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Biomedical subjects

R G Smith

Publications and source records attributed to R G Smith.

At least 127 records · Page 7Linked to original sources
PubMed1996

The AII amacrine network: coupling can increase correlated activity.

Retinal ganglion cells in the cat respond to single rhodopsin isomerizations with one to three spikes. This quantal signal is transmitted in the retina by the rod bipolar pathway: rod-->rod bipolar-->AII-->cone bipolar-->ganglion cell. The two-dimensional circuit underlying this pathway includes extensive convergence from rods to an AII amacrine cell, divergence from a rod to several AII and ganglion cells, and coupling between the AII amacrine cells. In this study we explored the function of coupling by reconstructing several AII amacrine cells and the gap junctions between them from electron micrographs; and simulating the AII network with and without coupling. The simulation showed that coupling in the AII network can: (1) improve the signal/noise ratio in the AII network; (2) improve the signal/noise ratio for a single rhodopsin isomerization striking in the periphery of the ganglion cell receptive field center, and therefore in most ganglion cells responding to a single isomerization; (3) expand the AII and ganglion cells' receptive field center; and (4) expand the "correlation field". All of these effects have one major outcome: an increase in correlation between ganglion cell activity. Well correlated activity between the ganglion cells could improve the brain's ability to discriminate few absorbed external photons from the high background of spontaneous thermal isomerizations. Based on the possible benefits of coupling in the AII network, we suggest that coupling occurs at low scotopic luminances.

Animals↗
PubMed1996

Variations in the clinical sulcus depth of healthy human gingiva: a longitudinal study.

Evidence is currently lacking that sulcus depths of fully erupted teeth remain unchanged in the presence of excellent oral hygiene and absence of overt gingival inflammation. In 44 healthy volunteers (age range 16-34 yr) exhibiting the above criteria, sulcus probing depths (PD) were measured with a flexible measuring strip at 6 mesio-buccal (MB) and 6 bucco-cervical (BC) sites on 6 occasions spanning a total period of 20 weeks. Analysis of the data obtained showed that PD had a total range of 0.5-4.5 mm, varying greatly between subjects, although each had a personally characteristic distribution of PD across different sites. Mean depths of MB sites and variations were greater than at BC sites. Fluctuations at BC sites may, however, be no more than measurement error whereas those at MB sites may be real, or may reflect the greater difficulty of access to MB sites than to BC ones.

Adolescent↗
PubMed1996

Anatomic variation of extrahepatic biliary tree structures: importance in treatment planning for radiation therapy.

PURPOSE: To demonstrate the variable location of biliary tree components and to assess two treatment planning rules of thumb used for locating porta hepatic nodes for radiation therapy. MATERIALS AND METHODS: The distance of the common hepatic duct bifurcation and duodenal papilla from adjacent vertebral bodies was measured on 34 cholangiograms, and their relationships to particular vertebral body levels were recorded. Adequacy of treatment volume to encompass porta hepatic lymph nodes was evaluated in 30 of these cholangiograms by constructing radiation portals according to the two rules of thumb. RESULTS: Location of the common hepatic duct bifurcation and duodenal papilla varied widely. The treatment portal encompassed 13% (four of 30) of cases when the first rule of thumb was used and 80% (24 of 30) of cases when the second rule of thumb was used. CONCLUSION: The wide variability of location of extrahepatic biliary tree structures suggests the need for individualized treatment planning so that sensitive and dose-limiting healthy tissues can be optimally excluded from radiation treatment portals. Computed tomography and other imaging modalities enable precise location of biliary tree components for radiation treatment planning.

Ampulla of Vater↗
PubMed1996

Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice.

