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Clinical distinctions between long-acting and short-acting benzodiazepines.

After their clinical introduction in the 1960s, the benzodiazepines rapidly became the most widely prescribed sedative/hypnotics because of their many advantages over barbiturates and other older agents. Along with this popularity came controversy, which has continued to this day. The most recent form this has taken has been the concern that the short-acting benzodiazepines may have a predisposition to induce certain forms of clinical complications. The author reviews the historical framework in which this controversy arose. In the late 1970s and early 1980s, it became increasingly clear that long-acting agents were associated with daytime sedation as well as cognitive and psychomotor impairment, particularly in the elderly. The short-acting benzodiazepines, which greatly reduced the frequency of these types of effects, rapidly became the most widely prescribed agents. A growing body of data indicates that the short-acting hypnotics are less likely to be associated with falls and hip fractures in the elderly and also have less respiratory depressant qualities, compared with the older long-acting agents. The short-acting compounds may also be more efficacious in inducing sleep during the first night of administration. In contrast, the long-acting agents may be more desirable in those cases in which daytime sedation is desired and may be associated with a delayed and milder withdrawal sleep disturbance. With the short-acting agents, however, sleep disturbance upon drug cessation is dose dependent and may be greatly reduced by tapering the dose.

Accidental Falls

Stability and reproducibility of the biologic activity of premixed short-acting and intermediate-acting insulins.

Mixtures of short-acting and intermediate-acting insulins often represent an effective regimen to achieve near-normal blood glucose values, yet controversy exists concerning the stability and predictability of such mixtures. In a study of diabetic patients, the biologic activity of a specific intermediate-acting insulin (insulatard) and a short-acting insulin (Velosulin) premixed in a 70:30 ratio was reproducible at three intervals and was stable for a period of up to three months. The serum levels of free insulin and the rate of onset and extent of the blood glucose lowering effects were not altered, showed two distinct peaks, and were comparable to those experienced with separate injections of equivalent doses of the intermediate-acting and short-acting insulins.

Adult

Delayed-type hypersensitivity initiation by early-acting cells that are antigen mismatched or MHC incompatible with late-acting, delayed-type hypersensitivity effector T cells.

The elicitation of delayed-type hypersensitivity (DTH) responses in mice is mediated by the sequential activities of two different Ag-specific, Thy-1+ cells. A required early phase of elicitation is due to DTH-initiating Thy-1+ cells that are CD3- and sIg- and produce Ag-specific factors that act like IgE antibodies in that they sensitize the tissues, so that after local challenge with Ag there is release of the vasoactive amine serotonin. Released serotonin locally recruits and activates CD4+ Th-1 classical DTH effector T cells that secrete lymphokines that attract and activate a nonspecific perivascular infiltrate of circulating, bone marrow-derived leukocytes. The current study used isolated subpopulations of DTH-initiating and DTH-effector T cells to determine whether the two phases of the elicitation of DTH were entirely separate. The contact sensitivity model of DTH was used. Early-acting DTH-initiating cells, and late-acting DTH-effector T cells were either from oxazolone (OX)-immune or picryl chloride (PCl)-immune CBA or BALB/c donors and were transferred to CBA or BALB/c recipients. The results showed that DTH-initiation could be mediated by polyclonal DTH-initiating cells that were Ag mismatched or MHC incompatible with late-acting DTH effector T cells. In fact DTH-initiating cells could be both Ag mismatched and MHC incompatible with late-acting T cells. In addition, potential interactions between different cell populations were ruled out by showing that DTH-initiation could be mediated by a DTH-initiating clone that was Ag or MHC mismatched with the late-acting DTH-effector T cells. Thus, the OX-specific BALB/c clone could initiate DTH for PCl-specific CBA cells in CBA recipients if the recipients were challenged with both OX and PCl, but not when they were challenged with OX or PCl alone. We suggest, at least for the elicitation of DTH reactions in mice, that a more comprehensive description of these responses should accommodate the fact that there are early and late phase responses that each begin with Ag specificity and end with non-specific humoral factors. Inasmuch as the two Thy-1+ cells of DTH can be of different Ag specificity, this suggests that some forms of delayed and chronic inflammation, might be initiated by an immediate hypersensitivity-like immune reactivity to one set of Ag, and could be prolonged and perpetuated by delayed reactivity to another set of Ag.

Animals

The extrachromosomal replication of Dictyostelium plasmid Ddp2 requires a cis-acting element and a plasmid-encoded trans-acting factor.

