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Biomedical subjects

A L Johnson

Publications and source records attributed to A L Johnson.

At least 19 recordsLinked to original sources
PubMed1992

Novel piperidine sigma receptor ligands as potential antipsychotic drugs.

sigma receptor ligands represent a new class of potential antipsychotic drugs. This paper presents the structure-activity relationships leading to novel disubstituted piperidine sigma ligands, which have little or no affinity for dopamine D2 receptors. Selectivity for sigma sites over dopamine D2 or serotonin 5-HT2 receptors appears to be governed by the chemical nature of the piperidine nitrogen substituent, its distance from the basic nitrogen, and its orientation relative to the other piperidine substituent. Several of these compounds have good oral potency in some animal models used to evaluate potential antipsychotic drugs. The N-cyclopropylmethyl ketones and ethers (e.g. 6i (DuP 734), 6q, 18a, and 18n) have the best in vivo potency. Compounds 6i (DuP 734) and 6q did not cause catalepsy in the rat, even at very high doses. On the basis of the pharmacology profiles of these sigma ligands, we propose these compounds may be effective antipsychotic drugs, which do not induce extrapyramidal side effects or tardive dyskinesia.

Animals↗
PubMed1992

SWI6 protein is required for transcription of the periodically expressed DNA synthesis genes in budding yeast.

In budding yeast many genes are expressed under cell-cycle control in late G1. These include a large group of DNA synthesis genes, the HO gene involved in mating-type switching, CTS1 (chitinase) and also CLN1 and CLN2 (ref. 4) encoding G1 cyclins. Two factors, encoded by the SWI4 and SWI6 genes, are required for HO (ref. 5), CLN (refs 6, 7) and CTS1 (ref. 3) gene expression and, at least in the HO promoter, bind to CACGA4 upstream sequences (CCBs). This motif is not found upstream of the DNA synthesis genes, which instead have a hexamer element, ACGCGT1 (MCB), an MluI restriction site, that is recognized by a cell-cycle regulated transcription complex DSC1 (ref. 1). This MluI-activation system consisting of the MCBs and DSC1 is conserved in fission yeast where a DSC1-like complex controls the cdc22+ ribonucleotide reductase gene. The Schizosaccharomyces pombe cdc10+ gene encodes a component of DSC1 (ref. 10) and, significantly, this has homology with both the Swi4 and Swi6 proteins. Here we show that Swi6 is an essential component of DSC1 and that deletion of SWI6 impairs the cell-cycle regulation of the DNA synthesis genes, as well as CLN1 and CLN2. Thus Swi6 is the common factor in regulation of all the above genes and may therefore be responsible for the timing of their expression in late G1.

Base Sequence↗
PubMed1992

Control of DNA synthesis genes in fission yeast by the cell-cycle gene cdc10+.

In the budding yeast Saccharomyces cerevisiae, cell-cycle control over DNA synthesis occurs partly through the coordinate expression in late G1 phase of many, if not all, of the genes required for DNA synthesis. A cis-acting hexamer element ACGCGT (an MluI restriction site) is responsible for coordinating transcriptional regulation of these genes at the G1/S phase boundary and we have identified a binding activity, DSC1, that recognizes these sequences in a cell-cycle-dependent manner. In the distantly related fission yeast Schizosaccharomyces pombe, only one of the known DNA synthesis genes, cdc22+, which encodes a subunit of ribonucleotide reductase, is periodically expressed in late G1 (ref. 6). The promoter region of cdc22+ has two MluI sites and five related sequences, suggesting that similar controls over DNA synthesis genes could occur in fission yeast. We report here a binding activity in fission yeast that is very similar to DSC1 in budding yeast. We also show that the fission yeast cdc10+ gene product, which is required for Start and entry into S phase, is a component of this binding activity.

Alleles↗
PubMed1992

DNA polymerase II, the probable homolog of mammalian DNA polymerase epsilon, replicates chromosomal DNA in the yeast Saccharomyces cerevisiae.

Two temperature-sensitive DNA polymerase II mutants (pol2-9 and pol2-18) of the yeast Saccharomyces cerevisiae were isolated by the plasmid shuffling method. DNA polymerase II activity partially purified from both mutants was thermolabile, while DNA polymerase I and III activities remained thermotolerant. At the restrictive temperature, the pol2 mutants were defective in chromosomal DNA replication and exhibited the dumbbell terminal morphology typical of DNA replication mutants. The POL2 transcript accumulated periodically during the cell cycle, peaking at the G1/S boundary in the same manner as the transcripts of more than 10 other DNA replication genes. These results indicate that DNA polymerase II participates in nuclear DNA replication. The similarities in structure and activities between the DNA polymerases of yeast and mammals make it likely that mammalian DNA polymerase epsilon too is required for chromosomal DNA replication.