The thiazolidinediones are novel insulin sensitizers that serve as orally active antidiabetic agents, in rodents, nonhuman primates, and man. We have examined the effects of 4-week oral administration of three thiazolidinediones (AD-5075, BRL 49653, and CS-045) on plasma glucose and triglyceride concentrations in obese hyperglycemic db/db mice. All three agents lower plasma glucose and triglyceride concentrations. Normal levels of glucose are achieved after treatment with AD-5075 (> 1.7 mg/kg) or BRL 49653 (> or = 30 mg/kg), whereas CS-045 (100 or 300 mg/kg) produces only modest reductions in either parameter. Although the thiazolidinediones have demonstrated insulin-sensitizing activities both in vivo and in vitro, their primary molecular target has been unclear. We have compared the in vivo antidiabetic actions described above with the in vitro activities on peroxisomal proliferator-activated receptor-gamma (PPAR gamma). Hamster PPAR gamma 1 was transiently expressed in COS-1 cells to study the binding of [3H]AD-5075. The concentrations of compounds needed to displace radiolabeled AD-5075 from PPAR gamma correlate with their in vivo potency; the Ki values for displacement by cold AD-5075, BRL 49653, and CS-045 are 22, 68, and 1600 nM, respectively. To examine activation of the receptor, it was transiently cotransfected into COS-1 cells with a reporter plasmid containing two copies of a peroxisome proliferator response element. The EC50 values for activation are 2, 6, and 140 nM for AD-5075, BRL 49653, and CS-045, respectively. We have also analyzed limited proteolytic digests of in vitro translated hamster PPAR gamma. The thiazolidinediones produce a conformational change in PPAR gamma analogous to those produced by agonists of other nuclear hormone receptors. In the presence of saturating concentrations of either AD-5075 or BRL 49653, a receptor fragment of 27 kDa is protected from proteolysis by trypsin. These data support the conclusion that the antidiabetic actions of the thiazolidinediones are directly mediated through binding to PPAR gamma and the resulting active conformation of the receptor. Therefore, binding and transactivation assays using PPAR gamma should serve to identify other novel therapeutic agents with potential antidiabetic activities.

Animals↗
PubMed1996

Growth hormone (GH) and insulin-like growth factor I responses after treatments with an orally active GH secretagogue L-163,255 in swine.

L-163,255 is a potent orally active spiropiperidine GH secretagogue. When administered iv or orally, L-163,255 caused GH to be increased in a dose-related manner, with a return to baseline by 90 min. After iv administrations of saline and L-163,255 at 1, 3, and 10 micrograms/kg, GH areas under the curves (GH AUCs) over 120 min were 377 +/- 136, 1151 +/- 413 (P < 0.05), 795 +/- 413 (P = NS), and 1770 +/- 416 ng.min/ml (P < 0.01), and peak GH concentrations were 8 +/- 3, 16 +/- 7 (P = NS), 17 +/- 5 (P = NS), and 43 +/- 12 ng/ml (P < 0.01), respectively. No changes in plasma cortisol concentrations were noted. After oral administrations at 3, 10, and 30 micrograms/kg, GH AUCs over 180 min were 1133 +/- 154, 1246 +/- 129 (P = NS), and 1551 +/- 210 ng.min/ml (P = NS), and peak GH concentrations were 7 +/- 2, 11 +/- 3 (P = NS), and 23 +/- 6 ng/ml (P < 0.01), respectively. After administration in feed, L-163,255 caused a dose-related increase in GH, with an initial peak observed at 60 min for both 30 and 300 micrograms/kg dose groups, and remained elevated above baseline through 180 min for the high dose group only. GH AUCS for 180 min posttreatment were 929 +/- 134 and 1897 +/- 244 ng.min/ml, and peak GH concentrations were 9 +/- 2 and 22 +/- 4 ng/ml for the 30 and 300 micrograms/kg doses prepared in 150 g feed, respectively. When provided in feed ad libitum over the 72-h period, mean plasma insulin-like growth factor I levels increased 15%, 62% (P < 0.01), and 109% (P < 0.01) in the untreated, treated with L-163,255 at 360 ppm, or treated with porcine somatotropin groups, respectively. Repeated iv administration of L-163,255 at 1 mg/kg once daily over 14 days resulted in an initial marked GH response, followed by a much reduced, but significantly elevated, GH response over the saline control values on subsequent treatment days. Repeated iv treatments with L-163,255 also resulted in an elevated insulin-like growth factor I level (approximately 60%) over that in saline controls. Compared to those in saline controls, plasma cortisol concentrations tended to be increased after the initial dose of L-163,255, but no significant increases were noted on days 7 and 14 in the L-163,255 group. The results of these studies indicate that L-163,255 is an orally active GH secretagogue suitable for long term efficacy studies in swine.

Administration, Oral↗
PubMed1996

Functional STAT 1 and 3 signaling by the leptin receptor (OB-R); reduced expression of the rat fatty leptin receptor in transfected cells.

The leptin receptor (OB-R) bears homology to members of the class I cytokine receptor family. We demonstrate that leptin binding to OB-R stimulates formation of STAT-1 and STAT-3 complexes, thereby defining transcriptional motifs for genes that are under leptin control. Transfected fa OB-R bound leptin with equal affinity to that of wild type OB-R. fa OB-R abundance was about 7 fold reduced compared to control cells. Surprisingly, the low level of fa OB-R is fully capable of activating the STAT signal transduction pathway. We discuss plausible explanations for the obese phenotype in Zucker fatty rats.

