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Biomedical subjects

R G Wiley

Publications and source records attributed to R G Wiley.

At least 109 records · Page 6Linked to original sources
PubMed1989

Anti-Thy-1 immunotoxin, OX7-saporin, destroys cerebellar Purkinje cells after intraventricular injection in rats.

Thy-1 is an abundant surface glycoprotein of rat neurons. OX7 is a monoclonal antibody with high affinity for Thy-1. This study sought to determine if intraventricularly administered OX7 could serve as a carrier to deliver cytotoxin to neurons, thus destroying those neurons. Saporin (Sap), a ribosome-inactivating protein was disulfide-coupled to OX7 (OX7-Sap). OX7-Sap, OX7, saporin alone, pooled non-immune mouse IgG, and an irrelevant immunotoxin, RFT-1-Sap, were injected into the lateral ventricles of anesthetized adult rats. Animals were observed for 1-8 days. OX7-Sap-injected animals developed coarse head tremor and gait/truncal ataxia in a dose-dependent manner beginning 24 h or more after injection. All control animals remained healthy. After OX7 or OX7-Sap injection, immunoperoxidase staining for mouse IgG was most intense and specific in the molecular and Purkinje cell layers of the cerebellar cortex. Cresyl violet staining demonstrated destruction of the Purkinje cell layer in the OX7-Sap-treated animals but not in controls. These results indicate that intraventricular injections of OX7 can be used to deliver biologically active moieties to the Purkinje cells. This approach may prove useful in analysis of Purkinje cell function and as a model of cerebellar degeneration.

Animals↗
PubMed1989

Anti-ricin antibody protects against systemic toxicity without affecting suicide transport.

Ricin is an effective suicide transport agent which reliably destroys sensory and motor neurons in anatomically selective fashion after peripheral nerve application. In the present study, we gave subcutaneous injections of commercially available antiricin antibody (ARA) at the time of ricin application to peripheral nerves. The ARA protected rats against systemic ricin poisoning without altering the suicide transport activity of ricin. This approach removes a significant barrier to the routine use of ricin and should prove useful when ricin is employed to ablate large peripheral nerves. However, antibody protection permits use of such large ricin doses that the toxin may diffuse within the CNS destroying neurons adjacent to those that project through the injected nerve. Consequently, antibody and ricin doses must be optimized for any particular experimental situation.

Animals↗
PubMed1989

CNS chloromas in patients presenting with eosinophilia.

A patient presented with hypereosinophilia for 3 years followed by acute leukemia with intracranial chloroma. Eight of 15 reported cases of myeloproliferative disorder accompanied by hypereosinophilia developed meningeal chloromas, suggesting a previously unrecognized association between eosinophilia, acute leukemia, and CNS chloroma.

Adult↗
PubMed1988

Cortical organization after treatment of a peripheral nerve with ricin: an evaluation of the relationship between sensory neuron death and cortical adjustments after nerve injury.

The present study was designed to assess whether cortical changes after peripheral nerve damage are related to the degree of death of primary sensory neurons in the damaged nerve. The cytotoxin ricin was injected into the sciatic nerves of adult rats to kill primary sensory neurons with axons through the injection site. Following periods of 6-101 days, the S-I hindpaw map was evaluated with neurophysiological techniques and compared with the hindpaw maps of previously studied normal adult rats and adult rats that had undergone adult or neonatal sciatic section at a comparable level of the nerve. These comparisons allowed evaluation of cortical functional organization following different degrees of sensory neuron loss after sciatic nerve injury. There were three main results. 1) The comparison of ricin-treated and normal adult rats indicated that ricin treatment interrupted inputs from the sciatic skin territory on the hindpaw and caused a limited increase in the size of the cortical area that was activated by stimulation of hindpaw skin innervated by the remaining saphenous nerve. 2) The cortical maps of rats that had undergone adult ricin treatment (relatively large primary neuron loss) or section during adulthood (small to moderate primary neuron loss) were similar. In both groups, only the saphenous hindpaw skin was represented in cortex, and the cortical area that was activated by stimulation of the saphenous hindpaw skin had undergone a comparable limited enlargement. 3) The comparison of ricin-treated adult rats (relatively large primary neuron loss) and adult rats that had undergone neonatal section (relatively large primary neuron loss) indicated that cortical organization differed after these treatments. In particular, after ricin treatment the cortical area that was activated by stimulation of the saphenous hindpaw skin was larger than the comparable area in neonatal denervates, and the topographical progressions between the hindpaw and adjacent body representations were not as variable as after neonatal section. These findings indicate that cortical maps are altered after injection of ricin into a nerve. The similarity in cortical organization after ricin treatment (relatively large sensory neuron loss) and nerve section in adults (relatively small sensory neuron loss) and the differences in cortical organization after ricin treatment and nerve section in neonates (both relatively large sensory neuron loss) indicate cortical changes do not covary as a simple function of the degree of peripheral neuron death.

