Search PubMed⌕ Search

Biomedical subjects

T W Bouldin

Publications and source records attributed to T W Bouldin.

At least 19 recordsLinked to original sources
PubMed1998

Regenerating sciatic nerve does not utilize circulating cholesterol.

The rapid accumulation of myelin in the peripheral nervous system during the early postnatal period requires large amounts of cholesterol, a major myelin lipid. All of the cholesterol accumulating in the developing rat sciatic nerve is synthesized locally within the nerve, rather than being derived from the supply in lipoproteins in the systemic circulation (Jurevics and Morell, J. Lipid Res. 5:112-120; 1994). Since this lack of utilization of circulating cholesterol may relate to exclusion by the blood-nerve barrier, we examined the sources of cholesterol needed for regeneration following nerve injury, when the blood-nerve barrier is breached. One sciatic nerve was crushed or transected, and at various times later, the rate of cholesterol accumulation was compared with the rate of local in vivo synthesis of cholesterol within the nerve, utilizing intraperitoneally injected 3H2O as precursor. The accumulation of additional cholesterol in nerve during regeneration and remyelination could all be accounted for by that locally synthesized within the nerve. There was also an increase in cholesterol esters in injured nerve segments; in crushed nerves, these levels decreased during regeneration and remyelination, consistent with reutilization of cholesterol originally salvaged by phagocytic macrophages and Schwann cells. Thus, regeneration and remyelination following injury in sciatic nerve utilizes both salvaged cholesterol and cholesterol synthesized locally within the nerve, but not cholesterol from the circulation.

Animals↗
PubMed1997

Tellurium causes dose-dependent coordinate down-regulation of myelin gene expression.

Exposure of developing rats to a diet containing elemental tellurium systemically inhibits cholesterol synthesis at the level of squalene epoxidase. At high tellurium exposure levels (> 0.1% in the diet), there is an associated segmental demyelination of the PNS. Low levels of dietary tellurium (0.0001%) led to in vivo inhibition of squalene epoxidase activity in sciatic nerve, and inhibition increased with increasing exposure levels. With increasing dose and increasing exposure times, there was an increasing degree of demyelination and increasing down-regulation of mRNA levels for myelin P0 protein, ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis), and HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis). Because these were all down-regulated in parallel, we conclude there is coordinate regulation of the entire program for myelin synthesis in Schwann cells. An anomaly was that at early time points and low tellurium levels, mRNA levels for HMG-CoA reductase were slightly elevated, presumably in response to tellurium-induced sterol deficits. We suggest the eventual down-regulation relates to a separate mechanism by which Schwann cells regulate cholesterol synthesis, related to the need for coordinate synthesis of myelin components. Levels of mRNA for the low-affinity nerve growth factor receptor (indicator of alterations in axon-Schwann cell interactions) and for lysozyme (marker for phagocytic macrophages) were both up-regulated in a dose- and time-dependent manner which correlated with the presence of segmental demyelination. Levels of mRNA coding for myelin-related proteins were down-regulated at low tellurium exposure levels, without demyelination or up-regulation of nerve growth factor receptor. This suggests the down-regulation is related to the tellurium-induced cholesterol deficit, and not to the loss of axonal contact associated with early stages of demyelination or to the entry of activated macrophages.

Acetates↗
PubMed1997

Postmortem MR imaging of the brains of patients with AIDS.

Forty-two postmortem formalin-fixed brains of known patients with AIDS were examined with T2-weighted MR imaging before brain cutting. The gross and microscopic brain findings were correlated with the T2 signal changes in the postmortem MR imaging. The brains included examples of progressive multifocal leukoencephalopathy with involvement of the central brain and cerebellum. The authors also encountered the coexistence of progressive multifocal leukoencephalopathy and HIV encephalitis, and the T2 signal changes for each were compared. The T2 signal changes of leptomeningeal and perivascular space cryptococcal infection and CMV ependymitis are documented. Several expressions of primary cerebral lymphoma, including large nodules, choroid plexus infiltration, and diffuse microscopic sites of tumor also are assessed.

