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Biomedical subjects

R L Johnson

Publications and source records attributed to R L Johnson.

At least 109 records · Page 6Linked to original sources
PubMed1996

Modulation of dopaminergic neurotransmission in the 6-hydroxydopamine lesioned rotational model by peptidomimetic analogues of L-prolyl-L-leucyl-glycinamide.

Melanocyte stimulating hormone release inhibiting factor (MIF-1), also known as L-prolyl-L-leucyl-glycinamide (PLG), has previously been found to have the ability to modulate dopamine D2-receptor agonist binding both in the striatum and limbic regions. In the present study the 6-hydroxydopamine unilateral lesion model of apomorphine-induced rotational behaviour, in Wistar rats, was used to assess the dopaminergic modulatory activity of PLG and two novel analogues, L-prolyl-L-prolyl-L-prolinamide (analogue A) and (2S, 5R, 7R)-1-Aza-7[3'(S)-1-(2',5'-dioxo-pyrrolidino[2,1-c]piperazino++ +)] -8-oxo-4-thiabicyclo[3.30]octane-2-carboxamide (analogue B). PLG and the two novel analogues showed a bell-shaped dose-response relationship, suggesting that analogue A, B and PLG all manifest their effect through a similar mechanism and exhibit a window of therapeutic efficacy. Analogue A was a 100 times, while analogue B was 10 times, more potent than PLG in increasing the contralateral rotational response when given in combination with apomorphine. Analogue A was also more efficacious than PLG or analogue B at increasing apomorphine-induced contralateral rotations. Intrastriatal administration of either analogue A or B resulted in a greater increase in apomorphine-induced rotations than the most efficacious intraperitoneally delivered dose. The results of the present study suggest that PLG and its two novel analogues are able to modulate dopamine receptor activity and may be possible therapeutic agents for the treatment of Parkinsonian symptoms as well as tardive dyskinesia.

Animals↗
PubMed1996

Human homolog of patched, a candidate gene for the basal cell nevus syndrome.

The basal cell nevus syndrome (BCNS) is characterized by developmental abnormalities and by the postnatal occurrence of cancers, especially basal cell carcinomas (BCCs), the most common human cancer. Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene. The ptc gene encodes a transmembrane protein that in Drosophila acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues. The human PTC gene appears to be crucial for proper embryonic development and for tumor suppression.

Adult↗
PubMed1996

Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog.

The signaling protein Hedgehog (Hh) controls cell fate and polarizes tissues in both flies and vertebrates. In flies, Hh exerts its effects by opposing the function of a novel transmembrane protein, Patched, while also locally inducing patched (ptc) transcription. We have identified a mouse homolog of ptc which in many tissues is transcribed near cells making either Sonic or Indian hedgehog. In addition, ectopic Sonic hedgehog expression in the mouse central nervous system induces ptc transcription. As in flies, mouse ptc transcription appears to be indicative of hedgehog signal reception. The results support the existence of a conserved signaling pathway used for pattern formation in insects and mammals.

Amino Acid Sequence↗
PubMed1996

Cost of traumatic spinal cord injury in a population-based registry.

This prospective study examines a population based cohort of 115 Coloradans identified as having an acute traumatic spinal cord injury by the Spinal Cord Injury Early Notification System in 1989. Comprehensive medical cost and complication data were collected for the first 2 years of survival. Unlike previous cost studies, this group represents the broad spectrum of spinal cord injured persons, reflected in a truly population based sample. Nearly 22 million dollars were spent during the first 2 years post injury on behalf of these Coloradans. Care provided to the 27 persons with Frankel A, B or C tetraplegia accounted for $10.9 million (50%); $7.6 million (35%) was spent providing care for the 36 people with Frankel A, B or C paraplegia; and the remaining $3.3 million (15%) was required for services provided to the 52 persons who had resolved to either Frankel D or E at acute care discharge. Of the $6.3 million that was spent post hospital discharge, $2.5 million (39%) is directly attributable to in-home care, and another $2.0 million (32%) is directly attributable to secondary medical complications. The most expensive complications occurred in the neurological, skin, respiratory and orthopedic body systems.

