; Stephenson, Mary D.; Rajcan-Separovic, Evica

    2016-01-01

    STUDY HYPOTHESIS Exome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL). STUDY FINDING We identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in miscarriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways. WHAT IS KNOWN ALREADY Next generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in ∼2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Whole exome sequencing (WES) was performed using Illumina HiSeq 2000 platform on seven euploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools. MAIN RESULTS AND THE ROLE OF CHANCE Compound heterozygous mutations in DYNC2H1 and ALOX15 were identified in miscarriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal

  4. Whole exome sequencing in recurrent early pregnancy loss.

    PubMed

    Qiao, Ying; Wen, Jiadi; Tang, Flamingo; Martell, Sally; Shomer, Naomi; Leung, Peter C K; Stephenson, Mary D; Rajcan-Separovic, Evica

    2016-05-01

    Exome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL). We identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in miscarriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways. Next generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in ∼2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause. Whole exome sequencing (WES) was performed using Illumina HiSeq 2000 platform on seven euploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools. Compound heterozygous mutations in DYNC2H1 and ALOX15 were identified in miscarriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal lethality in humans. ALOX15 is expressed in placenta and its dysregulation has been associated with inflammation, placental

  5. Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons In Vivo and In Vitro

    PubMed Central

    Trushina, Eugenia; Dyer, Roy B.; Badger, John D.; Ure, Daren; Eide, Lars; Tran, David D.; Vrieze, Brent T.; Legendre-Guillemin, Valerie; McPherson, Peter S.; Mandavilli, Bhaskar S.; Van Houten, Bennett; Zeitlin, Scott; McNiven, Mark; Aebersold, Ruedi; Hayden, Michael; Parisi, Joseph E.; Seeberg, Erling; Dragatsis, Ioannis; Doyle, Kelly; Bender, Anna; Chacko, Celin; McMurray, Cynthia T.

    2004-01-01

    Recent data in invertebrates demonstrated that huntingtin (htt) is essential for fast axonal trafficking. Here, we provide direct and functional evidence that htt is involved in fast axonal trafficking in mammals. Moreover, expression of full-length mutant htt (mhtt) impairs vesicular and mitochondrial trafficking in mammalian neurons in vitro and in whole animals in vivo. Particularly, mitochondria become progressively immobilized and stop more frequently in neurons from transgenic animals. These defects occurred early in development prior to the onset of measurable neurological or mitochondrial abnormalities. Consistent with a progressive loss of function, wild-type htt, trafficking motors, and mitochondrial components were selectively sequestered by mhtt in human Huntington's disease-affected brain. Data provide a model for how loss of htt function causes toxicity; mhtt-mediated aggregation sequesters htt and components of trafficking machinery leading to loss of mitochondrial motility and eventual mitochondrial dysfunction. PMID:15340079

  6. Axonal GABAA receptors.

    PubMed

    Trigo, Federico F; Marty, Alain; Stell, Brandon M

    2008-09-01

    Type A GABA receptors (GABA(A)Rs) are well established as the main inhibitory receptors in the mature mammalian forebrain. In recent years, evidence has accumulated showing that GABA(A)Rs are prevalent not only in the somatodendritic compartment of CNS neurons, but also in their axonal compartment. Evidence for axonal GABA(A)Rs includes new immunohistochemical and immunogold data: direct recording from single axonal terminals; and effects of local applications of GABA(A)R modulators on action potential generation, on axonal calcium signalling, and on neurotransmitter release. Strikingly, whereas presynaptic GABA(A)Rs have long been considered inhibitory, the new studies in the mammalian brain mostly indicate an excitatory action. Depending on the neuron that is under study, axonal GABA(A)Rs can be activated by ambient GABA, by GABA spillover, or by an autocrine action, to increase either action potential firing and/or transmitter release. In certain neurons, the excitatory effects of axonal GABA(A)Rs persist into adulthood. Altogether, axonal GABA(A)Rs appear as potent neuronal modulators of the mammalian CNS.

  7. Early photoreceptor outer segment loss and retinoschisis in Cohen syndrome.

    PubMed

    Uyhazi, Katherine E; Binenbaum, Gil; Carducci, Nicholas; Zackai, Elaine H; Aleman, Tomas S

    2018-06-01

    To describe early structural and functional retinal changes in a patient with Cohen syndrome. A 13-month-old Caucasian girl of Irish and Spanish ancestry was noted to have micrognathia and laryngomalacia at birth, which prompted a genetic evaluation that revealed biallelic deletions in COH1 (VPS13B) (a maternally inherited 60-kb deletion involving exons 26-32 and a paternally inherited 3.5-kb deletion within exon 17) consistent with Cohen syndrome. She underwent a complete ophthalmic examination, full-field flash electroretinography and retinal imaging with spectral domain optical coherence tomography. Central vision was central, steady, and maintained. There was bilateral myopic astigmatic refractive error. Fundus exam was notable for dark foveolar pigmentation, but no obvious abnormalities of either eye. Spectral domain optical coherence tomography cross sections through the fovea revealed a normal appearing photoreceptor outer nuclear layer but loss of the interdigitation signal between the photoreceptor outer segments and the apical retinal pigment epithelium. Retinoschisis involving the inner nuclear layer of both eyes and possible ganglion cell layer thinning were also noted. There was a detectable electroretinogram with similarly reduced amplitudes of rod- (white, 0.01 cd.s.m -2 ) and cone-mediated (3 cd.s.m -2 , 30 Hz) responses. Photoreceptor outer segment abnormalities and retinoschisis may represent the earliest structural retinal change detected by spectral domain optical coherence tomography in patients with Cohen syndrome, suggesting a complex pathophysiology with primary involvement of the photoreceptor cilium and disorganization of the structural integrity of the inner retina.

  8. Spectroscopic Axonal Damage of the Right Locus Coeruleus Relates to Selective Attention Impairment in Early Stage Relapsing-Remitting Multiple Sclerosis

    ERIC Educational Resources Information Center

    Gadea, Marien; Martinez-Bisbal, M. Carmen; Marti-Bonmati, Luis; Espert, Raul; Casanova, Bonaventura; Coret, Francisco; Celda, Bernardo

    2004-01-01

    Lower levels of N-acetylaspartate (NAA), a marker of axonal damage, have been found in the normal-appearing white matter (NAWM) of relapsing-remitting multiple sclerosis (RRMS) patients with low physical disability. However, its relation to the clinical status of these patients remains unclear. We explored the association between NAA levels…

  9. Schwann cell glycogen selectively supports myelinated axon function.

    PubMed

    Brown, Angus M; Evans, Richard D; Black, Joel; Ransom, Bruce R

    2012-09-01

    Interruption of energy supply to peripheral axons is a cause of axon loss. We determined whether glycogen was present in mammalian peripheral nerve, and whether it supported axon conduction during aglycemia. We used biochemical assay and electron microscopy to determine the presence of glycogen, and electrophysiology to monitor axon function. Glycogen was present in sciatic nerve, its concentration varying directly with ambient glucose. Electron microscopy detected glycogen granules primarily in myelinating Schwann cell cytoplasm, and these diminished after exposure to aglycemia. During aglycemia, conduction failure in large myelinated axons (A fibers) mirrored the time course of glycogen loss. Latency to compound action potential (CAP) failure was directly related to nerve glycogen content at aglycemia onset. Glycogen did not benefit the function of slow-conducting, small-diameter unmyelinated axons (C fibers) during aglycemia. Blocking glycogen breakdown pharmacologically accelerated CAP failure during aglycemia in A fibers, but not in C fibers. Lactate was as effective as glucose in supporting sciatic nerve function, and was continuously released into the extracellular space in the presence of glucose and fell rapidly during aglycemia. Our findings indicated that glycogen is present in peripheral nerve, primarily in myelinating Schwann cells, and exclusively supports large-diameter, myelinated axon conduction during aglycemia. Available evidence suggests that peripheral nerve glycogen breaks down during aglycemia and is passed, probably as lactate, to myelinated axons to support function. Unmyelinated axons are not protected by glycogen and are more vulnerable to dysfunction during periods of hypoglycemia. . Copyright © 2012 American Neurological Association.

  10. Schwann Cell Glycogen Selectively Supports Myelinated Axon Function

    PubMed Central

    Brown, Angus M; Evans, Richard D; Black, Joel; Ransom, Bruce R

    2012-01-01

    Objectives Interruption of energy supply to peripheral axons is a cause of axon loss. We determined if glycogen was present in mammalian peripheral nerve, and if it supported axon conduction during aglycemia. Methods We used biochemical assay and electron microscopy to determine the presence of glycogen, and electrophysiology to monitor axon function. Results Glycogen was present in sciatic nerve, its concentration varying directly with ambient [glucose]. Electron microscopy detected glycogen granules primarily in myelinating Schwann cell cytoplasm and these diminished after exposure to aglycemia. During aglycemia, conduction failure in large myelinated axons (A fibers) mirrored the time-course of glycogen loss. Latency to CAP failure was directly related to nerve glycogen content at aglycemia onset. Glycogen did not benefit the function of slow-conducting, small diameter unmyelinated axons (C fibers) during aglycemia. Blocking glycogen breakdown pharmacologically accelerated CAP failure during aglycemia in A fibers, but not in C fibers. Lactate was as effective as glucose in supporting sciatic nerve function, and was continuously released into the extracellular space in the presence of glucose and fell rapidly during aglycemia. Interpretation Our findings indicated that glycogen is present in peripheral nerve, primarily in myelinating Schwann cells, and exclusively supports large diameter, myelinated axon conduction during aglycemia. Available evidence suggests that peripheral nerve glycogen breaks down during aglycemia and is passed, probably as lactate, to myelinated axons to support function. Unmyelinated axons are not protected by glycogen and are more vulnerable to dysfunction during periods of hypoglycemia. PMID:23034913

  11. Axons take a dive

    PubMed Central

    Tong, Cheuk Ka; Cebrián-Silla, Arantxa; Paredes, Mercedes F; Huang, Eric J; García-Verdugo, Jose Manuel; Alvarez-Buylla, Arturo

    2015-01-01

    In the walls of the lateral ventricles of the adult mammalian brain, neural stem cells (NSCs) and ependymal (E1) cells share the apical surface of the ventricular–subventricular zone (V–SVZ). In a recent article, we show that supraependymal serotonergic (5HT) axons originating from the raphe nuclei in mice form an extensive plexus on the walls of the lateral ventricles where they contact E1 cells and NSCs. Here we further characterize the contacts between 5HT supraependymal axons and E1 cells in mice, and show that suprependymal axons tightly associated to E1 cells are also present in the walls of the human lateral ventricles. These observations raise interesting questions about the function of supraependymal axons in the regulation of E1 cells. PMID:26413556

  12. Axon Regeneration in C. elegans

    PubMed Central

    Hammarlund, Marc; Jin, Yishi

    2014-01-01

    Single axon transection by laser surgery has made C. elegans a new model for axon regeneration. Multiple conserved molecular signaling modules have been discovered through powerful genetic screening. in vivo imaging with single cell and axon resolution has revealed unprecedented cellular dynamics in regenerating axons. Information from C. elegans has greatly expanded our knowledge of the molecular and cellular mechanisms of axon regeneration. PMID:24794753

  13. Incidence and factors associated with early pregnancy losses in Simmental dairy cows.

    PubMed

    Zobel, R; Tkalčić, S; Pipal, I; Buić, V

    2011-09-01

    It has been suggested that management system, milk yield, parity, body condition score and ambient temperature can significantly influence the rate of early pregnancy loss in dairy cattle. The objectives of this study were to establish the extent and patterns of early pregnancy loss from days 32 to 86 of gestation, and to check relationships between management system, milk yield, ambient temperature (quartile), body condition score, bull and parity on the early pregnancy loss rate for Simmental dairy cattle in Croatia. Animals were housed in two dairy farms with two different management systems (pasture based-group A, n=435 and intensive-group B, n=425) with a total of 151 heifers and 709 cows. Overall pregnancy losses were recorded in 67 (7.79%) animals, with late embryonic losses in 30 (44.77%) and early fetal losses in 37 (55.23%) animals (P>0.05). Early pregnancy losses were twofold higher in group B when compared to the group A (P<0.05). More than the half of pregnancy losses were recorded during the III quartile (P<0.05). There was no significant relationship between the paternal bull and pregnancy loss rate. Low body condition score (BCS 2-3) was associated with the highest, while BCS 3.25-4 showed the lowest pregnancy loss rate (P<0.05). The pregnancy loss rate increased in parallel with parity and milk yield increase. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Retrograde and Wallerian Axonal Degeneration Occur Synchronously after Retinal Ganglion Cell Axotomy

    PubMed Central

    Kanamori, Akiyasu; Catrinescu, Maria-Magdalena; Belisle, Jonathan M.; Costantino, Santiago; Levin, Leonard A.

    2013-01-01

    Axonal injury and degeneration are pivotal pathological events in diseases of the nervous system. In the past decade, it has been recognized that the process of axonal degeneration is distinct from somal degeneration and that axoprotective strategies may be distinct from those that protect the soma. Preserving the cell body via neuroprotection cannot improve function if the axon is damaged, because the soma is still disconnected from its target. Therefore, understanding the mechanisms of axonal degeneration is critical for developing new therapeutic interventions for axonal disease treatment. We combined in vivo imaging with a multilaser confocal scanning laser ophthalmoscope and in vivo axotomy with a diode-pumped solid-state laser to assess the time course of Wallerian and retrograde degeneration of unmyelinated retinal ganglion cell axons in living rats for 4 weeks after intraretinal axotomy. Laser injury resulted in reproducible axon loss both distal and proximal to the site of injury. Longitudinal polarization-sensitive imaging of axons demonstrated that Wallerian and retrograde degeneration occurred synchronously. Neurofilament immunostaining of retinal whole-mounts confirmed axonal loss and demonstrated sparing of adjacent axons to the axotomy site. In vivo fluorescent imaging of axonal transport and photobleaching of labeled axons demonstrated that the laser axotomy model did not affect adjacent axon function. These results are consistent with a shared mechanism for Wallerian and retrograde degeneration. PMID:22642911

  15. Electrophysiology of Axonal Constrictions

    NASA Astrophysics Data System (ADS)

    Johnson, Christopher; Jung, Peter; Brown, Anthony

    2013-03-01

    Axons of myelinated neurons are constricted at the nodes of Ranvier, where they are directly exposed to the extracellular space and where the vast majority of the ion channels are located. These constrictions are generated by local regulation of the kinetics of neurofilaments the most important cytoskeletal elements of the axon. In this paper we discuss how this shape affects the electrophysiological function of the neuron. Specifically, although the nodes are short (about 1 μm) in comparison to the distance between nodes (hundreds of μm) they have a substantial influence on the conduction velocity of neurons. We show through computational modeling that nodal constrictions (all other features such as numbers of ion channels left constant) reduce the required fiber diameter for a given target conduction velocity by up to 50% in comparison to an unconstricted axon. We further show that the predicted optimal fiber morphologies closely match reported fiber morphologies. Supported by The National Science Foundation (IOS 1146789)

  16. Separation and Loss: A Handbook for Early Childhood Professionals.

    ERIC Educational Resources Information Center

    Mack, Cheryl; And Others

    Recognizing the importance of helping children develop coping skills to deal with daily separations and more serious losses, this handbook provides basic information and classroom support strategies for teachers and caregivers to use responsively with preschoolers. Parts 1 through 3 of the handbook provide a rationale for responding to the…

  17. Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis

    PubMed Central

    Iwai, Yuta; Shibuya, Kazumoto; Misawa, Sonoko; Sekiguchi, Yukari; Watanabe, Keisuke; Amino, Hiroshi; Kuwabara, Satoshi

    2016-01-01

    Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS. PMID:27383069

  18. MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2

    PubMed Central

    Walker, Lauren J; Summers, Daniel W; Sasaki, Yo; Brace, EJ; Milbrandt, Jeffrey; DiAntonio, Aaron

    2017-01-01

    Injury-induced (Wallerian) axonal degeneration is regulated via the opposing actions of pro-degenerative factors such as SARM1 and a MAPK signal and pro-survival factors, the most important of which is the NAD+ biosynthetic enzyme NMNAT2 that inhibits activation of the SARM1 pathway. Here we investigate the mechanism by which MAPK signaling facilitates axonal degeneration. We show that MAPK signaling promotes the turnover of the axonal survival factor NMNAT2 in cultured mammalian neurons as well as the Drosophila ortholog dNMNAT in motoneurons. The increased levels of NMNAT2 are required for the axonal protection caused by loss of MAPK signaling. Regulation of NMNAT2 by MAPK signaling does not require SARM1, and so cannot be downstream of SARM1. Hence, pro-degenerative MAPK signaling functions upstream of SARM1 by limiting the levels of the essential axonal survival factor NMNAT2 to promote injury-dependent SARM1 activation. These findings are consistent with a linear molecular pathway for the axonal degeneration program. DOI: http://dx.doi.org/10.7554/eLife.22540.001 PMID:28095293

  19. Oligodendroglia metabolically support axons and contribute to neurodegeneration

    PubMed Central

    Lee, Youngjin; Morrison, Brett M.; Li, Yun; Lengacher, Sylvain; Farah, Mohamed H.; Hoffman, Paul N.; Liu, Yiting; Tsingalia, Akivaga; Jin, Lin; Zhang, Ping-Wu; Pellerin, Luc; Magistretti, Pierre J.; Rothstein, Jeffrey D.

    2012-01-01

    Summary Oligodendroglia support axon survival and function through mechanisms independent of myelination and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been hypothesized. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and utilization. We show the most abundant lactate transporter in the CNS, monocarboxylate transporter 1 (MCT1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and mouse models of, amyotrophic lateral sclerosis (ALS), suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons. PMID:22801498

  20. Glia to axon RNA transfer.

    PubMed

    Sotelo, José Roberto; Canclini, Lucía; Kun, Alejandra; Sotelo-Silveira, José Roberto; Calliari, Aldo; Cal, Karina; Bresque, Mariana; Dipaolo, Andrés; Farias, Joaquina; Mercer, John A

    2014-03-01

    The existence of RNA in axons has been a matter of dispute for decades. Evidence for RNA and ribosomes has now accumulated to a point at which it is difficult to question, much of the disputes turned to the origin of these axonal RNAs. In this review, we focus on studies addressing the origin of axonal RNAs and ribosomes. The neuronal soma as the source of most axonal RNAs has been demonstrated and is indisputable. However, the surrounding glial cells may be a supplemental source of axonal RNAs, a matter scarcely investigated in the literature. Here, we review the few papers that have demonstrated that glial-to-axon RNA transfer is not only feasible, but likely. We describe this process in both invertebrate axons and vertebrate axons. Schwann cell to axon ribosomes transfer was conclusively demonstrated (Court et al. [2008]: J. Neurosci 28:11024-11029; Court et al. [2011]: Glia 59:1529-1539). However, mRNA transfer still remains to be demonstrated in a conclusive way. The intercellular transport of mRNA has interesting implications, particularly with respect to the integration of glial and axonal function. This evolving field is likely to impact our understanding of the cell biology of the axon in both normal and pathological conditions. Most importantly, if the synthesis of proteins in the axon can be controlled by interacting glia, the possibilities for clinical interventions in injury and neurodegeneration are greatly increased. Copyright © 2013 Wiley Periodicals, Inc.

  1. Loss of corticospinal tract integrity in early MS disease stages

    PubMed Central

    Neumann, Jens; Kaufmann, Jörn; Heidel, Jan; Stadler, Erhard; Sweeney-Reed, Catherine; Sailer, Michael; Schreiber, Stefanie

    2017-01-01

    Objective: We investigated corticospinal tract (CST) integrity in the absence of white matter (WM) lesions using diffusion tensor imaging (DTI) in early MS disease stages. Methods: Our study comprised 19 patients with clinically isolated syndrome (CIS), 11 patients with relapsing-remitting MS (RRMS), and 32 age- and sex-matched healthy controls, for whom MRI measures of CST integrity (fractional anisotropy [FA], mean diffusivity [MD]), T1- and T2-based lesion load, and brain volumes were available. The mean (SD) disease duration was 3.5 (2.1) months, and disability score was low (median Expanded Disability Status Scale 1.5) at the time of the study. Results: Patients with CIS and RRMS had significantly lower CST FA and higher CST MD values compared with controls. These findings were present, irrespective of whether WM lesions affected the CST. However, no group differences in the overall gray or WM volume were identified. Conclusions: In early MS disease stages, CST integrity is already affected in the absence of WM lesions or brain atrophy. PMID:28959706

  2. Physical Biology of Axonal Damage.

    PubMed

    de Rooij, Rijk; Kuhl, Ellen

    2018-01-01

    Excessive physical impacts to the head have direct implications on the structural integrity at the axonal level. Increasing evidence suggests that tau, an intrinsically disordered protein that stabilizes axonal microtubules, plays a critical role in the physical biology of axonal injury. However, the precise mechanisms of axonal damage remain incompletely understood. Here we propose a biophysical model of the axon to correlate the dynamic behavior of individual tau proteins under external physical forces to the evolution of axonal damage. To propagate damage across the scales, we adopt a consistent three-step strategy: First, we characterize the axonal response to external stretches and stretch rates for varying tau crosslink bond strengths using a discrete axonal damage model. Then, for each combination of stretch rates and bond strengths, we average the axonal force-stretch response of n = 10 discrete simulations, from which we derive and calibrate a homogenized constitutive model. Finally, we embed this homogenized model into a continuum axonal damage model of [1-d]-type in which d is a scalar damage parameter that is driven by the axonal stretch and stretch rate. We demonstrate that axonal damage emerges naturally from the interplay of physical forces and biological crosslinking. Our study reveals an emergent feature of the crosslink dynamics: With increasing loading rate, the axonal failure stretch increases, but axonal damage evolves earlier in time. For a wide range of physical stretch rates, from 0.1 to 10 /s, and biological bond strengths, from 1 to 100 pN, our model predicts a relatively narrow window of critical damage stretch thresholds, from 1.01 to 1.30, which agrees well with experimental observations. Our biophysical damage model can help explain the development and progression of axonal damage across the scales and will provide useful guidelines to identify critical damage level thresholds in response to excessive physical forces.

  3. Early Parental Loss and Intimate Relationships in Adulthood: A Nationwide Study

    ERIC Educational Resources Information Center

    Høeg, Beverley Lim; Johansen, Christoffer; Christensen, Jane; Frederiksen, Kirsten; Dalton, Susanne Oksbjerg; Dyregrov, Atle; Bøge, Per; Dencker, Annemarie; Bidstrup, Pernille Envold

    2018-01-01

    Being able to form and maintain intimate relationships is an essential part of development and the early loss of a parent may negatively affect this ability. This study investigates the association between parental loss before the age of 18 years and the formation and dissolution of marriage and cohabitation relationships in adulthood, in relation…

  4. Transdermal Nitroglycerin Therapy May Not Prevent Early Postmenopausal Bone Loss

    PubMed Central

    Wimalawansa, Sunil J.; Grimes, Julia P.; Wilson, Alan C.; Hoover, Donald R.

    2009-01-01

    Context: Osteoporosis is common among postmenopausal women; animal studies and human pilot studies support the concept of nitric oxide (NO) donors reducing bone mineral density loss. Objective: The objective of the study was to evaluate whether NO donor, nitroglycerin, prevents postmenopausal bone loss. Design: This was a 3-yr randomized, double blinded, single-center, placebo-controlled clinical trial. Setting: The single-center study was conducted at the University of Medicine and Dentistry-Robert Wood Johnson Medical School (New Brunswick, NJ). Participants: Participants included 186 postmenopausal women aged 40–65 yr, with lumbar bone mineral density (BMD) T-scores of 0 to −2.5. Intervention: Women, stratified by lumbar T-score (<−1.50 and ≥−1.50) and years since menopause (≤5 and >5 yr), were randomized to receive nitroglycerin ointment (22.5 mg as Nitro-Bid) or placebo ointment received daily for 3 yr. Both groups took 630 mg daily calcium plus 400 IU vitamin D supplements. Measurements: BMD was measured at 6 months and annually by dual-energy x-ray absorptiometry. Percent change in lumbar vertebrae BMD was the primary outcome. Hip BMD, total body bone mineral content, and height were secondary outcomes. Results: After 36 months of therapy, changes of −2.1% in the active group (n = 88) and −2.5% in the placebo group (n = 82) in lumbar spine BMD were seen (P = 0.59; 95% confidence interval −1.001, 1.975). Secondary outcomes also did not differ by intervention arm. The active group reported more headaches compared with the placebo group (57 vs. 14%, P < 0.001). Other adverse and serious adverse events were not different. Conclusions: BMD changes did not substantially differ between postmenopausal women who received the dose of nitroglycerin tested, in comparison with a placebo. Once-daily dosing with 22.5 mg of transdermal-administered nitroglycerin was not effective (compliance adjusted dose was only ∼16 mg/d); a sub-therapeutic dose. PMID

  5. Clinical progression in Parkinson disease and the neurobiology of axons.

    PubMed

    Cheng, Hsiao-Chun; Ulane, Christina M; Burke, Robert E

    2010-06-01

    Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson disease (PD) and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. Although there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that ongoing degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration.

  6. Predictors of Early-Onset Permanent Hearing Loss in Malnourished Infants in Sub-Saharan Africa

    ERIC Educational Resources Information Center

    Olusanya, Bolajoko O.

    2011-01-01

    The objective of this study was to determine the predictors of early-onset permanent hearing loss (EPHL) among undernourished infants in a low-income country where routine screening for developmental disabilities in early childhood is currently unattainable. All infants attending four community-based clinics for routine immunization who met the…

  7. Relationships between Early Child Factors and School Readiness Skills in Young Children with Hearing Loss

    ERIC Educational Resources Information Center

    Harrington, Marjorie; DesJardin, Jean L.; Shea, Lynn C.

    2010-01-01

    The goal of this longitudinal study is to examine the relationships between early child factors (i.e., age at identification, enrollment in early intervention, oral language skills) and school readiness skills (i.e., conceptual knowledge) in a group of young children with hearing loss (HL). Standardized language, cognition, and conceptual…

  8. Early pregnancy factor (EPF) as a marker for the diagnosis of subclinical embryonic loss.

    PubMed

    Shahani, S K; Moniz, C; Chitlange, S; Meherji, P

    1992-01-01

    The validation of EPF as a possible correlate of early fertilization has made it possible to study and detect fertilization of the ovum in normal fertile women (during the luteal phase) and also in women with infertility, where the fertilization of the ovum may not be affected but there may be impairment in early embryonic development which results in early embryo loss or subclinical embryo loss. Our results have suggested that using EPF as a marker, we could detect subclinical embryonic loss in 57.8% of the infertile women where more than one menstrual cycle was studied and the blood was collected 4-7 days after ovulation. After the missed period, 80% of the patients who were negative for EPF but positive for hCG had spontaneous abortions. It would be interesting to study how EPF behaves as a marker, to detect subclinical embryonic loss in diverse pathological situations such as recurrent abortions, parental age and translocation carrier parents.

  9. Axon Transport and Neuropathy

    PubMed Central

    Tourtellotte, Warren G.

    2017-01-01

    Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. PMID:26724390

  10. Decreased serum vitamin D levels in early spontaneous pregnancy loss.

    PubMed

    Hou, W; Yan, X-T; Bai, C-M; Zhang, X-W; Hui, L-Y; Yu, X-W

    2016-09-01

    Effects of vitamin D deficiency in pregnancy have been associated with some adverse pregnancy outcomes. The objective of this study was to analyze the relationship between vitamin D deficiency in childbearing aged women and pregnancy loss (PL) in the first trimester. This is a cross-sectional study. Plasma was collected from 60 nulliparous women with singleton at 7-9 weeks of gestation (30 with viable gestation and 30 with PL) and 60 non-gravid childbearing aged women (30 with a successful pregnancy history, and 30 with one or more spontaneous first-trimester PL history). Quantitation of serum 25-hydroxyvitamin D (25(OH)D) and 25-hydroxyvitamin D-1 alpha hydroxylase (CYP27B1) was assayed. By pregnancy/non-gravid, normal pregnant women had higher 25(OH)D (49.32 μg/l) and CYP27B1 (82.00 pg/ml) than PL women (34.49 μg/l and 37.87 pg/ml, both P<0.01); the non-gravid women with a successful pregnancy history also had higher 25(OH)D (39.56 μg/l) and CYP27B1 (39.04 pg/ml) than women with PL history (12.30 μg/l and 12.35 pg/ml, both P<0.01). The 96.7% of non-gravid women with PL history and 43.3% of PL women had serum 25(OH)D concentrations below 30 μg/l. There was a strong association between low vitamin D levels and PL (odds ratio 1.71; 95% confidence interval: 1.2-2.4, P<0.001). The regression analyses showed that PL was significantly inversely correlated with 25(OH)D (P<0.01) and CYP27B1 levels (P<0.01). Vitamin D deficiency associated with PL in the first trimester of pregnancy. Decreased serum vitamin D levels among childbearing aged women with the failed clinical pregnancies history may predispose to increased risk for PL.

  11. Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1.

    PubMed

    Steichen-Gersdorf, Elisabeth; Lorenz-Depiereux, Bettina; Strom, Tim Matthias; Shaw, Nicholas J

    2015-07-01

    Autosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto-nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (ENPP1) causes a wide spectrum of phenotypes, ranging from lethal generalized arterial calcification of infancy to hypophosphatemic rickets with hypertension. Hearing loss was not previously thought to be one of the features of the disease entities and was merely regarded as a complication rather than a part of the disease. We report two children who presented in mid to late childhood with progressive varus deformity of their legs due to hypophosphatemic rickets caused by mutations in the ENPP1 gene. Both children had evidence of progressive hearing loss requiring the use of hearing aids. This report of two unrelated infants with compound heterozygous mutations in ENPP1 and previously published cases confirms that mild to moderate hearing loss is frequently associated with ARHR2. Early onset conductive hearing loss may further distinguish the autosomal recessive ENPP1 related type from other types of hypophosphatemia.

  12. LONGITUDINAL IMPEDANCE OF THE SQUID GIANT AXON

    PubMed Central

    Cole, Kenneth S.; Baker, Richard F.

    1941-01-01

    Longitudinal alternating current impedance measurements have been made on the squid giant axon over the frequency range from 30 cycles per second to 200 kc. per second. Large sea water electrodes were used and the inter-electrode length was immersed in oil. The impedance at high frequency was approximately as predicted theoretically on the basis of the poorly conducting dielectric characteristics of the membrane previously determined. For the large majority of the axons, the impedance reached a maximum at a low frequency and the reactance then vanished at a frequency between 150 and 300 cycles per second. Below this frequency, the reactance was inductive, reaching a maximum and then approaching zero as the frequency was decreased. The inductive reactance is a property of the axon and requires that it contain an inductive structure. The variation of the impedance with interpolar distance indicates that the inductance is in the membrane. The impedance characteristics of the membrane as calculated from the measured longitudinal impedance of the axon may be expressed by an equivalent membrane circuit containing inductance, capacity, and resistance. For a square centimeter of membrane the capacity of 1 µf with dielectric loss is shunted by the series combination of a resistance of 400 ohms and an inductance of one-fifth henry. PMID:19873252

  13. Preconception B-vitamin and homocysteine status, conception, and early pregnancy loss.

    PubMed

    Ronnenberg, Alayne G; Venners, Scott A; Xu, Xiping; Chen, Changzhong; Wang, Lihua; Guang, Wenwei; Huang, Aiqun; Wang, Xiaobin

    2007-08-01

    Maternal vitamin status contributes to clinical spontaneous abortion, but the role of B-vitamin and homocysteine status in subclinical early pregnancy loss is unknown. Three-hundred sixty-four textile workers from Anqing, China, who conceived at least once during prospective observation (1996-1998), provided daily urine specimens for up to 1 year, and urinary human chorionic gonadotropin was assayed to detect conception and early pregnancy loss. Homocysteine, folate, and vitamins B6 and B12 were measured in preconception plasma. Relative to women in the lowest quartile of vitamin B6, those in the third and fourth quartiles had higher adjusted proportional hazard ratios of conception (hazard ratio (HR)=2.2, 95% confidence interval (CI): 1.3, 3.4; HR=1.6, 95% CI: 1.1, 2.3, respectively), and the adjusted odds ratio for early pregnancy loss in conceptive cycles was lower in the fourth quartile (odds ratio=0.5, 95% CI: 0.3, 1.0). Women with sufficient vitamin B6 had a higher adjusted hazard ratio of conception (HR=1.4, 95% CI: 1.1, 1.9) and a lower adjusted odds ratio of early pregnancy loss in conceptive cycles (odds ratio=0.7, 95% CI: 0.4, 1.1) than did women with vitamin B6 deficiency. Poor vitamin B6 status appears to decrease the probability of conception and to contribute to the risk of early pregnancy loss in this population.

  14. The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons

    PubMed Central

    2014-01-01

    6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment. PMID:24885281

  15. Early weight loss while on lorcaserin, diet and exercise as a predictor of week 52 weight-loss outcomes.

    PubMed

    Smith, Steven R; O'Neil, Patrick M; Astrup, Arne; Finer, Nicholas; Sanchez-Kam, Matilde; Fraher, Kyle; Fain, Randi; Shanahan, William R

    2014-10-01

    To identify an early treatment milestone that optimizes sensitivity and specificity for predicting ≥5% weight loss at Week (W) 52 in patients with and without type 2 diabetes on lorcaserin or placebo. Post hoc area under the curve for receiver operating characteristic analyses of data from three phase 3 trials comparing lifestyle modification+placebo with lifestyle modification+lorcaserin. A total of 6897 patients (18-65 years; BMI, 30-45 or 27-29.9 kg/m(2) with ≥1 comorbidity) were randomized to placebo or lorcaserin 10 mg bid. Changes (baseline to W52) in cardiometabolic parameters were assessed. Response (≥5% weight loss from baseline) at W12 was a strong predictor of W52 response. Lorcaserin patients with a W12 response achieved mean W52 weight losses of 10.6 kg (without diabetes) and 9.3 kg (with diabetes). Proportions achieving ≥5% and ≥10% weight loss at W52 were 85.5% and 49.8% (without diabetes), and 70.5% and 35.9% (with diabetes). Lorcaserin patients who did not achieve a W12 response lost 3.2 kg (without diabetes) and 2.8 kg (with diabetes) at W52. Responders had greater improvements in cardiometabolic risk factors than the modified intent-to-treat (MITT) population, consistent with greater weight loss. ≥5% weight loss by W12 predicts robust response to lorcaserin at 1 year. Copyright © 2014 The Authors Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).

  16. Signal propagation along the axon.

    PubMed

    Rama, Sylvain; Zbili, Mickaël; Debanne, Dominique

    2018-03-08

    Axons link distant brain regions and are usually considered as simple transmission cables in which reliable propagation occurs once an action potential has been generated. Safe propagation of action potentials relies on specific ion channel expression at strategic points of the axon such as nodes of Ranvier or axonal branch points. However, while action potentials are generally considered as the quantum of neuronal information, their signaling is not entirely digital. In fact, both their shape and their conduction speed have been shown to be modulated by activity, leading to regulations of synaptic latency and synaptic strength. We report here newly identified mechanisms of (1) safe spike propagation along the axon, (2) compartmentalization of action potential shape in the axon, (3) analog modulation of spike-evoked synaptic transmission and (4) alteration in conduction time after persistent regulation of axon morphology in central neurons. We discuss the contribution of these regulations in information processing. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. Defining the developmental parameters of temper loss in early childhood: implications for developmental psychopathology

    PubMed Central

    Wakschlag, Lauren S.; Choi, Seung W.; Carter, Alice S.; Hullsiek, Heide; Burns, James; McCarthy, Kimberly; Leibenluft, Ellen; Briggs-Gowan, Margaret J.

    2013-01-01

    Background Temper modulation problems are both a hallmark of early childhood and a common mental health concern. Thus, characterizing specific behavioral manifestations of temper loss along a dimension from normative misbehaviors to clinically significant problems is an important step toward identifying clinical thresholds. Methods Parent-reported patterns of temper loss were delineated in a diverse community sample of preschoolers (n = 1,490). A developmentally sensitive questionnaire, the Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB), was used to assess temper loss in terms of tantrum features and anger regulation. Specific aims were: (a) document the normative distribution of temper loss in preschoolers from normative misbehaviors to clinically concerning temper loss behaviors, and test for sociodemographic differences; (b) use Item Response Theory (IRT) to model a Temper Loss dimension; and (c) examine associations of temper loss and concurrent emotional and behavioral problems. Results Across sociodemographic subgroups, a unidimensional Temper Loss model fit the data well. Nearly all (83.7%) preschoolers had tantrums sometimes but only 8.6% had daily tantrums. Normative misbehaviors occurred more frequently than clinically concerning temper loss behaviors. Milder behaviors tended to reflect frustration in expectable contexts, whereas clinically concerning problem indicators were unpredictable, prolonged, and/or destructive. In multivariate models, Temper Loss was associated with emotional and behavioral problems. Conclusions Parent reports on a developmentally informed questionnaire, administered to a large and diverse sample, distinguished normative and problematic manifestations of preschool temper loss. A developmental, dimensional approach shows promise for elucidating the boundaries between normative early childhood temper loss and emergent psychopathology. PMID:22928674

  18. An αII Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration.

    PubMed

    Huang, Claire Yu-Mei; Zhang, Chuansheng; Zollinger, Daniel R; Leterrier, Christophe; Rasband, Matthew N

    2017-11-22

    Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with αII spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed αII spectrin-deficient mice of both sexes and found that, in myelinated axons, αII spectrin forms a periodic cytoskeleton with βIV and βII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of αII spectrin disrupts this organization. Avil-cre;Sptan1 f/f mice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K + channels. We show that the density of nodal βIV spectrin is constant among axons, but the density of nodal αII spectrin increases with axon diameter. Remarkably, Avil-cre;Sptan1 f/f mice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal αII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that αII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier. SIGNIFICANCE STATEMENT A periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in

  19. Developmental time windows for axon growth influence neuronal network topology.

    PubMed

    Lim, Sol; Kaiser, Marcus

    2015-04-01

    Early brain connectivity development consists of multiple stages: birth of neurons, their migration and the subsequent growth of axons and dendrites. Each stage occurs within a certain period of time depending on types of neurons and cortical layers. Forming synapses between neurons either by growing axons starting at similar times for all neurons (much-overlapped time windows) or at different time points (less-overlapped) may affect the topological and spatial properties of neuronal networks. Here, we explore the extreme cases of axon formation during early development, either starting at the same time for all neurons (parallel, i.e., maximally overlapped time windows) or occurring for each neuron separately one neuron after another (serial, i.e., no overlaps in time windows). For both cases, the number of potential and established synapses remained comparable. Topological and spatial properties, however, differed: Neurons that started axon growth early on in serial growth achieved higher out-degrees, higher local efficiency and longer axon lengths while neurons demonstrated more homogeneous connectivity patterns for parallel growth. Second, connection probability decreased more rapidly with distance between neurons for parallel growth than for serial growth. Third, bidirectional connections were more numerous for parallel growth. Finally, we tested our predictions with C. elegans data. Together, this indicates that time windows for axon growth influence the topological and spatial properties of neuronal networks opening up the possibility to a posteriori estimate developmental mechanisms based on network properties of a developed network.

  20. Early parental loss and depression history: associations with recent life stress in major depressive disorder.

    PubMed

    Slavich, George M; Monroe, Scott M; Gotlib, Ian H

    2011-09-01

    Although exposure to early adversity and prior experiences with depression have both been associated with lower levels of precipitating life stress in depression, it is unclear whether these stress sensitization effects are similar for all types of stress or whether they are specific to stressors that may be particularly depressogenic, such as those involving interpersonal loss. To investigate this issue, we administered structured, interview-based measures of early adversity, depression history, and recent life stress to one hundred adults who were diagnosed with major depressive disorder. As predicted, individuals who experienced early parental loss or prolonged separation (i.e., lasting one year or longer) and persons with more lifetime episodes of depression became depressed following lower levels of life stress occurring in the etiologically-central time period of three months prior to onset of depression. Importantly, however, additional analyses revealed that these effects were unique to stressors involving interpersonal loss. These data highlight potential stressor-specific effects in stress sensitization and demonstrate for the first time that individuals exposed to early parental loss or separation, and persons with greater histories of MDD, may be selectively sensitized to stressors involving interpersonal loss. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Exploring reasons for late identification of children with early-onset hearing loss.

    PubMed

    Fitzpatrick, Elizabeth M; Dos Santos, Johnny Cesconetto; Grandpierre, Viviane; Whittingham, JoAnne

    2017-09-01

    Several studies have shown that early identification of childhood hearing loss leads to better language outcomes. However, delays in the confirmation of hearing loss persist even in the presence of well-established universal newborn hearing screening programs (UNHS). The objective of this population-based study was to document the proportion of children who experienced delayed confirmation of congenital and early onset hearing loss in a UNHS program in one region of Canada. The study also sought to determine the reasons for delayed confirmation of hearing loss in children. Population level data related to age of first assessment, age of identification and clinical characteristics were collected prospectively for all children identified through the UNHS program. We documented the number of children who experienced delay (defined as more than 3 months) from initial audiologic assessment to confirmation of hearing loss. A detailed chart review was subsequently performed to examine the reasons for delay to confirmation. Of 418 children identified from 2003 to 2013, 182 (43.5%) presented with congenital or early onset hearing loss, of whom 30 (16.5%) experienced more than 3 months delay from initial audiologic assessment to confirmation of their hearing disorder. The median age of first assessment and confirmation of hearing loss for these 30 children was 3.7 months (IQR: 2.0, 7.6) and 13.8 months (IQR: 9.7, 26.1) respectively. Close examination of the factors related to delay to confirmation revealed that for the overwhelming majority of children, a constellation of factors contributed to late diagnosis. Several children (n = 22; 73.3%) presented with developmental/medical issues, 15 of whom also had middle ear dysfunction at assessment, and 9 of whom had documented family follow-up concerns. For the remaining eight children, additional reasons included ongoing middle ear dysfunction for five children, complicated by family follow-up concerns (n = 3) and mild

  2. Exclusion of Integrins from CNS Axons Is Regulated by Arf6 Activation and the AIS

    PubMed Central

    Franssen, Elske H. P.; Zhao, Rong-Rong; Koseki, Hiroaki; Kanamarlapudi, Venkateswarlu; Hoogenraad, Casper C.

    2015-01-01

    Integrins are adhesion and survival molecules involved in axon growth during CNS development, as well as axon regeneration after injury in the peripheral nervous system (PNS). Adult CNS axons do not regenerate after injury, partly due to a low intrinsic growth capacity. We have previously studied the role of integrins in axon growth in PNS axons; in the present study, we investigate whether integrin mechanisms involved in PNS regeneration may be altered or lacking from mature CNS axons by studying maturing CNS neurons in vitro. In rat cortical neurons, we find that integrins are present in axons during initial growth but later become restricted to the somato-dendritic domain. We investigated how this occurs and whether it can be altered to enhance axonal growth potential. We find a developmental change in integrin trafficking; transport becomes predominantly retrograde throughout axons, but not dendrites, as neurons mature. The directionality of transport is controlled through the activation state of ARF6, with developmental upregulation of the ARF6 GEF ARNO enhancing retrograde transport. Lowering ARF6 activity in mature neurons restores anterograde integrin flow, allows transport into axons, and increases axon growth. In addition, we found that the axon initial segment is partly responsible for exclusion of integrins and removal of this structure allows integrins into axons. Changing posttranslational modifications of tubulin with taxol also allows integrins into the proximal axon. The experiments suggest that the developmental loss of regenerative ability in CNS axons is due to exclusion of growth-related molecules due to changes in trafficking. PMID:26019348

  3. Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration

    PubMed Central

    Ma, Marek; Ferguson, Toby A.; Schoch, Kathleen M.; Li, Jian; Qian, Yaping; Shofer, Frances S.; Saatman, Kathryn E.; Neumar, Robert W.

    2013-01-01

    In both the central nervous system (CNS) and peripheral nervous system (PNS), transected axons undergo Wallerian degeneration. Even though Augustus Waller first described this process after transection of axons in 1850, the molecular mechanisms may be shared, at least in part, by many human diseases. Early pathology includes failure of synaptic transmission, target denervation, and granular disintegration of the axonal cytoskeleton (GDC). The Ca2+-dependent proteases calpains have been implicated in GDC but causality has not been established. To test the hypothesis that calpains play a causal role in axonal and synaptic degeneration in vivo, we studied transgenic mice that express human calpastatin (hCAST), the endogenous calpain inhibitor, in optic and sciatic nerve axons. Five days after optic nerve transection and 48 hours after sciatic nerve transection, robust neurofilament proteolysis observed in wild-type controls was reduced in hCAST transgenic mice. Protection of the axonal cytoskeleton in sciatic nerves of hCAST mice was nearly complete 48 hours post-transection. In addition, hCAST expression preserved the morphological integrity of neuromuscular junctions. However, compound muscle action potential amplitudes after nerve transection were similar in wild-type and hCAST mice. These results, in total, provide direct evidence that calpains are responsible for the morphological degeneration of the axon and synapse during Wallerian degeneration. PMID:23542511

  4. Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment.

    PubMed

    Sohn, Peter Dongmin; Tracy, Tara E; Son, Hye-In; Zhou, Yungui; Leite, Renata E P; Miller, Bruce L; Seeley, William W; Grinberg, Lea T; Gan, Li

    2016-06-29

    Neurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function. Loss of polarized distribution of the axonal protein tau is an early sign of Alzheimer's disease (AD) and other neurodegenerative disorders. The cytoskeletal network in the axon initial segment (AIS) forms a barrier between the axon and the somatodentritic compartment, contributing to axonal retention of tau. Although perturbation of the AIS cytoskeleton has been implicated in neurological disorders, the molecular triggers and functional consequence of AIS perturbation are incompletely understood. Here we report that tau acetylation and consequent destabilization of the AIS cytoskeleton promote the somatodendritic mislocalization of tau. AIS cytoskeletal proteins, including ankyrin G and βIV-spectrin, were downregulated in AD brains and negatively correlated with an increase in tau acetylated at K274 and K281. AIS proteins were also diminished in transgenic mice expressing tauK274/281Q, a tau mutant that mimics K274 and K281 acetylation. In primary neuronal cultures, the tauK274/281Q mutant caused hyperdynamic microtubules (MTs) in the AIS, shown by live-imaging of MT mobility and fluorescence recovery after photobleaching. Using photoconvertible tau constructs, we found that axonal tauK274/281Q was missorted into the somatodendritic compartment. Stabilizing MTs with epothilone D to restore the cytoskeletal barrier in the AIS prevented tau mislocalization in primary neuronal cultures. Together, these findings demonstrate that tau acetylation contributes to the pathogenesis of neurodegenerative disease by compromising the cytoskeletal sorting machinery in the AIS.

  5. High plasticity of axonal pathology in Alzheimer's disease mouse models.

    PubMed

    Blazquez-Llorca, Lidia; Valero-Freitag, Susana; Rodrigues, Eva Ferreira; Merchán-Pérez, Ángel; Rodríguez, J Rodrigo; Dorostkar, Mario M; DeFelipe, Javier; Herms, Jochen

    2017-02-07

    Axonal dystrophies (AxDs) are swollen and tortuous neuronal processes that are associated with extracellular depositions of amyloid β (Aβ) and have been observed to contribute to synaptic alterations occurring in Alzheimer's disease. Understanding the temporal course of this axonal pathology is of high relevance to comprehend the progression of the disease over time. We performed a long-term in vivo study (up to 210 days of two-photon imaging) with two transgenic mouse models (dE9xGFP-M and APP-PS1xGFP-M). Interestingly, AxDs were formed only in a quarter of GFP-expressing axons near Aβ-plaques, which indicates a selective vulnerability. AxDs, especially those reaching larger sizes, had long lifetimes and appeared as highly plastic structures with large variations in size and shape and axonal sprouting over time. In the case of the APP-PS1 mouse only, the formation of new long axonal segments in dystrophic axons (re-growth phenomenon) was observed. Moreover, new AxDs could appear at the same point of the axon where a previous AxD had been located before disappearance (re-formation phenomenon). In addition, we observed that most AxDs were formed and developed during the imaging period, and numerous AxDs had already disappeared by the end of this time. This work is the first in vivo study analyzing quantitatively the high plasticity of the axonal pathology around Aβ plaques. We hypothesized that a therapeutically early prevention of Aβ plaque formation or their growth might halt disease progression and promote functional axon regeneration and the recovery of neural circuits.

  6. Defining the Developmental Parameters of Temper Loss in Early Childhood: Implications for Developmental Psychopathology

    ERIC Educational Resources Information Center

    Wakschlag, Lauren S.; Choi, Seung W.; Carter, Alice S.; Hullsiek, Heide; Burns, James; McCarthy, Kimberly; Leibenluft, Ellen; Briggs-Gowan, Margaret J.

    2012-01-01

    Background: Temper modulation problems are both a hallmark of early childhood and a common mental health concern. Thus, characterizing specific behavioral manifestations of temper loss along a dimension from normative misbehaviors to clinically significant problems is an important step toward identifying clinical thresholds. Methods:…

  7. An Early Natural Auditory-Oral Intervention Approach for Children with Hearing Loss: A Qualitative Study

    ERIC Educational Resources Information Center

    Turan, Zerrin

    2010-01-01

    This study aims to examine the session goals and their realization during the session flow for a child with a hearing loss and his mother in an early intervention program. The study was designed as a case study. Video recordings of the intervention sessions, reflective journals, session plans, and the plan evaluations were used to collect and…

  8. The Emergence of Early Intervention for Children with Hearing Loss in China

    ERIC Educational Resources Information Center

    Shenglin, Liu; Raver, Sharon A.

    2011-01-01

    In the last decade, China began developing early intervention services for very young children with hearing loss, and their families. This article presents a broad description of some of these programs, including the national rehabilitation networks for speech and hearing training, increased attention on the development of professionals, the…

  9. Early Intervention for Children with Hearing Loss: Information Parents Receive about Supporting Children's Language

    ERIC Educational Resources Information Center

    Decker, Kalli B.; Vallotton, Claire D.

    2016-01-01

    Family-centered early intervention for children with hearing loss is intended to strengthen families' interactions with their children to support children's language development, and should include providing parents with information they can use as part of their everyday routines. However, little is known about the information received by families…

  10. Early Reading Development in Chinese-Speaking Children with Hearing Loss

    ERIC Educational Resources Information Center

    Chan, Yi-Chih; Yang, You-Jhen

    2018-01-01

    This study aims to explore early reading comprehension in Chinese-speaking children with hearing loss (HL) by examining character recognition and linguistic comprehension. Twenty-five children with HL received three measures relevant to character reading: phonological awareness (PA), morphological awareness (MA), and character recognition; two…

  11. Early hearing loss and language abilities in children with Down syndrome.

    PubMed

    Laws, Glynis; Hall, Amanda

    2014-01-01

    Although many children with Down syndrome experience hearing loss, there has been little research to investigate its impact on speech and language development. Studies that have investigated the association give inconsistent results. These have often been based on samples where children with the most severe hearing impairments have been excluded and so results do not generalize to the wider population with Down syndrome. Also, measuring children's hearing at the time of a language assessment does not take into account the fluctuating nature of hearing loss in children with Down syndrome or possible effects of losses in their early years. To investigate the impact of early hearing loss on language outcomes for children with Down syndrome. Retrospective audiology clinic records and parent report for 41 children were used to categorize them as either having had hearing difficulties from 2 to 4 years or more normal hearing. Differences between the groups on measures of language expression and comprehension, receptive vocabulary, a narrative task and speech accuracy were investigated. After accounting for the contributions of chronological age and nonverbal mental age to children's scores, there were significant differences between the groups on all measures. Early hearing loss has a significant impact on the speech and language development of children with Down syndrome. Results suggest that speech and language therapy should be provided when children are found to have ongoing hearing difficulties and that joint audiology and speech and language therapy clinics could be considered for preschool children. © 2014 Royal College of Speech and Language Therapists.

  12. Patterns of Early Skill Attainment and Loss in Young Children with Autism

    PubMed Central

    Thurm, Audrey; Manwaring, Stacy S.; Luckenbaugh, David A.; Lord, Catherine; Swedo, Susan E.

    2015-01-01

    The purpose of this study was to extend the literature on the ontogeny of autism spectrum disorder (ASD) by examining early attainment and loss of specific sociocommunicative skills in children with autism (AUT; n = 125), pervasive developmental disorder not otherwise specified (PDD-NOS; n = 42), nonspectrum developmental delays (n = 46), and typical development (n = 31). The ages of skill attainment and loss were obtained from a caregiver interview. The findings indicated that children with AUT, PDD-NOS, and developmental delays diverged from typically developing children in attainment of sociocommunicative skills early in the first year of life. Loss of at least one skill was reported in a majority of children with AUT and PDD-NOS. Significant delays in attainment of skills were also reported in children who lost skills. The wide variation in skill attainment and loss reported across children indicates that symptom onset and regression may be best represented continuously, with at least some early delay and loss present for a great majority of children with ASD. PMID:24274034

  13. Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination.

    PubMed

    Schultz, Verena; van der Meer, Franziska; Wrzos, Claudia; Scheidt, Uta; Bahn, Erik; Stadelmann, Christine; Brück, Wolfgang; Junker, Andreas

    2017-08-01

    Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we employed cuprizone- and focal lysolecithin-induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP- and SMI32- positive damaged axons and the density of SMI31-positive and silver impregnated preserved axons. Early de- and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

  14. The loss of the kinases SadA and SadB results in early neuronal apoptosis and a reduced number of progenitors.

    PubMed

    Dhumale, Pratibha; Menon, Sindhu; Chiang, Joanna; Püschel, Andreas W

    2018-01-01

    The neurons that form the mammalian neocortex originate from progenitor cells in the ventricular (VZ) and subventricular zone (SVZ). Newborn neurons are multipolar but become bipolar during their migration from the germinal layers to the cortical plate (CP) by forming a leading process and an axon that extends in the intermediate zone (IZ). Once they settle in the CP, neurons assume a highly polarized morphology with a single axon and multiple dendrites. The AMPK-related kinases SadA and SadB are intrinsic factors that are essential for axon formation during neuronal development downstream of Lkb1. The knockout of both genes encoding Sad kinases (Sada and Sadb) results not only in a loss of axons but also a decrease in the size of the cortical plate. The defect in axon formation has been linked to a function of Sad kinases in the regulation of microtubule binding proteins. However, the causes for the reduced size of the cortical plate in the Sada-/-;Sadb-/- knockout remain to be analyzed in detail. Here we show that neuronal cell death is increased and the number of neural progenitors is decreased in the Sada-/-;Sadb-/- CP. The reduced number of progenitors is a non-cell autonomous defect since they do not express Sad kinases. These defects are restricted to the neocortex while the hippocampus remains unaffected.

  15. Consequences of Early Conductive Hearing Loss on Long-Term Binaural Processing.

    PubMed

    Graydon, Kelley; Rance, Gary; Dowell, Richard; Van Dun, Bram

    The aim of the study was to investigate the long-term effects of early conductive hearing loss on binaural processing in school-age children. One hundred and eighteen children participated in the study, 82 children with a documented history of conductive hearing loss associated with otitis media and 36 controls who had documented histories showing no evidence of otitis media or conductive hearing loss. All children were demonstrated to have normal-hearing acuity and middle ear function at the time of assessment. The Listening in Spatialized Noise Sentence (LiSN-S) task and the masking level difference (MLD) task were used as the two different measures of binaural interaction ability. Children with a history of conductive hearing loss performed significantly poorer than controls on all LiSN-S conditions relying on binaural cues (DV90, p = <0.001 and SV90, p = 0.003). No significant difference was found between the groups in listening conditions without binaural cues. Fifteen children with a conductive hearing loss history (18%) showed results consistent with a spatial processing disorder. No significant difference was observed between the conductive hearing loss group and the controls on the MLD task. Furthermore, no correlations were found between LiSN-S and MLD. Results show a relationship between early conductive hearing loss and listening deficits that persist once hearing has returned to normal. Results also suggest that the two binaural interaction tasks (LiSN-S and MLD) may be measuring binaural processing at different levels. Findings highlight the need for a screening measure of functional listening ability in children with a history of early otitis media.

