Effects of Potential Agonist-Replacement Therapies for Stimulant Dependence on Inhibitory Control in Cocaine Abusers

Two experiments were conducted to determine whether methylphenidate or modafinil, two potential pharmacotherapies for stimulant dependence, would impair inhibitory behavior in cocaine users. Eleven cocaine abusers were administered methylphenidate (0, 15, 30, and 45 mg) or modafinil (0, 150, 300, and 450 mg) across four experimental sessions. A cued go–no-go task was used to measure response execution and inhibition. Subjective and cardiovascular measures were collected. Neither methylphenidate nor modafinil impaired inhibitory control, but produced prototypical subject-rated and cardiovascular effects. The results of these studies may have implications for the use of these drugs as agonist-replacement therapies for stimulant dependence.     

Influences of context, process and individual differences on nurses' readiness for change to Magnet status

Title.  Influences of context, process and individual differences on nurses' readiness for change to Magnet status.
Aim.  The aim of this study was to test hypotheses associated with a model which explains individuals' readiness in early stages of a change.
Background.  In an effort to improve the quality of nursing care, hospitals in the United States of America seek to obtain Magnet recognition. While it is commonly known that Magnet hospitals provide higher quality patient care, little is known about the variability in nurses' attitudes and behaviour within Magnet hospitals.
Method.  We collected data in 2006 from 310 Registered Nurses to investigate the factors that influence their willingness to embrace the changes necessary for the high levels of excellence accompanying Magnet status. Hierarchical linear modelling was used because the data were multi-level.
Results.  Both change-specific context, such as a culture of research exhibited by the manager, and formal education of the nurse moderated the positive influences of the organization's procedural justice actions. Specifically, procedural justice was stronger when the nurse manager demonstrated a culture of research, and negative effects of low justice were mitigated when nurses had a higher level of formal education.
Conclusion.  Preparing managers beforehand to appreciate and adopt new behaviours associated with a forthcoming organizational change should enhance the success of change practices as new changes are initiated. Moreover, education that exposes employees to the pending realities of their industry, such as nursing research, can play an important role in the development of positive beliefs about changes facing their organizations.     

Human sex differences in d‐amphetamine self‐administration

Women and men may respond differently to the effects of stimulants such as amphetamine and cocaine. Aim In order to assess potential sex differences in the reinforcing effects of d‐amphetamine, a retrospective‐analysis was conducted on data collected from three studies that employed similar d‐amphetamine self‐administration procedures and used identical subject‐rated drug‐effect measures. Methods Data from 10 women and 15 men were included in the analysis. In all studies, participants sampled placebo, low (8–10 mg) or high (16–20 mg) dose oral d‐amphetamine. Following sampling sessions, participants worked for capsules containing one eighth of the previously sampled dose on a modified progressive‐ratio schedule of reinforcement. We hypothesized that women and men would be differentially sensitive to the reinforcing effects of d‐amphetamine. A two‐way mixed‐model analysis of variance (sex and dose) and planned comparisons were used in the statistical analyses. Results The low dose of d‐amphetamine functioned as a reinforcer in women, but not men, whereas the high dose of d‐amphetamine functioned as a reinforcer in men, but not women. Men self‐administered significantly more capsules under the high dose condition than women. Conclusion The results of this study suggest that men are more sensitive to the reinforcing effects of a high dose of d‐amphetamine than women. Future research is needed that determines prospectively the reinforcing effects of weight‐adjusted doses of d‐amphetamine in women and men while controlling for menstrual cycle phase.     

Comprehensive management including interstitial brachytherapy for locally advanced or recurrent gynecologic malignancies

Radical therapy for locally advanced or recurrent gynecologic malignancies (LARGM) may include interstitial brachytherapy (IB) when intracavitary brachytherapy is impossible or inadequate and external beam teletherapy would be limited by surrounding normal tissue tolerance. Sixteen women received IB as all or part of their treatment at North Shore University Hospital for the treatment of locally advanced primary or recurrent tumors of gynecologic origin from May 1988 through September 1990. Primary sites included the vulva (3), vagina (2), cervix (7), and endometrium (4). Radiosensitizing chemotherapy was used in 8 patients. With a median follow-up of 23 months (range, 12-44 months), 11 patients (69%) have experienced continuous local control of their tumor and 4 patients (25%) have experienced severe complications. While significant risks may attend the use of IB, IB is an integral part of management for select patients with LARGM.     

