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Biomedical subjects

R G Smith

Publications and source records attributed to R G Smith.

At least 145 records · Page 8Linked to original sources
PubMed1995

Amyotrophic lateral sclerosis immunoglobulins increase Ca2+ currents in a motoneuron cell line.

The sporadic form of amyotrophic lateral sclerosis (ALS) is an idiopathic and eventually lethal disorder causing progressive degeneration of cortical and spinal motoneurons. Recent studies have shown that the majority of patients with sporadic ALS have serum antibodies that bind to purified L-type voltage-gated calcium channels and that antibody titer correlates with the rate of disease progression. Furthermore, antibodies purified from ALS patient sera have been found to alter the physiologic function of voltage-gated calcium channels in nonmotoneuron cell types. Using whole-cell patch-clamp techniques, immunoglobulins purified from sera of 5 of 6 patients with sporadic ALS are now shown to increase calcium currents in a hybrid motoneuron cell line, VSC4.1. These calcium currents are blocked by the polyamine funnel-web spider toxin FTX, which has previously been shown to block Ca2+ currents and evoked transmitter release at mammalian motoneuron terminals. These data provide additional evidence linking ALS to an autoimmune process and suggest that antibody-induced increases in calcium entry through voltage-gated calcium channels may occur in motoneurons in this disease, with possible deleterious effects in susceptible neurons.

Adult↗
PubMed1995

Altered muscle calcium channel binding kinetics in autoimmune motoneuron disease.

While skeletal muscle is not apparently affected directly in amyotrophic lateral sclerosis (ALS), immunoglobulin G fractions purified from patients with ALS (ALS IgG) bind dihydropyridine (DHP)-sensitive L-type voltage-gated calcium channel (VGCC) antigen isolated from skeletal muscle in ELISA and Western immunoblot, and alter VGCC function in vitro. To determine whether muscle VGCC properties are altered in ALS, VGCC-enriched subsarcolemmal membrane fractions were prepared from biopsied quadriceps muscle of patients with ALS, with other neurologic diseases, or without apparent muscle disease, and tested for DHP binding with [3H]PN200-110. ALS muscle VGCCs possessed eightfold higher binding affinities for [3H]PN200-110 than did VGCCs from muscle fractions of most other patients, independent of denervation-induced increases in DHP binding site number. Similarly elevated DHP binding affinities were observed in specimens from patients with autoimmune motor neuropathies, suggesting that ALS and immune mediated motoneuron disease share skeletal muscle L-type VGCC alterations.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Antibodies to calcium channels from ALS patients passively transferred to mice selectively increase intracellular calcium and induce ultrastructural changes in motoneurons.

Antibodies to Ca channels in ALS patients IgG can be demonstrated to enhance Ca current and cause cell injury and death in a motoneuron cell line in vitro. To determine whether these antibodies can alter neuronal calcium homeostasis in vivo IgG fractions from six ALS patients were injected intraperitoneally into mice, and neurons assayed by ultrastructural techniques for calcium content. After 24 h, all six ALS IgG by (40 mg/animal) increased vesicle number in spinal motoneuron axon terminals, and in boutons synapsing on spinal motoneurons. Using the oxalate-pyroantimonate technique for calcium precipitation, these antibodies produced dose-dependent calcium increases either in axon terminal synaptic vesicles and mitochondria, or in rough endoplasmic reticulum, mitochondria, and Golgi complex of spinal motoneuron and frontal cortex pyramidal cells. ALS IgG was itself internalized and also induced neurofilament H phosphorylation. The observed changes in ultrastructure and calcium compartmentation were restricted to motoneurons; normal and disease control IgG, which did not possess antibodies enhancing calcium entry, did not exert similar effects. These data demonstrate that ALS IgG containing Ca-channel antibodies can alter calcium homeostasis of motoneurons in vivo.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Experimental autoimmune nigral damage in guinea pigs.

An animal model of experimental autoimmune nigral damage (EAND) has been developed in guinea pigs by immunization with hybrid dopaminergic cells (MES 23.5). In such animals, loss of 40% of the substantia nigra (SN) neurons and damage to an additional 10% of SN neurons was associated with a 37-43% decrease of tyrosine hydroxylase (TH) activity and a 36% decrease of dopamine (DA) content in the nigral-striatum. Eight of the thirteen animals developed significant hypokinesia. The EAND model suggests that degeneration of dopaminergic neurons in SN can be caused by immune-mediated processes, which may help our understanding of the pathogenesis in Parkinson's disease.

