Biomedical subjects
Publications and source records attributed to R L Friede.
Frog sciatic nerves show a continuing addition of new myelinated and nonmyelinated fibers with body growth. Along with increases in fiber number there are also marked changes in axon calibers and in the relative thickness of the myelin sheaths. Our data show that frog nerves, as opposed to mammalian nerves, are composed of fibers of different ages, stages of growth and stages of myelination.
The brain of a 60-year-old patient with bronchial carcinoma presented a focal amyloid deposit in the white matter associated with myelin and axonal destruction. An additional lesion was found in the basal ganglia. This silent focal intracerebral accumulation of amyloid substance may be a prestadium of a "cerebral amyloidoma". The histochemical and immunohistochemical analysis of the accumulated amyloid indicated that it may belong to a novel type of amyloid.
A light and electron microscopic study was carried out of the numbers of myelinated fibres in 6 nerves of the rat for 7 age groups from birth to 73 weeks. The hypoglossal nerve and the mandibular branch of the facial nerve had short and early myelination periods, essentially complete by the second week. The glossopharyngeal nerve and the sympathetic rami communicantes myelinated late and over a protracted period. Myelination of the rami communicantes continued up to 20 weeks, followed by a marked loss of fibres in the 73 week animals. Intercostal and saphenous nerves had intermediary patterns. There was evidence of subpopulations myelinating at different times. Measurements of myelin sheath thickness showed variations of relative sheath thickness with age, between nerves and for subpopulations of nerves. Late myelination corresponded to relatively thin myelin sheaths. Statistical two-stage-density cluster analysis by computer was used for analysing complex fibre populations. The developmental changes of three subpopulations of the intercostal nerve are documented. Nerves also differed in their rates of axon growth. The increment in axon calibre was small and late for sympathetic fibres. Intercostal and facial nerve fibres had rapid axon growth with different growth rates for subpopulations.
Computer-assisted measurements of relative myelin sheath thickness (the g ratio) were made in 11 peripheral nerves of the rat. The scatter diagrams showed nerve-specific variations in the distribution of relative myelin sheath thickness. Myelinated fibers of less than 3.5 microns axon diameter had relatively thin myelin sheaths, particularly in the splanchnic, vagus and glossopharyngeal nerves. The oculomotor nerve had two fiber populations clearly set apart in terms of relative myelin sheath thickness. Thickly myelinated fibers were found in facial and hypoglossal nerves. No single functional modality was evident for the thinly myelinated fibers.
Myelin phagocytosis in Wallerian degeneration was studied using a model of murine sciatic nerve degeneration in millipore diffusion chambers in the peritoneal cavity of host mice. Immunocytological investigations showed the dependence of myelin digestion on the invasion of Fc-positive, Mac-1-positive and partly Ia-positive monocytes. Lymphocytes did not play a prominent role. Compared to Wallerian degeneration in situ, phagocytosis was decreased in nerves enclosed by millipore membranes on both sides of the chamber. The membrane acted as a trap for invading monocytes/macrophages. Neither tissue integrity nor genetic strain influenced the degree of phagocytosis. A modification of the experimental technique is introduced which permits myelin phagocytosis in the peritoneal cavity in a degree comparable to that in Wallerian degeneration in situ.
A 42-year-old woman had a 10-year history of external ophthalmoplegia, malabsorption resulting in chronic malnutrition, muscle atrophy and polyneuropathy. Computer tomography revealed hypodensity of her cerebral white matter. A metabolic disturbance consisted of lactic acidosis after moderate glucose loads with increased excretion of hydroxybutyric and fumaric acids. Post-mortem studies revealed gastrointestinal scleroderma as the morphological manifestation of her malabsorption syndrome, ocular and skeletal myopathy with ragged red fibers, peripheral neuropathy, vascular abnormalities of meningeal and peripheral nerve vessels. Biochemical examination of the liver and muscle tissues revealed a partial defect of cytochrome-c-oxidase (complex IV of the respiratory chain). This mitochondrial multisystem disorder may represent a separate entity to be classified between the spectrum of myoencephalopathies and oculo-gastrointestinal muscular dystrophy.
Highly cationic polyethyleneimine was used as an electron microscopic tracer for anionic sites in the axoplasm of rat sciatic and optic nerve fibres. Microtubules showed a markedly increased electron density and aggregated to form large groups, mostly located in the immediate proximity of membranous axoplasmic organelles. Walls of adjacent microtubules were fused; there was also fusion of microtubules with the membranes of smooth axoplasmic reticulum and with axolemma. In contrast, neurofilaments had unaltered electron density and axoplasmic distribution. Staining and clustering of microtubules were interpreted as electrostatic binding of cationic polyethyleneimine to acidic tubulin. These findings may be relevant to the role of microtubules in fast axonal transport.
This study reexamines peripheral neuropathy in infantile, juvenile and adult metachromatic leucodystrophy. A computer-assisted method was used which gives more detailed information on abnormal fibre structure from scatter diagrams of the g ratio (axon diameter/fibre diameter). The data show marked and statistically significant reductions in sheath thickness, particularly for the thick myelinated fibres, and most severe in the juvenile and adult forms. This is interpreted as evidence of remodelling of virtually the entire fibre population, without a clear-cut selectivity for either thin or thick fibres.
Changes of myelin proteins in mouse sciatic nerves were studied comparing nerves degenerating in situ with nerves enclosed in millipore diffusion chambers which eliminate invasion of non-resident cells. Nerves kept in chambers showed nearly complete preservation of myelin sheaths with a very slow degradation of myelin proteins. Nerves degenerating in situ showed rapid myelin phagocytosis by macrophages with almost complete disappearance of myelin proteins after 28 days. These data elucidate the role of macrophages for removal of myelin proteins.
