Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule betaPix.

The Pix/Cool proteins are involved in the regulation of cell morphology by binding to small Rho GTPases and kinases of the Pak family. Recently, it has been shown that betaPix/Cool-1 associates with the ubiquitin ligase Cbl, which appears to be a critical step in Cdc42-mediated inhibition of epidermal-growth-factor-receptor (EGFR) ubiquitylation and downregulation. Here we show that the SH3 domain of betaPix specifically interacts with a proline-arginine motif (PxxxPR) present within the ubiquitin ligase Cbl and Pak1 kinase. Owing to targeting of the same sequence, Cbl and Pak1 compete for binding to betaPix. In this complex, Cbl mediates ubiquitylation and subsequent degradation of betaPix. Our findings reveal a double feedback loop in which the Cdc42/betaPix complex blocks Cbl's ability to downregulate EGFR, while Cbl in turn promotes degradation of betaPix in order to escape this inhibition. Such a relationship provides a mechanism to fine-tune the kinetics of RTK endocytosis and degradation depending on the pool of active Cdc42 and the duration of EGFR signaling.

Psychiatric care behind locked doors. A study regarding the frequency of and the reasons for locked psychiatric wards in Sweden.

The general aim was to describe the frequency of and the reasons for locked doors at wards within Swedish psychiatric care. A questionnaire was answered by 193 ward managers. The findings demonstrated that 73% (n = 193) of the wards were locked on the day of investigation. Wards were sometimes locked in the absence of committed patients and sometimes open in the presence of committed patients. Wards were more often locked if at least one committed patient was present. Fewer wards for children and adolescents, than for adults and old people, were locked. More wards in the areas of Sweden's three largest cities, than in the rest of the country, were locked. Fourteen categories of reasons for locking wards were generated by a content analysis of answers to an open-ended question. Most answers were categorized as: prevent patients from escaping, legislation, provide patients and others with safety and security, prevent import and unwelcome visits, and staff's need of control. Staff working in psychiatric care ought to reflect upon and articulate reasons for, and decisions about, locking or opening entrance doors, with the limitation of patients' freedom in mind.

Auricular Acupuncture and Cognitive Behavioural Therapy for Insomnia: A Randomised Controlled Study.

Objective. The most effective nonpharmacological treatment for insomnia disorder is cognitive behavioural therapy-insomnia (CBT-i). However CBT-i may not suit everyone. Auricular acupuncture (AA) is a complementary treatment. Studies show that it may alleviate insomnia symptoms. The aim of this randomised controlled study was to compare treatment effects of AA with CBT-i and evaluate symptoms of insomnia severity, anxiety, and depression. Method. Fifty-nine participants, mean age 60.5 years (SD 9.4), with insomnia disorder were randomised to group treatment with AA or CBT-i. Self-report questionnaires, the Insomnia Severity Index (ISI), Dysfunctional Beliefs and Attitudes about Sleep scale (DBAS-16), Epworth Sleepiness Scale (ESS), and Hospital Anxiety and Depression scale (HAD), were collected at baseline, after treatment, and at 6-month follow-up. A series of linear mixed models were performed to examine treatment effect over time between and within the groups. Results. Significant between-group improvements were seen in favour of CBT-i in ISI after treatment and at the 6-month follow-up and in DBAS-16 after treatment. Both groups showed significant within-group postintervention improvements in ISI, and these changes were maintained six months later. The CBT-i group also showed a significant reduction in DBAS-16 after treatment and six months later. Conclusions. Compared to CBT-i, AA, as offered in this study, cannot be considered an effective stand-alone treatment for insomnia disorder. The trial is registered with ClinicalTrials.gov NCT01765959.

Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells.

The Cdx1 homeobox gene encodes for an intestine-specific transcription factor involved in the control of proliferation and differentiation of epithelial cells. Although it has been indicated that Cdx1 may act as a proto-oncogene in cultured fibroblasts, its direct role in the regulation of intestinal tumorigenesis has not been demonstrated. Here we show that expression of Cdx1 in an intestinal epithelial cell line (IEC-6) induces anchorage-independent growth in soft agar and promotes the formation of adenocarcinoma in vivo. The phenotype of Cdx1-induced tumors was exacerbated when IEC-6/Cdx1 cells were injected together with matrigel containing mitogens and extracellular matrix components. These changes were correlated with an increase in the GTP-bound form of Ras, modulation of Cdc42 and Rho-A activities, and accumulation of phosphatidyl inositol 3 (PI3) kinase products. Moreover, combined inhibition of Ras/Rho and PI3 kinase signaling by synthethic inhibitors blocked colony formation of IEC-6/Cdx1 cells in soft agar. Taken together, these results demonstrate a direct involvement of Cdx1, and its collaboration with Ras, Rho and PI3 kinase pathways, in transformation and tumorigenesis of intestinal epithelial cells.