Animals↗
PubMed1995

Alpha-1 subunits of voltage gated Ca2+ channels in the mesencephalon x neuroblastoma hybrid cell line MES23.5.

The identity of alpha 1 subunits from voltage operated Ca2+ channels was determined in the rat/mouse mesencephalon x N18TG2 hybridoma cell line MES23.5, by sequence analysis of reverse transcription-polymerase chain reaction products and antagonist binding. Sequences were derived from the L-(alpha 1D), Q-(alpha 1A) and omega-conotoxin GVIA sensitive N-type (alpha 1B) Ca2+ channel alpha 1 subunits. The amplified fragments, which are homologous to the region between domain III and IV of known alpha 1 subunits, reveal splice variation in the L- and Q-type alpha 1 subunit of MES23.5 cells. The transcripts of alpha 1 subunits in these cells were quantified by RNAase protection assay. The data show the existence of different Ca2+ channel types in a single cell line and may reflect multiple functions of voltage operated Ca2+ channels during growth, differentiation and transmitter release.

Amino Acid Sequence↗
PubMed1995

beta-Amyloid1-40 increases expression of beta-amyloid precursor protein in neuronal hybrid cells.

Studies of cell injury and death in Alzheimer's disease have suggested a prominent role for beta-amyloid peptide (beta-AP), a 40-43-amino-acid peptide derived from a larger membrane glycoprotein, beta-amyloid precursor protein (beta-APP). Previous experiments have demonstrated that beta-AP induces cytotoxicity in a neuronal hybrid cell line (MES 23.5) in vitro. Here, we demonstrate that beta-APP mRNA content is increased 3.5-fold in 24 h after treatment with beta-AP1-40. Accompanying beta-AP1-40-induced cell injury, levels of cell-associated beta-APP and a C-terminal intermediate fragment are increased up to 15-fold, and levels of secreted forms of beta-APP and 12- and 4-kDa fragments are also increased. Application of beta-APP antisense oligodeoxynucleotide reduces both cytotoxicity and beta-APP expression. 6-Hydroxydopamine application or glucose deprivation causes extensive cell damage, but they do not increase beta-APP expression. These results suggest a selective positive feedback mechanism whereby beta-AP may induce cytotoxicity and increase levels of potentially neurotrophic as well as amyloidogenic fragments of beta-APP with the net consequence of further neuronal damage.

Amyloid beta-Peptides↗
PubMed1995

Comparative staining in vitro and plaque inhibitory properties in vivo of 0.12% and 0.2% chlorhexidine mouthrinses.

The mere incorporation of an active ingredient in an oral hygiene product does not necessarily guarantee efficacy. As new formulations appear, it would seem prudent to at least screen for activity by comparison with an established product. The aim of this study was to compare a new 0.12% chlorhexidine containing rinse with a well researched 0.2% chlorhexidine rinse product. The rinses were firstly compared in vitro for dietary staining effects and in vivo for plaque inhibition. Both formulations in vitro produced progressive staining of acrylic specimens with increasing passages through a standard tea solution. The clinical investigation was a 3-treatment, randomised, double blind, crossover, 4-day plaque regrowth study, balanced for 1st and 2nd order residual effects and involving 24 volunteers. From a zero plaque baseline, volunteers suspended oral hygiene and rinsed 2 x per day with the allocated rinse. The chlorhexidine doses were 18 mg and 20 mg per rinse for the 0.12% and 0.2% formulations, respectively. Plaque was scored by area and index on day 5. The results showed that the 2 chlorhexidine rinses were similar in efficacy by comparison with the control rinse. These studies in vitro and in vivo indicate that the chlorhexidine in the new preparation is available and active and the product could find use in those preventive applications suggested for other chlorhexidine formulations.

Acrylic Resins↗
PubMed1995

Molecular approaches to amyotrophic lateral sclerosis.

