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Biomedical subjects

A J Windebank

Publications and source records attributed to A J Windebank.

At least 73 records · Page 4Linked to original sources
PubMed1995

Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes.

BACKGROUND: Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert-Eaton syndrome. The calcium-channel subtype that is responsible is not known. METHODS: We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex. RESULTS: P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced 45Ca influx in cultured small-cell carcinoma cell lines. Anti-P/Q-type calcium-channel antibodies were found in serum from all 32 patients with Lambert-Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with Lambert-Eaton syndrome without cancer. Anti-N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert-Eaton Syndrome. Lower titers of anti-P/Q-type and anti-N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma. CONCLUSIONS: The high frequency of P/Q-type calcium-channel antibodies found in patients with Lambert-Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.

Autoantibodies↗
PubMed1995

Effect of cisplatin and ACTH4-9 on neural transport in cisplatin induced neurotoxicity.

Cisplatin causes a dose limiting peripheral neuropathy, however, the biological mechanism by which this occurs is unknown. Murine N1E.115 neuroblastoma cells and neural crest derived pigment cells have similar transport mechanisms to human neural cells and were used to study the effect of cisplatin on cellular transport. Cisplatin reduced both the number and velocity of organelles moving in the anterograde and retrograde direction, compared to control cells. Cisplatin induced inhibition of transport was prevented by the simultaneous administration of ACTH4-9. This analog alone had no effect on N1E.115 organelle, or erythrophore granule, movement. In both N1E.115 and pigment cells cisplatin inhibited transport within 1 h of exposure to the drug. The degree of inhibition did not increase insignificantly if pigment cells were incubated in cisplatin for 48 h compared to acute exposure. Microtubules in both pigment cells and N1E.115 neurites retained their structural integrity suggesting that factors other than changes in gross microtubule morphology are responsible for cisplatin neurotoxicity. Cisplatin reduces N1E.115 neurite growth after 48 h incubation but this can be prevented by simultaneous use of ACTH4-9. This study demonstrates for the first time that cisplatin and ACTH4-9 affect fast axonal transport by specific mechanisms which appear related to their observed neurotoxic and neuroprotective roles, respectively.

Adrenocorticotropic Hormone↗
PubMed1995

Mechanism of suramin toxicity in stable myelinating dorsal root ganglion cultures.

Suramin is an experimental chemotherapeutic agent which produces a severe dose-related neuropathy. Suramin inhibits axonal growth from rat dorsal root ganglion neurons. This inhibition is dose dependent and reversed by increasing nerve growth factor concentrations. In this study, myelinating dorsal root ganglion cultures were exposed to various concentrations of suramin and nerve growth factor. Effects were assessed with quantitative light and electron microscopy. Using a systematic sampling technique, suramin was observed to produce dose and time-dependent myelinated fiber degeneration. With 9-day exposure, there was no effect with suramin concentrations of 100 microM or less. At 200 microM, 17% of the myelinated fibers were degenerating at 4 days and 53.3% by 9 days. At 300 microM, 72.7% of the myelinated fibers and at 1316 microM, 88.7% of the myelinated fibers were degenerating at 4 days. It appeared that secondary demyelination was the major process. Large multilamellar inclusion bodies filled Schwann cells, particularly those investing unmyelinated fibers and dorsal root ganglia neuron cell bodies. The size and frequency of these inclusions increased with prolonged exposure to suramin (300 microM). Immunohistochemistry revealed that the inclusions were composed primarily of GM1 ganglioside. These effects were not influenced by increasing nerve growth factor up to 500 ng/ml. We conclude that suramin causes injury to both axons and Schwann cells that is not prevented by NGF and produces and experimental form of GM1 gangliosidosis.

Animals↗
PubMed1995

Ciliary neurotrophic factor expression in Schwann cells is induced by axonal contact.