Aging↗
PubMed1988

Monoclonal anti-Thy 1 antibody (OX7) is axonally transported in rat nervous system.

Monoclonal anti-Thy 1 antibody (OX7) was pressure microinjected into vagus nerve, tongue or caudate nucleus of rats. Indirect anti-IgG immunoperoxidase staining showed that OX7 was axonally transported antero- and/or retrogradely from all injection sites. Histological examination and behavioral observations did not reveal neurotoxicity from these single OX7 injections. We conclude OX7 may prove useful as a carrier for selectively targeting molecules at neurons via endocytosis and axonal transport.

Animals↗
PubMed1988

Modeccin and volkensin but not abrin are effective suicide transport agents in rat CNS.

Suicide transport is a term applied to the technique of producing anatomically selective neural lesions using axonally transported cytotoxins. Because the cytotoxic lectins, abrin, modeccin and volkensin are effective suicide transport agents in the peripheral nervous system, the present study sought to determine if they were effective suicide transport agents in the rat CNS. Toxins were stereotactically pressure microinjected unilaterally into the caudate nucleus of rats. After 2-13 days survival, brain sections were processed for catecholamine histofluorescence or Nissl stained with Cresyl violet. All 3 agents produced extensive necrosis at the caudate injection site. In addition, modeccin and volkensin but not abrin produced destruction of neurons in the ipsilateral substantia nigra and intralaminar thalamus. Histofluorescence confirmed loss of dopaminergic neurons from the ipsilateral substantia nigra after modeccin or volkensin but not abrin injections. These results indicate that modeccin and volkensin are effective suicide transport agents within the rat CNS, presumably due to retrograde axonal transport of the toxins. These agents may prove extremely useful in producing anatomically selective lesions of neurons afferent to a toxin injection site.

Abrin↗
PubMed1988

Leukoencephalopathy complicating intraventricular catheters: clinical, radiographic and pathologic study of 10 cases.

Ten patients with implanted Ommaya devices developed pericatheter white matter lesions, apparent as focal lucenaries on computed tomographic scan sometimes with contrast enhancement and/or mass effect. Some of the patients had significant neurological signs that related to the lesion. Three of the patients had not received cytotoxic drugs through the reservoir, and two had received neither intrathecal chemotherapy nor cranial radiation therapy. The process appears to be related to back flow of cerebrospinal fluid, with or without contained cytotoxic drugs into the periventricular white matter. Patients with elevated intracranial pressure are at particular risk. Removal of the catheter relieves the condition.

Adult↗
PubMed1988

Synthesis and in vitro and in vivo activity of a hybrid composed of ricin B chain-barley ribosome-inactivating protein.

In our continued studies on hybrid proteins for use as cytotoxins and possible suicide transport agents, we have begun to investigate the use of ribosome-inactivating proteins (RIP) isolated from grain. The RIP from barley has been purified to homogeneity by modifications of the methods of Roberts and Selitrennikoff and crosslinked to the binding subunit B of the seed toxin ricin (RTB). The resulting hybrid was purified by a combination of gel filtration and affinity chromatography on acid-washed Sepharose 4B. This model suicide transport agent was assayed in vitro against K-562 cells and was found to be cytotoxic in a dose-dependent manner (ID50 = 0.15 micrograms/ml). Lactose inhibited the toxicity of the hybrid, indicating that cytotoxicity was dependent on the cell binding property of the ricin B moiety. In addition, free RIP and free ricin B, either alone or in combination, were nontoxic over this concentration range. The in vivo effects of the RTB-RIP hybrid were assessed by pressure microinjection into the vagus nerves of rats. Injection of 0.18 to 6.5 micrograms of conjugate resulted in death of vagal sensory but not motor neurons after 3-17 days. The cytotoxic changes in vagal sensory neurons were identical to those previously observed with a variety of RIP toxins such as ricin.

