Biomedical subjects

A J Windebank

Publications and source records attributed to A J Windebank.

At least 91 records · Page 5Linked to original sources

PubMed1993

Rapidly progressive aphasic dementia and motor neuron disease.

Articulatory and language impairment heralded rapidly progressive motor neuron disease in 7 patients aged 54 to 77 years. One patient had a family history of a similar disorder. Severe nonfluent aphasia developed in all 7 patients and 4 were anarthric within a year. Other cognitive domains were impaired, yet 2 patients lived alone until 1 month before their deaths. Four died within 2 years. Abnormalities were found on electromyography, computed tomography, magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography. Neuropathological examination in 3 patients showed bilateral hemispheric atrophy with neuronal loss and gliosis predominantly of superficial cortical layers. Pigmented and hypoglossal nuclei were relatively preserved. At all spinal levels there was degeneration of corticospinal tracts and loss of anterior horn cells with gliosis. Rapidly progressive aphasic dementia and motor neuron disease are a distinctive clinical entity whose nosology is poorly understood.

Aphasia↗

PubMed1993

Long-term follow-up of 121 patients with benign fasciculations.

Using the case records of Mayo Clinic patients, 121 patients with a diagnosis of benign fasciculations were identified. All had a normal neurological examination and normal electrophysiological studies, except for fasciculation potentials. Interviews by telephone were conducted 2 to 32 years after diagnosis. None of the patients developed symptomatic motor neuron disease. Forty individuals were in health care careers. A subset of 19 patients described acute onset of fasciculations following a viral infection. Benign fasciculations are not a preclude to progressive motor neuron disease.

Adult↗

PubMed1993

Relative importance of basement membrane and soluble growth factors in delayed and immediate regeneration of rat sciatic nerve.

Sciatic nerve regeneration was studied in two groups of rats. In group I, nerves were transected and transplanted immediately to the contralateral side. In group II, nerves were transected and transplanted 30 days later to the contralateral side. At 4 weeks, group II had an average nerve action potential amplitude of 784 +/- 292 microV and 43.2% +/- 6.7% of myelinated fibers were > 4 microns in diameter. In comparison, the respective measurements were 94 +/- 35.6 microV (p = 0.05) and 29.5% +/- 1.9% (p = 0.04) in group I. At 8 weeks, there were no significant differences in these measurements between groups. These data suggest that the environment in the distal stump improves early regeneration of nerve fibers when that stump was transected 30 days earlier. These and previous findings suggest that soluble trophic factors may be important in initiation of axonal regeneration.

Animals↗

PubMed1993

Seronegativity for type 1 antineuronal nuclear antibodies ('anti-Hu') in subacute sensory neuronopathy patients without cancer.

We followed 21 patients with sensory neuronopathy without evidence of cancer for up to 23 years. All were seronegative for type 1 antineuronal nuclear antibodies (ANNA-1, also called "anti-Hu"). We additionally studied 67 seropositive patients with sensory neuropathy or a related neurologic syndrome. Ninety-one percent of the seropositive patients had a small-cell lung carcinoma. One, with a normal chest x-ray, had been followed for 7 years for sensory neuronopathy of indeterminate cause before serologic testing for ANNA-1 led to the discovery of the tumor by CT. We conclude that ANNA-1 seropositivity in a patient with sensory neuronopathy is strong evidence for an underlying small-cell lung cancer.

Acute Disease↗

PubMed1992

P0 gene expression in Schwann cells is modulated by an increase of cAMP which is dependent on the presence of axons.

The role of cAMP in the regulation of P0 gene expression was investigated in Schwann cells of normal, regenerated, and permanently transected rat sciatic nerve. Forskolin treatment of endoneurial segments of rat sciatic nerve resulted in increased cAMP and P0 mRNA levels in normal and regenerated nerves but not in permanently transected nerves, where axonal regeneration is prevented. This increase of cAMP and P0 mRNA occurred within 30 and 90 min, respectively. P0 mRNA levels in the endoneurial segment of the permanently transected nerve were not increased with dibutyryl cAMP. The Schwann cells of the permanently transected nerve, however, retained the ability to myelinate 15 embryonic day (E15) dorsal root ganglia (DRG) neuron and neurite networks cultured in vitro. P0 mRNA levels increased within 4 days in transected endoneurium segments cocultured with E15 DRG neurons and neurites and further increased in 21 day myelinating cocultures. Although cAMP was not detectable in 4 day cocultures, it increased to detectable levels in 21 day cultures, suggesting that cAMP is involved in the myelinating process. These results indicate that the presence of the axon is required for the observed increase of cAMP and P0 mRNA levels and suggest that the increase of cAMP occurs within the axon which then presumably activates a different Schwann cell second messenger pathway to induce P0 gene expression.

