A search for a new anticonvulsant and anxiolytic benzodiazepine devoid of side effects and tolerance liability.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
D M Thompson
Publications and source records attributed to D M Thompson.
Imidazenil, a new anxiolytic and anticonvulsant drug, attenuates a benzodiazepine-induced cognition deficit in monkeys.
Imidazenil is a highly potent partial allosteric modulator of gamma-aminobutyric acid action at a great variety of gamma-aminobutyric acid(A) receptors, whereas alprazolam is a full allosteric modulator at these receptors. Data in rats indicate that imidazenil, like alprazolam, has pharmacological effects in animals indicative of anxiolytic, antipanic and anticonvulsant activity in humans, but unlike alprazolam, in animals imidazenil does not produce ataxia, sedation, tolerance or dependence nor does it potentiate the effects of ethanol. To extend the study of the imidazenil pharmacological profile, we administered this drug and alprazolam, alone and in combination, in monkeys working in a complex behavioral task. In one component of a multiple schedule (repeated acquisition or "learning"), patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four discriminative stimuli (geometric forms or numerals). In the other component (performance), the four-response chain was the same each session. The response chain in each component was maintained by food presentation under a fixed-ratio schedule. When alprazolam (0.01-0.32 mg/kg, p.o.) was administered alone, the overall response rate in both learning and performance decreased and the percent errors in both components increased with increasing doses. Learning, however, was more sensitive than performance; i.e., error-increasing effects were seen in learning at doses that had no effect on performance accuracy.(ABSTRACT TRUNCATED AT 250 WORDS)
Alprazolam↗
7-Chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization.
7-Chloro-3-Methyl-3-4-Dihydro-2H-1,2,4 Benzothiadiazine S,S Dioxide (IDRA 21), which attenuates the rapid autodesensitization of DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA)-selective glutamate receptors and increases excitatory synaptic strength, improves cognition (learning and memory), as revealed by its ability to improve performance in water maze and passive avoidance tests in rats. Normal rats trained to (15-20 sec) reach the exit platform rapidly in a water maze that included four incorrect choices were given oral IDRA 21 (4-120 mumol/kg) or vehicle and then exposed to a delayed retention trial in a maze that included seven incorrect choices. In this retention trial, the IDRA 21-treated rats performed considerably better than those that received the vehicle. Moreover, oral IDRA 21 (ED50 = 7.6 microM) attenuated the performance impairment induced by the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline in the water maze test. In this test and in a passive avoidance test, the performance impairment elicited by alprazolam, a full allosteric modulator at gamma-aminobutyric acid-A receptors, or by scopolamine, a competitive muscarinic receptor antagonist, was also reduced by oral administration of IDRA 21 (ED50 = 13 and 108 mumol/kg, against alprazolam and scopolamine, respectively); in all these tests, IDRA 21 was 20- to 30-fold more potent than aniracetam. Because IDRA 21 is a racemic molecule; the two stereoisomers were isolated and studied behaviorally. Only the (+) form was found to be behaviorally active. These results indicate that IDRA 21 given orally to rats presumably crosses the blood-brain barrier and acts stereoselectively on specific receptors that were operative during this behavioral procedure. Because the activity of IDRA 21 on rat cognition tests appears to be related to its ability to potentiate AMPA-activated currents, one can suggest that IDRA 21 improves cognition by acting on a stereoselective site of AMPA receptor that is operative in attenuating the rapid autodesensitization of these receptors.
Alprazolam↗
A new approach to quality.
Explore the source record for details and available documents.
Long-Term Care↗
The EndoA enhancer contains multiple ETS binding site repeats and is regulated by ETS proteins.
