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Biomedical subjects

T Gordon

Publications and source records attributed to T Gordon.

At least 91 records · Page 5Linked to original sources
PubMed1995

Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation.

The effects of prolonged denervation, independent from those of prolonged axotomy, on the recovery of muscle function were examined in a nerve cross-anastomosis paradigm. The tibialis anterior muscle was denervated for various durations by cutting the common peroneal nerve before a freshly cut tibial nerve was cross-sutured to its distal stump. Nerve regeneration and muscle reinnervation were quantified by means of electrophysiological and histochemical methods. Progressively fewer axons reinnervated the muscle with prolonged denervation; for example, beyond 6 months the mean (+/- SE) motor unit number was 15 +/- 4, which was far fewer than that after immediate nerve suture (137 +/- 21). The poor regeneration after prolonged denervation is not due to inability of the long-term denervated muscle to accept reinnervation because each regenerated axon reinnervated three- to fivefold more muscle fibers than normal. Rather, it is due to progressive deterioration of the intramuscular nerve sheaths because the effects of prolonged denervation were simulated by forcing regenerating axons to grow outside the sheaths. Fewer regenerated axons account for reinnervation of less than 50% of the muscle fibers in each muscle and contribute to the progressive decline in muscle force. Reinnervated muscle fibers failed to fully recover from denervation atrophy: muscle fiber cross-sectional area being 1171 +/- 84 microns2 as compared to 2700 +/- 47 microns2 after immediate nerve suture. Thus, the primary cause of the poor recovery after long-term denervation is a profound reduction in the number of axons that successfully regenerate through the deteriorating intramuscular nerve sheaths. Muscle force capacity is further compromised by the incomplete recovery of muscle fibers from denervation atrophy.

Anastomosis, Surgical↗
PubMed1995

Fatigue in adapted systems. Overuse and underuse paradigms.

Alterations in structural and biochemical properties of muscles that underlie physiological parameters of contractile force, speed and fatigability are described under conditions of 1) overuse: imposed electrical stimulation, natural exercise and functional overload; 2) reinnervation of denervated muscles; and 3) underusage: conditions of restricted use after spinal cord injury, weightlessness, immobilization and drug-induced neuromuscular blockade. These conditions demonstrate the remarkable plasticity of muscle fibers with obvious implications in health and disease. They also identify that the amount of neuromuscular activity and loading of muscle contractions are major factors determining susceptibility to fatigue and muscle strength, respectively.

Animals↗
PubMed1994

Restricted endothelial cell expression of gravin in vivo.

BACKGROUND: Gravin, a novel, high molecular weight, intracellular protein, is expressed in endothelial cells and several other adherent cell types in vitro. To gain insights into its function, we examined the distribution of gravin in tissues. METHODS: Affinity-purified polyclonal and monoclonal antibodies were raised against a bacterial fusion protein corresponding to the carboxyl terminus of gravin and against affinity-isolated gravin. The specificity of the antibodies was characterized by immunoblotting bacterial, cell, and tissue extracts. The characterized antibodies were used to localize gravin in baboon tissue sections by immunocytochemistry and immunofluorescence microscopy. RESULTS: The antibodies specifically immunoblotted the fusion protein and recognized either a band at 250 kDa or a doublet at 300 kDa on immunoblots of MG63 cells, HEL cells stimulated with phorbol ester, and several baboon tissues. In tissue sections, cell types that express gravin included fibroblasts, components of the peripheral and central nervous system, the adrenal medulla, the somatic layer of Bowman's capsule, cells associated with the glomerulus, and smooth muscle of certain organs. In contrast, most epithelia and all endothelia, with the exception of endothelia of the hepatic sinusoids and intestinal lacteals, lacked gravin. Levels of gravin mRNA expression in stimulated HEL cells increased dramatically when cells were stimulated in the presence of cycloheximide, suggesting that gravin expression may be partly regulated by protein-dependent mRNA catabolism. CONCLUSIONS: These data indicate that gravin expression is regulated in endothelial cells, possibly through protein-dependent mRNA catabolism. The strong expression of gravin in fibroblasts, neurons, and cells derived from neural crest in vivo and in adherent cells in vitro further suggests that this protein may play role in the modulation of cell motility and adhesion.