Animals↗
PubMed1988

A variant of the anti-Purkinje cell antibody in a patient with paraneoplastic cerebellar degeneration.

An anti-Purkinje cell antibody was found in the serum and CSF of a man with adenocarcinoma of the lung and paraneoplastic cerebellar degeneration (PCD). This antibody differed from the autoantibodies found in patients with gynecologic cancer and PCD in that it produced a different pattern of Purkinje cell cytoplasmic staining, did not react with PCD antigens in Purkinje cell Western blots, and the antigen had a different species distribution. Unlike the antinuclear antibody found in patients with PCD and small-cell lung carcinoma, the antigen was restricted to the cytoplasm of Purkinje cells. If autoantibodies are important in the pathogenesis of PCD, this case illustrates that they can recognize different antigenic epitopes in the nervous system, but cause similar clinicopathologic syndromes.

Adenocarcinoma↗
PubMed1988

Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer.

An antineuronal autoantibody has been identified in serum from 14 patients, 8 women and 6 men, with small-cell lung carcinoma (SCLC) and a neurologic disorder. Neurologic symptoms began prior to diagnosis of the SCLC in 12 patients. The dominant neurologic disorder was a subacute sensory neuronopathy (SSN) in eight patients, SSN plus lower motor neuron weakness (2 patients), SSN plus autonomic neuropathy (1 patient), cerebellar ataxia (1 patient), myelopathy (1 patient), and multifocal nervous system disease (encephalomyelitis) in one patient. The presence of the same autoantibody in patients with SSN, encephalomyelitis, and autonomic neuropathy suggests that these diseases are different manifestations of the same nosologic process. With one exception, treatment of the tumor, immunosuppressive drugs, and plasmapheresis did not influence the course of the neurologic illness. The autoantibody was not identified in sera from more than 400 controls subjects, including patients with SSN associated with other tumors, SSN without malignancy, other paraneoplastic syndromes, and SCLC without neurologic symptoms. The autoantibody is a highly specific marker of the paraneoplastic syndromes associated with SCLC and its detection in a patient not known to have cancer should prompt a careful search for SCLC.

Aged↗
PubMed1987

Time course and frequency dependence of synaptic vesicle depletion and recovery in electrically stimulated sympathetic ganglia.

The mammalian superior cervical sympathetic ganglion has been extensively used to study the kinetics of ACh metabolism and release. The present investigation examined the time course of changes in the number of synaptic vesicles and abundance of plasma membrane at preganglionic nerve terminals using stimulation protocols similar to those used in previous biochemical and electrophysiological studies. Continuous stimulation of the preganglionic trunk to the cat superior cervical ganglion in vivo produced an initially rapid fall in the number of clear synaptic vesicles followed by a subsequent plateau. Reciprocal changes in plasma membrane occurred with a similar time course. The plateau phase is interpreted as a steady-state where vesicle exocytosis is balanced by the rate of vesicle reformation from plasma membrane. During quiescent recovery, restoration of normal resting ultrastructure is initially rapid but slows with time as vesicle number and plasma membrane abundance approach pre-stimulation values, indicating that the rate of vesicle reformation at the end of stimulation is high and proportional to the number of vesicles incorporated into the plasma membrane. These results are interpreted as consistent with the 'vesicle hypothesis' of neurotransmitter release.

Acetylcholine↗
PubMed1987

Neck tumour with syncope due to paroxysmal sympathetic withdrawal.

A patient with recurrent squamous carcinoma metastatic to the neck after radical neck dissection and high dose radiation therapy developed paroxysmal hypotensive episodes that were severe, spontaneous and characterised by suppressed sympathetic but not enhanced parasympathetic activity. Intravenous pressors were successful in treating acute episodes but neither drug therapy nor surgical neck exploration reliably prevented syncopal attacks. Glossopharyngeal and/or vagal nerve infiltration by tumour with episodic activation of the afferent limb of the baroreflex arc producing vasodilatation primarily due to sympathetic withdrawal is the likely mechanism of life threatening syncope in this patient.

Adrenergic Fibers↗
PubMed1987

Comparison of spinal magnetic resonance imaging and myelography in cancer patients.