Dictyostelium discoideum plasmid Ddp2 from the wild strain WS380B is a 5.8-kilobase (kb) supercoiled circle with a copy number of 300 per haploid genome. We previously described the construction of an extrachromosomally replicating transformation vector pnDeI carrying 4.7 kb of Ddp2 sequences (B. Leiting, and A. Noegel, Plasmid 20:241-248, 1988). In order to reduce the sequences required for extrachromosomal maintenance in D. discoideum, we characterized Ddp2 by sequence analysis, by deletion experiments, by transcription mapping, by electrophoretic mobility shift assays, and by expression of its single open reading frame in Escherichia coli. Two elements were involved in replication of Ddp2: a cis-acting sequence located on a 592-base-pair (bp) fragment that consisted of 220 bp of essential and 372 bp of auxiliary sequences, and a 2.7-kb open reading frame which most likely encodes a trans-acting factor. The cis- and trans-acting elements did not overlap and were shown to act independently from the location of the sequences encoding the trans-acting factor.

Amino Acid Sequence

Hypochondriasis, acting out and counter-acting out.

The clinical picture of hypochondriasis is clear, the psychopathological structure less so. Hypochondriasis is characterized by a particular kind of acting out, basically medical, which in turn is likely to evoke medical counter-acting out on the part of the therapist. Acting out may be 'broad', as a character trait, and 'narrow', in close connection with the psychotherapeutic process. The medical acting out of the hypochondriac, 'broad' prior to therapy and occurring outside of the therapy situation, in the course of therapy becomes 'narrow' and contained within the boundaries of therapy.

Acting Out

Improved phenotyping of alpha 1-antichymotrypsin (ACT) by isoelectric focusing and immunoprinting: first demonstration of a deficient protein variant in the ACT system.

Genetic variation of human alpha 1-antichymotrypsin (ACT) was investigated in sera using thin-layer polyacrylamide gel isoelectric focusing (pH range 4.0-6.5) followed by immunoprinting with a monospecific anti-human ACT antibody. Sialidase-treated samples showed a microheterogeneous banding pattern which consisted of two major and several additional minor components with isoelectric points between pH 5.0 and 5.3. A population study of 200 unrelated individuals from southern Germany revealed no genetic variation. In a clinical investigation, however, we found a unique banding pattern in a female patient suffering from chronic obstructive pulmonary disease. In comparison with the monomorphic normal type the detected variant phenotype shows two additional bands that have lower intensities and are located cathodically to their major bands. Inheritance of the deficient IEF variant "ACT Bochum" was confirmed by a family study. To our knowledge this is the first genetic ACT mutant to be observed at the protein level.

Female

Regulation of plant genes specifically induced in nitrogen-fixing nodules: role of cis-acting elements and trans-acting factors in leghemoglobin gene expression.

Transgenic alfalfa plants harboring a gene fusion between the soybean leghemoglobin (lbc3) promoter region and the chloramphenicol acetyl transferase (cat) gene were used to determine the influence of rhizobial mutants on lb gene expression in nodules. The promoter region of the Sesbania rostrata glb3 (Srglb3) leghemoglobin gene was examined for the presence of conserved motifs homologous to binding site 1 and 2 of the soybean lbc3 promoter region, found to interact with a trans-acting factor present in soybean nodule nuclear extracts (Jensen EO, Marcker KA, Schell J, de Bruijn FJ, EMBO J 7:1265-1271, 1988). Subfragments of the S. rostrata glb3 (Srglb3) promoter region were examined for binding to trans-acting factors from nodule nuclear extracts. In addition to the binding sites previously identified (Metz BA, Welters P, Hoffmann HJ, Jensen EO, Schell J, de Bruijn FJ, Mol Gen Genet 214: 181-191), several other sites were found to interact with trans-acting factors. In most cases the same trans-acting factor(s) were shown to be involved. One fragment (202) was found to bind specifically to a different factor (protein) which was extremely heat-resistant (100 degrees C). The appearance of this factor was shown to be developmentally regulated since the expected protein-DNA complexes were first observed around 12 days after infection, concomitant with the production of leghemoglobin proteins. Fragments of the Srglb3 5' upstream region were fused to the beta-glucuronidase reporter gene with its own CAAT and TATA box region or those of the cauliflower mosaic virus 35S and nopaline synthase (nos) promoters.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence

The pharmacokinetics of two different concentrations of short-acting insulin, intermediate-acting insulin, and an insulin mixture following subcutaneous injection.

