Oral problems and genetic aspects of individuals with epilepsy.
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Dental Care for Chronically Ill↗
Biomedical subjects
R G Smith
Publications and source records attributed to R G Smith.
Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles.
L-692,429 is a substituted benzolactam that has recently been shown to stimulate GH secretion from rat pituitary cells in vitro with an ED50 of 60 nM. In the current studies, we evaluated the efficacy and specificity of L-692,429 as a GH secretagogue in beagles. L-692,429 at 0.1, 0.25, or 1.0 mg/kg or saline vehicle was administered iv to four male and four female beagles in a balanced cross-over design. Blood samples were collected up to 75 min posttreatment, and serum was assayed for GH, cortisol, PRL, and LH. Mean peak serum GH levels were significantly increased (P < 0.05) by L-692,429 to 13 +/- 2 (mean +/- SEM) ng/ml (0.1 mg/kg), 39 +/- 6 ng/ml (0.25 mg/kg), or 71 +/- 11 ng/ml (1.0 mg/kg) over the saline control value of 3.6 +/- 0.6 ng/ml. Mean peak GH levels occurred at 15 min and had returned to near-baseline levels by 75 min. There was no difference in response between sexes. Mean peak cortisol levels were significantly increased (P < 0.05) by 2.2-, 2.7-, and 3.1-fold above control levels (3.0 +/- 0.2 micrograms/dl) at 25-35 min and returned to near-baseline levels by 75 min. PRL was slightly decreased after L-692,429 treatment, whereas LH was not affected. In a second study, three groups of three male beagles each were administered 5.0 mg/kg L-692,429, iv; iv saline, or 2.2 U/kg ACTH, im. Blood was collected for 8 h posttreatment and assayed for GH, cortisol, ACTH, aldosterone, PRL, insulin, T3, and T4. L-692,429 administration significantly increased (P < 0.05) GH over the control level (6.0 +/- 3.6 ng/ml) to 133 +/- 14 ng/ml by 15 min, with a return to pretreatment levels by 120 min. Cortisol levels were significantly increased (P < 0.05) by 2.0-fold (L-692,429) or 2.9-fold (ACTH) over the saline control peak concentration of 5.6 +/- 1.6 micrograms/dl and were associated with concurrent increases in ACTH levels of 1.2-fold (L-692,429) or 2.1-fold (ACTH) over the saline control peak concentration of 67 +/- 20 pmol/L. Aldosterone, PRL, T3, and T4 were not significantly affected after L-692,429 administration; however, ACTH treatment significantly increased aldosterone (P < 0.05). These data demonstrate that L-692,429 is a novel nonpeptidyl secretagogue that stimulates a marked, but transient, increase in serum GH levels in the dog.(ABSTRACT TRUNCATED AT 400 WORDS)
Adrenocorticotropic Hormone↗
Acute and chronic respiratory effects of sodium borate particulate exposures.
This study examined work-related chronic abnormality in pulmonary function and work-related acute irritant symptoms associated with exposure to borate dust in mining and processing operations. Chronic effects were examined by pulmonary function at the beginning and end of a 7-year interval. Time-specific estimates of sodium borate particulate exposures were used to estimate cumulative exposure during the study interval. Change in pulmonary function over the 7 years was found unrelated to the estimate of cumulative exposure during that interval. Exposure-response associations also were examined with respect to short-term peak exposures and incidence of five symptoms of acute respiratory irritation. Hourly measures of health outcome and continuous measures of particulate exposure were made on each subject throughout the day. Whenever a subject reported one of the irritant symptoms, a symptom intensity score was also recorded along with the approximate time of onset. The findings indicated that exposure-response relationships were present for each of the specific symptoms at several symptom intensity levels. The associations were present when exposure was estimated by both day-long and short-term (15-min) time-weighted average exposures. Associations persisted after taking account of smoking, age, and the presence of a common cold. No significant difference in response rate was found between workers exposed to different types of sodium borate dusts.