Colorado↗
PubMed1996

Monoclonal origin of localised orbital amyloidosis detected by molecular analysis.

AIMS: Primary localised orbital amyloidosis is a rare disease. The purpose of this study was to describe two cases of primary orbital amyloidosis and emphasise the value of molecular analysis of immunoglobulin gene rearrangement in identifying a monoclonal population of cells responsible for the amyloid production. METHODS: Charts and biopsy specimens of each case were reviewed. Conventional light microscopy, immunohistochemistry, and polymerase chain reaction (PCR) analysis for immunoglobulin gene rearrangement were performed in both cases. RESULTS: An unusual presentation of localised primary amyloidosis with bilateral and extensive enlargement of multiple extraocular muscles was seen in case 1. The presence of amyloid deposits was confirmed by biopsy in both cases. Evidence of a monoclonal population of plasma cells was shown by immunohistochemical analysis in case 2 only. The monoclonal origin of the cells responsible for the amyloid deposition was determined by PCR analysis demonstrating immunoglobulin heavy chain gene rearrangement in both cases. CONCLUSIONS: A monoclonal population of plasma cells responsible for the amyloid deposition was present in these two cases. PCR analysis is extremely helpful in determining monoclonality, a finding that may have important therapeutic and prognostic implications.

Adult↗
PubMed1996

A modified rebreathing technique using an infrared gas analyzer.

To lower the cost and improve accessibility of the rebreathing technique for measuring cardiopulmonary function during exercise, we implemented a fast-response infrared (IR) gas-analyzer system to simultaneously measure lung diffusing capacity, cardiac output lung tissue volume, and lung volume by a rebreathing technique in five healthy subjects at rest and during steady-state exercise. Interferences by water vapor and CO2 on the analyzer were determined and corrected for. During rebreathing, a gas mixture of 0.4% C2H2-0.3% CH4-9% He-30% O2, and either 0.3% C18O or 0.3% C16O in a balance of N2 was simultaneously sampled by both a mass spectrometer and the IR analyzer, permitting paired comparisons. Measurements obtained by the two devices were not significantly different. We conclude that this modified rebreathing technique using the IR analyzer is accurate for the measurement of cardiopulmonary function at rest and during exercise.

Adult↗
PubMed1996

Conservation in hedgehog signaling: induction of a chicken patched homolog by Sonic hedgehog in the developing limb.

Hedgehog genes have been implicated in inductive signaling during development in a variety of organisms. A key element of the hedgehog signaling system is encoded by the gene patched. In Drosophila hedgehog regulates gene expression by antagonizing the action of patched. In addition, patched is itself a transcriptional target of hedgehog signaling. We have isolated a chicken patched homolog and find it to be strongly expressed adjacent to all tissues where members of the hedgehog family are expressed. As in Drosophila, ectopic expression of Sonic hedgehog leads to ectopic induction of chicken Patched. Based on this regulatory conservation, vertebrate Patched is likely to be directly downstream of Sonic hedgehog signaling. An important role of Sonic hedgehog is the regulation of anterior/posterior pattern in the developing limb bud. Since Patched is directly downstream of the hedgehog signal, the extent of high level Patched expression provides a measure of the distance that Sonic hedgehog diffuses and directly acts. On this basis, we find that Sonic hedgehog directly acts as a signal over only the posterior third of the limb bud. During limb patterning, secondary signals are secreted in both the mesoderm (e.g. Bone Morphogenetic Protein-2) and apical ectodermal ridge (e.g. Fibroblast Growth Factor-4) in response to Sonic hedgehog. Thus knowing which is the direct target tissue is essential for unraveling the molecular patterning of the limb. The expression of Patched provides a strong indication that the mesoderm and not the ectoderm is the direct target of Sonic hedgehog signaling in the limb bud. Finally we demonstrate that induction of Patched requires Sonic hedgehog but, unlike Bone Morphogenetic Protein-2 and Hox genes, does not require Fibroblast Growth Factor as a co-inducer. It is therefore a more direct target of Sonic hedgehog than previously reported patterning genes.