Animals↗
PubMed1996

Identification of a new G-protein-linked receptor for growth hormone secretagogues.

The potential application of small molecules in GH therapy has recently become a topic of increasing interest. The spiroindoline MK-0677, the benzolactam L-692,429, and the peptides, GHRP-6 and hexarelin, have been shown to possess potent and selective GH-secretory activity in several species including human. Moreover, these synthetic GH secretagogues act on a signal transduction pathway distinct from that of GHRH. A specific high affinity binding site in porcine and rat anterior pituitary membranes that mediates the activity of these secretagogues has now been identified. The binding affinity of these structurally diverse secretagogues is tightly correlated with GH-secretory activity. The binding is Mg(2+)-dependent, is inhibited by GTP-gamma-S, and is not displaced by GHRH and somatostatin. The receptor is distinct from that for GHRH and has the properties of a new G-protein-coupled receptor. It is speculated that these GH secretagogues mimic an unidentified natural hormone that regulates GH secretion in concert with GHRH and somatostatin.

Animals↗
PubMed1996

Autoimmunity and ALS.

Significant evidence has accrued suggesting that antibodies to voltage-gated calcium channel are observed in at least some patients with sporadic ALS (SALS) and that such antibodies alter the function of these ion channels in vitro and in vivo. Further, passive transfer of these immunoglobulin-containing fractions into mice produces changes at the neuromuscular junction that are very similar to changes observed in patients with SALS. These changes reflect local alterations in intracellular Ca2+ homeostasis and, in animal models, may also evidence early changes of motoneuron injury, such as Golgi apparatus swelling and fragmentation. Although not yet documented to induce motoneuron death in vivo, SALS immunoglobulins induce Ca(2+)-dependent apoptosis in a differentiated motoneuron hybrid cell line via a mechanism that involves oxidative injury. SALS immunoglobulin-mediated apoptosis in these cells is regulated by the presence of the same calcium-binding proteins that may modulate selective motoneuron vulnerability in SALS.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585.

To investigate the effect of hypophyseal transection (HST) on GH secretagogue activity of the non-peptidyl GH secretagogue L-692,585 in the conscious pig, male castrated swine were randomly assigned to either a hypophyseal stalk transection group (HST; n = 3) or to a sham-operated control group (SOC; n = 3). Treatments administered were L-692,585 (100 micrograms/kg), human GH-releasing factor(1-29)NH2 (GRF; 20 micrograms/kg) or L-692,585 (100 micrograms/kg) + GRF (20 micrograms/kg) on days -7 to -3 before surgery and days +3 to +8 after surgery. To evaluate the integrity of the pituitary gland, the animals were challenged with corticotropin-releasing hormone (CRH; 150 micrograms) or GnRH (150 ng/kg) both before and after surgery. Blood was collected from -60 to +180 min post treatment and assayed for GH, cortisol and LH. Before surgery, no significant difference (P > 0.05) in peak GH response (ng/ml) was present between the two groups (SOC vs HST) in response to L-692,585 (101 +/- 12 vs 71 +/- 9) or L-692,585 + GRF (171 +/- 21 vs 174 +/- 21). Only two out of three SOC vs three out of three HST pigs responded to GRF (13 +/- 2 vs 25 +/- 3) resulting in a significant difference between groups. Following surgery, significant differences were present in peak GH response (ng/ml) between SOC and HST groups following L-692,585 (79 +/- 6 vs 13.8 +/- 1.0); however, the response to L-692,585 + GRF was similar (115 +/- 8 vs 94 +/- 7). All animals responded to GRF; however, a significant difference was present between groups due to the magnitude of the responses. Whereas the cortisol responses (ng/ml) to L-692,585 in the SOC and HST groups were similar before surgery, a significant difference was present after surgery (44.4 +/- 6.4 vs 14.6 +/- 2.1). No significant difference was noted between the HST and SOC groups in response to CRH or GnRH either before or after surgery. These results indicated that L-692,585 induced an immediate GH response in the intact animal in contrast to GRF where the GH release was variable. L-692,585 also stimulated an immediate increase in cortisol levels. Transection of the hypophyseal stalk dramatically decreased but did not ablate the GH or cortisol response to L-692,585. Co-administration of L-692,585 + GRF induced an immediate GH response of similar magnitude in the intact and HST animal. We conclude that L-692,585 has a direct but limited action at the level of the pituitary and that an intact hypophyseal stalk is required for a maximal GH and cortisol response. L-692,585 acts with GRF at the level of the pituitary to induce a maximal GH response. These findings suggest that L-692,585 stimulates GH secretion by acting in combination with GRF and interrupting the inhibitory tone of somatostatin on the somatotroph.