In the PNS, ciliary neurotrophic factor (CNTF) is found in significant amounts in the adult sciatic nerve, localized to myelin-related Schwann cells (SCs). Levels are undetectable in newborn but high in adult animals. After crush injury, CNTF production is reduced, recovering only as the nerve regenerates; if regeneration does not occur, CNTF levels remain low. We have examined the coupling of CNTF expression to myelination in vitro and in vivo to determine if axon-SC contact without myelination is sufficient to induce CNTF expression. Embryonic day 15 (E15) rat dorsal root ganglion (DRG) neuron and SCs were cocultured. CNTF was not detected in the DRGs either at E15 or after 2 days in vitro (div) by western blotting. However, after 10 div, CNTF could be identified and remained at constant levels up to 30 div. Depriving the cultures of ascorbic acid prevents myelination but not axon-SC contact. This did not affect CNTF protein production. Using reverse transcriptase-linked PCR (RT-PCR) techniques, no CNTF message was present in DRG from day 14 or 15 fetal rats; but by 6 days in culture, message was detected in both myelinating and nonmyelinating cultures. Isolated SC cultures, without axonal contact, failed to express CNTF protein; however, mRNA was detected by RT-PCR. Embryonic SC can be induced to synthesize CNTF in culture by axonal contact. Active myelination is not required.

Animals↗
PubMed1995

Treatment of stable chronic demyelinating polyneuropathy with 3,4-diaminopyridine.

OBJECTIVE: To determine whether 3,4-diaminopyridine (3,4-DAP) would improve clinical or electrophysiologic function in patients with stable chronic demyelinating polyneuropathy. DESIGN: We conducted a prospective, randomized, placebo-controlled, blinded, crossover study of 3,4-DAP in 34 patients with demyelinating polyneuropathy. MATERIAL AND METHODS: Of the 17 men and 17 women, who were 21 to 80 years of age, 27 had hereditary motor and sensory neuropathy type I and 7 had acquired demyelinating polyneuropathy. Treatment consisted of stepped doses of 3,4-DAP (increasing to 20 mg four times daily) or placebo for 4 days. Pretreatment and posttreatment determination of the Neurologic Disability Score (NDS); isometric muscle strength testing; median, ulnar, and peroneal nerve conduction studies; and measurement of serum 3,4-DAP were performed. Quantitative computer-assisted sensory examinations were done in five patients. RESULTS: The results for the final day of treatment with 3,4-DAP or placebo and the differences between pretreatment and posttreatment findings for total NDS, sensory NDS, isometric muscle strength testing, compound muscle action potential amplitude, sensory nerve action potential amplitude, motor and sensory conduction velocities, and vibration and cold detection thresholds did not vary significantly. A small improvement of 4 points in the motor NDS (P < 0.05) was found. Five patients with electrophysiologic conduction block had no significant reduction in the degree of block. CONCLUSION: Because no improvement was noted in most measurements of neurologic function, despite use of high doses of drug, 3,4-DAP is unlikely to be beneficial in the treatment of stable chronic demyelinating polyneuropathy.

4-Aminopyridine↗
PubMed1995

Hereditary neuropathy with liability to pressure palsies and inherited brachial plexus neuropathy--two genetically distinct disorders.

OBJECTIVE: To determine whether hereditary neuropathy with liability to pressure palsies (HNPP) and inherited brachial plexus neuropathy (IBPN) are genetically distinct disorders and to evaluate the usefulness of fluorescence in situ hybridization (FISH) for diagnosing HNPP in individual patients. DESIGN: We studied representative metaphases from patients with HNPP and IBPN with use of FISH and a DNA probe. MATERIAL AND METHODS: With use of FISH, 14 persons from 4 unrelated families with HNPP and 7 members from 3 unrelated families with IBPN were studied. We used a DNA probe that hybridizes to chromosome 17p11.2 in an area thought to be deleted in HNPP. RESULTS: Each participant in this study who had HNPP showed deletion of this chromosome site. Each of the 10 control subjects and 7 patients with IBPN showed normal fluorescent signals on both number 17 chromosomes. CONCLUSION: These results demonstrate that HNPP and IBPN are genetically different. FISH with this probe is a sensitive and specific method for detecting the chromosomal deletion in individual patients without the use of family studies or linkage analysis.

Brachial Plexus Neuritis↗
PubMed1995

Drug-induced neuropathies.

Much progress has been made over the past 20 years in the description of the neurotoxic processes involved in drug-induced neuropathies. Essentially all of the clinical neuropathic syndromes resulting from these drugs have been extensively described. Current research centres not only on the delineation of the molecular mechanisms of these phenomena, but also on the possible therapeutic prevention of these neuropathies using novel neuroprotective agents. As more neurotoxic drugs (especially in chemotherapy) are developed, and with the future possibility of combination chemotherapy regimens with two or more neurotoxic agents, continued investigation in this area will remain vitally important. In addition, findings from this research may be applicable to other peripheral neurodegenerative processes that are not drug-induced.