Animals↗
PubMed1996

Spatial regulation of a zebrafish patched homologue reflects the roles of sonic hedgehog and protein kinase A in neural tube and somite patterning.

Signalling by members of the Hedgehog family of secreted proteins plays a central role in the development of vertebrate and invertebrate embryos. In Drosophila, transduction of the Hedgehog signal is intimately associated with the activity of protein kinase A and the product of the segment polarity gene patched. We have cloned a homologue of patched from the zebrafish Danio rerio and analysed the spatiotemporal regulation of its transcription during embryonic development in both wild-type and mutant animals. We find a striking correlation between the accumulation of patched1 transcripts and cells responding to sonic hedgehog activity both in the neurectoderm and mesoderm, suggesting that like its Drosophila counterpart, patched1 is regulated by sonic hedgehog activity. Consistent with this interpretation, mis-expression of sonic hedgehog results in ectopic activation of patched1 transcription. Using dominant negative and constitutively active forms of the protein kinase A subunits, we also show that expression of patched1 as well as of other sonic hedgehog targets, is regulated by protein kinase A activity. Taken together, our findings suggest that the mechanism of signalling by Hedgehog family proteins has been highly conserved during evolution.

Amino Acid Sequence↗
PubMed1996

Sonic hedgehog regulates patterning in early embryos.

Recently, a new family of genes, homologues of the Drosophila segment polarity gene hedgehog, has been cloned in vertebrates. One of them, Sonic hedgehog, is expressed in tissues that are known to be inductive centres for patterning early embryos, implicating Sonic hedgehog as an important signal in development. Functional experiments have demonstrated that Sonic hedgehog acts as a signalling molecule in patterning the anterior-posterior axis of the limb. By misexpression of Sonic hedgehog we show that Sonic hedgehog induces expression of Hoxd genes, known to be involved in patterning of the anterior-posterior axis of the limb, and Bmp-2, which might act as a secondary signal. We also demonstrate that Sonic hedgehog is not sufficient for these inductions. In fact, a signal from the mesoderm, Sonic hedgehog, and a signal from the ectoderm, Fgf-4, are required for the induction of Hoxd genes and Bmp-2.

Animals↗
PubMed1995

A molecular pathway determining left-right asymmetry in chick embryogenesis.

While significant progress has been made in understanding the molecular events underlying the early specification of the antero-posterior and dorso-ventral axes, little information is available regarding the cellular or molecular basis for left-right (LR) differences in animal morphogenesis. We describe the expression patterns of three genes involved in LR determination in chick embryos: activin receptor IIa, Sonic hedgehog (Shh), and cNR-1 (related to the mouse gene nodal). These genes are expressed asymmetrically during and after gastrulation and regulate the expression of one another in a sequential pathway. Moreover, manipulation of the sidedness of either activin protein or Shh expression alters heart situs. Together, these observations identify a cascade of molecular asymmetry in that determines morphological LR asymmetry in the chick embryo.

Activins↗
PubMed1995

Modulation of N-methyl-D-aspartate (NMDA) antagonist-induced darting behaviour by the peptidomimetic PAMTA.