  16. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study.

    PubMed

    Maahs, David M; Caramori, Luiza; Cherney, David Z I; Galecki, Andrzej T; Gao, Chuanyun; Jalal, Diana; Perkins, Bruce A; Pop-Busui, Rodica; Rossing, Peter; Mauer, Michael; Doria, Alessandro

    2013-08-01

    Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.

  17. [In the absence of early orthodontic treatment, is there a loss of chance?].

    PubMed

    Béry, A

    2006-06-01

    Chance is the probability that something will happen, and, in this sense, the absence of chance can be defined as the damage resulting from the disappearance of the probability of a favorable outcome (the contrary being the non-realization of the risk). This is autonomous damage that should be differentiated from final damage. Moral damage is a notion very close to the loss of chance even though it reposes on the indemnization of a final damage of an affection or malady. This article deals with these matters: an insufficient amount of information, the cause of final damage or the loss of chance, the loss of chance being a function of the deficit of information. In this sense, can the failure to begin early, appropriate dento-facial orthopedic treatment be considered a loss of chance for the child?

  18. Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.

    PubMed

    Wishart, Thomas M; Rooney, Timothy M; Lamont, Douglas J; Wright, Ann K; Morton, A Jennifer; Jackson, Mandy; Freeman, Marc R; Gillingwater, Thomas H

    2012-01-01

    Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study

  19. Early Weight Loss with Liraglutide 3.0 mg Predicts 1-Year Weight Loss and is Associated with Improvements in Clinical Markers.

    PubMed

    Fujioka, Ken; O'Neil, Patrick M; Davies, Melanie; Greenway, Frank; C W Lau, David; Claudius, Birgitte; Skjøth, Trine Vang; Bjørn Jensen, Christine; P H Wilding, John

    2016-11-01

    To identify an early response criterion for predicting ≥5% weight loss with liraglutide 3.0 mg at week 56 and to compare efficacy outcomes in early responders (ERs) and early nonresponders (ENRs). Using pooled data from the SCALE Obesity and Prediabetes and SCALE Diabetes trials, weight loss of ≥4% at 16 weeks best predicted ≥5% weight loss after 56 weeks. Weight loss and changes in cardiometabolic risk factors and health-related quality of life were evaluated in ERs (≥4% weight loss at week 16) and ENRs (<4% weight loss at week 16) completing 56 weeks' treatment. Proportions of ERs/ENRs to liraglutide 3.0 mg were 77.3%/22.7% (individuals without type 2 diabetes, T2D) and 62.7%/37.3% (those with T2D). Greater mean weight loss was observed in ERs versus ENRs: 10.8% versus 3.0% (without T2D) and 8.5% versus 3.1% (T2D). In both trials, greater proportions of ERs versus ENRs achieved ≥5%, >10%, and >15% weight loss at week 56 with liraglutide 3.0 mg. Greater improvements in cardiometabolic risk factors and health-related quality of life scores were observed in ERs versus ENRs. The early response criterion was clinically useful to identify individuals who would achieve clinically meaningful weight loss at 56 weeks. © 2016 The Authors Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).

  20. Early Weight Loss with Liraglutide 3.0 mg Predicts 1‐Year Weight Loss and is Associated with Improvements in Clinical Markers

    PubMed Central

    O'Neil, Patrick M.; Davies, Melanie; Greenway, Frank; C.W. Lau, David; Claudius, Birgitte; Skjøth, Trine Vang; Bjørn Jensen, Christine; P.H. Wilding, John

    2016-01-01

    Objective To identify an early response criterion for predicting ≥5% weight loss with liraglutide 3.0 mg at week 56 and to compare efficacy outcomes in early responders (ERs) and early nonresponders (ENRs). Methods Using pooled data from the SCALE Obesity and Prediabetes and SCALE Diabetes trials, weight loss of ≥4% at 16 weeks best predicted ≥5% weight loss after 56 weeks. Weight loss and changes in cardiometabolic risk factors and health‐related quality of life were evaluated in ERs (≥4% weight loss at week 16) and ENRs (<4% weight loss at week 16) completing 56 weeks’ treatment. Results Proportions of ERs/ENRs to liraglutide 3.0 mg were 77.3%/22.7% (individuals without type 2 diabetes, T2D) and 62.7%/37.3% (those with T2D). Greater mean weight loss was observed in ERs versus ENRs: 10.8% versus 3.0% (without T2D) and 8.5% versus 3.1% (T2D). In both trials, greater proportions of ERs versus ENRs achieved ≥5%, >10%, and >15% weight loss at week 56 with liraglutide 3.0 mg. Greater improvements in cardiometabolic risk factors and health‐related quality of life scores were observed in ERs versus ENRs. Conclusions The early response criterion was clinically useful to identify individuals who would achieve clinically meaningful weight loss at 56 weeks. PMID:27804269

  1. Regulation of axonal development by the nuclear protein hindsight (pebbled) in the Drosophila visual system.

    PubMed

    Oliva, Carlos; Sierralta, Jimena

    2010-08-15

    The molecules and networks involved in the process of acquisition and maintenance of the form of a mature neuron are not completely known. Using a misexpression screen we identified the gene hindsight as a gene involved in the process of acquisition of the neuronal morphogenesis in the Drosophila adult nervous system. hindsight encodes a transcription factor known for its role in early developmental processes such as embryonic germ band retraction and dorsal closure, as well as in the establishment of cell morphology, planar cell polarity, and epithelial integrity during retinal development. We describe here a novel function for HNT by showing that both loss and gain of function of HNT affects the pathfinding of the photoreceptors axons. By manipulating the timing and level of HNT expression, together with the number of cells manipulated we show here that the function of HNT in axonal guidance is independent of the HNT functions previously reported in retinal cells. Based on genetic interaction experiments we show that part of HNT function in axonal development is exerted through the regulation of genes involved in the dynamics of the actin cytoskeleton. Copyright 2010 Elsevier Inc. All rights reserved.

  2. An ex vivo laser-induced spinal cord injury model to assess mechanisms of axonal degeneration in real-time.

    PubMed

    Okada, Starlyn L M; Stivers, Nicole S; Stys, Peter K; Stirling, David P

    2014-11-25

    Injured CNS axons fail to regenerate and often retract away from the injury site. Axons spared from the initial injury may later undergo secondary axonal degeneration. Lack of growth cone formation, regeneration, and loss of additional myelinated axonal projections within the spinal cord greatly limits neurological recovery following injury. To assess how central myelinated axons of the spinal cord respond to injury, we developed an ex vivo living spinal cord model utilizing transgenic mice that express yellow fluorescent protein in axons and a focal and highly reproducible laser-induced spinal cord injury to document the fate of axons and myelin (lipophilic fluorescent dye Nile Red) over time using two-photon excitation time-lapse microscopy. Dynamic processes such as acute axonal injury, axonal retraction, and myelin degeneration are best studied in real-time. However, the non-focal nature of contusion-based injuries and movement artifacts encountered during in vivo spinal cord imaging make differentiating primary and secondary axonal injury responses using high resolution microscopy challenging. The ex vivo spinal cord model described here mimics several aspects of clinically relevant contusion/compression-induced axonal pathologies including axonal swelling, spheroid formation, axonal transection, and peri-axonal swelling providing a useful model to study these dynamic processes in real-time. Major advantages of this model are excellent spatiotemporal resolution that allows differentiation between the primary insult that directly injures axons and secondary injury mechanisms; controlled infusion of reagents directly to the perfusate bathing the cord; precise alterations of the environmental milieu (e.g., calcium, sodium ions, known contributors to axonal injury, but near impossible to manipulate in vivo); and murine models also offer an advantage as they provide an opportunity to visualize and manipulate genetically identified cell populations and subcellular

  3. Rapid loss of phosphorus during early pedogenesis along a glacier retreat choronosequence, Gongga Mountain (SW China).

    PubMed

    Wu, Yanhong; Zhou, Jun; Bing, Haijian; Sun, Hongyang; Wang, Jipeng

    2015-01-01

    The loss of phosphorus (P) during the early pedogenesis stage is important at the ecosystem level, and it also plays an important role in the global P cycle. The seasonal variation of total P (Pt) and its fractions along a young soil chronosequence (Hailuogou chronosequence) on the eastern slope of Gongga Mountain, SW China, was investigated based on the modified Hedley fractionation technique to understand P loss during the early pedogenesis stage. The results showed that the mineral P (mainly apatite) was the dominant fraction of Pt in the C horizon of the soil, and the seasonal difference in Pt and its fractions was insignificant. In the A horizon, Pt concentrations decreased markedly compared with those in the C horizon, and as the age of the soil increased, the inorganic P (Pi) significantly decreased and the organic P (Po) prominently increased. Seasonally, the P fractions exhibited various distributions in the A horizon. The variation of Pt and its fractions revealed that the P loss was rapid along the 120-year soil chronosequence. The P stocks in soils (0-30 cm) started to decrease at the 52 year site. And the P stock depletion reached almost 17.6% at the 120-year site. The loss of P from the soil of the Hailuogou chronosequence was mainly attributed to weathering, plant uptake, and transport by runoff. About 36% P loss was transported into plant biomass P at the 120 year site. The data obtained indicated that the glacier retreat chronosequence could be used to elucidate the fast rate of P loss during the early pedogenic stage.

  4. Temporal identity in axonal target layer recognition.

    PubMed

    Petrovic, Milan; Hummel, Thomas

    2008-12-11

    The segregation of axon and dendrite projections into distinct synaptic layers is a fundamental principle of nervous system organization and the structural basis for information processing in the brain. Layer-specific recognition molecules that allow projecting neurons to stabilize transient contacts and initiate synaptogenesis have been identified. However, most of the neuronal cell-surface molecules critical for layer organization are expressed broadly in the developing nervous system, raising the question of how these so-called permissive adhesion molecules support synaptic specificity. Here we show that the temporal expression dynamics of the zinc-finger protein sequoia is the major determinant of Drosophila photoreceptor connectivity into distinct synaptic layers. Neighbouring R8 and R7 photoreceptors show consecutive peaks of elevated sequoia expression, which correspond to their sequential target-layer innervation. Loss of sequoia in R7 leads to a projection switch into the R8 recipient layer, whereas a prolonged expression in R8 induces a redirection of their axons into the R7 layer. The sequoia-induced axon targeting is mediated through the ubiquitously expressed Cadherin-N cell adhesion molecule. Our data support a model in which recognition specificity during synaptic layer formation is generated through a temporally restricted axonal competence to respond to broadly expressed adhesion molecules. Because developing neurons innervating the same target area often project in a distinct, birth-order-dependent sequence, temporal identity seems to contain crucial information in generating not only cell type diversity during neuronal division but also connection diversity of projecting neurons.

  5. Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.

    PubMed

    Zhang, Liang; Trushin, Sergey; Christensen, Trace A; Tripathi, Utkarsh; Hong, Courtney; Geroux, Rachel E; Howell, Kyle G; Poduslo, Joseph F; Trushina, Eugenia

    2018-06-01

    Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer's Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Aβ peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Aβ peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Aβ peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Aβ peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Aβ species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Aβ aggregation or fibril formation alone without ensuring the efficient clearance of soluble Aβ may not be sufficient to alleviate the trafficking phenotype. Copyright © 2018 The Authors. Published by

  6. Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

    PubMed Central

    Zhang, Liang; Trushin, Sergey; Christensen, Trace A.; Tripathi, Utkarsh; Hong, Courtney; Geroux, Rachel E.; Howell, Kyle G.; Poduslo, Joseph F.; Trushina, Eugenia

    2018-01-01

    Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer’s Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Aβ peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Aβ peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Aβ peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Aβ peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Aβ species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Aβ aggregation or fibril formation alone without ensuring the efficient clearance of soluble Aβ may not be sufficient to alleviate the trafficking phenotype. PMID:29477640

  7. Axonal ensheathment and septate junction formation in the peripheral nervous system of Drosophila.

    PubMed

    Banerjee, Swati; Pillai, Anilkumar M; Paik, Raehum; Li, Jingjun; Bhat, Manzoor A

    2006-03-22

    Axonal insulation is critical for efficient action potential propagation and normal functioning of the nervous system. In Drosophila, the underlying basis of nerve ensheathment is the axonal insulation by glial cells and the establishment of septate junctions (SJs) between glial cell membranes. However, the details of the cellular and molecular mechanisms underlying axonal insulation and SJ formation are still obscure. Here, we report the characterization of axonal insulation in the Drosophila peripheral nervous system (PNS). Targeted expression of tau-green fluorescent protein in the glial cells and ultrastructural analysis of the peripheral nerves allowed us to visualize the glial ensheathment of axons. We show that individual or a group of axons are ensheathed by inner glial processes, which in turn are ensheathed by the outer perineurial glial cells. SJs are formed between the inner and outer glial membranes. We also show that Neurexin IV, Contactin, and Neuroglian are coexpressed in the peripheral glial membranes and that these proteins exist as a complex in the Drosophila nervous system. Mutations in neurexin IV, contactin, and neuroglian result in the disruption of blood-nerve barrier function in the PNS, and ultrastructural analyses of the mutant embryonic peripheral nerves show loss of glial SJs. Interestingly, the murine homologs of Neurexin IV, Contactin, and Neuroglian are expressed at the paranodal SJs and play a key role in axon-glial interactions of myelinated axons. Together, our data suggest that the molecular machinery underlying axonal insulation and axon-glial interactions may be conserved across species.

  8. The cellular immunity and oxidative stress markers in early pregnancy loss.

    PubMed

    Daglar, Korkut; Biberoglu, Ebru; Kirbas, Ayse; Dirican, Aylin Onder; Genc, Metin; Avci, Aslihan; Biberoglu, Kutay

    2016-01-01

    We investigated whether changes in cellular immunity and oxidative stress in pregnancy have any association with spontaneous miscarriage. Circulating adenosine deaminase (ADA) activity as a marker of cellular immunity and malondialdehyde (MDA) and catalase (CAT), glutathione peroxidase (GPx) as markers of T lymphocyte activation and parameters of oxidative stress and antioxidant defense were compared between 40 women with early pregnancy loss and another 40 women with ungoing healthy pregnancy. Women with miscarriage had higher serum ADA and GPx levels when compared with women with normal pregnancy (p = 0.034 and p < 0.001, respectively). Although serum MDA level was slightly higher in women with miscarriage, the difference was not significant (p = 0.083). CAT levels were alike in both groups. We have demonstrated an increased cellular immunity and perhaps a compensated oxidative stress related to increased antioxidant activation in women with early spontaneous pregnancy loss.

  9. Signs and symptoms associated with early pregnancy loss: findings from a population-based preconception cohort.

    PubMed

    Sapra, K J; Buck Louis, G M; Sundaram, R; Joseph, K S; Bates, L M; Galea, S; Ananth, C V

    2016-04-01

    What is the relationship between signs and symptoms of early pregnancy and pregnancy loss <20 weeks' gestation? Vaginal bleeding is associated with increased incidence of early pregnancy loss, with more severe bleeding and bleeding accompanied by lower abdominal cramping associated with greater incidence of loss; conversely, vomiting is associated with decreased incidence of early pregnancy loss, even in the setting of vaginal bleeding, while nausea alone is not. Two previous cohort studies with preconception enrollment suggested that bleeding is associated with loss while nausea is inversely associated with loss though these studies were limited by small study size and reporting after loss ascertainment. No prior preconception cohort study has examined multiple signs and symptoms in relation to pregnancy loss. Population-based preconception cohort of 501 couples discontinuing contraception to try for pregnancy in 16 counties in Michigan and Texas, USA. Participants were followed daily until positive home pregnancy test or 12 months of trying without an hCG pregnancy; women who became pregnant were followed daily from 2 to 7 weeks post-conception. Three hundred and forty-seven women had a positive home pregnancy test denoting hCG pregnancy. Three hundred and forty-one women remained after excluding ineligible pregnancies. Women recorded daily from 2 to 7 weeks post-conception their signs and symptoms, including vaginal bleeding (none, spotting, light, moderate and heavy), lower abdominal cramping, nausea and vomiting. Pregnancy losses were ascertained by a subsequent negative home pregnancy test, clinical confirmation or onset of menses, depending on gestational age at loss; time-to-loss was measured in days post-conception. Cumulative incidence functions and 95% confidence intervals (CIs) were constructed for each sign or symptom, and hazard ratios (HRs) and 95% CIs for presence compared with absence of signs or symptoms were estimated using Cox proportional

  10. Signs and symptoms associated with early pregnancy loss: findings from a population-based preconception cohort

    PubMed Central

    Sapra, K.J.; Buck Louis, G.M.; Sundaram, R.; Joseph, K.S.; Bates, L.M.; Galea, S.; Ananth, C.V.

    2016-01-01

    STUDY QUESTION What is the relationship between signs and symptoms of early pregnancy and pregnancy loss <20 weeks' gestation? SUMMARY ANSWER Vaginal bleeding is associated with increased incidence of early pregnancy loss, with more severe bleeding and bleeding accompanied by lower abdominal cramping associated with greater incidence of loss; conversely, vomiting is associated with decreased incidence of early pregnancy loss, even in the setting of vaginal bleeding, while nausea alone is not. WHAT IS KNOWN ALREADY Two previous cohort studies with preconception enrollment suggested that bleeding is associated with loss while nausea is inversely associated with loss though these studies were limited by small study size and reporting after loss ascertainment. No prior preconception cohort study has examined multiple signs and symptoms in relation to pregnancy loss. STUDY DESIGN, SIZE, DURATION Population-based preconception cohort of 501 couples discontinuing contraception to try for pregnancy in 16 counties in Michigan and Texas, USA. Participants were followed daily until positive home pregnancy test or 12 months of trying without an hCG pregnancy; women who became pregnant were followed daily from 2 to 7 weeks post-conception. PARTICIPANTS, SETTING, METHODS Three hundred and forty-seven women had a positive home pregnancy test denoting hCG pregnancy. Three hundred and forty-one women remained after excluding ineligible pregnancies. Women recorded daily from 2 to 7 weeks post-conception their signs and symptoms, including vaginal bleeding (none, spotting, light, moderate and heavy), lower abdominal cramping, nausea and vomiting. Pregnancy losses were ascertained by a subsequent negative home pregnancy test, clinical confirmation or onset of menses, depending on gestational age at loss; time-to-loss was measured in days post-conception. Cumulative incidence functions and 95% confidence intervals (CIs) were constructed for each sign or symptom, and hazard ratios (HRs

  11. Oligodendroglia: metabolic supporters of axons.

    PubMed

    Morrison, Brett M; Lee, Youngjin; Rothstein, Jeffrey D

    2013-12-01

    Axons are specialized extensions of neurons that are critical for the organization of the nervous system. To maintain function in axons that often extend some distance from the cell body, specialized mechanisms of energy delivery are likely to be necessary. Over the past decade, greater understanding of human demyelinating diseases and the development of animal models have suggested that oligodendroglia are critical for maintaining the function of axons. In this review, we discuss evidence for the vulnerability of neurons to energy deprivation, the importance of oligodendrocytes for axon function and survival, and recent data suggesting that transfer of energy metabolites from oligodendroglia to axons through monocarboxylate transporter 1 (MCT1) may be critical for the survival of axons. This pathway has important implications both for the basic biology of the nervous system and for human neurological disease. New insights into the role of oligodendroglial biology provide an exciting opportunity for revisions in nervous system biology, understanding myelin-based disorders, and therapeutics development. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Early behavioral adherence predicts short and long-term weight loss in the POUNDS LOST study

    PubMed Central

    Anton, Stephen D.; Han, Hongmei; Champagne, Catherine M.; Allen, Ray; LeBlanc, Eric; Ryan, Donna H.; Rood, Jennifer; McManus, Katherine; Laranjo, Nancy; Carey, Vincent J.; Loria, Catherine M.; Bray, George A.; Sacks, Frank M.

    2011-01-01

    The primary aim of this study was to test the association of early (first 6 months) adherence related to diet, self-monitoring, and attendance with changes in adiposity and cardiovascular risk factors. This study used data from the 24-month POUNDS LOST trial that tested the efficacy of four dietary macronutrient compositions for short-and long-term weight loss. A computer tracking system was used to record data on eight indicator variables related to adherence. Using canonical correlations at the 6 and 24 month measurement periods, early behavioral adherence was associated with changes in percent weight loss and waist circumference at 6 months (R = 0.52) and 24 months (R = 0.37), but was not associated with cardiovascular disease risk factor levels. Early dietary adherence was associated with changes in insulin at 6 months (R = 0.19), but not at 24 months (R = 0.08, ns). Early dietary adherence was not associated with changes in adiposity. PMID:20195742

  13. Partitioning loss rates of early juvenile blue crabs from seagrass habitats into mortality and emigration

    USGS Publications Warehouse

    Etherington, L.L.; Eggleston, D.B.; Stockhausen, W.T.

    2003-01-01

    Determining how post-settlement processes modify patterns of settlement is vital in understanding the spatial and temporal patterns of recruitment variability of species with open populations. Generally, either single components of post-settlement loss (mortality or emigration) are examined at a time, or else the total loss is examined without discrimination of mortality and emigration components. The role of mortality in the loss of early juvenile blue crabs, Callinectes sapidus, has been addressed in a few studies; however, the relative contribution of emigration has received little attention. We conducted mark-recapture experiments to examine the relative contribution of mortality and emigration to total loss rates of early juvenile blue crabs from seagrass habitats. Loss was partitioned into emigration and mortality components using a modified version of Jackson's (1939) square-within-a-square method. The field experiments assessed the effects of two size classes of early instars (J1-J2, J3-J5), two densities of juveniles (low: 16 m-2, high: 64 m-2), and time of day (day, night) on loss rates. In general, total loss rates of experimental juveniles and colonization rates by unmarked juveniles were extremely high (range = 10-57 crabs m-2/6 h and 17-51 crabs m-2/6 h, for loss and colonization, respectively). Total loss rates were higher at night than during the day, suggesting that juveniles (or potentially their predators) exhibit increased nocturnal activity. While colonization rates did not differ by time of day, J3-J5 juveniles demonstrated higher rates of colonization than J1-J2 crabs. Overall, there was high variability in both mortality and emigration, particularly for emigration. Average probabilities of mortality across all treatment combinations ranged from 0.25-0.67/6 h, while probabilities of emigration ranged from 0.29-0.72/6 h. Although mean mortality rates were greater than emigration rates in most treatments, the proportion of experimental trials

  14. Assembly and turnover of neurofilaments in growing axonal neurites.

    PubMed

    Boumil, Edward F; Vohnoutka, Rishel; Lee, Sangmook; Pant, Harish; Shea, Thomas B

    2018-01-26

    Neurofilaments (NFs) are thought to provide stability to the axon. We examined NF dynamics within axonal neurites of NB2a/d1 neuroblastoma by transient transfection with green fluorescent protein-tagged NF-heavy (GFP-H) under the control of a tetracycline-inducible promoter. Immunofluorescent and biochemical analyses demonstrated that GFP-H expressed early during neurite outgrowth associated with a population of centrally-situated, highly-phosphorylated crosslinked NFs along the length of axonal neurites ('bundled NFs'). By contrast, GFP-H expressed after considerable neurite outgrowth displayed markedly reduced association with bundled NFs and was instead more evenly distributed throughout the axon. This differential localization was maintained for up to 2 weeks in culture. Once considerable neurite outgrowth had progressed, GFP that had previously associated with the NF bundle during early expression was irreversibly depleted by photobleaching. Cessation of expression allowed monitoring of NF turnover. GFP-H associated bundled NFs underwent slower decay than GFP-H associated with surrounding, less-phosphorylated NFs. Notably, GFP associated with bundled NFs underwent similar decay rates within the core and edges of this bundle. These results are consistent with previous demonstration of a resident NF population within axonal neurites, but suggest that this population is more dynamic than previously considered. © 2018. Published by The Company of Biologists Ltd.

  15. Assembly and turnover of neurofilaments in growing axonal neurites

    PubMed Central

    Boumil, Edward F.; Vohnoutka, Rishel; Lee, Sangmook; Pant, Harish

    2018-01-01

    ABSTRACT Neurofilaments (NFs) are thought to provide stability to the axon. We examined NF dynamics within axonal neurites of NB2a/d1 neuroblastoma by transient transfection with green fluorescent protein-tagged NF-heavy (GFP-H) under the control of a tetracycline-inducible promoter. Immunofluorescent and biochemical analyses demonstrated that GFP-H expressed early during neurite outgrowth associated with a population of centrally-situated, highly-phosphorylated crosslinked NFs along the length of axonal neurites (‘bundled NFs’). By contrast, GFP-H expressed after considerable neurite outgrowth displayed markedly reduced association with bundled NFs and was instead more evenly distributed throughout the axon. This differential localization was maintained for up to 2 weeks in culture. Once considerable neurite outgrowth had progressed, GFP that had previously associated with the NF bundle during early expression was irreversibly depleted by photobleaching. Cessation of expression allowed monitoring of NF turnover. GFP-H associated bundled NFs underwent slower decay than GFP-H associated with surrounding, less-phosphorylated NFs. Notably, GFP associated with bundled NFs underwent similar decay rates within the core and edges of this bundle. These results are consistent with previous demonstration of a resident NF population within axonal neurites, but suggest that this population is more dynamic than previously considered. PMID:29158321

  16. Sensorineural hearing loss--a common finding in early-onset type 2 diabetes mellitus.

    PubMed

    Lerman-Garber, Israel; Cuevas-Ramos, Daniel; Valdés, Samantha; Enríquez, Lorena; Lobato, Marlette; Osornio, Melannie; Escobedo, Ana Rosa; Pascual-Ramos, Virginia; Mehta, Roopa; Ramírez-Anguiano, Jacqueline; Gómez-Pérez, Francisco J

    2012-01-01

    To evaluate the prevalence and potential associations of hearing impairment in patients 30 to 50 years old with diabetes diagnosed before age 40 years-early-onset type 2 diabetes mellitus (T2DM). The study cohorts consisted of 46 consecutive patients with early-onset T2DM and 47 age-matched control subjects with rheumatoid arthritis. All study subjects completed clinical, serologic, and auditory assessments. The patients with T2DM had a mean age of 42 ± 6 years and a mean disease duration of 11 ± 6 years. Microalbuminuria was present in 26.1%, proliferative retinopathy in 26.1%, and symptomatic peripheral neuropathy in 23.9%. The prevalence of unilateral or bilateral hearing loss was significantly higher in the patients with T2DM than in the patients with rheumatoid arthritis (21.7% versus 6.4%, respectively; P = .01). Most cases of hearing loss were mild and involved high or acute tones. After multivariate analysis with adjustment for age, there was a significant association between hearing loss and hemoglobin A1c (odds ratio, 1.3; 95% confidence interval, 1.02 to 1.81; P = .035). In the patients with T2DM, the lengthening of the brainstem response was not significantly increased; however, the wave morphologic features were abnormal and the reproducibility was poor in both ears in 11 patients (24%). Patients with early-onset T2DM and poor glycemic control have an increased prevalence of subclinical hearing loss and impaired auditory brainstem responses. Hearing impairment may be an underrecognized complication of diabetes.

  17. [CODEPEH 2014 recommendations for the early detection of delayed hearing loss].

    PubMed

    Núñez-Batalla, Faustino; Jáudenes-Casaubón, Carmen; Sequí-Canet, José Miguel; Vivanco-Allende, Ana; Zubicaray-Ugarteche, José

    2016-10-01

    The latest scientific literature considers early diagnosis of deafness as key element to define the educational prognosis and inclusion of the deaf child, as advantage can be taken in the critical period of development (0-4 years). Highly significant differences exist between those deaf persons who have been stimulated early and those who have received late or inappropriate intervention. Early identification of late-onset disorders requires special attention and knowledge of all childcare professionals. Programs and additional actions beyond neonatal screening should be designed and planned in order to ensure that every child with a significant hearing loss is detected early. For this purpose, the Committee for the Early Detection of Deafness (CODEPEH) would like to highlight the need for continuous monitoring on the hearing health of children. And, for this reason, CODEPEH drafts the recommendations included in the present document. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Progress towards early detection services for infants with hearing loss in developing countries

    PubMed Central

    Olusanya, Bolajoko O; Swanepoel, De Wet; Chapchap, Mônica J; Castillo, Salvador; Habib, Hamed; Mukari, Siti Z; Martinez, Norberto V; Lin, Hung-Ching; McPherson, Bradley

    2007-01-01

    Background Early detection of infants with permanent hearing loss through infant hearing screening is recognised and routinely offered as a vital component of early childhood care in developed countries. This article investigates the initiatives and progress towards early detection of infants with hearing loss in developing countries against the backdrop of the dearth of epidemiological data from this region. Methods A cross-sectional, descriptive study based on responses to a structured questionnaire eliciting information on the nature and scope of early hearing detection services; strategies for financing services; parental and professional attitudes towards screening; and the performance of screening programmes. Responses were complemented with relevant data from the internet and PubMed/Medline. Results Pilot projects using objective screening tests are on-going in a growing number of countries. Screening services are provided at public/private hospitals and/or community health centres and at no charge only in a few countries. Attitudes amongst parents and health care workers are typically positive towards such programmes. Screening efficiency, as measured by referral rate at discharge, was generally found to be lower than desired but several programmes achieved other international benchmarks. Coverage is generally above 90% but poor follow-up rates remain a challenge in some countries. The mean age of diagnosis is usually less than six months, even for community-based programmes. Conclusion Lack of adequate resources by many governments may limit rapid nationwide introduction of services for early hearing detection and intervention, but may not deter such services altogether. Parents may be required to pay for services in some settings in line with the existing practice where healthcare services are predominantly financed by out-of-pocket spending rather than public funding. However, governments and their international development partners need to complement

  19. Ultrasonographically documented early pregnancy loss in an Asian elephant (Elephas maximus).

    PubMed

    Lueders, Imke; Drews, Barbara; Niemuller, Cheryl; Gray, Charlie; Rich, Peter; Fickel, Jörns; Wibbelt, Gudrun; Göritz, Frank; Hildebrandt, Thomas B

    2010-01-01

    Early embryonic resorption or fetal loss is known to occur occasionally in captive elephants; however, this has mostly been reported anecdotally. The present study documents the case of a 24-year-old, multiparous Asian elephant cow that suffered embryonic death and resorption at around 18 weeks of gestation. From ovulation onwards, this female was sonographically examined 58 times. Blood was collected twice weekly for progestagen determination via enzyme immunoassay. On Day 42 after ovulation, a small quantity of fluid was detected in the uterine horn, which typically indicates the presence of a developing conceptus. Repeated inspections followed what appeared to be a normal pregnancy until Day 116. However, on Day 124, signs of embryonic life were absent. Progestagen concentrations started declining two weeks later, reaching baseline levels one month after embryonic death. Retrospectively, ultrasound examination revealed several abnormalities in the uterine horn. Besides an existing leiomyoma, multiple small cystic structures had formed in the endometrium at the implantation site and later in the placenta. These pathological findings were considered as possible contributors to the early pregnancy failure. PCR for endotheliotropic elephant herpes virus (EEHV) (which had occurred previously in the herd) as well as serology for other infectious organisms known to cause abortion in domestic animals did not yield any positive results. Although no definitive reason was found for this pregnancy to abort, this ultrasonographically and endocrinologically documented study of an early pregnancy loss provides important insights into the resorption process in Asian elephants.

  20. S6 Kinase Inhibits Intrinsic Axon Regeneration Capacity via AMP Kinase in Caenorhabditis elegans

    PubMed Central

    Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D.

    2014-01-01

    The ability of axons to regrow after injury is determined by the complex interplay of intrinsic growth programs and external cues. In Caenorhabditis elegans mechanosensory neuron, axons exhibit robust regenerative regrowth following laser axotomy. By surveying conserved metabolic signaling pathways, we have identified the ribosomal S6 kinase RSKS-1 as a new cell-autonomous inhibitor of axon regeneration. RSKS-1 is not required for axonal development but inhibits axon regrowth after injury in multiple neuron types. Loss of function in rsks-1 results in more rapid growth cone formation after injury and accelerates subsequent axon extension. The enhanced regrowth of rsks-1 mutants is partly dependent on the DLK-1 MAPK cascade. An essential output of RSKS-1 in axon regrowth is the metabolic sensor AMP kinase, AAK-2. We further show that the antidiabetic drug phenformin, which activates AMP kinase, can promote axon regrowth. Our data reveal a new function for an S6 kinase acting through an AMP kinase in regenerative growth of injured axons. PMID:24431434

  1. Quantifying the Benefit of Early Climate Change Mitigation in Avoiding Biodiversity Loss

    NASA Astrophysics Data System (ADS)

    Warren, R.; Vanderwal, J.; Price, J.; Welbergen, J.; Atkinson, I. M.; Ramirez-Villegas, J.; Osborn, T.; Shoo, L.; Jarvis, A.; Williams, S.; Lowe, J. A.

    2014-12-01

    Quantitative simulations of the global-scale benefits of climate change mitigation in avoiding biodiversity loss are presented. Previous studies have projected widespread global and regional impacts of climate change on biodiversity. However, these have focused on analysis of business-as-usual scenarios, with no explicit mitigation policy included. This study finds that early, stringent mitigation would avoid a large proportion of the impacts of climate change induced biodiversity loss projected for the 2080s. Furthermore, despite the large number of studies addressing extinction risks in particular species groups, few studies have explored the issue of potential range loss in common and widespread species. Our study is a comprehensive global scale analysis of 48,786 common and widespread species. We show that without climate change mitigation, 57+/-6% of the plants and 34+/-7% of the animals studied are likely to lose over 50% of their present climatic range by the 2080s. This estimate incorporates realistic, taxon-specific dispersal rates. With stringent mitigation, in which emissions peak in 2016 and are reduced by 5% annually thereafter, these losses are reduced by 60%. Furthermore, with stringent mitigation, global temperature rises more slowly, allowing an additional three decades for biodiversity to adapt to a temperature rise of 2C above pre-industrial levels. The work also shows that even with mitigation not all the impacts can now be avoided, and ecosystems and biodiversity generally has a very limited capacity to adapt. Delay in mitigation substantially reduces the percentage of impacts that can be avoided, for example if emissions do not peak until 2030, the percentage of losses that can be avoided declines to 40%. Since even small declines in common and widespread species can disrupt ecosystem function and services, these results indicate that without mitigation, globally widespread losses in ecosystem service provision are to be expected.

  2. Miscarriage, abortion or criminal feticide: understandings of early pregnancy loss in Britain, 1900-1950.

    PubMed

    Elliot, Rosemary

    2014-09-01

    This paper explores the close links in medical understandings of miscarriage and abortion in the first half of the twentieth century in Britain. In the absence of a clear legal framework for abortion, and the secrecy surrounding the practice, medical literature suggests contradictory and confused views about women presenting with clinical signs of pregnancy loss. On one hand, there was a lack of clarity as to whether pregnancy loss was natural or induced, with a clear tendency to assume that symptoms of miscarriage were the result of criminal interference gone wrong. On the other hand, women who did not present for treatment when miscarriage was underway were accused of neglecting their unborn children. The paper suggests that discourses around pregnancy loss were class-based, distrustful of female patients, and shaped by the wider context of fertility decline and concerns about infant mortality. The close historical connection between miscarriage and abortion offers some insight into why both the pro-life movement and miscarriage support advocates today draw on similar imagery and rhetoric about early fetal loss. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. [IDENTIFICATION OF CAUSES OF EARLY PREGNANCY LOSSES ACCORDING TO HYSTOMORPHOLOGIC FEATURES].

    PubMed

    Gotsiridze, K; Kintraia, N; Pailodze, M; Gogia, T; Tsaava, F

    2017-01-01

    Retrospective analysis of the early spontaneous abortions has been conducted (486 cases). Histomorphologic analysis of the curettage material contents erveledinvolutive-regressive developmental chsnges in 108 (22,28%) cases, in 370 cases (77.78%) pathologic changes, like inflammatory changes of deciduas and chorionic villis in 302 cases (80.2%), pathologic prematurity of chorionic vili in 48 cases (12.6%), hydatidiform mole in 28 cases (7.4%). As most cases of pregnancy loss has been reported at 7-9 weeks /172 cases/, we compared histomorphologic data revealed at 7-8 (71 cases) weeks to 5-6 (135 cases) and 10-12 weeks of gestation. Morphologic research data confimed, that at 7-8 weeks compared to 5-6 weeks leading reason ofpregnancy loss was inflammatory changes (OR-1,584), what can be cause of 110 pregnancy losses at 1000 pregnant women (AR-0.11). Data comparing7-9 weeks to 10-12 weeks pregnancy losses, confirm the priority of pathologic immaturity (OR-1,279) and hydatidiform mole (OR-1,557) and could be the risk of 100 cases of pregnancy termination at 1000 pregnant women (AR-0.10).Existing results are of great importance for the preconceptional preparation of women.

  4. Motoneuron axon pathfinding errors in zebrafish: Differential effects related to concentration and timing of nicotine exposure

    SciTech Connect

    Menelaou, Evdokia; Paul, Latoya T.; Perera, Surangi N.

    Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMNs). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15–30 μM). Previous work showed that the paralytic mutant zebrafish known as sofa potato exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at differentmore » developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window. - Highlights: • Embryonic nicotine exposure can specifically affect secondary motoneuron axons in a dose

  5. Chlorpyrifos-Oxon Disrupts Zebrafish Axonal Growth and Motor Behavior

    PubMed Central

    Yang, Dongren; Lauridsen, Holly; Buels, Kalmia; Chi, Lai-Har; La Du, Jane; Bruun, Donald A.; Olson, James R.; Tanguay, Robert L.; Lein, Pamela J.

    2011-01-01

    Axonal morphology is a critical determinant of neuronal connectivity, and perturbation of the rate or extent of axonal growth during development has been linked to neurobehavioral deficits in animal models and humans. We previously demonstrated that the organophosphorus pesticide (OP) chlorpyrifos (CPF) inhibits axonal growth in cultured neurons. In this study, we used a zebrafish model to determine whether CPF, its oxon metabolite (CPFO), or the excreted metabolite trichloro-2-pyridinol (TCPy) alter spatiotemporal patterns of axonal growth in vivo. Static waterborne exposure to CPFO, but not CPF or TCPy, at concentrations ≥ 0.03μM from 24- to 72-h post fertilization significantly inhibited acetylcholinesterase, and high-performance liquid chromatography detected significantly more TCPy in zebrafish exposed to 0.1μM CPFO versus 1.0μM CPF. These data suggest that zebrafish lack the metabolic enzymes to activate CPF during these early developmental stages. Consistent with this, CPFO, but not CPF, significantly inhibited axonal growth of sensory neurons, primary motoneurons, and secondary motoneurons at concentrations ≥ 0.1μM. Secondary motoneurons were the most sensitive to axonal growth inhibition by CPFO, which was observed at concentrations that did not cause mortality, gross developmental defects, or aberrant somatic muscle differentiation. CPFO effects on axonal growth correlated with adverse effects on touch-induced swimming behavior, suggesting the functional relevance of these structural changes. These data suggest that altered patterns of neuronal connectivity contribute to the developmental neurotoxicity of CPF and demonstrate the relevance of zebrafish as a model for studying OP developmental neurotoxicity. PMID:21346248

  6. Axon Regeneration Genes Identified by RNAi Screening in C. elegans

    PubMed Central

    Nix, Paola; Hammarlund, Marc; Hauth, Linda; Lachnit, Martina; Jorgensen, Erik M.

    2014-01-01

    Axons of the mammalian CNS lose the ability to regenerate soon after development due to both an inhibitory CNS environment and the loss of cell-intrinsic factors necessary for regeneration. The complex molecular events required for robust regeneration of mature neurons are not fully understood, particularly in vivo. To identify genes affecting axon regeneration in Caenorhabditis elegans, we performed both an RNAi-based screen for defective motor axon regeneration in unc-70/β-spectrin mutants and a candidate gene screen. From these screens, we identified at least 50 conserved genes with growth-promoting or growth-inhibiting functions. Through our analysis of mutants, we shed new light on certain aspects of regeneration, including the role of β-spectrin and membrane dynamics, the antagonistic activity of MAP kinase signaling pathways, and the role of stress in promoting axon regeneration. Many gene candidates had not previously been associated with axon regeneration and implicate new pathways of interest for therapeutic intervention. PMID:24403161

  7. Custom-fit minimally invasive total knee arthroplasty: effect on blood loss and early clinical outcomes.

    PubMed

    Pietsch, M; Djahani, O; Zweiger, Ch; Plattner, F; Radl, R; Tschauner, Ch; Hofmann, S

    2013-10-01

    Recently, new custom-fit pin guides in total knee arthroplasty (TKA) have been introduced. Use of these guides may reduce operating time. Use of the guides combined with the absence of intramedullary alignment jigs may lead to reduced blood loss and improved early outcomes. Our aim was to evaluate blood loss and early clinical outcomes in patients undergoing minimally invasive TKA using custom-fit magnetic resonance imaging (MRI)-based pin guides. A prospective study in 80 patients was carried out. Patients were divided randomly into 2 equal groups. In one group, intramedullary alignment jigs were used. In the second group, custom-fit MRI-based pin guides were used. All patients received the same cemented posterior-stabilized implant through a mini-midvastus approach. The volume in the drain bottles was recorded after 48 h. Hb loss was estimated by subtracting the postoperative from the preoperative Hb level. Transfusion requirements and surgical time were recorded. Outcome measures were Knee Society Scores (KSS), knee flexion, knee swelling and pain. There was lower mean drainage of blood in the custom-fit group (391 ml vs. 603 ml; p < 0.0001). There was no difference in estimated loss of Hb (3.6 g/dl vs. 4.1 g/dl; n.s.) and in transfusion requirements (7.5 % vs. 10 %; n.s.). Surgical time was reduced in the custom-fit group (12 min less; p = 0.001). KSS measured at week 2, 6 and 12 showed no significant difference between groups. Knee flexion measured on days 7, 10 and at week 6, 12 and knee swelling and pain measured on days 1, 3, 10 and at week 6, 12 showed no significant difference between groups. Using custom-fit pin guides reduces blood drainage, but not the estimated Hb loss in minimally invasive TKA and does not affect transfusion rate. Surgical time is reduced. There is no effect on the early clinical outcomes. Therapeutic study, Level I.

  8. Life course effects of early parental loss among very old African Americans.

    PubMed

    Johnson, Colleen L; Barer, Barbara M

    2002-03-01

    To analyze the life course effects of the early loss of one or both parents on very old Black Americans. Open-ended, semistructured interviews were used with a sample of 109 respondents aged 85 years and older. Correlations identified significant associations, and qualitative data illustrate life course trajectories of selected respondents. Those who lost a parent through death or desertion were less integrated into family and friendship groups in late life, and they had fewer social resources in general. Qualitative data describe three outcomes in the sample: those who grew up with both parents present, those who lost a parent but still reported a contented childhood, and those with disrupted families and negative effects. The respondents' open-ended commentary about their past lives and their current situation enhances understanding of connections between early life events and adaptation in old age.

  9. Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

    PubMed Central

    Whitmore, S.Scott; Sohn, Elliott H.; Chirco, Kathleen R.; Drack, Arlene V.; Stone, Edwin M.; Tucker, Budd A.; Mullins, Robert F.

    2015-01-01

    Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruch's membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies. PMID:25486088

  10. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy.

    PubMed

    Whitmore, S Scott; Sohn, Elliott H; Chirco, Kathleen R; Drack, Arlene V; Stone, Edwin M; Tucker, Budd A; Mullins, Robert F

    2015-03-01

    Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruch's membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Calcium overloading in traumatic axonal injury by lateral head rotation: a morphological evidence in rat model.

    PubMed

    He, Xiao-Sheng; Xiang, Zhang; Zhou, Fei; Fu, Luo-An; Shuang, Wang

    2004-05-01

    The study investigated morphologically axonal calcium overloading and its relationship with axonal structural changes. Twelve SD rats were divided into an injury and a sham group. The rat model of traumatic axonal injury (TAI) by lateral head rotation was produced. The oxalate-pyroantimonate technique for calcium localization was used to process the rat's medulla oblongata tissues with thin sections observed electron-microscopically for axonal structure and calcium precipitates on it. The axonal damage in medulla oblongata appeared at 2 h post-injury, gradually became diffuse and severe, and continued to exist at 24 hours. At 2 hours, calcium precipitates were deposited on separated lamellae and axolemma, but were rarely distributed in the axoplasm. At 6 hours, calcium precipitates occurred on separated lamellae and axolemma in much higher density, but on axoplasm in extremely small amounts. Some axons, though lacking structural changes of the myelin sheath, sequestered plenty of calcium deposits on their swollen mitochondria. At 24 hours, damaged axons presented with much more severe lamellae separation and calcium deposits. Axonal calcium overloading developed in rat TAI model using lateral head rotation. This was significantly related to structural damage in the axons. These findings suggest the feasibility of using calcium antagonists in cope the management of human DAI in its very early stage.

  12. Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport

    PubMed Central

    Rao, Mala V.; Garcia, Michael L.; Miyazaki, Yukio; Gotow, Takahiro; Yuan, Aidong; Mattina, Salvatore; Ward, Chris M.; Calcutt, Nigel A.; Uchiyama, Yasuo; Nixon, Ralph A.; Cleveland, Don W.

    2002-01-01

    The COOH-terminal tail of mammalian neurofilament heavy subunit (NF-H), the largest neurofilament subunit, contains 44-51 lysine–serine–proline repeats that are nearly stoichiometrically phosphorylated after assembly into neurofilaments in axons. Phosphorylation of these repeats has been implicated in promotion of radial growth of axons, control of nearest neighbor distances between neurofilaments or from neurofilaments to other structural components in axons, and as a determinant of slow axonal transport. These roles have now been tested through analysis of mice in which the NF-H gene was replaced by one deleted in the NF-H tail. Loss of the NF-H tail and all of its phosphorylation sites does not affect the number of neurofilaments, alter the ratios of the three neurofilament subunits, or affect the number of microtubules in axons. Additionally, it does not reduce interfilament spacing of most neurofilaments, the speed of action potential propagation, or mature cross-sectional areas of large motor or sensory axons, although its absence slows the speed of acquisition of normal diameters. Most surprisingly, at least in optic nerve axons, loss of the NF-H tail does not affect the rate of transport of neurofilament subunits. PMID:12186852

  13. Motoneuron axon pathfinding errors in zebrafish: Differential effects related to concentration and timing of nicotine exposure

    PubMed Central

    Menelaou, Evdokia; Paul, Latoya T.; Perera, Surangi N.; Svoboda, Kurt R.

    2015-01-01

    Nicotine exposure during embryonic stages of development can affect many neurodevelopmental processes. In the developing zebrafish, exposure to nicotine was reported to cause axonal pathfinding errors in the later born secondary motoneurons (SMN). These alterations in SMN axon morphology coincided with muscle degeneration at high nicotine concentrations (15–30µM). Previous work showed that the paralytic mutant zebrafish known as sofa potato, exhibited nicotine-induced effects onto SMN axons at these high concentrations but in the absence of any muscle deficits, indicating that pathfinding errors could occur independent of muscle effects. In this study, we used varying concentrations of nicotine at different developmental windows of exposure to specifically isolate its effects onto subpopulations of motoneuron axons. We found that nicotine exposure can affect SMN axon morphology in a dose-dependent manner. At low concentrations of nicotine, SMN axons exhibited pathfinding errors, in the absence of any nicotine-induced muscle abnormalities. Moreover, the nicotine exposure paradigms used affected the 3 subpopulations of SMN axons differently, but the dorsal projecting SMN axons were primarily affected. We then identified morphologically distinct pathfinding errors that best described the nicotine-induced effects on dorsal projecting SMN axons. To test whether SMN pathfinding was potentially influenced by alterations in the early born primary motoneuron (PMN), we performed dual labeling studies, where both PMN and SMN axons were simultaneously labeled with antibodies. We show that only a subset of the SMN axon pathfinding errors coincided with abnormal PMN axonal targeting in nicotine-exposed zebrafish. We conclude that nicotine exposure can exert differential effects depending on the levels of nicotine and developmental exposure window. PMID:25668718

  14. Oligodendrocytes: Myelination and Axonal Support

    PubMed Central

    Simons, Mikael; Nave, Klaus-Armin

    2016-01-01

    Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons. PMID:26101081

  15. An experimental demonstration that early-life competitive disadvantage accelerates telomere loss

    PubMed Central

    Nettle, Daniel; Monaghan, Pat; Gillespie, Robert; Brilot, Ben; Bedford, Thomas; Bateson, Melissa

    2015-01-01

    Adverse experiences in early life can exert powerful delayed effects on adult survival and health. Telomere attrition is a potentially important mechanism in such effects. One source of early-life adversity is the stress caused by competitive disadvantage. Although previous avian experiments suggest that competitive disadvantage may accelerate telomere attrition, they do not clearly isolate the effects of competitive disadvantage from other sources of variation. Here, we present data from an experiment in European starlings (Sturnus vulgaris) that used cross-fostering to expose siblings to divergent early experience. Birds were assigned either to competitive advantage (being larger than their brood competitors) or competitive disadvantage (being smaller than their brood competitors) between days 3 and 12 post-hatching. Disadvantage did not affect weight gain, but it increased telomere attrition, leading to shorter telomere length in disadvantaged birds by day 12. There were no effects of disadvantage on oxidative damage as measured by plasma lipid peroxidation. We thus found strong evidence that early-life competitive disadvantage can accelerate telomere loss. This could lead to faster age-related deterioration and poorer health in later life. PMID:25411450

  16. An experimental demonstration that early-life competitive disadvantage accelerates telomere loss.

    PubMed

    Nettle, Daniel; Monaghan, Pat; Gillespie, Robert; Brilot, Ben; Bedford, Thomas; Bateson, Melissa

    2015-01-07

    Adverse experiences in early life can exert powerful delayed effects on adult survival and health. Telomere attrition is a potentially important mechanism in such effects. One source of early-life adversity is the stress caused by competitive disadvantage. Although previous avian experiments suggest that competitive disadvantage may accelerate telomere attrition, they do not clearly isolate the effects of competitive disadvantage from other sources of variation. Here, we present data from an experiment in European starlings (Sturnus vulgaris) that used cross-fostering to expose siblings to divergent early experience. Birds were assigned either to competitive advantage (being larger than their brood competitors) or competitive disadvantage (being smaller than their brood competitors) between days 3 and 12 post-hatching. Disadvantage did not affect weight gain, but it increased telomere attrition, leading to shorter telomere length in disadvantaged birds by day 12. There were no effects of disadvantage on oxidative damage as measured by plasma lipid peroxidation. We thus found strong evidence that early-life competitive disadvantage can accelerate telomere loss. This could lead to faster age-related deterioration and poorer health in later life.

  17. The POU transcription factor UNC-86 controls the timing and ventral guidance of C. elegans axon growth

    PubMed Central

    Olsson-Carter, Katherine; Slack, Frank J.

    2012-01-01

    The in vivo mechanisms that coordinate the timing of axon growth and guidance are not well understood. In the C. elegans hermaphrodite specific neurons, the lin-4 microRNA controls the stage of axon initiation independent of the UNC-40 and SAX-3 ventral guidance receptors. lin-4 loss-of-function mutants exhibit marked delays in axon outgrowth, while lin-4 overexpression, leads to precocious growth in the L3. Here we show that loss of the POU transcription factor UNC-86 not only results in penetrant ventral axon growth defects in the HSNs, but also causes processes to extend in the L1, three stages earlier than wild-type. This temporal shift is not dependent on UNC-40 or SAX-3, and does not require the presence of lin-4. We propose that unc-86(lf) HSN axons are misguided due to the temporal decoupling of axon initiation and ventral guidance responses. PMID:21656875

  18. Association of increased S100A8 serum protein with early pregnancy loss.

    PubMed

    Nair, Rohini R; Khanna, Anuradha; Singh, Kiran

    2015-02-01

    The contribution of systemic S100A8 protein in menstrual cycle, pregnancy, and early pregnancy loss (EPL) is not known. Altered expression of S100A8 in maternal decidua is associated with recurrent early pregnancy loss. The objective of this study was to investigate the systemic level of S100A8 in different phases of menstrual cycle, different trimester of pregnancy, and in EPL. Level of S100A8 was investigated in serum samples of the subjects through enzyme-linked immunosorbent assay (ELISA). S100A8 levels were elevated during proliferative phase of menstrual cycle. We found no statistical difference in S100A8 level in different trimester of pregnancy. S100A8 level was found to be significantly elevated in patients with EPL. This is the first study evaluating the systemic level of S100A8 predicting its role during menstrual cycle and pregnancy. It opens a new perspective in which S100A8 can be used as a prognostic marker for EPL. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Predictors of early-onset permanent hearing loss in malnourished infants in Sub-Saharan Africa.

    PubMed

    Olusanya, Bolajoko O

    2011-01-01

    The objective of this study was to determine the predictors of early-onset permanent hearing loss (EPHL) among undernourished infants in a low-income country where routine screening for developmental disabilities in early childhood is currently unattainable. All infants attending four community-based clinics for routine immunization who met the criteria for undernutrition by the Growth Standards of the World Health Organization (WHO) based on weight-for-age, weight-for-length and body-mass-index-for-age were enlisted. EPHL was determined after two-stage screening with transient-evoked otoacoustic emissions, automated auditory brainstem response and diagnostic evaluation. Factors predictive of EPHL were explored with multivariable logistic regression analysis. Some 39 (1.7%) infants from 2254 undernourished infants were confirmed with hearing loss (>30 dB HL). Bilateral EPHL was mild in 7 (17.9%) and moderate-to-profound in 26 (66.7%). EPHL was unilateral in 6 (15.4%). Multiparity, chronological age of more than 30 days, the absence of skilled attendant at birth and severe neonatal jaundice were associated with an increased risk of EPHL while having a Christian mother and exclusive breast feeding had protective effect against EPHL. EPHL is highly prevalent among undernourished infants and associated with modifiable risk factors that can be addressed at the community-level and used as a basis for targeted intervention in resource-poor countries. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Relationship between oxidative stress and muscle mass loss in early postmenopause: an exploratory study.