A Kinase Anchor Proteins↗
PubMed1994

Neurotoxins in the study of neural regulation of membrane proteins in skeletal muscle.

The discovery and purification of several neurotoxins, including alpha-bungarotoxin and tetrodotoxin has provided very high-affinity ligands which have proved to be central to the elucidation of the neural control of skeletal muscle membrane proteins and to the purification and characterization of the nicotinic acetylcholine receptor (AChR) and the Na+ channel, respectively. This review describes the use of neurotoxins for quantification and localization of receptors and ion channels in normal and denervated skeletal muscles with particular emphasis on the appropriateness of the muscle preparation and ligand used in the studies. It is now clear that the nerve controls the synthesis and spatial distribution of AChRs and Na+ channels by regulating gene expression in extrajunctional and subjunctional nuclei. The down-regulation of extrajunctional AChRs is primarily mediated by neuromuscular activity and the concentration of AChRs and Na+ channels in specific membrane domains at the neuromuscular junction is controlled by a number of neurotrophic substances at the neuromuscular junction. These include agrin, ARIA, and CGRP.

Animals↗
PubMed1994

Muscle atrophy and procedures for training after spinal cord injury.

Functional electrical stimulation (FES) of paralyzed muscles holds promise as a strategy to assist patients in executing functional movements after spinal cord injuries. Muscle atrophy is one of the major problems that must be addressed for this approach to be successful. Loss of muscle mass may occur as a result of lesions to motoneurons in either the spinal cord or the central command pathway, or a combination of the two. For injuries to spinal motoneurons, muscle fibers undergo denervation atrophy. Damage to the central command pathway, on the other hand, results in disuse atrophy. In association with atrophy, the low contractile forces and inability of the muscles to sustain contractions are of direct therapeutic concern. In this review, methods aimed at recovery of function of paralyzed limbs by reducing susceptibility to fatigue and atrophy of paralyzed muscles are discussed. One is related to promoting nerve sprouting in partially denervated muscles to reinnervate muscle fibers and reverse denervation atrophy. The other regards training of paralyzed muscles to increase strength (muscle force) and endurance (fatigue resistance) by means of FES. Most training regimens with low-frequency FES increase muscle endurance. Efforts to design optimal regimens for increasing both muscle strength and endurance must involve consideration of several factors that are still controversial. These factors, which include muscle properties (such as fiber type composition and physiological type) and conditions imposed on the muscle (such as loading) during contractions elicited by FES, are discussed in detail.

Electric Stimulation Therapy↗
PubMed1994

Organization of single motor units in feline sartorius.

1. We depleted single motor units in feline sartorius muscles of glycogen by stimulating their motoneurons intracellularly. We mapped the intramuscular distribution of depleted fibers by inspecting histological cross-sections throughout the length of sartorius. 2. We selected ten depleted motor units for detailed study and quantitative analysis. Nine motor units were located in the anterior head of sartorius. One was located in a muscle whose distal half appeared to have been damaged some time before the acute experiment. A single motor unit was located in the medial head of sartorius. 3. Five motor units were composed of fast-twitch glycolytic (FG) muscle fibers, two of fast-twitch oxidative glycolytic (FOG) muscle fibers, and three of slow-twitch oxidative (SO) muscle fibers. Estimates of the numbers of depleted fibers in motor units of anterior sartorius indicated that FG motor units were larger (mean 566 fibers) than FOG and SO motor units (SO mean 190, FOG mean 156 fibers). The SO motor unit in the damaged muscle had 550 fibers. One motor unit depleted in the medial head of sartorius had 270 fibers with FG profiles. 4. Muscle fibers belonging to each anterior motor unit were never distributed throughout the whole cross-section of anterior sartorius at any proximodistal level. Furthermore, fibers were distributed nonuniformly along the proximodistal axis of the muscle. In most muscles at least a few depleted fibers were found at all proximodistal levels. However, in one normal muscle and the damaged muscle, depleted fibers were confined to the proximal end. 5. The fibers in the medial motor unit were confined to a strip that did not extend across the whole cross-section of the muscle head. Fibers within this strip were scattered quite evenly from origin to insertion. This medial FG motor unit occupied a smaller territory and contained fewer fibers than anterior motor units of the same histochemical type. 6. These results show that sartorius motor units are not distributed uniformly in the mediolateral plane; those in anterior sartorius were distributed asymmetrically in the proximodistal axis as well. This finding has important functional implications for the way in which we model force development and transmission in sartorius and other long muscles.

