Macroglobulinemic neuropathy. Experimental macroglobulinemic neuropathy in mice.
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Biomedical subjects
H C Powell
Publications and source records attributed to H C Powell.
Peripheral neuropathy in the Twitcher mutant. A new experimental model of endoneurial edema.
The Twitcher mouse (Twi/Twi) is a recently identified mutant experimental model for human globoid leukodystrophy. Affected mice develop neurologic abnormalities with demyelination of white matter and peripheral nerve due to an inherited enzyme deficiency. The neuropathy has unusual pathologic features:severe interstitial edema and infiltration by eosinophils. To investigate its pathogenesis and to identify the mechanism of demyelination, we studied vascular permeability and measured endoneurial fluid pressure. Significantly increased endoneurial fluid pressure was detected in clinically affected animals (average, 6.4 cm H2O) versus controls (1.7 cm H2O), and these data are the first measurements of EFP to be reported in mice. Increased vascular permeability to horseradish peroxidase was visualized by electron microscopy with leakage of horseradish peroxidase between endothelial cells and flooding of the endoneurial interstitium. Numerous eosinophils were present in the interstitium, as well as some polymorphonuclear cells, occasional erythrocytes, and degranulating mast cells. Abnormalities of nerve fibers included swelling of Schwann cells with intracytoplasmic inclusions, demyelination, and remyelination. As well as being a model for globoid leukodystrophy, the Twitcher is the first spontaneously occurring experimental model for endoneurial edema and increased endoneurial fluid pressure.
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Early changes in experimental allergic neuritis.
Edema and increased endoneurial fluid pressure (EFP) accompany the inflammatory process in experimental allergic neuritis. EFP was measured at regular intervals 6 to 21 days after intradermal inoculation of Lewis rats with an emulsion of peripheral nerve in complete Freund's adjuvant. Control rats received similar injections of an emulsion containing all other ingredients, except peripheral nerve. Altered vascular permeability was illustrated by leakage of horseradish peroxidase into rat sciatic nerve endoneurial space as early as 10 days after inoculation. A difference in EFP between controls and test animals became apparent after 11 days, and highest values were obtained 12 to 16 days postinoculation. Nerves were excised for histologic examination after EFP measurement. Severe endoneurial edema was present after 12 days and was associated with appreciable inflammatory cell infiltration. Inflammatory cells were clustered around small vessels and also were numerous in the subperineurial space which was expanded by edema. Degranulation of mast cells was also noted in association with edema and inflammation. Immunoperoxidase staining revealed immunoglobulin in the subperineurial and perivascular spaces 10 to 12 days postinoculation, but not in sections 6 to 9 days (postinoculation). These findings suggest suggest that altered vascular permeability is the earliest morphologic change in experimental allergic neuritis, followed by accumulation of antibody-containing edema fluid, penetration of the endoneurium by inflammatory cells, and increased EFP.
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Neonatal infection with the Daniels strain of Theiler's murine encephalomyelitis virus.
The clinical and pathologic manifestation of Theiler's murine encephalomyelitis are age related. Animals infected during the first week of life die of a fulminant encephalitis analogous to human poliomyelitis. By contrast, animals infected within 2 and 4 weeks of age survive but develop chronic relapsing demyelination and persistent infection of the central nervous system. The neonatal infection results in widespread necrosis beginning with neuronal vacuolar degeneration followed by inflammatory infiltrates. Electron microscopy reveals paracrystalline arrays of 27-nm viral particles characteristic of picornaviruses within neurons and macrophages. In addition, oligodendrocytes show reactive changes and intracytoplasmic vacuoles. Immunoperoxidase studies show viral antigen primarily localized within neurons of the cerebral cortex, basal ganglia, hippocampus, and anterior horn cells. Viral antigen is found within the apical dendrites and axonal projections of hippocampal pyramidal cells suggesting that Theiler's murine encephalomyelitis may travel intraaxonally.
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Pathology of multiple sclerosis.