Spinal involvement by systemic malignancy is common, and often leads to extradural compression of the spinal cord and/or nerve roots by metastases. Rapid, anatomically accurate diagnosis is essential to the successful management of these patients. We compared spinal magnetic resonance imaging (MRI) with conventional myelography in a series of 31 cancer patients being evaluated for myelopathy (N = 10), or back/radicular pain (N = 21). All patients were evaluated between April 1985 and July 1986, and underwent both studies within ten days of each other (median, two days). MRI was performed on a 0.5 Tesla Technicare unit with a body surface coil, and results compared with standard contrast myelography. All studies were reviewed separately and in a "blinded" fashion. MRI and myelography were comparable in detecting large lesions that produced complete subarachnoid block (five of ten patients with myelopathy, three of twenty-one patients with back/radicular pain). In 19 of 31 patients, smaller but clinically significant extradural lesions were found. In nine of 19 cases, these lesions were demonstrated equally well by both modalities; in nine of 19 cases, these lesions were demonstrated by myelography alone; in one of 19, a lesion was demonstrated by MRI alone. Given our current technology, myelography appeared superior to MRI as a single imaging modality. However, MRI may be an alternative in patients where total myelography is technically impossible or unusually hazardous.

Adolescent↗
PubMed1987

Cerebellar metastases: diagnostic and management considerations.

Prompted by several unsatisfactory outcomes, we reviewed the records of 59 patients with cerebellar metastases (26 solitary) with respect to clinical presentation, diagnosis, and natural history. Eighty-seven percent of patients initially complained of headache, gait disturbance, and/or dizziness. At time of diagnosis, 92% of patients with solitary cerebellar metastases and 74% of the overall series complained of headache and/or difficulty walking. In three of four cases, magnetic resonance imaging (MRI) was superior to x-ray computed tomography (CT) in detecting the cerebellar lesions. Several patients acutely deteriorated during evaluation or at the initiation of radiation therapy. We conclude that a cancer patient presenting with headache and gait difficulty with or without nausea/vomiting and dizziness should promptly undergo head CT scanning, and that MRI is useful even if CT is negative. In addition, we recommend that patients with documented cerebellar metastases receive high-dose glucocorticoid therapy for 48 to 72 hours before beginning radiation therapy. The presence of symptomatic hydrocephalus or failure to respond to glucocorticoids initially are particularly ominous features that may be best managed by early neurosurgical consultation before beginning radiation therapy.

Adult↗
PubMed1987

Oral yohimbine in human autonomic failure.

Yohimbine is an alpha 2-adrenoreceptor antagonist that acts to enhance sympathetic nervous system discharge and potentiate sympathetically mediated cardiovascular reflex responses. We therefore assessed the ability of yohimbine to increase sympathoadrenal discharge and raise blood pressure (BP) in patients with autonomic failure characterized by profound orthostatic hypotension. Yohimbine 5 mg orally in eight seated patients significantly elevated mean systolic BP by 33 mm Hg from 136 +/- 15 (mean +/- SD) to a maximum of 169 +/- 23 mm Hg (p less than 0.01), mean diastolic BP by 16 mm Hg from 77 +/- 9 to a maximum of 93 +/- 15 mm Hg (p less than 0.01), and mean heart rate (HR) by 10 beats per minute (BPM) from 68 +/- 12 to a maximum of 78 +/- 17 BPM (p less than 0.01). Plasma norepinephrine (NE) increased from 104 +/- 71 to a maximum of 196 +/- 182 pg/ml (p less than 0.05), but plasma epinephrine (E) did not increase significantly (31 +/- 18 versus a maximum of 39 +/- 21 pg/ml). In five patients given yohimbine 2.5 mg orally, BP, HR, NE, and E tended to increase, but the changes were not significant. Plasma yohimbine levels correlated significantly with the changes in mean arterial pressure (r = 0.61, p less than 0.01). Yohimbine raises BP and HR in patients with autonomic failure. These effects are dose- and concentration-dependent and mediated through increased sympathetic discharge. Yohimbine may be useful in the treatment of orthostatic hypotension associated with autonomic failure. It is unique among current modes of therapy for this disorder in that it enhances discharge of the patient's own sympathetic system.

Administration, Oral↗