Animals↗
PubMed1994

Effect of inhaled endotoxin on intraepithelial mucosubstances in F344 rat nasal and tracheobronchial airways.

Increased sputum production and chronic bronchitis are associated with occupational exposure to endotoxin-contaminated organic ducts. The present study examined whether repeated exposure to occupationally relevant concentrations of airborne endotoxin in the F344 rat can alter the volume density of stored intraepithelial mucosubstances (Vs) in the respiratory tract. Rats were exposed to saline or endotoxin aerosols for 3 h/day for 3 days and were killed 24 h after the last exposure. Quantitative histochemistry of Vs in airway epithelium was examined at three distinct levels of the respiratory tract (nose, trachea, and lung). Exposure to endotoxin produced a dose-dependent increase in Vs in the intrapulmonary airways. The quantity of Vs in the intrapulmonary airways was significantly increased in animals exposed to as little as 0.3 micrograms/m3 endotoxin. Significant increases in Vs were observed in the trachea only after exposure to > or = 3.1 micrograms/m3 endotoxin, whereas no significant changes were observed in the nasal airways even at concentrations as high as 52.4 micrograms/m3. These results are consistent with earlier findings in which repeated instillation of endotoxin produced significant increases in Vs in the epithelial lining of the pulmonary airways and demonstrate that inhaled endotoxin may play a role in the increase in sputum and chronic bronchitis reported for workers exposed to organic dusts.

Animals↗
PubMed1994

How does autoimmunity to La and Ro initiate and spread?

Autoimmunity to La(SS-B) and Ro(SS-A) is a paradigm for understanding the normal mechanisms of B cell and T cell tolerance and development of autoimmunity to clinically important sequestered autoantigens. Epitope mapping experiments have indicated that the autoantibody response is largely self antigen-driven but have failed to elucidate why these particular autoantigens are selected. Abnormal trafficking of La or Ro peptides in polarised epithelial cells and their presentation to autoreactive T cells, or selective release of ribonucleoproteins by injured epithelial cells, could explain the targeting of salivary and lacrimal epithelium in Sjogren's syndrome. There appears to be little, if any, immune tolerance to La in the T helper and B cell compartments. Both intra-and inter-molecular spreading of the autoimmune response have been observed for La. We present a model of recruited autoimmunity whereby capture and internalisation of La/Ro ribonucleoproteins by B cells and subsequent presentation of La or Ro determinants to autoreactive T cells could lead to inter-molecular spreading of the response.

Autoantigens↗
PubMed1993

Investigation of potential HIV transmission to the patients of an HIV-infected surgeon.

OBJECTIVE: To ascertain if a surgeon infected with the human immunodeficiency virus (HIV) transmitted HIV to patients during invasive surgical procedures. DESIGN: Survey of patients and acquired immunodeficiency syndrome (AIDS) case registries, and laboratory analysis of nucleotide sequence data. SETTING: One surgeon's private and institutional practices within one academic referral hospital. PATIENTS: A total of 1131 persons identified in hospital databases who underwent invasive surgical procedures from 1984 through 1990 and for whom the surgeon was listed as the admitting or operating surgeon. MEASUREMENT: Patients presumed to be living were surveyed by mailed questionnaire. The AIDS case registries were reviewed for all patients having undergone invasive procedures and death certificates were obtained. Person-hours of surgery during which exposure might have occurred were calculated for surgical procedures. RESULTS: Of 1131 patients, 101 were dead, 119 had no address, 413 had test results known, and 498 did not respond to the questionnaire. No study patient name was found in reported AIDS case registries. One newly detected, HIV-seropositive patient was determined (through nucleotide sequencing) to have been most probably infected in 1985 during a transfusion. There was no HIV transmission in 369 person-hours of surgical exposure, indicating that HIV transmission to patients is unlikely to occur more frequently than once per 1000 person-hours of surgical exposure. CONCLUSIONS: If study validity and resources permit, investigation of publicly disclosed, HIV-infected health care workers whose practices involve invasive procedures should be pursued. The risk of HIV transmission during surgery may be so small that it will be quantified only by pooling data from multiple, methodologically similar investigations.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Characterization of the mouse autoantigen La (SS-B). Identification of conserved RNA-binding motifs, a putative ATP binding site and reactivity of recombinant protein with poly(U) and human autoantibodies.

