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Z Sahenk

Publications and source records attributed to Z Sahenk.

At least 37 records · Page 2Linked to original sources
PubMed1994

CNTF potentiates peripheral nerve regeneration.

The effect of ciliary neurotrophic factor (CNTF) on peripheral nerve regeneration was studied in 6-week-old rats following sciatic nerve transection and juxtaposition of proximal and distal stumps. Rats received intraperitoneal recombinant human CNTF, 1 mg/kg every other day for 12 days. In all CNTF-treated animals, the distribution of the anterograde transport of [3H]leucine-labeled material within the distal stump showed a distinct peak activity 21-24 mm distal to the nerve transection site. In contrast, the radioactivity in control nerves declined rapidly, distributed as proximodistal gradient without a distinct peak. In addition, the amount of radioactivity returning from the growing axon tips in CNTF was significantly greater than controls. The correlative morphologic studies showed a well-advanced stage of myelination in regenerating axons in CNTF compared to controls. These combined in vivo correlative kinetic and morphological studies indicate that CNTF dramatically potentiates axonal regeneration by promoting a greater number of elongating axon tips into the distal stump.

Animals↗
PubMed1994

Immunosuppressive treatment of motor neuron syndromes. Attempts to distinguish a treatable disorder.

OBJECTIVE: To determine if response to immunosuppressive treatment in motor neuron syndromes could be predicted on the basis of clinical features, anti-GM1 antibodies, or conduction block. DESIGN: Prospective, uncontrolled, treatment trial using prednisone for 4 months followed by intravenous cyclophosphamide (3 g/m2) continued orally for 6 months. SETTING: All patients were referred to university hospital medical centers. PATIENTS: Sixty-five patients with motor neuron syndromes were treated with prednisone; 11 patients had elevated GM1 antibody titers, and 11 patients had conduction block. Forty-five patients received cyclophosphamide, eight of whom had elevated GM1 antibodies and 10 had conduction block. RESULTS: One patient responded to prednisone, and five patients responded to cyclophosphamide treatment. Only patients with a lower motor neuron syndrome and conduction block improved with either treatment. Response to treatment did not correlate with GM1 antibodies. CONCLUSIONS: GM1 antibodies did not serve as a marker for improvement in patients with motor neuron syndrome treated with immunosuppressive drugs. Patients with amyotrophic lateral sclerosis failed to improve irrespective of laboratory findings.

Adult↗
PubMed1994

Taxol neuropathy. Electrodiagnostic and sural nerve biopsy findings.

Taxol has recently been approved for the treatment of ovarian cancer that has failed to respond to other chemotherapeutic agents. A predominantly sensory neuropathy has been reported in patients receiving taxol, but corresponding nerve changes have not been described. The patient described herein received taxol at a dose of 275 mg/m2 every 21 days. The sural nerve biopsy performed after 17 courses of taxol (cumulative dose, 6603 mg) showed severe nerve fiber loss, axonal atrophy, and secondary demyelination. Axonal regeneration was absent. The findings are compatible with a cell body disease or a length-dependent, distal neuropathy with failure of axonal regeneration. The findings observed in taxol-induced neuropathy are important to document for comparison with other neoplastic and paraneoplastic neuropathies affecting patients with cancer.

Electrodiagnosis↗
PubMed1994

Inclusion body myositis: treatment with intravenous immunoglobulin.

We report the results of nine patients with inclusion body myositis treated with intravenous immunoglobulin in an open-label uncontrolled study. None of our patients improved on objective manual muscle testing or functional disability scores. One patient developed mild neutropenia, complicating the intravenous immunoglobulin treatment. Our results do not exclude the possibility that intravenous immunoglobulin could be beneficial in some patients by slowing the rate of deterioration or perhaps stabilizing the disease. However, given the lack of objective improvement and high cost of treatment, we would not recommend intravenous immunoglobulin in the treatment of inclusion body myositis unless a blinded, controlled trial demonstrates clear benefit.