To compare the pharmacokinetics of two different concentrations, containing either 40 or 100 IU/ml of short-acting human insulin (Velasulin HM), intermediate-acting human insulin (Insulatard HM), or an insulin mixture (25% short-acting insulin, 75% intermediate-acting insulin; Mixtard HM), three randomized, single-blind, crossover trials were performed using the euglycemic clamp technique. Eighteen healthy volunteers received insulin of either formulation subcutaneously in each of the studies (15 IU Velasulin, 20 IU Insulatard, or Mixtard). The blood glucose levels were maintained constant by glucose infusions. In the trial using Velasulin, the two different insulin concentrations were equivalent regarding the total absorption [area under the curve (AUC) of serum insulin: 126 +/- 28 and 123 +/- 35 mU/l x 12 h for U40 and U100 (mean +/- SD)], but not in regard to the rate of absorption (t max 1.3 +/- 0.4 and 2.4 +/- 1.0 h for U40 and U100). In the case of Insulatard, total absorption was not equivalent (AUC 153 +/- 35 and 128 +/- 37 ml/l x 24 h for U40 and U100), but the rate of absorption was equivalent (t max 4.8 +/- 2.9 and 5.3 +/- 4.6 h). In the Mixtard series, total absorption was equivalent (AUC 142 +/- 32 and 128 +/- 22 mU/l x 24 h), but the rate of absorption was not (t max 2.2 +/- 0.9 and 3.2 +/- 4.2 h for U40 and U100). The glucose requirement was not equivalent in each of the three series.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

The use of long-acting gonadotropin-releasing hormone agonist (GnRH-a; decapeptyl) and gonadotropins versus short-acting GnRH-a (buserelin) and gonadotropins before and during ovarian stimulation for in vitro fertilization (IVF).

The efficiency of two ovarian stimulation protocols using different gonadotropin-releasing hormone agonists (GnRH-a) for in vitro fertilization (IVF) was examined and compared with human menopausal gonadotropin (hMG)-only stimulation. Fifty-four patients who had 57 aspiration cycles were treated with protocol 1, which consisted of long-acting GnRH-a D-Trp6 (Decapeptyl Depot) and hMG. Protocol 2 entailed intranasal administration of short-acting GnRH-a (Buserelin) and human menopausal gonadotropin (hMG) in 66 women who underwent 70 aspiration cycles. Fifty-five patients who had 59 ovum pickups (OPU) treated with hMG only served as a control. No differences were observed in cycle parameters and hormonal concentrations among the three groups. The total clinical pregnancy rates per OPU for patients receiving protocols 1 and 2 were 12.3 and 27.1%, respectively (P less than 0.05). The pregnancy loss was significantly lower in protocol 2 than in protocol 1 (26.3 versus 71.4%; P less than 0.05). Our data show superiority of short-acting GnRH-a over the long-acting agents in achievement of pregnancy and its outcome, though neither was significantly different from the hMG-only protocol.

Adult

[Comparison of a long-acting and short-acting GnRH analog in combination with gonadotropins in in vitro fertilization under various indications].

The occurrence of a premature luteinizing hormone (LH)-surge during gonadotropin stimulation for in-vitro fertilization leads to cancellation of the cycle. Moreover, insufficient follicular maturation is often caused by elevated basal gonadotropin levels. Therefore the gonadotropin releasing hormone (GnRH) agonist, D-TRP6-LHRH, was applied to patients exhibiting premature LH-surges, hyperandrogenemia or incipient premature menopause. 119 cycles were treated, using a long-acting versus a short-acting GnRH agonistic analogue. In protocol 1, patients received daily subcutaneous injections of 100-500 micrograms of a short-acting compound. In protocol 2, a long-acting bolus of 3.2 mg was given intramuscularly. Concomitant human gonadotropin (HMG) stimulation started in protocol 1 after clinical and biochemical evidence of pituitary suppression and in protocol 2 after a fixed suppression interval of 14 days. In protocol 1 higher estrogen levels were reached with more oocytes harvested. The pregnancy rate per transfer was increased from 3.5% to 18%, with most pregnancies occurring with protocol 2. The cancellation rate of 13.4% was mainly due to insufficient follicular development in patients, in whom premature menopause was suspected. Hyper-androgenemic patients with an elevated LH/FSH-ratio exhibited the best follicular recruitment with the highest pregnancy rate of 25% per transfer. Thus combined GnRH-agonist/gonadotropin stimulation offers a causal treatment for patients susceptible to premature LH-surges and for hyperandrogenemic patients.

Adult

Comparative efficacy of short-acting and long-acting quinidine for maintenance of sinus rhythm after electrical conversion of atrial fibrillation.