New discoveries are expanding our knowledge of mechanisms involved in amyotrophic lateral sclerosis (ALS) pathogenesis. Some recent advances in our understanding of motoneuron death in familial ALS (fALS) and sporadic ALS (sALS) are reviewed, with emphasis on molecular similarities that may further unite these phenotypically linked diseases.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Definitive radiation therapy for extrahepatic bile duct carcinoma.

PURPOSE: To evaluate retrospectively the role of radiation therapy for extrahepatic bile duct (EHBD) carcinoma. MATERIALS AND METHODS: Twenty-seven patients with local-regional EHBD carcinomas were treated with definitive radiation therapy. Radiation therapy was delivered by means of external beam radiation therapy (EBRT) alone or combined with transcatheter iridium-192 brachytherapy. The median total dose was 54 Gy (range, 30-144 Gy). Survival rates were calculated and compared by using the log-rank test. Possible prognostic factors affecting survival were evaluated by means of univariate analysis. RESULTS: The median survival of all patients was 13 months, with 1- and 2-year actuarial survival rates of 52% and 10%, respectively. Univariate analysis revealed that men, patients with tumors limited to the bile duct, and patients receiving EBRT doses of at least 45 Gy had significantly better outcomes. Local-regional recurrence was the main cause of treatment failure (82%). Two patients developed gastric outlet obstruction. CONCLUSION: Patients with locally advanced EHBD carcinomas have a low survival rate. Certain factors, however, appear to have prognostic significance.

Adenocarcinoma↗
PubMed1995

Central actions of peptide and non-peptide growth hormone secretagogues in the rat.

Evidence for a central site of action of growth-hormone-releasing peptide (GHRP-6) was sought by (1) counting the number of Fos-positive nuclei within the brain following intracerebroventricular or intravenous injection of peptide and non-peptide GH secretagogues and (2) characterizing the electrophysiological responses of neuroendocrine arcuate neurones (recorded in vivo) following intravenous injection of GHRP-6. Conscious male rates were chronically implanted with intracerebroventricular or intravenous catheters. Dense nuclear Fos staining was induced throughout the ventral arcuate nucleus of rats injected intracerebroventricularly with low doses of GHRP-6 but not in rats injected with the endogenous GH-releasing hormone GHRH or in vehicle-treated controls. The non-peptidyl GH secretagogues L-692,585 and L-692,429 also induced Fos expression in the arcuate nucleus, and the pattern of distribution was similar to that described for GHRP-6. No increase in Fos expression was observed in rats given a systemic injection of a high dose of GHRH. In pentobarbitone-anaesthetized male rats, the effects of intravenous injection of GHRP-6 on the electrical activity of arcuate neurones was predominantly excitatory for putative neuroendocrine cells and inhibitory for the remaining unidentified cells. These results suggest that (1) GHRP-6 and non-peptidyl GH secretagogues have a central site of action involving the activation of a subpopulation of arcuate neurones and (2) this action is not mimicked by the central or peripheral effects of GHRH.

Animals↗
PubMed1995

5 alpha-Androstan-3 alpha,17 beta-diol is a hormone: stimulation of cAMP accumulation in human and dog prostate.

5 alpha-Androstan-3 alpha, 17 beta-diol (3 alpha-diol) is a well known metabolite of dihydrostestosterone (DHT) and the concentration of its glucuronide in serum is looked upon as a marker of DHT activity in skin and prostate. The data in this communication show that 3 alpha-diol is a potent agonist of the human and canine prostatic SHBG-[SHBG receptor]. It causes a robust rise in intracellular cAMP within minutes; the 1/2 max. response occurs at a concentration equal to its concentration in male plasma. Estradiol is the only other agonist in this system. All other steroids that bind to SHBG are antagonists.

Androstane-3,17-diol↗
PubMed1995

Consistent GH responses to repeated injection of GH-releasing hexapeptide (GHRP-6) and the non-peptide GH secretagogue, L-692,585.