Adult↗
The functions of self-injurious behavior: an experimental-epidemiological analysis.
Data are summarized from 152 single-subject analyses of the reinforcing functions of self-injurious behavior (SIB). Individuals with developmental disabilities referred for assessment and/or treatment over an 11-year period were exposed to a series of conditions in which the effects of antecedent and consequent events on SIB were examined systematically by way of multielement, reversal, or combined designs. Data were collected during approximately 4,000 experimental sessions (1,000 hr), with the length of assessment for individuals ranging from 8 to 66 sessions (M = 26.2) conducted over 2 to 16.5 hr (M = 6.5). Differential or uniformly high responding was observed in 145 (95.4%) of the cases. Social-negative reinforcement (escape from task demands or other sources of aversive stimulation) accounted for 58 cases, which was the largest proportion of the sample (38.1%). Social-positive reinforcement (either attention or access to food or materials) accounted for 40 (26.3%) of the cases, automatic (sensory) reinforcement accounted for 39 (25.7%), and multiple controlling variables accounted for 8 (5.3%). Seven sets of data (4.6%) showed either cyclical or inconsistent patterns of responding that were uninterpretable. Overall results indicated that functional analysis methodologies are extremely effective in identifying the environmental determinants of SIB on an individual basis and, subsequently, in guiding the process of treatment selection. Furthermore, an accumulation of assessment data from such analyses across a large number of individuals provides perhaps the most rigorous approach to an epidemiological study of behavioral function.
Adolescent↗
Reemergence and extinction of self-injurious escape behavior during stimulus (instructional) fading.
Based on results of a functional analysis indicating that the self-injurious behavior (SIB) of 3 individuals was maintained by negative reinforcement (escape from instructional situations), the effects of stimulus (instructional) fading were evaluated in a multiple baseline design across subjects. The rate of instructions was reduced to zero at the beginning of treatment and was gradually increased (faded in) across sessions as long as SIB remained low. However, if SIB remained high for 10 consecutive sessions, extinction was implemented until SIB decreased, at which point extinction was withdrawn and fading was resumed. Treatment was completed when the rate of instructions was the same as in baseline (two per minute), and SIB remained below 0.5 responses per minute for two consecutive sessions. Results showed that instructional fading (without extinction) virtually eliminated SIB initially, but these effects were not maintained. All 3 subjects required multiple exposures to extinction and over 150 treatment sessions in order to meet the end-of-treatment criteria. Advantages and limitations of fading procedures without an extinction component, as well as extensions of both interventions to other clinical problems, are discussed.
Adult↗
Transfer of behavioral function as a contributing factor in treatment relapse.
When relapse occurs following successful treatment to reduce problem behavior, it is often attributed to inconsistent implementation of maintenance programs. Although less likely, another potential cause for relapse is a change in the behavior's maintaining contingency over time. To examine this possibility, additional assessment was conducted with 4 individuals who were rereferred to a day-treatment program due to recurrence of their self-injurious behavior (SIB) 2 months to 2 years following successful treatment. In each case, the original treatment had been developed and implemented based on the outcome of functional analysis assessments. For 1 subject, results of a second functional analysis were consistent with those from the original assessment, indicating that the function of her SIB had remained unchanged. For the other 3 subjects, results of the second assessment suggested that their SIB had acquired new or additional functions. These findings indicate that factors other than program inconsistency can lead to relapse, and that clinical reevaluation for such cases should include a current functional analysis to determine if new treatment components are needed.
Adult↗
Momentum and extinction effects on self-injurious escape behavior and noncompliance.