Amino Acid Sequence↗
PubMed1992

Treatment of growth deformities with external skeletal fixation.

Growth deformities of the long bones are usually caused by premature closure of the physis. The most commonly affected bones are the radius, ulna, and tibia. Premature closure of the physis can result in shortened, angular, and rotational bone deformities, especially when one bone of a paired bone system like the radius and ulna is affected. Adjacent joints may develop osteoarthritis. Corrective osteotomy to realign in joint surfaces is indicated in mature animals. Bilateral or type II external fixation frames are used to stabilize the osteotomies. The advantages of ESF are: (1) The transfixation pins can be used as guide pins to realign joints. (2) The fixation allows rigid stabilization of the osteotomy site. (3) Postoperative correction of alignment can be achieved. (4) Implant removal after bone union is simple.

Animals↗
PubMed1992

Rationale for the chemical development of angiotensin II receptor antagonists.

The renin-angiotensin system (RAS) has been demonstrated to be a key element in blood pressure regulation and fluid volume homeostasis. Since angiotensin II (AII) is the effector molecule of the RAS, the most direct approach to block this system is to antagonize AII at the level of its receptor. Therefore, at Du Pont Merck the working hypothesis has been that the identification of metabolically stable and orally effective AII-receptor antagonists would constitute a new and superior class of agents useful in treating hypertension and congestive heart failure. Our program began with a detailed pharmacologic evaluation of some simple N-benzylimidazoles, originally described by Takeda Chemical Industries in Osaka, Japan. They were found to be a series of weak but selective AII-receptor antagonists with a competitive mode of action. We embarked on a program aimed to design and synthesize more potent and orally effective nonpeptide antagonists, while attempting to preserve their selective affinity for the AII receptor. The first major breakthrough in our efforts to increase the potency of these compounds came with the development of a series of N-benzylimidazole phthalamic acid derivatives. Although effective at lowering blood pressure when administered intravenously, the phthalamic acids were devoid of oral activity. The first orally active AII antagonists came with the discovery of the biphenyl carboxylic acids. Although these compounds are absorbed after oral dosing, their bioavailability was less than desired. In the hope of improving the oral absorption of these biphenyls, we investigated a variety of acidic groups as bioisosteric replacements for the carboxylic acid. The key to the discovery of nonpeptide AII-receptor antagonists with improved oral activity and duration of action resulted from replacing the carboxylic acid group with the isosteric but more lipophilic tetrazole ring. Hence, our efforts culminated in the discovery of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt), a highly potent angiotensin type 1 (AT1) selective receptor antagonist with a long duration of action. Losartan is currently undergoing clinical investigation for the treatment of hypertension. The history, including the rationale for the design of the compounds, and ensuing structure-activity relationships of losartan and related analogs will be described. Many of the newer compounds exceed the potency of losartan, and the best compounds in the series rival the affinity of the endogenous ligand, AII, for its receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin II↗
PubMed1992

Plasminogen activator activity and thymidine incorporation in avian granulosa cells during follicular development and the periovulatory period.

The hormonal and second messenger regulation of plasminogen activator (PA) activities in avian granulosa and theca cells has been documented. However, the physiological role(s) of PAs in the avian ovary remains poorly understood. The present studies were designed to evaluate PA activity in hen granulosa cells collected from the most mature (F1) preovulatory follicle at three discrete time points relative to a spontaneous ovulation and from follicles collected at various stages of follicular development. Levels of PA activity in the granulosa layer of the F1 follicle declined by greater than 90% as follicles were collected closer to their anticipated time of ovulation (e.g., from 17-16 h to 0.75-0.15 h; p less than 0.05). Timing of tissue collection was confirmed by evaluation of serum progesterone levels, which peaked as expected at the 6-5-h time point. During follicular development, PA activity was several times greater in rapidly growing follicles (6-12 mm, 1-3 wk prior to ovulation) than in slowly growing (1-5 mm) or preovulatory (F3 and F1) follicles (p less than 0.05). Granulosa cells of these rapidly growing follicles also incorporated significantly higher levels of 3H-thymidine than did granulosa cells of mature follicles (p less than 0.05), suggesting a higher level of DNA synthesis. Similarly, granulosa cells of the mitotically active germinal disc region of the F1 granulosa layer were found to possess at least 3-fold higher (p less than 0.05) levels of PA activity and a 2-fold greater level of 3H-thymidine incorporation than the more mature granulosa cells isolated from the remaining F1 granulosa layer.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Do prophylactic anticonvulsant drugs alter the pattern of seizures after craniotomy?