Aged↗
PubMed1993

Gene delivery to spinal motor neurons.

This study demonstrates the direct delivery of plasmid gene constructs into spinal motor neurons utilizing retrograde axoplasmic transport. The plasmid vectors contained the Lac Z gene under the control of both the Rous sarcoma virus (RSV) and Simian virus (SV)40 promoters. beta-Galactosidase expression was observed in alpha and gamma motor neurons by histochemical staining following direct injection into the sciatic nerve or gastrocnemius muscle. The presence of LacZ gene constructs was confirmed by the polymerase chain reaction (PCR). The ability to introduce gene constructs into motor neurons allows for the study of gene regulation and permits the development of gene therapy strategies for motor neuron diseases including the spinal muscular atrophies (SMA) and amyotrophic lateral sclerosis (ALS).

Animals↗
PubMed1993

Polyneuropathy complicating bone marrow and solid organ transplantation.

We report a generalized polyneuropathy coincident with the occurrence of graft-versus-host disease in four patients undergoing bone marrow transplantation and accompanying solid organ rejection (heart and kidney) in two patients. The neuropathy affected proximal and distal muscles, demonstrated hyporeflexia or areflexia, and usually had elevated CSF protein. Electrophysiologic studies did not meet strict criteria for demyelination. The signs of neuropathy improved after immunosuppressive treatment or simultaneous to the resolution of graft-versus-host disease or tissue rejection. Polyneuropathy must be considered as a potential complication of tissue transplantation.

Adult↗
PubMed1992

Alterations in slow transport kinetics induced by estramustine phosphate, an agent binding to microtubule-associated proteins.

Estramustine phosphate (EP) disassembles microtubules by binding to microtubule-associated proteins (MAPs) rather than tubulin. In this study, EP-induced alterations of MAP integrity caused a unique form of axonal atrophy in rats. Initially, EP-induced axonal atrophy occurred in both proximal and distal axons of the sciatic nerve, characterized by an increase in neurofilament packing density, associated with a decrease in axonal area. In chronic exposure, distal axonal atrophy was associated with decreased numbers of microtubules, while the neurofilament number remained unaltered for the myelin spiral length. Continued exposure caused enlargement of proximal axons associated with an increase in neurofilament content. Correlative slow transport studies done at two different times, 7 and 14 days after [35S] methionine injection showed that EP retards the transport of cytoskeletal proteins migrating with both components of slow transport (SCa and SCb). However, there was a differential effect on SCb which showed progressive slowing along the nerve while the rate of SCa stayed relatively constant. In this model, the early occurring distal axonal atrophy can best be explained by reduced cytoskeletal components, particularly those traveling in SCb. Later in the course of intoxication, a relatively constant rate of SCa permitted continuous transport of neurofilament triplets, accounting for unaltered numbers of neurofilaments in distal axons with increased packing density. This model of axonal atrophy is unique because spacing of neurofilaments, not numbers determined axon size. Furthermore, EP-induced dissociation of the SCa and SCb kinetics suggests that MAPs play a role in the orderly, cohesive migration of slow transport components, essential for the normal organization of cytoskeleton.

Animals↗
PubMed1991

The Bruns-Garland syndrome (diabetic amyotrophy). Revisited 100 years later.

A group of 17 patients had proximal diabetic neuropathy characterized by abrupt onset of asymmetric pain and weakness. Fourteen patients had unilateral onset that later involved the other extremity in 3 days to 8 months. All patients reported stepwise or steady progression during 2 to 18 months that was documented during serial examinations. In 16 patients, both proximal and distal muscles were involved. Sural nerve biopsy specimens demonstrated multifocal variability in nerve fiber density manifesting as nonrandom fiber loss between and within fascicles compared with age-matched controls. These findings demonstrate that patients may have a rapidly evolving course of proximal diabetic neuropathy followed by continued progression for many months and emphasize the overlap between proximal diabetic neuropathies of presumed different types. Our cases and others cast doubt on notions supporting two distinct types of proximal diabetic neuropathies represented by the rapid evolution of asymmetric weakness on an ischemic basis, in contrast to a more slowly progressive condition of metabolic pathogenesis.