MS has certain salient morphologic features that distinguish it from other disorders of white matter and that may represent points of departure for investigation.
Astrocytes↗
Pathology of diabetic neuropathy: new observations, new hypotheses.
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Animals↗
Microgravimetric analysis of nerve edema.
A technique for microgravimetric analysis of nerve edema was used to demonstrate increased water content in hexachlorophene neuropathy. The method was modified from one used previously to quantify brain edema by using density gradient columns prepared with two nonaqueous fluids of high and low specific gravity. This method revealed a wide separation between hexachlorophene-treated and control nerves. Gradient position was then related to specific gravity, which averaged 1.03426 in hexachlorophene-treated nerves versus 1.04921 for control nerves. This, in turn, was correlated with the percentage of water in the tissue. Water content of hexachlorophene-intoxicated nerves was approximately 10% greater than control nerves. A major advantage of this technique is its sensitivity in detecting edema in small tissue samples.
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Nerve regeneration in silicone chambers: influence of gap length and of distal stump components.
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Elevated hemoglobin A1 in streptozotocin diabetic rats and in rats on sucrose and galactose-enriched diets.
Increased hemoglobin A1 (HbA1) occurs in diabetes mellitus as a direct consequence of hyperglycemia, which causes postsynthetic modification of hemoglobin proportional to blood glucose concentration. Glycosylation of hemoglobin is demonstrable also in vitro, not only by glucose, but with other reducing sugars such as galactose. The purpose of this study was to show that increased HbA1 could be induced by feeding rats a diet enriched either by galactose or sucrose. A third experimental group consisted of rats made diabetic by injection of streptozotocin. Exposure to a diet of 40% galactose resulted in a diabetes-like state with polyuria, weight loss, muscle atrophy, fat depletion, bilateral cataracts, peripheral neuropathy and significantly elevated HbA1. Blood glucose levels were not elevated and after four months of galactose feeding there was hypoglycemia. Total HbA1 was determined by a microcolumn chromatographic procedure, recently made available for clinical use. Increased HbA1 was also found in rats which received a diet of 68% sucrose for several months. The highest values of HbA1 were determined in streptozotocin diabetic rats and there was significant correlation with plasma glucose concentration. Development of experimental models for increased HbA1 by dietary exposure makes it possible to relate increases in HbA1 to measured amounts of sugar included in the diet. Increased HbA1 in galactosemic and diabetic rats provides a biochemical marker which may be correlated with the evolving morphologic changes such as basement membrane thickening occurring in certain tissues in diabetes mellitus.
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Reduced nerve blood flow in hexachlorophene neuropathy: relationship to elevated endoneurial fluid pressure.
To test the hypothesis that increased endoneurial fluid pressure (EFP) causes a reduction in nerve blood flow (NBF) in the vasa nervorum, we adapted a noninvasive method for measurement of nerve blood flow which was originally developed for measurement of local cerebral blood flow. This technique measures tissue distribution to the radioisotope, 14C-iodoantipyrine, and was used to compare NBF in sciatic nerves of rats with increased EFP induced by feeding them hexachlorophene (HCP), a neurotoxin which causes edema exclusively to the nervous system and confined to the myelin sheath. Elevation of interstitial fluid pressure in peripheral nerves from control values of 2.0 +/- 1.0 cm H2O to over approximately 6 cm H2O was associated with a statistically significant reduction in nerve blood flow from 14.8 +/- 5.9 to 7.8 +/- 2.5 ml/100 g of tissue/minute (min). These results support the hypothesis that increased endoneurial fluid pressure exacerbates the neuropathy by diminishing local blood flow.
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In vivo regeneration of cut nerves encased in silicone tubes: growth across a six-millimeter gap.