Animals↗

PubMed1992

The distinctive clinical features of paraneoplastic sensory neuronopathy.

A 15-year experience with paraneoplastic sensory neuronopathy at the Mayo Clinic is reviewed. Of 26 patients with paraneoplastic sensory neuropathy, 19 had small cell lung cancer, 4 had breast cancer, and 3 had other neoplasms. There was a striking predominance of females (20:6). Neuropathic symptoms (pain, paresthesia, sensory loss) were asymmetric at onset, with a predilection for the upper limbs; in three patients, symptoms were confined to the arms. Electrophysiologic testing revealed absent sensory responses and normal or minimally altered motor responses. Slightly more than half the patients had associated autonomic, cerebellar, or cerebral abnormalities. In some patients, treatment of the neoplasm seemed to halt progression of the neuronopathy, but none had neurologic improvement and most continued to worsen, even when the oncologic response was good. Distinguishing between paraneoplastic and nonparaneoplastic sensory neuronopathies can be difficult, but prominent neuropathic pain, neurologic dysfunction involving more than the peripheral sensory system, or an increased cerebrospinal fluid protein value should prompt a careful search for a cancer.

Action Potentials↗

PubMed1992

Emulsifier for intravenous cyclosporin inhibits neurite outgrowth, causes deficits in rapid axonal transport and leads to structural abnormalities in differentiating N1E.115 neuroblastoma.

The emulsifier for cyclosporin in clinical i.v. formulations, Cremophor EL, has recently come into question as a possible source of neurotoxic side effects in immunosuppressant therapy. To address this issue we tested Cremophor EL and cyclosporin on an in vitro neuronal model, the differentiating N1E.115 neuroblastoma cell. In terms of effects on elaboration of neurites by these cells, Cremophor accounted for nearly all the neurotoxicity of clinically formulated cyclosporin. At a concentration of 0.005% (v/v), Cremophor EL halved the number of cells that extended neurites after 48 hr in serum-free medium. Average neurite length was also reduced substantially. Inhibition of neurite outgrowth first became apparent 24 hr after exposure to Cremophor EL. Neurites that did grow in the presence of Cremophor were disfigured by a series of regularly spaced, gross dilatations (beads) filled with large (0.2-0.5 microns) lipid vesicles. Abnormalities of rapid axonal transport were documented in the beaded neurites by means of video-enhanced contrast, differential interference-contrast microscopy. Velocity of retrograde transport remained normal, but the velocity of anterograde transport and the total bidirectional flux of organelles were both reduced. It seems likely that the inhibition of neurite outgrowth, the swellings of the neurites and the abnormalities of transport are interrelated phenomena.

Animals↗

PubMed1991

Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance.

BACKGROUND: Polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) has been treated with plasma exchange, intravenous immune globulin, and chemotherapy, but the effectiveness of these treatments remains uncertain. METHODS: We randomly assigned 39 patients with stable or worsening neuropathy and MGUS of the IgG, IgA, or IgM type to receive either plasma exchange twice weekly for three weeks or sham plasma exchange, in a double-blind trial. The patients who initially underwent sham plasma exchange subsequently underwent plasma exchange in an open trial. RESULTS: In the double-blind trial, the average neuropathy disability score improved by 2 points from base line (from 62.5 to 60.5) in the sham-exchange group and by 12 points (from 58.3 to 46.3) in the plasma-exchange group (P = 0.06). A similar difference was observed in the weakness score, a component of the neuropathy disability score (improvement, 1 and 10 points, respectively; P = 0.07). After treatment the summed compound muscle action potentials of motor nerves were 1.2 mV lower (worse) than at base line in the sham-exchange group and 0.4 mV higher (better) in the plasma-exchange group (P = 0.07). The greater degree of improvement with plasma exchange was equal in magnitude to or greater than the difference between not being able to walk on the heels or toes and being able to perform these activities. Changes in the vibratory detection threshold, summed motor-nerve conduction velocity, and sensory-nerve action potentials did not differ significantly between the treatment groups. In the open trial, in which patients who initially underwent sham exchange were treated with plasma exchange, the neuropathy disability score (P = 0.04), weakness score (P = 0.07), and summed compound muscle action potentials (P = 0.07) improved more with plasma exchange than they had with sham exchange. In both the double-blind and the open trial, those with IgG or IgA gammopathy had a better response to plasma exchange than those with IgM gammopathy. CONCLUSIONS: Plasma exchange appears to be efficacious in neuropathy associated with MGUS, especially of the IgG or IgA type.