Humans↗
PubMed1994

Role of nerve growth factor in suramin neurotoxicity studied in vitro.

We determined whether suramin neurotoxicity can be prevented by nerve growth factor (NGF) and if this interaction occurs at the level of the NGF receptor. Neurite outgrowth from rat dorsal root ganglia in vitro was measured serially in the presence of suramin (100-600 microM) alone or with beta-NGF (50-1,000 ng/ml). Competitive NGF receptor-binding studies were done with 125I-labeled NGF in the presence or absence of suramin. Neurite growth was inhibited in a dose-dependent manner, but at usual neurotoxic levels this inhibition could be overcome completely by increasing the concentration of NGF. Receptor-binding assays showed similar dose-dependent inhibition of 125I-labeled NGF binding. In the presence of suramin, the dissociation constant for high-affinity binding was decreased from 1.2 x 10(-11) to 3.9 x 10(-10) and low-affinity binding from 2.7 x 10(-9) to 1.2 x 10(-8). Increasing doses of suramin inhibited 125I-labeled NGF specific binding in a dose-dependent fashion, and doses of suramin > or = 1,000 microM were able to completely inhibit 125I-labeled NGF specific binding. Suramin-induced dorsal root ganglia damage can be ameliorated by high-dose NGF. This effect is most likely due to competition between suramin and NGF at the high-affinity NGF receptor.

Animals↗
PubMed1994

A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy is a paralytic syndrome, causing considerable disability and even death. In controlled clinical trials, plasma exchange prevented or ameliorated neurological deficits, but the efficacy of immune globulin infusion remains unproved. Also unknown is whether immune globulin infusion is as effective, or more effective, than plasma exchange and what dosages and frequencies are best. In this observer-blinded study, using some objective end points not subject to bias (e.g., summated compound muscle action potential), 20 patients with progressive or static polyneuropathy were randomly assigned to receive either of the two treatments for 6 weeks, followed by a washout period, and then were assigned to receive the other treatment. Plasma exchange (twice a week for 3 weeks then once a week for 3 weeks) and immune globulin infusion (0.4 gm/kg once a week for 3 weeks, then 0.2 gm/kg once a week for the next 3 weeks) were used. End points assessed before and after treatment schedules were neurological disability score; muscle weakness of the neurological disability score; summated compound muscle action potentials of ulnar, median, and peroneal nerves; summated sensory nerve action potentials of ulnar and sural nerves; and vibratory detection threshold of the great toe using CASE IV. Observers were masked as to treatment used. Of 20 patients, 13 received both treatments whereas 4 did not worsen sufficiently to receive the second treatment--1 patient left the study during and 2 after the first treatment to receive unscheduled treatment elsewhere.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Fractures in an aging population of poliomyelitis survivors: a community-based study in Olmsted County, Minnesota.

OBJECTIVE: To determine the incidence of fractures in a cohort of survivors of paralytic poliomyelitis ("polio"). DESIGN: We conducted a population-based retrospective cohort study of residents of Olmsted County, Minnesota, who had an initial diagnosis of polio between 1935 and 1959 and survived the acute illness. MATERIALS AND METHODS: A comprehensive medical records-linkage system was used to retrieve all diagnoses of poliomyelitis in residents of the county for the specified 25-year period. For the 277 study subjects, the medical records were searched for the occurrence of fracture from the time of initial diagnosis of polio until death or the most recent clinical contact. All fractures were classified on the basis of type of associated injury and skeletal site of involvement. The influence of polio on the incidence of fractures was evaluated by estimating the cumulative incidence of new fractures after the diagnosis of polio and the standardized morbidity ratio. The relative influence of various factors on the risk of fracture was determined. RESULTS: Of the 277 Olmsted County residents with polio, 87 experienced 161 fractures, and the estimated cumulative incidence of any fracture after 40 years was 48%. The cumulative incidence of any limb fracture was 41% and was less than the expected value of 44% (P = 0.001). Only the risk of distal femoral and proximal humeral fractures was significantly higher than that among Olmsted County residents in general. The increased risk seemed to be associated with weakness and disuse of the involved limbs rather than with generalized osteoporosis. Theoretically, a greater capacity for bone remodeling in response to changes in muscle use might have protected patients with polio in childhood, but such persons were as likely to sustain a fracture as those with adult-onset poliomyelitis. CONCLUSION: These data indicate that survivors of paralytic poliomyelitis do not have an unusual risk of fracture except in affected limbs.