Action Potentials↗
PubMed1991

Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments.

Inclusion body myositis (IBM) represents a serious debilitating disease of muscle without identifiable cause or treatment. Muscle biopsy specimens have characteristic rimmed vacuoles, varying degrees of inflammation, and, most importantly, cytoplasmic and intranuclear filamentous inclusions of unknown composition. Fresh-frozen sections of muscle biopsy specimens from 24 IBM cases were stained with Congo red dye (pH, 10.5 to 11.0). Control biopsy specimens included polymyositis, dermatomyositis, hereditary vacuolar myopathies of unknown cause, acid maltase deficiency, distal myopathy, oculopharyngeal dystrophy, and chloroquine myopathy. Sections were also immunostained with antibody to transthyretin, human P component, and immunoglobulin light chains. In the vacuolated fibers in IBM, amyloidogenic green-birefringent deposits were seen. Some deposits were delicate and wispy appearing, and others were plaque-like. The size of deposits varied, measuring 1 x 2 to 8 microns, and rarely up to 20 microns in length. The number of amyloid-positive fibers correlated with the number of vacuolated fibers. Similar deposits were seen in one case of distal myopathy and one hereditary vacuolar myopathy. Other control cases were negative for amyloid deposits. Antibody staining for known amyloidogenic proteins was negative. This study demonstrates that the filaments in IBM share properties with amyloid proteins. The location implies that this amyloid material is formed intracellularly, rather than having a systemic derivation. The association of amyloid deposits with autophagic vacuoles in IBM raises the likely possibility that the filaments represent a modification of a normal protein within an acidic degradative vacuolar compartment. An alternative possibility, considering the shared properties of IBM filaments and prions (which include size and amyloidogenic properties), is that IBM represents a human prion disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Weak-base amines inhibit the anterograde-to-retrograde conversion of axonally transported vesicles in nerve terminals.

Acidotropic weak-base amines were used to investigate the role of acidic compartments in the pathway of aterograde-to-retrograde conversion of axonally transported vesicles in axon terminals. A local concentrated population of nascent axon tips was produced by transecting the rat sciatic nerve in situ to allow local and direct exposure of the axon tips to test solutions. Immersion of the nascent axon tips in solutions containing 10 mM ammonium choloride or 10 mM propylamine caused the axon tips to become distended by an accumulation of elongated membranous tubules and occasional large vacuoles that were both distinct from retrograde organelles. To test whether this accumulation was the result of an impairment of anterograde-to-retrograde conversion, a radioactive pulse-labelling method was used together with a retrograde collection ligature, to quantify the proportion of anterogradely transported proteins that returned from the axon tips by retrograde transport. Exposure of the axon tips to 10 mM ammonium chloride caused the anterogradely transported membrane proteins to accumulate in the axon tips and reduced by about 50% the amount of protein that returned to the retrograde collection ligature. These observations implicate the involvement of acidic membranous compartments in the anterograde-to-retrograde conversion pathway that leads to the formation of retrograde organelles in axon tips. Exposure of nerves to Acridine Orange, which is a vital acidotropic fluorescent dye, confirmed the presence of acidic compartments in the axon tips. Based on these observations, we propose that the membranous tubules that accumulated in the axon tips in the presence of weak-base amines represent a transient intermediate in the pathway of anterograde-to-retrograde conversion of axonally transported vesicles in axon terminals, and that acidic membranous compartments within axon terminals are required for the conversion of these tubules into retrograde organelles.

Acridine Orange↗
PubMed1990

Immunocytochemical evidence for the retrograde transport of intraaxonal cathepsin D: possible relevance to the dying-back process.

