Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood

Fate of myelin lipids during degeneration and regeneration of peripheral nerve: an autoradiographic study

Four weeks after labeling myelin lipids with an intraneural injection of 3H-acetate, sciatic nerves were crushed, and the distribution of radiolabeled myelin lipids was followed by autoradiography from 1 d to 10 weeks later. Just prior to crush, silver grains were localized to the myelin sheath. Three days after crush, axons were degenerating and myelin sheaths were breaking down; silver grains appeared over lipid droplets within Schwann cells, fibroblasts, and macrophages. One week after crush the basal-lamina-delimited Schwann-cell tubes (Bungner bands) contained myelin debris, and some tubes already contained regenerating axons. Schwann cells were often displaced to the periphery of the tubes by phagocytes containing heavily labeled myelin debris; extratubal macrophages within the endoneurium contained labeled lipid droplets but no myelin debris. Two weeks after nerve crush silver grains were associated with newly formed myelin around regenerating axons. Many extratubal endoneurial macrophages now contained labeled myelin debris and lipid droplets. By 3 weeks myelination of regenerating axons was advanced, and the myelin sheaths were well labeled. Extratubal macrophages had become the major labeled structure within the nerve because they contained large amounts of labeled myelin debris and lipid droplets. From 4 to 10 weeks after nerve crush the new myelin sheaths continued to thicken and to be well labeled. Debris- laden extratubal macrophages remained the major site of labeled material within the endoneurium. Our results confirm that there is reutilization of myelin cholesterol by Schwann cells to form new myelin, and indicate that some lipid catabolism takes place in Schwann cells and endoneurial fibroblasts prior to infiltration of the nerve by macrophages. However, most of the myelin debris is phagocytized by macrophages within 1–2 weeks following nerve injury. These debris-laden macrophages persist within the nerve for many weeks, indicating that much of the salvaged cholesterol is not reutilized for myelin regeneration

Impaired peripheral nerve regeneration in a mutant strain of mice (Enr) with a Schwann cell defect

Schwann cell-axon interactions in the development, maintenance, and regeneration of the normal peripheral nervous system are complex. A previously described transgene-induced insertional mutation (BPFD#36), now referred to as Enervated (Enr), results in disrupted Schwann cell- axon interactions. In this report, after a crush or transection injury to Enr peripheral nerves, we demonstrate impaired nerve regeneration. There are fewer myelinated fibers per mm2 and thinner myelin sheaths surrounding regenerating axons in the nerves of homozygous mutant mice compared to wild type mice at 28 d after crush injury to the sciatic nerve. Abnormal Schwann cell-axon interactions remain in Enr/Enr animals as evidenced by the relatively frequent ultrastructural finding of unmyelinated large diameter axons in the regenerating nerves. Additionally, nerve graft experiments indicate that the impairment in regeneration is due to a Schwann cell defect. Morphologic and morphometric findings in conjunction with molecular analysis of regenerating nerves suggest that the Enr defect causes a disruption in the ability of “early ” Schwann cells to differentiate to a more mature phenotype. In mutant homozygous and wild type nerves at 7 d after crush injury there are similar levels of mRNA for the low-affinity nerve growth factor receptor, but in the mutant homozygous regenerating nerves there is 11-fold less mRNA for glial fibrillary acidic protein, a more mature phenotypic marker of Schwann cells. This Schwann cell differentiation defect likely accounts for both the peripheral neuropathy and impaired nerve regeneration observed in Enr mice

Pathogenesis of trimethyltin neuronal toxicity. Ultrastructural and cytochemical observations.

The ultrastructural cytopathologic and cytochemical effects of trimethyltin (TMT) neurotoxicity were delineated in hippocampal and pyriform neurons of acutely intoxicated adult rats. TMT produced neuronal necrosis that preferentially involved hippocampal formation pyriform cortex. The first subcellular alterations were multifocal collection of dense-cored vesicles and tubules and membrane-delimited vacuoles in the cytoplasm of the perikaryon and proximal dendrite. Ultrastructural cytochemical examination revealed that the vesicles and tubules had acid phosphatase activity analagous to Golgi-associated endoplasmic reticulum (GERL). Shortly after the appearance of the GERL-like vesicles and tubules, autophagic vacuoles and polymorphic dense bodies accumulated in the neuronal cytoplasm. Some dense bodies appeared to arise from the dense-cored tubules. Neuronal necrosis was characterized by increased electron density of the cytoplasm and large, electron-dense intranuclear masses. Alterations of mitochondria and other organelles were not observed in the early stages of cell injury. No light- or electron-microscopic alterations were found in liver or kidney. Comparable subcellular alterations were observed in adult and neonatal rats chronically intoxicated with TMT. A series of other trialkyl and tricyclic tins and dimethyltin did not produce similar pathologic findings. The GERL-like accumulations are unique in neuronal cytopathology. These findings suggests that GERL and autophagy play an important role in the pathogenesis of TMT-induced neuronal injury