EndoA is a type II keratin and with EndoB (type I keratin), constitutes intermediate filaments in various simple epithelial tissues. EndoA is developmentally regulated and has an enhancer that is located at the 3'- end of the gene. This enhancer contains two single and five dual Ets binding sites. Thus far, no other promoter or enhancer has been shown to contain as many potential clustered Ets binding sites. To study the transcriptional regulation of EndoA by the ETS family proteins, we amplified the EndoA enhancer fragment from mouse genomic DNA by PCR, and cloned it into the pBLCAT2 vector upstream from the CAT reporter gene. Several pBLCAT-ENDOA clones were sequenced to verify the presence of all the ETS binding sites. Clones that did not show any point mutations in the ETS binding sites were chosen to study the transcription regulation by ETS1, ETS2 and ERGB/FLI-1 gene products. EMSA results indicated that the ETS1, ETS2 and ERGB/FLI-1 proteins bind to the enhancer sequence, and DNase I protection data demonstrated that the ETS proteins protect all seven EBS core sequences. Cotransfection of the COS cells with the pBLCAT-ENDOA construct, along with increasing amounts of different ETS expression vectors, resulted in a significant induction of CAT reporter gene expression. Previously, we have shown that the overexpression of the ETS1 gene transforms NIH3T3, and these transformed cells (7AQS2.1) produce high levels of ETS1 protein (Seth & Papas, 1990). In this report, we show that the undifferentiated P19 EC cells do not express detectable levels of ETS1; however, an elevated level of ETS1 is expressed in differentiated derivatives of these cells. We therefore used these two cell lines to examine the activity of the EndoA enhancer with the ETS1 product. Transfection of the pBLCAT-ENDOA construct alone in undifferentiated P19 EC cells results in very low CAT gene expression; however, upon differentiation with retinoic acid the level of CAT gene activity increases dramatically. Similarly, an increase in CAT expression from the same construct (pBLCAT-ENDOA) was also observed in 7AQS2.1 cells. Our results therefore indicate that the EndoA enhancer is regulated by ETS proteins via interaction with multiple ETS-binding site sequences.
Animals↗
Congenital cystic hygroma involving the larynx presenting as an airway emergency.
Cystic hygroma is a benign, painless, soft, compressible malformation of the lymphatic system. The head and neck region is the most common place of presentation. These lesions most commonly present shortly after birth with 40% presenting in the newborn period. With the increased use of prenatal ultrasonography, cystic hygromas are being diagnosed in the antenatal period; thus, appropriate measures to secure the airway of the infant can be prearranged prior to birth. This article reports a case where a multispecialty approach was undertaken to assure the survival of an infant born with a large cervical cystic hygroma with laryngeal and base tongue involvement by the tumor. This article also reviews the incidence of laryngeal involvement of cystic hygromas and airway management in the acute period and long term.
Airway Obstruction↗
Tight glucose control results in normal perinatal outcome in 150 patients with gestational diabetes.
OBJECTIVE: To determine whether tight control of blood glucose is associated with normal outcomes in gestational diabetes. METHODS: We studied 150 consecutive patients with gestational diabetes referred to a diabetes in pregnancy clinic. Selection criteria were an abnormal glucose tolerance test, diabetic management by one physician, capillary blood glucose monitoring in the prenatal period, and delivery at Grace Hospital. Degree of glucose control during pregnancy and maternal and perinatal outcomes were determined by chart review. RESULTS: Overall average glucose levels were 4.9 mmol/L (89 mg/dL) before meals and 6.7 mmol/L (122 mg/dL) 1 hour after meals. Thirty-one percent of the patients were treated with insulin in the prenatal period. In this series, there was no perinatal mortality and no increased incidence of large or small for gestational age infants, cesarean delivery, preterm labor, pregnancy-induced hypertension, neonatal respiratory distress, hypoglycemia, polycythemia, symptomatic hyperbilirubinemia, symptomatic hypocalcemia, or congenital malformations. CONCLUSIONS: Tight glucose control is associated with normal perinatal outcome in gestational diabetes.