To facilitate the study of autoimmunity to the nuclear Ag La (SS-B) we have isolated and characterized cDNA encoding the mouse La (SS-B) protein. Mouse La (SS-B) protein has 76.7% identity to both human and bovine La (SS-B) proteins and the previously recognized RNP-binding motifs were noted to be highly conserved across the three species. Examination of the primary sequence of human and bovine La (SS-B) newly identifies the site of a potential ATP-binding motif G/AXXXXGK which is preserved in mouse La (SS-B) despite a unique 16 amino acid insertion present in this region of the mouse protein. Analysis of mouse genomic DNA suggests a single gene encodes mouse La (SS-B) and no restriction fragment polymorphisms were identified in the three mouse strains investigated. Two alternate 5' untranslated regions were identified in mouse La (SS-B) cDNA and La (SS-B) mRNA was identified in a wide range of murine tissues consistent with its ubiquitous expression. Recombinant mouse La (SS-B) protein purified from Escherichia coli was shown to bind to poly(U) agarose and to react with sera containing anti-La (SS-B) antibodies obtained from patients with Sjögren's syndrome. The ability to produce recombinant mouse La (SS-B) should provide a valuable reagent for the study of the cellular autoimmune response as well as immunologic tolerance to La (SS-B) Ag in mice.

Adenosine Triphosphate↗
PubMed1993

Alteration of pulmonary macrophage intracellular pH regulation by sulfuric acid aerosol exposures.

In vivo exposure to sulfuric acid aerosols produces profound effects on pulmonary macrophage (PM phi) phagocytic function and cytokine release and perturbs intracellular pH (pHi) homeostasis. Because pHi influences a multitude of cellular processes, we sought to investigate the mechanism by which acid aerosol exposure affects its regulation. Guinea pigs underwent a single or 5 repeated 3-hr exposures to sulfuric acid aerosol (969 and 974 micrograms/m3 for single and repeated exposures, respectively). PM phi harvested immediately after exposure were incubated in HCO3-free media and their pHi recovery from an intracellular acid load was examined. The overall pHi recovery was depressed after single and multiple exposures to sulfuric acid aerosol. delta pHi (the difference between initial pHi and the one measured at 150 sec) decreased by 15.6 and 23.3% (p < 0.05) for single and repeated exposures, respectively. Initial dpHi/dt (maximum pHi recovery rate) after cytoplasmic acidification diminished by 20.3 and 32.2%, which were not statistically significant (p = 0.08 for repeated exposure). To determine whether the activity of the H(+)-ATPase pump the Na(+)-H+ exchanger was specifically altered by the acid exposures, PM phi were first incubated in Na+ and HCO3-free media with NBD-Cl (7-chloro-4-nitrobenz-2-oxa-1,3-diazol, blocking H(+)-ATPase and leaving only the Na(+)-H+ exchanger in effect) and then challenged with 30 mM NaCl. The pHi recovery of PM phi after Na challenge was significantly reduced in acid aerosol exposed guinea pigs (p < 0.05) compared to controls (for delta pHi, 18.2% lower in single exposure and 22.7% in multiple exposure groups; for initial dpHi/dt, 26.9% lower in single exposure and 22.4% in multiple exposure groups). In contrast, the H(+)-ATPase pump was inconsistently affected as indicated by delta pHi and initial dpHi/dt measured in the presence of MIA (amiloride-5-N-methylisobutyl, inhibiting the Na(+)-H+ exchanger and leaving only the H(+)-ATPase pump in effect). These results suggest that in vivo exposure to sulfuric acid aerosols induces alterations in pHi regulation in guinea pig PM phi attributable to changes in Na(+)-H+ exchanger activity.

Administration, Inhalation↗
PubMed1993

Recovery potential of muscle after partial denervation: a comparison between rats and humans.