A total of 276 patients with a high risk of developing postoperative seizures were randomised to treatment with carbamazepine or phenytoin for six or 24 months, or to no treatment. No significant differences were found (though the confidence limits were fairly wide) between the regimes in respect of the incidence of seizures or death. In a substantial proportion of the patients postoperative epilepsy remained a continuing disability. A high incidence of drug-related side effects was found in the treatment groups. Prophylactic anticonvulsants cannot therefore be recommended routinely following supratentorial craniotomy.

Actuarial Analysis↗
PubMed1992

Effects of gonadotropin-releasing hormone infused in a pulsatile or continuous fashion on serum gonadotropin concentrations and ovulation in the mare.

Studies were conducted to compare continuous vs pulsatile i.v. infusion of GnRH on serum gonadotropin concentrations and ovulation in seasonally anestrous mares and in cycling mares. Anestrous mares (Exp. 1) received no treatment (control; n = 3), 2, or 20 micrograms of GnRH/h continuous infusion (CI) (n = 4 and n = 6, respectively), or 20 micrograms of GnRH/h pulsatile infusion (PI) (n = 5). After initiation of GnRH infusion, serum LH levels increased earlier, and to a greater extent, in the PI group than in other groups (P less than .05). In contrast, serum FSH concentrations did not differ among groups. The number of days to development of the first 35-mm follicle was not different among GnRH treatment groups; however, mares receiving PI ovulated on d 9.4 of treatment, 2.8 d earlier than those receiving 20 micrograms of GnRH/h CI (P less than .05). Mares given 2 micrograms of GnRH/h CI failed to ovulate spontaneously after 16 d of treatment, but each one ovulated within 2 to 4 d after injection of 2,000 IU of hCG on d 16. Control mares did not ovulate or show any significant follicular development throughout the experiment. Cycling mares (Exp. 2) received no treatment (control; n = 6), 20 micrograms of GnRH/h CI, or 20 micrograms of GnRH/h PI (n = 4) beginning on d 16 of an estrous cycle (d 0 = day of ovulation). Serum LH concentrations in all groups increased after initiation of treatment; however, on the day of ovulation LH concentrations were lower in the CI group than in the PI or control groups (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

Zinc-induced molt: evidence for a direct inhibitory effect on granulosa cell steroidogenesis.

Results from previous studies indicate that the use of dietary zinc may provide an effective means to initiate an induced molt in laying hens. Although much evidence indicates that high concentrations of zinc (10,000 to 20,000 ppm) cause the cessation of lay primarily by depressing feed intake, recent data suggest that lower concentrations (2,800 ppm) in a calcium-deficient diet may act via a direct action on the ovary. Therefore, a series of in vitro studies was conducted to evaluate whether zinc can affect granulosa cell progesterone production. Incubation of granulosa cells from the largest preovulatory (F1) follicle with zinc as zinc sulfate (.1 to 10 microM) had no effect on basal progesterone production. By contrast, ovine luteinizing hormone-stimulated progesterone production was inhibited (P less than .05) in a dose-related fashion by zinc in both the sulfate and acetate forms (1 to 10 microM). Furthermore, zinc attenuated oLH- and forskolin-induced cyclic adenosine monophosphate (cAMP) formation, and inhibited 8-bromo-cAMP- and calcium ionophore (A23187)-induced progesterone production. Such results indicate both pre- and post-cAMP sites of action for zinc's inhibitory actions on progesterone production in F1 granulosa cells. Finally, ovine follicle-stimulating hormone-stimulated cAMP accumulation and progesterone production in granulosa cells collected from 9- to 12-mm follicles (a stage of development representing the early, rapid growth phase) were suppressed (P less than .05) by co-incubation of cells with zinc.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1992

Molt induced by dietary zinc in a low-calcium diet.

Three experiments were designed to test the hypothesis that zinc has a specific effect independent of anorexia during induction of molt. In Experiment 1, hens were fed a low-calcium (.08%) basal molt diet to which was added 0, 110, 620, or 1,120 mg/kg (ppm) zinc as zinc sulfate heptahydrate (ZnSO4.7H2O) for 7 days and 0, 1, 400, 2,800, or 4,200 ppm zinc, respectively, for the following 14 days. In Experiment 2, hens were provided ad libitum access to the low-calcium basal molt diet with 2,800 ppm added zinc for 14 days during which a paired control hen received a similar amount of the low-calcium basal molt diet. In Experiment 3, hens were fed the low-calcium basal molt diet on a restricted basis amended with either 0 or 2,800 ppm zinc on a restricted basis for 10 days. In Experiment 1, all hens that consumed zinc had significantly fewer days to last oviposition as compared with control hens, and this occurred without significant differences in body weight or feed consumption for the lowest zinc group. When compared with the control group, higher levels of zinc did decrease body weight and feed consumption. In Experiment 2, the hens consuming the diet with 2,800 ppm zinc (Zn2800) reached last oviposition significantly sooner than control hens, although the Zn2800 hens actually consumed more feed. In Experiment 3, the Zn2800 hens lost more body weight than control hens due partially to earlier reproductive tract regression. Serum luteinizing hormone was increased in the Zn2800 hens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cloning DPB3, the gene encoding the third subunit of DNA polymerase II of Saccharomyces cerevisiae.