Action Potentials↗

PubMed1991

Motor neuron disease (amyotrophic lateral sclerosis).

Amyotrophic lateral sclerosis is an insidiously developing, adult-onset, progressive anterior horn cell degeneration with associated degeneration of descending motor pathways. It has been recognized as an important clinical syndrome since the middle of the 19th century. Despite increasing clinical and research interest in this condition, its cause remains obscure, even in the broadest terms. Epidemiologic characteristics of the disease have been interpreted as evidence of both genetic and environmental causes. A major change in the view of this disease is the widely developing perception that it is a disease of elderly persons more than of middle-aged adults as was previously taught. Etiologic hypotheses encompass a broad range of postulated pathophysiologic mechanisms, and we review these in detail. The clinical limits of the disease can now be better defined by using modern diagnostic techniques. Although interest in supportive symptomatic therapy is growing, no intervention has yet been shown to modify the biologically determined motor system degeneration.

Amyotrophic Lateral Sclerosis↗

PubMed1991

Effects of alterations in pulmonary function and sleep variables on survival in patients with amyotrophic lateral sclerosis.

Breathing abnormalities and nocturnal hypoventilation occur in patients with amyotrophic lateral sclerosis (ALS). A prospective study was undertaken to determine the relationship of pulmonary function test abnormalities with quality of sleep and survival in 21 patients with ALS. Results of spirometry including determination of maximal respiratory pressures and arterial blood gases were compared with several formal polysomnographic variables and then also with 18-month survival. The patients had mild to moderate pulmonary function deficits, but the quality of sleep was best related to age (mean age, 58.5 years). The results of pulmonary function tests and arterial blood gas measurements did not correlate well with the presence of nocturnal breathing events or survival time, but the maximal inspiratory pressure was 86% sensitive for predicting the presence of a nocturnal oxygen saturation nadir of 80% or less and 100% sensitive for predicting 18-month survival. Although obstructive breathing events occurred, the primary explanation for the decline in nocturnal oxygen saturation was hypoventilation. We conclude that routine pulmonary function tests may be useful for screening for reductions in nocturnal oxygen saturation and also may have prognostic value. Further studies may determine whether treatment of nocturnal hypoventilation will have an effect on survival in patients with ALS who have breathing impairment.

Adult↗

PubMed1991

Ultrastructural changes produced in dorsal root ganglia in vitro by exposure to ethylene oxide from hemodialyzers.

Ethylene oxide (EO) gas, used to sterilize hemodialysis equipment, is a known neurotoxin and residual gas remains in dialyzers after airing. If tissue culture medium is incubated in dialyzers and then rat dorsal root ganglion (DRG) cultures are exposed to this medium, characteristic changes occur. These include axonal swellings and the death of neurons after five days. Electron microscope findings were compared between DRG grown in control medium containing 10% calf serum, DRG incubated in the same medium exposed to the blood compartment of capillary flow or plate dialyzers and DRG grown in medium supplemented with 10% dialysis patient serum. Electron microscope findings included frequent axonal swellings with the accumulations of membrane bound vesicles and the apparent disruption of microtubules. There were also conspicuous accumulations of membrane bound vesicles, dense bodies, myeloid figures, and areas of vesicular degeneration in Schwann cells. These changes were seen with dialyzer exposed medium or with medium containing patient serum but not with controls or with medium incubated in plate dialyzers. The changes were similar to those reported in nerve biopsy specimens from patients with known EO neuropathy.

Animals↗

PubMed1991

Late effects of paralytic poliomyelitis in Olmsted County, Minnesota.