Animals↗
PubMed1996

Self-restraint as positive reinforcement for self-injurious behavior.

Many individuals who engage in self-injurious behavior (SIB) also exhibit self-restraint. We compared rates of SIB exhibited by a 32-year-old woman diagnosed with profound retardation across conditions in which access to restraint was (a) continuously available, (b) presented as a consequence for SIB, or (c) unavailable. Rates of SIB increased when access to restraint was contingent upon SIB and decreased when restraint was unavailable, suggesting that self-restraint functioned as positive reinforcement for SIB.

Adult↗
PubMed1996

Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland.

Hormone replacement should provide a serum hormone profile similar to that found in normal physiology. This is generally impractical because hormones are usually released episodically and therefore require frequent administration. However, rather than replacing the hormone directly, in theory, one could administer a mimic or amplifier of the pulse generator that controls pulsatile release of the particular hormone. Using growth hormone (GH) as a paradigm we sought such a mimetic that would provide episodic GH release when administered by the oral route. A GH secretagogue MK0677, is described that has these ideal properties; following oral administration MK0677 amplifies episodic GH release. Mechanistically, it synergizes with growth hormone releasing hormone (GHRH) through a receptor and signal transduction pathway distinct from that of GHRH and is a functional antagonist of somatostatin (SRIF). MK0677 also acts on the arcuate nucleus and appears to stimulate GHRH release. By using 35S-MK0677, a new G-protein coupled receptor for MK0677 was characterized in the plasma membrane fraction of pituitary and hypothalamic tissue. The receptor is present in very low abundance and couples to phospholipase C. Other ligands selective for this receptor also cause synchronization of well-defined pathways leading to GH release. Repeated oral treatment of dogs once daily with MK0677 initiates amplified pulsatile GH release accompanied by increases in IGF-1 that are sustained. The unique biological properties of MK0677 and other synthetic ligands that bind to the same receptor force us to predict that these ligands mimic a naturally occurring hormone that regulates pulsatile GH release. Understanding the regulatory mechanisms involved in this paradigm has broad implications for the control of pulsatile rhythms in the endocrine system.

Amino Acid Sequence↗
PubMed1996

Calbindin D28K forms a Ca(2+)-dissociable complex with mellitin in vitro.

Calbindin D28K (CB), a cytosolic calcium binding protein (CBP), forms a macromolecular complex with the polypeptide mellitin (ME) the absence of calcium, which can be reversibly dissociated by the addition of Ca2+. The molar ratio of CB:ME constituted in this complex is 1:4, suggesting that CB interacts with the tetrameric form of ME. Like free tetrameric ME, the CB:ME complex does not migrate into 15% non-denaturing polyacrylamide electrophoretic gels, although both constituents migrate normally after irreversible complex denaturation by heating in sodium dodecyl sulphate (SDS). The interaction of these two proteins can be distinguished from the association of calmodulin (CM) with ME, which forms a reversibly dissociable, equimolar complex in the presence of Ca2+ and a stable non-migrating complex (molar ratio = 1:12) in its absence. Thus, CB and CM appear to bind ME under different Ca2+ regulatory control, suggesting possible roles for CB as a Ca(2+)-dependent regulatory binding protein.

Animals↗
PubMed1996

Bridge to transplantation with the CardioWest total artificial heart: the international experience 1993 to 1995.

BACKGROUND: After reapproval by the Food and Drug Administration of the CardioWest total artificial heart for clinical investigation, an international study was started in January 1993 to ascertain the safety and efficacy of this device for bridging to heart transplantation. To date, 40 devices have been implanted in five centers. METHODS: Retrospective data collection from participating centers provided enough material for analysis of patient selection, patient survival, adverse events, and comparison with contemporary devices used for bridge to transplantation. RESULTS AND CONCLUSIONS: Twelve patients (30%) died after implantation and before transplantation after an average of 10.6 +/- 10 days of support. The major cause of death in this group was multiorgan failure. Twenty-eight patients (70%) were supported 36 +/- 36 days before transplantation. There were two deaths after transplantation (1 rejection, 1 multiorgan failure) leaving 26 patients (65% of the total patients and 93% of those who were transplanted) who survived to discharge from the hospital. There was one late death from rejection at one month post discharge. The mean survival time of the 25 surviving patients is 12 months. These results compare favorably with those of other contemporary devices used for bridge to transplantation.