DNA polymerase II purified from Saccharomyces cerevisiae contains polypeptides with apparent molecular masses of greater than 200, 80, 34, 30 and 29 kDa, the two largest of which (subunits A and B) are encoded by the essential genes POL2 and DPB2. By probing a lambda gt11 expression library of yeast DNA with antiserum against DNA polymerase II, we isolated a single gene, DPB3, that encodes both the 34- and 30-kDa polypeptides (subunit C and C'). The nucleotide sequence of DPB3 contained an open reading frame encoding a 23-kDa protein, significantly smaller than the observed molecular masses, 34- or 30-kDa, which might represent post-translationally modified forms of the DPB3 product. The predicted amino acid sequence contained a possible NTP-binding motif and a glutamate-rich region. NTP-binding motif and a glutamate-rich region. A dpb3 deletion mutant (dpb3 delta) was viable and yielded a DNA polymerase II lacking the 34- and 30-kDa polypeptides. dpb3 delta strains exhibited an increased spontaneous mutation rate, suggesting that the DPB3 product is required to maintain fidelity of chromosomal replication. Since a fifth, 29-kDa polypeptide was present in DNA polymerase II preparations from wild-type cell extracts throughout purification, the subunit composition appears to be A, B, C (or C and C') and D. The 5' nontranscribed region of DPB3 contained the MulI-related sequence ACGCGA, while the 0.9-kb DPB3 transcript accumulated periodically during the cell cycle and peaked at the G1/S boundary. The level of DPB3 transcript thus appears to be under the same cell cycle control as those of POL2, DPB2 and other DNA replication genes. DPB3 was mapped to chromosome II, 30 cM distal to his7.

Amino Acid Sequence↗
PubMed1991

Coordination of expression of DNA synthesis genes in budding yeast by a cell-cycle regulated trans factor.

All of the DNA synthesis genes of budding yeast examined so far are periodically expressed and hence under cell-cycle control (Table 1). Expression occurs near the G1/S phase boundary and the genes seem to be coordinately regulated (reviewed in ref. 4). The upstream promoter sequences of these genes have only a hexamer element, ACGCGT (an MluI restriction site), in common. Here we show that this hexamer is able to impart periodic expression to a heterologous gene and, significantly, this expression occurs coincidentally with that of CDC9, one of the DNA synthesis genes (Table 1). We have also identified a protein that binds specifically to these sequences in a similar periodic manner. These ACGCGT sequences and the transcription factor that binds to them therefore seem to be the elements controlling both the periodic expression and coordinate regulation of the DNA synthesis genes.

Cell Cycle↗
PubMed1991

The yeast DNA ligase gene CDC9 is controlled by six orientation specific upstream activating sequences that respond to cellular proliferation but which alone cannot mediate cell cycle regulation.

By fusing the CDC9 structural gene to the PGK upstream sequences and the CDC9 upstream to lacZ, we showed that the cell cycle expression of CDC9 is largely due to transcriptional regulation. To investigate the role of six ATGATT upstream repeats in CDC9 regulation, synthetic copies of the sequence were attached to a heterologous gene. The repeats stimulated transcription strongly and additively, but, unlike conventional yeast UAS elements, only when present in one orientation. Transcription driven by the repeats declines in cells held at START of the cell cycle or in stationary phase, as occurs with CDC9. However, the repeats by themselves cannot impart cell cycle regulation to a heterologous gene. CDC9 may therefore be controlled by an activating system operating through the repeats that is sensitive to cellular proliferation and a separate mechanism that governs the periodic expression in the cell cycle.

Base Sequence↗
PubMed1991

Plasma uric acid in patients receiving anticonvulsant monotherapy.

In newly diagnosed adult patients with epilepsy followed prospectively on monotherapy, carbamazepine and phenytoin were associated with a fall in plasma uric acid, but sodium valproate and phenobarbitone were associated with a rise in plasma uric acid. The mechanisms and significance of these findings are discussed.

Adolescent↗