Broad-spectrum antiviral activity of PNU-183792, a 4-oxo-dihydroquinoline, against human and animal herpesviruses

We identified a novel class of 4-oxo-dihydroquinolines represented by PNU-183792 which specifically inhibit herpesvirus polymerases. PNU-183792 was highly active against human cytomegalovirus (HCMV, IC(50) value 0.69 microM), varicella zoster virus (VZV, IC(50) value 0.37 microM) and herpes simplex virus (HSV, IC(50) value 0.58 microM) polymerases but was inactive (IC(50) value >40 microM) against human alpha (alpha), gamma (gamma), or delta (delta) polymerases. In vitro antiviral activity against HCMV was determined using cytopathic effect, plaque reduction and virus yield reduction assays (IC(50) ranging from 0.3 to 2.4 microM). PNU-183792 antiviral activity against both VZV (IC(50) value 0.1 microM) and HSV (IC(50) ranging from 3 to 5 microM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC(50) ranging 0.1-0.7 microM) in cell culture assays against simian varicella virus (SVV), murine cytomegalovirus (MCMV) and rat cytomegalovirus (RCMV). Cell culture activity was compared with the appropriate licensed drugs ganciclovir (GCV), cidofovir (CDV) and acyclovir (ACV). PNU-183792 was also active against both GCV-resistant and CDV-resistant HCMV and against ACV-resistant HSV. Toxicity assays using four different species of proliferating mammalian cells indicated PNU-183792 was not cytotoxic at relevant drug concentrations (CC(50) value >100 microM). PNU-183792 was inactive against unrelated DNA and RNA viruses indicating specificity for herpesviruses. In animals, PNU-183792 was orally bioavailable and was efficacious in a model of lethal MCMV infection.     

Psychosis in bipolar disorder: phenomenology and impact on morbidity and course of illness

Although psychosis is common in bipolar disorder, few studies have examined the prognostic significance of psychotic features. In addition, some studies suggest that the presence of mood-incongruent psychosis, in particular, is associated with poorer outcome compared with mood-congruent psychosis. We assesses the phenomenology and prevalence of mood-congruent and mood-incongruent psychotic symptoms in 352 patients with bipolar I disorder participating in the Stanley Foundation Bipolar Treatment Network. We compared the demographic and clinical features, and measures of psychosocial and vocational functioning in patients with and without a history of psychosis. The phenomenology of psychosis in this cohort of patients with bipolar disorder was similar to that reported in earlier studies and supported the lack of diagnostic specificity of any one type of psychotic symptom. There were no significant differences between patients with and without a history of psychosis on any demographic, psychosocial, vocational, or course of illness variables. Only family history of bipolar disorder was significantly more common in patients with nonpsychotic bipolar disorder compared to patients with a history of psychosis. Among bipolar patients with a history of psychosis, only the proportion of women and lifetime prevalence rates of anxiety disorders occurred significantly more in patients with mood-incongruent delusions. In this large cohort of outpatients with bipolar I disorder, neither a history of psychosis nor of mood-incongruent psychosis had prognostic significance at entry into the Network. The lack of observable prognostic impact may have been, in part, due to the relatively high morbidity and poor functional outcome of a substantial portion of the total cohort.     

Absolute quantification of proteins and phosphoproteins from cell lysates by tandem MS

A need exists for technologies that permit the direct quantification of differences in protein and posttranslationally modified protein expression levels. Here we present a strategy for the absolute quantification (termed AQUA) of proteins and their modification states. Peptides are synthesized with incorporated stable isotopes as ideal internal standards to mimic native peptides formed by proteolysis. These synthetic peptides can also be prepared with covalent modifications (e.g., phosphorylation, methylation, acetylation, etc.) that are chemically identical to naturally occurring posttranslational modifications. Such AQUA internal standard peptides are then used to precisely and quantitatively measure the absolute levels of proteins and posttranslationally modified proteins after proteolysis by using a selected reaction monitoring analysis in a tandem mass spectrometer. In the present work, the AQUA strategy was used to (i) quantify low abundance yeast proteins involved in gene silencing, (ii) quantitatively determine the cell cycle-dependent phosphorylation of Ser-1126 of human separase protein, and (iii) identify kinases capable of phosphorylating Ser-1501 of separase in an in vitro kinase assay. The methods described here represent focused, alternative approaches for studying the dynamically changing proteome.