Previous research on applications of behavioral momentum has indicated that a high-probability (high-p) instructional sequence, in which a series of instructions for which there is a high probability of compliance is presented immediately before an instruction for which there is a low probability of compliance, is an effective method for increasing compliance. It is not clear, however, whether the procedure is effective when individuals actively attempt to escape from the instructional situation. In this study, we examined the effects of the high-p sequence, when implemented first alone and then later with an extinction component, as treatment for the self-injurious escape behavior of 2 individuals. Results showed that when the instructional sequence was implemented without extinction, rates of self-injury increased and percentage of compliance decreased. In addition, the percentage of trials occasioning escape behavior increased for both high- and low-probability instructions. When an extinction component was added to the high-p sequence, rates of self-injury and the percentage of trials containing self-injury decreased, and compliance increased. These findings suggest that extinction may be an important component of treatment when escape behavior such as self-injury accompanies noncompliance in instructional contexts and competes with compliant behavior.
Adult↗
Pioneers in the profession. Gordon C. Harrold.
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Environmental Health↗
IgG from amyotrophic lateral sclerosis patients increases current through P-type calcium channels in mammalian cerebellar Purkinje cells and in isolated channel protein in lipid bilayer.
The effect of the IgG from amyotrophic lateral sclerosis (ALS) patients was tested on the voltage-dependent barium currents (IBa) in mammalian dissociated Purkinje cells and in isolated P-type calcium channels in lipid bilayers. Whole cell clamp of Purkinje cells demonstrates that ALS IgG increases the amplitude of IBa without modifying their voltage kinetics. This increased IBa could be blocked by a purified nonpeptide toxin from Agelenopsis aperta venom (purified funnel-web spider toxin) or by a synthetic polyamine analog (synthetic funnel-web spider toxin) and by a peptide toxin from the same spider venom, omega-Aga-IVA. Similar results were obtained on single-channel recordings from purified P channel protein. The addition of ALS IgG increased single-channel IBa open time without affecting slope conductance. The results described above were not seen with normal human IgG nor with boiled ALS IgG. It is concluded that ALS IgG enhances inward current through P-type calcium channels. Since P-type Ca2+ channels are present in motoneuron axon terminals, we propose that the enhanced calcium current triggered by ALS IgG may contribute to neuronal damage in ALS.
Amyotrophic Lateral Sclerosis↗
Isoabzymes: structurally and mechanistically similar catalytic antibodies from the same immunization.
Mechanistic and structural comparisons of five catalytic monoclonal antibodies generated from the same hybridoma fusion indicated that all five hydrolyze phenyl acetate by subtle variations of the same mechanism. All of the antibodies showed a pre-steady-state multi-turnover burst in which kcat and Km declined but kcat/Km did not change. The burst of one of the antibodies, 20G9, has previously been found to result from inhibition by the product, phenol. Although all of the antibodies showed the burst, their individual values for kcat, Km, and hapten Ki differed substantially. Three of the antibodies that were investigated for the effect of pH on kcat showed an acid limb pK of 9.5-9.6. Substrate inhibition was seen in four of the five antibodies. Variable region nucleotide sequencing of the heavy and light chains confirmed that all five antibodies were structurally similar and also revealed several potentially critical tyrosines. Despite their structural similarities, analysis of their sequences suggested that the antibodies are products of distinct, independent rearrangements of immunoglobulin gene segments that took place in different progenitor B cells. A plot of Ki for hapten inhibition vs Km/kcat for substrate hydrolysis for the mechanistically related antibodies ("isoabzymes") gave a linear relationship suggesting a catalytic role for transition-state complementarity. Taken together with previous work [Martin et al. (1991) Biochemistry 30, 9757-9761], the data conform to a mechanism in which the antibodies exploit both transition-state complementarity and an acyl-tyrosyl intermediate during phenyl acetate hydrolysis.
Amino Acid Sequence↗
Gingival enlargement in a patient medicated with amlodipine.
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Adult↗
A nonpeptidyl growth hormone secretagogue.
A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.
Amino Acid Sequence↗
Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study.
Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.
Adolescent↗
Can neurotrophic factors prevent or reverse motoneuron injury in amyotrophic lateral sclerosis?
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Amyotrophic Lateral Sclerosis↗
Use of the Symbion biventricular assist device in bridging to transplantation.