Immunocytochemical localization of cathepsin D was studied in rat nerves using an antibody to cathepsin D (CD). In normal or control nerves, immunoreactive CD was present in the cytoplasm of Schwann cells but not in axons. In ligated or transected nerves, intraaxonal CD appeared as granular or elongated particles increasing with time at the cut end of the distal stump. In the proximal stump of transected nerves, CD was detected in the nascent axon tips, as well as in a length of axon extending up to the first node of Ranvier. In swollen axons induced by 2,5-hexanedione (HD), CD was associated with granular particles in areas where bidirectional organelle movement was impaired. This study represents the first documentation of intraaxonal CD and provides evidence that immunoreactive CD originates at the nerve terminal in conjunction with the anterograde-to-retrograde (A-R) conversion process of axoplasmic transport. When the A-R conversion process is induced at more proximal sites in the nerve by transection, CD can be observed. In circumstances where axoplasmic transport is impaired, such as nerves exposed to 2,5-HD or ligated and transected nerves, CD-positive granular particles were seen in association with retrogradely moving organelles and their accumulation was related to sites of preferential axonal degeneration.

Animals↗
PubMed1990

Distal terminal axonopathy produced by 2,4-dithiobiuret: effects of long-term intoxication in rats.

It has been well established that 2,4-dithiobiuret (DTB) intoxication in rats produces a rapidly progressive hindlimb paralysis within days. The cause of this has, until recently, been explained on the basis of a physiological abnormality that involves a prejunctional impairment in the neuromuscular transmission alone. The morphological correlate of the electrophysiological abnormalities has now been provided. This study describes the sequential morphological alterations resulting from a chronic long-term DTB intoxication (1 mg/kg per day, IP) in the rat nervous system up to 48 days. The findings indicate that DTB neurotoxicity evolves as a central peripheral distal axonopathy initially affecting the motor nerve terminals which show accumulation of interconnecting branched tubulovesicular profiles. With continued exposure, nerve terminal swelling and degeneration took place. Similar pathological changes in distal axons were observed progressively involving the small intramuscular nerve bundles close to the nerve terminals. Central nervous system axons in the long descending tracts of spinal cord and the cerebellar vermis showed similar changes but to a lesser extent in later stage of intoxication.

Animals↗
PubMed1990

Recurrent respiratory insufficiency and depressed ventilatory drive complicating mitochondrial myopathies.

Three patients with mitochondrial myopathies and progressive external ophthalmoplegia had repeated episodes of respiratory failure requiring assisted ventilation. Studies in these patients and asymptomatic family members, as well as a sporadic case of Kearns-Sayre syndrome, demonstrated markedly depressed ventilatory drive responses to hypoxia. In 2 patients, there was also decreased drive to hypercapnia. The reduced ventilatory drive appears to be due to an altered neural control system that may cause episodic life-threatening hypoventilation occurring especially in relation to surgery, sedation, or intercurrent infection.

Adult↗
PubMed1988

Inhibition of proteolysis blocks anterograde-retrograde conversion of axonally transported vesicles.

To test the hypothesis that proteolysis is required for anterograde-retrograde (A-R) conversion of membranous organelles at axon tips, a new experimental paradigm was developed. By cutting the sciatic nerves of rats, a concentrated population of axon tips was produced, and proteases in the axon tips were locally inhibited by immersing the cut end of the nerve into a solution containing protease inhibitors (E-64 or leupeptin). Membranous organelles were pulse-labeled with [3H]leucine at the nerve cell body, and the amount of retrogradely transported radiolabeled vesicles from the axon tips was quantified with a proximal collection ligature. The results show that protease inhibition decreased the amount of radioactivity that was transported retrogradely from the axon tips and correspondingly increased the amount that remained in the tips. Ultrastructural analyses showed that the protease-inhibited axon tips were greatly distended by 40-80 nm membranous tubules. By contrast, the control axon tips had relatively few of these membranous tubules. These results show that protease inhibition at the axon tip blocks the removal of membranous elements from the axon tips by retrograde transport. We propose that proteolysis is an A-R converting mechanism which is critically required at the axon tip for the conversion of 40-80 nm membranous tubules into retrograde organelles. Apparently, the 40-80 nm membranous tubules are normally transient intermediates in the A-R conversion pathway, and they rapidly accumulate in the axon tip if the mechanisms that convert them into retrograde organelles are blocked. These 40-80 nm tubules also accumulate in certain pathologies and in the aging process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Characterization of a murine model for human bismuth encephalopathy.