Adult↗
ETS family proteins activate transcription from HIV-1 long terminal repeat.
ets is a multigene family and its members share a common ETS DNA-binding domain. ETS proteins activate transcription via binding to a purine-rich GGAA core sequence located in promoters/enhancers of various genes, including several that are transcriptionally active in T cells. The ETS1, ETS2, and ERBG/Hu-FLI-1 gene expression pattern also suggests a role for these genes in cells of hematopoietic lineage. The HIV-1 LTR core enhancer contains two 10-base pair direct repeat sequences (left and right) that are required for regulation of HIV-1 mRNA expression by host transcription factors, including NF kappa B. Two ETS-binding sites are present in the core enhancer of all the HIV-1 isolates reported so far. In our studies, we utilized HIV-1 HXB2 and HIV-1 Z2Z6 core enhancers because the Z2Z6 strain has a single point mutation flanking the right ETS-binding site. We demonstrate that the ETS1, ETS2, and ERGB/Hu-FLI-1 proteins can trans-activate transcription from both the HXB2 and Z2Z6 core enhancer when linked to a reporter (cat) gene. In addition, we show that the DNA binding and trans-activation with the Z2Z6 core enhancer is at least 40-fold higher than that observed with the HXB2 core enhancer. Further, we provide evidence that the marked increase in binding and trans-activation with Z2Z6 core enhancer sequences is due to the substitution of a flanking T residue in HXB2 TGGAA) by a C residue in Z2Z6 (CGGAA) isolate, thus generating an optimal ETS-binding core (CGGAA) sequence.
Animals↗
Prolonged desensitization required for treatment of generalized allergy to human insulin.
Explore the source record for details and available documents.
Adult↗
Transactivation of GATA-1 promoter with ETS1, ETS2 and ERGB/Hu-FLI-1 proteins: stabilization of the ETS1 protein binding on GATA-1 promoter sequences by monoclonal antibody.
Ets family proteins activate transcription via binding to the GGAA core sequence located in the promoter/enhancer elements of many cellular and viral genes. GATA-1 is an erythroid-specific transcription factor. The promoter of the chicken GATA-1 gene contains multiple ets binding sites (EBS), two of them are present in palindromic form. The GATA-1 promoter has been shown to be activated by the E26 virus. In this study, we have analysed whether the palidromic EBS of the chicken GATA-1 promoter is a target for binding and activation by members of the cellular ets gene family products. The results herein indicate that both EBS in the palindrome are required for DNA-binding because mutations in either site reduces the activity by at least 95%. Moreover, DNA binding of ETS1 to the EBS palindrome is dramatically stabilized in the presence of a specific monoclonal antibody whose epitope maps between amino acid positions 240-260. Although each of the single sites bind, the efficiency of binding is extremely low. Furthermore, for efficient binding the two sites must be in an inverted configuration because of the fact that the oligonucleotide containing the left and right EBS in the same orientation binds 10-fold less than the oligonucleotide containing the EBS palindrome. Additionally, we show that the transcription of a reporter gene (CAT) either linked to the GATA-1 EBS palindrome or GATA-1 promoter can be activated by cotransfection with ETS1, alternatively-spliced ETS1, ETS2 or ERGB/Hu-FLI-1 expression vectors.
Animals↗
C-ets-1 protooncogene expression alters the growth properties of immortalized rat fibroblasts.
Ets family genes have been cloned and characterized from a variety of species ranging from human to Drosophila. The ets proteins encode transcription factors that activate transcription via specific binding to GGAA core sequence present in various promoter/enhancers. To investigate the role of ets protooncogene expression on the growth properties of rat embryo fibroblasts (REF), we constructed and introduced ets expression vectors into primary, as well as immortalized REF cells. The transfected cells contained multiple copies of the vector DNA, and the Northern blot analysis demonstrated overexpression of the c-ets-1-specific mRNA. Although the expression of the ets genes was unable to immortalize primary rat embryo fibroblasts, the expression of ets-1 in REF-1 cells enabled their growth in serum-free medium and effected tumorigenic activity in nude mice.
Animals↗
Differential interaction of cholecystokinin with morphine and phencyclidine: effects on operant behavior in pigeons.