Adult↗
PubMed1995

Induction of c-fos mRNA in the arcuate nucleus of normal and mutant growth hormone-deficient mice by a synthetic non-peptidyl growth hormone secretagogue.

We have studied by in situ hybridization histochemistry the mRNA expression of the c-fos immediate early gene in the brains of wild type and dwarf(dw/dw) and little(lit/lit) mutant mice after systemic injections of the synthetic GH secretagogues GHRP-6 and L-163,191. Both GH secretagogues induced a marked c-fos mRNA expression in the arcuate-ventromedial hypothalamus (ARC-VMH) of both control and mutant mice indicating a possible action on growth hormone releasing hormone (GHRH) neurones in the ARC-VMH. Both dw/dw and lit/lit mice showed a 5-fold elevation in GHRH mRNA expression in the ARC-VMH compared with control animals under basal conditions. Since lit/lit mice have a reduced ability to secrete GH and lack a functional GHRH receptor while dw/dw mice lack both GH and presumably GHRH receptors, the GH-secretagogue-induced c-fos mRNA in the brain of these mutants are unlikely to be mediated by an indirect action of GH or a interaction of the synthetic GH-secretagogue with the GHRH receptor.

Animals↗
PubMed1995

Cell death induced by beta-amyloid 1-40 in MES 23.5 hybrid clone: the role of nitric oxide and NMDA-gated channel activation leading to apoptosis.

The molecular events associated with beta-amyloid-induced neuronal injury remain incompletely characterized. Using a substantia nigra/neuroblastoma hybrid cell line (MES 23.5) synthetic beta-amyloid 1-40 induced a time and dose-dependent apoptotic cell death which was characterized by cell shrinkage and fragmentation of DNA, and was inhibited by aurintricarboxylic acid (ATA), and cycloheximide (CHX). Following beta-amyloid 1-40 treatment, cyclic GMP, an index of NO synthesis, was increased in MES 23.5 cells. The NO scavenger hemoglobin, as well as the NO synthase inhibitors NG-monomethyl-L-arginine acetate (L-NMMA) and L-N5-(1-iminoethyl)ornithine hydrochloride (L-NI0) attenuated such increases. These same inhibitors and scavengers also significantly prevented cytotoxicity. beta-Amyloid also induced an early and transient increase in intracellular calcium as monitored with laser scanning confocal microscopy and Fluo-3 imaging. These induced calcium transients could be significantly blocked by the N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801. Pretreatment with MK-801 or removal of extracellular Ca2+ also reduced beta-amyloid-induced NO production and neurotoxicity. Furthermore, beta-amyloid neurotoxicity was greatly enhanced in the absence of Mg2+ or in the presence of glutamate or NMDA. These data suggest that beta-amyloid can lead to apoptotic cell death through a NO mediated process possibly triggered by Ca2+ entry through activated NMDA-gated channels.

Amyloid beta-Peptides↗
PubMed1995

Does activation of the TAL1 gene occur in a majority of patients with T-cell acute lymphoblastic leukemia? A pediatric oncology group study.

Almost 25% of patients with T-cell acute lymphoblastic leukemia (T-ALL) have tumor-specific rearrangements of the TAL1 gene. Although TAL1 expression has not been observed in normal lymphocytes, TAL1 gene products are readily detected in leukemic cells that harbor a rearranged TAL1 allele. Hence, it has been proposed that ectopic expression of TAL1 promotes the development of T-ALL. In this report, we show that TAL1 is expressed in the leukemic cells of most patients with T-ALL, including many that do not display an apparent TAL1 gene alteration. A polymorphic dinucleotide repeat in the transcribed sequences of TAL1 was used to determine the allele specificity of TAL1 transcription in primary T-ALL cells. Monoallelic expression of TAL1 was observed in the leukemic cells of all patients (8 of 8) bearing a TAL1 gene rearrangement. In the leukemic cells of patients without detectable TAL1 rearrangements, TAL1 transcription occurred in either a monoallelic (3 of 7 patients) or a biallelic (4 of 7 patients) fashion. Thus, TAL1 activation in these patients may result from subtle alterations in cis-acting regulatory sequences (affecting expression of a single TAL1 allele) or changes in trans-acting factors that control TAL1 transcription (affecting expression of both TAL1 alleles).

Alleles↗