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Biomedical subjects

J A Halter

Publications and source records attributed to J A Halter.

16 recordsLinked to original sources
PubMed2001

GenePath: a computer program for genetic pathway discovery from mutant data.

The sequencing of the human genome and the genomes of several model organisms is the first step toward the long-term objective of genetic research: the identification of all genes, and the discovery of their functions and mutual interactions. This article presents a methodology and a computer program called GenePath to support the discovery of gene function. GenePath uses mutant data and available genetic knowledge to identify potential genetic pathways. Several pilot applications based on experimental results from Dictyostelium and C. elegans confirmed the usefulness of the proposed schema. Our results suggest that GenePath is a valuable tool that can be used as an intelligent assistant to support genetic reasoning.

Animals↗
PubMed2000

Intravenous infusion of 4-AP in chronic spinal cord injured subjects.

STUDY DESIGN: A prospective double blind cross over trial of intravenous 4-Aminopyridine (4-AP). OBJECTIVE: To determine the efficacy of this drug in the treatment of spinal cord injured (SCI) patients for neurologic impairment, pain and spasticity. SETTING: The post anesthesia care unit (PACU) of a tertiary care acute hospital. METHODS: Twelve paraplegic patients were enrolled in a double blind cross over intravenous trial of 4-Aminopyridine (4-AP). Thirty milligrams of 4-AP or placebo were administered over a 2 h period. Patients were serially examined during and after the infusion clinically for pain, sensorimotor function, hypertonicity and motor control using electromyography (EMG). Samples of blood and cerebrospinal fluid (CSF) were also analyzed at similar intervals. RESULTS: Despite penetration of 4-AP into the CSF, no significant differences were noted in the clinical and EMG parameters at the times measured. Individual changes in sensory function were reported by some patients in both the placebo and 4-AP trials, however mean values were not robust. Frequently, patients complained of unpleasant symptoms during the 4-AP infusion. CONCLUSION: The intravenous route may not be the best way to administer this drug as no short term benefits were observed.

4-Aminopyridine↗
PubMed2000

Intrathecal administration of 4-aminopyridine in chronic spinal injured patients.

STUDY DESIGN: Intrathecal administration of 4-aminopyridine (4-AP) in chronic spinal cord injured (SCI) patients. OBJECTIVE: To determine the safety and effects of intrathecal administration of 4-AP in a small population of chronic SCI patients. SETTING: The post anesthesia care unit of a tertiary care hospital. METHODS: Following animal mode studies to establish dosing safety, six subjects with chronic SCI were examined. In each subject, an intrathecal catheter was placed with the tip as close to the lesion level as possible. 4-AP was infused at 5 microg/h for a period of 4-5 h. Vital signs were recorded and sensory-motor physical examinations and pain questionnaires were administered for 24 h. In two patients, samples of cerebrospinal fluid for analysis were drawn from a second intrathecal catheter. RESULTS: No adverse systemic side effects were noted. One patient showed transient improvement in sensory function; two showed transient increases in spasticity; three showed transient increases in cutaneomuscular reflexes and two showed an apparent small increase in volitional motor control. The concentration of 4-aminopyridine in the cerebrospinal fluid reached a peak of 163 ng/ml at 4 h in one subject and 122 ng/ml at 5 h in the other subject examined. CONCLUSION: Intrathecal administration of 4-aminopyridine at a rate of 5 microg/h does not appear to cause adverse effects and may modify spinal cord function. This route of administration allows local cerebrospinal fluid concentrations equivalent to those produced by maximum tolerable systemic doses, which require 1000 times more drug substance to be delivered to the subject as a whole. Intrathecal administration offers the potential to focus therapeutic effects to the lesion site while minimizing systemic side effects.

4-Aminopyridine↗
PubMed1999

A general approach to modeling conduction and concentration dynamics in excitable cells of concentric cylindrical geometry.