We identified a cohort of 300 individuals who had paralytic polio between 1935 and 1955. All lived in Olmsted County, Minnesota. From the 247 survivors, we selected 50 subjects for detailed historical, functional, psychological, clinical, and electrophysiologic evaluation. Sixty-four percent of these 50 survivors complained of new symptoms of muscle pain, fatigue, and weakness after a period of prolonged stability. This led to changes in lifestyle or activity in only 18%. The likelihood of expressing new complaints was not related to present age or interval since polio, and electrophysiologic testing did not distinguish between those with or without new problems. The development of new difficulties in a limb was most strongly predicted by significant paralysis of that limb at the time of the acute illness. Patients with leg weakness were twice as likely to complain of new problems compared to those with arm weakness. Elevated creatine kinase levels were present only in those with new complaints.

Cohort Studies↗

PubMed1991

The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.

A cross-sectional survey and subsequent longitudinal study among diabetic residents of Rochester, MN--The Rochester Diabetic Neuropathy Study (RDNS)--is population-based and uses quantitative, validated, and unique end points to detect, classify, and stage neuropathy. Nondiabetic persons, drawn from the same population, serve as controls. For patients 10 to 70 years old, the RDNS cohort is representative of diabetics living in Rochester, MN. We assessed reproducibility of tests used to characterize and quantitate severity of neuropathy in 20 diabetic subjects without neuropathy and with varying severities of neuropathy. Using intraclass correlation coefficient (rI) as a measure of test reproducibility, we found high rI (usually 0.9 or better) with small confidence intervals for the Neurologic Disability Score (NDS); weakness subset of NDS (W-NDS); vibratory and cooling detection thresholds (using computer-assisted sensory examination [CASE] IV); compound muscle action potentials; sensory nerve action potentials; and motor nerve conduction velocities. There was good agreement among three trained observers for NDS and the W-NDS.

Action Potentials↗

PubMed1990

Role of axons in the regulation of P0 biosynthesis by Schwann cells.

The role of axons in the expression of the major myelin glycoprotein, P0, has been investigated using neuron/Schwann cell cultures. These cultures were either nonmyelinating or myelinating due to growth in defined medium or in medium containing serum and chick embryo extract, respectively. The neurons and Schwann cells used in the studies were derived from embryonic day 15 rat dorsal root ganglia (DRG), and the Schwann cells from these ganglia are shown not to synthesize appreciable levels of P0 prior to growth in culture. Myelinating cultures of Schwann cells and neurons grown together for 18-21 days synthesize P0 that is readily identified by immunoblotting. The nonmyelinating cultures, which do not assemble basal lamina, also synthesize P0 that is detectable by either [3H]mannose precursor incorporation or by immunoblotting. The steady-state level of P0 in the nonmyelinating cultures is less than that of the myelinating cultures, and the P0 that is synthesized by the former appears to be catabolized shortly after its biosynthesis. Since nonmyelinating Schwann cells synthesize P0 when in contact with neurites in vitro, we have examined the ability of such nonmyelinating cells to express the glycoprotein in vivo. Very little steady-state P0 is detected in immunoblots of the adult rat cervical sympathetic trunk (CST), a nerve in which approximately 99% of the axons are nonmyelinated. Similarly, the amounts of [3H]mannose and [3H]amino acids that are incorporated into newly synthesized P0 are much lower in the CST than in the adult sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Axonal regulation of Schwann cell glycolipid biosynthesis.

Schwann cell biosynthesis of glycolipids was studied by in vitro incorporation of [3H]galactose into neonatal rat sciatic nerves before and after endoneurial explant culture and in culture of purified Schwann cells. In neonatal nerves prior to culture, [3H]galactose was actively incorporated into galactocerebrosides (GalCe), monogalactosyl diacylglycerol (MGDG), and the sulfatides (Su). In contrast, the incorporation of [3H]galactose into MGDG, GalCe, and Su was nearly undetected in endoneurial explants after 4 days in vitro (div). Instead, there was increased 3H-labeling of glucocerebrosides (GlcCe) and its homologues, with tetrahexosylceramides (GL-4) being a major product, which continued through 8 div. This shift in glycolipid biosynthesis was further demonstrated in the purified Schwann cell cultures. These observations, together with our early findings in the permanent transection paradigm support a direct role of axons in specifying Schwann cell biosynthesis of the GalCe, MGDG, and Su and that the absence of this Schwann cell-axon interaction results in the phenotypic expression of glucocerebroside homologues by the Schwann cell.

Animals↗

PubMed1990

Kinetics of production of a novel growth factor after peripheral nerve injury.