To extend previous operant research in rats with morphine and cholecystokinin (CCK), these two substances were given alone and in combination to pigeons. In one component of a multiple schedule, responding of pigeons (key pecking) was reinforced under a fixed-ratio (FR 50) schedule of food presentation. In the other component, responding had no programmed consequence (timeout). Each session consisted of four 10-min timeout components alternating with four 5-min FR components. In Experiment 1, cumulative dose-effect curves for morphine were obtained by giving an IM injection before each of four FR components; successive injections increased the cumulative dose by 1/4 log-unit steps. In general, as the cumulative dose of morphine increased, the overall response rate in each FR component decreased. Dose-dependent decreases in response rate also occurred when single noncumulative doses of CCK were administered alone 20 min prior to the start of the session. This effect of CCK alone diminished as the session progressed. When CCK was given as a pretreatment before cumulative doses of morphine, the morphine dose-effect curve for response rate shifted to the left. At intermediate doses of CCK, the "potentiation" was so complete that two of three subjects failed to respond during any of the four FR components (i.e., the dose-effect curve for morphine had shifted approximately 1 log-unit to the left). In order to evaluate the pharmacological specificity of this effect, cumulative doses of phencyclidine were administered in combination with CCK (Experiment 2). Unlike the interaction between morphine and CCK, the interaction between phencyclidine and CCK was reciprocal.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Association between rDNA alleles and quantitative traits in doubled haploid populations of barley.
Doubled haploids (DH) were generated from reciprocal F1 hybrids which were heterozygous for alleles at the Nor-H3 locus on chromosome 5H of barley. The r-DNA alleles did not deviate significantly from the expected 1:1 ratio and the DH progenies were classified into two groups based on the allelic constitution of the Nor-H3 locus. The DHs were grown in a randomized, replicated field experiment and a range of agronomic and quality traits were recorded. The Nor-H3 locus was associated with a significant portion of the genetic variation for: yield, thousand corn weight, water sensitivity and milling energy requirement of the grain. However, the magnitude of the differences between groups was dependent on the direction of the cross. The milling energy requirement of the grain was consistently associated with alleles at the Nor-H3 locus. These results are presented in relation to the dynamics of rDNA evolution and variability. The potential of molecular markers in conjunction with doubled haploids to map quantitative traits in barley is also discussed.
Alleles↗
Degradation products of the mRNA encoding the small subunit of ribulose-1,5-bisphosphate carboxylase in soybean and transgenic petunia.
The degradation of a soybean ribulose-1,5-bisphosphate carboxylase small subunit RNA, SRS4, was investigated in soybean seedlings and in petunia plants transformed with an SRS4 gene construct. Polyacrylamide RNA gel blot, primer extension, and S1 nuclease analyses were used to identify and map fragments of the SRS4 mRNA generated in vivo. We showed that SRS4 mRNA is degraded to a characteristic set of fragments in soybean and transgenic petunia and that degradation is not dependent on position of insertion of the gene construct within the genome, on the expression level of the SRS4 mRNA, or on the rbcS promoter. Degradation products lacked poly(A) tails and fractionated with poly(A)-depleted RNA on oligo(dT)-sepharose columns. These products pelleted with polysomes and were released from polysomes prepared with EDTA. Sequences at the 5' end of the SRS4 mRNA were more stable than those at the 3' end of the mRNA. Three models for SRS4 mRNA degradation involving endonucleolytic and exonucleolytic degradation were presented to explain the origin of the 5' proximal fragments.
Base Sequence↗
The ERGB/Fli-1 gene: isolation and characterization of a new member of the family of human ETS transcription factors.