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens

Abstract Giant axonal neuropathy (GAN; ORPHA: 643; OMIM# 256850) is a rare, hereditary, pediatric neurodegenerative disorder associated with intracellular accumulations of intermediate filaments (IFs). GAN knockout (KO) mouse models mirror the IF dysregulation and widespread nervous system pathology seen in human GAN. Validation of therapeutic efficacy and viral vector delivery systems with these GAN KO models has provided the springboard for the development of a viral vector being delivered intrathecally in an ongoing Phase I gene therapy clinical trial for the treatment of children with GAN ( https://clinicaltrials.gov/ct2/show/NCT02362438 ). During the course of a comprehensive pathologic characterization of the GAN KO mouse, we discovered the very early and unexpected involvement of the ocular lens. Light microscopy revealed the presence of intracytoplasmic inclusion bodies within lens epithelial cells. The inclusion bodies showed strong immunohistochemical positivity for glial fibrillary acidic protein (GFAP). We confirmed that intracytoplasmic inclusion bodies are also present within lens epithelial cells in human GAN. These IF inclusion bodies in lens epithelial cells are unique to GAN. Similar IF inclusion bodies in lens epithelial cells have not been reported previously in experimental animal models or human diseases. Since current paradigms in drug discovery and drug repurposing for IF-associated disorders are often hindered by lack of validated targets, our findings suggest that lens epithelial cells in the GAN KO mouse may provide a potential target, in vivo and in vitro, for evaluating drug efficacy and alternative therapeutic approaches in promoting the clearance of IF inclusions in GAN and other diseases characterized by intracellular IF accumulations

Fatal Pediatric COVID-19 Case With Seizures and Fulminant Cerebral Edema

The novel coronavirus, SARS-CoV-2, can present with a wide range of neurological manifestations, in both adult and pediatric populations. We describe here the case of a previously healthy 8-year-old girl who presented with seizures, encephalopathy, and rapidly progressive, diffuse, and ultimately fatal cerebral edema in the setting of acute COVID-19 infection. CSF analysis, microbiological testing, and neuropathology yielded no evidence of infection or acute inflammation within the central nervous system. Acute fulminant cerebral edema (AFCE) is an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema. AFCE occurs as a rare complication of a variety of common pediatric infections and a CNS pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema. This report suggests that COVID-19 infection can precipitate AFCE, and highlights the need for high suspicion and early recognition thereof

L 2 -topological invariants of 3-manifolds

We give results on the L 2 -Betti numbers and Novikov-Shubin invariants of compact manifolds, especially 3-manifolds. We first study the Betti numbers and Novikov-Shubin invariants of a chain complex of Hilbert modules over a finite von Neumann algebra. We establish inequalities among the Novikov-Shubin invariants of the terms in a short exact sequence of chain complexes. Our algebraic results, along with some analytic results on geometric 3-manifolds, are used to compute the L 2 -Betti numbers of compact 3-manifolds which satisfy a weak form of the geometrization conjecture, and to compute or estimate their Novikov-Shubin invariants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46581/1/222_2005_Article_BF01241121.pd

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

The Soft X-ray Imager (SXI) on the SMILE Mission

The Soft X-ray Imager (SXI) is part of the scientific payload of the Solar wind Magnetosphere Ionosphere Link Explorer (SMILE) mission. SMILE is a joint science mission between the European Space Agency (ESA) and the Chinese Academy of Sciences (CAS) and is due for launch in 2025. SXI is a compact X-ray telescope with a wide field-of-view (FOV) capable of encompassing large portions of Earth’s magnetosphere from the vantage point of the SMILE orbit. SXI is sensitive to the soft X-rays produced by the Solar Wind Charge eXchange (SWCX) process produced when heavy ions of solar wind origin interact with neutral particles in Earth’s exosphere. SWCX provides a mechanism for boundary detection within the magnetosphere, such as the position of Earth’s magnetopause, because the solar wind heavy ions have a very low density in regions of closed magnetic field lines. The sensitivity of the SXI is such that it can potentially track movements of the magnetopause on timescales of a few minutes and the orbit of SMILE will enable such movements to be tracked for segments lasting many hours. SXI is led by the University of Leicester in the United Kingdom (UK) with collaborating organisations on hardware, software and science support within the UK, Europe, China and the United States