An epidemic of bismuth (Bi)-related neurotoxicity in France remains poorly understood, partly because no satisfactory animal model exists. We have now characterized such a model. Single or multiple intraperitoneal injections of Bi subnitrate into female mice produced neurologic signs (myoclonus, ataxia, tremors, convulsions) and blood (1.2 micrograms/g) and brain (8.4 micrograms/g) Bi levels like those in human cases. Hydrocephalus and axonal swellings in spinal cord were the major neuropathologic lesions.

Animals↗
PubMed1987

Carbon disulfide axonopathy. Another experimental model characterized by acceleration of neurofilament transport and distinct changes of axonal size.

The role of axonal transport in the development of structural changes of axons can be examined using experimental models. Two different compounds, 2,5-hexanedione (2,5-HD) and carbon disulfide (CS2), cause axonopathies characterized by the formation of neurofilaments (NF) containing enlargements in preterminal regions of central and peripheral axons. These axonopathies are excellent experimental models of the giant axonal neuropathies, a group of acquired and inherited human diseases of the central and peripheral nervous system. We previously reported that following administration of 2,5-HD, transport of NF is accelerated while number of NF and cross-sectional area are decreased in regions of the axon proximal to the enlargements. We proposed that acceleration of NF transport leads to a 'longitudinal' redistribution of NF which are decreased proximally and increased distally where they form the NF containing axonal enlargements. We have now carried out morphometric, transport and immunocytochemical studies in primary visual axons of rats exposed to CS2. NF-containing axonal enlargements were observed in optic tract and superior colliculus and they increased in number in a proximodistal direction. There was no detectable axonal degeneration and the cross-sectional area of axons proximal to the enlargements was decreased. Transport of NF was markedly accelerated. Immunostaining showed that all 3 NF subunits and phosphorylated epitopes of the 200-kDa NF subunit were present in the NF-containing axonal enlargements. All these findings were similar to those previously observed in the 2,5-HD axonopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Axonal tubulin and microtubules: morphologic evidence for stable regions on axonal microtubules.

Biochemical studies indicate that axonal tubulin is composed of at least two distinct pools that differ in cold solubility and biochemical composition [Brady et al: J. Cell Biol. 99:1716-1724]. To determine the morphologic correlate of cold-insoluble tubulin, segments of rat optic nerves were exposed to a series of in vitro experimental conditions that affect microtubules (MTs), including cold, podophyllotoxin (PT), triflupromazine (TFP), and taxol, and then examined by electron microscopy. Longitudinal sections of control axons showed MTs oriented parallel to the long axis of the axons. Axons exposed to cold, PT, and TFP showed short segments of MTs in association with cytoskeletal disarray. Morphometric studies were used to distinguish between a simple malorientation of MTs (undulation or zigzags in their course) and the loss of labile segments of MTs, leaving the stable portions behind. The lengths of MT segments were measured in longitudinal sections, and the numbers of MTs were determined in the cross sections. All MT segment-length histograms showed a unimodal distribution. Cold and PT produced a simple shift of the control histogram to the shorter length MTs. In cross sections the numbers of MTs in cold- and PT-exposed axons were significantly decreased, indicating that the presence of short segments of MTs in the longitudinal plane of sections was due to a loss of portions of MTs. Taxol, an agent that promotes MT assembly, reversed the cold effect partially and resulted in increases in both MT segment length and number. These studies indicate that stable MT segments are portions of longer MTs containing both stable and labile regions. Furthermore, these findings are consistent with the hypothesis that cold-insoluble tubulin functions as a transportable MT-organizing complex in the axon.

Alkaloids↗