All cellular ets proteins contain a region of high amino acid identity to those found in the last two exons of the ets-1 gene (C domain). We have identified and characterized a new member of the human ETS gene family, ERGB. The ERGB gene shows extensive amino acid identity to the human ERG and the mouse Fli-1 genes. The ERGB gene is found to be transcriptionally active in a variety of human cell lines and tissues, in contrast to the more restrictive expression pattern of the ERG gene. The ERGB gene encodes for a 3.2-kilobase mRNA containing an open reading frame of 451 amino acids. The ERGB gene, like human ETS1, is located on chromosome 11 and is transposed to chromosome 4 as a result of the translocation t(4;11) associated with leukemia. Pulse-field gel analysis suggests that ETS1 and ERGB are more than 200 kilobases apart. Similar to the other members of the ets family (ets 1, ets 2), this new member is also able to trans-activate transcription of a reporter gene linked to the ETS-binding sequences derived from either the GATA-1 promoter or an optimal Ets-binding site.
Amino Acid Sequence↗
Cocaine self-administration in pigeons.
Pigeons with chronic indwelling intravenous catheters responded under a multiple schedule of food and cocaine presentation. In one component, responding was maintained by food presentation under a fixed-ratio (FR 50) schedule, whereas in the other component, responding was maintained under the same schedule by IV infusions of cocaine (0.03 or 0.1 mg/kg/injection). A 30-s timeout followed each cocaine infusion. Components alternated after 3 presentations of either food or cocaine, and each session was terminated after 18 cocaine infusions or 2 h, whichever occurred first. In general, under baseline conditions, the response rate was higher in the food component than in the drug component. Under control conditions where saline was substituted for cocaine, the response rate gradually decreased across sessions, while food-maintained responding was generally unaffected. Substituting doses lower or higher than the training dose decreased the rate of cocaine-maintained responding. Food-maintained responding only decreased at higher doses of cocaine. When blackout periods were substituted for the food component (Experiment 2), the response rate in the cocaine component decreased and then stabilized at levels well above zero. Saline substitution on this baseline produced a further decrease in the rate of FR responding. In Experiment 3, the effects of pretreatment with haloperidol (0.056 or 0.1 mg/kg) on both food- and cocaine-maintained responding were examined using a multiple schedule similar to that used in Experiment 1. Each dose was given for a period of 7-10 days. In general, haloperidol dose-dependently decreased both the overall rate of cocaine-maintained responding and the percent of available reinforcers obtained, while having little or no effect on food-maintained responding. This research indicates that cocaine can serve as a reinforcing stimulus for maintaining self-administration behavior in pigeons, and that this behavior is sensitive to antagonism by haloperidol.
Animals↗
Transcriptional and post-transcriptional processes regulate expression of RNA encoding the small subunit of ribulose-1,5-biphosphate carboxylase differently in petunia and in soybean.
The effects of white light, far-red light and darkness on the in vitro transcription and RNA levels of the small subunit of ribulose-1,5-bisphosphate carboxylase (rbcS) were investigated in petunia and in soybean. In petunia plants treated with 48 hours of darkness the in vitro transcription rate of two of the rbcS subfamilies of petunia, rbcS A and rbcS C, declined 32- and 8-fold respectively, whereas treatment of dark-adapted plants with light caused the in vitro transcription rate of these subfamilies to return to their light-grown levels. Relative RNA levels of rbcS A and rbcS C declined in parallel with in vitro transcription rate changes upon treatment of petunia plants with darkness. However, while relative RNA levels of rbcS C changed in parallel with in vitro transcription rate under all conditions of far-red light and white light tested, there were differences between the changes in rbcS A in vitro transcription rate and RNA levels which were consistent with post-transcriptional regulation of rbcS A RNA. In addition we observed that nuclei isolated from the leaves of plants which were exposed to darkness for periods of 72 hours or longer were transcriptionally inactive. Similar experiments on the in vitro transcription and relative levels of the rbcS RNA in soybean seedlings have lead to the hypothesis that rbcS RNA is less stable in light than in darkness. In contrast, small decreases in rbcS in vitro transcription rate in mature soybean plants treated with darkness were accompanied by large decreases in rbcS RNA, suggesting that rbcS RNA was degraded more rapidly in darkness than in light in these plants. We have shown that differences in the modulation of rbcS RNA levels by post-transcriptional mechanisms exist between plants which belong to different orders, and between different developmental states of the same plant species.
Gene Expression Regulation↗