    PubMed

    Zacarías-Flores, Mariano; Sánchez-Rodríguez, Martha A; García-Anaya, Oswaldo Daniel; Correa-Muñoz, Elsa; Mendoza-Núñez, Víctor Manuel

    2018-04-09

    Endocrine changes due to menopause have been associated to oxidative stress and muscle mass loss. The study objective was to determine the relationship between both variables in early postmenopause. An exploratory, cross-sectional study was conducted in 107 pre- and postmenopausal women (aged 40-57 years). Levels of serum lipid peroxides and uric acid and enzymes superoxide dismutase and glutathione peroxidase, as well as total plasma antioxidant capacity were measured as oxidative stress markers. Muscle mass using bioelectrical impedance and muscle strength using dynamometry were also measured. Muscle mass, skeletal muscle index, fat-free mass, and body mass index were calculated. More than 90% of participants were diagnosed with overweight or obesity. Postmenopausal women had lower values of muscle mass and strength markers, with a negative correlation between lipid peroxide level and skeletal muscle index (r= -0.326, p<.05), and a positive correlation between uric acid and skeletal muscle index (r=0.295, p<.05). A multivariate model including oxidative stress markers, age, and waist circumference showed lipid peroxide level to be the main contributor to explain the decrease in skeletal muscle mass in postmenopause, since for every 0.1μmol/l increase in lipid peroxide level, skeletal muscle index decreases by 3.03 units. Our findings suggest an association between increased oxidative stress and muscle mass loss in early postmenopause. Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

  1. Selective alterations of neurons and circuits related to early memory loss in Alzheimer’s disease

    PubMed Central

    Llorens-Martín, Maria; Blazquez-Llorca, Lidia; Benavides-Piccione, Ruth; Rabano, Alberto; Hernandez, Felix; Avila, Jesus; DeFelipe, Javier

    2014-01-01

    A progressive loss of episodic memory is a well-known clinical symptom that characterizes Alzheimer’s disease (AD). The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal cortex (EC). Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses. The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the perforant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII → dentate gyrus → CA3 → CA1) and monosynaptic (ECIII → CA1) circuits. Thus, the study of the early pathological changes in these circuits is of great interest. In this review, we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occur in AD in relation to the possible differential alterations of these two main circuits. PMID:24904307

  2. Selective alterations of neurons and circuits related to early memory loss in Alzheimer's disease.

    PubMed

    Llorens-Martín, Maria; Blazquez-Llorca, Lidia; Benavides-Piccione, Ruth; Rabano, Alberto; Hernandez, Felix; Avila, Jesus; DeFelipe, Javier

    2014-01-01

    A progressive loss of episodic memory is a well-known clinical symptom that characterizes Alzheimer's disease (AD). The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal cortex (EC). Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses. The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the perforant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII → dentate gyrus → CA3 → CA1) and monosynaptic (ECIII → CA1) circuits. Thus, the study of the early pathological changes in these circuits is of great interest. In this review, we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occur in AD in relation to the possible differential alterations of these two main circuits.

  3. Association Between Vascular Density and Loss of Protective RAS During Early NPDR by Fractal Dimension

    NASA Technical Reports Server (NTRS)

    Radhakrishnan, Krisnan; Vyas, Ruchi J.; Murray, Matthew; Predovic, Marina; Lim, Shiyin; Bryant, Douglas; Yaqian, Duan; Grant, Maria B.; Chalam, K. V.; Parsons-Wingerter, Patricia

    2017-01-01

    Purpose: Our hypothesis predicts that blood vessels within the retina increase in density during early-stage nonproliferative diabetic retinopathy (NPDR), based on previous results of a small retrospective study. For the current prospective study, the remodeling of arteries and veins during progression of early NPDR is assessed by a repertoire of parameters that includes the fractal dimension (D(sub f) ). In complex structures such as branching vascular trees, D(sub f) is a sensitive measure of space-filing capacity. The renin-angiotensin system (RAS) is implicated in DR pathogenesis and the function of circulating angiogenic cells (CACs), a critical bone marrow-derived population instrumental in vascular repair. Methods: Arterial and venous branching patterns were extracted from images of 6 normal controls and 3 early NPDR subjects (2 moderate, 1 mild) acquired by Heidelberg Spectralis (Registered Trademark) OCT following fluorescein angiography (FA). The vascular branching patterns were analyzed by NASAs VESsel GENeration Analysis (VESGEN) software, in which skeletonized representations were generated automatically to yield D(sub f) by the box-counting method. For binary 2D images, D(sub f) varies between limiting Euclidean dimensions of 1 and 2. Peripheral blood of diabetics and controls was collected for CD34+ CAC isolation. The gene expression of RAS in CACs was assessed by qPCR for Mas receptor to Ang-(1-7). The vasoreparative function of the CACs was measured by migration ability toward CXCL12 (SDF-1). Results: By D(sub f), venous and arterial densities were 1.370 +/- 0.006 and 1.329 +/- 0.016 for early NPDR, compared to 1.318 +/- 0.012 and 1.320 +/- 0.036 for control. The space filling capacity in early NPDR measured by D(sub f), a sensitive parameter, therefore demonstrated a pronounced increase for veins, but not for arteries. Mas receptor mRNA in CACs was increased in diabetics without DR but reduced with onset of NPDR, indicating possible loss of

  4. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise.

    PubMed

    McQueen, Dana B; Bernardi, Lia A; Stephenson, Mary D

    2014-04-01

    To assess the prevalence of chronic endometritis in women with a history of recurrent early pregnancy loss (REPL) and/or fetal demise (FD). Observational cohort study using prospectively collected data. Recurrent pregnancy loss program in an academic medical center. Three hundred ninety-five women with a history of two or more pregnancy losses of less than 10 weeks' size or a fetal demise of 10 or more weeks' size. All women had an endometrial biopsy. Chronic endometritis was treated with antibiotics, and a second endometrial biopsy was recommended as a "test of cure." Subsequent live-birth rate (LBR). The overall prevalence of chronic endometritis was 9% (35/395) in this cohort; 7% (21/285) in the REPL group, 14% (8/57) in the FD group, and 11% (6/53) in the combined REPL/FD group. The cure rate was 100% after a course(s) of antibiotics. The subsequent cumulative LBR was 88% (21/24) for the treated chronic endometritis group versus 74% (180/244) for the group without chronic endometritis. The per-pregnancy LBR for the treated chronic endometritis group was 7% (7/98) before treatment versus 56% (28/50) after treatment. There was a high prevalence of chronic endometritis in this cohort. The test of cure was 100% with antibiotics. Subsequent LBRs after treatment were encouraging. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  5. Natural killer cells and regulatory T cells in early pregnancy loss

    PubMed Central

    SHARMA, SURENDRA

    2015-01-01

    Survival of the allogeneic embryo in the uterus depends on the maintenance of immune tolerance at the maternal-fetal interface. The pregnant uterus is replete with activated maternal immune cells. How this immune tolerance is acquired and maintained has been a topic of intense investigation. The key immune cells that predominantly populate the pregnant uterus are natural killer (NK) cells. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation. In placental mammals, an array of highly orchestrated immune elements to support successful pregnancy outcome has been incorporated. This includes active cooperation between maternal immune cells, particularly NK cells, and trophoblast cells. This intricate process is required for placentation, immune regulation and to remodel the blood supply to the fetus. During the past decade, various types of maternal immune cells have been thought to be involved in cross-talk with trophoblasts and in programming immune tolerance. RegulatoryT cells (Tregs) have attracted a great deal of attention in promoting implantation and immune tolerance beyond implantation. However, what has not been fully addressed is how this immune-trophoblast axis breaks down during adverse pregnancy outcomes, particularly early pregnancy loss, and in response to unscheduled inflammation. Intense research efforts have begun to shed light on the roles of NK cells and Tregs in early pregnancy loss, although much remains to be unraveled in order to fully characterize the mechanisms underlying their detrimental activity. An increased understanding of host-environment interactions that lead to the cytotoxic phenotype of these otherwise pregnancy compatible maternal immune cells is important for prediction, prevention and treatment of pregnancy maladies, particularly recurrent pregnancy loss. In this review, we discuss relevant information from experimental and human

  6. Intragraft vascular occlusive sickle crisis with early renal allograft loss in occult sickle cell trait.

    PubMed

    Kim, Lisa; Garfinkel, Marc R; Chang, Anthony; Kadambi, Pradeep V; Meehan, Shane M

    2011-07-01

    Early renal allograft failure due to sickle cell trait is rare. We present clinical and pathologic findings in 2 cases of early renal allograft failure associated with renal vein thrombosis and extensive erythrocyte sickling. Hemoglobin AS was identified in retrospect. In case 1, a 41-year-old female recipient of a deceased donor renal transplant developed abdominal pain and acute allograft failure on day 16, necessitating immediate nephrectomy. In case 2, the transplanted kidney in a 58-year-old female recipient was noted to be mottled blue within minutes of reperfusion. At 24 hours, the patient was oliguric; and the graft was removed. Transplant nephrectomies had diffuse enlargement with diffuse, nonhemorrhagic, cortical, and medullary necrosis. Extensive sickle vascular occlusion was evident in renal vein branches; interlobar, interlobular, and arcuate veins; vasa recta; and peritubular capillaries. The renal arteries had sickle vascular occlusion in case 1. Glomeruli had only focal sickle vascular occlusion. The erythrocytes in sickle vascular occlusion had abundant cytoplasmic filaments by electron microscopy. Acute rejection was not identified in either case. Protein C and S levels, factor V Leiden, and lupus anticoagulant assays were within normal limits. Hemoglobin analysis revealed hemoglobin S of 21.8% and 25.6%, respectively. Renal allograft necrosis with intragraft sickle crisis, characterized by extensive vascular occlusive erythrocyte sickling and prominent renal vein thrombosis, was observed in 2 patients with sickle cell trait. Occult sickle cell trait may be a risk factor for early renal allograft loss. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Optofluidic control of axonal guidance

    NASA Astrophysics Data System (ADS)

    Gu, Ling; Ordonez, Simon; Black, Bryan; Mohanty, Samarendra K.

    2013-03-01

    Significant efforts are being made for control on axonal guidance due to its importance in nerve regeneration and in the formation of functional neuronal circuitry in-vitro. These include several physical (topographic modification, optical force, and electric field), chemical (surface functionalization cues) and hybrid (electro-chemical, photochemical etc) methods. Here, we report comparison of the effect of linear flow versus microfluidic flow produced by an opticallydriven micromotor in guiding retinal ganglion axons. A circularly polarized laser tweezers was used to hold, position and spin birefringent calcite particle near growth cone, which in turn resulted in microfluidic flow. The flow rate and resulting shear-force on axons could be controlled by a varying the power of the laser tweezers beam. The calcite particles were placed separately in one chamber and single particle was transported through microfluidic channel to another chamber containing the retina explant. In presence of flow, the turning of axons was found to strongly correlate with the direction of flow. Turning angle as high as 90° was achieved. Optofluidic-manipulation can be applied to other types of mammalian neurons and also can be extended to stimulate mechano-sensing neurons.

  8. Early ligation of the dorsal pancreatic artery with a mesenteric approach reduces intraoperative blood loss during pancreatoduodenectomy.

    PubMed

    Iede, Kiyotsugu; Nakao, Akimasa; Oshima, Kenji; Suzuki, Ryota; Yamada, Hironori; Oshima, Yukiko; Kobayashi, Hironobu; Kimura, Yasunori

    2018-05-10

    Early ligation of the inferior pancreatoduodenal artery has been advocated to reduce blood loss during pancreatoduodenectomy. However, the impact of early ligation of the dorsal pancreatic artery (DPA) remains unclear. This study was performed to investigate the clinical implications of early ligation of the DPA. From October 2014 to April 2017, 34 consecutive patients underwent pancreatoduodenectomy using a mesenteric approach. The patients were divided into the early DPA ligation group (n = 15) and late DPA ligation group (n = 19). The clinical features were retrospectively compared between the two groups (H29-044). Preoperative multidetector row computed tomography and intraoperative findings revealed that the right branch of the DPA supplied the pancreatic head region in all cases. Intraoperative blood loss was significantly lower in the early than late ligation group (median, 609 ml [range, 94-1013 ml] vs. 764 ml [range, 367-1828 ml], respectively; P = 0.008]. Multivariable analysis revealed that early DPA ligation was independently associated with blood loss (P = 0.023). The DPAs arising from the superior mesenteric artery underwent early ligation at a significantly higher rate. Early ligation of the DPA during pancreaticoduodenectomy with a mesenteric approach could reduce intraoperative blood loss. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  9. Polar processing in a split vortex: early winter Arctic ozone loss in 2012/13

    NASA Astrophysics Data System (ADS)

    Manney, G. L.; Lawrence, Z. D.; Santee, M. L.; Livesey, N. J.; Lambert, A.; Pitts, M. C.

    2015-02-01

    A sudden stratospheric warming (SSW) in early January 2013 caused the polar vortex to split. After the lower stratospheric vortex split on 8 January, the two offspring vortices - one over Canada and the other over Siberia - remained intact, well-confined, and largely at latitudes that received sunlight until they reunited at the end of January. As the SSW began, temperatures abruptly rose above chlorine activation thresholds throughout the lower stratosphere. The vortex was very disturbed prior to the SSW, and was exposed to much more sunlight than usual in December 2012 and January 2013. Aura Microwave Limb Sounder (MLS) nitric acid (HNO3) data and observations from CALIPSO (Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations) indicate extensive polar stratospheric cloud (PSC) activity, with evidence of PSCs containing solid nitric acid trihydrate particles during much of December 2012. Consistent with the sunlight exposure and PSC activity, MLS observations show that chlorine monoxide (ClO) became enhanced early in December. Despite the cessation of PSC activity with the onset of the SSW, enhanced vortex ClO persisted until mid-February, indicating lingering chlorine activation. The smaller Canadian offspring vortex had lower temperatures, lower HNO3, lower hydrogen chloride (HCl), and higher ClO in late January than the Siberian vortex. Chlorine deactivation began later in the Canadian than in the Siberian vortex. HNO3 remained depressed within the vortices after temperatures rose above the PSC existence threshold, and passive transport calculations indicate vortex-averaged denitrification of about 4 ppbv; the resulting low HNO3 values persisted until the vortex dissipated in mid-February. Consistent with the strong chlorine activation and exposure to sunlight, MLS measurements show rapid ozone loss commencing in mid-December and continuing through January. Lagrangian transport estimates suggest ~ 0.7-0.8 ppmv (parts per million by volume) vortex

  10. ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

    PubMed Central

    Konopacki, Filip A.; Dwivedy, Asha; Bellon, Anaïs; Blower, Michael D.

    2016-01-01

    Endocytosis and local protein synthesis (LPS) act coordinately to mediate the chemotropic responses of axons, but the link between these two processes is poorly understood. The endosomal sorting complex required for transport (ESCRT) is a key regulator of cargo sorting in the endocytic pathway, and here we have investigated the role of ESCRT-II, a critical ESCRT component, in Xenopus retinal ganglion cell (RGC) axons. We show that ESCRT-II is present in RGC axonal growth cones (GCs) where it co-localizes with endocytic vesicle GTPases and, unexpectedly, with the Netrin-1 receptor, deleted in colorectal cancer (DCC). ESCRT-II knockdown (KD) decreases endocytosis and, strikingly, reduces DCC in GCs and leads to axon growth and guidance defects. ESCRT-II-depleted axons fail to turn in response to a Netrin-1 gradient in vitro and many axons fail to exit the eye in vivo. These defects, similar to Netrin-1/DCC loss-of-function phenotypes, can be rescued in whole (in vitro) or in part (in vivo) by expressing DCC. In addition, ESCRT-II KD impairs LPS in GCs and live imaging reveals that ESCRT-II transports mRNAs in axons. Collectively, our results show that the ESCRT-II-mediated endocytic pathway regulates both DCC and LPS in the axonal compartment and suggest that ESCRT-II aids gradient sensing in GCs by coupling endocytosis to LPS. PMID:27248654

  11. Electrolyte-carbohydrate beverage prevents water loss in the early stage of high altitude training.

    PubMed

    Yanagisawa, Kae; Ito, Osamu; Nagai, Satsuki; Onishi, Shohei

    2012-01-01

    To prevent water loss in the early stage of high altitude training, we focused on the effect of electrolyte-carbohydrate beverage (EC). Subjects were 16 male university students who belonged to a ski club. They had ski training at an altitude of 1,800 m. The water (WT) group drank only water, and the EC group drank only an electrolyte-carbohydrate beverage. They arrived at the training site in the late afternoon. The study started at 7 pm on the day of arrival and continued until noon of the 4(th) day. In the first 12 hours, 1 L of beverages were given. On the second and third days, 2.5 L of beverages were given. All subjects ate the same meals. Each morning while in fasting condition, subjects were weighed and blood was withdrawn for various parameters (hemoglobin, hematocrit, sodium, potassium and aldosterone). Urine was collected at 12 hour intervals for a total 60 hours (5 times). The urine volume, gravity, sodium and potassium concentrations were measured. Peripheral oxygen saturation and heart rate were measured during sleep with a pulse oximeter. Liquid intakes in both groups were similar, hence the electrolytes intake was higher in the EC group than in the WT group. The total urine volume was lower in the EC group than in the WT group, respectively (p<0.05). Plasma volume decreased in the WT group and increased in the EC group but a significant difference was not observed in the final value. Aldosterone concentration tended to be less in the EC group than in the WT group. Electrolyte-carbohydrate beverage in the early stage of high altitude training may be effective in decreasing urinary output and preventing loss of blood plasma volume.

  12. Early Loss of Splenic Tfh Cells in SIV-Infected Rhesus Macaques

    PubMed Central

    Moukambi, Félicien; Rabezanahary, Henintsoa; Rodrigues, Vasco; Racine, Gina; Robitaille, Lynda; Krust, Bernard; Andreani, Guadalupe; Soundaramourty, Calayselvy; Silvestre, Ricardo; Laforge, Mireille; Estaquier, Jérôme

    2015-01-01

    Follicular T helper cells (Tfh), a subset of CD4 T lymphocytes, provide crucial help to B cells in the production of antigen-specific antibodies. Although several studies have analyzed the dynamics of Tfh cells in peripheral blood and lymph nodes (LNs) during Aids, none has yet addressed the impact of SIV infection on the dynamics of Tfh cells in the spleen, the primary organ of B cell activation. We show here a significant decrease in splenic Tfh cells in SIVmac251-infected rhesus macaques (RMs) during the acute phase of infection, which persists thereafter. This profound loss is associated with lack of sustained expression of the Tfh-defining transcription factors, Bcl-6 and c-Maf but with higher expression of the repressors KLF2 and Foxo1. In this context of Tfh abortive differentiation and loss, we found decreased percentages of memory B cell subsets and lower titers of SIV-specific IgG. We further demonstrate a drastic remodeling of the lymphoid architecture of the spleen and LNs, which disrupts the crucial cell-cell interactions necessary to maintain memory B cells and Tfh cells. Finally, our data demonstrated the early infection of Tfh cells. Paradoxically, the frequencies of SIV DNA were higher in splenic Tfh cells of RMs progressing more slowly suggesting sanctuaries for SIV in the spleen. Our findings provide important information regarding the impact of HIV/SIV infection on Tfh cells, and provide new clues for future vaccine strategies. PMID:26640894

  13. Frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss.

    PubMed

    Boots, Christina E; Bernardi, Lia A; Stephenson, Mary D

    2014-08-01

    To determine whether the frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss (REPL). Observational cohort study using prospectively collected data. Academic RPL program. A total of 372 women with REPL, defined as ≥2 pregnancy losses<10 weeks, and at least one ultrasound-documented miscarriage with chromosome results. Body mass index (BMI) was measured at the initial consultation and at each subsequent pregnancy. Conventional cytogenetic analysis and, when indicated, microsatellite analysis and/or comparative genomic hybridization was performed. Frequency of euploid miscarriage in obese (BMI≥30 kg/m2) and nonobese (BMI<30 kg/m2) subjects, before and subsequent to REPL evaluation. There were 578 miscarriages with chromosome results. Of the subjects, 18% were obese at the time of miscarriage. The mean maternal age at miscarriage was similar between the obese and nonobese groups. Due to the high rate of maternal cell contamination in the prior miscarriages, only subsequent miscarriages with chromosome results were included in the primary analysis. Of the 117 subsequent miscarriages, the frequency of an euploid miscarriage among obese women was 58% compared with 37% of nonobese women (relative risk=1.63; 95% confidence interval 1.08-2.47). Obese women with REPL have an increased frequency of euploid miscarriage, which is a known risk factor for subsequent miscarriage. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  14. Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss.

    PubMed

    Bernardi, Lia A; Cohen, Ronald N; Stephenson, Mary D

    2013-11-01

    To assess the impact of subclinical hypothyroidism (SCH) in women with recurrent early pregnancy loss (REPL). Observational cohort study. REPL program in an academic medical center. 286 women with a history of ≥2 pregnancy losses <10 weeks. From 2004-2007, no treatment for women with SCH (thyroid-stimulating hormone [TSH] >2.5 mIU/L with a normal free thyroxine or free thyroxine index); from 2008 onward, levothyroxine treatment prepregnancy to maintain TSH ≤2.5 mIU/L. Live-birth rate (LBR). The prevalence of SCH was 55 (19%) of 286 in this REPL cohort. The cumulative LBR was 27 (69%) of 39 for women with SCH versus 104 (74%) of 141 for euthyroid women. The per-pregnancy LBR was 34 (49%) of 69 for SCH versus 129 (58%) of 221 for euthyroid women. When the LBR was compared between treated and untreated SCH, the cumulative LBR was 17 (71%) of 24 versus 10 (67%) of 15, respectively. The per-pregnancy LBR for SCH treated versus untreated women was 22 (48%) of 46 versus 12 (52%) of 23, respectively. Although there was a high prevalence of SCH in the REPL cohort, there was no statistically significant difference in the subsequent live-birth rate when comparing women with SCH and euthyroid women, or treated and untreated SCH. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  15. The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling

    PubMed Central

    Franquinho, Filipa; Nogueira-Rodrigues, Joana; Duarte, Joana M.; Esteves, Sofia S.; Carter-Su, Christin; Monaco, Anthony P.; Molnár, Zoltán; Velayos-Baeza, Antonio; Brites, Pedro; Sousa, Mónica M.

    2017-01-01

    Abstract KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration. PMID:28334068

  16. Axonal transport rate decreased at the onset of optic neuritis in EAE mice

    PubMed Central

    Lin, Tsen-Hsuan; Kim, Joong Hee; Perez-Torres, Carlos; Chiang, Chia-Wen; Trinkaus, Kathryn; Cross, Anne H.; Song, Sheng-Kwei

    2014-01-01

    Optic neuritis is frequently the first symptom of multiple sclerosis (MS), an inflammatory demyelinating neurodegenerative disease. Impaired axonal transport has been considered as an early event of neurodegenerative diseases. However, few studies have assessed the integrity of axonal transport in MS or its animal models. We hypothesize that axonal transport impairment occurs at the onset of optic neuritis in experimental autoimmune encephalomyelitis (EAE) mice. In this study, we employed manganese-enhanced MRI (MEMRI) to assess axonal transport in optic nerves in EAE mice at the onset of optic neuritis. Axonal transport was assessed as (a) optic nerve Mn2+ accumulation rate (in % signal change/hour) by measuring the rate of increased total optic nerve signal enhancement, and (b) Mn2+ transport rate (in mm/hour) by measuring the rate of change in optic nerve length enhanced by Mn2+. Compared to sham-treated healthy mice, Mn2+ accumulation rate was significantly decreased by 19% and 38% for EAE mice with moderate and severe optic neuritis, respectively. The axonal transport rate of Mn2+ was significantly decreased by 43% and 65% for EAE mice with moderate and severe optic neuritis, respectively. The degree of axonal transport deficit correlated with the extent of impaired visual function and diminished microtubule-associated tubulins, as well as the severity of inflammation, demyelination, and axonal injury at the onset of optic neuritis. PMID:24936685

  17. Early Warning Signals for Abrupt Change Raise False Alarm During Sea Ice Loss

    NASA Astrophysics Data System (ADS)

    Wagner, T. J. W.; Eisenman, I.

    2015-12-01

    Uncovering universal early warning signals for critical transitions has become a coveted goal in diverse scientific disciplines, ranging from climate science to financial mathematics. There has been a flurry of recent research proposing such signals, with increasing autocorrelation and increasing variance being among the most widely discussed candidates. A number of studies have suggested that increasing autocorrelation alone may suffice to signal an impending transition, although some others have questioned this. Here, we consider variance and autocorrelation in the context of sea ice loss in an idealized model of the global climate system. The model features no bifurcation, nor increased rate of retreat, as the ice disappears. Nonetheless, the autocorrelation of summer sea ice area is found to increase with diminishing sea ice cover in a global warming scenario. The variance, by contrast, decreases. A simple physical mechanism is proposed to explain the occurrence of increasing autocorrelation but not variance in the model when there is no approaching bifurcation. Additionally, a similar mechanism is shown to allow an increase in both indicators with no physically attainable bifurcation. This implies that relying on autocorrelation and variance as early warning signals can raise false alarms in the climate system, warning of "tipping points" that are not actually there.

  18. False alarms: How early warning signals falsely predict abrupt sea ice loss

    NASA Astrophysics Data System (ADS)

    Wagner, Till J. W.; Eisenman, Ian

    2016-04-01

    Uncovering universal early warning signals for critical transitions has become a coveted goal in diverse scientific disciplines, ranging from climate science to financial mathematics. There has been a flurry of recent research proposing such signals, with increasing autocorrelation and increasing variance being among the most widely discussed candidates. A number of studies have suggested that increasing autocorrelation alone may suffice to signal an impending transition, although some others have questioned this. Here we consider variance and autocorrelation in the context of sea ice loss in an idealized model of the global climate system. The model features no bifurcation, nor increased rate of retreat, as the ice disappears. Nonetheless, the autocorrelation of summer sea ice area is found to increase in a global warming scenario. The variance, by contrast, decreases. A simple physical mechanism is proposed to explain the occurrence of increasing autocorrelation but not variance when there is no approaching bifurcation. Additionally, a similar mechanism is shown to allow an increase in both indicators with no physically attainable bifurcation. This implies that relying on autocorrelation and variance as early warning signals can raise false alarms in the climate system, warning of "tipping points" that are not actually there.

  19. Temporary conductive hearing loss in early life impairs spatial memory of rats in adulthood.

    PubMed

    Zhao, Han; Wang, Li; Chen, Liang; Zhang, Jinsheng; Sun, Wei; Salvi, Richard J; Huang, Yi-Na; Wang, Ming; Chen, Lin

    2018-05-31

    It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y-maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y-maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long-term potentiation and the reduced NMDA receptor-mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

  20. Analysis of Loss-of-Coolant Accidents in the NIST Research Reactor - Early Phase

    SciTech Connect

    Baek, Joo S.; Diamond, David

    A study of the fuel temperature during the early phase of a loss-of-coolant accident (LOCA) in the NIST research reactor (NBSR) was completed. Previous studies had been reported in the preliminary safety analysis report for the conversion of the NBSR from high-enriched uranium (HEU) fuel to low-enriched (LEU) fuel. Those studies had focused on the most vulnerable LOCA situation, namely, a double-ended guillotine break in the time period after reactor trip when water is drained from either the coolant channels inside the fuel elements or the region outside the fuel elements. The current study fills in a gap in themore » analysis which is the early phase of the event when there may still be water present but the reactor is at power or immediately after reactor trip and pumps have tripped. The calculations were done, for both the current HEU-fueled core and the proposed LEU core, with the TRACE thermal-hydraulic systems code. Several break locations and different break sizes were considered. In all cases the increase in the clad (or fuel meat) temperature was relatively small so that a large margin to the temperature threshold for blistering (the Safety Limit for the NBSR) remained.« less

  1. The sensitivity of harassment to orbit: mass loss from early-type dwarfs in galaxy clusters

    NASA Astrophysics Data System (ADS)

    Smith, R.; Sánchez-Janssen, R.; Beasley, M. A.; Candlish, G. N.; Gibson, B. K.; Puzia, T. H.; Janz, J.; Knebe, A.; Aguerri, J. A. L.; Lisker, T.; Hensler, G.; Fellhauer, M.; Ferrarese, L.; Yi, S. K.

    2015-12-01

    We conduct a comprehensive numerical study of the orbital dependence of harassment on early-type dwarfs consisting of 168 different orbits within a realistic, Virgo-like cluster, varying in eccentricity and pericentre distance. We find harassment is only effective at stripping stars or truncating their stellar discs for orbits that enter deep into the cluster core. Comparing to the orbital distribution in cosmological simulations, we find that the majority of the orbits (more than three quarters) result in no stellar mass loss. We also study the effects on the radial profiles of the globular cluster systems of early-type dwarfs. We find these are significantly altered only if harassment is very strong. This suggests that perhaps most early-type dwarfs in clusters such as Virgo have not suffered any tidal stripping of stars or globular clusters due to harassment, as these components are safely embedded deep within their dark matter halo. We demonstrate that this result is actually consistent with an earlier study of harassment of dwarf galaxies, despite the apparent contradiction. Those few dwarf models that do suffer stellar stripping are found out to the virial radius of the cluster at redshift = 0, which mixes them in with less strongly harassed galaxies. However when placed on phase-space diagrams, strongly harassed galaxies are found offset to lower velocities compared to weakly harassed galaxies. This remains true in a cosmological simulation, even when haloes have a wide range of masses and concentrations. Thus phase-space diagrams may be a useful tool for determining the relative likelihood that galaxies have been strongly or weakly harassed.

  2. Diffuse axonal injury by assault.

    PubMed

    Imajo, T; Challener, R C; Roessmann, U

    1987-09-01

    A case of diffuse axonal injury (DAI) by assault is reported. The majority of DAI cases documented have been due to traffic accidents and some due to falls from height. DAI is caused by angular or rotational acceleration of the victim's head. The condition is common and is the second most important head injury after subdural hematoma with regard to death. Its clinical picture is characterized by immediate and prolonged coma or demented state. Because of the subtle nature of histological changes in DAI, awareness and intentional search for the lesion is essential. The triad of DAI is as follows: focal lesions (hemorrhages and/or lacerations) in the corpus callosum and brain stem, and microscopic demonstration of axonal damage--retraction balls. The concept of DAI will elucidate and enhance the understanding of many head trauma cases.

  3. Dystrophic Serotonin Axons in Postmortem Brains from Young Autism Patients

    PubMed Central

    Azmitia, Efrain C.; Singh, Jorawer S.; Hou, Xiao P.; Wiegel, Jerzy

    2014-01-01

    Autism causes neuropathological changes in varied anatomical loci. A coherent neural mechanism to explain the spectrum of autistic symptomatology has not been proposed because most anatomical researchers focus on point-to-point functional neural systems (e.g. auditory, social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. Their cell bodies are found in the midbrain but they project their axons throughout the neural axis beginning in the fetal brain. This global system is implicated in autism by animal models and by biochemical, imaging, pharmacological, and genetics studies. However, no anatomical studies of the 5-HT innervation of autistic donors have been reported. Our review presents immunocytochemical evidence of an increase in 5-HT axons in post-mortem brain tissue from autism donors aged 2.8 to 29 years relative to controls. This increase is observed in the principle ascending fiber bundles of the medial and lateral forebrain bundles, and in the innervation density of the amygdala and the piriform, superior temporal, and parahippocampal cortices. In autistic donors eight years of age and up, several types of dystrophic 5-HT axons were seen in the termination fields. One class of these dystrophic axons, the thick heavily stained axons, was not seen in the brains of patients with neurodegenerative diseases. These findings provide morphological evidence for the involvement of serotonin neurons in the early etiology of autism, and suggest a diet therapy may be effective to blunt serotonin’s trophic actions during early brain development in children. PMID:21901837

  4. Dystrophic serotonin axons in postmortem brains from young autism patients.

    PubMed

    Azmitia, Efrain C; Singh, Jorawer S; Hou, Xiao P; Wegiel, Jerzy

    2011-10-01

    Autism causes neuropathological changes in varied anatomical loci. A coherent neural mechanism to explain the spectrum of autistic symptomatology has not been proposed because most anatomical researchers focus on point-to-point functional neural systems (e.g., auditory and social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. Disorders Research Program, AS073234, Program Project (JW). Their cell bodies are found in the midbrain but they project their axons throughout the neural axis beginning in the fetal brain. This global system is implicated in autism by animal models and by biochemical, imaging, pharmacological, and genetics studies. However, no anatomical studies of the 5-HT innervation of autistic donors have been reported. Our review presents immunocytochemical evidence of an increase in 5-HT axons in postmortem brain tissue from autism donors aged 2.8-29 years relative to controls. This increase is observed in the principle ascending fiber bundles of the medial and lateral forebrain bundles, and in the innervation density of the amygdala and the piriform, superior temporal, and parahippocampal cortices. In autistic donors 8 years of age and up, several types of dystrophic 5-HT axons were seen in the termination fields. One class of these dystrophic axons, the thick heavily stained axons, was not seen in the brains of patients with neurodegenerative diseases. These findings provide morphological evidence for the involvement of serotonin neurons in the early etiology of autism, and suggest new therapies may be effective to blunt serotonin's trophic actions during early brain development in children. Copyright © 2011 Wiley-Liss, Inc.

  5. N-acetyl-aspartate levels correlate with intra-axonal compartment parameters from diffusion MRI.

    PubMed

    Grossman, Elan J; Kirov, Ivan I; Gonen, Oded; Novikov, Dmitry S; Davitz, Matthew S; Lui, Yvonne W; Grossman, Robert I; Inglese, Matilde; Fieremans, Els

    2015-09-01

    Diffusion MRI combined with biophysical modeling allows for the description of a white matter (WM) fiber bundle in terms of compartment specific white matter tract integrity (WMTI) metrics, which include intra-axonal diffusivity (Daxon), extra-axonal axial diffusivity (De||), extra-axonal radial diffusivity (De┴), axonal water fraction (AWF), and tortuosity (α) of extra-axonal space. Here we derive these parameters from diffusion kurtosis imaging to examine their relationship to concentrations of global WM N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-Inositol (mI), as measured with proton MR spectroscopy ((1)H-MRS), in a cohort of 25 patients with mild traumatic brain injury (MTBI). We found statistically significant (p<0.05) positive correlations between NAA and Daxon, AWF, α, and fractional anisotropy; negative correlations between NAA and De,┴ and the overall radial diffusivity (D┴). These correlations were supported by similar findings in regional analysis of the genu and splenium of the corpus callosum. Furthermore, a positive correlation in global WM was noted between Daxon and Cr, as well as a positive correlation between De|| and Cho, and a positive trend between De|| and mI. The specific correlations between NAA, an endogenous probe of the neuronal intracellular space, and WMTI metrics related to the intra-axonal space, combined with the specific correlations of De|| with mI and Cho, both predominantly present extra-axonally, corroborate the overarching assumption of many advanced modeling approaches that diffusion imaging can disentangle between the intra- and extra-axonal compartments in WM fiber bundles. Our findings are also generally consistent with what is known about the pathophysiology of MTBI, which appears to involve both intra-axonal injury (as reflected by a positive trend between NAA and Daxon) as well as axonal shrinkage, demyelination, degeneration, and/or loss (as reflected by correlations between NAA and De

  6. Optic nerve axons and acquired alterations in the appearance of the optic disc.

    PubMed Central

    Wirtschafter, J D

    1983-01-01

    The pathophysiologic events in optic nerve axons have recently been recognized as crucial to an understanding of clinically significant acquired alterations in the ophthalmoscopic appearance of the optic disc. Stasis and related abnormalities of axonal transport appear to explain most aspects of optic nerve head swelling, including optic disc drusen and retinal cottonwool spots. Loss of axoplasm and axonal death can be invoked to interpret optic disc pallor, thinning and narrowing of rim tissue, changes in the size and outline of the optic cup, laminar dots, atrophy of the retinal nerve fiber layer, and acquired demyelination and myelination of the retinal nerve fiber layer. It is speculated that the axons may also play a role in the mechanical support of the lamina cribrosa in resisting the pressure gradient across the pars scleralis of the optic nerve head. Axons and their associated glial cells may be involved in those cases where "reversibility" of cupping of the optic disc has been reported. The structure, physiology, and experimental pathologic findings of the optic nerve head have been reviewed. Many aspects concerning the final anatomic appearance of the optic nerve head have been explained. However, many questions remain concerning the intermediate mechanisms by which increased intracranial pressure retards the various components of axonal transport in papilledema and by which increased IOP causes axonal loss in glaucoma. Investigation of the molecular biology of axonal constituents and their responses to abnormalities in their physical and chemical milieu could extend our understanding of the events that result from mechanical compression and local ischemia. Moreover, we have identified a need to further explore the role of axons in the pathophysiology of optic disc cupping. Images FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 11 FIGURE 12 FIGURE 13 PMID:6203209

  7. EARLY SENESCENCE1 Encodes a SCAR-LIKE PROTEIN2 That Affects Water Loss in Rice1[OPEN

    PubMed Central

    Rao, Yuchun; Yang, Yaolong; Xu, Jie; Li, Xiaojing; Leng, Yujia; Dai, Liping; Huang, Lichao; Shao, Guosheng; Ren, Deyong; Hu, Jiang; Guo, Longbiao; Pan, Jianwei; Zeng, Dali

    2015-01-01

    The global problem of drought threatens agricultural production and constrains the development of sustainable agricultural practices. In plants, excessive water loss causes drought stress and induces early senescence. In this study, we isolated a rice (Oryza sativa) mutant, designated as early senescence1 (es1), which exhibits early leaf senescence. The es1-1 leaves undergo water loss at the seedling stage (as reflected by whitening of the leaf margin and wilting) and display early senescence at the three-leaf stage. We used map-based cloning to identify ES1, which encodes a SCAR-LIKE PROTEIN2, a component of the suppressor of cAMP receptor/Wiskott-Aldrich syndrome protein family verprolin-homologous complex involved in actin polymerization and function. The es1-1 mutants exhibited significantly higher stomatal density. This resulted in excessive water loss and accelerated water flow in es1-1, also enhancing the water absorption capacity of the roots and the water transport capacity of the stems as well as promoting the in vivo enrichment of metal ions cotransported with water. The expression of ES1 is higher in the leaves and leaf sheaths than in other tissues, consistent with its role in controlling water loss from leaves. GREEN FLUORESCENT PROTEIN-ES1 fusion proteins were ubiquitously distributed in the cytoplasm of plant cells. Collectively, our data suggest that ES1 is important for regulating water loss in rice. PMID:26243619

  8. Prevalence of early loss of primary teeth in 5-10-year-old school children in Chidambaram town.

    PubMed

    Ahamed, S Syed Shaheed; Reddy, Venugopal N; Krishnakumar, R; Mohan, Muthu G; Sugumaran, Durai K; Rao, Arun P

    2012-01-01

    The premature loss of primary teeth may reduce arch length required for the succeeding tooth and, hence, predisposes crowding, rotation and impaction of the permanent teeth. There are only limited studies carried out about the prevalence of early loss of primary teeth. The present study was performed to evaluate the prevalence of early loss of primary teeth in school children in Chidambaram town in Tamilnadu, India. A total of 1121 school children (561 boys and 560 girls) between 5 and 10 years of age were selected for the study. An experienced examiner performed all clinical examinations under natural light. Data including age and missing tooth was collected. Microsoft Excel/2000 (Microsoft Office XP) data spreadsheet was used and later exported to the Statistical Package for Social Science (SPSS) for Windows (version 10.0). Descriptive statistics was applied and, from the results, chi-square tests were applied at a level of significance of 5% (P < 0.05). The results showed that 16.5% of the sample had early loss of primary teeth, but no differences were observed between genders (P > 0.05). The greatest prevalence was found among the 8-year olds (5.08%), and the most commonly missing teeth were the right lower primary first molars (16.82%). It can be concluded that the prevalence of early loss was high and that the lower primary molars were the most commonly missing teeth in the present study.

  9. Co-Localization of Sodium Channel Na[v]1.6 and the Sodium--Calcium Exchanger at Sites of Axonal Injury in the Spinal Cord in EAE

    ERIC Educational Resources Information Center

    Craner, Matthew J.; Hains, Bryan C.; Lo, Albert C.; Black, Joel A.; Waxman, Stephen G.

    2004-01-01

    Axonal degeneration contributes to the development of non-remitting neurological deficits and disability in multiple sclerosis, but the molecular mechanisms that underlie axonal loss in multiple sclerosis are not clearly understood. Studies of white matter axonal injury have demonstrated that voltage-gated sodium channels can provide a route for…

  10. Amyloid-β expression in retrosplenial cortex of 3xTg-AD mice: relationship to cholinergic axonal afferents from medial septum

    PubMed Central

    Robertson, Richard T.; Baratta, Janie; Yu, Jen; LaFerla, Frank M.

    2009-01-01

    Triple transgenic (3xTg-AD) mice harboring the presenilin 1, amyloid precursor protein, and tau transgenes (Oddo et al., 2003) display prominent levels of amyloid-beta (Aβ) immunoreactivity in forebrain regions. The Aβ immunoreactivity is first seen intracellularly in neurons and later as extracellular plaque deposits. The present study examined Aβ immunoreactivity that occurs in layer III of the granular division of retrosplenial cortex (RSg). This pattern of Aβ immunoreactivity in layer III of RSg develops relatively late, and is seen in animals older than 14 mo. The appearance of the Aβ immunoreactivity is similar to an axonal terminal field and thus may offer a unique opportunity to study the relationship between afferent projections and the formation of Aβ deposits. Axonal tract tracing techniques demonstrated that the pattern of axon terminal labeling in layer III of RSg, following placement of DiI in medial septum, is remarkably similar to the pattern of cholinergic axons in RSg, as detected by acetylcholinesterase histochemical staining, choline acetyltransferase immunoreactivity, or p75 receptor immunoreactivity; this pattern also is strikingly similar to the band of Aβ immunoreactivity. In animals sustaining early damage to the medial septal nucleus (prior to the advent of Aβ immunoreactivity), the band of Aβ in layer III of RSg does not develop; the corresponding band of cholinergic markers also is eliminated. In older animals (after the appearance of the Aβ immunoreactivity) damage to cholinergic afferents by electrolytic lesions, immunotoxin lesions, or cutting the cingulate bundle, result in a rapid loss of the cholinergic markers and a slower reduction of Aβ immunoreactivity. These results suggest that the septal cholinergic axonal projections transport Aβ or APP to layer III of RSg. PMID:19772895

  11. Continuation of metformin reduces early pregnancy loss in obese Pakistani women with polycystic ovarian syndrome.

    PubMed

    Nawaz, Fauzia Haq; Rizvi, Javed

    2010-01-01

    Polycystic ovarian syndrome (PCOS) is the most common cause of anovulatory infertility worldwide. In addition to a poor conception rate, pregnancy loss rates are significantly higher (30-50%) during the first trimester in women with PCOS. Insulin resistance (IR) in this syndrome is not only implicated toward early pregnancy loss (EPL) but also pathognomic for various obstetrical complications during pregnancy. We evaluated the role of Metformin in the reduction of EPL in women with PCOS who conceived spontaneously or after induction ovulation with or without Metformin. The primary objective was to evaluate the effectiveness of Metformin in the reduction of EPL in women with PCOS. Secondary outcomes like gestational diabetes, pregnancy-induced hypertension and intrauterine growth restriction were also analyzed at the end of the study. This case-control study was conducted from March 2005 to March 2008 in the infertility and antenatal clinics of the Department of Obstetrics and Gynecology of Aga Khan University Hospital, Karachi, Pakistan. A total of 197 infertile women with PCOS were included. 'Cases' were women with PCOS who conceived while taking Metformin and it whom it was continued throughout pregnancy. 'Controls' were women in whom Metformin was either stopped in first trimester after confirmation of pregnancy (by serum betaHCG or by ultrasound) or they conceived spontaneously without the use of Metformin. All 197 women in this study had a confirmed diagnosis of PCOS (Rotterdam criteria). These women were followed till the final outcome of pregnancy was achieved. Both groups were compared for risk of EPL. It was found that continuation of Metformin during pregnancy reduces EPL, i.e. 8.8 vs. 29.4% in cases and controls, respectively (p < 0.001). In the subset of women with a prior history of miscarriage, the pregnancy loss rate was 12.5% in the Metformin versus 49.4% in control group (p = 0.002). Metformin continuation during pregnancy significantly reduces EPL

  12. Effect of alendronate on early bone loss of renal transplant recipients.

    PubMed

    Abediazar, S; Nakhjavani, M R

    2011-03-01

    Renal transplant recipients (RTRs) are at risk of developing osteoporosis and osteopenia due to underlying renal osteodystrophy, hypophosphatemia, and immunosuppression. This process occurs more frequently in the first year after renal transplantation (RTX), resulting in eventual bone loss and fractures. The purpose of this study was to evaluate the effect of low-dose alendronate to prevent early bone loss after RTX. We prospectively studied 43 successful RTR including 22 men and 21-women with a mean overall age of 39.16±11.73 years, mean body mass index of 23.6±3.73, and mean dialysis duration of 25.73±17.67 months. We matched them based on age and sex: the alendronate-treated group received vitamin D (Vit D) during the study plus 30 mg alendronate weekly from 1 month after RTX. The control group only received Vit D. We measured serum calcium, phosphate, alkaline phosphatase, blood urea, creatinine, and intact parathyroid hormone (iPTH) at the pretransplant baseline and monthly thereafter as well as BMD of the lumbar spine, femur, and radius pretransplant baseline versus 3 and 6 months after RTX. At 6 month after RTX, the lumbar BMD in the alendronate group increased significantly from 0.819±0.11 to 0.863±0.14 (P<.01), while it decreased in the control group from 0.897±0.17 to 0.817±0.16 (P<.001). There was also a significant increase in radius BMD (P<.001) and a nonsignificant increase in femoral BMD in the alendronate versus a significant decrease of femoral and radius BMD (P<.001) in the control group at 6 months. Upon multivariate analysis, there was a significant correlation between alendronate and spine BMD (r=.45, P<.001) but no linear regression between age, sex, BMI, dialysis duration of or iPTH with femoral, spine, or radius BMD changes at month 6. Low-dose alendronate was significantly useful to mitigate fast bone loss and increase BMD immediately after RTX. Copyright © 2011. Published by Elsevier Inc.

  13. Cell intrinsic control of axon regeneration

    PubMed Central

    Mar, Fernando M; Bonni, Azad; Sousa, Mónica M

    2014-01-01

    Although neurons execute a cell intrinsic program of axonal growth during development, following the establishment of connections, the developmental growth capacity declines. Besides environmental challenges, this switch largely accounts for the failure of adult central nervous system (CNS) axons to regenerate. Here, we discuss the cell intrinsic control of axon regeneration, including not only the regulation of transcriptional and epigenetic mechanisms, but also the modulation of local protein translation, retrograde and anterograde axonal transport, and microtubule dynamics. We further explore the causes underlying the failure of CNS neurons to mount a vigorous regenerative response, and the paradigms demonstrating the activation of cell intrinsic axon growth programs. Finally, we present potential mechanisms to support axon regeneration, as these may represent future therapeutic approaches to promote recovery following CNS injury and disease. PMID:24531721

  14. Axonal/Glial Upregulation of EphB/ephrin-B Signaling in Mouse Experimental Ocular Hypertension

    PubMed Central

    Tran, Tony; Sretavan, David

    2010-01-01

    Purpose. To use a laser-induced ocular hypertension (LIOH) mouse model to examine the optic nerve head (ONH) expression of EphB/ephrin-B, previously shown to be upregulated in glaucomatous DBA/2J mice. To relate ephrin-B reverse signaling with states of axonal response to disease. Methods. LIOH was induced unilaterally in CD-1 mice by laser photocoagulation of limbal and episcleral veins. Intraocular pressure (IOP) was measured with a tonometer. EphB/ephrin-B mRNA expression was assessed by in situ hybridization on eyecup cryosections and real-time PCR. Cell specific markers were used to identify the cellular origin of EphB/ephrin-B expression. Activation of ephrin-B signaling was investigated with a phosphospecific antibody on cryosections and retinal whole-mounts. Results. Upregulation of EphB/ephrin-B expression occurred early within a day of IOP elevation. A transient increase of phosphorylation-dependent ephrin-B (pEB) reverse signaling was observed in ONH axons, microglia, and some astrocytes. Morphologically unaffected retinal ganglion cell (RGC) axons differed from axons with reactive aberrant trajectories by exhibiting increased pEB activation, whereas pEB levels in morphologically affected axons were comparable to those of controls. Conclusions. An Eph-ephrin signaling network is activated at the ONH after LIOH in CD-1 mice, either before or coincident with the initial morphologic signs of RGC axon damage reported previously. Of note, ephrin-B reverse signaling was transiently upregulated in RGC axons at the ONH early in their response to IOP elevation but was downregulated in axons that had been damaged by glaucomatous injury and exhibited aberrant trajectories. Ephrin-B reverse signaling may mark RGC axons for damage or confer a protective advantage against injury. PMID:19815726

  15. Maternal serum amyloid A level as a novel marker of primary unexplained recurrent early pregnancy loss.

    PubMed

    Ibrahim, Moustafa I; Ramy, Ahmed R; Abdelhamid, Ahmed S; Ellaithy, Mohamed I; Omar, Amna; Harara, Rany M; Fathy, Hayam; Abolouz, Ashraf S

    2017-03-01

    To assess maternal serum amyloid A (SAA) levels among women with primary unexplained recurrent early pregnancy loss (REPL). A prospective study was conducted among women with missed spontaneous abortion in the first trimester at Ain Shams University Maternity Hospital, Cairo, Egypt, between January 21 and December 25, 2014. Women with at least two consecutive primary unexplained REPLs and no previous live births were enrolled. A control group was formed of women with no history of REPL who had at least one previous uneventful pregnancy with no adverse outcomes. Serum samples were collected to measure SAA levels. The main outcome was the association between SAA and primary unexplained REPL. Each group contained 96 participants. Median SAA level was significantly higher among women with REPL (50.0 μg/mL, interquartile range 26.0-69.0) than among women in the control group (11.6 μg/mL, interquartile range 6.2-15.5; P<0.001). The SAA level was an independent indicator of primary unexplained REPL, after adjusting for maternal age and gestational age (odds ratio 1.12, 95% confidence interval 1.06-1.19; P<0.001). Elevated SAA levels found among women with primary unexplained REPL could represent a novel biomarker for this complication of pregnancy. © 2016 International Federation of Gynecology and Obstetrics.

  16. Beyond usual care: the economic consequences of expanding treatment options in early pregnancy loss.

    PubMed

    Dalton, Vanessa K; Liang, Angela; Hutton, David W; Zochowski, Melissa K; Fendrick, A Mark

    2015-02-01

    The objective of this study was to estimate the economic consequences of expanding options for early pregnancy loss (EPL) treatment beyond expectant management and operating room surgical evacuation (usual care). We constructed a decision model using a hypothetical cohort of women undergoing EPL management within a 30 day horizon. Treatment options under the usual care arm include expectant management and surgical uterine evacuation in an operating room (OR). Treatment options under the expanded care arm included all evidence-based safe and effective treatment options for EPL: expectant management, misoprostol treatment, surgical uterine evacuation in an office setting, and surgical uterine evacuation in an OR. Probabilities of entering various treatment pathways were based on previously published observational studies. The cost per case was US $241.29 lower for women undergoing treatment in the expanded care model as compared with the usual care model (US $1033.29 per case vs US $1274.58 per case, expanded care and usual care, respectively). The model was the most sensitive to the failure rate of the expectant management arm, the cost of the OR surgical procedure, the proportion of women undergoing an OR surgical procedure under usual care, and the additional cost per patient associated with implementing and using the expanded care model. This study demonstrates that expanding women's treatment options for EPL beyond what is typically available can result in lower direct medical expenditures. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Evaluation of early fetal loss induced by gavage with eastern tent caterpillars in pregnant mares.

    PubMed

    Bernard, William V; LeBlanc, Michelle M; Webb, Bruce A; Stromberg, Arnold J

    2004-09-01

    To determine whether gavage of pregnant mares (housed without access to pasture) with starved eastern tent caterpillars (ETCs) or their excreta is associated with early fetal loss (EFL), panophthalmitis, or pericarditis. Randomized clinical trial. 15 mares. 15 mares with fetuses from 40 to 80 days of gestation (dGa) were randomly assigned to 1 of 3 groups and received 2.5 g of ETC excreta, 50 g of starved ETCs, or 500 mL of water, respectively, once daily for 10 days. Mares were housed in box stalls, walked twice daily, and not allowed access to pasture for 12 days before or during the 21-day trial. 4 of 5 mares gavaged with starved ETCs (group 2) aborted on trial days 8 (2 mares), 10, and 13. No control mares or mares that received excreta aborted. Differences between the ETC group and other groups were significant. Abortion occurred on 49, 64, 70, and 96 dGa. Allantoic fluids became hyperechoic the day before or the day of fetal death. Alpha streptococci were recovered from 1 fetus and Serratia marcescens from 3 fetuses. Neither panophthalmitis nor pericarditis was seen. The abortifacient component of the ETCs was not elucidated. These findings suggest that mares with fetuses from 40 to 120 days of gestation should not be exposed to ETCs because they may induce abortion.

  18. [Compliance with current standards for the early detection of neonatal hearing loss].

    PubMed

    Rojas-Godoy, Andrea L; Gómez-Gómez, Olga; Rivas-Muñoz, Fabio A

    2014-01-01

    Assessing compliance with the section "Assessment of hearing" stipulated in the Technical Standard to Detect Alteration in children aged less than 10 years-old in Bogota. This was a cross-sectional study which involved reviewing the medical records of all children born between July 1st and December 31st 2010 in two healthcare institutions in Bogota. Records were selected in which any of the following risk factors appeared: neonatal hyperbilirubinaemia involving phototherapy, neonatal exposure to ototoxic substances and/or <1.500 gr low birth weight. It was also ascertained whether children had been referred to an auditory evoked potential test as the prescribed screening test for neonatal hearing, as stipulated in mandatory Colombian technical standards for detecting abnormal growth and developmental in children aged less than ten years-old. Neither of the two institutions was making the aforementioned referral test. The results indicated significant difficulties in adherence to the protocol for the early detection of hearing loss regarding pertinent/current neonatal Colombian regulations.

  19. Delayed diagnosis of childhood deafness: the value of false negatives in the Programme for Early Detection of Neonatal Hearing Loss.

    PubMed

    Martínez-Pacheco, María C; Ferrán de la Cierva, Luis; García-Purriños, Francisco J

    Despite its importance, the existence of false negatives (patients who are told they hear well, but they have some degree of hipacusia) is rarely evaluated in programs for early detection of hearing loss. The aim of this study is to determine the variables that can lead to a delayed diagnosis, especially the existence of false negatives and the lack of registration of risk factors. A retrospective study of prevalence has been carried out, in which the medical records of children diagnosed with sensorineural hearing loss born within 2005 and 2012 in the health centers of study have been analyzed. Of the 32 children with sensorineural hearing loss, 16 passed the OAE, 12 did not passed the OAE, and in four they were not carried out. Of the children who passed the OAE, 57% have severe hearing loss. 66% of children with hearing loss presented a risk factor for hearing loss at birth, being the most frecuent family history of hearing loss, but only 7% of those with family history of hearing loss were included in the risk group. The results of the study indicate that the late diagnosis of hearing loss is related to the presence of false negatives to the OAE and the non-registration of risk factors. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

  20. Prospective assessment of early fetal loss using an immunoenzymometric screening assay for detection of urinary human chorionic gonadotropin.

    PubMed

    Taylor, C A; Overstreet, J W; Samuels, S J; Boyers, S P; Canfield, R E; O'Connor, J F; Hanson, F W; Lasley, B L

    1992-06-01

    To develop an economical, nonradiometric immunoenzymometric assay (IEMA) for the detection of urinary human chorionic gonadotropin (hCG) in studies of early fetal loss. To be effective, the IEMA must have a sensitivity equal to the standard immunoradiometric assay (IRMA) and sufficient specificity to eliminate the need for screening most nonconceptive cycles with the expensive and labor-intensive IRMA. Two different assays were used to measure hCG in daily early morning urine samples from potential conceptive cycles. Women undergoing donor artificial insemination (AI) were evaluated in a prospective study. Ninety-two women volunteers were selected on the basis of apparent normal reproductive health. Artificial insemination with nonfrozen donor semen was performed by cervical cup twice each menstrual cycle at 48-hour intervals, and daily urine samples were self-collected throughout the menstrual cycle. An IEMA was developed to detect urinary hCG using the same antibodies as in the standard IRMA; a study was designed to determine whether this nonradiometric assay could successfully detect the early fetal loss that was detected by the IRMA. Of 224 menstrual cycles analyzed by both assays, a total of six early fetal losses were detected by the IRMA. When the tentative screening rule was set to allow all six of these losses and 95% of future losses to be detected by the IEMA, an additional 34 false-positive results were detected by the IEMA. The specificity of the IEMA with this rule was calculated to be 84%. An IEMA based on the same antibodies used for the standard IRMA can serve as an efficient screening assay for the detection of early fetal loss. When the IEMA is used in this manner, nearly 80% of screened menstrual cycles can be eliminated without further testing by the IRMA.