Previous experiments with nerves enclosed in millipore diffusion chambers had shown that myelin degradation during Wallerian degeneration depends on invasion by non-resident cells. The present study was aimed at a more precise identification of the invading cell population. Monoclonal antibody studies of degenerating nerves showed many cells with the Fc marker; cells having the Lyt-1, Lyt-2, Ia or Mac-1 markers were sparse or absent. Nerves transplanted into mice of the Chediak-Higashi bg/bg strain were invaded by cells lacking the bg/bg marker (giant lysosomes), while cotransplanted muscle tissue was invaded by cells with the bg/bg marker. Blocking monocytes with silica reduced both cell invasion and myelin degradation in degenerating nerves. These observations show that Wallerian degeneration of peripheral nerve fibers involves a subset of monocytes which are silica-sensitive and have Fc receptors but no bg/bg giant lysosomes.
Peripheral neuropathy marked by reduced nerve conduction velocities was found in four unrelated children, between the ages of 15 months and 9 years, whose autopsies revealed Leigh's subacute necrotizing encephalomyelopathy. Sural nerve biopsies disclosed primary demyelination and remyelination, as well as loss of myelinated and unmyelinated axons. The use of morphometric and electron microscopic studies shows that these techniques may reveal peripheral neuropathy in Leigh's disease more often than light microscopic methods alone.
A short guide is given for the planning of nerve fiber morphometry using computer-assisted methods. A new computer program is introduced which allows, among other factors, correction for myelin sheath shrinkage. If myelin shrinkage is not corrected for, there will be false high values for axon caliber and false low values for sheath thickness. The magnitude of the skew produced by this factor is shown on hand from computer editing.
Tissue sections of rat sciatic nerves were incubated at various pH ranges to study the effects of proton titration on myelin fine structure by transmission electron microscopy. It was found that the major dense line of the sheath can open and close reversibly in response to proton titration at a pH range compatible with in vivo conditions. Opened and closed major dense lines coexisted in the sheath, but the number of opened lines increased with increasing pH. There was a pattern of periodicity in the opening of dense lines in that either one, two, or three opened lines alternated with one closed line. The local opening or closing of a dense line, furthermore, was often associated with reciprocal changes in the two adjacent dense lines, highly suggestive of the interaction of electric fields between the myelin membranes. These observations show that energy can be stored within the myelin leaflet.
The thickness of the myelin sheath of nerve fibers was traditionally assessed solely as a function of axon caliber. Studies concerning the additional effect of variation in internode length are of relatively recent date. Carefully calibrated measurements of sheath thickness and internode geometry were used in this study to define an equation to predict the approximate number of lamellae from axon caliber and internode length, for normal and regenerated peripheral nerve fibers, and for fibers from hypomyelinated murine mutants. The definition of sheath thickness thus obtained was compared with different assumptions on the biophysical nature of myelin sheath resistance. The observed relations between sheath thickness and internode geometry were not compatible with an effective adjustment of sheath thickness to a radial flow of current across the sheath. Conversely, sheath thickness was found to vary in such a way that the resistance of the spiral path between the lamellae was matched precisely to axonal current density. The calculated resistance of the spiral leakage path, furthermore, was equal to measured sheath resistance. This new concept reconciles low sheath resistance with a high resistance of the myelin leaflet, yielding, at the same time, a fine tuning of sheath resistance to variations of internode geometry.
The neuropathy caused by a single dose of isoniazid in rats was studied with a computer-assisted morphometric method. Scatter diagrams of the g ratio (quotient fibre diameter/axon diameter) define regenerating fibres as a distinct population, distinguishable from the surviving fibres by reduced sheath thickness and reduced axon calibre. There was also evidence of a subtle direct toxic effect on the entire fibre population, causing axon shrinkage masked by readjustment of the myelin sheath.
The distribution of fiber branching in the proximal intramuscular motor nerves of the gracilis and gastrocnemius muscles of the rat was studied in whole-mount preparations of teased nerves. Branchings of nerve fibers were clustered at fascicular divisions. Such concurrence of fascicular and fiber branchings determines the dispersion of the single muscle fibers belonging to a motor unit. The distribution of fiber branching reveals the wiring pattern of muscle fibers. These patterns differed for the gracilis and gastrocnemius muscles in correspondence with their functional organization.
The angiogenesis of the rat cerebrum was studied under pathologic conditions caused by the administration of the neurotoxin methylazoxymethanol acetate (MAMAc) in the time (E14) of neuroblast migration. The sinovenous junction of the main superficial cerebral veins and the morphological changes of the veins were examined by a quantitative analytic method. The hypoplastic areas of the brains showed extremely malformed venous systems with pathologic changes of the sinovenous junctions depending on the degree of disturbance of the neuroblast migration. These findings suggest the primary role of the neuronal maturation in the angioarchitectonic development and the direct dependency of the vascular differentiation on the neuroblast migration of the drained territory.
The angioarchitecture of the superficial and basal arterial system of the hypoplastic rat brain caused by the administration of the neurotoxin, methylazoxymethanol acetate (MAMAc), at the time of neuroblast migration was studied. Increased variation of the arterial branching of the basal main stem of arteries and local vessel changes were observed. The findings suggest a close relationship between vascular and neuronal development, showing a generalized disturbance and local adaptation of vasculature to the altered neuronal architecture of the corresponding hypoplastic areas.