We describe an experimental in vivo system for studying peripheral nerve regeneration, in which the proximal stump of a transected nerve regrows through a transparent silicone chamber toward the distal stump. Physical separation permits examination of the effects of the humoral and/or cellular influences from the distal stump on regenerating fibers before they invade the distal segment itself. A small segment of the rat sciatic nerve was resected, leaving a 6 mm gap which was then encased by a cylindrical silicone chamber. Within the first weeks, a nerve trunk regenerated along the central axis of the chamber bridged the gap between the proximal and distal stumps. When the distal nerve stump was omitted from the distal opening of the chamber, only a thin structure with a few small-caliber fibers extended across the gap. In each instance regenerating nerve appeared as a cord-like structure completely surrounded by clear fluid, a feature which permits easy collection of the extracellular fluid for analysis of its chemical properties and biological activity. This feature also allows in vivo manipulation of the humoral environment in which nerve regeneration occurs.
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Canine GM1 gangliosidosis. An ultrastructural and biochemical study.
The ultrastructural and biochemical features of canine GM1 gangliosidosis were studied. beta-Galactosidase activity assayed using both skin fibroblast tissue culture strains and fresh skin revealed enzyme activities in three groups (normals, heterozygotes, and homozygotes) corresponding to an autosomal recessive inheritance. The concentration of ganglioside GM1 was greatly increased in cerebral gray matter and kidney. A striking elevation of tissue oligosaccharides was found in liver, kidney, and spleen. Most neurons in the cerebral cortex and deep gray matter were filled by spherical lamellated inclusions. Hepatocytes contained vacuoles with an amorphous granular material which may correspond to the accumulation of galactose-oligosaccharides determined chemically. The disease in dogs has features similar to both the infantile and juvenile form of human GM1 gangliosidosis.
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Central and peripheral nervous system complications.
Symptomatic neuropathy is a common manifestation of diabetes mellitus, and sensory, motor, or autonomic symptoms occur in approximately 10% of all diabetic patients. Animal models may be useful to study the metabolic and electrophysiologic abnormalities peculiar to diabetic neuropathy. Genetic animal models, including the Chinese hamster, ob/ob mouse, db/db mouse, BB-wistar rat, and SSDR rat or chemically induced or nutritional models of diabetes mellitus provide the potential to use animals to study human neuropathy; however, to date, few characteristics of human diabetic neuropathy have been clearly demonstrated in any of these animal models. Better characterization of the neuropathy of existing animal models with emphasis on evaluation over long periods of time is recommended. These studies should include a cross-disciplinary approach using biochemical, electrophysiologic and morphologic techniques. Specific future approaches to study diabetic neuropathy using chemical models is outlined in this chapter.
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Changes in Schwann cells and vessels in lead neuropathy.
Transmission electron microscopy (TEM) of peripheral nerve in rats receiving 6% lead carbonate for 4-10 weeks provided evidence of a specific Schwann cell injury, associated with demyelination. Intranuclear inclusions in Schwann cells appeared within 2 weeks of administration of a lead-containing diet. Swelling of Schwann cells and disintegration of their cytoplasm was evident at 4 weeks. Distinctive electron-dense inclusions appeared in both Schwann and endothelial cells during the period of intoxication and were ultrastructurally identical to pathognomonic inclusions of lead poisoning seen in renal tubular epithelial cells. Scanning microscopy (SEM) with electron-probe microanalysis was used to identify the lead-containing deposits. In addition to Schwann cell changes, vessels revealed endothelial cell injury and alteread permeability to macromolecules. Since morphologic changes of Schwann cells precede the development of altered vascular permeability and endoneurial edema, it appears that lead gains access to the endoneurium prior to the development of altered vascular permeability, suggesting that edema and altered endoneurial fluid pressure are epiphenomena that supervene after demyelination occurs. Remyelination, Schwann cell proliferation and formation of onion bulbs are manifestations of persistent toxic injury to myelin-sustaining cells, resulting in chronic demyelination.
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Experimental syphilitic orchitis in rabbits: ultrastructural appearance of Treponema pallidum during phagocytosis and dissolution by macrophages in vivo.