  1. Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS-1 cohort.

    PubMed

    Wills, Anne-Marie; Li, Ruosha; Pérez, Adriana; Ren, Xuehan; Boyd, James

    2017-08-01

    Weight loss is a common symptom of Parkinson's disease and is associated with impaired quality of life. Predictors of weight loss have not been studied in large clinical cohorts. We previously observed an association between change in body mass index and change in Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores. In this study, we performed a secondary analysis of longitudinal data (1-6 years) from 1619 participants in the NINDS Exploratory Trials in PD Long-term Study-1 (NET-PD LS1) to explore predictors of weight loss in a large prospective clinical trial cohort of early treated Parkinson's disease. The NET-PD LS1 study was a double-blind randomized placebo controlled clinical trial of creatine monohydrate 10 gm/day in early treated PD (within 5 years of diagnosis and within 2 years of starting dopaminergic medications). Linear mixed models were used to estimate the effect of baseline clinical covariates on weight change over time. On average, participants lost only 0.6 kg per year. Higher age, baseline weight, female gender, higher baseline UPDRS scores, greater postural instability, difficulty eating and drinking, lower cognitive scores and baseline levodopa use (compared to dopamine agonists) were all associated with weight loss. Surprisingly baseline difficulty swallowing, dyskinesia, depression, intestinal hypomotility (constipation) and self-reported nausea/vomiting/anorexia were not significantly associated with weight loss in this cohort of early treated Parkinson's disease patients. On average, participants with Parkinson's disease experience little weight loss during the first 1-6 years after starting dopaminergic replacement therapy, however levodopa use and postural instability were both predictors of early weight loss. Trial Registration clinicaltrials.gov identifier# NCT00449865.

  2. GDF10 Is a Signal for Axonal Sprouting and Functional Recovery after Stroke

    PubMed Central

    Li, S; Nie, EH; Yin, Y; Benowitz, LI; Tung, S; Vinters, HV; Bahjat, FR; Stenzel-Poore, MP; Kawaguchi, R; Coppola, G; Carmichael, ST

    2016-01-01

    Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and Differentiation Factor 10 (GDF10) is induced in peri-infarct neurons in mouse, non-human primate and human. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGFβRI/II signaling. Using pharmacogenetic gain and loss of function studies, GDF10 produces axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocks axonal sprouting and reduces recovery. RNA-seq from peri-infarct cortical neurons indicates that GDF10 downregulates PTEN and upregulates PI3 kinase signaling and induces specific axonal guidance molecules. Unsupervised genome-wide association analysis of the GDF10 transcriptome shows that it is not related to neurodevelopment but may partially overlap with other CNS injury patterns. GDF10 is a stroke-induced signal for axonal sprouting and functional recovery. PMID:26502261

  3. Jab1 regulates Schwann cell proliferation and axonal sorting through p27

    PubMed Central

    Porrello, Emanuela; Rivellini, Cristina; Dina, Giorgia; Triolo, Daniela; Del Carro, Ubaldo; Ungaro, Daniela; Panattoni, Martina; Feltri, Maria Laura; Wrabetz, Lawrence; Pardi, Ruggero; Quattrini, Angelo

    2014-01-01

    Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211– and, possibly, neuregulin 1 (Nrg1)–derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain–binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies. PMID:24344238

  4. Chromosome 3p allele loss in early invasive breast cancer: detailed mapping and association with clinicopathological features

    PubMed Central

    Martinez, A; Walker, R A; Shaw, J A; Dearing, S J; Maher, E R; Latif, F

    2001-01-01

    Aims—Chromosome 3p allele loss is a frequent event in many common sporadic cancers including lung, breast, kidney, ovarian, and head and neck cancer. To analyse the extent and frequency of 3p allelic losses in T1N0 and T1N1 invasive sporadic breast cancer, 19 microsatellite markers spread along 3p were analysed in 40 such breast carcinomas with known clinicopathological parameters. Methods—Loss of heterozygosity analysis was carried out using 3p microsatellite markers that were non-randomly distributed and chosen to represent regions that show hemizygous and/or homozygous losses in lung cancer (lung cancer tumour suppressor gene region 1 ( LCTSGR1) at 3p21.3 and LCTSGR2 at 3p12), and regions demonstrating suppression of tumorigenicity in breast, kidney, lung, and ovarian cancer. Results—Allelic loss was seen at one or more loci in 22 of these clinically early stage sporadic breast tumours, but none had complete 3p allele loss. Several regions with non-overlapping deletions were defined, namely: (1) 18 tumours showed loss at 3p21–22, a physical distance of 12 Mb; (2) 11 tumours showed loss at 3p12 within a physical distance of 1 Mb, this region is contained within LCTSGR2; (3) six tumours showed loss at 3p25–24, including the von Hippel-Lindau (VHL) locus; (4) five tumours showed loss at 3p14.2, including the fragile histidine triad (FHIT) locus. Conclusions—This is the largest study to date defining the extent and range of 3p allelic losses in early stage invasive breast cancer and the results indicate that region 3p21–22 containing LCTSGR1 and a region at 3p12 within LCTSGR2 are the most frequent sites of 3p allelic loss in these breast carcinomas. This suggests that tumour suppressor genes located in these regions may play important roles in the development of breast cancer. There was an association between increasing 3p allelic loss and increasing tumour grade and loss of progesterone (p = 0.0098) and oestrogen (p = 0.0472) receptor expression

  5. Chromosome 3p allele loss in early invasive breast cancer: detailed mapping and association with clinicopathological features.

    PubMed

    Martinez, A; Walker, R A; Shaw, J A; Dearing, S J; Maher, E R; Latif, F

    2001-10-01

    Chromosome 3p allele loss is a frequent event in many common sporadic cancers including lung, breast, kidney, ovarian, and head and neck cancer. To analyse the extent and frequency of 3p allelic losses in T1N0 and T1N1 invasive sporadic breast cancer, 19 microsatellite markers spread along 3p were analysed in 40 such breast carcinomas with known clinicopathological parameters. Loss of heterozygosity analysis was carried out using 3p microsatellite markers that were non-randomly distributed and chosen to represent regions that show hemizygous and/or homozygous losses in lung cancer (lung cancer tumour suppressor gene region 1 ( LCTSGR1) at 3p21.3 and LCTSGR2 at 3p12), and regions demonstrating suppression of tumorigenicity in breast, kidney, lung, and ovarian cancer. Allelic loss was seen at one or more loci in 22 of these clinically early stage sporadic breast tumours, but none had complete 3p allele loss. Several regions with non-overlapping deletions were defined, namely: (1) 18 tumours showed loss at 3p21-22, a physical distance of 12 Mb; (2) 11 tumours showed loss at 3p12 within a physical distance of 1 Mb, this region is contained within LCTSGR2; (3) six tumours showed loss at 3p25-24, including the von Hippel-Lindau (VHL) locus; (4) five tumours showed loss at 3p14.2, including the fragile histidine triad (FHIT) locus. This is the largest study to date defining the extent and range of 3p allelic losses in early stage invasive breast cancer and the results indicate that region 3p21-22 containing LCTSGR1 and a region at 3p12 within LCTSGR2 are the most frequent sites of 3p allelic loss in these breast carcinomas. This suggests that tumour suppressor genes located in these regions may play important roles in the development of breast cancer. There was an association between increasing 3p allelic loss and increasing tumour grade and loss of progesterone (p = 0.0098) and oestrogen (p = 0.0472) receptor expression, indicating a link between 3p allelic loss and the

  6. Axonal regeneration in zebrafish spinal cord

    PubMed Central

    Hui, Subhra Prakash

    2018-01-01

    Abstract In the present review we discuss two interrelated events—axonal damage and repair—known to occur after spinal cord injury (SCI) in the zebrafish. Adult zebrafish are capable of regenerating axonal tracts and can restore full functionality after SCI. Unlike fish, axon regeneration in the adult mammalian central nervous system is extremely limited. As a consequence of an injury there is very little repair of disengaged axons and therefore functional deficit persists after SCI in adult mammals. In contrast, peripheral nervous system axons readily regenerate following injury and hence allow functional recovery both in mammals and fish. A better mechanistic understanding of these three scenarios could provide a more comprehensive insight into the success or failure of axonal regeneration after SCI. This review summarizes the present understanding of the cellular and molecular basis of axonal regeneration, in both the peripheral nervous system and the central nervous system, and large scale gene expression analysis is used to focus on different events during regeneration. The discovery and identification of genes involved in zebrafish spinal cord regeneration and subsequent functional experimentation will provide more insight into the endogenous mechanism of myelination and remyelination. Furthermore, precise knowledge of the mechanism underlying the extraordinary axonal regeneration process in zebrafish will also allow us to unravel the potential therapeutic strategies to be implemented for enhancing regrowth and remyelination of axons in mammals. PMID:29721326

  7. Axonal regeneration in zebrafish spinal cord.

    PubMed

    Ghosh, Sukla; Hui, Subhra Prakash

    2018-03-01

    In the present review we discuss two interrelated events-axonal damage and repair-known to occur after spinal cord injury (SCI) in the zebrafish. Adult zebrafish are capable of regenerating axonal tracts and can restore full functionality after SCI. Unlike fish, axon regeneration in the adult mammalian central nervous system is extremely limited. As a consequence of an injury there is very little repair of disengaged axons and therefore functional deficit persists after SCI in adult mammals. In contrast, peripheral nervous system axons readily regenerate following injury and hence allow functional recovery both in mammals and fish. A better mechanistic understanding of these three scenarios could provide a more comprehensive insight into the success or failure of axonal regeneration after SCI. This review summarizes the present understanding of the cellular and molecular basis of axonal regeneration, in both the peripheral nervous system and the central nervous system, and large scale gene expression analysis is used to focus on different events during regeneration. The discovery and identification of genes involved in zebrafish spinal cord regeneration and subsequent functional experimentation will provide more insight into the endogenous mechanism of myelination and remyelination. Furthermore, precise knowledge of the mechanism underlying the extraordinary axonal regeneration process in zebrafish will also allow us to unravel the potential therapeutic strategies to be implemented for enhancing regrowth and remyelination of axons in mammals.

  8. Early consumption of blueberry diet protects against sex steroid deficiency-induced bone loss in adult female rats

    USDA-ARS?s Scientific Manuscript database

    We studied the effects of blueberry consumption in early development on bone loss in ovariectomized (OVX) female rats later in life. Weanling female rats were fed AIN-93G semi-purified diets supplemented with 10% whole blueberry powder from PND 21 to PND34 (short-term group), or PND21 to PND81 (chro...

  9. Action Potential Dynamics in Fine Axons Probed with an Axonally Targeted Optical Voltage Sensor.

    PubMed

    Ma, Yihe; Bayguinov, Peter O; Jackson, Meyer B

    2017-01-01

    The complex and malleable conduction properties of axons determine how action potentials propagate through extensive axonal arbors to reach synaptic terminals. The excitability of axonal membranes plays a major role in neural circuit function, but because most axons are too thin for conventional electrical recording, their properties remain largely unexplored. To overcome this obstacle, we used a genetically encoded hybrid voltage sensor (hVOS) harboring an axonal targeting motif. Expressing this probe in transgenic mice enabled us to monitor voltage changes optically in two populations of axons in hippocampal slices, the large axons of dentate granule cells (mossy fibers) in the stratum lucidum of the CA3 region and the much finer axons of hilar mossy cells in the inner molecular layer of the dentate gyrus. Action potentials propagated with distinct velocities in each type of axon. Repetitive firing broadened action potentials in both populations, but at an intermediate frequency the degree of broadening differed. Repetitive firing also attenuated action potential amplitudes in both mossy cell and granule cell axons. These results indicate that the features of use-dependent action potential broadening, and possible failure, observed previously in large nerve terminals also appear in much finer unmyelinated axons. Subtle differences in the frequency dependences could influence the propagation of activity through different pathways to excite different populations of neurons. The axonally targeted hVOS probe used here opens up the diverse repertoire of neuronal processes to detailed biophysical study.

  10. Glia initiate brain assembly through non-canonical Chimaerin/Furin axon guidance in C. elegans

    PubMed Central

    Rapti, Georgia; Li, Chang; Shan, Alan; Lu, Yun; Shaham, Shai

    2017-01-01

    Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet pioneer-neuron identities, their guidance substrates, and their interactions, are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans glia are key for assembly initiation, guiding pioneer and follower axons using distinct signals. Pioneer sublateral neurons, with unique growth properties, anatomy, and innervation, cooperate with glia to mediate follower-axon guidance. We further identify a CHIN-1/Chimaerin-KPC-1/Furin double mutant that severely disrupts assembly. CHIN-1/Chimaerin and KPC-1/Furin function non-canonically in glia and pioneer neurons for guidance-cue trafficking. We exploit this bottleneck to define roles for glial Netrin and Semaphorin in pioneer- and follower-axon guidance, respectively, and for glial and pioneer-neuron Flamingo/CELSR in follower-axon navigation. Altogether, our studies reveal previously-unknown glial roles in pioneer-axon guidance, suggesting conserved brain-assembly principles. PMID:28846083

  11. Calpain-mediated cleavage of collapsin response mediator protein-2 drives acute axonal degeneration

    PubMed Central

    Zhang, Jian-Nan; Michel, Uwe; Lenz, Christof; Friedel, Caroline C.; Köster, Sarah; d’Hedouville, Zara; Tönges, Lars; Urlaub, Henning; Bähr, Mathias; Lingor, Paul; Koch, Jan C.

    2016-01-01

    Axonal degeneration is a key initiating event in many neurological diseases. Focal lesions to axons result in a rapid disintegration of the perilesional axon by acute axonal degeneration (AAD) within several hours. However, the underlying molecular mechanisms of AAD are only incompletely understood. Here, we studied AAD in vivo through live-imaging of the rat optic nerve and in vitro in primary rat cortical neurons in microfluidic chambers. We found that calpain is activated early during AAD of the optic nerve and that calpain inhibition completely inhibits axonal fragmentation on the proximal side of the crush while it attenuates AAD on the distal side. A screening of calpain targets revealed that collapsin response mediator protein-2 (CRMP2) is a main downstream target of calpain activation in AAD. CRMP2-overexpression delayed bulb formation and rescued impairment of axonal mitochondrial transport after axotomy in vitro. In vivo, CRMP2-overexpression effectively protected the proximal axon from fragmentation within 6 hours after crush. Finally, a proteomic analysis of the optic nerve was performed at 6 hours after crush, which identified further proteins regulated during AAD, including several interactors of CRMP2. These findings reveal CRMP2 as an important mediator of AAD and define it as a putative therapeutic target. PMID:27845394

  12. Degenerative alterations of the cementum-periodontal ligament complex and early tooth loss in a young patient with periodontal disease.

    PubMed

    Petruţiu, S A; Buiga, Petronela; Roman, Alexandra; Danciu, Theodora; Mihu, Carmen Mihaela; Mihu, D

    2012-01-01

    Premature exfoliation of primary or permanent teeth in children or adolescents is extremely rare and it can be a manifestation of an underlying systemic disease. This study aims to present the histological aspects associated with early tooth loss in a case of periodontal disease developed without local inflammation and with minimal periodontal pockets and attachment loss. The maxillary left second premolar was extracted together with a gingival collar attached to the root surface. The histological analysis recorded the resorption of the cementum in multiple areas of the entire root surface with the connective tissue of the desmodontium invading the lacunae defects. The connective tissue rich in cells occupied the periodontal ligamentar space and the resorptive areas. No inflammation was obvious in the periodontal ligament connective tissue. This report may warn clinicians about the possibility of the association of cemental abnormalities with early tooth loss.

  13. Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx

    PubMed Central

    Yamagishi, Yuya; Tessier-Lavigne, Marc

    2015-01-01

    Calcium is a key regulator of axon degeneration caused by trauma and disease, but its specific spatial and temporal dynamics in injured axons remain unclear. To clarify the function of calcium in axon degeneration, we observed calcium dynamics in single injured neurons in live zebrafish larvae and tested the temporal requirement for calcium in zebrafish neurons and cultured mouse DRG neurons. Using laser axotomy to induce Wallerian degeneration (WD) in zebrafish peripheral sensory axons, we monitored calcium dynamics from injury to fragmentation, revealing two stereotyped phases of axonal calcium influx. First, axotomy triggered a transient local calcium wave originating at the injury site. This initial calcium wave only disrupted mitochondria near the injury site and was not altered by expression of the protective WD slow (WldS) protein. Inducing multiple waves with additional axotomies did not change the kinetics of degeneration. In contrast, a second phase of calcium influx occurring minutes before fragmentation spread as a wave throughout the axon, entered mitochondria, and was abolished by WldS expression. In live zebrafish, chelating calcium after the first wave, but before the second wave, delayed the progress of fragmentation. In cultured DRG neurons, chelating calcium early in the process of WD did not alter degeneration, but chelating calcium late in WD delayed fragmentation. We propose that a terminal calcium wave is a key instructive component of the axon degeneration program. SIGNIFICANCE STATEMENT Axon degeneration resulting from trauma or neurodegenerative disease can cause devastating deficits in neural function. Understanding the molecular and cellular events that execute axon degeneration is essential for developing treatments to address these conditions. Calcium is known to contribute to axon degeneration, but its temporal requirements in this process have been unclear. Live calcium imaging in severed zebrafish neurons and temporally controlled

  14. Optic nerve head axonal transport in rabbits with hereditary glaucoma.

    PubMed

    Bunt-Milam, A H; Dennis, M B; Bensinger, R E

    1987-04-01

    transport as occurs in the LS of the monkey and cat ONH when IOP is elevated acutely. This anatomic difference appears to be protective against axonal damage, since bu/bu rabbits with chronic IOP elevation did not show significant loss of optic axons. These results are consistent with the proposed 'mechanical' theory of ONH damage resulting from increased IOP. Electron-microscopic radioautography revealed that chronically elevated IOP in bu/bu rabbits, which caused small foci of blocked ONH axonal transport against ONH beams, also caused degeneration of a few optic nerve terminals in the superior colliculi as the disease progressed.(ABSTRACT TRUNCATED AT 400 WORDS)

  15. The Microtubule Regulatory Protein Stathmin Is Required to Maintain the Integrity of Axonal Microtubules in Drosophila

    PubMed Central

    Duncan, Jason E.; Lytle, Nikki K.; Zuniga, Alfredo; Goldstein, Lawrence S. B.

    2013-01-01

    Axonal transport, a form of long-distance, bi-directional intracellular transport that occurs between the cell body and synaptic terminal, is critical in maintaining the function and viability of neurons. We have identified a requirement for the stathmin (stai) gene in the maintenance of axonal microtubules and regulation of axonal transport in Drosophila . The stai gene encodes a cytosolic phosphoprotein that regulates microtubule dynamics by partitioning tubulin dimers between pools of soluble tubulin and polymerized microtubules, and by directly binding to microtubules and promoting depolymerization. Analysis of stai function in Drosophila , which has a single stai gene, circumvents potential complications with studies performed in vertebrate systems in which mutant phenotypes may be compensated by genetic redundancy of other members of the stai gene family. This has allowed us to identify an essential function for stai in the maintenance of the integrity of axonal microtubules. In addition to the severe disruption in the abundance and architecture of microtubules in the axons of stai mutant Drosophila , we also observe additional neurological phenotypes associated with loss of stai function including a posterior paralysis and tail-flip phenotype in third instar larvae, aberrant accumulation of transported membranous organelles in stai deficient axons, a progressive bang-sensitive response to mechanical stimulation reminiscent of the class of Drosophila mutants used to model human epileptic seizures, and a reduced adult lifespan. Reductions in the levels of Kinesin-1, the primary anterograde motor in axonal transport, enhance these phenotypes. Collectively, our results indicate that stai has an important role in neuronal function, likely through the maintenance of microtubule integrity in the axons of nerves of the peripheral nervous system necessary to support and sustain long-distance axonal transport. PMID:23840848

  16. The axonal transport of mitochondria

    PubMed Central

    Saxton, William M.; Hollenbeck, Peter J.

    2012-01-01

    Vigorous transport of cytoplasmic components along axons over substantial distances is crucial for the maintenance of neuron structure and function. The transport of mitochondria, which serves to distribute mitochondrial functions in a dynamic and non-uniform fashion, has attracted special interest in recent years following the discovery of functional connections among microtubules, motor proteins and mitochondria, and their influences on neurodegenerative diseases. Although the motor proteins that drive mitochondrial movement are now well characterized, the mechanisms by which anterograde and retrograde movement are coordinated with one another and with stationary axonal mitochondria are not yet understood. In this Commentary, we review why mitochondria move and how they move, focusing particularly on recent studies of transport regulation, which implicate control of motor activity by specific cell-signaling pathways, regulation of motor access to transport tracks and static microtubule–mitochondrion linkers. A detailed mechanism for modulating anterograde mitochondrial transport has been identified that involves Miro, a mitochondrial Ca2+-binding GTPase, which with associated proteins, can bind and control kinesin-1. Elements of the Miro complex also have important roles in mitochondrial fission–fusion dynamics, highlighting questions about the interdependence of biogenesis, transport, dynamics, maintenance and degradation. PMID:22619228

  17. Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair

    PubMed Central

    Reumann, Marie K.; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Steven B.; Lukashova, Lyudmila; Boskey, Adele L.; Mayer-Kuckuk, Philipp

    2011-01-01

    Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1−/− mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1−/− mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1−/− callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. PMID:21726677

  18. Loss of heterozygosity at D8S262: an early genetic event of hepatocarcinogenesis.

    PubMed

    Zhu, Qiao; Gong, Li; Liu, Xiaoyan; Wang, Jun; Ren, Pin; Zhang, Wendong; Yao, Li; Han, Xiujuan; Zhu, Shaojun; Lan, Miao; Li, Yanhong; Zhang, Wei

    2015-06-16

    Hepatocellular carcinoma (HCC) is a multi-factor, multi-step, multi-gene and complicated process resulting from the accumulation of sequential genetic and epigenetic alterations. An important change among them is from precancerous lesions to HCC. However, only few studies have been reported about the sequential genetic changes during hepatocarcinogenesis. We observed firstly molecular karyotypes of 10 matched HCC using Affymetrix single-nucleotide polymorphism (SNP) 6.0 arrays, and found chromosomal fragments with high incidence (more than 70%) of loss of heterozygosity (LOH). Then, we selected 28 microsatellite markers at some gene spanning these chromosomal fragments, and examined the frequency of LOH of 128 matched HCC and 43 matched precancerous lesions-dysplastic nodules (DN) by a PCR-based analysis. Finally, we investigated the expression of proteins encoded by these genes in HCC, DN and the surrounding hepatic tissues. The result of Affymetrix SNP6.0 arrays demonstrated that more than 70% (7/10) cases had chromosomal fragment deletion on 4q13.3-35.1, 8p23.2-21.2, 16q11.2-24.3, and 17p13.3-12. Among 28 microsatellite markers selected, LOH frequencies at D8S262 for DN and HCC were found to be the highest, 51.2% and 72.7%, respectively. Immunohistochemically, the positive rate of its adjacent gene CSMD1 in HCC, DN, and the surrounding hepatic tissues were 27.3% (35/128), 75% (33/44), and 82% (105/128), respectively. LOH at D8S262 may be associated with an early genetic event of hepatocarcinogenesis, and a predictor for the monitor and prevention of HCC. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1557074981159099 .

  19. Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair.

    PubMed

    Reumann, Marie K; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Stephen B; Lukashova, Lyudmila; Boskey, Adele L; Mayer-Kuckuk, Philipp

    2011-10-01

    Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1(-/-) mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1(-/-) mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1(-/-) callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Effects of early pregnancy diagnosis by per rectal palpation of the amniotic sac on pregnancy loss in dairy cattle.

    PubMed

    Romano, Juan E; Fahning, Melvyn L

    2013-11-15

    To determine effects of per rectal amniotic sac palpation (ASP) for pregnancy diagnosis during early gestation on pregnancy loss in lactating cows. Controlled, randomized block design. 368 pregnant dairy cows. Pregnancy was detected via transrectal ultrasonography (TRUS) at day 29 (day of estrus = day 0), and cows were allocated into a control group (n = 167 cows) and ASP group (180). Control cows were not subjected to pregnancy diagnosis via palpation per rectum. Per rectal ASP was performed between days 34 and 43 by only 1 experienced veterinarian. All cows were reevaluated with TRUS on days 45, 60, and 90. 21 cows were removed because of illness. Pregnancy loss between days 29 and 90 occurred in 44 of 347 (12.7%) cows. Pregnancy loss for the control and ASP groups from days 29 to 90 occurred in 22 of 167 (13.2%) and 22 of 180 (12.2%) cows, respectively. Late embryonic pregnancy loss (days 29 to 45) for the control and ASP groups occurred in 18 (10.8%) and 15 (8.3%) cows, respectively. Early fetal pregnancy loss (days 46 to 60) for the control and ASP groups occurred in 2 of 149 (1.3%) and 6 of 165 (3.6%) cows, respectively, and late fetal pregnancy loss (days 61 to 90) for the same groups occurred in 2 of 147 (1.4%) and 1 of 159 (0.6%) cows, respectively. Pregnancy diagnosis via per rectal ASP during early gestation did not increase pregnancy loss in dairy cattle.

  1. Molecular mechanisms of optic axon guidance

    NASA Astrophysics Data System (ADS)

    Inatani, Masaru

    2005-12-01

    Axon guidance is one of the critical processes during vertebrate central nervous system (CNS) development. The optic nerve, which contains the axons of retinal ganglion cells, has been used as a powerful model to elucidate some of the mechanisms underlying axon guidance because it is easily manipulated experimentally, and its function is well understood. Recent molecular biology studies have revealed that numerous guidance molecules control the development of the visual pathway. This review introduces the molecular mechanisms involved in each critical step during optic axon guidance. Axonal projections to the optic disc are thought to depend on adhesion molecules and inhibitory extracellular matrices such as chondroitin sulfate. The formation of the head of the optic nerve and the optic chiasm require ligand-receptor interactions between netrin-1 and the deleted in colorectal cancer receptor, and Slit proteins and Robo receptors, respectively. The gradient distributions of ephrin ligands and Eph receptors are essential for correct ipsilateral projections at the optic chiasm and the topographic mapping of axons in the superior colliculus/optic tectum. The precise gradient is regulated by transcription factors determining the retinal dorso-ventral and nasal-temporal polarities. Moreover, the axon guidance activities by Slit and semaphorin 5A require the existence of heparan sulfate, which binds to numerous guidance molecules. Recent discoveries about the molecular mechanisms underlying optic nerve guidance will facilitate progress in CNS developmental biology and axon-regeneration therapy.

  2. Commissural axons of the mouse cochlear nucleus.

    PubMed

    Brown, M Christian; Drottar, Marie; Benson, Thane E; Darrow, Keith

    2013-05-01

    The axons of commissural neurons that project from one cochlear nucleus to the other were studied after labeling with anterograde tracer. Injections were made into the dorsal subdivision of the cochlear nucleus in order to restrict labeling only to the group of commissural neurons that gave off collaterals to, or were located in, this subdivision. The number of labeled commissural axons in each injection was correlated with the number of labeled radiate multipolar neurons, suggesting radiate neurons as the predominant origin of the axons. The radiate commissural axons are thick and myelinated, and they exit the dorsal acoustic stria of the injected cochlear nucleus to cross the brainstem in the dorsal half, near the crossing position of the olivocochlear bundle. They enter the opposite cochlear nucleus via the dorsal and ventral acoustic stria and at its medial border. Reconstructions of single axons demonstrate that terminations are mostly in the core and typically within a single subdivision of the cochlear nucleus. Extents of termination range from narrow to broad along both the dorsoventral (i.e., tonotopic) and the rostrocaudal dimensions. In the electron microscope, labeled swellings form synapses that are symmetric (in that there is little postsynaptic density), a characteristic of inhibitory synapses. Our labeled axons do not appear to include excitatory commissural axons that end in edge regions of the nucleus. Radiate commissural axons could mediate the broadband inhibition observed in responses to contralateral sound, and they may balance input from the two ears with a quick time course. Copyright © 2012 Wiley Periodicals, Inc.

  3. Netrin1 establishes multiple boundaries for axon growth in the developing spinal cord.

    PubMed

    Varadarajan, Supraja G; Butler, Samantha J

    2017-10-01

    The canonical model for netrin1 function proposed that it acted as a long-range chemotropic axon guidance cue. In the developing spinal cord, floor-plate (FP)-derived netrin1 was thought to act as a diffusible attractant to draw commissural axons to the ventral midline. However, our recent studies have shown that netrin1 is dispensable in the FP for axon guidance. We have rather found that netrin1 acts locally: netrin1 is produced by neural progenitor cells (NPCs) in the ventricular zone (VZ), and deposited on the pial surface as a haptotactic adhesive substrate that guides Dcc + axon growth. Here, we further demonstrate that this netrin1 pial-substrate has an early role orienting pioneering spinal axons, directing them to extend ventrally. However, as development proceeds, commissural axons choose to grow around a boundary of netrin1 expressing cells in VZ, instead of continuing to extend alongside the netrin1 pial-substrate in the ventral spinal cord. This observation suggests netrin1 may supply a more complex activity than pure adhesion, with netrin1-expressing cells also supplying a growth boundary for axons. Supporting this possibility, we have observed that additional domains of netrin1 expression arise adjacent to the dorsal root entry zone (DREZ) in E12.5 mice that are also required to sculpt axonal growth. Together, our studies suggest that netrin1 provides "hederal" boundaries: a local growth substrate that promotes axon extension, while also preventing local innervation of netrin1-expressing domains. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Acquisition and Early Losses of Rare Gases from the Deep Earth

    NASA Technical Reports Server (NTRS)

    Porcelli, D.; Cassen, P.; Woolum, D.; Wasserburg, G. J.

    1998-01-01

    Direct observations show that the deep Earth contains rare gases of solar composition distinct from those in the atmosphere. We examine the implications of mantle rare gas characteristics on acquisition of rare gases from the solar nebula and subsequent losses due to a large impact. Deep mantle rare gas concentrations and isotopic compositions can be obtained from a model of transport and distribution of mantle rare gases. This model assumes the lower mantle closed early, while the upper mantle is open to subduction from the atmosphere and mass transfer from the lower mantle. Constraints are derived that can be incorporated into models for terrestrial volatile acquisition: (1) Calculated lower-mantle Xe-isotopic ratios indicate that the fraction of radiogenic Xe produced by I-129 and Pu-244 during the first about 10(exp 8) yr was lost, a conclusion also drawn for atmospheric Xe. Thus, either the Earth was made from materials that had lost >99% of rare gases about (0.7-2) x 10(exp 8) yr after the solar system formed, or gases were then lost from the fully formed Earth. (2) Concentrations of 3He and 20Ne in the lower mantle were established after these losses. (3) Neon-isotopic data indicates that mantle Ne has solar composition. The model allows for solar Ar/Ne and Xe/Ne in the lower mantle if a dominant fraction of upper mantle Ar and Xe are subduction-derived. If Earth formed in the presence of the solar nebula, it could have been melted by accretional energy and the blanketing effect of a massive, nebula-derived atmosphere. Gases from this atmosphere would have been sequestered within the molten Earth by dissolution at the surface and downward mixing. It was found that too much Ne would be dissolved in the Earth unless the atmosphere began to escape when the Earth was only partially assembled. Here we consider conditions required to initially dissolve sufficient rare gases to account for the present lower mantle concentrations after subsequent losses at 10(exp 8

  5. Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function.

    PubMed

    Cioni, Jean-Michel; Wong, Hovy Ho-Wai; Bressan, Dario; Kodama, Lay; Harris, William A; Holt, Christine E

    2018-03-07

    The axons of retinal ganglion cells (RGCs) are topographically sorted before they arrive at the optic tectum. This pre-target sorting, typical of axon tracts throughout the brain, is poorly understood. Here, we show that cytoplasmic FMR1-interacting proteins (CYFIPs) fulfill non-redundant functions in RGCs, with CYFIP1 mediating axon growth and CYFIP2 specifically involved in axon sorting. We find that CYFIP2 mediates homotypic and heterotypic contact-triggered fasciculation and repulsion responses between dorsal and ventral axons. CYFIP2 associates with transporting ribonucleoprotein particles in axons and regulates translation. Axon-axon contact stimulates CYFIP2 to move into growth cones where it joins the actin nucleating WAVE regulatory complex (WRC) in the periphery and regulates actin remodeling and filopodial dynamics. CYFIP2's function in axon sorting is mediated by its binding to the WRC but not its translational regulation. Together, these findings uncover CYFIP2 as a key regulatory link between axon-axon interactions, filopodial dynamics, and optic tract sorting. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Exploring Trauma, Loss and Healing: Spirituality, "Te Whariki" and Early Childhood Education

    ERIC Educational Resources Information Center

    Bone, Jane

    2008-01-01

    Attention to spirituality is proposed to be a means of restoring and supporting well-being in early childhood educational contexts. In Aotearoa, New Zealand, the spiritual dimension is included in the early childhood curriculum "Te Whariki". This holistic approach to education supported research in three different early childhood…

  7. Axonal synapse sorting in medial entorhinal cortex

    NASA Astrophysics Data System (ADS)

    Schmidt, Helene; Gour, Anjali; Straehle, Jakob; Boergens, Kevin M.; Brecht, Michael; Helmstaedter, Moritz

    2017-09-01

    Research on neuronal connectivity in the cerebral cortex has focused on the existence and strength of synapses between neurons, and their location on the cell bodies and dendrites of postsynaptic neurons. The synaptic architecture of individual presynaptic axonal trees, however, remains largely unknown. Here we used dense reconstructions from three-dimensional electron microscopy in rats to study the synaptic organization of local presynaptic axons in layer 2 of the medial entorhinal cortex, the site of grid-like spatial representations. We observe path-length-dependent axonal synapse sorting, such that axons of excitatory neurons sequentially target inhibitory neurons followed by excitatory neurons. Connectivity analysis revealed a cellular feedforward inhibition circuit involving wide, myelinated inhibitory axons and dendritic synapse clustering. Simulations show that this high-precision circuit can control the propagation of synchronized activity in the medial entorhinal cortex, which is known for temporally precise discharges.

  8. The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

    PubMed Central

    Chisholm, Andrew D.; Hutter, Harald; Jin, Yishi; Wadsworth, William G.

    2016-01-01

    The correct wiring of neuronal circuits depends on outgrowth and guidance of neuronal processes during development. In the past two decades, great progress has been made in understanding the molecular basis of axon outgrowth and guidance. Genetic analysis in Caenorhabditis elegans has played a key role in elucidating conserved pathways regulating axon guidance, including Netrin signaling, the slit Slit/Robo pathway, Wnt signaling, and others. Axon guidance factors were first identified by screens for mutations affecting animal behavior, and by direct visual screens for axon guidance defects. Genetic analysis of these pathways has revealed the complex and combinatorial nature of guidance cues, and has delineated how cues guide growth cones via receptor activity and cytoskeletal rearrangement. Several axon guidance pathways also affect directed migrations of non-neuronal cells in C. elegans, with implications for normal and pathological cell migrations in situations such as tumor metastasis. The small number of neurons and highly stereotyped axonal architecture of the C. elegans nervous system allow analysis of axon guidance at the level of single identified axons, and permit in vivo tests of prevailing models of axon guidance. C. elegans axons also have a robust capacity to undergo regenerative regrowth after precise laser injury (axotomy). Although such axon regrowth shares some similarities with developmental axon outgrowth, screens for regrowth mutants have revealed regeneration-specific pathways and factors that were not identified in developmental screens. Several areas remain poorly understood, including how major axon tracts are formed in the embryo, and the function of axon regeneration in the natural environment. PMID:28114100

  9. Meninges-derived cues control axon guidance.

    PubMed

    Suter, Tracey A C S; DeLoughery, Zachary J; Jaworski, Alexander

    2017-10-01

    The axons of developing neurons travel long distances along stereotyped pathways under the direction of extracellular cues sensed by the axonal growth cone. Guidance cues are either secreted proteins that diffuse freely or bind the extracellular matrix, or membrane-anchored proteins. Different populations of axons express distinct sets of receptors for guidance cues, which results in differential responses to specific ligands. The full repertoire of axon guidance cues and receptors and the identity of the tissues producing these cues remain to be elucidated. The meninges are connective tissue layers enveloping the vertebrate brain and spinal cord that serve to protect the central nervous system (CNS). The meninges also instruct nervous system development by regulating the generation and migration of neural progenitors, but it has not been determined whether they help guide axons to their targets. Here, we investigate a possible role for the meninges in neuronal wiring. Using mouse neural tissue explants, we show that developing spinal cord meninges produce secreted attractive and repulsive cues that can guide multiple types of axons in vitro. We find that motor and sensory neurons, which project axons across the CNS-peripheral nervous system (PNS) boundary, are attracted by meninges. Conversely, axons of both ipsi- and contralaterally projecting dorsal spinal cord interneurons are repelled by meninges. The responses of these axonal populations to the meninges are consistent with their trajectories relative to meninges in vivo, suggesting that meningeal guidance factors contribute to nervous system wiring and control which axons are able to traverse the CNS-PNS boundary. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Spectraplakins promote microtubule-mediated axonal growth by functioning as structural MAPs and EB1-dependent +TIPs

    PubMed Central

    Alves-Silva, J.; Sánchez-Soriano, N.; Beaven, R.; Klein, M.; Parkin, J.; Millard, T.H.; Bellen, H. J; Venken, K. J.T.; Ballestrem, C.; Kammerer, R.A.; Prokop, A.

    2013-01-01

    The correct outgrowth of axons is essential for the development and regeneration of nervous systems. Axon growth is primarily driven by microtubules. Key regulators of microtubules in this context are the spectraplakins, a family of evolutionarily conserved actin-microtubule linkers. Loss of function of the mouse spectraplakin ACF7 or of its close Drosophila homologue Short stop/Shot similarly cause severe axon shortening and microtubule disorganisation. How spectraplakins perform these functions is not known. Here we show that axonal growth promoting roles of Shot require interaction with EB1 (End binding protein) at polymerising plus ends of microtubules. We show that binding of Shot to EB1 requires SxIP motifs in Shot’s carboxyterminal tail (Ctail), mutations of these motifs abolish Shot functions in axonal growth, loss of EB1 function phenocopies Shot loss, and genetic interaction studies reveal strong functional links between Shot and EB1 in axonal growth and microtubule organisation. In addition, we report that Shot localises along microtubule shafts and stabilises them against pharmacologically induced depolymerisation. This function is EB1-independent but requires net positive charges within Ctail which essentially contribute to the microtubule shaft association of Shot. Therefore, spectraplakins are true members of two important classes of neuronal microtubule regulating proteins: +TIPs (plus end regulators) and structural MAPs (microtubule associated proteins). From our data we deduce a model that relates the different features of the spectraplakin carboxy-terminus to the two functions of Shot during axonal growth. PMID:22764224

  11. Early Detection of Hearing Loss: The Case for Listening to Mothers

    ERIC Educational Resources Information Center

    Marchbank, Alison Margaret

    2011-01-01

    This article is drawn from a larger doctoral study that explored hearing mothers' experiences of discovering that their babies had a permanent hearing loss in Australia in 2008. The particular focus for this paper is the period in time after a concern is flagged, either by a newborn hearing screener or the mother herself, until a hearing loss is…

  12. Plant diversity does not buffer drought effects on early-stage litter mass loss rates and microbial properties.

    PubMed

    Vogel, Anja; Eisenhauer, Nico; Weigelt, Alexandra; Scherer-Lorenzen, Michael

    2013-09-01

    Human activities are decreasing biodiversity and changing the climate worldwide. Both global change drivers have been shown to affect ecosystem functioning, but they may also act in concert in a non-additive way. We studied early-stage litter mass loss rates and soil microbial properties (basal respiration and microbial biomass) during the summer season in response to plant species richness and summer drought in a large grassland biodiversity experiment, the Jena Experiment, Germany. In line with our expectations, decreasing plant diversity and summer drought decreased litter mass loss rates and soil microbial properties. In contrast to our hypotheses, however, this was only true for mass loss of standard litter (wheat straw) used in all plots, and not for plant community-specific litter mass loss. We found no interactive effects between global change drivers, that is, drought reduced litter mass loss rates and soil microbial properties irrespective of plant diversity. High mass loss rates of plant community-specific litter and low responsiveness to drought relative to the standard litter indicate that soil microbial communities were adapted to decomposing community-specific plant litter material including lower susceptibility to dry conditions during summer months. Moreover, higher microbial enzymatic diversity at high plant diversity may have caused elevated mass loss of standard litter. Our results indicate that plant diversity loss and summer drought independently impede soil processes. However, soil decomposer communities may be highly adapted to decomposing plant community-specific litter material, even in situations of environmental stress. Results of standard litter mass loss moreover suggest that decomposer communities under diverse plant communities are able to cope with a greater variety of plant inputs possibly making them less responsive to biotic changes. © 2013 John Wiley & Sons Ltd.

  13. C. elegans dystroglycan coordinates responsiveness of follower axons to dorsal/ventral and anterior/posterior guidance cues

    PubMed Central

    Johnson, Robert P.; Kramer, James M.

    2012-01-01

    Neural development in metazoans is characterized by the establishment of initial process tracts by pioneer axons and the subsequent extension of follower axons along these pioneer processes. Mechanisms governing the fidelity of follower extension along pioneered routes are largely unknown. In C. elegans, formation of the right angle-shaped lumbar commissure connecting the lumbar and preanal ganglia is an example of pioneer/follower dynamics. We find that the dystroglycan ortholog DGN-1 mediates the fidelity of follower lumbar commissure axon extension along the pioneer axon route. In dgn-1 mutants, the axon of the pioneer PVQ neuron faithfully establishes the lumbar commissure, but axons of follower lumbar neurons, such as PVC, frequently bypass the lumbar commissure and extend along an oblique trajectory directly toward the preanal ganglion. In contrast, disruption of the UNC-6/netrin guidance pathway principally perturbs PVQ ventral guidance to pioneer the lumbar commissure. Loss of DGN-1 in unc-6 mutants has a quantitatively similar effect on follower axon guidance regardless of PVQ axon route, indicating that DGN-1 does not mediate follower/pioneer adhesion. Instead, DGN-1 appears to block premature responsiveness of follower axons to a preanal ganglion-directed guidance cue which mediates ventral-to-anterior reorientation of lumbar commissure axons. Deletion analysis shows that only the most N-terminal DGN-1 domain is required for these activities. These studies suggest that dystroglycan modulation of growth cone responsiveness to conflicting guidance cues is important for restricting follower axon extension to the tracts laid down by pioneers. PMID:22275151

  14. Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain Injury

    PubMed Central

    Tsitsopoulos, Parmenion P.; Abu Hamdeh, Sami; Marklund, Niklas

    2017-01-01

    Traumatic brain injury (TBI) is a multidimensional and highly complex disease commonly resulting in widespread injury to axons, due to rapid inertial acceleration/deceleration forces transmitted to the brain during impact. Axonal injury leads to brain network dysfunction, significantly contributing to cognitive and functional impairments frequently observed in TBI survivors. Diffuse axonal injury (DAI) is a clinical entity suggested by impaired level of consciousness and coma on clinical examination and characterized by widespread injury to the hemispheric white matter tracts, the corpus callosum and the brain stem. The clinical course of DAI is commonly unpredictable and it remains a challenging entity with limited therapeutic options, to date. Although axonal integrity may be disrupted at impact, the majority of axonal pathology evolves over time, resulting from delayed activation of complex intracellular biochemical cascades. Activation of these secondary biochemical pathways may lead to axonal transection, named secondary axotomy, and be responsible for the clinical decline of DAI patients. Advances in the neurocritical care of TBI patients have been achieved by refinements in multimodality monitoring for prevention and early detection of secondary injury factors, which can be applied also to DAI. There is an emerging role for biomarkers in blood, cerebrospinal fluid, and interstitial fluid using microdialysis in the evaluation of axonal injury in TBI. These biomarker studies have assessed various axonal and neuroglial markers as well as inflammatory mediators, such as cytokines and chemokines. Moreover, modern neuroimaging can detect subtle or overt DAI/white matter changes in diffuse TBI patients across all injury severities using magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography. Importantly, serial neuroimaging studies provide evidence for evolving axonal injury. Since axonal injury may be a key risk factor for

  15. Mitochondria localize to injured axons to support regeneration

    PubMed Central

    Han, Sung Min; Baig, Huma S.; Hammarlund, Marc

    2016-01-01

    SUMMARY Axon regeneration is essential to restore the nervous system after axon injury. However, the neuronal cell biology that underlies axon regeneration is incompletely understood. Here we use in vivo single-neuron analysis to investigate the relationship between nerve injury, mitochondrial localization, and axon regeneration. Mitochondria translocate into injured axons, so that average mitochondria density increases after injury. Moreover, single-neuron analysis reveals that axons that fail to increase mitochondria have poor regeneration. Experimental alterations to axonal mitochondrial distribution or mitochondrial respiratory chain function result in corresponding changes to regeneration outcomes. Axonal mitochondria are specifically required for growth cone migration, identifying a key energy challenge for injured neurons. Finally, mitochondrial localization to the axon after injury is regulated in part by dual-leucine zipper kinase-1 (DLK-1), a conserved regulator of axon regeneration. These data identify regulation of axonal mitochondria as a new cell biological mechanism that helps determine the regenerative response of injured neurons. PMID:28009276

  16. Frizzled-3a and slit2 genetically interact to modulate midline axon crossing in the telencephalon.

    PubMed

    Hofmeister, Wolfgang; Devine, Christine A; Rothnagel, Joseph A; Key, Brian

    2012-07-01

    The anterior commissure forms the first axon connections between the two sides of the embryonic telencephalon. We investigated the role of the transmembrane receptor Frizzled-3a in the development of this commissure using zebrafish as an experimental model. Knock down of Frizzled-3a resulted in complete loss of the anterior commissure. This defect was accompanied by a loss of the glial bridge, expansion of the slit2 expression domain and perturbation of the midline telencephalic-diencephalic boundary. Blocking Slit2 activity following knock down of Frizzled-3a effectively rescued the anterior commissure defect which suggested that Frizzled-3a was indirectly controlling the growth of axons across the rostral midline. We have shown here that Frizzled-3a is essential for normal development of the commissural plate and that loss-of-function causes Slit2-dependent defects in axon midline crossing in the embryonic vertebrate forebrain. These data supports a model whereby Wnt signaling through Frizzled-3a attenuates expression of Slit2 in the rostral midline of the forebrain. The absence of Slit2 facilitates the formation of a midline bridge of glial cells which is used as a substrate for commissural axons. In the absence of this platform of glia, commissural axons fail to cross the rostral midline of the forebrain. Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.

  17. Early Parenting Moderates the Association between Parental Depression and Neural Reactivity to Rewards and Losses in Offspring.

    PubMed

    Kujawa, Autumn; Proudfit, Greg H; Laptook, Rebecca; Klein, Daniel N

    2015-07-01

    Children of parents with depression exhibit neural abnormalities in reward processing. Examining contributions of parenting could provide insight into the development of these abnormalities and to the etiology of depression. We evaluated whether early parenting moderates the effects of parental depression on a neural measure of reward and loss processing in mid-late childhood. Parenting was assessed when children were preschoolers. At age nine, children completed an event-related potential assessment and the feedback negativity (FN) was measured following rewards and losses ( N =344). Maternal authoritative parenting moderated the effect of maternal depression; among offspring of mothers with histories of depression, low authoritative parenting predicted a blunted FN. Observed maternal positive parenting interacted with paternal depression in a comparable manner, indicating that maternal parenting may buffer the effects of paternal depression. Early parenting may be important in shaping the neural systems involved in reward processing among children at high risk for depression.

  18. Early Parenting Moderates the Association between Parental Depression and Neural Reactivity to Rewards and Losses in Offspring

    PubMed Central

    Kujawa, Autumn; Proudfit, Greg H.; Laptook, Rebecca; Klein, Daniel N.

    2014-01-01

    Children of parents with depression exhibit neural abnormalities in reward processing. Examining contributions of parenting could provide insight into the development of these abnormalities and to the etiology of depression. We evaluated whether early parenting moderates the effects of parental depression on a neural measure of reward and loss processing in mid-late childhood. Parenting was assessed when children were preschoolers. At age nine, children completed an event-related potential assessment and the feedback negativity (FN) was measured following rewards and losses (N=344). Maternal authoritative parenting moderated the effect of maternal depression; among offspring of mothers with histories of depression, low authoritative parenting predicted a blunted FN. Observed maternal positive parenting interacted with paternal depression in a comparable manner, indicating that maternal parenting may buffer the effects of paternal depression. Early parenting may be important in shaping the neural systems involved in reward processing among children at high risk for depression. PMID:26167423

  19. Evaluation of early weight loss thresholds for identifying nonresponders to an intensive lifestyle intervention.

    PubMed

    Unick, Jessica L; Hogan, Patricia E; Neiberg, Rebecca H; Cheskin, Lawrence J; Dutton, Gareth R; Evans-Hudnall, Gina; Jeffery, Robert; Kitabchi, Abbas E; Nelson, Julie A; Pi-Sunyer, F Xavier; West, Delia Smith; Wing, Rena R

    2014-07-01

    Weight losses in lifestyle interventions are variable, yet prediction of long-term success is difficult. The utility of using various weight loss thresholds in the first 2 months of treatment for predicting 1-year outcomes was examined. Participants included 2327 adults with type 2 diabetes (BMI:35.8 ± 6.0) randomized to the intensive lifestyle intervention (ILI) of the Look AHEAD trial. ILI included weekly behavioral sessions designed to increase physical activity and reduce caloric intake. 1-month, 2-month, and 1-year weight changes were calculated. Participants failing to achieve a ≥2% weight loss at Month 1 were 5.6 (95% CI:4.5, 7.0) times more likely to also not achieve a ≥10% weight loss at Year 1, compared to those losing ≥2% initially. These odds were increased to 11.6 (95% CI:8.6, 15.6) when using a 3% weight loss threshold at Month 2. Only 15.2% and 8.2% of individuals failing to achieve the ≥2% and ≥3% thresholds at Months 1 and 2, respectively, go on to achieve a ≥10% weight loss at Year 1. Given the association between initial and 1-year weight loss, the first few months of treatment may be an opportune time to identify those who are unsuccessful and utilize rescue efforts. clinicaltrials.gov Identifier: NCT00017953. © 2014 The Obesity Society.

  20. Vesicular glutamate release from central axons contributes to myelin damage.

    PubMed

    Doyle, Sean; Hansen, Daniel Bloch; Vella, Jasmine; Bond, Peter; Harper, Glenn; Zammit, Christian; Valentino, Mario; Fern, Robert

    2018-03-12

    The axon myelin sheath is prone to injury associated with N-methyl-D-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury.

  1. KINETICS OF ION MOVEMENT IN THE SQUID GIANT AXON

    PubMed Central

    Shanes, Abraham M.; Berman, Morris D.

    1955-01-01

    The loss of Na22, K42, and Cl36 from single giant axons of the squid, Loligo pealii, following exposure to an artificial sea water containing these radioisotopes, occurs in two stages, an initial rapid one followed by an exponential decline. The time constants of the latter stage for the 3 ion species are, respectively, 290, 200, and 175 minutes. The outflux of sodium is depressed while that of potassium is accelerated in the absence of oxygen; the emergence of potassium is slowed by cocaine, while that of sodium is unaffected. One cm. ends of the axons take up about twice as much radiosodium as the central segment; this difference in activity is largely preserved during exposure to inactive solution. Such marked differences are not observed with radiopotassium. From the experimental data estimates are given of the influxes and outfluxes of the individual ions. The kinetics of outflux suggests a cortical layer of measureable thickness which contains the ions in different proportions from those in the medium and which governs the rate of emergence of these ions from the axon as though it contained very few but large (relative to ion dimensions) pores. PMID:13271727

  2. Bilateral spinal anterior horn lesions in acute motor axonal neuropathy.

    PubMed

    Sawada, Daisuke; Fujii, Katsunori; Misawa, Sonoko; Shiohama, Tadashi; Fukuhara, Tomoyuki; Fujita, Mayuko; Kuwabara, Satoshi; Shimojo, Naoki

    2018-05-28

    Guillain-Barré syndrome is an acute immune-mediated peripheral polyneuropathy. Neuroimaging findings from patients with this syndrome have revealed gadolinium enhancement in the cauda equina and in the anterior and posterior nerve roots, but intra-spinal lesions have never been described. Herein, we report, for the first time, bilateral spinal anterior horn lesions in a patient with an acute motor axonal neuropathy form of Guillain-Barré syndrome. The patient was a previously healthy 13-year-old Japanese girl, who exhibited acute-onset flaccid tetraplegia and loss of tendon reflexes. Nerve conduction studies revealed motor axonal damage, leading to the diagnosis of acute motor axonal neuropathy. Notably, spinal magnetic resonance imaging revealed bilateral anterior horn lesions on T2-weighted imaging at the Th11-12 levels, as well as gadolinium enhancement of the cauda equina and anterior and posterior nerve roots. The anterior horn lesions were most prominent on day 18, and their signal intensity declined thereafter. Although intravenous treatment with immunoglobulins was immediately administered, the motor function was not completely regained. We propose that anterior spinal lesions might be responsible for the prolonged neurological disability of patients with Guillain-Barré syndrome, possibly produced by retrograde progression from the affected anterior nerve roots to the intramedullary roots, and the anterior horn motor neurons. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  3. Early Intervention Practices for Children with Hearing Loss: Impact of Professional Development

    ERIC Educational Resources Information Center

    Martin-Prudent, Angi; Lartz, Maribeth; Borders, Christina; Meehan, Tracy

    2016-01-01

    Early identification and appropriate intervention services for children who are deaf or hard of hearing significantly increase the likelihood of better language, speech, and social-emotional development. However, current research suggests that there is a critical shortage of professionals trained to provide early intervention services to deaf and…

  4. ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A.

    PubMed

    Romi, Erez; Gokhman, Irena; Wong, Eitan; Antonovsky, Niv; Ludwig, Andreas; Sagi, Irit; Saftig, Paul; Tessier-Lavigne, Marc; Yaron, Avraham

    2014-06-05

    During embryonic development, axons can gain and lose sensitivity to guidance cues, and this flexibility is essential for the correct wiring of the nervous system. Yet, the underlying molecular mechanisms are largely unknown. Here we show that receptor cleavage by ADAM (A Disintegrin And Metalloprotease) metalloproteases promotes murine sensory axons loss of responsiveness to the chemorepellant Sema3A. Genetic ablation of ADAM10 and ADAM17 disrupts the developmental downregulation of Neuropilin-1 (Nrp1), the receptor for Sema3A, in sensory axons. Moreover, this is correlated with gain of repulsive response to Sema3A. Overexpression of Nrp1 in neurons reverses axonal desensitization to Sema3A, but this is hampered in a mutant Nrp1 with high susceptibility to cleavage. Lastly, we detect guidance errors of proprioceptive axons in ADAM knockouts that are consistent with enhanced response to Sema3A. Our results provide the first evidence for involvement of ADAMs in regulating developmental switch in responsiveness to axonal guidance cues.