GH release is normally stimulated by the naturally occurring GH-releasing factor (GRF). However, smaller GH-releasing peptides (GHRPs) and non-peptide analogues have been described which stimulate GH release in animals and man. Although these compounds release GH in vitro, their in vivo activity in conscious animals has proved more difficult to study since the GH responses are variable, and prone to desensitization. We now compare the GH-releasing properties of GHRP-6 and a novel benzolactam GH secretagogue L-692,585 using chronically cannulated guinea pigs and automated blood micro-sampling to study the effects of repeated exposure to these secretagogues. L-692,585 was approximately tenfold less potent than GHRP-6 for GH release, but it synergized strongly with GRF. Serial injections of GRF, GHRP-6 or L-692,585 at intervals of 60 or 90 min produced variable GH release which followed a cyclic pattern of responsiveness. Prolonging the pulse interval to 3 h produced more regular responses to both GHRP-6 and L-692,585. Continuous i.v. infusion of low doses of either secretagogue elicited an initial GH release, and amplified the spontaneous GH secretory pattern over the next 6 h. We conclude that L-692,585 and GHRP-6 share similar in vivo, their in vivo activity in conscious animals has frequent injections is similar for all three secretagogues, and is a property of the conscious animal rather than of any secretagogue type. More consistent responses can be obtained with less frequent injections that more closely match the endogenous GH rhythm, whereas continuous exposure to these secretagogues leads to amplified endogenous secretion. Our results show that the interpretation of in vivo effects of these peptide and non-peptide secretagogues will need to take account of their interaction with the endogenous mechanisms governing GH release.

Animals↗
PubMed1995

An analysis of the reinforcing properties of hand mouthing.

Hand mouthing often has been described as a stereotypic response that is maintained by nonsocial (automatic) reinforcement; however, data supporting this conclusion can be found in relatively few studies. This series of studies presents an experimental analysis of conditions associated with the maintenance of hand mouthing. In Experiment 1, a functional analysis was conducted for 12 individuals who engaged in chronic hand mouthing, to determine whether the behavior is usually maintained independent of social contingencies. Results obtained for 10 subjects were consistent with an automatic reinforcement hypothesis; the remaining 2 subjects' hand mouthing was maintained by social-positive reinforcement. Based on these results, Experiment 2 was designed to identify the specific reinforcing properties of hand mouthing. Each of 4 subjects was provided with a toy that substituted for hand mouthing, and preference for a specific topography of toy manipulation (hand-toy contact or mouth-toy contact) was measured. Results indicated that hand stimulation was the predominant reinforcer for all subjects. Experiment 3 provided an extension of Experiment 2 in that the same responses were measured across a variety of toys presented to each of 5 subjects. Results again indicated that hand stimulation was the predominant reinforcer for all subjects. Implications of these results are discussed with relevance to treatment.

Adult↗
PubMed1995

Direct assessment of quality of care in a geriatric nursing home.

Direct observation was used to examine multiple aspects of care provided in a proprietary nursing home. The samples were taken at random intervals, 7 days per week for 5 weeks, across several categories of environmental and resident conditions as well as staff and resident activity. Results showed a high degee of compliance with predefined standards (based on current federal regulations) for environmental and resident conditions. Overall distributions of resident and staff activity showed results similar to those found in previous studies, with residents spending most of their time engaged in nonsocial activity and staff spending the majority of their time engaged in nonresident work. When data were analyzed across areas of the facility, times of day, and weekdays versus weekends, some differences were noted. Weekend versus weekday comparisons showed higher resident:staff ratios on weekends and more resident inactivity, but no significant differences in environmental or resident conditions. In addition, more frequent resident care, resident interaction, and resident activity were observed in Medicare units than in non-Medicare units. Results are discussed in terms of federal requirements for monitoring the quality of care in nursing homes and the potential use of time sampling expressly for this purpose.

Journal Article↗
PubMed1995

Analysis of establishing operations for self-injury maintained by escape.

Self-injurious behavior (SIB) can be maintained through negative reinforcement when, in the context of training or task requirements, it produces escape as a consequence. Several studies have demonstrated methods for identifying and treating SIB maintained by negative reinforcement; however, few analyses of the establishing operations associated with demand situations have been conducted. The current series of studies illustrates a method for identifying some establishing operations for escape by systematically altering certain dimensions of the demand context while maintaining an escape contingency for SIB. Dimensions assessed in these studies included task novelty, duration of instructional sessions, and rate of task presentation. Data indicate that these variables can have establishing properties for behavior maintained by escape. Implications of the results are discussed, as are potential refinements and extensions of the assessment procedures.

Journal Article↗