In response to transection injury, the distal segment of sciatic nerve produces a soluble factor which stimulates neurite outgrowth from 15 day embryonic rat dorsal root ganglion (DRG) neurons, and PC12 cells. This activity enhances survival of large sensory neurons, promotes myelination and has been designated SN. The expression of SN, undetectable in the perineurium and proximal segments, occurs solely in the endoneurium distal to the site of permanent transection. When the distal portion is removed immediately after transection, homogenized and the supernatant tested, there is little neurite promoting activity in the normal nerve. For the first 10 days after transection the major soluble factor present in the distal segment is NGF. The amount of neurite promoting activity increases after 10 days and appears to plateau at 30-35 days while the proportion that is inhibited by anti-NGF decreases. In a competitive receptor binding assay, SN does not compete with 125I-NGF for receptors on either DRG or PC12 cells. Separation using polyacrylamide-agarose followed by HPLC demonstrates that SN migrates with polypeptides of molecular weights 17.2 and 19.1 kDa.

Animals↗

PubMed1990

Adrenal medullary transplantation into the brain for treatment of Parkinson's disease: clinical outcome and neurochemical studies.

Transplantation of adrenal medulla into the caudate nucleus as treatment for Parkinson's disease was performed in eight patients. Although our previous 6-month follow-up revealed early modest improvement, an extension of that follow-up to 1 year disclosed no additional gains in any patient. At the end of 1 year, only one patient could be categorized as moderately improved; three patients were mildly improved, and four patients were unimproved. The rationale for transplanting adrenal medulla was to reestablish a physiologic source of dopamine to the striatum. We measured cerebrospinal fluid (CSF) and plasma catecholamines and metabolites before and after transplantation. Conjugated dopamine (the predominant form of dopamine found in the CSF) and homovanillic acid (the major dopamine metabolite) were modestly and inconsistently increased in the CSF. Conjugated and free epinephrine and norepinephrine, as well as 3-methoxy-4-hydroxyphenylglycol concentrations were not increased in CSF after graft placement, an indication that the adrenal chromaffin cells were no longer producing high levels of these nondopamine catecholamines and metabolites. CSF cortisol concentrations were not increased after transplantation, compared with values from controls, consistent with low numbers of functioning adrenal cortical cells contaminating the graft (or poor survival). Posttransplantation CSF did not induce a neurotrophic effect in cell cultures of 15-day embryonic rat dorsal root ganglion or PC12 (rat pheochromocytoma) cell lines. Survival of samples of patients' adrenal medullary tissue for 2 weeks in tissue culture attested to the viability of the graft at the time of transplantation. The relative concentrations of dopamine to epinephrine or norepinephrine increased in these cultured adrenal medullary cells, presumably because of loss of the glucocorticoid influence on catecholamine synthesis. A wide variety of factors could have contributed to our failure to replicate the earlier impressive results of adrenal-to-brain transplantation reported by others. Continued transplantation studies in animal models of parkinsonism are necessary for better elucidation of these factors.

Activities of Daily Living↗

PubMed1990

Catabolic regulation of the expression of the major myelin glycoprotein by Schwann cells in culture.

Previous studies have suggested that neonatal Schwann cell cultures deprived of axonal contact do not express components of the myelin membrane, including the major myelin glycoprotein, P0. In contrast, Schwann cells from permanently transected, adult nerve exhibit continued biosynthesis of P0 after culture, suggesting that the ability to express the myelin glycoprotein may depend on the degree of cellular differentiation. To examine further the ability of Schwann cell cultures to express P0 as a function of age, we have performed precursor incorporation studies on endoneurial explants from 4- to 12-day-old rat sciatic nerves after 5 days in culture. The data reveal that explants from 12-day-old animals synthesize detectable levels of this integral myelin protein when assayed by [3H]mannose incorporation, even though there is no apparent myelin assembly in the cultures. Pulse-chase analysis of cultures from 12-day-old rats demonstrates that [3H]mannose-labeled P0 is substantially degraded within 3 h. This catabolism largely can be prevented by the addition of swainsonine, ammonium chloride, or L-methionine methyl ester to the pulse-chase media. The former agent alters oligosaccharide processing whereas the latter two compounds inhibit lysosomal function. The P0 synthesized by the 12-day explant cultures following the addition of swainsonine is readily fucosylated, implying that the protein has progressed at least as far as the medial Golgi before its exit and subsequent catabolism. If cultures from 4-, 6-, and 8-day-old animals are analyzed for P0 biosynthesis by [3H]mannose incorporation in the presence of swainsonine, detectable levels of the glycoprotein are seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