  5. Stress Induces AMP-Dependent Loss of Potency Factors Id2 and Cdx2 in Early Embryos and Stem Cells

    PubMed Central

    Xie, Yufen; Awonuga, Awoniyi; Liu, Jian; Rings, Edmond; Puscheck, Elizabeth Ella

    2013-01-01

    The AMP-activated protein kinase (AMPK) mediates rapid, stress-induced loss of the inhibitor of differentiation (Id)2 in blastocysts and trophoblast stem cells (TSC), and a lasting differentiation in TSC. However, it is not known if AMPK regulates other potency factors or regulates them before the blastocyst stage. The caudal-related homeodomain protein (Cdx)2 is a regulatory gene for determining TSC, the earliest placental lineage in the preimplantation mouse embryo, but is expressed in the oocyte and in early cleavage stage embryos before TSC arise. We assayed the expression of putative potency-maintaining phosphorylated Cdx2 ser60 in the oocyte, two-cell stage embryo, blastocyst, and in TSC. We studied the loss of Cdx2 phospho ser60 expression induced by hyperosmolar stress and its underlying mechanisms. Hyperosmolar stress caused rapid loss of nuclear Cdx2 phospho ser60 and Id2 in the two-cell stage embryo by 0.5 h. Stress-induced Cdx2 phospho ser60 and Id2 loss is reversed by the AMPK inhibitor compound C and is induced by the AMPK agonist 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide in the absence of stress. In the two-cell stage embryo and TSC hyperosmolar, stress caused AMPK-mediated loss of Cdx2 phospho ser60 as detected by immunofluorescence and immunoblot. We propose that AMPK may be the master regulatory enzyme for mediating stress-induced loss of potency as AMPK is also required for stress-induced loss of Id2 in blastocysts and TSC. Since AMPK mediates potency loss in embryos and stem cells it will be important to measure, test mechanisms for, and manage the AMPK function to optimize the stem cell and embryo quality in vitro and in vivo. PMID:23316940

  6. Axonal inclusions in the crab Hemigrapsus nudus.

    PubMed

    Smith, R S

    1978-10-01

    Light microscopic examination of living giant axons from the walking legs of Hemigrapsus nudus revealed intra-axonal inclusions which were usually several tens of micrometers long and about 5 micron wide. The inclusions were filled with small light-scattering particles. The inclusions were shown, by thin section electron microscopy, to be composed largely 68% by volume) of mitochondria. Each inclusion was surrounded by membrane bounded spaces which are presumed to represent a part of the smooth endoplasmic reticulum. Similar inclusions were not found in the leg axons of a variety of other decapod crustaceans.

  7. Ionic Current Measurements in the Squid Giant Axon Membrane

    PubMed Central

    Cole, Kenneth S.; Moore, John W.

    1960-01-01

    The concepts, experiments, and interpretations of ionic current measurements after a step change of the squid axon membrane potential require the potential to be constant for the duration and the membrane area measured. An experimental approach to this ideal has been developed. Electrometer, operational, and control amplifiers produce the step potential between internal micropipette and external potential electrodes within 40 microseconds and a few millivolts. With an internal current electrode effective resistance of 2 ohm cm.2, the membrane potential and current may be constant within a few millivolts and 10 per cent out to near the electrode ends. The maximum membrane current patterns of the best axons are several times larger but of the type described by Cole and analyzed by Hodgkin and Huxley when the change of potential is adequately controlled. The occasional obvious distortions are attributed to the marginal adequacy of potential control to be expected from the characteristics of the current electrodes and the axon. Improvements are expected only to increase stability and accuracy. No reason has been found either to question the qualitative characteristics of the early measurements or to so discredit the analyses made of them. PMID:13694548

  8. Coexpression of high-voltage-activated ion channels Kv3.4 and Cav1.2 in pioneer axons during pathfinding in the developing rat forebrain.

    PubMed

    Huang, Chia-Yi; Chu, Dachen; Hwang, Wei-Chao; Tsaur, Meei-Ling

    2012-11-01

    Precise axon pathfinding is crucial for establishment of the initial neuronal network during development. Pioneer axons navigate without the help of preexisting axons and pave the way for follower axons that project later. Voltage-gated ion channels make up the intrinsic electrical activity of pioneer axons and regulate axon pathfinding. To elucidate which channel molecules are present in pioneer axons, immunohistochemical analysis was performed to examine 14 voltage-gated ion channels (Kv1.1-Kv1.3, Kv3.1-Kv3.4, Kv4.3, Cav1.2, Cav1.3, Cav2.2, Nav1.2, Nav1.6, and Nav1.9) in nine axonal tracts in the developing rat forebrain, including the optic nerve, corpus callosum, corticofugal fibers, thalamocortical axons, lateral olfactory tract, hippocamposeptal projection, anterior commissure, hippocampal commissure, and medial longitudinal fasciculus. We found A-type K⁺ channel Kv3.4 in both pioneer axons and early follower axons and L-type Ca²⁺ channel Cav1.2 in pioneer axons and early and late follower axons. Spatially, Kv3.4 and Cav1.2 were colocalized with markers of pioneer neurons and pioneer axons, such as deleted in colorectal cancer (DCC), in most fiber tracts examined. Temporally, Kv3.4 and Cav1.2 were expressed abundantly in most fiber tracts during axon pathfinding but were downregulated beginning in synaptogenesis. By contrast, delayed rectifier Kv channels (e.g., Kv1.1) and Nav channels (e.g., Nav1.2) were absent from these fiber tracts (except for the corpus callosum) during pathfinding of pioneer axons. These data suggest that Kv3.4 and Cav1.2, two high-voltage-activated ion channels, may act together to control Ca²⁺ -dependent electrical activity of pioneer axons and play important roles during axon pathfinding. Copyright © 2012 Wiley Periodicals, Inc.

  9. Neural cell adhesion molecule, NCAM, regulates thalamocortical axon pathfinding and the organization of the cortical somatosensory representation in mouse

    PubMed Central

    Enriquez-Barreto, Lilian; Palazzetti, Cecilia; Brennaman, Leann H.; Maness, Patricia F.; Fairén, Alfonso

    2012-01-01

    To study the potential role of neural cell adhesion molecule (NCAM) in the development of thalamocortical (TC) axon topography, wild type, and NCAM null mutant mice were analyzed for NCAM expression, projection, and targeting of TC afferents within the somatosensory area of the neocortex. Here we report that NCAM and its α-2,8-linked polysialic acid (PSA) are expressed in developing TC axons during projection to the neocortex. Pathfinding of TC axons in wild type and null mutant mice was mapped using anterograde DiI labeling. At embryonic day E16.5, null mutant mice displayed misguided TC axons in the dorsal telencephalon, but not in the ventral telencephalon, an intermediate target that initially sorts TC axons toward correct neocortical areas. During the early postnatal period, rostrolateral TC axons within the internal capsule along the ventral telencephalon adopted distorted trajectories in the ventral telencephalon and failed to reach the neocortex in NCAM null mutant animals. NCAM null mutants showed abnormal segregation of layer IV barrels in a restricted portion of the somatosensory cortex. As shown by Nissl and cytochrome oxidase staining, barrels of the anterolateral barrel subfield (ALBSF) and the most distal barrels of the posteromedial barrel subfield (PMBSF) did not segregate properly in null mutant mice. These results indicate a novel role for NCAM in axonal pathfinding and topographic sorting of TC axons, which may be important for the function of specific territories of sensory representation in the somatosensory cortex. PMID:22723769

  10. Regulation of branching dynamics by axon-intrinsic asymmetries in Tyrosine Kinase Receptor signaling

    PubMed Central

    Zschätzsch, Marlen; Oliva, Carlos; Langen, Marion; De Geest, Natalie; Özel, Mehmet Neset; Williamson, W Ryan; Lemon, William C; Soldano, Alessia; Munck, Sebastian; Hiesinger, P Robin; Sanchez-Soriano, Natalia; Hassan, Bassem A

    2014-01-01

    Axonal branching allows a neuron to connect to several targets, increasing neuronal circuit complexity. While axonal branching is well described, the mechanisms that control it remain largely unknown. We find that in the Drosophila CNS branches develop through a process of excessive growth followed by pruning. In vivo high-resolution live imaging of developing brains as well as loss and gain of function experiments show that activation of Epidermal Growth Factor Receptor (EGFR) is necessary for branch dynamics and the final branching pattern. Live imaging also reveals that intrinsic asymmetry in EGFR localization regulates the balance between dynamic and static filopodia. Elimination of signaling asymmetry by either loss or gain of EGFR function results in reduced dynamics leading to excessive branch formation. In summary, we propose that the dynamic process of axon branch development is mediated by differential local distribution of signaling receptors. DOI: http://dx.doi.org/10.7554/eLife.01699.001 PMID:24755286

  11. Prepregnancy and early adulthood body mass index and adult weight change in relation to fetal loss.

    PubMed

    Gaskins, Audrey J; Rich-Edwards, Janet W; Colaci, Daniela S; Afeiche, Myriam C; Toth, Thomas L; Gillman, Matthew W; Missmer, Stacey A; Chavarro, Jorge E

    2014-10-01

    To examine prospectively the relationships of prepregnancy body mass index (BMI), BMI at age 18 years, and weight change since age 18 years with risk of fetal loss. Our prospective cohort study included 25,719 pregnancies reported by 17,027 women in the Nurses' Health Study II between 1990 and 2009. In 1989, height, current weight, and weight at age 18 years were self-reported. Current weight was updated every 2 years thereafter. Pregnancies were self-reported, with case pregnancies lost spontaneously and comparison pregnancies ending in ectopic pregnancy, induced abortion, or live birth. Incident fetal loss was reported in 4,494 (17.5%) pregnancies. Compared with those of normal BMI, the multivariate relative risks of fetal loss were 1.07 (95% CI [confidence interval] 1.00-1.15) for overweight women, 1.10 (95% CI 0.98-1.23) for class I obese women, and 1.27 (95% CI 1.11-1.45) for class II and class III obese women (P trend ≤ .001). Body mass index at age 18 years was not associated with fetal loss (P trend=.59). Compared with women who maintained a stable weight (± 4 kg) between age 18 years and before pregnancy, women who lost weight had a 20% (95% CI 9-29%) lower risk of fetal loss. This association was stronger among women who were overweight at age 18 years. Being overweight or obese before pregnancy was associated with higher risk of fetal loss. In women overweight or obese at age 18 years, losing 4 kg or more was associated with a lower risk of fetal loss. : II.

  12. Scar modulation in subacute and chronic CNS lesions: Effects on axonal regeneration.

    PubMed

    Stichel, Christine C.; Lausberg, Friederike; Hermanns, Susanne; Müller, Hans Werner

    1999-01-01

    After injury of the adult mammalian CNS axonal regeneration across or around the lesion scar is negligible. Previously, we have shown that the lesion-induced basal membrane (BM) within the lesion center participates in a growth barrier for axon regeneration and that its reduction by means of pharmacological or immunochemical treatment is a prerequisite and sufficient condition for regrowing axons to cross the lesion site. The present study was designed to further investigate this observation by analyzing the effect of a delayed treatment on the regeneration of both subacutely and chronically lesioned axons.Adult rats underwent unilateral transection of the postcommissural fornix. At one to five days after transection one group of animals received a local injection of 2, 2'-dipyridyl (DPY), an inhibitor of collagen triple helix formation and synthesis. Another group received a second transection within the former lesion site followed by an immediate DPY-injection at five days or 4 weeks after transection. Six weeks after the last surgery BM deposition and axonal regeneration were analysed using immunocytochemical methods.A local injection of DPY clearly reduced the lesion-induced BM deposition when applied within the first 3 days after transection. Under these conditions regrowing axons still crossed the former impermeable lesion site and regenerated within their normal pathway up to their former target, the mammillary body. However, in late subacute (5 d) and chronic stages (4 w) the double transection+injection paradigm failed to reduce BM deposition and, in consequence, also to induce axonal regeneration.These results demonstrate the potential of the collagen IV-reducing strategy to promote axonal regeneration across the lesion scar not only in acute but also in early subacute traumatic injuries.

  13. Detection of Early Loss of Color Vision in Age-Related Macular Degeneration - With Emphasis on Drusen and Reticular Pseudodrusen.

    PubMed

    Vemala, Roopa; Sivaprasad, Sobha; Barbur, John L

    2017-05-01

    To evaluate chromatic sensitivity in patients with age-related macular degeneration (AMD) characterized by drusen and reticular pseudodrusen. To investigate whether the severity of color vision loss can distinguish between various stages of AMD and hence be used as an index of progression toward advanced AMD. Chromatic sensitivity was measured by using the Color Assessment and Diagnosis (CAD) test in asymptomatic individuals with early and intermediate AMD and compared to normative data. All study participants had logMAR visual acuity of 0.3 or better. The CAD thresholds measured in eyes with and without reticular pseudodrusen were also compared and related to central macular thickness (CMT). Student's t-test P values < 0.05 were considered significant. All early- and intermediate-AMD eyes (n = 90) had chromatic sensitivity loss in either RG (red/green) or YB (yellow/blue), or both (P < 0.0001) as compared to age-matched normal subjects. The eyes exhibited a range of CAD thresholds affecting both color mechanisms, but YB color thresholds were in general higher than RG thresholds (P < 0.001). Intermediate-AMD patients exhibited large intersubject variability. In general, eyes with reticular pseudodrusen and eyes with CMT < 200 μm had significantly higher CAD thresholds. The anatomic integrity of cone photoreceptors remains relatively unaffected in early and intermediate stages of AMD. The processing of cone signals in the retina can, however, be heavily disrupted with subsequent loss of both YB and RG chromatic sensitivity. The greatest losses were observed in eyes with reticular pseudodrusen.

  14. Axon tension regulates fasciculation/defasciculation through the control of axon shaft zippering

    PubMed Central

    Šmít, Daniel; Fouquet, Coralie; Pincet, Frédéric; Zapotocky, Martin; Trembleau, Alain

    2017-01-01

    While axon fasciculation plays a key role in the development of neural networks, very little is known about its dynamics and the underlying biophysical mechanisms. In a model system composed of neurons grown ex vivo from explants of embryonic mouse olfactory epithelia, we observed that axons dynamically interact with each other through their shafts, leading to zippering and unzippering behavior that regulates their fasciculation. Taking advantage of this new preparation suitable for studying such interactions, we carried out a detailed biophysical analysis of zippering, occurring either spontaneously or induced by micromanipulations and pharmacological treatments. We show that zippering arises from the competition of axon-axon adhesion and mechanical tension in the axons, and provide the first quantification of the force of axon-axon adhesion. Furthermore, we introduce a biophysical model of the zippering dynamics, and we quantitatively relate the individual zipper properties to global characteristics of the developing axon network. Our study uncovers a new role of mechanical tension in neural development: the regulation of axon fasciculation. DOI: http://dx.doi.org/10.7554/eLife.19907.001 PMID:28422009

  15. Early pest development and loss of biological control are associated with urban warming.

    PubMed

    Meineke, Emily K; Dunn, Robert R; Frank, Steven D

    2014-11-01

    Climate warming is predicted to cause many changes in ectotherm communities, one of which is phenological mismatch, wherein one species' development advances relative to an associated species or community. Phenological mismatches already lead to loss of pollination services, and we predict that they also cause loss of biological control. Here, we provide evidence that a pest develops earlier due to urban warming but that phenology of its parasitoid community does not similarly advance. This mismatch is associated with greater egg production that likely leads to more pests on trees. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  16. Otoprotective effects of mouse nerve growth factor in DBA/2J mice with early-onset progressive hearing loss.

    PubMed

    Wang, Qingzhu; Zhao, Hongchun; Zheng, Tihua; Wang, Wenjun; Zhang, Xiaolin; Wang, Andi; Li, Bo; Wang, Yanfei; Zheng, Qingyin

    2017-10-01

    As it displays progressive hair-cell loss and degeneration of spiral ganglion neurons (SGNs) characterized by early-onset progressive hearing loss (ePHL), DBA/2J is an inbred mouse strain widely used in hearing research. Mouse nerve growth factor (mNGF), as a common exogenous nerve growth factor (NGF), has been studied extensively for its ability to promote neuronal survival and growth. To determine whether mNGF can ameliorate progressive hearing loss (PHL) in DBA/2J mice, saline or mNGF was given to DBA/2J mice of either sex by daily intramuscular injection from the 1st to the 9th week after birth. At 5, 7, and 9 weeks of age, in comparison with vehicle groups, mNGF groups experienced decreased auditory-evoked brainstem response (ABR) thresholds and increased distortion product otoacoustic emission (DPOAE) amplitudes, the prevention of hair cell loss, and the inhibition of apoptosis of SGNs. Downregulation of Bak/Bax and Caspase genes and proteins in cochleae of mice receiving the mNGF treatment was detected by real-time PCR, Western blot, and immunohistochemistry. This suggests that the Bak-dependent mitochondrial apoptosis pathway may be involved in the otoprotective mechanism of mNGF in progressive hearing loss of DBA/2J mice. Our results demonstrate that mNGF can act as an otoprotectant in the DBA/2J mice for the early intervention of PHL and, thus, could become of great value in clinical applications. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  17. Identifying Early Onset of Hearing Loss in Young Adults With Diabetes Mellitus Type 2 Using High Frequency Audiometry.

    PubMed

    Vignesh, S S; Jaya, V; Moses, Anand; Muraleedharan, A

    2015-09-01

    Diabetes mellitus (DM) is a metabolic disorder caused by hyperglycemia which leads to dysfunction of various organs. Hearing acuity is equally hindered by this disorder. Among individuals with DM audiological characteristics of DM type 1 are of great concern in the literature. This study aims at establishing high frequency audiometry (HFA) as a useful tool in identifying early onset of hearing loss in individuals with DM type 2. 20 non-diabetic participants and 20 individuals with DM type 2 in the age range of 20-40 years were considered for the study. Subjects in both groups underwent otoscopic examination, PTA at 0.25, 0.5, 1, 2, 4 and 8 kHz and HFA at 9, 10, 11.2, 12.5, 14 and 16 kHz. Results revealed statistically significant difference in thresholds of both PTA and HFA at all frequencies across the group, but the mean threshold difference between the diabetic and non-diabetic group was marked in HFA than in PTA. In the diabetic subjects the thresholds of PTA was within 25 dBHL at all frequencies when compared to the thresholds of HFA. Individuals with DM type 2 showed bilateral symmetrical mild hearing loss in HFA and the hearing loss increased with ascending test frequencies from 9,000 to 16,000 Hz. Mild hearing loss in HFA is an indicator for early onset of hearing loss in DM type 2. Hence this present study emphasis the clinical utility of HFA in young adults with DM type 2.

  18. Regulation of Conduction Time along Axons

    PubMed Central

    Seidl, Armin H.

    2013-01-01

    Timely delivery of information is essential for proper function of the nervous system. Precise regulation of nerve conduction velocity is needed for correct exertion of motor skills, sensory integration and cognitive functions. In vertebrates, the rapid transmission of signals along nerve fibers is made possible by the myelination of axons and the resulting saltatory conduction in between nodes of Ranvier. Myelin is a specialization of glia cells and is provided by oligodendrocytes in the central nervous system. Myelination not only maximizes conduction velocity, but also provides a means to systematically regulate conduction times in the nervous system. Systematic regulation of conduction velocity along axons, and thus systematic regulation of conduction time in between neural areas, is a common occurrence in the nervous system. To date, little is understood about the mechanism that underlies systematic conduction velocity regulation and conduction time synchrony. Node assembly, internode distance (node spacing) and axon diameter - all parameters determining the speed of signal propagation along axons - are controlled by myelinating glia. Therefore, an interaction between glial cells and neurons has been suggested. This review summarizes examples of neural systems in which conduction velocity is regulated by anatomical variations along axons. While functional implications in these systems are not always clear, recent studies in the auditory system of birds and mammals present examples of conduction velocity regulation in systems with high temporal precision and a defined biological function. Together these findings suggest an active process that shapes the interaction between axons and myelinating glia to control conduction velocity along axons. Future studies involving these systems may provide further insight into how specific conduction times in the brain are established and maintained in development. Throughout the text, conduction velocity is used for the

  19. Con-nectin axons and dendrites.

    PubMed

    Beaudoin, Gerard M J

    2006-07-03

    Unlike adherens junctions, synapses are asymmetric connections, usually between axons and dendrites, that rely on various cell adhesion molecules for structural stability and function. Two cell types of adhesion molecules found at adherens junctions, cadherins and nectins, are thought to mediate homophilic interaction between neighboring cells. In this issue, Togashi et al. (see p. 141) demonstrate that the differential localization of two heterophilic interacting nectins mediates the selective attraction of axons and dendrites in cooperation with cadherins.

  20. Commissural Axons of the Mouse Cochlear Nucleus

    PubMed Central

    Brown, M. Christian; Drottar, Marie; Benson, Thane E.; Darrow, Keith

    2012-01-01

    The axons of commissural neurons that project from one cochlear nucleus to the other were studied after labeling with anterograde tracer. Injections were made into the dorsal subdivision of the cochlear nucleus in order to restrict labeling only to the group of commissural neurons that gave off collaterals to, or were located in, this subdivision. The number of labeled commissural axons in each injection was correlated with the number of labeled radiate multipolar neurons, suggesting radiate neurons as the predominant origin of the axons. The radiate commissural axons are thick and myelinated, and they exit the dorsal acoustic stria of the injected cochlear nucleus to cross the brainstem in the dorsal half, near the crossing position of the olivocochlear bundle. They enter the opposite cochlear nucleus via the dorsal and ventral acoustic stria and at its medial border. Reconstructions of single axons demonstrate that terminations are mostly in the core and typically within a single subdivision of the cochlear nucleus. Extents of termination range from narrow to broad along both the dorso-ventral (i.e. tonotopic) and rostro-caudal dimensions. In the electron microscope, labeled swellings form synapses that are symmetric (in that there is little postsynaptic density), a characteristic of inhibitory synapses. Our labeled axons do not appear to include excitatory commissural axons that end in edge regions of the nucleus. Radiate commissural axons could mediate the broad-band inhibition observed in responses to contralateral sound, and they may balance input from the two ears on a quick time course. PMID:23124982

  1. Loss of MyD88 alters neuroinflammatory response and attenuates early Purkinje cell loss in a spinocerebellar ataxia type 6 mouse model

    PubMed Central

    Aikawa, Tomonori; Mogushi, Kaoru; Iijima-Tsutsui, Kumiko; Ishikawa, Kinya; Sakurai, Miyano; Tanaka, Hiroshi; Mizusawa, Hidehiro; Watase, Kei

    2015-01-01

    Spinocerebellar ataxia type 6 (SCA6) is dominantly inherited neurodegenerative disease, caused by an expansion of CAG repeat encoding a polyglutamine (PolyQ) tract in the Cav2.1 voltage-gated calcium channel. Its key pathological features include selective degeneration of the cerebellar Purkinje cells (PCs), a common target for PolyQ-induced toxicity in various SCAs. Mutant Cav2.1 confers toxicity primarily through a toxic gain-of-function mechanism; however, its molecular basis remains elusive. Here, we studied the cerebellar gene expression patterns of young Sca6-MPI118Q/118Q knockin (KI) mice, which expressed mutant Cav2.1 from an endogenous locus and recapitulated many phenotypic features of human SCA6. Transcriptional signatures in the MPI118Q/118Q mice were distinct from those in the Sca1154Q/2Q mice, a faithful SCA1 KI mouse model. Temporal expression profiles of the candidate genes revealed that the up-regulation of genes associated with microglial activation was initiated before PC degeneration and was augmented as the disease progressed. Histological analysis of the MPI118Q/118Q cerebellum showed the predominance of M1-like pro-inflammatory microglia and it was concomitant with elevated expression levels of tumor necrosis factor, interleukin-6, Toll-like receptor (TLR) 2 and 7. Genetic ablation of MyD88, a major adaptor protein conveying TLR signaling, altered expression patterns of M1/M2 microglial phenotypic markers in the MPI118Q/118Q cerebellum. More importantly, it ameliorated PC loss and partially rescued motor impairments in the early disease phase. These results suggest that early neuroinflammatory response may play an important role in the pathogenesis of SCA6 and its modulation could pave the way for slowing the disease progression during the early stage of the disease. PMID:26034136

  2. Loss of Language in Early Development of Autism and Specific Language Impairment

    ERIC Educational Resources Information Center

    Pickles, Andrew; Simonoff, Emily; Conti-Ramsden, Gina; Falcaro, Milena; Simkin, Zoe; Charman, Tony; Chandler, Susie; Loucas, Tom; Baird, Gillian

    2009-01-01

    Background: Several authors have highlighted areas of overlap in symptoms and impairment among children with autism spectrum disorder (ASD) and children with specific language impairment (SLI). By contrast, loss of language and broadly defined regression have been reported as relatively specific to autism. We compare the incidence of language loss…

  3. Early Hearing Loss and Language Abilities in Children with Down Syndrome

    ERIC Educational Resources Information Center

    Laws, Glynis; Hall, Amanda

    2014-01-01

    Background: Although many children with Down syndrome experience hearing loss, there has been little research to investigate its impact on speech and language development. Studies that have investigated the association give inconsistent results. These have often been based on samples where children with the most severe hearing impairments have…

  4. Coarticulation in Early Vocalizations by Children with Hearing Loss: A Locus Perspective

    ERIC Educational Resources Information Center

    Morrison, Helen Mccaffrey

    2012-01-01

    Locus equations derived from productions by three children with hearing loss revealed sensory and motor influences on anticipatory coarticulation. Participants who received auditory access to speech via hearing aids and cochlear implants at different ages (5-39 months) were recorded at approximately 6 and 12 months after hearing technology…

  5. Initial Weight Loss Response as an Indicator for Providing Early Rescue Efforts to Improve Long-term Treatment Outcomes.

    PubMed

    Unick, Jessica L; Pellegrini, Christine A; Demos, Kathryn E; Dorfman, Leah

    2017-09-01

    There is a large variability in response to behavioral weight loss (WL) programs. Reducing rates of obesity and diabetes may require more individuals to achieve clinically significant WL post-treatment. Given that WL within the first 1-2 months of a WL program is associated with long-term WL, it may be possible to improve treatment outcomes by identifying and providing additional intervention to those with poor initial success (i.e., "early non-responders"). We review the current literature regarding early non-response to WL programs and discuss how adaptive interventions can be leveraged as a strategy to "rescue" early non-responders. Preliminary findings suggest that adaptive interventions, specifically stepped care approaches, offer promise for improving outcomes among early non-responders. Future studies need to determine the optimal time point and threshold for intervening and the type of early intervention to employ. Clinicians and researchers should consider the discussed factors when making treatment decisions.

  6. Auditory development in early amplified children: factors influencing auditory-based communication outcomes in children with hearing loss.

    PubMed

    Sininger, Yvonne S; Grimes, Alison; Christensen, Elizabeth

    2010-04-01

    demonstrated the importance of early amplification on communication outcomes. This demonstration required a participant pool that included children who have been fit at very early ages and who represent all degrees of hearing loss. Limitations of longitudinal studies include selection biases. Families who enroll tend to have high levels of education and rate highly on cooperation and compliance measures. Although valuable information can be extracted from prospective studies, not all factors can be evaluated because of enrollment constraints.

  7. Loss of LRIG1 locus increases risk of early and late relapse of stage I/II breast cancer.

    PubMed

    Thompson, Patricia A; Ljuslinder, Ingrid; Tsavachidis, Spyros; Brewster, Abenaa; Sahin, Aysegul; Hedman, Håkan; Henriksson, Roger; Bondy, Melissa L; Melin, Beatrice S

    2014-06-01

    Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse≥5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients. ©2014 American Association for Cancer Research.

  8. A Model of Early Intervention for Children with Hearing Loss Provided through Telepractice

    ERIC Educational Resources Information Center

    Houston, K. Todd; Stredler-Brown, Arlene

    2012-01-01

    Children who are deaf and hard of hearing and their families need access to appropriate early intervention services that are delivered by professionals who are well trained and experienced using their chosen communication approach. Unfortunately, a lack of qualified practitioners, especially in remote and rural communities, and limited funding can…

  9. Association Between Increased Vascular Density and Loss of Protective RAS in Early-stage NPDR

    NASA Technical Reports Server (NTRS)

    Radhakrishnan, Krishnan; Raghunandan, Sneha; Vyas, Ruchi J.; Vu, Amanda C.; Bryant, Douglas; Yaqian, Duan; Knecht, Brenda E.; Grant, Maria B.; Chalam, K. V.; Parsons-Wingerter, Patricia

    2016-01-01

    Our hypothesis predicts that retinal blood vessels increase in density during early-stage progression to moderate nonproliferative diabetic retinopathy (NPDR). The renin-angiotensin system (RAS) is implicated in the pathogenesis of DR and in the function of circulating angiogenic cells (CACs), a critical bone marrow-derived population that is instrumental in vascular repair.

  10. Shock-induced CO2 loss from CaCO3: Implications for early planetary atmospheres

    NASA Technical Reports Server (NTRS)

    Lange, M. A.; Ahrens, T. J.

    1984-01-01

    Recovered samples from shock recovery experiments on single crystal calcite were subjected to thermogravimetric analysis to determine the amount of post-shock CO2, the decarbonization interval and the activation energy, for the removal of remaining CO2 in shock-loaded calcite. Comparison of post-shock CO2 with that initially present determines shock-induced CO2 loss as a function of shock pressure. Incipient to complete CO2 loss occurs over a pressure range of approximately 10 to approximately 70 GPa. Optical and scanning electron microscopy reveal structural changes, which are related to the shock-loading. The occurrence of dark, diffuse areas, which can be resolved as highly vesicular areas as observed with a scanning electron microscope are interpreted as representing quenched partial melts, into which shock-released CO2 was injected. The experimental results are used to constrain models of shock-produced, primary CO2 atmospheres on the accreting terrestrial planets.

  11. Early pregnancy factor (EPF) as a marker for detecting subclinical embryonic loss in clomiphene citrate-treated women.

    PubMed

    Shahani, S K; Moniz, C L; Gokral, J S; Meherji, P K

    1995-05-01

    A discrepancy exists between the apparently normal ovulation and the pregnancy rates in women treated with clomiphene citrate (CC). Our previous studies have indicated that immuno-suppressive "early pregnancy factor" (EPF) is a novel marker to detect subclinical embryonic loss in infertile women. In the present study EPF was used as a marker to detect subclinical embryonic loss in women treated with CC with/without gonadotropins. In some of the women treated with CC, conception was assisted by artificial insemination with husband's semen (AIH). Our results have indicated that fertilization occurred (EPF + ve) in 47.7% (52/109) of women treated with CC with/without gonadotropins; 13.46% (7/52) retained the fetus and continued pregnancy till full term, whereas 78.9% (41/52) did not retain the fetuses. In the group where after stimulation, conception was assisted by AIH, fertilization was observed in 38.24% (26/68), retention in 11.54% (3/26) but subclinical embryonic loss was observed in 80.8% (21/26) cases. Thus, our results have indicated that subclinical embryonic loss may account for some of the discrepancy observed between the apparently normal ovulation and the pregnancy rates in women treated with clomiphene citrate.

  12. Social inclusion for children with hearing loss in listening and spoken Language early intervention: an exploratory study.

    PubMed

    Constantinescu-Sharpe, Gabriella; Phillips, Rebecca L; Davis, Aleisha; Dornan, Dimity; Hogan, Anthony

    2017-03-14

    Social inclusion is a common focus of listening and spoken language (LSL) early intervention for children with hearing loss. This exploratory study compared the social inclusion of young children with hearing loss educated using a listening and spoken language approach with population data. A framework for understanding the scope of social inclusion is presented in the Background. This framework guided the use of a shortened, modified version of the Longitudinal Study of Australian Children (LSAC) to measure two of the five facets of social inclusion ('education' and 'interacting with society and fulfilling social goals'). The survey was completed by parents of children with hearing loss aged 4-5 years who were educated using a LSL approach (n = 78; 37% who responded). These responses were compared to those obtained for typical hearing children in the LSAC dataset (n = 3265). Analyses revealed that most children with hearing loss had comparable outcomes to those with typical hearing on the 'education' and 'interacting with society and fulfilling social roles' facets of social inclusion. These exploratory findings are positive and warrant further investigation across all five facets of the framework to identify which factors influence social inclusion.

  13. External Validation of Early Weight Loss Nomograms for Exclusively Breastfed Newborns.

    PubMed

    Schaefer, Eric W; Flaherman, Valerie J; Kuzniewicz, Michael W; Li, Sherian X; Walsh, Eileen M; Paul, Ian M

    2015-12-01

    Nomograms that show hour-by-hour percentiles of weight loss during the birth hospitalization were recently developed to aid clinical care of breastfeeding newborns. The nomograms for breastfed neonates were based on a sample of 108,907 newborns delivered at 14 Kaiser Permanente medical centers in Northern California (United States). The objective of this study was to externally validate the published nomograms for newborn weight loss using data from a geographically distinct population. Data were compiled from the Penn State Milton S. Hershey Medical Center located in Hershey, PA. For singleton neonates delivered at ≥36 weeks of gestation between January 2013 and September 2014, weights were obtained between 6 hours and 48 hours (vaginal delivery) or 60 hours (cesarean delivery) for neonates who were exclusively breastfeeding. Quantile regression methods appropriate for repeated measures were used to estimate 50th, 75th, 90th, and 95th percentiles of weight loss as a function of time after birth. These percentile estimates were compared with the published nomograms. Of the 1,587 newborns who met inclusion criteria, 1,148 were delivered vaginally, and 439 were delivered via cesarean section. These newborns contributed 1,815 weights for vaginal deliveries (1.6 per newborn) and 893 weights for cesarean deliveries (2.0 per newborn). Percentile estimates from this Penn State sample were similar to the published nomograms. Deviations in percentile estimates for the Penn State sample were similar to deviations observed after fitting the same model separately to each medical center that made up the Kaiser Permanente sample. The published newborn weight loss nomograms for breastfed neonates were externally validated in a geographically distinct population.

  14. Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

    PubMed

    Horton, Sarah J; Giotopoulos, George; Yun, Haiyang; Vohra, Shabana; Sheppard, Olivia; Bashford-Rogers, Rachael; Rashid, Mamunur; Clipson, Alexandra; Chan, Wai-In; Sasca, Daniel; Yiangou, Loukia; Osaki, Hikari; Basheer, Faisal; Gallipoli, Paolo; Burrows, Natalie; Erdem, Ayşegül; Sybirna, Anastasiya; Foerster, Sarah; Zhao, Wanfeng; Sustic, Tonci; Petrunkina Harrison, Anna; Laurenti, Elisa; Okosun, Jessica; Hodson, Daniel; Wright, Penny; Smith, Ken G; Maxwell, Patrick; Fitzgibbon, Jude; Du, Ming Q; Adams, David J; Huntly, Brian J P

    2017-09-01

    Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

  15. Empirical mass-loss rates for 25 O and early B stars, derived from Copernicus observations

    NASA Technical Reports Server (NTRS)

    Gathier, R.; Lamers, H. J. G. L. M.; Snow, T. P.

    1981-01-01

    Ultraviolet line profiles are fitted with theoretical line profiles in the cases of 25 stars covering a spectral type range from O4 to B1, including all luminosity classes. Ion column densities are compared for the determination of wind ionization, and it is found that the O VI/N V ratio is dependent on the mean density of the wind and not on effective temperature value, while the Si IV/N V ratio is temperature-dependent. The column densities are used to derive a mass-loss rate parameter that is empirically correlated against the mass-loss rate by means of standard stars with well-determined rates from IR or radio data. The empirical mass-loss rates obtained are compared with those derived by others and found to vary by as much as a factor of 10, which is shown to be due to uncertainties or errors in the ionization fractions of models used for wind ionization balance prediction.

  16. Spatial analysis improves the detection of early corneal nerve fiber loss in patients with recently diagnosed type 2 diabetes

    PubMed Central

    Winter, Karsten; Strom, Alexander; Zhivov, Andrey; Allgeier, Stephan; Papanas, Nikolaos; Ziegler, Iris; Brüggemann, Jutta; Ringel, Bernd; Peschel, Sabine; Köhler, Bernd; Stachs, Oliver; Guthoff, Rudolf F.; Roden, Michael

    2017-01-01

    Corneal confocal microscopy (CCM) has revealed reduced corneal nerve fiber (CNF) length and density (CNFL, CNFD) in patients with diabetes, but the spatial pattern of CNF loss has not been studied. We aimed to determine whether spatial analysis of the distribution of corneal nerve branching points (CNBPs) may contribute to improving the detection of early CNF loss. We hypothesized that early CNF decline follows a clustered rather than random distribution pattern of CNBPs. CCM, nerve conduction studies (NCS), and quantitative sensory testing (QST) were performed in a cross-sectional study including 86 patients recently diagnosed with type 2 diabetes and 47 control subjects. In addition to CNFL, CNFD, and branch density (CNBD), CNBPs were analyzed using spatial point pattern analysis (SPPA) including 10 indices and functional statistics. Compared to controls, patients with diabetes showed lower CNBP density and higher nearest neighbor distances, and all SPPA parameters indicated increased clustering of CNBPs (all P<0.05). SPPA parameters were abnormally increased >97.5th percentile of controls in up to 23.5% of patients. When combining an individual SPPA parameter with CNFL, ≥1 of 2 indices were >99th or <1st percentile of controls in 28.6% of patients compared to 2.1% of controls, while for the conventional CNFL/CNFD/CNBD combination the corresponding rates were 16.3% vs 2.1%. SPPA parameters correlated with CNFL and several NCS and QST indices in the controls (all P<0.001), whereas in patients with diabetes these correlations were markedly weaker or lost. In conclusion, SPPA reveals increased clustering of early CNF loss and substantially improves its detection when combined with a conventional CCM measure in patients with recently diagnosed type 2 diabetes. PMID:28296936

  17. Early improvement in food cravings are associated with long-term weight loss success in a large clinical sample

    PubMed Central

    Dalton, M; Finlayson, G; Walsh, B; Halseth, A E; Duarte, C; Blundell, J E

    2017-01-01

    Background: Food cravings are associated with dysregulated eating behaviour and obesity, and may impede successful weight loss attempts. Gaining control over food craving is therefore a component in the management of obesity. The current paper examined whether early changes in control over food craving (assessed using the Craving Control subscale on the Control of Eating Questionnaire (CoEQ)) was predictive of weight loss in four phase 3 clinical trials investigating a sustained-release combination of naltrexone/bupropion (NB) in obese adults. The underlying component structure of the CoEQ was also examined. Method: In an integrated analysis of four 56-week phase 3 clinical trials, subjects completed the CoEQ and had their body weight measured at baseline and at weeks 8, 16, 28 and 56. All analyses were conducted on subjects who had complete weight and CoEQ measurements at baseline and week 56, and had completed 56 weeks of NB (n=1310) or placebo (n=736). A latent growth curve model was used to examine whether early changes in the CoEQ subscales were associated with decreases in weight loss over time. Confirmatory factor analysis (CFA) was used to determine the psychometric properties of the CoEQ. Results: The factor structure of the CoEQ was consistent with previous findings with a four-factor solution being confirmed: Craving Control, Positive Mood, Craving for Sweet and Craving for Savoury with good internal consistency (Cronbach’s α=0.72–0.92). Subjects with the greatest improvement in Craving Control at week 8 exhibited a greater weight loss at week 56. Conclusions: These findings highlight the importance of the experience of food cravings in the treatment of obesity and support the use of the CoEQ as a psychometric tool for the measurement of food cravings in research and the pharmacological management of obesity. PMID:28373674

  18. Evolution of the Mauthner axon cap.

    PubMed

    Bierman, Hilary S; Zottoli, Steven J; Hale, Melina E

    2009-01-01

    Studies of vertebrate brain evolution have focused primarily on patterns of gene expression or changes in size and organization of major brain regions. The Mauthner cell, an important reticulospinal neuron that functions in the startle response of many species, provides an opportunity for evolutionary comparisons at the cellular level. Despite broad interspecific similarities in Mauthner cell morphology, the motor patterns and startle behaviors it initiates vary markedly. Response diversity has been hypothesized to result, in part, from differences in the structure and function of the Mauthner cell-associated axon cap. We used light microscopy techniques to compare axon cap morphology across a wide range of species, including all four extant basal actinopterygian orders, representatives of a variety of teleost lineages and lungfishes, and we combined our data with published descriptions of axon cap structure. The 'composite' axon cap, observed in teleosts, is an organized conglomeration of glia and fibers of inhibitory and excitatory interneurons. Lungfish, amphibian tadpoles and several basal actinopterygian fishes have 'simple' axon caps that appear to lack glia and include few fibers. Several other basal actinopterygian fishes have 'simple-dense' caps that include greater numbers of fibers than simple caps, but lack the additional elements and organization of composite caps. Phylogenetic mapping shows that through evolution there are discrete transitions in axon cap morphology occurring at the base of gnathostomes, within basal actinopterygians, and at the base of the teleost radiation. Comparing axon cap evolution to the evolution of startle behavior and motor pattern provides insight into the relationship between Mauthner cell-associated structures and their functions in behavior. Copyright 2009 S. Karger AG, Basel.

  19. A Qualitative Study on Knowledge and Attitude towards Risk Factors, Early Identification and Intervention of Infant Hearing Loss among Puerperal Mothers- A Short Survey

    PubMed Central

    Dudda, Ravi; Muniyappa, Hanumanth Prasad; Lakshmi, M.S

    2017-01-01

    Introduction Maternal active participation and their support are critical for the success of early hearing loss detection program. Erroneous maternal decisions may have large life long consequences on the infant’s life. The mothers’ knowledge and their attitudes towards infant hearing loss is the basis for their decisions. Aim The present study was done to determine the mothers’ knowledge and their attitude towards risk factors of infant hearing loss, its early identification and intervention and also awareness of effect of consanguinity on hearing loss. Materials and Methods In this cross-sectional questionnaire survey study, a total of 100 mothers were interviewed using the questionnaire which consisted of three sections namely risk factors, early identification and early intervention of hearing loss. Chi-square test was used to establish relationship between consanguineous and non-consanguineous mother’s responses to its effect on hearing loss. A p-value < 0.05 was considered as significant. Results Mothers’ awareness was significantly high for visible causes (ear pain/discharge, head injury and slap to ear) of hearing loss. Positive attitude was seen for importance of screening programs and follow up testing. Moderate level of awareness was found on hazards of consanguinity and benefits of early identification. However, mothers were least aware of neonatal jaundice, NICU admission (>5 days), signs of late-onset and neural hearing loss, management of hearing loss, hearing aid fitting and therapy necessity, which might interfere in early detection and intervention of hearing loss. Conclusion It is crucial to educate mothers on few risk factors and management of hearing loss to reduce its consequences. PMID:28892940

  20. A Qualitative Study on Knowledge and Attitude towards Risk Factors, Early Identification and Intervention of Infant Hearing Loss among Puerperal Mothers- A Short Survey.

    PubMed

    Dudda, Ravi; Muniyappa, Hanumanth Prasad; Puttaraju, Sahana; Lakshmi, M S

    2017-07-01

    Maternal active participation and their support are critical for the success of early hearing loss detection program. Erroneous maternal decisions may have large life long consequences on the infant's life. The mothers' knowledge and their attitudes towards infant hearing loss is the basis for their decisions. The present study was done to determine the mothers' knowledge and their attitude towards risk factors of infant hearing loss, its early identification and intervention and also awareness of effect of consanguinity on hearing loss. In this cross-sectional questionnaire survey study, a total of 100 mothers were interviewed using the questionnaire which consisted of three sections namely risk factors, early identification and early intervention of hearing loss. Chi-square test was used to establish relationship between consanguineous and non-consanguineous mother's responses to its effect on hearing loss. A p-value < 0.05 was considered as significant. Mothers' awareness was significantly high for visible causes (ear pain/discharge, head injury and slap to ear) of hearing loss. Positive attitude was seen for importance of screening programs and follow up testing. Moderate level of awareness was found on hazards of consanguinity and benefits of early identification. However, mothers were least aware of neonatal jaundice, NICU admission (>5 days), signs of late-onset and neural hearing loss, management of hearing loss, hearing aid fitting and therapy necessity, which might interfere in early detection and intervention of hearing loss. It is crucial to educate mothers on few risk factors and management of hearing loss to reduce its consequences.

  1. Association Between Increased Vascular Density and Loss of Protective RAS in Early-Stage NPDR

    NASA Technical Reports Server (NTRS)

    Radhakrishnan, Krishnan; Raghunandan, Sneha; Vyas, Ruchi J.; Vu, Amanda C.; Bryant, Douglas; Yaqian, Duan; Knecht, Brenda E.; Grant, Maria B.; Chalam, K . V.; Parsons-Wingerter, Patricia

    2016-01-01

    Our hypothesis predicts that retinal blood vessels increase in density during early-stage progression to moderate nonproliferative diabetic retinopathy (NPDR). The prevailing paradigm of NPDR progression is that vessels drop out prior to abnormal, vision-impairing regrowth at late-stage proliferative diabetic retinopathy (DR). However, surprising results for our previous preliminary study 1 with NASA's VESsel GENeration Analysis (VESGEN) software showed that vessels proliferated considerably during moderate NPDR compared to drop out at both mild and severe NPDR. Validation of our hypothesis will support development of successful early-stage regenerative therapies such as vascular repair by circulating angiogenic cells (CACs). The renin-angiotensin system (RAS)is implicated in the pathogenesis of DR and in the function of CACs, a critical bone marrow-derived population that is instrumental in vascular repair.

  2. Excitability properties of motor axons in adults with cerebral palsy

    PubMed Central

    Klein, Cliff S.; Zhou, Ping; Marciniak, Christina

    2015-01-01

    Cerebral palsy (CP) is a permanent disorder caused by a lesion to the developing brain that significantly impairs motor function. The neurophysiological mechanisms underlying motor impairment are not well understood. Specifically, few have addressed whether motoneuron or peripheral axon properties are altered in CP, even though disruption of descending inputs to the spinal cord may cause them to change. In the present study, we have compared nerve excitability properties in seven adults with CP and fourteen healthy controls using threshold tracking techniques by stimulating the median nerve at the wrist and recording the compound muscle action potential over the abductor pollicis brevis. The excitability properties in the CP subjects were found to be abnormal. Early and late depolarizing and hyperpolarizing threshold electrotonus was significantly larger (i.e., fanning out), and resting current–threshold (I/V) slope was smaller, in CP compared to control. In addition resting threshold and rheobase tended to be larger in CP. According to a modeling analysis of the data, an increase in leakage current under or through the myelin sheath, i.e., the Barrett–Barrett conductance, combined with a slight hyperpolarization of the resting membrane potential, best explained the group differences in excitability properties. There was a trend for those with greater impairment in gross motor function to have more abnormal axon properties. The findings indicate plasticity of motor axon properties far removed from the site of the lesion. We suspect that this plasticity is caused by disruption of descending inputs to the motoneurons at an early age around the time of their injury. PMID:26089791

  3. Unpacking Early Work Experiences of Young Adults With Rheumatic Disease: An Examination of Absenteeism, Job Disruptions, and Productivity Loss.

    PubMed

    Jetha, Arif; Badley, Elizabeth; Beaton, Dorcas; Fortin, Paul R; Shiff, Natalie J; Gignac, Monique A M

    2015-09-01

    To examine work absenteeism, job disruptions, and perceived productivity loss and factors associated with each outcome in young adults living with systemic lupus erythematosus (SLE) and juvenile arthritis (JA). One hundred forty-three young adults, ages 18-30 years with SLE (54.5%) and JA (45.5%), completed an online survey of work experiences. Demographic, health (e.g., fatigue, disease activity), psychosocial (e.g., independence, social support), and work context (e.g., career satisfaction, job control, self-disclosure) information was collected. Participants were asked about absenteeism, job disruptions, and perceived productivity loss in the last 6 months. Log Poisson regression analyses examined factors associated with work outcomes. A majority of participants (59%) were employed and reported a well-managed health condition. Employed respondents were satisfied with their career progress and indicated moderate job control. More than 40% of participants reported absenteeism, job disruptions, and productivity loss. Greater job control and self-disclosure, and less social support, were related to a higher likelihood of absenteeism. More disease activity was related to a greater likelihood of reporting job disruptions. Lower fatigue and higher job control were associated with a reduced likelihood of a productivity loss. Young adult respondents with rheumatic disease experienced challenges with employment, including absenteeism, job disruptions, and productivity loss. While related to greater absenteeism, job control could play a role in a young person's ability to manage their health condition and sustain productive employment. Greater attention should also be paid to understanding health factors and social support in early work experiences. © 2015, American College of Rheumatology.

  4. Slow Muscle Precursors Lay Down a Collagen XV Matrix Fingerprint to Guide Motor Axon Navigation.

    PubMed

    Guillon, Emilie; Bretaud, Sandrine; Ruggiero, Florence

    2016-03-02

    The extracellular matrix (ECM) provides local positional information to guide motoneuron axons toward their muscle target. Collagen XV is a basement membrane component mainly expressed in skeletal muscle. We have identified two zebrafish paralogs of the human COL15A1 gene, col15a1a and col15a1b, which display distinct expression patterns. Here we show that col15a1b is expressed and deposited in the motor path ECM by slow muscle precursors also called adaxial cells. We further demonstrate that collagen XV-B deposition is both temporally and spatially regulated before motor axon extension from the spinal cord in such a way that it remains in this region after the adaxial cells have migrated toward the periphery of the myotome. Loss- and gain-of-function experiments in zebrafish embryos demonstrate that col15a1b expression and subsequent collagen XV-B deposition and organization in the motor path ECM depend on a previously undescribed two-step mechanism involving Hedgehog/Gli and unplugged/MuSK signaling pathways. In silico analysis predicts a putative Gli binding site in the col15a1b proximal promoter. Using col15a1b promoter-reporter constructs, we demonstrate that col15a1b participates in the slow muscle genetic program as a direct target of Hedgehog/Gli signaling. Loss and gain of col15a1b function provoke pathfinding errors in primary and secondary motoneuron axons both at and beyond the choice point where axon pathway selection takes place. These defects result in muscle atrophy and compromised swimming behavior, a phenotype partially rescued by injection of a smyhc1:col15a1b construct. These reveal an unexpected and novel role for collagen XV in motor axon pathfinding and neuromuscular development. In addition to the archetypal axon guidance cues, the extracellular matrix provides local information that guides motor axons from the spinal cord to their muscle targets. Many of the proteins involved are unknown. Using the zebrafish model, we identified an

  5. A survey of mass-loss effects in early-type stars

    NASA Technical Reports Server (NTRS)

    Snow, T. P., Jr.

    1976-01-01

    Intermediate-resolution data obtained with the Copernicus satellite are surveyed in order to define the region in the H-R diagram where mass loss occurs. The survey includes 40 stars, providing good coverage of supergiants from O4 to A2 and main-sequence stars from O4 to B7 as well as spotty coverage of late O giants and intermediate to late B stars. The spectral transitions examined are primarily resonance lines of ions of abundant elements plus some lines arising from excited states (e.g., C III at 1175.7 A and Si IV at 1122.5 A). Observed P Cygni profiles are discussed along with interesting features of some individual profiles. The data are shown to indicate that mass-loss effects occur over a wide portion of the H-R diagram, that mass ejection generally occurs when the holometric magnitude is greater than -6.0, and that the mass-ejection rate is usually high enough to produce P Cygni profile whenever the N V feature at 1240 A is present in a spectrum.

  6. Partial Denervation of Subbasal Axons Persists Following Debridement Wounds to the Mouse Cornea

    PubMed Central

    Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri; Kyne, Briana M.; Saban, Daniel R.; Stepp, Mary Ann

    2015-01-01

    Although sensory reinnervation occurs after injury in the PNS, poor reinnervation in the elderly and those with diabetes often leads to pathology. Here we quantify subbasal axon density in the central and peripheral mouse cornea over time after three different types of injury. The mouse cornea is highly innervated with a dense array of subbasal nerves that form a spiral called the vortex at the corneal center or apex; these nerves are readily detected within flat mounted corneas. After anesthesia, corneal epithelial cells were removed using either a dulled blade or a rotating burr within an area demarcated centrally with a 1.5 mm trephine. A third wound type, superficial trephination, involved demarcating the area with the 1.5 mm trephine but not removing cells. By 7d after superficial trephination, subbasal axon density returns to control levels; by 28d the vortex reforms. Although axon density is similar to control 14d after dulled blade and rotating burr wounding, defects in axon morphology at the corneal apex remain. After 14d, axons retract from the center leaving the subbasal axon density reduced by 37.2% and 36.8% at 28d after dulled blade and rotating burr wounding, respectively, compared to control. Assessment of inflammation using flow cytometry shows that persistent inflammation is not a factor in the incomplete reinnervation. Expression of mRNAs encoding 22 regeneration associated genes (RAGs) involved in axon targeting assessed by QPCR reveals that netrin-1 and ephrin signaling are altered after wounding. Subpopulations of corneal epithelial basal cells at the corneal apex stop expressing ki67 as early as 7d after injury and by 14d and 28d after wounding, many of these basal cells undergo apoptosis and die. While subbasal axons are restored to their normal density and morphology after superficial trephination, subbasal axon recovery is partial after debridement wounds. The increase in corneal epithelial basal cell apoptosis at the apex observed at 14d

  7. Partial denervation of sub-basal axons persists following debridement wounds to the mouse cornea.

    PubMed

    Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri; Kyne, Briana M; Saban, Daniel R; Stepp, Mary Ann

    2015-11-01

    Although sensory reinnervation occurs after injury in the peripheral nervous system, poor reinnervation in the elderly and those with diabetes often leads to pathology. Here we quantify sub-basal axon density in the central and peripheral mouse cornea over time after three different types of injury. The mouse cornea is highly innervated with a dense array of sub-basal nerves that form a spiral called the vortex at the corneal center or apex; these nerves are readily detected within flat mounted corneas. After anesthesia, corneal epithelial cells were removed using either a dulled blade or a rotating burr within an area demarcated centrally with a 1.5 mm trephine. A third wound type, superficial trephination, involved demarcating the area with the 1.5 mm trephine but not removing cells. By 7 days after superficial trephination, sub-basal axon density returns to control levels; by 28 days the vortex reforms. Although axon density is similar to control 14 days after dulled blade and rotating burr wounding, defects in axon morphology at the corneal apex remain. After 14 days, axons retract from the center leaving the sub-basal axon density reduced by 37.2 and 36.8% at 28 days after dulled blade and rotating burr wounding, respectively, compared with control. Assessment of inflammation using flow cytometry shows that persistent inflammation is not a factor in the incomplete reinnervation. Expression of mRNAs encoding 22 regeneration-associated genes involved in axon targeting assessed by QPCR reveals that netrin-1 and ephrin signaling are altered after wounding. Subpopulations of corneal epithelial basal cells at the corneal apex stop expressing ki67 as early as 7 days after injury and by 14 and 28 days after wounding, many of these basal cells undergo apoptosis and die. Although sub-basal axons are restored to their normal density and morphology after superficial trephination, sub-basal axon recovery is partial after debridement wounds. The increase in corneal

  8. Evidence for Sprouting of Dopamine and Serotonin Axons in the Pallidum of Parkinsonian Monkeys

    PubMed Central

    Gagnon, Dave; Eid, Lara; Coudé, Dymka; Whissel, Carl; Di Paolo, Thérèse; Parent, André; Parent, Martin

    2018-01-01

    This light and electron microscopie immunohistochemical quantitative study aimed at determining the state of the dopamine (DA) and serotonin (5-HT) innervations of the internal (GPi) and external (GPe) segments of the pallidum in cynomolgus monkeys (Macaca fascicularis) rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to the prominent DA denervation of striatum, the GPi in MPTP monkeys was found to be markedly enriched in DA (TH+) axon varicosities. The posterior sensorimotor region of this major output structure of the basal ganglia was about 8 times more intensely innervated in MPTP monkeys (0.71 ± 0.08 × 106 TH+ axon varicosities/mm3) than in controls (0.09 ± 0.01 × 106). MPTP intoxication also induced a two-fold increase in the density of 5-HT (SERT+) axon varicosities in both GPe and GPi. This augmentation was particularly pronounced anteriorly in the so-called associative and limbic pallidal territories. The total length of the labeled pallidal axons was also significantly increased in MPTP monkeys compared to controls, but the number of DA and 5-HT axon varicosities per axon length unit remained the same in the two groups, indicating that the DA and 5-HT pallidal hyperinnervations seen in MPTP monkeys result from axon sprouting rather than from the appearance of newly formed axon varicosities on non-growing axons. At the ultrastructural level, pallidal TH+ and SERT+ axons were morphologically similar in MPTP and controls, and their synaptic incidence was very low suggesting a volumic mode of transmission. Altogether, our data reveal a significant sprouting of DA and 5-HT pallidal afferents in parkinsonian monkeys, the functional significance of which remains to be determined. We suggest that the marked DA hyperinnervation of the GPi represents a neuroadaptive change designed to normalize pallidal firing patterns associated with the delayed appearance of motor symptoms, whereas the 5-HT

  9. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis

    PubMed Central

    Zambonin, Jessica L.; Zhao, Chao; Ohno, Nobuhiko; Campbell, Graham R.; Engeham, Sarah; Ziabreva, Iryna; Schwarz, Nadine; Lee, Sok Ee; Frischer, Josa M.; Turnbull, Doug M.; Trapp, Bruce D.; Lassmann, Hans; Franklin, Robin J. M.