AIDS-Related Opportunistic Infections↗
PubMed1995

NGFR-mRNA expression in sciatic nerve: a sensitive indicator of early stages of axonopathy.

Expression of the low-affinity nerve growth factor receptor (NGFR) in the sciatic nerve (particularly Schwann cells) is high during development but is downregulated upon establishment of the mature axon-Schwann cell relationship. NGFR is re-expressed by Schwann cells if this relationship is altered by degeneration of axons (axotomy) or myelin (tellurium intoxication). To determine the sensitivity of NGFR expression to axonal injury, we have assayed NGFR-mRNA levels in proximal and distal regions of nerves exposed to the axonopathic agents acrylamide and isoniazid, as well as in proximal and distal stumps of axotomized nerves. NGFR-mRNA was elevated in all three models and correlated regionally with sites of axonal perturbation. In distal regions of acrylamide- and isoniazid-intoxicated nerves, NGFR-mRNA was elevated at least 2 days prior to visible signs of axonal degeneration as assayed by morphological techniques utilizing light microscopy. NGFR-mRNA was also elevated in proximal regions of axotomized and acrylamide-intoxicated nerves prior to signs of axonal degeneration. In these models, increased mRNA expression correlated with alterations in the size distribution of axonal cross sections. The common response in all of these situations indicates that NGFR expression, in addition to being a marker for axonal degeneration, is also a sensitive indicator of less profound perturbations in normal axon-Schwann cell interactions, including early stages of axonopathy. We suggest that assay for NGFR-mRNA may be utilized as a rapid and simple method (relative to more labor-intensive morphological methods) to screen for peripheral neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamide↗
PubMed1995

Nerve regeneration and cholesterol reutilization occur in the absence of apolipoproteins E and A-I in mice.

Apolipoproteins have been implicated in the salvage and reutilization of myelin cholesterol during Wallerian degeneration and the subsequent nerve regeneration. Current evidence suggests that myelin cholesterol complexes with apolipoproteins E and A-I to form lipoproteins that are taken up via low-density lipoprotein receptors on myelinating Schwann cells. We recently reported, however, that apolipoprotein E is not required for nerve regeneration or reutilization of myelin cholesterol. We have now investigated nerve regeneration and the reutilization of cholesterol in mutant mice deficient in both apolipoproteins E and A-I. Morphologic examination of nerves 4 and 12 weeks after crush injury revealed that regeneration proceeded at a normal rate in the absence of these apolipoproteins. Autoradiography of regenerating nerves indicated that prelabeled myelin lipid was reutilized in the regenerating myelin. 3-Hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was down-regulated in the regenerating nerves, indicative of cholesterol uptake via lipoproteins. Prelabeled myelin cholesterol was present in lipoprotein fractions isolated from crushed nerves of mutant mice. These data suggest that there is considerable redundancy in the process of cholesterol reutilization within nerve, and that apolipoproteins other than apolipoproteins E and A-I may be involved in the recycling of myelin cholesterol.

Adenine↗
PubMed1995

Fatty acids from degenerating myelin lipids are conserved and reutilized for myelin synthesis during regeneration in peripheral nerve.

Following nerve crush, cholesterol from degenerating myelin is conserved and reutilized for new myelin synthesis during nerve regeneration. The possibility that other myelin lipids are salvaged and reutilized has not been investigated previously. We examined the fate of myelin phospholipids and their fatty acyl moieties following nerve crush by electron microscopic autoradiography of myelin lipids prelabeled with [3H]oleate or [2-3H]-glycerol. Both precursors were incorporated predominantly (> 90%) into phospholipids; > 85% of the [3H]-oleate was incorporated as oleate, with the remainder in longer-chain fatty acids. Before nerve crush, both labels were restricted to myelin sheaths. Following nerve crush and subsequent regeneration, over half the label from [3H]oleate, but little from [2-3H]glycerol, remained in nerve. The oleate label was present as fatty acyl moieties in phospholipids and was localized to newly formed myelin sheaths. Among the extracellular soluble lipids within the degenerating nerve, the bulk of the labeled phospholipids floated at the same density as lipoprotein particles. These data indicate that myelin phospholipids are completely hydrolyzed during nerve degeneration, that at least half the resultant free fatty acids are salvaged and reutilized for new myelin synthesis, and that these salvaged fatty acids are transported by a lipoprotein-mediated mechanism similar to that functioning in cholesterol reutilization.