This paper discusses mathematical approaches for modeling the propagation of the action potential and ion concentration dynamics in a general class of excitable cells and cell assemblies of concentric cylindrical geometry. Examples include myelinated and unmyelinated axons, single strands of interconnected cardiac cells and outer hair cells. A key feature in some of the cells is the presence of a small working volume such as the periaxonal space between the myelin sheath and the axon in the myelinated axon and the extracisternal space between the plasma membrane and the subsurface cisterna of the outer hair cell. Proper treatment of these cell types requires a modeling approach which can readily address these anatomical properties and the non-uniform biophysical properties of the concentric membranes and the ionic composition of the volumes between the membranes. An electrodiffusion approach is first developed in which the Nernst-Planck equation is used to characterize axial ion fluxes. It is then demonstrated that this "full" model can be stepwise reduced, eventually becoming equivalent to the standard cable equation formulation. This is done in a manner that permits direct comparisons between the full and simplified models by running simulations using a single parameter set. An intermediate approach where the contributions of the axial currents to ion concentration changes and the effect of varying ion concentrations on solution conductivities are ignored is derived and is found adequate in many cases. Two application examples are given: a "cardiac strand" model, for which the intermediate formulation is shown sufficient and a model of the myelinated axon, for which the full electrodiffusion formulation is clearly necessary. The latter finding is due to spatial inhomogeneities in the anatomy and distribution of ion channels and transporters in the myelinated axon and the restricted periaxonal space between the myelin sheath and the axon.

Action Potentials↗
PubMed1997

The influence of the subsurface cisterna on the electrical properties of the outer hair cell.

A distributed-parameter computational model of the outer hair cell was used to predict the potentials resulting from current injection. A good fit was found to the length-dependent whole cell conductance and capacitance. The fit required the presence of the subsurface cisterna and a low (0.001 mS/cm2) specific conductivity for the plasma membrane of the lateral wall. The lateral wall could not be space clamped as significant longitudinal currents pass through the extracisternal space vs the axial core. A reduction in the width of the extracisternal space decreased the whole-cell conductance and capacitance. Position-dependent phase shifts were noted during injection of sinusoidal currents (0.001575 rad/micron). These predictions support a role for extracisternal longitudinal potential gradients in experimentally observed non-linear capacitance and electromotility.

Animals↗
PubMed1995

Operantly conditioned motoneuron plasticity: possible role of sodium channels.

1. Learning is traditionally thought to depend on synaptic plasticity. However, recent work shows that operantly conditioned decrease in the primate H reflex is associated with an increase in the depolarization needed to fire the spinal motoneuron (VDEP) and a decrease in its conduction velocity (CV). Furthermore, the increase in VDEP appears to be largely responsible for the H-reflex decrease. The conjunction of these changes in VDEP and CV suggests that an alteration in Na+ channel properties throughout the soma and axon could be responsible. 2. A mathematical model of the mammalian myelinated axon was used to test whether a positive shift in the voltage dependence of Na+ channel activation, a decrease in Na+ channel peak permeability, or changes in other fiber properties could have accounted for the experimental findings. 3. A positive shift of 2.2 mV in Na+ channel activation reproduced the experimentally observed changes in VDEP and CV, whereas a reduction in Na+ channel permeability or changes in other fiber properties did not. 4. These results are consistent with the hypothesis that operantly conditioned decrease in the primate H reflex is largely due to a positive shift in the voltage dependence of Na+ channel activation. Recent studies suggest that change in activation of protein kinase C may mediate this effect.

Action Potentials↗
PubMed1993

Surface and epidural lumbosacral spinal cord evoked potentials in chronic spinal cord injury.

Nine patients were examined in the chronic stage of spinal cord injury (12 to 56 months postinjury). Surface lumbosacral spinal cord evoked potentials (LSEPs) were obtained using electrodes placed over the S1, L2, L4, and T12 vertebral levels, referenced to a T6 surface electrode. Epidural LSEPs were obtained using a multielectrode lead placed percutaneously into the epidural space for evaluation of the efficacy of spinal cord stimulation for modification of pain and spasticity. The LSEPs resulting from supramaximal stimulation of the tibial nerve at the popliteal fossa were composed of propagating and stationary action potential components. Based on the surface LSEP amplitudes and latencies established in healthy subjects, the data was divided into normal (less than 2 SD), marginal (between 2 and 2.5 SD), and abnormal (greater than 2.5 SD) categories. Comparison of surface and epidural LSEPs at the T12 vertebral level for the normal group (n = 6, 4 incomplete and 2 complete) revealed a mean epidural/surface amplitude ratio of 9.44 and a latency for the major negative component of 15.2 +/- 0.6 ms for the epidural versus 14.8 +/- 0.6 ms for the surface LSEP. In cases where the lead was progressively removed and LSEPs recorded (n = 4) the propagating components rapidly attenuated and increased in duration while the stationary components attenuated but did not change in duration. The LSEPs for the marginal group (n = 2, 1 incomplete and 1 complete) showed similar epidural/surface amplitude ratios. In the abnormal case (n = 1, complete) surface LSEPs were absent but epidural LSEPs were present but with stationary and propagating components of low amplitude. This study demonstrates the ability of the epidural LSEP to provide more information than the surface LSEP of the functional condition of the lumbosacral spinal cord, particularly regarding the character of the propagating action potentials and in cases when the surface LSEPs appear to be of very low amplitude or absent.