From 1988 to 1991 13 patients received Symbion biventricular assist devices in attempts to bridge them to cardiac transplantation. All 7 of those who had cardiac transplants survived to hospital discharge. One death occurred 60 days after transplantation because of rejection. All other patients who received transplants are surviving. Implant times in this group varied from 10 to 164 days (mean, 55 days). There were two embolic neurologic events and two significant infections, and 2 of the survivors were dialyzed for reversible renal failure before transplantation. Of those who died on device support, 3 presented on centrifugal pump support. The three other deaths were caused by graft rejection, multiple organ failure, and multiple peripheral emboli. Biventricular assist devices optimally provide cardiac outputs of 4 to 5 L/min, can be quickly inserted often without requiring cardiopulmonary bypass, are easily explanted, and seem best suited for patients weighing less than 80 kg.
Adult↗
Evidence for autoimmunity in amyotrophic lateral sclerosis.
Although the etiology and pathogenesis of ALS is unknown, increasing evidence supports a role for autoimmune mechanisms in motoneuron degeneration and death. An animal model, experimental autoimmune gray matter disease, can be induced by the inoculation of spinal cord gray matter. The experimental disease is characterized by weakness secondary to the loss of upper and lower motoneurons, accompanied by inflammatory foci within the spinal cord, and IgG at the neuromuscular junction and within UMN and LMN. In human ALS, IgG is present within the UMN and LMN, and T-lymphocytes and activated microglia have been identified within spinal cord gray matter and motor cortex. ALS IgG can passively transfer physiological changes of the neuromuscular junction to mice resulting in enhanced release of acetylcholine. The ALS IgG selectively interact with calcium channels and alter channel function. These data suggest a potential role for autoimmune mechanisms in the destruction and loss of motoneurons in ALS.
Amyotrophic Lateral Sclerosis↗
Vimentin-crossreactive antibodies induce cell death in primary cultures of embryonic spinal cord.
Sera from guinea pigs inoculated with spinal cord gray matter were cytotoxic for embryonic day 14 (ED14) primary spinal cord cell cultures. All cell types including astroglia and neurons were affected. Immunoglobulin (IgG) from inoculated animals and biologically active complement proteins were both identified as necessary components for the observed cytotoxicity. Adsorption with cytoskeletal constituents removed the cytotoxic effect. Adsorption with purified vimentin substantially reduced cytotoxicity, while adsorption with glial fibrillary acid protein (GFAP) had no cytoprotective effects. Antiserum from vimentin-immunized guinea pigs was also toxic to spinal cord cell cultures. Antibody and complement-mediated toxicity appeared to result from interaction with vimentin bound to the surface of embryonic cultured glia and neurons, although interaction with a cross-reacting epitope could not be definitely excluded. Cytotoxic vimentin-directed antibody was not noted in control sera, and the presence of this antibody in guinea pig and human sera did not correlate with the clinicopathological state.
Adsorption↗
Experimental immune-mediated motor neuron diseases: models for human ALS.
Amyotrophic lateral sclerosis is an idiopathic, ultimately fatal disease, clinically manifest as progressive weakness and spasticity, associated with the loss of motoneurons. Circumstantial evidence supports a role for autoimmune processes in the progression of this human disorder. Two immune-mediated animal models have been developed in our laboratory for motor neuron loss. Experimental autoimmune motor neuron disease is a lower motor syndrome induced in guinea pigs by the repeated injection of a purified bovine spinal motor neuron antigen. Affected animals demonstrate extremity weakness, associated with electromyographic and morphologic evidence of denervation, a loss of spinal cord motor neurons, high antibody titers against motor neurons, and localization of IgG immunoreactivity to the neuromuscular junction and motor neuron cytoplasm. Experimental autoimmune grey matter disease is a more acute and severe disorder involving both upper and lower motor neurons, induced in guinea pigs by inoculation of a bovine ventral spinal cord homogenate, in which scattered foci of denervation are observed in the motor cortex and ventral spinal cord. Similarities between these diseases and human ALS are reviewed.
Amyotrophic Lateral Sclerosis↗