Animals↗
PubMed1995

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.

Animals↗
PubMed1994

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 (Büngner 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.

Animals↗
PubMed1993

Ocular and associated neuropathologic observations in suspected whiplash shaken infant syndrome. A retrospective study of 12 cases.

We examined the eyes of 12 infants who died with the clinical and pathologic diagnosis of the shaken baby syndrome. The ocular histopathologic findings and the neuropathologic findings were compared. Preretinal, intraretinal, and subretinal hemorrhages were observed; hemorrhages of the superficial retinal layers and subsensory retinal space predominated. Retinal hemorrhages were found in 12 cases, intracranial hemorrhage was found in 11 cases, and cerebral edema was found in 10 cases. The intraretinal and periretinal hemorrhages were most prevalent at the posterior pole. Five cases had retinal folds. There was a low incidence of optic disc edema and choroidal hemorrhage.

Brain Edema↗
PubMed1993

Nerve regeneration occurs in the absence of apolipoprotein E in mice.

The concentration of apolipoprotein E (apoE), a high-affinity ligand for the low-density lipoprotein receptor, increases dramatically in peripheral nerve following injury. This endoneurial apoE is thought to play an important role in the redistribution of lipids from the degenerating axonal and myelin membranes to the regenerating axons and myelin sheaths. The importance of apoE in nerve repair was examined using mutant mice that lack apoE. We show that at 2 and 4 weeks following sciatic nerve crush, regenerating nerves in apoE-deficient mice were morphologically similar to regenerating nerves in control animals, indicating that apoE is not essential for peripheral nerve repair. Moreover, cholesterol synthesis was reduced in regenerating nerves of apoE-deficient mice as much as in regenerating nerves of control animals. These results suggest that the intraneural conservation and reutilization of cholesterol following nerve injury do not require apoE.

Animals↗
PubMed1992

Acrylamide exposure preferentially impairs axonal transport of glycoproteins in myelinated axons.

The right L5 dorsal root ganglion of adult rats exposed to acrylamide (40 mg/kg body weight/day for nine consecutive days) was injected with either [3H]methionine or [3H]glucosamine. After allowing incorporation into macromolecules and axonal transport to proceed for 5 hr, the distribution of radioactivity in cross sections and longitudinal sections of sciatic nerve was determined by autoradiography. Control and treated animals showed no difference in distribution of label within the sciatic nerve with respect to rapidly transported proteins labelled with [3H]methionine. In control animals the distribution of rapidly transported glycoproteins labelled with [3H]glucosamine was similar to that found for [3H]methionine-labelled proteins. In contrast, acrylamide-exposed rats had a very different distribution of labelled glycoproteins; there was a marked paucity of label in the myelinated axons. We interpret this result as indicating that acrylamide preferentially inhibits glycosylation or axonal transport of glycoproteins in neurons bearing myelinated axons.

Acrylamide↗
PubMed1992

Immunocytochemical and ultrastructural studies of upper motor neurons in amyotrophic lateral sclerosis.

The pathological alterations in upper motor neurons were investigated in 27 cases of adult-onset sporadic amyotrophic lateral sclerosis (ALS). No significant cytoskeletal alterations were found in the Betz cells of any of the cases except one, although cytoskeletal pathology was consistently present in lower motor neurons. The one case had severe circumscribed atrophy of the precentral gyrus and, microscopically, had argentophilic intracytoplasmic inclusions in Betz cells and other pyramidal neurons in the primary motor area as eell as in the lower motor neurons. Immunocytochemically these inclusions contained the epitope of phosphorylated neurofilament and ubiquitin and ultrastructurally consisted of granule-associated filaments with neurofilaments. This is the first demonstration of alterations of cytoskeleton and ubiquitination in the giant cells of Betz, an established subset of upper motor neurons in ALS. Thus, although uncommon, cytoskeletal changes can be found in upper motor neurons in some ALS cases.