Adolescent↗
PubMed1993

The influence of nodal constriction on conduction velocity in myelinated nerve fibers.

Myelinated nerve fibers exhibit a complex anatomy in the nodal region which includes a marked nodal-paranodal constriction and an intricate paranodal structure where the myelin sheath is separated from the axon by a narrow periaxonal space. In this study, a recently developed computational model of the mammalian myelinated nerve fiber based on electron microscopic data was employed to examine the effect of the nodal-paranodal axonal radius and periaxonal space width on the conduction of action potentials. These findings indicate that the nodal-paranodal constriction promotes higher conduction velocities by minimizing the component of the nodal capacity contributed by the paranodal axolemma. Model prediction of optimal nodal-paranodal radii is correlated with radii determined in experimental anatomical studies.

Action Potentials↗
PubMed1992

Use of tissue adhesive to secure spinal epidural stimulating electrodes: technical note.

Securing spinal cord stimulating electrodes (SCS) within the epidural space is often a challenging task. Complications of the technique include development of cerebrospinal fluid leaks and electrode migration. We report four patients who underwent a limited laminectomy for placement of epidural spinal cord stimulating electrodes to relieve pain and/or spasticity. Suturing electrodes to the dura was not possible, and a tissue adhesive was used. Two-year follow-up shows no migration of the electrodes. Tissue adhesive of "fibrin glue" is a viable alternative for securing epidural SCS electrodes.

Adult↗
PubMed1991

A distributed-parameter model of the myelinated nerve fiber.

This paper presents a new model for the characterization of electrical activity in the nodal, paranodal and internodal regions of isolated amphibian and mammalian myelinated nerve fibers. It differs from previous models in the following ways: (1) in its ability to incorporate detailed anatomical and electrophysiological data; (2) in its approach to the myelinated nerve fiber as a multi-axial cable; and (3) in the numerical algorithm used to obtain distributed model equation solutions for potential and current. The morphometric properties are taken from detailed electron microscopic anatomical studies (Berthold & Rydmark, 1983a, Experientia 39, 964-976). The internodal axolemma is characterized as an excitable membrane and model-generated nodal and internodal membrane action potentials are presented. A system of describing equations for the equivalent network model is derived, based on the application of Kirchoff's Current Law, which take the form of multiple cross-coupled parabolic partial differential equations. An implicit numerical integration method is developed and the numerical solution implemented on a parallel processor. Non-uniform spatial step sizes are used, enabling detailed representation of the nodal region while minimizing the number of total segments necessary to represent the overall fiber. Conduction velocities of 20.2 m sec-1 at 20 degrees C for a 15 microns diameter amphibian fiber and 57.6 m sec-1 at 37 degrees C for a 17.5 microns diameter mammalian fiber are achieved, which agrees qualitatively with published experimental data at similar temperatures (Huxley & Stämpfli, 1949, J. Physiol., Lond. 108, 315-339; Rasminsky, 1973, Arch, Neurol. 28, 287-292). The simulation results demonstrate the ability of this model to produce detailed representations of the transaxonal, transmyelin and transfiber potentials and currents, as well as the longitudinal extra-axonal, periaxonal and intra-axonal currents. Also indicated is the potential contribution of the paranodal axolemma to nodal activity as well as the presence of significant longitudinal currents in the periaxonal space adjacent to the node of Ranvier.

Action Potentials↗
PubMed1991

Conduction in bullfrog atrial strands: simulations of the role of disc and extracellular resistance.