The N-Methyl-D-Aspartate (NMDA) receptor has attracted much attention in recent years due to its involvement in both the functions and dysfunctions of CNS neurotransmission. The existence of multiple sites by which NMDA receptor channel function can be pharmacologically modified and the interaction between glutamate and other neurotransmitter systems such as dopamine, provide exciting therapeutic avenues for related CNS disorders. In the present study, a novel synthetic analogue of the endogenous brain peptide L-prolyl-L-leucyl glycinamide (PLG) has demonstrated a significant modulatory action on the NMDA receptor. On the basis of radioligand binding studies, the novel synthetic peptide 5-[1(S)-(2(S)-pyrrolidinylcarbonyl)amino-3-methylbutyl]-2- tetrazolylacetamide (PAMTA) has been suggested to act at a polyamine site on the NMDA receptor complex. Scatchard analysis of [3H]MK-801 binding revealed that in the presence of 100 microM PAMTA, a single binding site was obtained with the Kd being increased from 2.5 +/- 0.2 nM to 6.2 +/- 0.1 nM. The ability of PAMTA to inhibit the binding of [3H]MK-801 was sensitive to the presence of both spermidine (polyamine agonist) and arcaine (polyamine antagonist). Analyses of the binding profiles of various NMDA receptor antagonists support PAMTA's interaction with the polyamine site on this receptor complex. Furthermore, we have investigated the behavioural profile of the peptidomimetic PAMTA, by studying its effect on stereotypic behaviours induced by the NMDA receptor antagonist, CPP (3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid). Male Sprague-Dawley rats cannulated bilaterally into the medial prefrontal cortex were injected with PAMTA, CPP, a CPP/PAMTA combination, or a saline control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Determinants of postnatal weight in infant rhesus monkeys: implications for the study of interindividual differences in neonatal growth.

This paper provides an analysis of infant body weights obtained from a sample of 38 rhesus monkey infants (Macaca mulatta) aged 29-165 days, i.e., animals still nutritionally dependent on their mothers. We examine the data on neonatal weights in relation to a number of factors, most notably, the sex of the infants, and the age and adiposity of their mothers. The infant body weights represent cross-sectional rather than longitudinal data; because they were mostly free-ranging animals, the infants were weighted just once each. Nevertheless, the results of our analysis strongly suggest that early postnatal growth in free-ranging rhesus is dependent on both maternal fatness and age. They also suggest that, although male infants are generally heavier than like-aged female infants, they do not grow any faster during the early postnatal period. Here, we speculate that the associations between infant size and both maternal age and adiposity are the result of between-mother differences in lactational output.

Adipose Tissue↗
PubMed1995

Fetal acoustic stimulation, an adjunct to external cephalic version: a blinded, randomized crossover study.

OBJECTIVE: Our purpose was to determine whether fetal acoustic stimulation can improve the chance of successful external cephalic version in patients at 36 to 38 weeks' gestation with fetal midline spine position. STUDY DESIGN: A randomized, blinded crossover trial was performed. In this "N of 1" study, the patient served as her own control. RESULTS: Twenty-six patients were enrolled in the study, and three were excluded due to engagement of the fetal breech. In the initial trial with fetal acoustic stimulation to the maternal abdomen, 12 of 12 (100%) changed position to spine lateral and 11 of 12 (92%) were successfully verted. In the control group (fetal acoustic stimulation to nurse's arm), none of 11 (0%) changed position to spine lateral and one of 11 (9%) were successfully verted (p < 0.0001). In the crossover trial eight of 10 (80%) of the original placebo (control) patients were successfully verted after fetal acoustic stimulation to the maternal abdomen and none of 1 (0%) from the original treatment group were successfully verted after placebo fetal acoustic stimulation (p < 0.0001). Combined data from the original and crossover trials indicates 19 of 22 (86%) successful versions after fetal acoustic stimulation to maternal abdomen compared with one of 12 (8%) that had successful external cephalic version after placebo fetal acoustic stimulation. CONCLUSION: Fetal acoustic stimulation shifts fetal position to spine lateral, which increases successful version of fetuses with midline fetal spine presentations.

Acoustic Stimulation↗
PubMed1995

Effects of quisqualic acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus.