Adult↗
PubMed1992

Immunocytochemical and ultrastructural studies of eosinophilic granular bodies in astrocytic tumors.

Eosinophilic granular bodies (EGBs) are studied immunocytochemically and ultrastructurally in a case of low-grade and a case of high-grade astrocytoma. EGBs are recognized as brightly eosinophilic round bodies of variable size in hematoxylin and eosin-stained sections. Immunocytochemically some EGBs are positive for antibodies raised against alpha B-crystallin, ubiquitin and glial fibrillary acidic protein with the staining patterns for each being different from one another. Ultrastructurally EGBs consist of membrane-bound round body of various diameter ranging from 50 nm to 20 microns. Small EGBs contain electron-dense homogeneous material with occasional myelin figures, while electron-dense homogeneous material or loose granular profiles. Our studies demonstrate (1) ultrastructural variety of EGB; (2) and alpha B-crystallin epitope in EGB; and (3) the presence of EGB in high-grade as well as low-grade astrocytoma.

Adult↗
PubMed1992

Subclinical central nervous system infection with JC virus in patients with AIDS.

Immunocompromised patients, particularly those with AIDS, develop progressive multifocal leukoencephalopathy (PML) due to central nervous system infection with JC virus (JCV). It is unknown whether JCV infection in the central nervous system can occur in the absence of PML symptoms. To address this question, autopsy specimens from patients with AIDS were examined. The brains of a group of patients without AIDS or central nervous system disease were also examined. JCV DNA was detected by the polymerase chain reaction in brain tissue from 4 (31%) of 13 human immunodeficiency virus (HIV)-positive patients. JCV was also detected in 1 elderly HIV-negative patient but not in the 11 other control brains. JCV was not detected in 22 myocardial specimens obtained at autopsy from HIV-negative patients nor 10 peripheral blood specimens from HIV-positive patients. The presence of JCV in brains of patients without clinically evident PML suggests that JCV may be present in the central nervous system without clinical disease.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Pathological study of corticospinal-tract degeneration in Friedreich's ataxia.

The pattern of fibre degeneration in the lateral corticospinal tract (LCST) was studied in a case of Friedreich's ataxia (FA). There was preferential involvement of the lateral area of the LCST in the cervical spinal cord. More caudally, the degeneration involved the entire area of the LCST and did not reveal a medial to lateral gradient of involvement. We suggest that this distinctive pattern of tract degeneration is a consequence of the somatotopic organization of the LCST, with the dying-back degeneration preferentially affecting those LCST fibers that extend to the lumbo-sacral spinal cord. This pattern of tract degeneration may be a useful morphological marker of dying-back degeneration in corticospinal tracts.

Adult↗
PubMed1992

Lupus-related myelopathy: report of three cases and review of the literature.

Transverse myelopathy is an uncommon complication of systemic lupus erythematosus (SLE). Three patients with SLE are reported who developed transverse myelopathy, including the neuropathological findings in one patient on whom necropsy was performed. Paraparesis was present in all three cases, but definite sensory changes were present in only one patient. In two patients, the CSF findings were remarkable for elevated protein and depressed glucose concentrations. Microscopic examination of the brain demonstrated small, scattered foci of recent necrosis consistent with microinfarctions. Striking abnormalities were found in the spinal cord at all levels, including multiple foci of vacuolar spongy degeneration in the peripheral white matter, as well as ballooning of myelin sheaths, swollen axons, myelin pallor, and loss of glial nuclei. The pathological findings in previously reported cases of SLE-related transverse myelopathy are reviewed, and the possible pathogenesis of the findings in our case are discussed.

Adolescent↗