    2011-01-01

    Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in

  10. Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis.

    PubMed

    Zambonin, Jessica L; Zhao, Chao; Ohno, Nobuhiko; Campbell, Graham R; Engeham, Sarah; Ziabreva, Iryna; Schwarz, Nadine; Lee, Sok Ee; Frischer, Josa M; Turnbull, Doug M; Trapp, Bruce D; Lassmann, Hans; Franklin, Robin J M; Mahad, Don J

    2011-07-01

    Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in

  11. Effect of Long-Term Cannabis Use on Axonal Fibre Connectivity

    ERIC Educational Resources Information Center

    Zalesky, Andrew; Solowij, Nadia; Yucel, Murat; Lubman, Dan I.; Takagi, Michael; Harding, Ian H.; Lorenzetti, Valentina; Wang, Ruopeng; Searle, Karissa; Pantelis, Christos; Seal, Marc

    2012-01-01

    Cannabis use typically begins during adolescence and early adulthood, a period when cannabinoid receptors are still abundant in white matter pathways across the brain. However, few studies to date have explored the impact of regular cannabis use on white matter structure, with no previous studies examining its impact on axonal connectivity. The…

  12. Guidance of retinal axons in mammals.

    PubMed

    Herrera, Eloísa; Erskine, Lynda; Morenilla-Palao, Cruz

    2017-11-26

    In order to navigate through the surrounding environment many mammals, including humans, primarily rely on vision. The eye, composed of the choroid, sclera, retinal pigmented epithelium, cornea, lens, iris and retina, is the structure that receives the light and converts it into electrical impulses. The retina contains six major types of neurons involving in receiving and modifying visual information and passing it onto higher visual processing centres in the brain. Visual information is relayed to the brain via the axons of retinal ganglion cells (RGCs), a projection known as the optic pathway. The proper formation of this pathway during development is essential for normal vision in the adult individual. Along this pathway there are several points where visual axons face 'choices' in their direction of growth. Understanding how these choices are made has advanced significantly our knowledge of axon guidance mechanisms. Thus, the development of the visual pathway has served as an extremely useful model to reveal general principles of axon pathfinding throughout the nervous system. However, due to its particularities, some cellular and molecular mechanisms are specific for the visual circuit. Here we review both general and specific mechanisms involved in the guidance of mammalian RGC axons when they are traveling from the retina to the brain to establish precise and stereotyped connections that will sustain vision. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Optimization of CRISPR/Cas9 genome editing for loss-of-function in the early chick embryo.

    PubMed

    Gandhi, Shashank; Piacentino, Michael L; Vieceli, Felipe M; Bronner, Marianne E

    2017-12-01

    The advent of CRISPR/Cas9 has made genome editing possible in virtually any organism, including those not previously amenable to genetic manipulations. Here, we present an optimization of CRISPR/Cas9 for application to early avian embryos with improved efficiency via a three-fold strategy. First, we employed Cas9 protein flanked with two nuclear localization signal sequences for improved nuclear localization. Second, we used a modified guide RNA (gRNA) scaffold that obviates premature termination of transcription and unstable Cas9-gRNA interactions. Third, we used a chick-specific U6 promoter that yields 4-fold higher gRNA expression than the previously utilized human U6. For rapid screening of gRNAs for in vivo applications, we also generated a chicken fibroblast cell line that constitutively expresses Cas9. As proof of principle, we performed electroporation-based loss-of-function studies in the early chick embryo to knock out Pax7 and Sox10, key transcription factors with known functions in neural crest development. The results show that CRISPR/Cas9-mediated deletion causes loss of their respective proteins and transcripts, as well as predicted downstream targets. Taken together, the results reveal the utility of this optimized CRISPR/Cas9 method for targeted gene knockout in chicken embryos in a manner that is reproducible, robust and specific. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC

    PubMed Central

    Petersen, Lars F.; Klimowicz, Alexander C.; Otsuka, Shannon; Elegbede, Anifat A.; Petrillo, Stephanie K.; Williamson, Tyler; Williamson, Chris T.; Konno, Mie; Lees-Miller, Susan P.; Hao, Desiree; Morris, Don; Magliocco, Anthony M.; Bebb, D. Gwyn

    2017-01-01

    Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Tissue microarrays, containing 165 formalin-fixed, paraffin-embedded resected NSCLC tumours from patients diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, between 2003 and 2006, were analyzed for ATM expression using quantitative fluorescence immunohistochemistry. Both malignant cell-specific ATM expression and the ratio of ATM expression within malignant tumour cells compared to that in the surrounding tumour stroma, defined as the ATM expression index (ATM-EI), were measured and correlated with clinical outcome. ATM loss was identified in 21.8% of patients, and was unaffected by clinical pathological variables. Patients with low ATM-EI tumours had worse survival outcomes compared to those with high ATM-EI (p < 0.01). This effect was pronounced in stage II/III patients, even after adjusting for other clinical co-variates (p < 0.001). Additionally, we provide evidence that ATM-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. Taken together, these results indicate that ATM loss seems to be an early event in NSCLC carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients. PMID:28418844

  15. Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC.

    PubMed

    Petersen, Lars F; Klimowicz, Alexander C; Otsuka, Shannon; Elegbede, Anifat A; Petrillo, Stephanie K; Williamson, Tyler; Williamson, Chris T; Konno, Mie; Lees-Miller, Susan P; Hao, Desiree; Morris, Don; Magliocco, Anthony M; Bebb, D Gwyn

    2017-06-13

    Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Tissue microarrays, containing 165 formalin-fixed, paraffin-embedded resected NSCLC tumours from patients diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, between 2003 and 2006, were analyzed for ATM expression using quantitative fluorescence immunohistochemistry. Both malignant cell-specific ATM expression and the ratio of ATM expression within malignant tumour cells compared to that in the surrounding tumour stroma, defined as the ATM expression index (ATM-EI), were measured and correlated with clinical outcome. ATM loss was identified in 21.8% of patients, and was unaffected by clinical pathological variables. Patients with low ATM-EI tumours had worse survival outcomes compared to those with high ATM-EI (p < 0.01). This effect was pronounced in stage II/III patients, even after adjusting for other clinical co-variates (p < 0.001). Additionally, we provide evidence that ATM-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. Taken together, these results indicate that ATM loss seems to be an early event in NSCLC carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients.

  16. Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila.

    PubMed

    Hing, H; Xiao, J; Harden, N; Lim, L; Zipursky, S L

    1999-06-25

    The SH2/SH3 adaptor protein Dock has been proposed to transduce signals from guidance receptors to the actin cytoskeleton in Drosophila photoreceptor (R cell) growth cones. Here, we demonstrate that Drosophila p21-activated kinase (Pak) is required in a Dock pathway regulating R cell axon guidance and targeting. Dock and Pak colocalize to R cell axons and growth cones, physically interact, and their loss-of-function phenotypes are indistinguishable. Normal patterns of R cell connectivity require Pak's kinase activity and binding sites for both Dock and Cdc42/Rac. A membrane-tethered form of Pak (Pak(myr) acts as a dominant gain-of-function protein. Retinal expression of Pak(myr) rescues the R cell connectivity phenotype in dock mutants. These data establish Pak as a critical regulator of axon guidance and a downstream effector of Dock in vivo.

  17. Two receptor tyrosine phosphatases dictate the depth of axonal stabilizing layer in the visual system

    PubMed Central

    Takechi, Hiroki; Kawamura, Hinata

    2017-01-01

    Formation of a functional neuronal network requires not only precise target recognition, but also stabilization of axonal contacts within their appropriate synaptic layers. Little is known about the molecular mechanisms underlying the stabilization of axonal connections after reaching their specifically targeted layers. Here, we show that two receptor protein tyrosine phosphatases (RPTPs), LAR and Ptp69D, act redundantly in photoreceptor afferents to stabilize axonal connections to the specific layers of the Drosophila visual system. Surprisingly, by combining loss-of-function and genetic rescue experiments, we found that the depth of the final layer of stable termination relied primarily on the cumulative amount of LAR and Ptp69D cytoplasmic activity, while specific features of their ectodomains contribute to the choice between two synaptic layers, M3 and M6, in the medulla. These data demonstrate how the combination of overlapping downstream but diversified upstream properties of two RPTPs can shape layer-specific wiring. PMID:29116043

  18. Early spring, severe frost events, and drought induce rapid carbon loss in high elevation meadows.

    PubMed

    Arnold, Chelsea; Ghezzehei, Teamrat A; Berhe, Asmeret Asefaw

    2014-01-01

    By the end of the 20th century, the onset of spring in the Sierra Nevada mountain range of California has been occurring on average three weeks earlier than historic records. Superimposed on this trend is an increase in the presence of highly anomalous "extreme" years, where spring arrives either significantly late or early. The timing of the onset of continuous snowpack coupled to the date at which the snowmelt season is initiated play an important role in the development and sustainability of mountain ecosystems. In this study, we assess the impact of extreme winter precipitation variation on aboveground net primary productivity and soil respiration over three years (2011 to 2013). We found that the duration of snow cover, particularly the timing of the onset of a continuous snowpack and presence of early spring frost events contributed to a dramatic change in ecosystem processes. We found an average 100% increase in soil respiration in 2012 and 2103, compared to 2011, and an average 39% decline in aboveground net primary productivity observed over the same time period. The overall growing season length increased by 57 days in 2012 and 61 days in 2013. These results demonstrate the dependency of these keystone ecosystems on a stable climate and indicate that even small changes in climate can potentially alter their resiliency.

  19. Axon and dendrite geography predict the specificity of synaptic connections in a functioning spinal cord network.

    PubMed

    Li, Wen-Chang; Cooke, Tom; Sautois, Bart; Soffe, Stephen R; Borisyuk, Roman; Roberts, Alan

    2007-09-10

    How specific are the synaptic connections formed as neuronal networks develop and can simple rules account for the formation of functioning circuits? These questions are assessed in the spinal circuits controlling swimming in hatchling frog tadpoles. This is possible because detailed information is now available on the identity and synaptic connections of the main types of neuron. The probabilities of synapses between 7 types of identified spinal neuron were measured directly by making electrical recordings from 500 pairs of neurons. For the same neuron types, the dorso-ventral distributions of axons and dendrites were measured and then used to calculate the probabilities that axons would encounter particular dendrites and so potentially form synaptic connections. Surprisingly, synapses were found between all types of neuron but contact probabilities could be predicted simply by the anatomical overlap of their axons and dendrites. These results suggested that synapse formation may not require axons to recognise specific, correct dendrites. To test the plausibility of simpler hypotheses, we first made computational models that were able to generate longitudinal axon growth paths and reproduce the axon distribution patterns and synaptic contact probabilities found in the spinal cord. To test if probabilistic rules could produce functioning spinal networks, we then made realistic computational models of spinal cord neurons, giving them established cell-specific properties and connecting them into networks using the contact probabilities we had determined. A majority of these networks produced robust swimming activity. Simple factors such as morphogen gradients controlling dorso-ventral soma, dendrite and axon positions may sufficiently constrain the synaptic connections made between different types of neuron as the spinal cord first develops and allow functional networks to form. Our analysis implies that detailed cellular recognition between spinal neuron types may

  20. Axonal transport: cargo-specific mechanisms of motility and regulation.

    PubMed

    Maday, Sandra; Twelvetrees, Alison E; Moughamian, Armen J; Holzbaur, Erika L F

    2014-10-22

    Axonal transport is essential for neuronal function, and many neurodevelopmental and neurodegenerative diseases result from mutations in the axonal transport machinery. Anterograde transport supplies distal axons with newly synthesized proteins and lipids, including synaptic components required to maintain presynaptic activity. Retrograde transport is required to maintain homeostasis by removing aging proteins and organelles from the distal axon for degradation and recycling of components. Retrograde axonal transport also plays a major role in neurotrophic and injury response signaling. This review provides an overview of axonal transport pathways and discusses their role in neuronal function.

  1. Schooling and wage income losses due to early-childhood growth faltering in developing countries: national, regional, and global estimates.

    PubMed

    Fink, Günther; Peet, Evan; Danaei, Goodarz; Andrews, Kathryn; McCoy, Dana Charles; Sudfeld, Christopher R; Smith Fawzi, Mary C; Ezzati, Majid; Fawzi, Wafaie W

    2016-07-01

    The growth of >300 million children <5 y old was mildly, moderately, or severely stunted worldwide in 2010. However, national estimates of the human capital and financial losses due to growth faltering in early childhood are not available. We quantified the economic cost of growth faltering in developing countries. We combined the most recent country-level estimates of linear growth delays from the Nutrition Impact Model Study with estimates of returns to education in developing countries to estimate the impact of early-life growth faltering on educational attainment and future incomes. Primary outcomes were total years of educational attainment lost as well as the net present value of future wage earnings lost per child and birth cohort due to growth faltering in 137 developing countries. Bootstrapped standard errors were computed to account for uncertainty in modeling inputs. Our estimates suggest that early-life growth faltering in developing countries caused a total loss of 69.4 million y of educational attainment (95% CI: 41.7 million, 92.6 million y) per birth cohort. Educational attainment losses were largest in South Asia (27.6 million y; 95% CI: 20.0 million, 35.8 million y) as well as in Eastern (10.3 million y; 95% CI: 7.2 million, 12.9 million y) and Western sub-Saharan Africa (8.8 million y; 95% CI: 6.4 million, 11.5 million y). Globally, growth faltering in developing countries caused a total economic cost of $176.8 billion (95% CI: $100.9 billion, $262.6 billion)/birth cohort at nominal exchange rates, and $616.5 billion (95% CI: $365.3 billion, $898.9 billion) at purchasing power parity-adjusted exchange rates. At the regional level, economic costs were largest in South Asia ($46.6 billion; 95% CI: $33.3 billion, $61.1 billion), followed by Latin America ($44.7 billion; 95% CI: $19.2 billion, $74.6 billion) and sub-Saharan Africa ($34.2 billion; 95% CI: $24.4 billion, $45.3 billion). Our results indicate that the annual cost of early

  2. Substantia Nigra Volume Loss Before Basal Forebrain Degeneration in Early Parkinson Disease

    PubMed Central

    Ziegler, David A.; Wonderlick, Julien S.; Ashourian, Paymon; Hansen, Leslie A.; Young, Jeremy C.; Murphy, Alex J.; Koppuzha, Cecily K.; Growdon, John H.; Corkin, Suzanne

    2017-01-01

    Objective To test the hypothesis that degeneration of the substantia nigra pars compacta (SNc) precedes that of the cholinergic basal forebrain (BF) in Parkinson disease (PD) using new multispectral structural magnetic resonance (MR) imaging tools to measure the volumes of the SNc and BF. Design Matched case-control study. Setting The Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), and the Massachusetts General Hospital/MIT Morris Udall Center of Excellence in Parkinson Disease Research. Patients Participants included 29 patients with PD (Hoehn and Yahr [H&Y] stages 1–3) and 27 matched healthy control subjects. Main Outcome Measures We acquired multiecho T1-weighted, multiecho proton density, T2-weighted, and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences from each participant. For the SNc, we created a weighted mean of the multiple echoes, yielding a single volume with a high ratio of contrast to noise. We visualized the BF using T2-weighted FLAIR images. For each participant, we manually labeled the 2 structures and calculated their volumes. Results Relative to the controls, 13 patients with H&Y stage 1 PD had significantly decreased SNc volumes. Sixteen patients with H&Y stage 2 or 3 PD showed little additional volume loss. In contrast, the BF volume loss occurred later in the disease, with a significant decrease apparent in patients having H&Y stage 2 or 3 PD compared with the controls and the patients having H&Y stage 1 PD. The latter group did not differ significantly from the controls. Conclusion Our results support the proposed neuropathological trajectory in PD and establish novel multispectral methods as MR imaging biomarkers for tracking the degeneration of the SNc and BF. PMID:23183921

  3. The pattern of early lung parenchymal and air space injury following acute blood loss.

    PubMed

    Younger, J G; Taqi, A S; Jost, P F; Till, G O; Johnson, K J; Stern, S A; Hirschl, R B

    1998-07-01

    Acute lung injury is a frequent clinical occurrence following blood loss and trauma. The nature of this injury remains poorly understood. To examine the relative parenchymal and intra-alveolar distribution of inflammation in a rat model of hemorrhage and resuscitation. Rats were anesthetized and subjected to hemorrhage followed by resuscitation with shed blood and saline. Myeloperoxidase activity of lung homogenates and cytology of bronchoalveolar lavage fluid were used to measure total lung and intra-alveolar neutrophil invasion. Extravasation of i.v.-administered [125I]-albumin was used to determine total lung and alveolar permeability. Permeability results were analyzed using their base-10 logarithmic transformations. 86 animals were studied. Whole-lung myeloperoxidase activity was increased (control = 0.34 +/- 0.16 units, injured = 0.84 +/- 0.43 units, p < 0.01), while there was no difference in intra-alveolar leukocyte counts (injured = 1.85 +/- 1.30 x 10(5)/mL, control = 2.44 +/- 1.75 x 10(5)/mL, p = 0.40), suggesting that the cellular component of the injury was more severe in the intravascular and interstitial spaces. There was a strong trend toward increased permeability in the interstitial compartment, and a significant increase in permeability in the intra-alveolar compartment (whole-lung permeability: control = -0.27 +/- 0.19 units, injured = 0.10 +/- 0.55 units, p = 0.06; alveolar permeability: control = -2.00 +/- 0.47 units, injured = -1.32 +/- 0.49 units, p < 0.01), suggesting that the loss of integrity to macromolecules was not limited to the interstitium. Hemorrhage and resuscitation resulted in an acute lung injury characterized by extravasation of intravascular protein into both the interstitium and the intra-alveolar space. Neutrophil invasion of the lung was demonstrable only in the interstitial compartment.

  4. Early potential effects of resveratrol supplementation on skeletal muscle adaptation involved in exercise-induced weight loss in obese mice.

    PubMed

    Sun, Jingyu; Zhang, Chen; Kim, MinJeong; Su, Yajuan; Qin, Lili; Dong, Jingmei; Zhou, Yunhe; Ding, Shuzhe

    2018-04-01

    Exercise and resveratrol supplementation exhibit anti-obesity functions in the long term but have not been fully investigated yet in terms of their early potential effectiveness. Mice fed with high-fat diet were categorized into control (Cont), exercise (Ex), resveratrol supplementation (Res), and exercise combined with resveratrol supplementation (Ex + Res) groups. In the four-week period of weight loss, exercise combined with resveratrol supplementation exerted no additional effects on body weight loss but significantly improved whole-body glucose and lipid homeostasis. The combined treatment significantly decreased intrahepatic lipid content but did not affect intramyocellular lipid content. Moreover, the treatment significantly increased the contents of mtDNA and cytochrome c, the expression levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and its downstream transcription factors, and the activities of ATPase and citrate synthase. However, exercise, resveratrol, and their combination did not promote myofiber specification toward slow-twitch type. The effects of exercise combined with resveratrol supplementation on weight loss could be partly due to enhanced mitochondrial biogenesis and not to fiber-type shift in skeletal muscle tissues. [BMB Reports 2018; 51(4): 200-205].

  5. Loss of Robustness and Addiction to IGF1 during Early Keratinocyte Transformation by Human Papilloma Virus 16

    PubMed Central

    Geiger, Tamar; Levitzki, Alexander

    2007-01-01

    Infection of keratinocytes with high risk human Papilloma virus causes immortalization, and when followed by further mutations, leads to cervical cancer and other anogenital tumors. Here we monitor the progressive loss of robustness in an in vitro model of the early stages of transformation that comprises normal keratinocytes and progressive passages of HPV16 immortalized cells. As transformation progresses, the cells acquire higher proliferation rates and gain the ability to grow in soft agar. Concurrently, the cells lose robustness, becoming more sensitive to serum starvation and DNA damage by Cisplatin. Loss of robustness in the course of transformation correlates with significant reductions in the activities of the anti-apoptotic proteins PKB/Akt, Erk, Jnk and p38 both under normal growth conditions and upon stress. In parallel, loss of robustness is manifested by the shrinkage of the number of growth factors that can rescue starving cells from apoptosis, with the emergence of dependence solely on IGF1. Treatment with IGF1 activates PKB/Akt and Jnk and through them inhibits p53, rescuing the cells from starvation. We conclude that transformation in this model induces higher susceptibility of cells to stress due to reduced anti-apoptotic signaling and hyper-activation of p53 upon stress. PMID:17622350

  6. Immunohistochemical and transcriptome analyses indicate complex breakdown of axonal transport mechanisms in canine distemper leukoencephalitis.

    PubMed

    Spitzbarth, Ingo; Lempp, Charlotte; Kegler, Kristel; Ulrich, Reiner; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang; Seehusen, Frauke

    2016-07-01

    CDV-DL (Canine distemper virus-induced demyelinating leukoencephalitis) represents a spontaneously occurring animal model for demyelinating disorders. Axonopathy represents a key pathomechanism in this disease; however, its underlying pathogenesis has not been addressed in detail so far. This study aimed at the characterization of axonal cytoskeletal, transport, and potential regenerative changes with a parallel focus upon Schwann cell remyelination. Immunohistochemistry of canine cerebellar tissue as well as a comparative analysis of genes from an independent microarray study were performed. Increased axonal immunoreactivity for nonphosphorylated neurofilament was followed by loss of cytoskeletal and motor proteins. Interestingly, a subset of genes encoding for neurofilament subunits and motor proteins was up-regulated in the chronic stage compared to dogs with subacute CDV-DL. However, immunohistochemically, hints for axonal regeneration were restricted to up-regulated axonal positivity of hypoxia-inducible factor 1 alpha, while growth-associated protein 43, erythropoietin and its receptor were not or even down-regulated. Periaxin-positive structures, indicative of Schwann cell remyelination, were only detected within few advanced lesions. The present findings demonstrate a complex sequence of axonal cytoskeletal breakdown mechanisms. Moreover, though sparse, this is the first report of Schwann cell remyelination in CDV-DL. Facilitation of these very limited endogenous regenerative responses represents an important topic for future research.

  7. Formation of compact myelin is required for maturation of the axonal cytoskeleton

    NASA Technical Reports Server (NTRS)

    Brady, S. T.; Witt, A. S.; Kirkpatrick, L. L.; de Waegh, S. M.; Readhead, C.; Tu, P. H.; Lee, V. M.

    1999-01-01

    Although traditional roles ascribed to myelinating glial cells are structural and supportive, the importance of compact myelin for proper functioning of the nervous system can be inferred from mutations in myelin proteins and neuropathologies associated with loss of myelin. Myelinating Schwann cells are known to affect local properties of peripheral axons (de Waegh et al., 1992), but little is known about effects of oligodendrocytes on CNS axons. The shiverer mutant mouse has a deletion in the myelin basic protein gene that eliminates compact myelin in the CNS. In shiverer mice, both local axonal features like phosphorylation of cytoskeletal proteins and neuronal perikaryon functions like cytoskeletal gene expression are altered. This leads to changes in the organization and composition of the axonal cytoskeleton in shiverer unmyelinated axons relative to age-matched wild-type myelinated fibers, although connectivity and patterns of neuronal activity are comparable. Remarkably, transgenic shiverer mice with thin myelin sheaths display an intermediate phenotype indicating that CNS neurons are sensitive to myelin sheath thickness. These results indicate that formation of a normal compact myelin sheath is required for normal maturation of the neuronal cytoskeleton in large CNS neurons.

  8. X11/Mint Genes Control Polarized Localization of Axonal Membrane Proteins in Vivo

    PubMed Central

    Gross, Garrett G.; Lone, G. Mohiddin; Leung, Lok Kwan; Hartenstein, Volker

    2013-01-01

    Mislocalization of axonal proteins can result in misassembly and/or miswiring of neural circuits, causing disease. To date, only a handful of genes that control polarized localization of axonal membrane proteins have been identified. Here we report that Drosophila X11/Mint proteins are required for targeting several proteins, including human amyloid precursor protein (APP) and Drosophila APP-like protein (APPL), to axonal membranes and for their exclusion from dendrites of the mushroom body in Drosophila, a brain structure involved in learning and memory. Axonal localization of APP is mediated by an endocytic motif, and loss of X11/Mint results in a dramatic increase in cell-surface levels of APPL, especially on dendrites. Mutations in genes required for endocytosis show similar mislocalization of these proteins to dendrites, and strongly enhance defects seen in X11/Mint mutants. These results suggest that X11/Mint-dependent endocytosis in dendrites may serve to promote the axonal localization of membrane proteins. Since X11/Mint binds to APP, and abnormal trafficking of APP contributes to Alzheimer's disease, deregulation of X11/Mint may be important for Alzheimer's disease pathogenesis. PMID:23658195

  9. Predictors of Early Reading Skill in 5-Year-Old Children With Hearing Loss Who Use Spoken Language

    PubMed Central

    Ching, Teresa Y.C.; Crowe, Kathryn; Day, Julia; Seeto, Mark

    2013-01-01

    This research investigated the concurrent association between early reading skills and phonological awareness (PA), print knowledge, language, cognitive, and demographic variables in 101 5-year-old children with prelingual hearing losses ranging from mild to profound who communicated primarily using spoken language. All participants were fitted with hearing aids (n = 71) or cochlear implants (n = 30). They completed standardized assessments of PA, receptive vocabulary, letter knowledge, word and non-word reading, passage comprehension, math reasoning, and nonverbal cognitive ability. Multiple regressions revealed that PA (assessed using judgments of similarity based on words’ initial or final sounds) made a significant, independent contribution to children’s early reading ability (for both letters and words/non-words) after controlling for variation in receptive vocabulary, nonverbal cognitive ability, and a range of demographic variables (including gender, degree of hearing loss, communication mode, type of sensory device, age at fitting of sensory devices, and level of maternal education). Importantly, the relationship between PA and reading was specific to reading and did not generalize to another academic ability, math reasoning. Additional multiple regressions showed that letter knowledge (names or sounds) was superior in children whose mothers had undertaken post-secondary education, and that better receptive vocabulary was associated with less severe hearing loss, use of a cochlear implant, and earlier age at implant switch-on. Earlier fitting of hearing aids or cochlear implants was not, however, significantly associated with better PA or reading outcomes in this cohort of children, most of whom were fitted with sensory devices before 3 years of age. PMID:24563553

  10. Acute motor-sensory axonal neuropathy with hyperreflexia in Guillain-Barré syndrome.

    PubMed

    Tosun, Ayşe; Dursun, Şiar; Akyildiz, Utku Ogan; Oktay, Seçil; Tataroğlu, Cengiz

    2015-04-01

    Guillain-Barré syndrome is an acute inflammatory autoimmune polyradiculoneuritis. Progressive motor weakness and areflexia are essential for its diagnosis. Hyperreflexia has rarely been reported in the early healing period of Guillain-Barré syndrome following Campylobacter jejuni infection in patients with acute motor axonal neuropathy with antiganglioside antibody positivity. In this study, we report a 12-year-old girl presenting with complaints of inability to walk, numbness in hands and feet, and hyperactive deep tendon reflexes since the onset of the clinical picture, diagnosed with acute motor-sensory axonal neuropathy type of Guillain-Barré syndrome. © The Author(s) 2014.

  11. Role of inflammatory proteins S100A8 and S100A9 in pathophysiology of recurrent early pregnancy loss.

    PubMed

    Nair, R R; Khanna, A; Singh, K

    2013-09-01

    Altered expression of inflammatory molecule at the maternal fetal interface is associated with early pregnancy loss. S100A8 and S100A9 are inflammatory proteins and they exhibit cytokine like function enhancing leukocyte recruitment to the inflammatory site. Reports from mouse model suggest the role of S100A8 with the vasculature of the decidual tissue and leukocyte recruitment during early pregnancy. Hence we hypothesized that maternal overexpression of S100A8 & S100A9 might increase the recruitment of inflammatory leukocytes in maternal-fetal interface resulting in uteroplacental perfusion deficiency, development of thrombotic events, and placental hypoxia, eventually embryo abortion. In the present study we investigated altered expression of S100A8 and S100A9 in 25 recurrent early pregnancy loss (REPL) patients compared to 40 induced abortion subjects as controls. S100A8 and S100A9 mRNA were evaluated using semi-quantitative RT-PCR and quantitative real-time PCR. To determine if differential expression pattern of these transcripts is translated to protein western blot analysis was performed.S100A8 and S100A9 mRNA and protein level were significantly increased in endometrial decidua tissue (p < 0.05) of REPL patients as compared to controls. This is the first report predicting the role of inflammatory molecules S100A8 & S100A9 in REPL. It opens a new perspective for understanding significance of S100A8 and S100A9 in pregnancy maintenance and outcome. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Preclinical Evaluation of a Decision Support Medical Monitoring System for Early Detection of Potential Hemodynamic Decompensation During Blood Loss in Humans

    DTIC Science & Technology

    2013-09-01

    Hemodynamic Decompensation During Blood Loss in Humans PRINCIPAL INVESTIGATOR: Michael J. Joyner, M.D. CONTRACTING ORGANIZATION: Mayo Clinic...Medical Monitoring System for Early Detection of Potential Hemodynamic Decompensation During Blood Loss in Humans 5c. PROGRAM ELEMENT NUMBER 6...loss and hemorrhage in humans. The aim Is to be able to detect subtle changes in hemodynamic variables that provide prodromal clues to Impending

  13. Microfluidic device for unidirectional axon growth

    NASA Astrophysics Data System (ADS)

    Malishev, E.; Pimashkin, A.; Gladkov, A.; Pigareva, Y.; Bukatin, A.; Kazantsev, V.; Mukhina, I.; Dubina, M.

    2015-11-01

    In order to better understand the communication and connectivity development of neuron networks, we designed microfluidic devices with several chambers for growing dissociated neuronal cultures from mice fetal hippocampus (E18). The chambers were connected with microchannels providing unidirectional axonal growth between “Source” and “Target” neural sub-networks. Experiments were performed in a hippocampal cultures plated in a poly-dimethylsiloxane (PDMS) microfluidic chip, aligned with a 60 microelectrode array (MEA). Axonal growth through microchannels was observed with brightfield, phase-contrast and fluorescence microscopy, and after 7 days in vitro electrical activity was recorded. Visual inspection and spike propagation analysis showed the predominant axonal growth in microchannels in a direction from “Source” to “Target”.

  14. Photothermal tomography for the functional and structural evaluation, and early mineral loss monitoring in bones.

    PubMed

    Kaiplavil, Sreekumar; Mandelis, Andreas; Wang, Xueding; Feng, Ting

    2014-08-01

    Salient features of a new non-ionizing bone diagnostics technique, truncated-correlation photothermal coherence tomography (TC-PCT), exhibiting optical-grade contrast and capable of resolving the trabecular network in three dimensions through the cortical region with and without a soft-tissue overlayer are presented. The absolute nature and early demineralization-detection capability of a marker called thermal wave occupation index, estimated using the proposed modality, have been established. Selective imaging of regions of a specific mineral density range has been demonstrated in a mouse femur. The method is maximum-permissible-exposure compatible. In a matrix of bone and soft-tissue a depth range of ~3.8 mm has been achieved, which can be increased through instrumental and modulation waveform optimization. Furthermore, photoacoustic microscopy, a comparable modality with TC-PCT, has been used to resolve the trabecular structure and for comparison with the photothermal tomography.

  15. Photothermal tomography for the functional and structural evaluation, and early mineral loss monitoring in bones

    PubMed Central

    Kaiplavil, Sreekumar; Mandelis, Andreas; Wang, Xueding; Feng, Ting

    2014-01-01

    Salient features of a new non-ionizing bone diagnostics technique, truncated-correlation photothermal coherence tomography (TC-PCT), exhibiting optical-grade contrast and capable of resolving the trabecular network in three dimensions through the cortical region with and without a soft-tissue overlayer are presented. The absolute nature and early demineralization-detection capability of a marker called thermal wave occupation index, estimated using the proposed modality, have been established. Selective imaging of regions of a specific mineral density range has been demonstrated in a mouse femur. The method is maximum-permissible-exposure compatible. In a matrix of bone and soft-tissue a depth range of ~3.8 mm has been achieved, which can be increased through instrumental and modulation waveform optimization. Furthermore, photoacoustic microscopy, a comparable modality with TC-PCT, has been used to resolve the trabecular structure and for comparison with the photothermal tomography. PMID:25136480

  16. Early loss of the glucagon response to hypoglycemia in adolescents with type 1 diabetes.

    PubMed

    Siafarikas, Aris; Johnston, Robert J; Bulsara, Max K; O'Leary, Peter; Jones, Timothy W; Davis, Elizabeth A

    2012-08-01

    To assess the glucagon response to hypoglycemia and identify influencing factors in patients with type 1 diabetes compared with nondiabetic control subjects. Hyperinsulinemic hypoglycemic clamp studies were performed in all participants. The glucagon response to both hypoglycemia and arginine was measured, as well as epinephrine, cortisol, and growth hormone responses to hypoglycemia. Residual β-cell function was assessed using fasting and stimulated C-peptide. Twenty-eight nonobese adolescents with type 1 diabetes (14 female, mean age 14.9 years [range 11.2-19.8]) and 12 healthy control subjects (6 female, 15.3 years [12.8-18.7]) participated in the study. Median duration of type 1 diabetes was 0.66 years (range 0.01-9.9). The glucagon peak to arginine stimulation was similar between groups (P = 0.27). In contrast, the glucagon peak to hypoglycemia was reduced in the group with diabetes (95% CI): 68 (62-74) vs. 96 (87-115) pg/mL (P < 0.001). This response was greater than 3 SDs from baseline for only 7% of subjects with type 1 diabetes in comparison with 83% of control subjects and was lost at a median duration of diabetes of 8 months and as early as 1 month after diagnosis (R = -0.41, P < 0.01). There was no correlation in response with height, weight, BMI, and HbA(1c). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were present in both groups. The glucagon response to hypoglycemia in adolescents with type 1 diabetes is influenced by the duration of diabetes and can be lost early in the course of the disease.

  17. Early loss of subchondral bone following microfracture is counteracted by bone marrow aspirate in a translational model of osteochondral repair

    PubMed Central

    Gao, Liang; Orth, Patrick; Müller-Brandt, Kathrin; Goebel, Lars K. H.; Cucchiarini, Magali; Madry, Henning

    2017-01-01

    Microfracture of cartilage defects may induce alterations of the subchondral bone in the mid- and long-term, yet very little is known about their onset. Possibly, these changes may be avoided by an enhanced microfracture technique with additional application of bone marrow aspirate. In this study, full-thickness chondral defects in the knee joints of minipigs were either treated with (1) debridement down to the subchondral bone plate alone, (2) debridement with microfracture, or (3) microfracture with additional application of bone marrow aspirate. At 4 weeks after microfracture, the loss of subchondral bone below the defects largely exceeded the original microfracture holes. Of note, a significant increase of osteoclast density was identified in defects treated with microfracture alone compared with debridement only. Both changes were significantly counteracted by the adjunct treatment with bone marrow. Debridement and microfracture without or with bone marrow were equivalent regarding the early cartilage repair. These data suggest that microfracture induced a substantial early resorption of the subchondral bone and also highlight the potential value of bone marrow aspirate as an adjunct to counteract these alterations. Clinical studies are warranted to further elucidate early events of osteochondral repair and the effect of enhanced microfracture techniques. PMID:28345610

  18. Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ

    NASA Astrophysics Data System (ADS)

    Zarei, Kasra; Scheetz, Todd E.; Christopher, Mark; Miller, Kathy; Hedberg-Buenz, Adam; Tandon, Anamika; Anderson, Michael G.; Fingert, John H.; Abràmoff, Michael David

    2016-05-01

    We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ’s performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glaucoma. AxonJ produced reliable axon counts with high sensitivity of 0.959 and high precision of 0.907, high repeatability of 0.95 when compared to a gold-standard of manual assessments and high correlation of 0.882 to the glaucoma damage staging of a previously published dataset. AxonJ allows analyses that are quantitative, consistent, fully-automated, parameter-free, and rapid on whole optic nerve sections at 40x. As a freely available ImageJ plugin that requires no highly specialized equipment to utilize, AxonJ represents a powerful new community resource augmenting studies of the optic nerve using mice.

  19. Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ.

    PubMed

    Zarei, Kasra; Scheetz, Todd E; Christopher, Mark; Miller, Kathy; Hedberg-Buenz, Adam; Tandon, Anamika; Anderson, Michael G; Fingert, John H; Abràmoff, Michael David

    2016-05-26

    We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ's performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glaucoma. AxonJ produced reliable axon counts with high sensitivity of 0.959 and high precision of 0.907, high repeatability of 0.95 when compared to a gold-standard of manual assessments and high correlation of 0.882 to the glaucoma damage staging of a previously published dataset. AxonJ allows analyses that are quantitative, consistent, fully-automated, parameter-free, and rapid on whole optic nerve sections at 40x. As a freely available ImageJ plugin that requires no highly specialized equipment to utilize, AxonJ represents a powerful new community resource augmenting studies of the optic nerve using mice.

  20. The effects of delivery route and anesthesia type on early postnatal weight loss in newborns: the role of vasoactive hormones.

    PubMed

    Okumus, Nurullah; Atalay, Yildiz; Onal, Eray E; Turkyilmaz, Canan; Senel, Saliha; Gunaydin, Berrin; Pasaoglu, Hatice; Koc, Esin; Ergenekon, Ebru; Unal, Suna

    2011-01-01

    To investigate the effects of delivery route and maternal anesthesia type and the roles of vasoactive hormones on early postnatal weight loss in term newborns. Ninety-four term infants delivered vaginally (group 1, n=31), cesarean section (C/S) with general anesthesia (GA) (group 2, n=29), and C/S with epidural anesthesia (EA) (group 3, n=34) were included in this study. All infants were weighed at birth and on the second day of life and intravenous (IV) fluid infused to the mothers for the last 6 h prior to delivery was recorded. Serum electrolytes, osmolality, N-terminal proANP (NT-proANP), brain natriuretic peptide (BNP), aldosterone and plasma antidiuretic hormone (ADH) concentrations were measured at cord blood and on the second day of life. Our research showed that postnatal weight loss of infants was higher in C/S than vaginal deliveries (5.7% vs. 1.3%) (p < 0.0001) and in EA group than GA group (6.8% vs. 4.3%) (p < 0.0001). Postnatal weight losses were correlated with IV fluid volume infused to the mothers for the last 6 h prior to delivery (R = 0.814, p = 0.000) and with serum NT-proANP (R = 0.418, p = 0.000), BNP (R = 0.454, p = 0.000), and ADH (R = 0.509, p = 0.000) but not with aldosterone concentrations (p > 0.05). Large amounts of IV fluid given to the mothers who were applied EA prior to the delivery affect their offsprings' postnatal weight loss via certain vasoactive hormones.

  1. Synaptic Phospholipid Signaling Modulates Axon Outgrowth via Glutamate-dependent Ca2+-mediated Molecular Pathways.

    PubMed

    Vogt, Johannes; Kirischuk, Sergei; Unichenko, Petr; Schlüter, Leslie; Pelosi, Assunta; Endle, Heiko; Yang, Jenq-Wei; Schmarowski, Nikolai; Cheng, Jin; Thalman, Carine; Strauss, Ulf; Prokudin, Alexey; Bharati, B Suman; Aoki, Junken; Chun, Jerold; Lutz, Beat; Luhmann, Heiko J; Nitsch, Robert

    2017-01-01

    Altered synaptic bioactive lipid signaling has been recently shown to augment neuronal excitation in the hippocampus of adult animals by activation of presynaptic LPA2-receptors leading to increased presynaptic glutamate release. Here, we show that this results in higher postsynaptic Ca2+ levels and in premature onset of spontaneous neuronal activity in the developing entorhinal cortex. Interestingly, increased synchronized neuronal activity led to reduced axon growth velocity of entorhinal neurons which project via the perforant path to the hippocampus. This was due to Ca2+-dependent molecular signaling to the axon affecting stabilization of the actin cytoskeleton. The spontaneous activity affected the entire entorhinal cortical network and thus led to reduced overall axon fiber numbers in the mature perforant path that is known to be important for specific memory functions. Our data show that precise regulation of early cortical activity by bioactive lipids is of critical importance for proper circuit formation. © The Author 2016. Published by Oxford University Press.

  2. Ephrin-B3 coordinates timed axon targeting and amygdala spinogenesis for innate fear behaviour.

    PubMed

    Zhu, Xiao-Na; Liu, Xian-Dong; Sun, Suya; Zhuang, Hanyi; Yang, Jing-Yu; Henkemeyer, Mark; Xu, Nan-Jie

    2016-03-24

    Innate emotion response to environmental stimuli is a fundamental brain function that is controlled by specific neural circuits. Dysfunction of early emotional circuits may lead to neurodevelopmental disorders such as autism and schizophrenia. However, how the functional circuits are formed to prime initial emotional behaviours remain elusive. We reveal here using gene-targeted mutations an essential role for ephrin-B3 ligand-like activity in the development of innate fear in the neonatal brain. We further demonstrate that ephrin-B3 controls axon targeting and coordinates spinogenesis and neuronal activity within the amygdala. The morphological and behavioural abnormalities in ephrin-B3 mutant mice are rescued by conditional knock-in of wild-type ephrin-B3 during the critical period when axon targeting and fear responses are initiated. Our results thus define a key axonal molecule that participates in the wiring of amygdala circuits and helps bring about fear emotion during the important adolescence period.

  3. Fray, a Drosophila serine/threonine kinase homologous to mammalian PASK, is required for axonal ensheathment

    NASA Technical Reports Server (NTRS)

    Leiserson, W. M.; Harkins, E. W.; Keshishian, H.

    2000-01-01

    Fray is a serine/threonine kinase expressed by the peripheral glia of Drosophila, whose function is required for normal axonal ensheathment. Null fray mutants die early in larval development and have nerves with severe swelling and axonal defasciculation. The phenotype is associated with a failure of the ensheathing glia to correctly wrap peripheral axons. When the fray cDNA is expressed in the ensheathing glia of fray mutants, normal nerve morphology is restored. Fray belongs to a novel family of Ser/Thr kinases, the PF kinases, whose closest relatives are the PAK kinases. Rescue of the Drosophila mutant phenotype with PASK, the rat homolog of Fray, demonstrates a functional homology among these proteins and suggests that the Fray signaling pathway is widely conserved.

  4. Axonal regeneration through acellular muscle grafts

    PubMed Central

    HALL, SUSAN

    1997-01-01

    The management of peripheral nerve injury remains a major clinical problem. Progress in this field will almost certainly depend upon manipulating the pathophysiological processes which are triggered by traumatic injuries. One of the most important determinants of functional outcome after the reconstruction of a transected peripheral nerve is the length of the gap between proximal and distal nerve stumps. Long defects (> 2 cm) must be bridged by a suitable conduit in order to support axonal regrowth. This review examines the cellular and acellular elements which facilitate axonal regrowth and the use of acellular muscle grafts in the repair of injuries in the peripheral nervous system. PMID:9034882

  5. Loss of Roquin induces early death and immune deregulation but not autoimmunity.

    PubMed

    Bertossi, Arianna; Aichinger, Martin; Sansonetti, Paola; Lech, Maciej; Neff, Frauke; Pal, Martin; Wunderlich, F Thomas; Anders, Hans-Joachim; Klein, Ludger; Schmidt-Supprian, Marc

    2011-08-29

    The substitution of one amino acid in the Roquin protein by the sanroque mutation induces a dramatic autoimmune syndrome in mice. This is believed to occur through ectopic expression of inducible T cell co-stimulator (ICOS) and unrestrained differentiation of follicular T helper cells, which induce spontaneous germinal center reactions to self-antigens. In this study, we demonstrate that tissue-specific ablation of Roquin in T or B cells, in the entire hematopoietic system, or in epithelial cells of transplanted thymi did not cause autoimmunity. Loss of Roquin induced elevated expression of ICOS through T cell-intrinsic and -extrinsic mechanisms, which itself was not sufficient to break self-tolerance. Instead, ablation of Roquin in the hematopoietic system caused defined changes in immune homeostasis, including the expansion of macrophages, eosinophils, and T cell subsets, most dramatically CD8 effector-like T cells, through cell-autonomous and nonautonomous mechanisms. Germline Roquin deficiency led to perinatal lethality, which was partially rescued on the genetic background of an outbred strain. However, not even complete absence of Roquin resulted in overt self-reactivity, suggesting that the sanroque mutation induces autoimmunity through an as yet unknown mechanism. © 2011 Bertossi et al.

  6. Plasma HVA levels following debrisoquine administration do not reflect cerebral dopamine loss in early Parkinson's disease.

    PubMed

    Rose, S; Hindmarsh, J G; Steiger, M J; Bhatt, M; Quinn, N P; Jenner, P; Marsden, C D

    1994-06-01

    Plasma levels of homovanillic acid (pHVA) following debrisoquine (DBQ) administration may be indicative of central dopaminergic activity. The effect of DBQ (10-20 mg) administration on pHVA in young healthy volunteers was studied to establish a protocol for use in de novo patients with Parkinson's disease. Subsequently, pHVA in de novo patients with Parkinson's disease were measured and compared to young healthy volunteers. Following DBQ (10 mg) administration to healthy volunteers, pHVA fell with time to a maximum of 62% of control values at 6 h. The decrease in pHVA was not affected by loading with DBQ (10 mg) 10 h previously (pHVA: 67.6 +/- 5.8% of preDBQ levels) or increasing the dose to 20 mg (56.1 +/- 11.8% of preDBQ levels) compared to a single 10 mg dose of debrisoquine (66.5 +/- 4.5% of preDBQ levels). pHVA was reduced in both de novo patients with Parkinson's disease and in healthy volunteers following DBQ (10 mg) administration. However, there was no difference in pHVA before or after DBQ administration when comparing the two groups. These results suggest that, following DBQ administration, pHVA does not reflect dopamine neuronal loss in de novo patients with Parkinson's disease, so it is unlikely to detect the disease before the clinical symptoms manifest themselves.

  7. A retrograde apoptotic signal originating in NGF-deprived distal axons of rat sympathetic neurons in compartmented cultures.

    PubMed

    Mok, Sue-Ann; Lund, Karen; Campenot, Robert B

    2009-05-01

    Previous investigations of retrograde survival signaling by nerve growth factor (NGF) and other neurotrophins have supported diverse mechanisms, but all proposed mechanisms have in common the generation of survival signals retrogradely transmitted to the neuronal cell bodies. We report the finding of a retrograde apoptotic signal in axons that is suppressed by local NGF signaling. NGF withdrawal from distal axons alone was sufficient to activate the pro-apoptotic transcription factor, c-jun, in the cell bodies. Providing NGF directly to cell bodies, thereby restoring a source of NGF-induced survival signals, could not prevent c-jun activation caused by NGF withdrawal from the distal axons. This is evidence that c-jun is not activated due to loss of survival signals at the cell bodies. Moreover, blocking axonal transport with colchicine inhibited c-jun activation caused by NGF deprivation suggesting that a retrogradely transported pro-apoptotic signal, rather than loss of a retrogradely transported survival signal, caused c-jun activation. Additional experiments showed that activation of c-jun, pro-caspase-3 cleavage, and apoptosis were blocked by the protein kinase C inhibitors, rottlerin and chelerythrine, only when applied to distal axons suggesting that they block the axon-specific pro-apoptotic signal. The rottlerin-sensitive mechanism was found to regulate glycogen synthase kinase 3 (GSK3) activity. The effect of siRNA knockdown, and pharmacological inhibition of GSK3 suggests that GSK3 is required for apoptosis caused by NGF deprivation and may function as a retrograde carrier of the axon apoptotic signal. The existence of a retrograde death signaling system in axons that is suppressed by neurotrophins has broad implications for neurodevelopment and for discovering treatments for neurodegenerative diseases and neurotrauma.

  8. Development of an assay for a biomarker of pregnancy and early fetal loss

    SciTech Connect

    Canfield, R.E.; O'Connor, J.F.; Birken, S.

    1987-10-01

    Human chorionic gonadotropin (hCG) is a glycoprotein hormone, secreted by the syncytiotrophoblast cells of the fertilized ovum, that enters the maternal circulation at the time of endometrial implantation. It is composed of two nonidentical subunits; ..cap alpha.. and ..beta.., with molecular weights of 14 kD and 23 kD, respectively. Human chorionic gonadotropin binds to the same receptor as hLH and displays the same biological response, namely, to stimulate the declining function of the corpus luteum to produce progestins and estrogen late in the menstrual cycle. The differences in the structures of hCG and hLH have been exploited to develop antibodiesmore » that can measure hCG specifically in the presence of hLH. Two-site antibody binding assays have been developed, based on a surface immunological concept of hCG epitopes, that involve four distinct regions to which antibodies against hCG can bind simultaneously. Antibody cooperative effects, in conjunction with kinetic advantages derived from the concentration factors by use of the sandwich assay technique (immunoradiometric assay, IRMA), have enabled development of extremely sensitive and specific measurement protocols for urinary hCG. The assay described herein permits the detection of pregnancy on an average 25.4 days after the first day of the preceding menses, as opposed to 29.5 days for conventional radioimmunoassay techniques. In addition, the greater sensitivity and specificity of this assay method has permitted the detection of episodes of fetal loss not detected by radioimmunoassay of urine specimens. A large scale epidemiological study is in progress using this assay technique as a way to identify pregnancies that are lost before becoming clinically apparent.« less

  9. Early cortical metabolic rearrangement related to clinical data in idiopathic sudden sensorineural hearing loss.

    PubMed

    Micarelli, Alessandro; Chiaravalloti, Agostino; Viziano, Andrea; Danieli, Roberta; Schillaci, Orazio; Alessandrini, Marco

    2017-07-01

    Results in studies concerning cortical changes in idiopathic sudden sensorineural hearing loss (ISSNHL) are not homogeneous, in particular due to the different neuroimaging techniques implemented and the diverse stages of ISSNHL studied. Considering the recent advances in state-of-the-art positron emission tomography (PET) cameras, the aim of this study was to gain more insight into the neuroanatomical differences associated with the earliest stages of unilateral ISSNHL and clinical-perceptual performance changes. After an audiological examination including the mean auditory threshold (mean AT), mean speech discrimination score (mean SDS) and Tinnitus Handicap Inventory (THI), 14 right-handed ISSNHL patients underwent brain [ 18 F]fluorodeoxyglucose (FDG)-PET within 72 h of the onset of symptoms. When compared to an homogeneous group of 35 healthy subjects by means of statistical parametric mapping, a relative increase in FDG uptake was found in the right superior and medial frontal gyrus as well as in the right anterior cingulate cortex in ISSNHL patients. Conversely, the same group showed a significant relative decrease in FDG uptake in the right middle temporal, precentral and postcentral gyrus as well as in the left posterior cingulate cortex, left lingual, superior, middle temporal and middle frontal gyrus and in the left insula. Regression analysis showed a positive correlation between mean THI and glucose consumption in the right anterior cingulate cortex and a positive correlation between mean SDS and glucose consumption in the left precentral gyrus. The relative changes in FDG uptake found in these brain regions and the positive correlation with mean SDS and THI scores in ISSNHL could possibly highlight new aspects of cerebral rearrangement, contributing to further explain changes in those functions that support speech recognition during the sudden impairment of unilateral auditory input. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Pathophysiologic insights into motor axonal function in Kennedy disease.

    PubMed

    Vucic, Steve; Kiernan, Matthew C

    2007-11-06

    Kennedy disease (KD), or spinobulbomuscular atrophy, is a slowly progressive inherited neurodegenerative disorder, marked by prominent fasciculations that typically precede the development of other symptoms. Although the genetic basis of KD relates to triplet (CAG) repeat expansion in the androgen receptor (AR) gene on the X chromosome, the mechanisms underlying the clinical presentation in KD have yet to be established. Consequently, the present study applied axonal excitability techniques to investigate the pathophysiologic mechanisms associated with KD. Peripheral nerve excitability studies were undertaken in 7 patients with KD with compound muscle action potentials (CMAP) recorded from the right abductor pollicis brevis. Strength-duration time constant (KD 0.54 +/- 0.03 msec; controls, 0.41 +/- 0.02 msec, p < 0.01) and the hyperpolarizing current/threshold gradient (KD 0.42 +/- 0.01; controls, 0.37 +/- 0.01, p < 0.05) were significantly increased in KD. Strength-duration time constant correlated with the CMAP amplitude (R = 0.68) and the fasciculation frequency (R = 0.62). Threshold electrotonus revealed greater changes in response to subthreshold depolarizing (KD TEd [90 to 100 msec], 50.75 +/- 1.98%; controls TEd [90 to 100 msec], 45.67 +/- 0.67%, p < 0.01) and hyperpolarizing (KD TEh [90 to 100 msec], 128.5 +/- 6.9%; controls TEh [90 to 100 msec], 120.5 +/- 2.4%) conditioning pulses. Measurements of refractoriness, superexcitability, and late subexcitability changed appropriately for axonal hyperpolarization, perhaps reflecting the effects of increased ectopic activity. In total, the increase in the strength-duration time constant may be the primary event, occurring early in course of the disease, contributing to the development of axonal hyperexcitability in Kennedy disease, and thereby to the generation of fasciculations, a characteristic hallmark of the disease.

  11. Inhibiting poly(ADP-ribosylation) improves axon regeneration.

    PubMed

    Byrne, Alexandra B; McWhirter, Rebecca D; Sekine, Yuichi; Strittmatter, Stephen M; Miller, David M; Hammarlund, Marc

    2016-10-04

    The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration.

  12. Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice

    PubMed Central

    Voorhees, Jaymie R.; Genova, Rachel M.; Britt, Jeremiah K.; McDaniel, Latisha; Harper, Matthew M.

    2016-01-01

    Abstract Axonal degeneration is a prominent feature of many forms of neurodegeneration, and also an early event in blast-mediated traumatic brain injury (TBI), the signature injury of soldiers in Iraq and Afghanistan. It is not known, however, whether this axonal degeneration is what drives development of subsequent neurologic deficits after the injury. The Wallerian degeneration slow strain (WldS) of mice is resistant to some forms of axonal degeneration because of a triplicated fusion gene encoding the first 70 amino acids of Ufd2a, a ubiquitin-chain assembly factor, that is linked to the complete coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (NMAT1). Here, we demonstrate that resistance of WldS mice to axonal degeneration after blast-mediated TBI is associated with preserved function in hippocampal-dependent spatial memory, cerebellar-dependent motor balance, and retinal and optic nerve–dependent visual function. Thus, early axonal degeneration is likely a critical driver of subsequent neurobehavioral complications of blast-mediated TBI. Future therapeutic strategies targeted specifically at mitigating axonal degeneration may provide a uniquely beneficial approach to treating patients suffering from the effects of blast-mediated TBI. PMID:27822499

  13. Acute Axonal Degeneration Drives Development of Cognitive, Motor, and Visual Deficits after Blast-Mediated Traumatic Brain Injury in Mice.