Adolescent↗
PubMed1994

Neuropathy associated with hyperlipidemia.

We describe six patients with painful polyneuropathy associated with hyperlipidemia. Each had mild, slowly progressive neuropathy characterized by pain in feet, without proximal extension or involvement of hands. Weakness and autonomic symptoms and signs were absent. Three patients had normal tendon reflexes; three others had decreased ankle reflexes. Serum cholesterol levels were moderately increased; serum triglyceride levels were exceedingly high. In one patient, symptoms resolved with correction of hypertriglyceridemia. No other cause of peripheral neuropathy was found. Marked increases in serum triglycerides may cause painful small-fiber neuropathy.

Adult↗
PubMed1994

The effect of nerve growth factor, ciliary neurotrophic factor, and ACTH analogs on cisplatin neurotoxicity in vitro.

Cisplatin, used to treat ovarian, bladder, and testicular cancers, causes a sensory dose-limiting neuropathy. Preliminary observations in humans and animals suggest that nerve damage may be prevented by ACTH analogs, particularly those belonging to the melanocortin class, and by nerve growth factor (NGF). We established a rat embryo dorsal root ganglion model to study cisplatin neurotoxicity. The drug reproducibly inhibited axonal growth at concentrations similar to that known to produce toxicity in neurons. The inhibition was prevented in a dose-dependent fashion by simultaneous exposure to alpha-melanocyte stimulating hormone (alpha-MSH) or ACTH but not by excess NGF or ciliary neurotrophic factor (CNTF). The ACTH peptides were not effective in preventing suramin-induced neurotoxicity in the same model. Drug interaction and dose-response studies showed that ACTH and alpha-MSH do not act by potentiation of NGF action. ACTH analogs appear to protect against cisplatin-induced neurotoxicity directly at the cellular level.

Adrenocorticotropic Hormone↗
PubMed1994

Brachial and lumbar neuropathies.

Sporadic acute brachial plexus neuropathy occurs in approximately 1.64/100,000 population, but may present in epidemic form. Sporadic lumbosacral plexus neuropathy is far less common and has to be distinguished from more common disorders affecting the plexus and roots such as diabetes. Early this century, when serum therapy became popular to treat or prevent prevalent infectious diseases, it became apparent that a plexopathy could follow treatment. It has thus been assumed that many of the cases are due to an autoimmune or inflammatory lesion of the plexus. A wide variety of vaccines, infections and medications seem able to precipitate the disorder. Recent work has shown that cultured lymphocytes from affected patients, but not controls, are able to mount a blastogenic response to components of cadaver brachial plexus. This response seems to be selective not only to the brachial plexus, but also to discrete components of the plexus. The recovery rate in brachial plexus neuropathy is good, being almost 90% at 3 years. Recovery with lumbosacral disease is less satisfactory. Histological material and descriptions of acute brachial plexus neuropathy are rare. There is some evidence that an inflammatory process is present, but the role of demyelination and axonal atrophy in producing the observed clinical signs, is still uncertain. Virtually nothing is known about the histological changes in lumbosacral plexus neuropathy. Treatment is mainly supportive, but important in limiting disability. Steroids may help relieve pain in the acute stages, but do not seem to alter the prognosis.

Biopsy↗
PubMed1994

Potential neurotoxicity of the solvent vehicle for cyclosporine.

Nervous system complications resulting from i.v. administration of cyclosporine (CS) are especially frequent in liver transplant recipients. Because CS is insoluble in water, the i.v. preparation is formulated in a polyoxyethylated castor oil and ethyl alcohol. Rat dorsal root ganglion neurons exposed in vitro to the i.v. preparation exhibited axonal swelling and degeneration. No effect of CS (dissolved directly in serum) was seen on testing individual components of the i.v. solution. However, 0.1% polyoxyethylated castor oil (volume of solute/volume of solvent) produced axonal swelling and degeneration and 0.001% polyoxyethylated castor oil produced demyelination in vitro. Polyoxyethylated castor oil is manufactured by reacting castor oil with ethylene oxide, and we speculate that residual ethylene oxide or a polymerization product may be responsible for the in vitro neurotoxicity. Although little is known about the pharmacokinetics of polyoxyethylated castor oil, plasma levels of 0.001 to 0.01% polyoxyethylated castor oil (volume of solute/volume of solvent) are probably achieved with therapeutic doses of the i.v. CS preparation.

Animals↗