A number of fundamental properties of intercellular conduction in simulated cylindrical strands of cardiac tissue are examined. The paper is based on recent biophysical information describing the transmembrane ionic currents in bullfrog atrial cells as well as anatomical data on the structures (gap junctions) responsible for the coupling between cells in that tissue. A mathematical model of the single bullfrog atrial cell based on suction microelectrode single-cell voltage clamp data is employed, as well as a modified version of the well-known model of Heppner and Plonsey, to characterized the resistive connections between adjacent cells in a cardiac strand. In addition, the simulated cellular strand is assumed to be encased in a cylindrical, resistive endothelial sheath, thus forming an idealized atrial trabeculum; the trabeculum is immersed in an extensive volume conductor. It is possible to simulate both uniform and discontinuous conduction in this atrial strand model by appropriately changing the resistance of the intercalated discs that occur at cell boundaries. The conduction velocity achieved in the normal or control case is within the range of conduction velocities that have been measured for bullfrog atrial trabeculae using optical methods. Extracellular resistance is shown to have a significant effect on both conduction velocity and the critical value of disc resistance at which discontinuous conduction first occurs. Since the atrial cell model employed in this study is based on experimental data and can accurately simulate the atrial action potential, the transmembrane ionic currents generated by the model are capable of providing detailed information concerning the mechanisms of intercellular current spread, particularly in the region of the intercalated disc.

Animals↗
PubMed1991

Recovery of amino acid neurotransmitters from the spinal cord during posterior epidural stimulation: a preliminary study.

Continuous posterior epidural spinal cord stimulation (SCS) has been an effective method for treating spasticity. The mechanisms of SCS include activation of inhibitory segmental neuronal systems and suprasegmental structures that produce inhibitory descending control. The neurochemical correlates of the mechanism of action have not been clearly defined. Microdialysis of the spinal cord extracellular space in an in vivo preparation during continuous epidural SCS was performed. The recovery of amino acid neurotransmitters, aspartate, glutamate, gamma-aminobutyric acid (GABA), glycine, and taurine from stimulated animals was compared to non-stimulated animals. Evoked potentials from the cortex and spinal cord of the stimulated animals were recorded to insure that there had been adequate epidural stimulation and normal segmental cord function. A significant increase in the concentration of glycine was seen after 90 minutes of continuous stimulation. The levels of the other amino acids were not significantly elevated. These results suggest that amelioration of spasticity with epidural SCS may involve enhanced glycine release, the major inhibitory neurotransmitter of the spinal cord.

Amino Acids↗
PubMed1989

Spinal cord evoked injury potentials in patients with acute spinal cord injury.

Six patients were examined in the acute stage of spinal cord injury, between 11 h and 12 days posttrauma. Quadripolar epidural electrodes were positioned either percutaneously using a Tuohy needle or directly into the epidural space during surgical intervention. These electrodes were combined with a common reference to obtain monopolar recordings of spinal cord evoked potentials resulting from either median nerve stimulation at the wrist or tibial nerve stimulation at the popliteal fossa. Spinal cord evoked injury potentials (SCEIPs), stationary potentials with positive polarity on the distal aspect of the lesion and negative polarity on the proximal aspect, were recorded in all cases. The average amplitude (n = 3) of the SCEIP resulting from tibial nerve stimulation as measured across the lesion was 13.5 microV with an average duration of 12.7 msec. For median nerve stimulation, the average amplitude (n = 3) of the SCEIP was 16.3 microV with an average duration of 6.7 msec. There was a change in polarity in all cases over a distance of less than 6 mm, the distance between the electrode contacts on the epidural electrode. In one case, recordings were performed initially at 11 h and repeated at 21 days posttrauma. In the latter recording, the SCEIP was still present but was five times smaller in amplitude. Coincidentally, the patient also showed clinical signs of improvement in sensory and motor spinal cord function. This study demonstrates the feasibility of recording the SCEIP in patients with acute spinal cord injury, describes the features of these SCEIPs, discusses their origins, and explores the utility of recording the SCEIP as an aid in determining the severity of the injury as well as a means of monitoring changes in spinal cord function.

Action Potentials↗
PubMed1989

Electrophrenic respiration in patients with high quadriplegia.

After determining that 15 patients with high spinal cord injuries who were permanently apneic had viable phrenic nerves, electrophrenic respiration units were implanted. Thirteen of the patients (86%) achieved full-time respiration and two more achieved half-time respiration. Despite the loss of 8 patients to unrelated problems, 7 now use electrophrenic respiration continuously, one having done so for 16 years. The patient selection criteria, neurophysiological evaluation method, surgical procedure, postoperative care, and methods for diagnosis of system failures are presented. A comparison of the cervical and thoracic procedures is made. The cervical approach is preferred. Complications consisted primarily of equipment failures. For the external components there were several cases of antenna connection and battery connection failures. The implanted receivers failed in 6 cases with an average lifetime of 48 months, ranging from 24 to 108 months. In one case fibrosis around the electrode resulted in failure to stimulate the phrenic nerve effectively. In another case, infection required removal of the system which was reimplanted later and has continued to provide successful ventilation.

Adolescent↗