    PubMed

    Yin, Terry C; Voorhees, Jaymie R; Genova, Rachel M; Davis, Kevin C; Madison, Ashley M; Britt, Jeremiah K; Cintrón-Pérez, Coral J; McDaniel, Latisha; Harper, Matthew M; Pieper, Andrew A

    2016-01-01

    Axonal degeneration is a prominent feature of many forms of neurodegeneration, and also an early event in blast-mediated traumatic brain injury (TBI), the signature injury of soldiers in Iraq and Afghanistan. It is not known, however, whether this axonal degeneration is what drives development of subsequent neurologic deficits after the injury. The Wallerian degeneration slow strain ( WldS ) of mice is resistant to some forms of axonal degeneration because of a triplicated fusion gene encoding the first 70 amino acids of Ufd2a, a ubiquitin-chain assembly factor, that is linked to the complete coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (NMAT1). Here, we demonstrate that resistance of WldS mice to axonal degeneration after blast-mediated TBI is associated with preserved function in hippocampal-dependent spatial memory, cerebellar-dependent motor balance, and retinal and optic nerve-dependent visual function. Thus, early axonal degeneration is likely a critical driver of subsequent neurobehavioral complications of blast-mediated TBI. Future therapeutic strategies targeted specifically at mitigating axonal degeneration may provide a uniquely beneficial approach to treating patients suffering from the effects of blast-mediated TBI.

  14. Long-term effects of early parental loss due to divorce on the HPA axis.

    PubMed

    Bloch, Miki; Peleg, Ido; Koren, Danny; Aner, Hamotal; Klein, Ehud

    2007-04-01

    We investigated the long-term effects of divorce and early separation from one parent on HPA axis reactivity, in young adults without psychopathology. Participants were 44 young subjects, 22 whose parents divorced before they reached age 10, and 22 controls. Psychiatric symptomatology was measured with the Brief Symptom Inventory (BSI), family perceived stress by the Dyadic Adjustment Scale (DAS), and bonding by the Parental Bonding Instrument (PBI). Assessment of HPA axis function included baseline morning cortisol and ACTH and cortisol response to a CRH stimulation test. No baseline or stimulated group differences were observed for ACTH. Cortisol levels were consistently but insignificantly lower in the divorce group throughout the CRH stimulation reaching statistical significance only at 5 min (p<0.03). Group by time effect reached a trend level (p<0.06). A correlation was found between psychiatric symptomatology and PBI scores; however, both parameters did not correlate with HPA axis activity. A significant correlation was found between DAS scores and ACTH. A regression model revealed a contributing effect for both family stress and child-parent bonding to stimulated ACTH levels. These preliminary findings suggest that even in the absence of adult psychopathology, a history of childhood separation from one parent due to divorce may lead to detectable, albeit mild, long-term alterations in HPA axis activity. Furthermore, they suggest that level of stress at home and parental bonding are important determinants of this effect. It is likely that divorce has significant and sustained effects on children's HPA axis only in the context of a traumatic separation.

  15. Loss of Bmal1 decreases oocyte fertilization, early embryo development and implantation potential in female mice.

    PubMed

    Xu, Jian; Li, Yan; Wang, Yizi; Xu, Yanwen; Zhou, Canquan

    2016-10-01

    Biological clock genes expressed in reproductive tissues play important roles in maintaining the normal functions of reproductive system. However, disruption of female circadian rhythm on oocyte fertilization, preimplantation embryo development and blastocyst implantation potential is still unclear. In this study, ovulation, in vivo and in vitro oocyte fertilization, embryo development, implantation and intracellular reactive oxygen species (ROS) levels in ovary and oviduct were studied in female Bmal1+/+ and Bmal1-/- mice. The number of naturally ovulated oocyte in Bmal1-/- mice decreased (5.2 ± 0.8 vs 7.8 ± 0.8, P < 0.001), with an increasing abnormal oocyte ratio (20.4 ± 3.5 vs 11.7 ± 2.0%, P = 0.001) after superovulation. Significantly lower fertilization rate and obtained blastocyst number were observed in Bmal1-/- female mice either mated with wild-type in vivo or fertilized by sperm from wild-type male mice in vitro (all P < 0.05). Interestingly, in vitro fertilization rate of oocytes derived from Bmal1-/- increased significantly compared with in vivo study (P < 0.01). After transferring blastocysts derived from Bmal1+/+ and Bmal1-/- female mice to pseudopregnant mice, the implantation sites of the latter decreased 5 days later (8.0 ± 0.8 vs 5.3 ± 1.0, P = 0.005). The intracellular ROS levels in the ovary on proestrus day and in the oviduct on metestrus day increased significantly in Bmal1-/- mice compared with that of Bmal1+/+ mice. Deletion of the core biological clock gene Bmal1 significantly decreases oocyte fertilization rate, early embryo development and implantation potential in female mice, and these may be possibly caused by excess ROS levels generated in ovary and oviduct.

  16. Compensatory axon sprouting for very slow axonal die-back in a transgenic model of spinal muscular atrophy type III.

    PubMed

    Udina, Esther; Putman, Charles T; Harris, Luke R; Tyreman, Neil; Cook, Victoria E; Gordon, Tessa

    2017-03-01

    Smn +/- transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back. Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn +/- transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn +/- transgenic mouse increases their susceptibility to cell death demonstrated

  17. Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells.

    PubMed

    Whitmore, S Scott; Braun, Terry A; Skeie, Jessica M; Haas, Christine M; Sohn, Elliott H; Stone, Edwin M; Scheetz, Todd E; Mullins, Robert F

    2013-01-01

    Age-related macular degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE) and choroid from early AMD and control maculas with exon-based arrays. Gene expression levels in nine human donor eyes with early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using the Database for Annotation, Visualization and Integrated Discovery (DAVID), and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. The complement factor H (CFH) genotype was also assessed, and differential expression was analyzed regarding high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Seventy-five genes were identified as differentially expressed (raw p value <0.01; ≥50% fold change, mean log2 expression level in AMD or control ≥ median of all average gene expression values); however, no genes were significant (adj. p value <0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change <0.5; raw p value <0.01), 18 genes were identified by DAVID analysis as associated with vision or neurologic processes. The GSEA of the RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis of the CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p value=0.0008). GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are

  18. Spectraplakins promote microtubule-mediated axonal growth by functioning as structural microtubule-associated proteins and EB1-dependent +TIPs (tip interacting proteins).

    PubMed

    Alves-Silva, Juliana; Sánchez-Soriano, Natalia; Beaven, Robin; Klein, Melanie; Parkin, Jill; Millard, Thomas H; Bellen, Hugo J; Venken, Koen J T; Ballestrem, Christoph; Kammerer, Richard A; Prokop, Andreas

    2012-07-04

    The correct outgrowth of axons is essential for the development and regeneration of nervous systems. Axon growth is primarily driven by microtubules. Key regulators of microtubules in this context are the spectraplakins, a family of evolutionarily conserved actin-microtubule linkers. Loss of function of the mouse spectraplakin ACF7 or of its close Drosophila homolog Short stop/Shot similarly cause severe axon shortening and microtubule disorganization. How spectraplakins perform these functions is not known. Here we show that axonal growth-promoting roles of Shot require interaction with EB1 (End binding protein) at polymerizing plus ends of microtubules. We show that binding of Shot to EB1 requires SxIP motifs in Shot's C-terminal tail (Ctail), mutations of these motifs abolish Shot functions in axonal growth, loss of EB1 function phenocopies Shot loss, and genetic interaction studies reveal strong functional links between Shot and EB1 in axonal growth and microtubule organization. In addition, we report that Shot localizes along microtubule shafts and stabilizes them against pharmacologically induced depolymerization. This function is EB1-independent but requires net positive charges within Ctail which essentially contribute to the microtubule shaft association of Shot. Therefore, spectraplakins are true members of two important classes of neuronal microtubule regulating proteins: +TIPs (tip interacting proteins; plus end regulators) and structural MAPs (microtubule-associated proteins). From our data we deduce a model that relates the different features of the spectraplakin C terminus to the two functions of Shot during axonal growth.

  19. The Pseudopod System for Axon-Glia Interactions: Stimulation and Isolation of Schwann Cell Protrusions that Form in Response to Axonal Membranes.

    PubMed

    Poitelon, Yannick; Feltri, M Laura

    2018-01-01

    In the peripheral nervous system, axons dictate the differentiation state of Schwann cells. Most of this axonal influence on Schwann cells is due to juxtacrine interactions between axonal transmembrane molecules (e.g., the neuregulin growth factor) and receptors on the Schwann cell (e.g., the ErbB2/ErbB3 receptor). The fleeting nature of this interaction together with the lack of synchronicity in the development of the Schwann cell population limits our capability to study this phenomenon in vivo. Here we present a simple Boyden Chamber-based method to study this important cell-cell interaction event. We isolate the early protrusions of Schwann cells that are generated in response to juxtacrine stimulation by sensory neuronal membranes. This method is compatible with a large array of current biochemical analyses and provides an effective approach to study biomolecules that are differentially localized in Schwann cell protrusions and cell bodies in response to axonal signals. A similar approach can be extended to different kinds of cell-cell interactions.

  20. Sonic Hedgehog switches on Wnt/planar cell polarity signaling in commissural axon growth cones by reducing levels of Shisa2

    PubMed Central

    Onishi, Keisuke

    2017-01-01

    Commissural axons switch on responsiveness to Wnt attraction during midline crossing and turn anteriorly only after exiting the floor plate. We report here that Sonic Hedgehog (Shh)-Smoothened signaling downregulates Shisa2, which inhibits the glycosylation and cell surface presentation of Frizzled3 in rodent commissural axon growth cones. Constitutive Shisa2 expression causes randomized turning of post-crossing commissural axons along the anterior–posterior (A–P) axis. Loss of Shisa2 led to precocious anterior turning of commissural axons before or during midline crossing. Post-crossing commissural axon turning is completely randomized along the A–P axis when Wntless, which is essential for Wnt secretion, is conditionally knocked out in the floor plate. This regulatory link between Shh and planar cell polarity (PCP) signaling may also occur in other developmental processes. PMID:28885142

  1. Spatial temperature gradients guide axonal outgrowth

    PubMed Central

    Black, Bryan; Vishwakarma, Vivek; Dhakal, Kamal; Bhattarai, Samik; Pradhan, Prabhakar; Jain, Ankur; Kim, Young-tae; Mohanty, Samarendra

    2016-01-01

    Formation of neural networks during development and regeneration after injury depends on accuracy of axonal pathfinding, which is primarily believed to be influenced by chemical cues. Recently, there is growing evidence that physical cues can play crucial role in axonal guidance. However, detailed mechanism involved in such guidance cues is lacking. By using weakly-focused near-infrared continuous wave (CW) laser microbeam in the path of an advancing axon, we discovered that the beam acts as a repulsive guidance cue. Here, we report that this highly-effective at-a-distance guidance is the result of a temperature field produced by the near-infrared laser light absorption. Since light absorption by extracellular medium increases when the laser wavelength was red shifted, the threshold laser power for reliable guidance was significantly lower in the near-infrared as compared to the visible spectrum. The spatial temperature gradient caused by the near-infrared laser beam at-a-distance was found to activate temperature-sensitive membrane receptors, resulting in an influx of calcium. The repulsive guidance effect was significantly reduced when extracellular calcium was depleted or in the presence of TRPV1-antagonist. Further, direct heating using micro-heater confirmed that the axonal guidance is caused by shallow temperature-gradient, eliminating the role of any non-photothermal effects. PMID:27460512

  2. Spatial temperature gradients guide axonal outgrowth

    NASA Astrophysics Data System (ADS)

    Black, Bryan; Vishwakarma, Vivek; Dhakal, Kamal; Bhattarai, Samik; Pradhan, Prabhakar; Jain, Ankur; Kim, Young-Tae; Mohanty, Samarendra

    2016-07-01

    Formation of neural networks during development and regeneration after injury depends on accuracy of axonal pathfinding, which is primarily believed to be influenced by chemical cues. Recently, there is growing evidence that physical cues can play crucial role in axonal guidance. However, detailed mechanism involved in such guidance cues is lacking. By using weakly-focused near-infrared continuous wave (CW) laser microbeam in the path of an advancing axon, we discovered that the beam acts as a repulsive guidance cue. Here, we report that this highly-effective at-a-distance guidance is the result of a temperature field produced by the near-infrared laser light absorption. Since light absorption by extracellular medium increases when the laser wavelength was red shifted, the threshold laser power for reliable guidance was significantly lower in the near-infrared as compared to the visible spectrum. The spatial temperature gradient caused by the near-infrared laser beam at-a-distance was found to activate temperature-sensitive membrane receptors, resulting in an influx of calcium. The repulsive guidance effect was significantly reduced when extracellular calcium was depleted or in the presence of TRPV1-antagonist. Further, direct heating using micro-heater confirmed that the axonal guidance is caused by shallow temperature-gradient, eliminating the role of any non-photothermal effects.

  3. A model of axonal transport drug delivery

    NASA Astrophysics Data System (ADS)

    Kuznetsov, Andrey V.

    2012-04-01

    In this paper a model of targeted drug delivery by means of active (motor-driven) axonal transport is developed. The model is motivated by recent experimental research by Filler et al. (A.G. Filler, G.T. Whiteside, M. Bacon, M. Frederickson, F.A. Howe, M.D. Rabinowitz, A.J. Sokoloff, T.W. Deacon, C. Abell, R. Munglani, J.R. Griffiths, B.A. Bell, A.M.L. Lever, Tri-partite complex for axonal transport drug delivery achieves pharmacological effect, Bmc Neuroscience 11 (2010) 8) that reported synthesis and pharmacological efficiency tests of a tri-partite complex designed for axonal transport drug delivery. The developed model accounts for two populations of pharmaceutical agent complexes (PACs): PACs that are transported retrogradely by dynein motors and PACs that are accumulated in the axon at the Nodes of Ranvier. The transitions between these two populations of PACs are described by first-order reactions. An analytical solution of the coupled system of transient equations describing conservations of these two populations of PACs is obtained by using Laplace transform. Numerical results for various combinations of parameter values are presented and their physical significance is discussed.

  4. Mechanosensitivity in axon growth and guidance

    NASA Astrophysics Data System (ADS)

    Urbach, Jeff

    2013-03-01

    In the developing nervous system, axons respond to a diverse array of cues to generate the intricate connection network required for proper function. The growth cone, a highly motile structure at the tip of a growing axon, integrates information about the local environment and modulates outgrowth and guidance, but little is known about effects of external mechanical cues and internal mechanical forces on growth cone behavior. We have investigated axon outgrowth and force generation on soft elastic substrates for dorsal root ganglion (DRG) neurons (from the peripheral nervous system) and hippocampal neurons (from the central) to see how the mechanics of the microenvironment affect different populations. We find that force generation and stiffness-dependent outgrowth are strongly dependent on cell type. We also observe very different internal dynamics and substrate coupling in the two populations, suggesting that the difference in force generation is due to stronger adhesions and therefore stronger substrate engagement in the peripheral nervous system neurons. We will discuss the biological origins of these differences, and recent analyses of the dynamic aspects of growth cone force generation and the implications for the role of mechanosensitivity in axon guidance. In collaboration with D. Koch, W. Rosoff, and H. M. Geller. Supported by NINDS grant 1R01NS064250-01 (J.S.U.) and the NHLBI Intramural Research Program (H.M.G.).

  5. Modeling molecular mechanisms in the axon

    NASA Astrophysics Data System (ADS)

    de Rooij, R.; Miller, K. E.; Kuhl, E.

    2017-03-01

    Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

  6. Floor plate chemoattracts crossed axons and chemorepels uncrossed axons in the vertebrate brain.

    PubMed

    Tamada, A; Shirasaki, R; Murakami, F

    1995-05-01

    In the bilaterally symmetrical vertebrate CNS, all developing axons must choose between remaining on the same side of the midline or growing across it. The mechanism underlying this axonal pathfinding is, however, poorly understood. Here we demonstrate that the ventral midline floor plate (FP) chemorepels two types of ipsilaterally projecting axons, one from the alar plate and another from the basal plate in the mesencephalon. We further demonstrate that the FP chemoattracts contralaterally projecting myelencephalic as well as metencephalic axons. The FP at all axial levels displayed both chemoattractive and chemorepellent activities, suggesting that FP chemoattraction and chemorepulsion may be at work throughout the neuraxis. Chemotropic guidance by the FP may therefore play a key role in the establishment of neuronal projection laterality.

  7. Neuronal Dynamics and Axonal Flow, V. The Semisolid State of the Moving Axonal Column

    PubMed Central

    Weiss, Paul A.

    1972-01-01

    Evidence assembled since the first comprehensive description of “axonal flow”, by deformation analysis, electron microscopy, cinemicrography, and microrheology, has confirmed that the axon of the mature neuron is (a) a semisolid column; (b) in cellulifugal motion at about 1 μm/min (1 mm per day); (c) continuously reproduced at its perikaryal base; (d) propelled by a microperistaltic pulse wave in its surface; and (e) undergoing internal dissolution at the nerve ending. The axon thus “flows” as a structural entity (“axonal flow”), in contradistinction to fast “intraaxonal transport” of molecules and molecular assemblies along internal routes and by mechanisms that are still unknown. Images PMID:4111049

  8. Presynaptic Membrane Receptors Modulate ACh Release, Axonal Competition and Synapse Elimination during Neuromuscular Junction Development.

    PubMed

    Tomàs, Josep; Garcia, Neus; Lanuza, Maria A; Santafé, Manel M; Tomàs, Marta; Nadal, Laura; Hurtado, Erica; Simó, Anna; Cilleros, Víctor

    2017-01-01

    During the histogenesis of the nervous system a lush production of neurons, which establish an excessive number of synapses, is followed by a drop in both neurons and synaptic contacts as maturation proceeds. Hebbian competition between axons with different activities leads to the loss of roughly half of the neurons initially produced so connectivity is refined and specificity gained. The skeletal muscle fibers in the newborn neuromuscular junction (NMJ) are polyinnervated but by the end of the competition, 2 weeks later, the NMJ are innervated by only one axon. This peripheral synapse has long been used as a convenient model for synapse development. In the last few years, we have studied transmitter release and the local involvement of the presynaptic muscarinic acetylcholine autoreceptors (mAChR), adenosine autoreceptors (AR) and trophic factor receptors (TFR, for neurotrophins and trophic cytokines) during the development of NMJ and in the adult. This review article brings together previously published data and proposes a molecular background for developmental axonal competition and loss. At the end of the first week postnatal, these receptors modulate transmitter release in the various nerve terminals on polyinnervated NMJ and contribute to axonal competition and synapse elimination.

  9. "These are not good things for other people to know": how rural Tanzanian women's experiences of pregnancy loss and early neonatal death may impact survey data quality.

    PubMed

    Haws, Rachel A; Mashasi, Irene; Mrisho, Mwifadhi; Schellenberg, Joanna Armstrong; Darmstadt, Gary L; Winch, Peter J

    2010-11-01

    Little research in low-income countries has compared the social and cultural ramifications of loss in childbearing, yet the social experience of pregnancy loss and early neonatal death may affect demographers' ability to measure their incidence. Ninety-five qualitative reproductive narratives were collected from 50 women in rural southern Tanzania who had recently suffered infertility, miscarriage, stillbirth or early neonatal death. An additional 31 interviews with new mothers and female elders were used to assess childbearing norms and social consequences of loss in childbearing. We found that like pregnancy, stillbirth and early neonatal death are hidden because they heighten women's vulnerability to social and physical harm, and women's discourse and behaviors are under strong social control. To protect themselves from sorcery, spiritual interference, and gossip--as well as stigma should a spontaneous loss be viewed as an induced abortion--women conceal pregnancies and are advised not to mourn or grieve for "immature" (late-term) losses. Twelve of 30 respondents with pregnancy losses had been accused of inducing an abortion; 3 of these had been subsequently divorced. Incommensurability between Western biomedical and local categories of reproductive loss also complicates measurement of losses. Similar gender inequalities and understandings of pregnancy and reproductive loss in other low-resource settings likely result in underreporting of these losses elsewhere. Cultural, terminological, and methodological factors that contribute to inaccurate measurement of stillbirth and early neonatal death must be considered in designing surveys and other research methods to measure pregnancy, stillbirth, and other sensitive reproductive events. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice

    PubMed Central

    Trueba-Sáiz, A; Cavada, C; Fernandez, A M; Leon, T; González, D A; Fortea Ormaechea, J; Lleó, A; Del Ser, T; Nuñez, A; Torres-Aleman, I

    2013-01-01

    Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymptomatic AD mice this reduction is already manifested as a decreased brain input of serum IGF-I in response to environmental enrichment. To explore a potential diagnostic use of this early loss of IGF-I input, we monitored electrocorticogram (ECG) responses to systemic IGF-I in mice. Whereas control mice showed enhanced ECG activity after IGF-I, presymptomatic AD mice showed blunted ECG responses. Because nonhuman primates showed identically enhanced electroencephalogram (EEG) activity in response to systemic IGF-I, loss of the EEG signature of serum IGF-I may be exploited as a disease biomarker in AD patients. PMID:24301648

  11. LOSS OF SESTRIN 2 POTENTIATES THE EARLY ONSET OF AGE-RELATED SENSORY CELL DEGENERATION IN THE COCHLEA

    PubMed Central

    ZHANG, CELIA; SUN, WEI; LI, JI; XIONG, BINBIN; FRYE, MITCHELL D.; DING, DALIAN; SALVI, RICHARD; KIM, MI-JUNG; SOMEYA, SHINICHI; HU, BO HUA

    2017-01-01

    Sestrin 2 (SESN2) is a stress-inducible protein that protects tissues from oxidative stress and delays the aging process. However, its role in maintaining the functional and structural integrity of the cochlea is largely unknown. Here, we report the expression of SESN2 protein in the sensory epithelium, particularly in hair cells. Using C57BL/6J mice, a mouse model of age-related cochlear degeneration, we observed a significant age-related reduction in SESN2 expression in cochlear tissues that was associated with early onset hearing loss and accelerated age-related sensory cell degeneration that progressed from the base toward the apex of the cochlea. Hair cell death occurred by caspase-8 mediated apoptosis. Compared to C57BL/6J control mice, Sesn2 KO mice displayed enhanced expression of proinflammatory genes and activation of basilar membrane macrophages, suggesting that loss of SESN2 function provokes the immune response. Together, these results suggest that Sesn2 plays an important role in cochlear homeostasis and immune responses to stress. PMID:28818524

  12. Overexpression of mutant HSP27 causes axonal neuropathy in mice.

    PubMed

    Lee, Jinho; Jung, Sung-Chul; Joo, Jaesoon; Choi, Yu-Ri; Moon, Hyo Won; Kwak, Geon; Yeo, Ha Kyung; Lee, Ji-Su; Ahn, Hye-Jee; Jung, Namhee; Hwang, Sunhee; Rheey, Jingeun; Woo, So-Youn; Kim, Ji Yon; Hong, Young Bin; Choi, Byung-Ok

    2015-06-19

    Mutations in heat shock 27 kDa protein 1 (HSP27 or HSPB1) cause distal hereditary motor neuropathy (dHMN) or Charcot-Marie-Tooth disease type 2 F (CMT2F) according to unknown factors. Mutant HSP27 proteins affect axonal transport by reducing acetylated tubulin. We generated a transgenic mouse model overexpressing HSP27-S135F mutant protein driven by Cytomegalovirus (CMV) immediate early promoter. The mouse phenotype was similar to dHMN patients in that they exhibit motor neuropathy. To determine the phenotypic aberration of transgenic mice, behavior test, magnetic resonance imaging (MRI), electrophysiological study, and pathology were performed. Rotarod test showed that founder mice exhibited lowered motor performance. MRI also revealed marked fatty infiltration in the anterior and posterior compartments at calf level. Electrophysiologically, compound muscle action potential (CMAP) but not motor nerve conduction velocity (MNCV) was reduced in the transgenic mice. Toluidine staining with semi-thin section of sciatic nerve showed the ratio of large myelinated axon fiber was reduced, which might cause reduced locomotion in the transgenic mice. Electron microscopy also revealed abundant aberrant myelination. Immunohistochemically, neuronal dysfunctions included elevated level of phosphorylated neurofilament and reduced level of acetylated tubulin in the sural nerve of transgenic mice. There was no additional phenotype besides motor neuronal defects. Overexpression of HSP27-S135F protein causes peripheral neuropathy. The mouse model can be applied to future development of therapeutic strategies for dHMN or CMT2F.

  13. Profiling biomarkers of traumatic axonal injury: From mouse to man.

    PubMed

    Manivannan, Susruta; Makwana, Milan; Ahmed, Aminul Islam; Zaben, Malik

    2018-05-18

    Traumatic brain injury (TBI) poses a major public health problem on a global scale. Its burden results from high mortality and significant morbidity in survivors. This stems, in part, from an ongoing inadequacy in diagnostic and prognostic indicators despite significant technological advances. Traumatic axonal injury (TAI) is a key driver of the ongoing pathological process following TBI, causing chronic neurological deficits and disability. The science underpinning biomarkers of TAI has been a subject of many reviews in recent literature. However, in this review we provide a comprehensive account of biomarkers from animal models to clinical studies, bridging the gap between experimental science and clinical medicine. We have discussed pathogenesis, temporal kinetics, relationships to neuro-imaging, and, most importantly, clinical applicability in order to provide a holistic perspective of how this could improve TBI diagnosis and predict clinical outcome in a real-life setting. We conclude that early and reliable identification of axonal injury post-TBI with the help of body fluid biomarkers could enhance current care of TBI patients by (i) increasing speed and accuracy of diagnosis, (ii) providing invaluable prognostic information, (iii) allow efficient allocation of rehabilitation services, and (iv) provide potential therapeutic targets. The optimal model for assessing TAI is likely to involve multiple components, including several blood biomarkers and neuro-imaging modalities, at different time points. Copyright © 2018. Published by Elsevier B.V.

  14. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

    PubMed Central

    Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; Gingras, Marie-Claude; Muthuswamy, Lakshmi B.; Johns, Amber L.; Miller, David K.; Wilson, Peter J.; Patch, Ann-Marie; Wu, Jianmin; Chang, David K.; Cowley, Mark J.; Gardiner, Brooke B.; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J.; Gill, Anthony J.; Pinho, Andreia V.; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J. Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R. Scott; Humphris, Jeremy L.; Kaplan, Warren; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chou, Angela; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Daly, Roger J.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M.; Fisher, William E.; Brunicardi, F. Charles; Hodges, Sally E.; Reid, Jeffrey G.; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R.; Dinh, Huyen; Buhay, Christian J.; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E.; Yung, Christina K.; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A.; Petersen, Gloria M.; Gallinger, Steven; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A.; Mann, Karen M.; Jenkins, Nancy A.; Perez-Mancera, Pedro A.; Adams, David J.; Largaespada, David A.; Wessels, Lodewyk F. A.; Rust, Alistair G.; Stein, Lincoln D.; Tuveson, David A.; Copeland, Neal G.; Musgrove, Elizabeth A.; Scarpa, Aldo; Eshleman, James R.; Hudson, Thomas J.; Sutherland, Robert L.; Wheeler, David A.; Pearson, John V.; McPherson, John D.; Gibbs, Richard A.; Grimmond, Sean M.

    2012-01-01

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. PMID:23103869

  15. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    PubMed

    Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

    2012-11-15

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

  16. The Effect of Non-Infectious Wound Complications after Mastectomy on Subsequent Surgical Procedures and Early Implant Loss

    PubMed Central

    Nickel, Katelin B; Fox, Ida K; Margenthaler, Julie A; Wallace, Anna E; Fraser, Victoria J; Olsen, Margaret A

    2016-01-01

    Background Non-infectious wound complications (NIWCs) following mastectomy are not routinely tracked and data are generally limited to single-center studies. Our objective was to determine the rates of NIWCs among women undergoing mastectomy and assess the impact of immediate reconstruction (IR). Study Design We established a retrospective cohort using commercial claims data of women aged 18–64 years with procedure codes for mastectomy from 1/2004–12/2011. NIWCs within 180 days after operation were identified by ICD-9-CM diagnosis codes and rates were compared among mastectomy with and without autologous flap and/or implant IR. Results 18,696 procedures (10,836 [58%] with IR) among 18,085 women were identified. The overall NIWC rate was 9.2% (1,714/18,696); 56% required surgical treatment. The NIWC rates were 5.8% (455/7,860) after mastectomy-only, 10.3% (843/8,217) after mastectomy + implant, 17.4% (337/1,942) after mastectomy + flap, and 11.7% (79/677) after mastectomy + flap and implant (p<0.001). The rates of individual NIWCs varied by specific complication and procedure type, ranging from 0.5% for fat necrosis after mastectomy-only to 7.2% for dehiscence after mastectomy + flap. The percentage of NIWCs resulting in surgical wound care varied from 50% (210/416) for mastectomy + flap to 60% (507/843) for mastectomy + implant. Early implant removal within 60 days occurred after 6.2% of mastectomy + implant; 66% of the early implant removals were due to NIWCs and/or surgical site infection. Conclusions The rate of NIWC was approximately two-fold higher after mastectomy with IR than after mastectomy-only. NIWCs were associated with additional surgical treatment, particularly in women with implant reconstruction, and with early implant loss. PMID:27010582

  17. Loss of syd-1 from R7 Neurons Disrupts Two Distinct Phases of Presynaptic Development

    PubMed Central

    Holbrook, Scott; Finley, Jennifer K.; Lyons, Eric L.

    2012-01-01

    Genetic analyses in both worm and fly have identified the RhoGAP-like protein Syd-1 as a key positive regulator of presynaptic assembly. In worm, loss of syd-1 can be fully rescued by overexpressing wild-type Liprin-α, suggesting that the primary function of Syd-1 in this process is to recruit Liprin-α. We show that loss of syd-1 from Drosophila R7 photoreceptors causes two morphological defects that occur at distinct developmental time points. First, syd-1 mutant R7 axons often fail to form terminal boutons in their normal M6 target layer. Later, those mutant axons that do contact M6 often project thin extensions beyond it. We find that the earlier defect coincides with a failure to localize synaptic vesicles, suggesting that it reflects a failure in presynaptic assembly. We then analyze the relationship between syd-1 and Liprin-α in R7s. We find that loss of Liprin-α causes a stronger early R7 defect and provide a possible explanation for this disparity: we show that Liprin-α promotes Kinesin-3/Unc-104/Imac-mediated axon transport independently of Syd-1 and that Kinesin-3/Unc-104/Imac is required for normal R7 bouton formation. Unlike loss of syd-1, loss of Liprin-α does not cause late R7 extensions. We show that overexpressing Liprin-α partly rescues the early but not the late syd-1 mutant R7 defect. We therefore conclude that the two defects are caused by distinct molecular mechanisms. We find that Trio overexpression rescues both syd-1 defects and that trio and syd-1 have similar loss- and gain-of-function phenotypes, suggesting that the primary function of Syd-1 in R7s may be to promote Trio activity. PMID:23238725

  18. Nanoscopic compartmentalization of membrane protein motion at the axon initial segment.

    PubMed

    Albrecht, David; Winterflood, Christian M; Sadeghi, Mohsen; Tschager, Thomas; Noé, Frank; Ewers, Helge

    2016-10-10

    The axon initial segment (AIS) is enriched in specific adaptor, cytoskeletal, and transmembrane molecules. During AIS establishment, a membrane diffusion barrier is formed between the axonal and somatodendritic domains. Recently, an axonal periodic pattern of actin, spectrin, and ankyrin forming 190-nm-spaced, ring-like structures has been discovered. However, whether this structure is related to the diffusion barrier function is unclear. Here, we performed single-particle tracking time-course experiments on hippocampal neurons during AIS development. We analyzed the mobility of lipid-anchored molecules by high-speed single-particle tracking and correlated positions of membrane molecules with the nanoscopic organization of the AIS cytoskeleton. We observe a strong reduction in mobility early in AIS development. Membrane protein motion in the AIS plasma membrane is confined to a repetitive pattern of ∼190-nm-spaced segments along the AIS axis as early as day in vitro 4, and this pattern alternates with actin rings. Mathematical modeling shows that diffusion barriers between the segments significantly reduce lateral diffusion along the axon. © 2016 Albrecht et al.

  19. Sonic Hedgehog Has a Dual Effect on the Growth of Retinal Ganglion Axons Depending on Its Concentration

    PubMed Central

    Kolpak, Adrianne; Zhang, Jinhua; Bao, Zheng-Zheng

    2006-01-01

    The stereotypical projection of retinal ganglion cell (RGC) axons to the optic disc has served as a good model system for studying axon guidance. By both in vitro and in vivo experiments, we show that a secreted molecule, Sonic hedgehog (Shh), may play a critical role in the process. It is expressed in a dynamic pattern in the ganglion cell layer with a relatively higher expression in the center of the retina. Through gel culture and stripe assays, we show that Shh has a dual effect on RGC axonal growth, acting as a positive factor at low concentrations and a negative factor at high concentrations. Results from time-lapse video microscopic and stripe assay experiments further suggest that the effects of Shh on axons are not likely attributable to indirect transcriptional regulation by Shh. Overexpression of Shh protein or inhibition of Shh function inside the retina resulted in a complete loss of centrally directed projection of RGC axons, suggesting that precise regulation of Shh level inside the retina is critical for the projection of RGC axons to the optic disc. PMID:15800198

  20. Zebrafish foxP2 Zinc Finger Nuclease Mutant Has Normal Axon Pathfinding

    PubMed Central

    Xing, Lingyan; Hoshijima, Kazuyuki; Grunwald, David J.; Fujimoto, Esther; Quist, Tyler S.; Sneddon, Jacob; Chien, Chi-Bin; Stevenson, Tamara J.; Bonkowsky, Joshua L.

    2012-01-01

    foxP2, a forkhead-domain transcription factor, is critical for speech and language development in humans, but its role in the establishment of CNS connectivity is unclear. While in vitro studies have identified axon guidance molecules as targets of foxP2 regulation, and cell culture assays suggest a role for foxP2 in neurite outgrowth, in vivo studies have been lacking regarding a role for foxP2 in axon pathfinding. We used a modified zinc finger nuclease methodology to generate mutations in the zebrafish foxP2 gene. Using PCR-based high resolution melt curve analysis (HRMA) of G0 founder animals, we screened and identified three mutants carrying nonsense mutations in the 2nd coding exon: a 17 base-pair (bp) deletion, an 8bp deletion, and a 4bp insertion. Sequence analysis of cDNA confirmed that these were frameshift mutations with predicted early protein truncations. Homozygous mutant fish were viable and fertile, with unchanged body morphology, and no apparent differences in CNS apoptosis, proliferation, or patterning at embryonic stages. There was a reduction in expression of the known foxP2 target gene cntnap2 that was rescued by injection of wild-type foxP2 transcript. When we examined axon pathfinding using a pan-axonal marker or transgenic lines, including a foxP2-neuron-specific enhancer, we did not observe any axon guidance errors. Our findings suggest that foxP2 is not necessary for axon pathfinding during development. PMID:22937139

  1. Zebrafish foxP2 zinc finger nuclease mutant has normal axon pathfinding.

    PubMed

    Xing, Lingyan; Hoshijima, Kazuyuki; Grunwald, David J; Fujimoto, Esther; Quist, Tyler S; Sneddon, Jacob; Chien, Chi-Bin; Stevenson, Tamara J; Bonkowsky, Joshua L

    2012-01-01

    foxP2, a forkhead-domain transcription factor, is critical for speech and language development in humans, but its role in the establishment of CNS connectivity is unclear. While in vitro studies have identified axon guidance molecules as targets of foxP2 regulation, and cell culture assays suggest a role for foxP2 in neurite outgrowth, in vivo studies have been lacking regarding a role for foxP2 in axon pathfinding. We used a modified zinc finger nuclease methodology to generate mutations in the zebrafish foxP2 gene. Using PCR-based high resolution melt curve analysis (HRMA) of G0 founder animals, we screened and identified three mutants carrying nonsense mutations in the 2(nd) coding exon: a 17 base-pair (bp) deletion, an 8bp deletion, and a 4bp insertion. Sequence analysis of cDNA confirmed that these were frameshift mutations with predicted early protein truncations. Homozygous mutant fish were viable and fertile, with unchanged body morphology, and no apparent differences in CNS apoptosis, proliferation, or patterning at embryonic stages. There was a reduction in expression of the known foxP2 target gene cntnap2 that was rescued by injection of wild-type foxP2 transcript. When we examined axon pathfinding using a pan-axonal marker or transgenic lines, including a foxP2-neuron-specific enhancer, we did not observe any axon guidance errors. Our findings suggest that foxP2 is not necessary for axon pathfinding during development.

  2. A Select Subset of Electron Transport Chain Genes Associated with Optic Atrophy Link Mitochondria to Axon Regeneration in Caenorhabditis elegans.

    PubMed

    Knowlton, Wendy M; Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D; Jin, Yishi

    2017-01-01

    The role of mitochondria within injured neurons is an area of active interest since these organelles are vital for the production of cellular energy in the form of ATP. Using mechanosensory neurons of the nematode Caenorhabditis elegans to test regeneration after neuronal injury in vivo , we surveyed genes related to mitochondrial function for effects on axon regrowth after laser axotomy. Genes involved in mitochondrial transport, calcium uptake, mitophagy, or fission and fusion were largely dispensable for axon regrowth, with the exception of eat-3/Opa1 . Surprisingly, many genes encoding components of the electron transport chain were dispensable for regrowth, except for the iron-sulfur proteins gas-1, nduf-2.2, nduf-7 , and isp-1 , and the putative oxidoreductase rad-8 . In these mutants, axonal development was essentially normal and axons responded normally to injury by forming regenerative growth cones, but were impaired in subsequent axon extension. Overexpression of nduf-2.2 or isp-1 was sufficient to enhance regrowth, suggesting that mitochondrial function is rate-limiting in axon regeneration. Moreover, loss of function in isp-1 reduced the enhanced regeneration caused by either a gain-of-function mutation in the calcium channel EGL-19 or overexpression of the MAP kinase DLK-1. While the cellular function of RAD-8 remains unclear, our genetic analyses place rad-8 in the same pathway as other electron transport genes in axon regeneration. Unexpectedly, rad-8 regrowth defects were suppressed by altered function in the ubiquinone biosynthesis gene clk-1 . Furthermore, we found that inhibition of the mitochondrial unfolded protein response via deletion of atfs-1 suppressed the defective regrowth in nduf-2.2 mutants. Together, our data indicate that while axon regeneration is not significantly affected by general dysfunction of cellular respiration, it is sensitive to the proper functioning of a select subset of electron transport chain genes, or to the

  3. A Select Subset of Electron Transport Chain Genes Associated with Optic Atrophy Link Mitochondria to Axon Regeneration in Caenorhabditis elegans

    PubMed Central

    Knowlton, Wendy M.; Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D.; Jin, Yishi

    2017-01-01

    The role of mitochondria within injured neurons is an area of active interest since these organelles are vital for the production of cellular energy in the form of ATP. Using mechanosensory neurons of the nematode Caenorhabditis elegans to test regeneration after neuronal injury in vivo, we surveyed genes related to mitochondrial function for effects on axon regrowth after laser axotomy. Genes involved in mitochondrial transport, calcium uptake, mitophagy, or fission and fusion were largely dispensable for axon regrowth, with the exception of eat-3/Opa1. Surprisingly, many genes encoding components of the electron transport chain were dispensable for regrowth, except for the iron-sulfur proteins gas-1, nduf-2.2, nduf-7, and isp-1, and the putative oxidoreductase rad-8. In these mutants, axonal development was essentially normal and axons responded normally to injury by forming regenerative growth cones, but were impaired in subsequent axon extension. Overexpression of nduf-2.2 or isp-1 was sufficient to enhance regrowth, suggesting that mitochondrial function is rate-limiting in axon regeneration. Moreover, loss of function in isp-1 reduced the enhanced regeneration caused by either a gain-of-function mutation in the calcium channel EGL-19 or overexpression of the MAP kinase DLK-1. While the cellular function of RAD-8 remains unclear, our genetic analyses place rad-8 in the same pathway as other electron transport genes in axon regeneration. Unexpectedly, rad-8 regrowth defects were suppressed by altered function in the ubiquinone biosynthesis gene clk-1. Furthermore, we found that inhibition of the mitochondrial unfolded protein response via deletion of atfs-1 suppressed the defective regrowth in nduf-2.2 mutants. Together, our data indicate that while axon regeneration is not significantly affected by general dysfunction of cellular respiration, it is sensitive to the proper functioning of a select subset of electron transport chain genes, or to the cellular

  4. Mechanosensing is critical for axon growth in the developing brain

    PubMed Central

    Pillai, Eva K.; Sheridan, Graham K.; Svoboda, Hanno; Viana, Matheus; da F. Costa, Luciano; Guck, Jochen; Holt, Christine E.; Franze, Kristian

    2016-01-01

    During nervous system development, neurons extend axons along well-defined pathways. The current understanding of axon pathfinding is based mainly on chemical signalling. However, growing neurons interact not only chemically but also mechanically with their environment. Here we identify mechanical signals as important regulators of axon pathfinding. In vitro, substrate stiffness determined growth patterns of Xenopus retinal ganglion cell (RGC) axons. In vivo atomic force microscopy revealed striking stiffness gradient patterns in the embryonic brain. RGC axons grew towards the tissue’s softer side, which was reproduced in vitro in the absence of chemical gradients. To test the importance of mechanical signals for axon growth in vivo, we altered brain stiffness, blocked mechanotransduction pharmacologically, and knocked down the mechanosensitive ion channel Piezo1. All treatments resulted in aberrant axonal growth and pathfinding errors, suggesting that local tissue stiffness–read out by mechanosensitive ion channels–is critically involved in instructing neuronal growth in vivo. PMID:27643431

  5. Molecular, Cellular and Functional Events in Axonal Sprouting after Stroke

    PubMed Central

    Kathirvelu, Balachander; Schweppe, Catherine A; Nie, Esther H

    2016-01-01

    Stroke is the leading cause of adult disability. Yet there is a limited degree of recovery in this disease. One of the mechanisms of recovery is the formation of new connections in the brain and spinal cord after stroke: post-stroke axonal sprouting. Studies indicate that post-stroke axonal sprouting occurs in mice, rats, primates and humans. Inducing post-stroke axonal sprouting in specific connections enhances recovery; blocking axonal sprouting impairs recovery. Behavioral activity patterns after stroke modify the axonal sprouting response. A unique regenerative molecular program mediates this aspect of tissue repair in the CNS. The types of connections that are formed after stroke indicate three patterns of axonal sprouting after stroke: Reactive, Reparative and Unbounded Axonal Sprouting. These differ in mechanism, location, relationship to behavioral recovery and, importantly, in their prospect for therapeutic manipulation to enhance tissue repair. PMID:26874223

  6. Contribution of cytoskeletal elements to the axonal mechanical properties

    PubMed Central

    2013-01-01

    Background Microtubules, microfilaments, and neurofilaments are cytoskeletal elements that affect cell morphology, cellular processes, and mechanical structures in neural cells. The objective of the current study was to investigate the contribution of each type of cytoskeletal element to the mechanical properties of axons of dorsal root and sympathetic ganglia cells in chick embryos. Results Microtubules, microfilaments, and neurofilaments in axons were disrupted by nocodazole, cytochalasin D, and acrylamide, respectively, or a combination of the three. An atomic force microscope (AFM) was then used to compress the treated axons, and the resulting corresponding force-deformation information was analyzed to estimate the mechanical properties of axons that were partially or fully disrupted. Conclusion We have found that the mechanical stiffness was most reduced in microtubules-disrupted-axons, followed by neurofilaments-disrupted- and microfilaments-disrupted-axons. This suggests that microtubules contribute the most of the mechanical stiffness to axons. PMID:24007256

  7. Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.

    PubMed

    Higuchi, Yujiro; Okunushi, Ryuta; Hara, Taichi; Hashiguchi, Akihiro; Yuan, Junhui; Yoshimura, Akiko; Murayama, Kei; Ohtake, Akira; Ando, Masahiro; Hiramatsu, Yu; Ishihara, Satoshi; Tanabe, Hajime; Okamoto, Yuji; Matsuura, Eiji; Ueda, Takehiro; Toda, Tatsushi; Yamashita, Sumimasa; Yamada, Kenichiro; Koide, Takashi; Yaguchi, Hiroaki; Mitsui, Jun; Ishiura, Hiroyuki; Yoshimura, Jun; Doi, Koichiro; Morishita, Shinichi; Sato, Ken; Nakagawa, Masanori; Yamaguchi, Masamitsu; Tsuji, Shoji; Takashima, Hiroshi

    2018-06-01

    Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition

  8. The EGF and FGF receptors mediate neuroglian function to control growth cone decisions during sensory axon guidance in Drosophila.

    PubMed

    García-Alonso, L; Romani, S; Jiménez, F

    2000-12-01

    Cell adhesion molecules (CAMs) implement the process of axon guidance by promoting specific selection and attachment to substrates. We show that, in Drosophila, loss-of-function conditions of either the Neuroglian CAM, the FGF receptor coded by the gene heartless, or the EGF receptor coded by DER display a similar phenotype of abnormal substrate selection and axon guidance by peripheral sensory neurons. Moreover, neuroglian loss-of-function phenotype can be suppressed by the expression of gain-of-function conditions of heartless or DER. The results are consistent with a scenario where the activity of these receptor tyrosine kinases is controlled by Neuroglian at choice points where sensory axons select between alternative substrates for extension.

  9. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration.

    PubMed

    Essuman, Kow; Summers, Daniel W; Sasaki, Yo; Mao, Xianrong; DiAntonio, Aaron; Milbrandt, Jeffrey

    2017-03-22

    Axonal degeneration is an early and prominent feature of many neurological disorders. SARM1 is the central executioner of the axonal degeneration pathway that culminates in depletion of axonal NAD + , yet the identity of the underlying NAD + -depleting enzyme(s) is unknown. Here, in a series of experiments using purified proteins from mammalian cells, bacteria, and a cell-free protein translation system, we show that the SARM1-TIR domain itself has intrinsic NADase activity-cleaving NAD + into ADP-ribose (ADPR), cyclic ADPR, and nicotinamide, with nicotinamide serving as a feedback inhibitor of the enzyme. Using traumatic and vincristine-induced injury models in neurons, we demonstrate that the NADase activity of full-length SARM1 is required in axons to promote axonal NAD + depletion and axonal degeneration after injury. Hence, the SARM1 enzyme represents a novel therapeutic target for axonopathies. Moreover, the widely utilized TIR domain is a protein motif that can possess enzymatic activity. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. [Early loss of heterozygosity on chromosome arm 16q in flat epithelial atypia of the breast. Detection by microsatellite analyses].

    PubMed

    Schmidt, H; Dahrenmöller, C; Agelepoulos, K; Hungermann, D; Böcker, W

    2008-11-01

    With the improvement of breast carcinoma screening, pre-malignant cell lesions such as flat epithelial atypia (FEA) are detected more frequently. Several studies have demonstrated that FEA show features of a ductal neoplasia, but is it really a precursor lesion? We have started a comparative genetic analysis of a panel of nine microsatellite markers on six different chromosomal regions to investigate whether FEAs show the same characteristic genetic alterations as ductal carcinomas in situ (DCISs) and invasive carcinoma of the breast. FEAs, DCISs and invasive carcinomas of the same patients were microdissected using PALM micro laser technology. DNA was isolated using the QIAamp DNA Micro Kit (QIAGEN). We have investigated a set of the polymorphic microsatellite markers D7S522, D8S522, NEFL, D10S541 (PTEN), D13S153 (RB1), D16S400, D16S402, D16S422 and D17S855 (BRCA1) using multiplex PCR for the detection of allelic imbalances. Most of the investigated FEAs showed a lower frequency of loss of heterozygosity than associated DCISs or invasive carcinomas. However, we were able to detect the same alterations in FEAs as in DCISs or invasive carcinomas in a number of cases. Notably, the microsatellite marker on 16q showed more prevalent allelic imbalances in FEAs than the other investigated markers. One of the hallmarks in the pathogenesis of a large subgroup of invasive breast carcinomas is the early loss of chromosome arm 16q. In this study, we were able to detect frequent genetic alterations on chromosome 16q in FEAs, associated DCISs and invasive carcinomas. This suggests that FEA is a precursor lesion in the low-grade pathway.

  11. Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos‐like syndrome

    PubMed Central

    Uzumcu, A; Norgett, E E; Dindar, A; Uyguner, O; Nisli, K; Kayserili, H; Sahin, S E; Dupont, E; Severs, N J; Leigh, I M; Yuksel‐Apak, M; Kelsell, D P; Wollnik, B

    2006-01-01

    Background Desmosomes are cellular junctions important for intercellular adhesion and anchoring the intermediate filament (IF) cytoskeleton to the cell membrane. Desmoplakin (DSP) is the most abundant desmosomal protein with 2 isoforms produced by alternative splicing. Methods We describe a patient with a recessively inherited arrhythmogenic dilated cardiomyopathy with left and right ventricular involvement, epidermolytic palmoplantar keratoderma, and woolly hair. The patient showed a severe heart phenotype with an early onset and rapid progression to heart failure at 4 years of age. Results A homozygous nonsense mutation, R1267X, was found in exon 23 of the desmoplakin gene, which results in an isoform specific truncation of the larger DSPI isoform. The loss of most of the DSPI specific rod domain and C‐terminal area was confirmed by Western blotting and immunofluorescence. We further showed that the truncated DSPI transcript is unstable, leading to a loss of DSPI. DSPI is reported to be an obligate constituent of desmosomes and the only isoform present in cardiac tissue. To address this, we reviewed the expression of DSP isoforms in the heart. Our data suggest that DSPI is the major cardiac isoform but we also show that specific compartments of the heart have detectable DSPII expression. Conclusions This is the first description of a phenotype caused by a mutation affecting only one DSP isoform. Our findings emphasise the importance of desmoplakin and desmosomes in epidermal and cardiac function and additionally highlight the possibility that the different isoforms of desmoplakin may have distinct functional properties within the desmosome. PMID:16467215

  12. Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures.

    PubMed

    Al-Maawali, Almundher; Barry, Brenda J; Rajab, Anna; El-Quessny, Malak; Seman, Ann; Coury, Stephanie Newton; Barkovich, A James; Yang, Edward; Walsh, Christopher A; Mochida, Ganeshwaran H; Stoler, Joan M

    2016-02-01

    Exome sequencing identified homozygous loss-of-function variants in DIAPH1 (c.2769delT; p.F923fs and c.3145C>T; p.R1049X) in four affected individuals from two unrelated consanguineous families. The affected individuals in our report were diagnosed with postnatal microcephaly, early-onset epilepsy, severe vision impairment, and pulmonary symptoms including bronchiectasis and recurrent respiratory infections. A heterozygous DIAPH1 mutation was originally reported in one family with autosomal dominant deafness. Recently, however, a homozygous nonsense DIAPH1 mutation (c.2332C4T; p.Q778X) was reported in five siblings in a single family affected by microcephaly, blindness, early onset seizures, developmental delay, and bronchiectasis. The role of DIAPH1 was supported using parametric linkage analysis, RNA and protein studies in their patients' cell lines and further studies in human neural progenitors cells and a diap1 knockout mouse. In this report, the proband was initially brought to medical attention for profound metopic synostosis. Additional concerns arose when his head circumference did not increase after surgical release at 5 months of age and he was diagnosed with microcephaly and epilepsy at 6 months of age. Clinical exome analysis identified a homozygous DIAPH1 mutation. Another homozygous DIAPH1 mutation was identified in the research exome analysis of a second family with three siblings presenting with a similar phenotype. Importantly, no hearing impairment is reported in the homozygous affected individuals or in the heterozygous carrier parents in any of the families demonstrating the autosomal recessive microcephaly phenotype. These additional families provide further evidence of the likely causal relationship between DIAPH1 mutations and a neurodevelopmental disorder. © 2016 Wiley Periodicals, Inc.

  13. Can early weight loss, eating behaviors and socioeconomic factors predict successful weight loss at 12- and 24-months in adolescents with obesity and insulin resistance participating in a randomised controlled trial?

    PubMed

    Gow, Megan L; Baur, Louise A; Ho, Mandy; Chisholm, Kerryn; Noakes, Manny; Cowell, Chris T; Garnett, Sarah P

    2016-04-01

    Lifestyle interventions in adolescents with obesity can result in weight loss following active intervention but individual responses vary widely. This study aimed to identify predictors of weight loss at 12- and 24-months in adolescents with obesity and clinical features of insulin resistance. Adolescents (n = 111, 66 girls, aged 10-17 years) were participants in a randomised controlled trial, the RESIST study, examining the effects of two diets differing in macronutrient content on insulin sensitivity. Eighty-five completed the 12-month program and 24-month follow-up data were available for 42 adolescents. Change in weight was determined by BMI expressed as a percentage of the 95th percentile (BMI95). The study physician collected socioeconomic data at baseline. Physical activity and screen time, and psychological dimensions of eating behavior were self-reported using the validated CLASS and EPI-C questionnaires, respectively. Stepwise multiple regressions were conducted to identify models that best predicted change in BMI95 at 12- and 24-months. Mean BMI95 was reduced at 12-months compared with baseline (mean difference [MD] ± SE: -6.9 ± 1.0, P < 0.001) but adolescents had significant re-gain from 12- to 24-months (MD ± SE: 3.7 ± 1.5, P = 0.017). Participants who achieved greater 12-month weight loss had: greater 3-month weight loss, a father with a higher education, lower baseline external eating and parental pressure to eat scores and two parents living at home. Participants who achieved greater 24-month weight loss had: greater 12-month weight loss and a lower baseline emotional eating score. Early weight loss is consistently identified as a strong predictor of long-term weight loss. This could be because early weight loss identifies those more motivated and engaged individuals. Patients who have baseline factors predictive of long-term weight loss failure may benefit from additional support during the intervention. Additionally

  14. Axonal flip-flops and oscillators.

    PubMed

    Baker, M D

    2000-11-01

    The strange and unpleasant sensations (paraesthesiae) or asynchronous motor-unit activation (fasciculation) that result from a period of limb ischaemia are examples of ectopic discharge in peripheral nerves. Ectopic activity also results from demyelination and is associated with serious neurological conditions, such as multiple sclerosis. A build-up of extracellular K(+) in the internode and persistent Na(+) currents are now implicated in generating the different forms of activity arising in normal and demyelinated axons.

  15. Ionized calcium concentrations in squid axons

    PubMed Central

    1976-01-01

    Values for ionized [Ca] in squid axons were obtained by measuring the light emission from a 0.1-mul drop of aequorin confined to a plastic dialysis tube of 140-mum diameter located axially. Ionized Ca had a mean value of 20 x 10(-9) M as judged by the subsequent introduction of CaEGTA/EGTA buffer (ratio ca. 0.1) into the axoplasm, and light measurement on a second aequorin drop. Ionized Ca in axoplasma was also measured by introducing arsenazo dye into an axon by injection and measuring the Ca complex of such a dye by multichannel spectrophotometry. Values so obtained were ca. 50 x 10(-9) M as calibrated against CaEGTA/EGTA buffer mixtures. Wth a freshly isolated axon in 10 mM Ca seawater, the aequorin glow invariably increased with time; a seawater [Ca] of 2-3 mM allowed a steady state with respect to [Ca]. Replacement of Na+ in seawater with choline led to a large increase in light emission from aequorin. Li seawater partially reversed this change and the reintroduction of Na+ brought light levels back to their initial value. Stimulation at 60/s for 2-5 min produced an increase in aequorin glow about 0.1% of that represented by the known Ca influx, suggesting operationally the presence of substantial Ca buffering. Treatment of an axon with CN produced a very large increase in aequorin glow and in Ca arsenazo formation only if the external seawater contained Ca. PMID:818340

  16. Multifunctional Silk Nerve Guides for Axon Outgrowth

    NASA Astrophysics Data System (ADS)

    Tupaj, Marie C.