The response to partial denervation is compared for the tibialis anterior muscle in the rat and the thenar muscle group in the human. Partial denervation in the human was a result of spinal cord injury, while partial denervation in the rat was induced by sectioning of the L4 ventral root. In some animals, a spinal cord transection at the T12-13 level was also performed to determine whether spinal cord injury affected the sprouting capability of motoneurons caudal to the injury site. Motor units were isolated by intramuscular microstimulation in the human and by ventral root splitting in a terminal experiment in the rat. Motor unit numbers were estimated by dividing the amplitude of the electromyogram (EMG) and the peak twitch force in response to maximum stimulation of the muscle nerve by the average unit EMG and twitch force, respectively. In both the rat and the human, surviving motor units enlarged as a function of the degree of partial denervation. Moreover, all surviving motor units appeared to enlarge proportionately. The limit to sprouting was tested systematically in the rat. On average, single motor units enlarged up to about five times their original size, resulting in the ability to compensate for up to 80% of motoneuron loss. The reason for this limit remains unclear, but histological data suggest that sprouting may be confined to the more distal regions of the motor axon, such that reinnervation of denervated muscle fibers is confined to the territory of the original motor unit.

Animals↗
PubMed1993

Increased pulmonary response to inhaled endotoxin in lactating rats.

An important aspect of risk assessment is identification of subpopulations particularly susceptible to the effects of inhaled pollutants. The present study examined whether female rats were more sensitive during lactation to the acute pulmonary injury produced by inhaled endotoxin. Lactating and age-matched virgin female rats were exposed to aerosols of saline or endotoxin for 3 h and lavaged at 24 h after exposure. No significant differences in lactate dehydrogenase, beta-glucuronidase, total protein, and total cell and PMN counts were observed between virgin and lactating rats after exposure to saline. Each marker of pulmonary injury except beta-glucuronidase was 1.5- to 3-fold greater in lactating than in virgin female rats exposed to 29.6 micrograms/m3 endotoxin. PMNs (6-fold), total cell counts, and protein were also significantly increased (p < 0.05) in lactating rats exposed to 1.3 micrograms/m3 endotoxin, a concentration reported to occur in a number of agricultural settings. These results demonstrate that the physiologic state of lactation is associated with an increased sensitivity to the acute pulmonary injury produced by inhaled endotoxin and are consistent with previous work demonstrating a similar increased sensitivity to ozone exposure. The possibility of a similar pattern of enhanced response in analogous groups of humans merits examination.

Administration, Inhalation↗
PubMed1993

Identification of a human-specific epitope in a conserved region of the La/SS-B autoantigen.

Human anti-La/SS-B autoantibodies are known to react with highly conserved epitopes suggested to be functional or active sites on the La/SS-B polypeptide. This study was designed to determine whether the autoantibodies also react with poorly conserved regions of La/SS-B as predicted by an antigen-driven autoimmune response. Binding of human autoantibodies to purified human, mouse, and bovine recombinant fragments representing immunodominant regions of the La/SS-B polypeptide was compared using Western blotting and ELISA. A cross-reactive epitope was located in the highly conserved NH2-terminal region of La/SS-B. Significantly, human-specific epitopes were identified in both the conserved RNA-recognition motif and a poorly conserved COOH-terminal fragment, providing direct evidence for an autoantigen-driven response. The lack of autoantibody cross-reactivity with a conserved domain of mouse and bovine La/SS-B implies that a small number of residues in human autoepitopes may be critical for autoimmunogenicity.

Amino Acid Sequence↗
PubMed1993

Factors associated with serum alkaline phosphatase level.

Serum alkaline phosphatase was measured in a large population of government employees and their dependents, aged 12 years and older. It was found that the concentrations of this enzyme were very high in early adolescence, fell to a low point after the completion of bone growth, and rose thereafter. The concentration was higher in males than females until the age of 50 years; after that it was higher in females. In employees and their spouses (aged 19 years and older), the greater the weight (or weight for height), the higher the concentration. The taller the person, the lower the level of this enzyme. The more cigarettes smoked per day, the higher the enzyme concentration. There was also a weak but statistically significant association of alkaline phosphatase with serum glucose concentrations and blood pressure but not with antihypertensive medications. Other factors were also considered. Some of these factors, particularly age and weight, are associated with substantial difference in the concentration of alkaline phosphatase and could conceivably affect the clinical interpretation of test results.

Adolescent↗