The ultrastructural distribution of Treponema pallidum and the host inflammatory response during experimental testicular infection of rabbits have been examined. During the inductive phase of experimental orchitis both organisms and inflammatory cells, primarily lymphocytes, are coated by amorphous material not seen in other cellular inflammatory reactions. Phagocytosis of organisms by macrophages occurs during the reactive phase. Phagocytic vesicles contain T. pallidum and are frequently lined by amorphous material. T. pallidum do not appear structurally abnormal prior to phagocytosis; destruction of T. pallidum, manifested by swelling and lysis of the organisms, occurs within phagocytic vacuoles. We conclude that removal of organisms during the reactive stage of experimental syphilis is accomplished by phagocytosis and digestion of organisms by macrophages, resulting from a delayed hypersensitivity reaction initiated by specifically sensitized T cells. The presence of amorphous "ground substance" material does not block the inflammatory response and inhibits neither phagocytosis nor digestion by macrophages.
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Biophysical and pathological effects of cryogenic nerve lesion.
Changes in endoneurial fluid pressure (EFP) and morphology were studied in rat sciatic nerves frozen for 60 seconds with a cryoprobe designed for human cryoanalgesia. The onset of increased EFP was rapid, and a peak of 23 cm H2O was reached within 90 minutes after injury. EFP levels returned to normal 32 days after freezing. The peak value represents the highest EFP yet recorded in an experimental neuropathy. Microscopic examination revealed severe vascular injury as the probable mechanism of edema, with leakage of horseradish peroxidase tracer at the site of injury and diapedesis of polymorphonuclear cells through vessel walls. Wallerian degeneration was also observed in segments of nerve distal to the site of injury. Analysis of EFP data revealed a biphasic pattern of endoneurial edema: initial marked pressure elevation subsides within hours but is followed by a second peak several days later. We interpret this to suggest superposition of two separate pathological processes following cold injury. At first, extensive vascular damage permits plasma and cellular extravasation, which rapidly increases EFP. Subsequently, nerve fibers undergo wallerian degeneration, a process associated with elevated EFP, which is maximal 6 days after injury.
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Galactose neuropathy. Permeability studies, mechanism of edema, and mast cell abnormalities.
Galactose neuropathy is characterized by progressive endoneurial edema manifested by a gradual increase in endoneurial fluid pressure. Edema accumulates via a unique mechanism of osmotic force generated by products of the polyol pathway, synthesized within the endoneurial compartment. This paper presents morphologic findings showing firstly, that blood nerve barrier permeability to horseradish peroxidase complexes appears unchanged and secondly, peripheral nerve edema in this condition is restricted to extraganglionic endoneurium sparing the spinal ganglia and adjacent roots. Thirdly, mast cells accumulated in significant numbers and electron microscopy revealed degranulation. There was no evidence of edema in Schwann cell cytoplasm, the putative site of galactitol accumulation via the sorbitol pathway. These findings are discussed with respect to diabetic neuropathy for which galactose intoxication is a useful experimental model.
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Endoneurial fluid pressure in experimental models of diabetic neuropathy.
The sorbitol pathway has been suggested as a biochemical mechanism for peripheral neuropathy in diabetes, due to accumulation of osmotically active polyols which cause endoneurial edema. The purpose of this study was to compare endoneurial fluid pressure (EFP) in the peripheral nerves of rats in three experimental models: streptozotocin diabetes, galactose neuropathy, and sucrose intoxication. Endoneurial fluid pressure was measured in 27 diabetic rats at intervals of 4 to 51 weeks after inoculation with streptozotocin and in ten control rats. Elevated fluid pressure was observed in only two diabetic animals, and there was no significant difference in mean EFP between test animals and controls. By contrast, elevated EFP was found in 9 of 11 rats who received a 68% sucrose diet for 48-51 weeks. The mean EFP in these animals was approximately twice normal, and sucrose intoxication thus appears to be a more effective model than streptozotocin diabetes for nerve edema associated with the sorbitol pathway.
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