    Peripheral nerve regeneration is a critical issue as 2.8% of trauma patients present with this type of injury, estimating a total of 200,000 nerve repair procedures yearly in the United States. While the peripheral nervous system exhibits slow regeneration, at a rate of 0.5 mm -- 9 mm/day following trauma, this regenerative ability is only possible under certain conditions. Clinical repairs have changed slightly in the last 30 years and standard methods of treatment include suturing damaged nerve ends, allografting, and autografting, with the autograft the gold standard of these approaches. Unfortunately, the use of autografts requires a second surgery and there is a shortage of nerves available for grafting. Allografts are a second option however allografts have lower success rates and are accompanied by the need of immunosuppressant drugs. Recently there has been a focus on developing nerve guides as an "off the shelf" approach. Although some natural and synthetic guidance channels have been approved by the FDA, these nerve guides are unfunctionalized and repair only short gaps, less than 3 cm in length. The goal of this project was to identify strategies for functionalizing peripheral nerve conduits for the outgrowth of neuron axons in vitro . To accomplish this, two strategies (bioelectrical and biophysical) were indentified for increasing axon outgrowth and promoting axon guidance. Bioelectrical strategies exploited electrical stimulation for increasing neurite outgrowth. Biophysical strategies tested a range of surface topographies for axon guidance. Novel methods were developed for integrating electrical and biophysical strategies into silk films in 2D. Finally, a functionalized nerve conduit system was developed that integrated all strategies for the purpose of attaching, elongating, and guiding nervous tissue in vitro. Future directions of this work include silk conduit translation into a rat sciatic nerve model in vivo for the purpose of repairing long

  17. Synaptic Democracy and Vesicular Transport in Axons

    NASA Astrophysics Data System (ADS)

    Bressloff, Paul C.; Levien, Ethan

    2015-04-01

    Synaptic democracy concerns the general problem of how regions of an axon or dendrite far from the cell body (soma) of a neuron can play an effective role in neuronal function. For example, stimulated synapses far from the soma are unlikely to influence the firing of a neuron unless some sort of active dendritic processing occurs. Analogously, the motor-driven transport of newly synthesized proteins from the soma to presynaptic targets along the axon tends to favor the delivery of resources to proximal synapses. Both of these phenomena reflect fundamental limitations of transport processes based on a localized source. In this Letter, we show that a more democratic distribution of proteins along an axon can be achieved by making the transport process less efficient. This involves two components: bidirectional or "stop-and-go" motor transport (which can be modeled in terms of advection-diffusion), and reversible interactions between motor-cargo complexes and synaptic targets. Both of these features have recently been observed experimentally. Our model suggests that, just as in human societies, there needs to be a balance between "efficiency" and "equality".

  18. Dystrophic Serotonergic Axons in Neurodegenerative Diseases

    PubMed Central

    Azmitia, Efrain C.; Nixon, Ralph

    2012-01-01

    Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and Diffuse Lewy-Body dementia (DLBD) have diverse neuropathologic features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathologically normal (control) brains (n=3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers of passage appeared thick, smooth, and un-branched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in number and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric analysis revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphologic evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n=3 slices for each region (3) from each brain (4), total slices was n=36) and lack of extensive clinical characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue PMID:18502405

  19. Possible Effects of Synaptic Imbalances on Oligodendrocyte–Axonic Interactions in Schizophrenia: A Hypothetical Model

    PubMed Central

    Mitterauer, Bernhard J.; Kofler-Westergren, Birgitta

    2011-01-01

    A model of glial–neuronal interactions is proposed that could be explanatory for the demyelination identified in brains with schizophrenia. It is based on two hypotheses: (1) that glia–neuron systems are functionally viable and important for normal brain function, and (2) that disruption of this postulated function disturbs the glial categorization function, as shown by formal analysis. According to this model, in schizophrenia receptors on astrocytes in glial–neuronal synaptic units are not functional, loosing their modulatory influence on synaptic neurotransmission. Hence, an unconstrained neurotransmission flux occurs that hyperactivates the axon and floods the cognate receptors of neurotransmitters on oligodendrocytes. The excess of neurotransmitters may have a toxic effect on oligodendrocytes and myelin, causing demyelination. In parallel, an increasing impairment of axons may disconnect neuronal networks. It is formally shown how oligodendrocytes normally categorize axonic information processing via their processes. Demyelination decomposes the oligodendrocyte–axonic system making it incapable to generate categories of information. This incoherence may be responsible for symptoms of disorganization in schizophrenia, such as thought disorder, inappropriate affect and incommunicable motor behavior. In parallel, the loss of oligodendrocytes affects gap junctions in the panglial syncytium, presumably responsible for memory impairment in schizophrenia. PMID:21647404

  20. A regenerative microchannel neural interface for recording from and stimulating peripheral axons in vivo

    NASA Astrophysics Data System (ADS)

    FitzGerald, James J.; Lago, Natalia; Benmerah, Samia; Serra, Jordi; Watling, Christopher P.; Cameron, Ruth E.; Tarte, Edward; Lacour, Stéphanie P.; McMahon, Stephen B.; Fawcett, James W.

    2012-02-01

    Neural interfaces are implanted devices that couple the nervous system to electronic circuitry. They are intended for long term use to control assistive technologies such as muscle stimulators or prosthetics that compensate for loss of function due to injury. Here we present a novel design of interface for peripheral nerves. Recording from axons is complicated by the small size of extracellular potentials and the concentration of current flow at nodes of Ranvier. Confining axons to microchannels of ˜100 µm diameter produces amplified potentials that are independent of node position. After implantation of microchannel arrays into rat sciatic nerve, axons regenerated through the channels forming ‘mini-fascicles’, each typically containing ˜100 myelinated fibres and one or more blood vessels. Regenerated motor axons reconnected to distal muscles, as demonstrated by the recovery of an electromyogram and partial prevention of muscle atrophy. Efferent motor potentials and afferent signals evoked by muscle stretch or cutaneous stimulation were easily recorded from the mini-fascicles and were in the range of 35-170 µV. Individual motor units in distal musculature were activated from channels using stimulus currents in the microampere range. Microchannel interfaces are a potential solution for applications such as prosthetic limb control or enhancing recovery after nerve injury.

  1. Regulation of mitochondria-dynactin interaction and mitochondrial retrograde transport in axons.

    PubMed

    Drerup, Catherine M; Herbert, Amy L; Monk, Kelly R; Nechiporuk, Alex V

    2017-04-17

    Mitochondrial transport in axons is critical for neural circuit health and function. While several proteins have been found that modulate bidirectional mitochondrial motility, factors that regulate unidirectional mitochondrial transport have been harder to identify. In a genetic screen, we found a zebrafish strain in which mitochondria fail to attach to the dynein retrograde motor. This strain carries a loss-of-function mutation in actr10 , a member of the dynein-associated complex dynactin. The abnormal axon morphology and mitochondrial retrograde transport defects observed in actr10 mutants are distinct from dynein and dynactin mutant axonal phenotypes. In addition, Actr10 lacking the dynactin binding domain maintains its ability to bind mitochondria, arguing for a role for Actr10 in dynactin-mitochondria interaction. Finally, genetic interaction studies implicated Drp1 as a partner in Actr10-dependent mitochondrial retrograde transport. Together, this work identifies Actr10 as a factor necessary for dynactin-mitochondria interaction, enhancing our understanding of how mitochondria properly localize in axons.

  2. Horizontal Transfers and Gene Losses in the Phospholipid Pathway of Bartonella Reveal Clues about Early Ecological Niches

    PubMed Central

    Zhu, Qiyun; Kosoy, Michael; Olival, Kevin J.; Dittmar, Katharina

    2014-01-01

    Bartonellae are mammalian pathogens vectored by blood-feeding arthropods. Although of increasing medical importance, little is known about their ecological past, and host associations are underexplored. Previous studies suggest an influence of horizontal gene transfers in ecological niche colonization by acquisition of host pathogenicity genes. We here expand these analyses to metabolic pathways of 28 Bartonella genomes, and experimentally explore the distribution of bartonellae in 21 species of blood-feeding arthropods. Across genomes, repeated gene losses and horizontal gains in the phospholipid pathway were found. The evolutionary timing of these patterns suggests functional consequences likely leading to an early intracellular lifestyle for stem bartonellae. Comparative phylogenomic analyses discover three independent lineage-specific reacquisitions of a core metabolic gene—NAD(P)H-dependent glycerol-3-phosphate dehydrogenase (gpsA)—from Gammaproteobacteria and Epsilonproteobacteria. Transferred genes are significantly closely related to invertebrate Arsenophonus-, and Serratia-like endosymbionts, and mammalian Helicobacter-like pathogens, supporting a cellular association with arthropods and mammals at the base of extant Bartonella spp. Our studies suggest that the horizontal reacquisitions had a key impact on bartonellae lineage specific ecological and functional evolution. PMID:25106622

  3. BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology.

    PubMed

    Wilson, E N; Do Carmo, S; Iulita, M F; Hall, H; Ducatenzeiler, A; Marks, A R; Allard, S; Jia, D T; Windheim, J; Cuello, A C

    2017-08-01

    Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.

  4. BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

    PubMed Central

    Wilson, E N; Do Carmo, S; Iulita, M F; Hall, H; Ducatenzeiler, A; Marks, A R; Allard, S; Jia, D T; Windheim, J; Cuello, A C

    2017-01-01

    Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer’s disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD. PMID:28763060

  5. Dependence of regenerated sensory axons on continuous neurotrophin-3 delivery.

    PubMed

    Hou, Shaoping; Nicholson, LaShae; van Niekerk, Erna; Motsch, Melanie; Blesch, Armin

    2012-09-19

    Previous studies have shown that injured dorsal column sensory axons extend across a spinal cord lesion site if axons are guided by a gradient of neurotrophin-3 (NT-3) rostral to the lesion. Here we examined whether continuous NT-3 delivery is necessary to sustain regenerated axons in the injured spinal cord. Using tetracycline-regulated (tet-off) lentiviral gene delivery, NT-3 expression was tightly controlled by doxycycline administration. To examine axon growth responses to regulated NT-3 expression, adult rats underwent a C3 dorsal funiculus lesion. The lesion site was filled with bone marrow stromal cells, tet-off-NT-3 virus was injected rostral to the lesion site, and the intrinsic growth capacity of sensory neurons was activated by a conditioning lesion. When NT-3 gene expression was turned on, cholera toxin β-subunit-labeled sensory axons regenerated into and beyond the lesion/graft site. Surprisingly, the number of regenerated axons significantly declined when NT-3 expression was turned off, whereas continued NT-3 expression sustained regenerated axons. Quantification of axon numbers beyond the lesion demonstrated a significant decline of axon growth in animals with transient NT-3 expression, only some axons that had regenerated over longer distance were sustained. Regenerated axons were located in white matter and did not form axodendritic synapses but expressed presynaptic markers when closely associated with NG2-labeled cells. A decline in axon density was also observed within cellular grafts after NT-3 expression was turned off possibly via reduction in L1 and laminin expression in Schwann cells. Thus, multiple mechanisms underlie the inability of transient NT-3 expression to fully sustain regenerated sensory axons.

  6. βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy.

    PubMed

    Wang, Chih-Chuan; Ortiz-González, Xilma R; Yum, Sabrina W; Gill, Sara M; White, Amy; Kelter, Erin; Seaver, Laurie H; Lee, Sansan; Wiley, Graham; Gaffney, Patrick M; Wierenga, Klaas J; Rasband, Matthew N

    2018-06-07

    βIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into βIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na + channels and no nodal KCNQ2 K + channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and βI spectrin can cluster Na + channels and partially compensate for the loss of AnkG and βIV spectrin at nodes of Ranvier, AnkR and βI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K + channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction. Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. Axon Regeneration in C. elegans: worming our way to mechanisms of axon regeneration

    PubMed Central

    Byrne, Alexandra B.; Hammarlund, Marc

    2016-01-01

    How axons repair themselves after injury is a fundamental question in neurobiology. With its conserved genome, relatively simple nervous system, and transparent body, C. elegans has recently emerged as a productive model to uncover the cellular mechanisms that regulate and execute axon regeneration. In this review, we discuss the strengths and weaknesses of the C. elegans model of regeneration. We explore the technical advances that enable the use of C. elegans for in vivo regeneration studies, review findings in C. elegans that have contributed to our understanding of the regeneration response across species, discuss the potential of C. elegans research to provide insight into mechanisms that function in the injured mammalian nervous system, and present potential future directions of axon regeneration research using C. elegans. PMID:27569538

  8. A history of early life parental loss or separation is associated with successful cognitive-behavioral therapy in major depressive disorder.

    PubMed

    Niciu, Mark J; Abdallah, Chadi G; Fenton, Lisa R; Fasula, Madonna K; Black, Anne; Anderson, George M; Sanacora, Gerard

    2015-11-15

    There is a clinical need for evidence-based psychotherapy response biomarkers in major depressive disorder (MDD). Based on previous studies, we hypothesized that lower 24-h urinary cortisol levels and a history of early life stress/trauma would predict an improved antidepressant response to cognitive-behavioral therapy (CBT). 50 currently depressed MDD subjects were enrolled. 24-h urine was collected and measured for cortisol levels by radioimmunoassay (RIA). Subjects were also administered early life stress/trauma measures at baseline: Global Perceived Early-Life Stress (GPELS), The Early Life Trauma Inventory (ELTI) and Klein Loss Scale (KLS). The efficacy of a twelve-week course of once-weekly CBT was evaluated by the primary outcome measure, the 24-item Hamilton Depression Rating Scale (HDRS24), at baseline and every four weeks, and the Beck Depression Inventory at baseline and weekly thereafter. 42 subjects had at least one complete follow-up visit (≥4 weeks of CBT), and 30 subjects completed the full 12-week course. Baseline 24-h urinary cortisol levels did not correlate with CBT's antidepressant response. Higher KLS scores, a measure of early life parental loss or separation, correlated with delta HDRS24 (rs=-0.39, padjusted=0.05). Complementary general linear model analysis revealed enhanced CBT efficacy in patients with a history of early life parental loss or separation [F(1,35)=6.65, p=0.01]. Small sample size, Treatment-naïve population. Early life parental separation or loss positively correlated with CBT's antidepressant efficacy in our sample and may warrant further study in larger clinical samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Uncoupling nicotine mediated motoneuron axonal pathfinding errors and muscle degeneration in zebrafish

    SciTech Connect

    Welsh, Lillian; Tanguay, Robert L.; Svoboda, Kurt R.

    Zebrafish embryos offer a unique opportunity to investigate the mechanisms by which nicotine exposure impacts early vertebrate development. Embryos exposed to nicotine become functionally paralyzed by 42 hpf suggesting that the neuromuscular system is compromised in exposed embryos. We previously demonstrated that secondary spinal motoneurons in nicotine-exposed embryos were delayed in development and that their axons made pathfinding errors (Svoboda, K.R., Vijayaraghaven, S., Tanguay, R.L., 2002. Nicotinic receptors mediate changes in spinal motoneuron development and axonal pathfinding in embryonic zebrafish exposed to nicotine. J. Neurosci. 22, 10731-10741). In that study, we did not consider the potential role that altered skeletalmore » muscle development caused by nicotine exposure could play in contributing to the errors in spinal motoneuron axon pathfinding. In this study, we show that an alteration in skeletal muscle development occurs in tandem with alterations in spinal motoneuron development upon exposure to nicotine. The alteration in the muscle involves the binding of nicotine to the muscle-specific AChRs. The nicotine-induced alteration in muscle development does not occur in the zebrafish mutant (sofa potato, [sop]), which lacks muscle-specific AChRs. Even though muscle development is unaffected by nicotine exposure in sop mutants, motoneuron axonal pathfinding errors still occur in these mutants, indicating a direct effect of nicotine exposure on nervous system development.« less

  10. L1CAM/Neuroglian controls the axon-axon interactions establishing layered and lobular mushroom body architecture.

    PubMed

    Siegenthaler, Dominique; Enneking, Eva-Maria; Moreno, Eliza; Pielage, Jan

    2015-03-30

    The establishment of neuronal circuits depends on the guidance of axons both along and in between axonal populations of different identity; however, the molecular principles controlling axon-axon interactions in vivo remain largely elusive. We demonstrate that the Drosophila melanogaster L1CAM homologue Neuroglian mediates adhesion between functionally distinct mushroom body axon populations to enforce and control appropriate projections into distinct axonal layers and lobes essential for olfactory learning and memory. We addressed the regulatory mechanisms controlling homophilic Neuroglian-mediated cell adhesion by analyzing targeted mutations of extra- and intracellular Neuroglian domains in combination with cell type-specific rescue assays in vivo. We demonstrate independent and cooperative domain requirements: intercalating growth depends on homophilic adhesion mediated by extracellular Ig domains. For functional cluster formation, intracellular Ankyrin2 association is sufficient on one side of the trans-axonal complex whereas Moesin association is likely required simultaneously in both interacting axonal populations. Together, our results provide novel mechanistic insights into cell adhesion molecule-mediated axon-axon interactions that enable precise assembly of complex neuronal circuits. © 2015 Siegenthaler et al.

  11. ARF6 directs axon transport and traffic of integrins and regulates axon growth in adult DRG neurons.

    PubMed

    Eva, Richard; Crisp, Sarah; Marland, Jamie R K; Norman, Jim C; Kanamarlapudi, Venkateswarlu; ffrench-Constant, Charles; Fawcett, James W

    2012-07-25

    Integrins are involved in axon growth and regeneration. Manipulation of integrins is a route to promoting axon regeneration and understanding regeneration failure in the CNS. Expression of α9 integrin promotes axon regeneration, so we have investigated α9β1 trafficking and transport in axons and at the growth cone. We have previously found that α9 and β1 integrins traffic via Rab11-positive recycling endosomes in peripheral axons and growth cones. However, transport via Rab11 is slow, while rapid transport occurs in vesicles lacking Rab11. We have further studied α9 and β1 integrin transport and traffic in adult rat dorsal root ganglion axons and PC12 cells. Integrins are in ARF6 vesicles during rapid axonal transport and during trafficking in the growth cone. We report that rapid axonal transport of these integrins and their trafficking at the cell surface is regulated by ARF6. ARF6 inactivation by expression of ACAP1 leads to increased recycling of β1 integrins to the neuronal surface and to increased anterograde axonal transport. ARF6 activation by expression of the neuronal guanine nucleotide exchange factors, ARNO or EFA6, increases retrograde integrin transport in axons and increases integrin internalization. ARF6 inactivation increases integrin-mediated outgrowth, while activation decreases it. The coordinated changes in integrin transport and recycling resulting from ARF6 activation or inactivation are the probable mechanism behind this regulation of axon growth. Our data suggest a novel mechanism of integrin traffic and transport in peripheral axons, regulated by the activation state of ARF6, and suggest that ARF6 might be targeted to enhance integrin-dependent axon regeneration after injury.

  12. Sodium influxes in internally perfused squid giant axon during voltage clamp.

    PubMed

    Atwater, I; Bezanilla, F; Rojas, E

    1969-05-01

    1. An experimental method for measuring ionic influxes during voltage clamp in the giant axon of Dosidicus is described; the technique combines intracellular perfusion with a method for controlling membrane potential.2. Sodium influx determinations were carried out while applying rectangular pulses of membrane depolarization. The ratio ;measured sodium influx/computed ionic flux during the early current' is 0.92 +/- 0.12.3. Plots of measured sodium influx and computed ionic flux during the early current against membrane potential are very similar. There was evidence that the membrane potential at which the sodium influx vanishes is the potential at which the early current reverses.

  13. Sodium influxes in internally perfused squid giant axon during voltage clamp

    PubMed Central

    Atwater, I.; Bezanilla, F.; Rojas, E.

    1969-01-01

    1. An experimental method for measuring ionic influxes during voltage clamp in the giant axon of Dosidicus is described; the technique combines intracellular perfusion with a method for controlling membrane potential. 2. Sodium influx determinations were carried out while applying rectangular pulses of membrane depolarization. The ratio `measured sodium influx/computed ionic flux during the early current' is 0·92 ± 0·12. 3. Plots of measured sodium influx and computed ionic flux during the early current against membrane potential are very similar. There was evidence that the membrane potential at which the sodium influx vanishes is the potential at which the early current reverses. PMID:5767887

  14. Can injured adult CNS axons regenerate by recapitulating development?

    PubMed

    Hilton, Brett J; Bradke, Frank

    2017-10-01

    In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS. © 2017. Published by The Company of Biologists Ltd.

  15. Reduced vital capacity after methacholine challenge in early childhood--is it due to trapped air or loss of motivation.

    PubMed

    Vilozni, Daphna; Hakim, Fahed; Adler, Adi; Livnat, Galit; Bar-Yishay, Ephraim; Bentur, Lea

    2009-01-01

    In a previous study we assessed the feasibility of measuring bronchial-reactivity (BHR) in young asthmatic children by the determination of PC(20)-FEV(1) along with clinical end-of-test criteria during a methacholine challenge test (MCT). The end-point was associated with a significant reduction in both flow and vital capacity values. The findings could be due to the children's loss of motivation, which may preclude use of this test. Alternatively, if it reflects air trapping during airway obstruction, it might reinforce its applicability in preschool age children. To elucidate the mechanism of low vital capacity at PC(20)-FEV(1) in preschool age children. Twenty-eight children (3.3-6.9 years) with recurrent respiratory symptoms. An MCT was carried out using tripling doses (0.06-13.9 mg/ml) delivered by a dosimeter. Spirometry was measured at baseline and after each inhalation in duplicate sets. Whole body plethysmography was measured at baseline and at end-of-test (defined by clinical criteria) according to the recommendations for older populations. Plethysmography was reliably performed by 20 children before and after MCT. At baseline, lung function was within the healthy range. At end-of-test (PC(20)-FEV(1)=4.02+/-3.47 mg/ml), the spirometry parameters and specific conductance values were markedly reduced in correlation with a significant increase in residual volume and resistance. The study shows that diminished vital capacity is due to the increase in FRC at end-of-test. Our findings support the use of PC(20)-FEV(1) during BHR in young children and suggest that lung volume measurement by a plethysmograph may be feasible in early childhood. Larger studies should be performed to establish the clinical applicability of PC20-FEV1 determination in the preschool age.

  16. Association of fatty acids and lipids metabolism in placenta with early spontaneous pregnancy loss in Chinese women.

    PubMed

    Li, Kelei; Zhang, Xiaotian; Chen, Gong; Pei, Lijun; Xiao, Hailong; Jiang, Jiajing; Li, Jiaomei; Zheng, Xiaoying; Li, Duo

    2018-02-21

    The aim of the present study was to evaluate the association of fatty acids and lipids metabolism in placenta with early spontaneous pregnancy loss (ESPL) in Chinese women. Seventy women with ESPL and 29 healthy pregnant women who asked for legal induced abortion were included in the case and control groups, respectively. The gestational age of the subject foetuses in both the case and control groups ranged from 4 to 10 weeks. The total fatty acids composition in the decidual and villous tissues was detected by gas-liquid chromatography using a standard method. Metabonomics analysis of the decidual and villous tissues was conducted by ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOFMS). The total C18:3n-3 in the decidual and villous tissues, total n-3 polyunsaturated fatty acid (n-3 PUFA) in the decidual tissue, and total C18:2n-6 in the villous tissue were all significantly lower in the case group than in the control group. The ratio of C20:4n-6/C20:5n-3 in villous tissue was significantly higher, but prostaglandin I 2 as well as hydroxyeicosapentaenoic acid, leukotriene B 5 and thromboxane B 3 in the villous tissue were significantly lower in the case group than in the control group. In addition, the low content of lysophosphatide in the decidual and villous tissues and the low content of diacylglycerol in the villous tissue were also associated with the occurance of ESPL. In conclusion, the lack of essential fatty acids, high ratio of C20:4n-6/C20:5n-3, abnormal eicosanoids metabolism and low content of lysophosphatide and diacylglycerol in the placenta were all potential risk factors for ESPL in Chinese.

  17. Genetic variants in autism-related CNTNAP2 impair axonal growth of cortical neurons.

    PubMed

    Canali, Giorgia; Garcia, Marta; Hivert, Bruno; Pinatel, Delphine; Goullancourt, Aline; Oguievetskaia, Ksenia; Saint-Martin, Margaux; Girault, Jean-Antoine; Faivre-Sarrailh, Catherine; Goutebroze, Laurence

    2018-06-01

    The CNTNAP2 gene, coding for the cell adhesion glycoprotein Caspr2, is thought to be one of the major susceptibility genes for autism spectrum disorder (ASD). A large number of rare heterozygous missense CNTNAP2 variants have been identified in ASD patients. However, most of them are inherited from an unaffected parent, questioning their clinical significance. In the present study, we evaluate their impact on neurodevelopmental functions of Caspr2 in a heterozygous genetic background. Performing cortical neuron cultures from mouse embryos, we demonstrate that Caspr2 plays a dose-dependent role in axon growth in vitro. Loss of one Cntnap2 allele is sufficient to elicit axonal growth alteration, revealing a situation that may be relevant for CNTNAP2 heterozygosity in ASD patients. Then, we show that the two ASD variants I869T and G731S, which present impaired binding to Contactin2/TAG-1, do not rescue axonal growth deficits. We find that the variant R1119H leading to protein trafficking defects and retention in the endoplasmic reticulum has a dominant-negative effect on heterozygous Cntnap2 cortical neuron axon growth, through oligomerization with wild-type Caspr2. Finally, we identify an additional variant (N407S) with a dominant-negative effect on axon growth although it is well-localized at the membrane and properly binds to Contactin2. Thus, our data identify a new neurodevelopmental function for Caspr2, the dysregulation of which may contribute to clinical manifestations of ASD, and provide evidence that CNTNAP2 heterozygous missense variants may contribute to pathogenicity in ASD, through selective mechanisms.

  18. Chronic intermittent ethanol induced axon and myelin degeneration is attenuated by calpain inhibition

    PubMed Central

    Samantaray, Supriti; Knaryan, Varduhi H.; Patel, Kaushal S.; Mulholland, Patrick J.; Becker, Howard C.; Banik, Naren L.

    2015-01-01

    Chronic alcohol consumption causes multifaceted damage to the central nervous system (CNS), underlying mechanisms of which are gradually being unraveled. In our previous studies, activation of calpain, a calcium-activated neutral protease has been found to cause detrimental alterations in spinal motor neurons following ethanol (EtOH) exposure in vitro. However, it is not known whether calpain plays a pivotal role in chronic EtOH exposure-induced structural damage to CNS in vivo. To test the possible involvement of calpain in EtOH-associated neurodegenerative mechanisms the present investigation was conducted in a well-established mouse model of alcohol dependence - chronic intermittent EtOH (CIE) exposure and withdrawal. Our studies indicated significant loss of axonal proteins (neurofilament light and heavy, 50-60 %), myelin proteins (myelin basic protein, 20-40 % proteolipid protein, 25 %) and enzyme (2′, 3′-cyclic-nucleotide 3′-phosphodiesterase, 21-55 %) following CIE in multiple regions of brain including hippocampus, corpus callosum, cerebellum, and importantly in spinal cord. These CIE-induced deleterious effects escalated after withdrawal in each CNS region tested. Increased expression and activity of calpain along with enhanced ratio of active calpain to calpastatin (sole endogenous inhibitor) was observed after withdrawal compared to EtOH exposure. Pharmacological inhibition of calpain with calpeptin (25 μg/kg) prior to each EtOH vapor inhalation significantly attenuated damage to axons and myelin as demonstrated by immuno-profiles of axonal and myelin proteins, and Luxol Fast Blue staining. Calpain inhibition significantly protected the ultrastructural integrity of axons and myelin compared to control as confirmed by electron microscopy. Together, these findings confirm CIE exposure and withdrawal induced structural alterations in axons and myelin, predominantly after withdrawal and corroborate calpain inhibition as a potential protective strategy

  19. Genetic analysis of an overlapping functional requirement for L1- and NCAM-type proteins during sensory axon guidance in Drosophila.

    PubMed

    Kristiansen, Lars V; Velasquez, Emma; Romani, Susana; Baars, Sigrid; Berezin, Vladimir; Bock, Elisabeth; Hortsch, Michael; Garcia-Alonso, Luis

    2005-01-01

    L1- and NCAM-type cell adhesion molecules represent distinct protein families that function as specific receptors for different axon guidance cues. However, both L1 and NCAM proteins promote axonal growth by inducing neuronal tyrosine kinase activity and are coexpressed in subsets of axon tracts in arthropods and vertebrates. We have studied the functional requirements for the Drosophila L1- and NCAM-type proteins, Neuroglian (Nrg) and Fasciclin II (FasII), during postembryonic sensory axon guidance. The rescue of the Neuroglian loss-of-function (LOF) phenotype by transgenically expressed L1- and NCAM-type proteins demonstrates a functional interchangeability between these proteins in Drosophila photoreceptor pioneer axons, where both proteins are normally coexpressed. In contrast, the ectopic expression of Fasciclin II in mechanosensory neurons causes a strong enhancement of the axonal misguidance phenotype. Moreover, our findings demonstrate that this functionally redundant specificity to mediate axon guidance has been conserved in their vertebrate homologs, L1-CAM and NCAM.

  20. Concussive Brain Trauma in the Mouse Results in Acute Cognitive Deficits and Sustained Impairment of Axonal Function

    PubMed Central

    Creed, Jennifer A.; DiLeonardi, Ann Mae; Fox, Douglas P.; Tessler, Alan R.

    2011-01-01

    Abstract Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function. PMID:21299360

  1. Neuronal growth cones respond to laser-induced axonal damage

    PubMed Central

    Wu, Tao; Mohanty, Samarendra; Gomez-Godinez, Veronica; Shi, Linda Z.; Liaw, Lih-Huei; Miotke, Jill; Meyer, Ronald L.; Berns, Michael W.

    2012-01-01

    Although it is well known that damage to neurons results in release of substances that inhibit axonal growth, release of chemical signals from damaged axons that attract axon growth cones has not been observed. In this study, a 532 nm 12 ns laser was focused to a diffraction-limited spot to produce site-specific damage to single goldfish axons in vitro. The axons underwent a localized decrease in thickness (‘thinning’) within seconds. Analysis by fluorescence and transmission electron microscopy indicated that there was no gross rupture of the cell membrane. Mitochondrial transport along the axonal cytoskeleton immediately stopped at the damage site, but recovered over several minutes. Within seconds of damage nearby growth cones extended filopodia towards the injury and were often observed to contact the damaged site. Turning of the growth cone towards the injured axon also was observed. Repair of the laser-induced damage was evidenced by recovery of the axon thickness as well as restoration of mitochondrial movement. We describe a new process of growth cone response to damaged axons. This has been possible through the interface of optics (laser subcellular surgery), fluorescence and electron microscopy, and a goldfish retinal ganglion cell culture model. PMID:21831892

  2. Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI.

    PubMed

    Urban, Mark W; Ghosh, Biswarup; Strojny, Laura R; Block, Cole G; Blazejewski, Sara M; Wright, Megan C; Smith, George M; Lepore, Angelo C

    2018-05-01

    Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality in individuals suffering from traumatic cervical spinal cord injury (SCI). Repair of CNS axons after SCI remains a therapeutic challenge, despite current efforts. SCI disrupts inspiratory signals originating in the rostral ventral respiratory group (rVRG) of the medulla from their phrenic motor neuron (PhMN) targets, resulting in loss of diaphragm function. Using a rat model of cervical hemisection SCI, we aimed to restore rVRG-PhMN-diaphragm circuitry by stimulating regeneration of injured rVRG axons via targeted induction of Rheb (ras homolog enriched in brain), a signaling molecule that regulates neuronal-intrinsic axon growth potential. Following C2 hemisection, we performed intra-rVRG injection of an adeno-associated virus serotype-2 (AAV2) vector that drives expression of a constitutively-active form of Rheb (cRheb). rVRG neuron-specific cRheb expression robustly increased mTOR pathway activity within the transduced rVRG neuron population ipsilateral to the hemisection, as assessed by levels of phosphorylated ribosomal S6 kinase. By co-injecting our novel AAV2-mCherry/WGA anterograde/trans-synaptic axonal tracer into rVRG, we found that cRheb expression promoted regeneration of injured rVRG axons into the lesion site, while we observed no rVRG axon regrowth with AAV2-GFP control. AAV2-cRheb also significantly reduced rVRG axonal dieback within the intact spinal cord rostral to the lesion. However, cRheb expression did not promote any recovery of ipsilateral hemi-diaphragm function, as assessed by inspiratory electromyography (EMG) burst amplitudes. This lack of functional recovery was likely because regrowing rVRG fibers did not extend back into the caudal spinal cord to synaptically reinnervate PhMNs that we retrogradely-labeled with cholera toxin B from the ipsilateral hemi-diaphragm. Our findings demonstrate that enhancing neuronal

  3. Visualization of Motor Axon Navigation and Quantification of Axon Arborization In Mouse Embryos Using Light Sheet Fluorescence Microscopy.

    PubMed

    Liau, Ee Shan; Yen, Ya-Ping; Chen, Jun-An

    2018-05-11

    Spinal motor neurons (MNs) extend their axons to communicate with their innervating targets, thereby controlling movement and complex tasks in vertebrates. Thus, it is critical to uncover the molecular mechanisms of how motor axons navigate to, arborize, and innervate their peripheral muscle targets during development and degeneration. Although transgenic Hb9::GFP mouse lines have long served to visualize motor axon trajectories during embryonic development, detailed descriptions of the full spectrum of axon terminal arborization remain incomplete due to the pattern complexity and limitations of current optical microscopy. Here, we describe an improved protocol that combines light sheet fluorescence microscopy (LSFM) and robust image analysis to qualitatively and quantitatively visualize developing motor axons. This system can be easily adopted to cross genetic mutants or MN disease models with Hb9::GFP lines, revealing novel molecular mechanisms that lead to defects in motor axon navigation and arborization.

  4. Therapy development for diffuse axonal injury.

    PubMed

    Smith, Douglas H; Hicks, Ramona; Povlishock, John T

    2013-03-01

    Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes

  5. Modeling the early evolution of massive OB stars with an experimental wind routine. The first bi-stability jump and the angular momentum loss problem

    NASA Astrophysics Data System (ADS)

    Keszthelyi, Z.; Puls, J.; Wade, G. A.

    2017-02-01

    Context. Stellar evolution models of massive stars are very sensitive to the adopted mass-loss scheme. The magnitude and evolution of mass-loss rates significantly affect the main sequence evolution, and the properties of post-main sequence objects, including their rotational velocities. Aims: Driven by potential discrepancies between theoretically predicted and observationally derived mass-loss rates in the OB star range, we aim in particular to investigate the response to mass-loss rates that are lower than currently adopted, in parallel with the mass-loss behavior at the "first" bi-stability jump. Methods: We performed 1D hydrodynamical model calculations of single 20-60 M⊙ Galactic (Z = 0.014) stars where the effects of stellar winds are already significant in the main sequence phase. We have developed an experimental wind routine to examine the behavior and response of the models under the influence of different mass-loss rates. This observationally guided, simple and flexible wind routine is not a new mass-loss description but a useful tool based on the wind-momentum luminosity relation and other scaling relations, and provides a meaningful base for various tests and comparisons. Results: The main result of this study indicates a dichotomy between solutions of currently debated problems regarding mass-loss rates of hot massive stars. In a fully diffusive approach, and for commonly adopted initial rotational velocities, lower mass-loss rates than theoretically predicted require to invoke an additional source of angular momentum loss (either due to bi-stability braking, or yet unidentified) to brake down surface rotational velocities. On the other hand, a large jump in the mass-loss rates due to the bi-stability mechanism (a factor of 5-7 predicted by Vink et al. (2000, A&A, 362, 295), but a factor of 10-20 in modern models of massive stars) is challenged by observational results, and might be avoided if the early mass-loss rates agreed with the theoretically

  6. AxonPacking: An Open-Source Software to Simulate Arrangements of Axons in White Matter

    PubMed Central

    Mingasson, Tom; Duval, Tanguy; Stikov, Nikola; Cohen-Adad, Julien

    2017-01-01

    HIGHLIGHTS AxonPacking: Open-source software for simulating white matter microstructure.Validation on a theoretical disk packing problem.Reproducible and stable for various densities and diameter distributions.Can be used to study interplay between myelin/fiber density and restricted fraction. Quantitative Magnetic Resonance Imaging (MRI) can provide parameters that describe white matter microstructure, such as the fiber volume fraction (FVF), the myelin volume fraction (MVF) or the axon volume fraction (AVF) via the fraction of restricted water (fr). While already being used for clinical application, the complex interplay between these parameters requires thorough validation via simulations. These simulations required a realistic, controlled and adaptable model of the white matter axons with the surrounding myelin sheath. While there already exist useful algorithms to perform this task, none of them combine optimisation of axon packing, presence of myelin sheath and availability as free and open source software. Here, we introduce a novel disk packing algorithm that addresses these issues. The performance of the algorithm is tested in term of reproducibility over 50 runs, resulting density, and stability over iterations. This tool was then used to derive multiple values of FVF and to study the impact of this parameter on fr and MVF in light of the known microstructure based on histology sample. The standard deviation of the axon density over runs was lower than 10−3 and the expected hexagonal packing for monodisperse disks was obtained with a density close to the optimal density (obtained: 0.892, theoretical: 0.907). Using an FVF ranging within [0.58, 0.82] and a mean inter-axon gap ranging within [0.1, 1.1] μm, MVF ranged within [0.32, 0.44] and fr ranged within [0.39, 0.71], which is consistent with the histology. The proposed algorithm is implemented in the open-source software AxonPacking (https://github.com/neuropoly/axonpacking) and can be useful for

  7. Recording axonal conduction to evaluate the integration of pluripotent cell-derived neurons into a neuronal network.

    PubMed

    Shimba, Kenta; Sakai, Koji; Takayama, Yuzo; Kotani, Kiyoshi; Jimbo, Yasuhiko

    2015-10-01

    Stem cell transplantation is a promising therapy to treat neurodegenerative disorders, and a number of in vitro models have been developed for studying interactions between grafted neurons and the host neuronal network to promote drug discovery. However, methods capable of evaluating the process by which stem cells integrate into the host neuronal network are lacking. In this study, we applied an axonal conduction-based analysis to a co-culture study of primary and differentiated neurons. Mouse cortical neurons and neuronal cells differentiated from P19 embryonal carcinoma cells, a model for early neural differentiation of pluripotent stem cells, were co-cultured in a microfabricated device. The somata of these cells were separated by the co-culture device, but their axons were able to elongate through microtunnels and then form synaptic contacts. Propagating action potentials were recorded from these axons by microelectrodes embedded at the bottom of the microtunnels and sorted into clusters representing individual axons. While the number of axons of cortical neurons increased until 14 days in vitro and then decreased, those of P19 neurons increased throughout the culture period. Network burst analysis showed that P19 neurons participated in approximately 80% of the bursting activity after 14 days in vitro. Interestingly, the axonal conduction delay of P19 neurons was significantly greater than that of cortical neurons, suggesting that there are some physiological differences in their axons. These results suggest that our method is feasible to evaluate the process by which stem cell-derived neurons integrate into a host neuronal network.

  8. Polygalae Radix Extract Prevents Axonal Degeneration and Memory Deficits in a Transgenic Mouse Model of Alzheimer’s Disease

    PubMed Central

    Kuboyama, Tomoharu; Hirotsu, Keisuke; Arai, Tetsuya; Yamasaki, Hiroo; Tohda, Chihiro

    2017-01-01

    Memory impairments in Alzheimer’s disease (AD) occur due to degenerated axons and disrupted neural networks. Since only limited recovery is possible after the destruction of neural networks, preventing axonal degeneration during the early stages of disease progression is necessary to prevent AD. Polygalae Radix (roots of Polygala tenuifolia; PR) is a traditional herbal medicine used for sedation and amnesia. In this study, we aimed to clarify and analyze the preventive effects of PR against memory deficits in a transgenic AD mouse model, 5XFAD. 5XFAD mice demonstrated memory deficits at the age of 5 months. Thus, the water extract of Polygalae Radix (PR extract) was orally administered to 4-month-old 5XFAD mice that did not show signs of memory impairment. After consecutive administrations for 56 days, the PR extract prevented cognitive deficit and axon degeneration associated with the accumulation of amyloid β (Aβ) plaques in the perirhinal cortex of the 5XFAD mice. PR extract did not influence the formation of Aβ plaques in the brain of the 5XFAD mice. In cultured neurons, the PR extract prevented axonal growth cone collapse and axonal atrophy induced by Aβ. Additionally, it prevented Aβ-induced endocytosis at the growth cone of cultured neurons. Our previous study reported that endocytosis inhibition was enough to prevent Aβ-induced growth cone collapse, axonal degeneration, and memory impairments. Therefore, the PR extract possibly prevented axonal degeneration and memory impairment by inhibiting endocytosis. PR is the first preventive drug candidate for AD that inhibits endocytosis in neurons. PMID:29184495

  9. Virtual tissue engineering and optic pathways: plotting the course of the axons in the retinal nerve fiber layer.

    PubMed

    Carreras, Francisco Javier; Medina, Javier; Ruiz-Lozano, Mariola; Carreras, Ignacio; Castro, Juan Luis

    2014-04-17

    As part of a larger project on virtual tissue engineering of the optic pathways, we describe the conditions that guide axons extending from the retina to the optic nerve head and formulate algorithms that meet such conditions. To find the entrance site on the optic nerve head of each axon, we challenge the fibers to comply with current models of axonal pathfinding. First, we build a retinal map using a single type of retinal ganglion cell (RGC) using density functions from the literature. Dendritic arbors are equated to receptive fields. Shape and size of retinal surface and optic nerve head (ONH) are defined. A computer model relates each soma to the corresponding entry point of its axon into the optic disc. Weights are given to the heuristics that guide the preference entry order in the nerve. Retinal ganglion cells from the area centralis saturate the temporal section of the disc. Retinal ganglion cells temporal to the area centralis curve their paths surrounding the fovea; some of these cells enter the disc centrally rather than peripherally. Nasal regions of the disc receive mixed axons from the far periphery of the temporal hemiretina, together with axons from the nasal half. The model plots the course of the axon using Bezier curves and compares them with clinical data, for a coincidence level of 86% or higher. Our model is able to simulate basic data of the early optic pathways including certain singularities and to mimic mechanisms operating during development, such as timing and fasciculation. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  10. Marginal Bone Loss Around Early-Loaded SLA and SLActive Implants: Radiological Follow-Up Evaluation Up to 6.5 Years.

    PubMed

    Şener-Yamaner, Işil Damla; Yamaner, Gökhan; Sertgöz, Atilla; Çanakçi, Cenk Fatih; Özcan, Mutlu

    2017-08-01

    The aim of this study was to compare marginal bone loss around early-loaded SLA and SLActive tissue-level implants (Straumann Dental Implants; Institut Straumann AG, Basel, Switzerland) after a mean of 81-month follow-up period. One hundred seven SLA and 68 SLActive implants were placed in 55 patients and loaded with final restoration after 8 and 3 weeks of healing time, respectively. Marginal bone loss around implants was determined radiographically at initial and after a mean observation time ranging between 20 and 81 months. The effect of location (mandible vs maxilla), smoking habit, sex, implant length and diameter, and the type of prosthesis on the marginal bone loss was evaluated. The overall cumulative survival rate was 98.2% being 99% for SLA implants and 97% for SLActive implants. After 20-month follow-up period, mean marginal bone loss values for the SLA and SLActive implants were 0.24 and 0.17 mm, respectively. After 81 months, mean marginal bone loss for the SLA and SLActive implants reached 0.71 and 0.53 mm, respectively. Marginal bone loss was affected by the length and type of implant and patients' smoking habit after a mean observation time of 20 months. However, none of the parameters had any significant effect on the marginal bone loss after a follow-up period of 81 months. With both SLA and SLActive implants, successful clinical results could be achieved up to 6.5 years of follow-up period.

  11. Early weight loss predicts the reduction of obesity in men with erectile dysfunction and hypogonadism undergoing long-term testosterone replacement therapy.

    PubMed

    Salman, Mahmoud; Yassin, Dany-Jan; Shoukfeh, Huda; Nettleship, Joanne Elisabeth; Yassin, Aksam

    2017-03-01

    We and others have previously shown that testosterone replacement therapy (TRT) results in sustained weight loss in the majority of middle-aged hypogonadal men. Previously, however, a small proportion failed to lose at least 5% of their baseline weight. The reason for this is not yet understood. In the present study, we sought to identify early indicators that may predict successful long-term weight loss, defined as a reduction of at least 5% of total body weight relative to baseline weight (T0), in men with hypogonadism undergoing TRT. Eight parameters measured were assessed as potential predictors of sustained weight loss: loss of 3% or more of baseline weight after 1 year of TU treatment, severe hypogonadism, BMI, waist circumference, International Prostate Symptom Score (IPSS), glycated hemoglobin (HbA 1C ), age and use of vardenafil. Among the eight measured parameters, three factors were significantly associated with sustained weight loss over the entire period of TU treatment: (1) a loss of 3% of the baseline body weight after 1 year of TRT; (2) baseline BMI over 30; and (3) a waist circumference >102 cm. Age was not a predictor of weight loss.

  12. Disparities in reproductive outcomes according to the endometrial preparation protocol in frozen embryo transfer : The risk of early pregnancy loss in frozen embryo transfer cycles.

    PubMed

    Hatoum, I; Bellon, L; Swierkowski, N; Ouazana, M; Bouba, S; Fathallah, K; Paillusson, B; Bailly, M; Boitrelle, F; Alter, L; Bergère, M; Selva, J; Wainer, R

    2018-03-01

    The purpose of this study was to determine the effect of stimulated and artificial endometrial preparation protocols on reproductive outcomes in frozen embryo transfer (FET) cycles. We performed a retrospective study of 1926 FET cycles over a 3.5-year period in the Fertility Unit at a University Hospital. Stimulated and artificial protocols were used for endometrial preparation. The embryos for FET were obtained from either in vitro fertilization or intracytoplasmic sperm injection cycles. Live birth rate and early pregnancy loss rates were retrospectively compared. In artificial protocols, oral or vaginal administration of oestradiol 2 mg two or three times a day was followed by vaginal supplementation with progesterone 200 mg two or three times a day. In stimulated protocols, recombinant follicle-stimulating hormone was administered from day 4 onward. Vaginal ultrasound was used for endometrial and ovarian monitoring. A pregnancy test was performed 14 days after FET. If it was positive, oestradiol and progesterone were administered up until the 12th week of gestation in artificial cycles. We defined early pregnancy losses as biochemical pregnancies (preclinical losses) and miscarriages. Data on 865 artificial cycles (45% of the total) and 1061 stimulated cycles (55%) were collected. Early pregnancy loss rate was significantly lower for stimulated cycles (34.2%) than for artificial cycles (56.9%), and the live birth rate was significantly higher for stimulated cycles (59.7%) than for artificial cycles (29.1%). In frozen embryo transfer, artificial cycles were associated with more early pregnancy loss and lower live birth rate than stimulated cycles.

  13. Axonal Regeneration after Sciatic Nerve Lesion Is Delayed but Complete in GFAP- and Vimentin-Deficient Mice

    PubMed Central

    Berg, Alexander; Zelano, Johan; Pekna, Marcela; Wilhelmsson, Ulrika; Pekny, Milos; Cullheim, Staffan

    2013-01-01

    Peripheral axotomy of motoneurons triggers Wallerian degeneration of injured axons distal to the lesion, followed by axon regeneration. Centrally, axotomy induces loss of synapses (synaptic stripping) from the surface of lesioned motoneurons in the spinal cord. At the lesion site, reactive Schwann cells provide trophic support and guidance for outgrowing axons. The mechanisms of synaptic stripping remain elusive, but reactive astrocytes and microglia appear to be important in this process. We studied axonal regeneration and synaptic stripping of motoneurons after a sciatic nerve lesion in mice lacking the intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin, which are upregulated in reactive astrocytes and Schwann cells. Seven days after sciatic nerve transection, ultrastructural analysis of synaptic density on the somata of injured motoneurons revealed more remaining boutons covering injured somata in GFAP–/–Vim–/– mice. After sciatic nerve crush in GFAP–/–Vim–/– mice, the fraction of reinnervated motor endplates on muscle fibers of the gastrocnemius muscle was reduced 13 days after the injury, and axonal regeneration and functional recovery were delayed but complete. Thus, the absence of GFAP and vimentin in glial cells does not seem to affect the outcome after peripheral motoneuron injury but may have an important effect on the response dynamics. PMID:24223940

  14. Frequency-dependent reliability of spike propagation is function of axonal voltage-gated sodium channels in cerebellar Purkinje cells.

    PubMed

    Yang, Zhilai; Wang, Jin-Hui

    2013-12-01

    The spike propagation on nerve axons, like synaptic transmission, is essential to ensure neuronal communication. The secure propagation of sequential spikes toward axonal terminals has been challenged in the neurons with a high firing rate, such as cerebellar Purkinje cells. The shortfall of spike propagation makes some digital spikes disappearing at axonal terminals, such that the elucidation of the mechanisms underlying spike propagation reliability is crucial to find the strategy of preventing loss of neuronal codes. As the spike propagation failure is influenced by the membrane potentials, this process is likely caused by altering the functional status of voltage-gated sodium channels (VGSC). We examined this hypothesis in Purkinje cells by using pair-recordings at their somata and axonal blebs in cerebellar slices. The reliability of spike propagation was deteriorated by elevating spike frequency. The frequency-dependent reliability of spike propagation was attenuated by inactivating VGSCs and improved by removing their inactivation. Thus, the functional status of axonal VGSCs influences the reliability of spike propagation.

  15. Demonstration of ion channel synthesis by isolated squid giant axon provides functional evidence for localized axonal membrane protein translation.

    PubMed

    Mathur, Chhavi; Johnson, Kory R; Tong, Brian A; Miranda, Pablo; Srikumar, Deepa; Basilio, Daniel; Latorre, Ramon; Bezanilla, Francisco; Holmgren, Miguel

    2018-02-02

    Local translation of membrane proteins in neuronal subcellular domains like soma, dendrites and axon termini is well-documented. In this study, we isolated the electrical signaling unit of an axon by dissecting giant axons from mature squids (Dosidicus gigas). Axoplasm extracted from these axons was found to contain ribosomal RNAs, ~8000 messenger RNA species, many encoding the translation machinery, membrane proteins, translocon and signal recognition particle (SRP) subunits, endomembrane-associated proteins, and unprecedented proportions of SRP RNA (~68% identical to human homolog). While these components support endoplasmic reticulum-dependent protein synthesis, functional assessment of a newly synthesized membrane protein in axolemma of an isolated axon is technically challenging. Ion channels are ideal proteins for this purpose because their functional dynamics can be directly evaluated by applying voltage clamp across the axon membrane. We delivered in vitro transcribed RNA encoding native or Drosophila voltage-activated Shaker K V channel into excised squid giant axons. We found that total K + currents increased in both cases; with added inactivation kinetics on those axons injected with RNA encoding the Shaker channel. These results provide unambiguous evidence that isolated axons can exhibit de novo synthesis, assembly and membrane incorporation of fully functional oligomeric membrane proteins.

  16. Pregnancy Loss and Miscarriage

    MedlinePlus

    ... Pinterest Email Print About Pregnancy Loss (Before 20 Weeks of Pregnancy) Pregnancy loss is the unexpected loss of a fetus before the 20th week of pregnancy. It is sometimes called miscarriage, early ...

  17. Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons.

    PubMed

    Gamage, Kanchana K; Cheng, Irene; Park, Rachel E; Karim, Mardeen S; Edamura, Kazusa; Hughes, Christopher; Spano, Anthony J; Erisir, Alev; Deppmann, Christopher D

    2017-03-20

    Axon degeneration during development is required to sculpt a functional nervous system and is also a hallmark of pathological insult, such as injury [1, 2]. Despite similar morphological characteristics, very little overlap in molecular mechanisms has been reported between pathological and developmental degeneration [3-5]. In the peripheral nervous system (PNS), developmental axon pruning relies on receptor-mediated extrinsic degeneration mechanisms to determine which axons are maintained or degenerated [5-7]. Receptors have not been implicated in Wallerian axon degeneration; instead, axon autonomous, intrinsic mechanisms are thought to be the primary driver for this type of axon disintegration [8-10]. Here we survey the role of neuronally expressed, paralogous tumor necrosis factor receptor super family (TNFRSF) members in Wallerian degeneration. We find that an orphan receptor, death receptor 6 (DR6), is required to drive axon degeneration after axotomy in sympathetic and sensory neurons cultured in microfluidic devices. We sought to validate these in vitro findings in vivo using a transected sciatic nerve model. Consistent with the in vitro findings, DR6 -/- animals displayed preserved axons up to 4 weeks after injury. In contrast to phenotypes observed in Wld s and Sarm1 -/- mice, preserved axons in DR6 -/- animals display profound myelin remodeling. This indicates that deterioration of axons and myelin after axotomy are mechanistically distinct processes. Finally, we find that JNK signaling after injury requires DR6, suggesting a link between this novel extrinsic pathway and the axon autonomous, intrinsic pathways that have become established for Wallerian degeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. A role for myelin-associated peroxisomes in maintaining paranodal loops and axonal integrity.

    PubMed

    Kassmann, Celia M; Quintes, Susanne; Rietdorf, Jens; Möbius, Wiebke; Sereda, Michael Werner; Nientiedt, Tobias; Saher, Gesine; Baes, Myriam; Nave, Klaus-Armin

    2011-07-21

    Demyelinating diseases of the nervous system cause axon loss but the underlying mechanisms are not well understood. Here we show by confocal and electron microscopy that in myelin-forming glia peroxisomes are associated with myelin membranes. When peroxisome biogenesis is experimentally perturbed in Pex5 conditional mouse mutants, myelination by Schwann cells appears initially normal. However, in nerves of older mice paranodal loops become physically unstable and develop swellings filled with vesicles and electron-dense material. This novel model of a demyelinating neuropathy demonstrates that peroxisomes serve an important function in the peripheral myelin compartment, required for long-term axonal integrity. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  19. Evolutionary forward genomics reveals novel insights into the genes and pathways dysregulated in recurrent early pregnancy loss.

    PubMed

    Kosova, Gülüm; Stephenson, Mary D; Lynch, Vincent J; Ober, Carole

    2015-03-01

    Are the genes that gained novel expression in the endometria of Eutherian (placental) mammals more likely to be dysregulated in patients with endometrial-associated recurrent early pregnancy loss (REPL)? There was a significant enrichment of genes dysregulated in REPL patients among the Eutherian-specific endometrial genes. Pregnancy loss is the most common complication of human pregnancy. REPL has multiple etiologies, including dysregulation of endometrial function, leading to 'suboptimal' implantation. Although the implantation process is tightly regulated in Eutherian (placental) mammals, the molecular factors contributing to dysregulated endometrial gene expression patterns in women with REPL are largely unknown. Endometrial biopsies were obtained from 32 REPL patients during the mid-luteal phase, and evaluated for glandular development arrest based on elevated nuclear cyclin E levels in gland cells,