Forty patients with chronic atrial fibrillation, apparently unrelated to any overt heart disease, were randomly allocated to two groups after restoration of sinus rhythm by direct current shock. The patients in group A were given 4 daily doses of quinidine polygalacturonate, while those in group B were given 2 daily doses of a long-acting quinidine preparation, quinidine arabogalactan sulphate. The percentage of early relapses (within the first month following DC shock) was not significantly different in the two groups: 44-4% in group A and 35% in group B (P greater than 0-50). On the other hand, there were fewer late relapses with long-acting quinidine. After 18 months of treatment, 27-8% of patient in group A remained in sinus rhythm, compared with 61% in group B (P less than 0-05). The average amount of quinidine actually ingested by the patients in group A was smaller than that in group B. However, this could not entirely account for the difference observed in the incidence of relapse since with short-acting quinidine the proportion of patients remaining in sinu rhythm was similar whether the dose was decreased or not. The incidence of gastrointestinal side-effects was the same in the two groups and there were no seriou complications that could be attributed to treatment. It is concluded that long-acting quinidine preparations are more effective than conventional quinidine in preventing late relapses of atrial fibrillation.

Aged

Assessment of antianginal efficacy of long-acting sustained release isosorbide dinitrate in comparison with short-acting isosorbide dinitrate.

A quadruple blind randomized cross-over study evaluated the therapeutic efficacy of twice a day long acting sustained release isosorbide dinitrate (SRISDN) in comparison with 4 times daily of the short acting isosorbide dinitrate in 18 patients with stable angina pectoris (NYHA class II-III) with a positive exercise treadmill test. The antianginal effect of sustained release isosorbide dinitrate (SRISDN) (exercise duration 472.61 +/- 112.49 sec and anginal episodes per week (1.33 +/- 1.18) was not significantly different (p less than 0.05) when compared to conventional isosorbide dinitrate (exercise duration 468.33 +/- 135.28 sec and anginal episodes per week 1.55 +/- 104). Twice a day long acting sustained release isosorbide dinitrate is as effective as four times a day conventional short acting isosorbide dinitrate. Such a regimen is likely to lead to a better patient compliance and ease of antianginal therapy.

Adult

Double-blind placebo cross-over study of long-acting (chlordesmethyldiazepam) versus short-acting (lorazepam) benzodiazepines in generalized anxiety disorders.

Chlordesmethyldiazepam a long-acting benzodiazepine was compared with lorazepam a short-acting one in a double-blind placebo cross-over study against generalized anxiety disorders. Chlordesmethyldiazepam therapy was more effective than lorazepam. Clinical efficacy, drowsiness and insomnia seem well correlated with pharmacokinetic properties of these two benzodiazepines. These results further support the use of a long-acting benzodiazepine rather than a short-acting one as an anti-anxiety agent.

Adult

cis-acting sequences and trans-acting factors required for constitutive expression of a microinjected HSP70 gene after the midblastula transition of Xenopus laevis embryogenesis.

Microinjected human HSP70 promoter-chloramphenical acetyl transferase (CAT) chimeric genes are constitutively expressed immediately after the midblastula transition of Xenopus embryogenesis. Analysis of a series of 5'-deletion mutants in the HSP70 promoter revealed that sequences within 74 bases of the transcriptional start site were sufficient for strong basal activity. We investigated the role of specific sequences in the basal promoter by injecting HSP70-CAT vectors containing linker-scanner mutations in the basal elements (CCAAT, purine-rich element, GC-element, ATF/AP1, and TATA). Our data reveal that deletion of any of these cis-acting elements in the basal promoter prevents expression after the midblastula stage of development. Furthermore, we have identified specific binding activities in embryonic nuclear extracts that complex with basal promoter elements (CCAAT, ATF, and GC) of the heterologous HSP70 promoter. These trans-acting factors are detectable in nuclear extracts of early blastula embryos, and their respective binding activity increases dramatically after the midblastula transition. The expression of the human HSP70 gene after the midblastula transition of Xenopus embryogenesis requires an array of cis-acting elements, which interact with specific Xenopus transcription factors.

Animals

Short-acting versus long-acting benzodiazepines: discontinuation effects in panic disorders.

An increasing body of evidence suggests that benzodiazepines--which have long been considered the drugs of choice in the treatment of various anxiety disorders due to their relative lack of side effects, lack of adverse drug reaction, their safety, and increased efficacy over other agents--are effective in the treatment of panic disorders. Originally, the benzodiazepines were believed to be devoid of dependence-inducing properties, even at high doses. Recent evidence, however, suggests that discontinuation of both high and normal doses of both short- and long-acting benzodiazepines generally results in similar withdrawal symptoms, including anxiety and sleep and perceptual disturbances. This article presents a brief review of benzodiazepine withdrawal, with an emphasis on the discontinuation of these drugs following treatment of panic disorders. In particular, short-acting and long-acting drugs may present different features following long-term treatment and withdrawal. Preliminary results from a study comparing alprazolam and diazepam are presented to illustrate this point in contrast to expectations: the problems associated with withdrawal of both agents were comparable.

Alprazolam