L-Glutamic acid (L-Glu) and L-aspartic acid (L-Asp) activate several receptor subtypes, including metabotropic Glu receptors coupled to phosphoinositide (PI) hydrolysis. Quisqualic acid (Quis) is the most potent agonist of these receptors. There is evidence that activation of these receptors may cause a long lasting sensitization of neurons to depolarization, a phenomenon called the Quis effect. The purpose of the current studies was to use Quis analogs and the recently identified metabotropic receptor antagonist, (+)-alpha-methyl-4-carboxy-phenylglycine((+)-MCPG), to define the structural properties required for interaction with the metabotropic receptors coupled to PI hydrolysis and to determine if the Quis effect is mediated by these receptors. The effects of Quis analogs on PI hydrolysis were studied in the absence or presence of the metabotropic receptor-specific agonist 1SR,3RS-1-amino-1,3-cyclopentanedicarboxylic acid (1SR,3RS-ACPD) in neonatal rat hippocampus. Some of the compounds that induce the Quis effect also stimulate PI hydrolysis, including Quis itself and 9 (homoquisqualic acid). Not all of the Quis analogs that stimulate PI hydrolysis, however, induce the Quis effect, including 7A (EC50 = 750 +/- 150 microM) and (RS)-4-bromohomoibotenic acid (BrHI) (EC50 = 130 +/- 40 microM). Although (+)-MCPG blocked PI hydrolysis stimulated by Quis (IC50 = 370 +/- 70 microM), it had no effect on the induction of the Quis effect. Other Quis analogs did not stimulate PI hydrolysis but rather blocked the effects of 1SR,3RS-ACPD. The IC50 values were 240 +/- 70 microM for 2, 250 +/- 90 microM for 3, and 640 +/- 200 microM for 4. Data for inhibition by 2 and 3 were consistent with non-competitive mechanisms of action. These studies provide new information about the structural features of Quis required for interaction with metabotropic receptors coupled to PI hydrolysis and provide evidence that the Quis effect is not mediated by (+)-MCPG sensitive subtypes of these receptors.

ATP-Binding Cassette Transporters↗
PubMed1995

Utilization and effectiveness of methylprednisolone in a population-based sample of spinal cord injured persons.

The announcement and publication of the second National Acute Spinal Cord Injury Study (NASCIS II) project's findings regarding the role of high dose methylprednisolone in improving neurological outcomes following acute traumatic spinal cord injury generated widespread excitement and interest. To determine the association between this interest and actual use and implementation of the protocol, Colorado's comprehensive population-based spinal cord injury surveillance data were examined. The medical records of 218 SCI survivors injured between May 1, 1990 and December 31, 1991, and of 145 persons spinal cord injured 2 years later, during 1993, were reviewed to determine the rapidity and extent of NASCIS II implementation by Colorado's hospitals, factors associated with use and non-use of the protocol, changing usage trends over time, and the short term neurological outcomes of patients who received the protocol. Clear documentation of the protocol's usage was present for only 46% of the reported patients' medical records in 1990-91, and 61% in 1993. Small, emergency triage facilities were significantly more likely to use the protocol than larger acute care hospitals, and patients with initially incomplete injuries were less likely to receive the drug. There were no significant differences in neurological outcomes, using the Frankel classification system, between those who received the protocol and those who did not. The limitations and implications of these findings are discussed.

Humans↗
PubMed1995

The risk of mortality among older adults over an eight-year period.

Mortality risks over an 8-year period are assessed among the 7,527 older adults interviewed as part of the Longitudinal Study on Aging. Using a modified version of the behavioral model, hierarchical methods are used to sequentially introduce the predisposing and enabling characteristics, disease history, disabilities and functional limitations, perceived health, and health services utilization both at and after baseline. Based on their partial r statistics (shown in parentheses), the proportional hazard analyses identify the mean annual number of hospital episodes after baseline (.13), age (.07), female gender (-.05), non-kin social supports (-.03), body mass (-.03), and having a history of diabetes (.03) as the six most salient predictors. These six variables account for 80% of the overall model fit.

Activities of Daily Living↗