Plasma levels and effects of metoprolol after single and multiple oral doses.

Five patients with moderate hypertension were given placebo and at least 3 single oral doses (25, 50, 75, 100, or 150 mg) of metoprolol as well as multiple doses at at least 2 dose levels (25, 50, or 100 mg thrice daily). Blood pressure, pulse rate at rest, plasma renin activity, and drug plasma concentration were intensively monitored during 7.5 hr after each dose. Pulse rate, systolic blood pressure, and plasma renin activity decreased after the single oral doses, but diastolic blood pressure did not decrease consistently. The correlation coefficients between percentage decrease in systolic blood pressure and pulse rate and total plasma concentrations were higher individually than in the group. The corresponding regression equations were different between individuals and for systolic blood pressure there was a 700% difference in regression coefficients. The acute changes in diastolic blood pressure and plasma renin activity were not related to metoprolol plasma concentrations. The decrease in systolic blood pressure and pulse rate on multiple doses could not be predicted from the response after single doses.

Prazosin kinetics in hypertension.

Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) and after increasing multiple doses (0.5 to 5 mg three times daily) in eight patients with hypertension. After intravenous administration the kinetics could be described by a linear two-compartment open model. Terminal half-life (t1/2 beta) was about 3 hr and apparent volume of distribution (Vd beta) about 0.6 l/kg. After oral doses bioavailability ranged between 55% and 82%. Since total plasma clearance was low (0.14 l/kg x hr) incomplete bioavailability was the result of incomplete absorption rather than of first-pass liver metabolism. The estimated extraction ratio was about 14%. Renal clearance was negligible; only 1% to 2% of the dose was recovered unchanged in urine. Binding to plasma proteins to both albumin and alpha 1-acid glycoprotein was substantial (97%), with albumin being most important. Increasing multiple doses showed that prazosin followed first-order kinetics with a linear correlation between dose and steady-state plasma concentration (P less than 0.001). There were substantial variations in plasma concentrations between patients and there were also day-to-day variations in concentration within the same patient.

Prazosin dynamics in hypertension: relationship to plasma concentration.

The antihypertensive effects of prazosin in relation to its kinetics were studied after single doses (intravenous and oral, 0.5 mg) and during increasing multiple doses (0.5 to 5 mg three times a day). There was a fall in systolic and diastolic blood pressures of 10% to 14%, which was greater in the standing than in the sitting position. Prazosin plasma concentrations correlated with dose (P less than 0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P less than 0.01) during the beta-elimination phase in all patients. In only five of eight patients, however, did mean plasma concentration and antihypertensive effect during continuous treatment with different doses correlate. The maximal fall in systolic blood pressure correlated (P less than 0.01) with that after the first oral steady-state dose (0.5 mg three times daily), which indicates limited possibility of early identification of prazosin responders. There were no signs of overshoot of blood pressure when prazosin was withdrawn for a week. On rechallenge with a single oral dose of 2.5 mg prazosin there were no signs of enhanced hypotensive effect.

Influence of pentobarbital on metoprolol plasma levels.

Induction of microsomal enzymes with barbiturates in rats has little effect on the metabolism of metoprolol, compared with propranolol and alprenolol, which undergo extensive hepatic extraction in animals and man. Our study was designed to examine whether the metabolism of metoprolol is inducable by barbiturate in man. In 8 healthy subjects the area under the plasma concentration/time curve after 0.1 gm metoprolol was reduced by a mean of 32% after treatment with 0.1 gm pentobarbital at bedtime for 10 days. There was considerable interindividual variability in the reduction after pentobarbital treatment (2% to 46%).

Influence of pentobarbital on effect and plasma levels of alprenolol and 4-hydroxy-alprenolol.

Six healthy subjects were given placebo and a single oral 0.2-gm dose of alprenolol (Aptin) before and after 0.1 gm pentobarbital at bedtime for 10 days. The plasma concentrations of alprenolol and its metabolite 4-hydroxy-alprenolol and the inhibition of exercise tachycardia were studied for 7 hr after the alprenolol. Alprenolol and 4-hydroxy-alprenolol plasma levels were decreased by about 40% by pentobarbital but plasma half-lives were unchanged. The inhibition of exercise tachycardia during a 7-hr period was reduced from 14.0% to 10.7% by pentobarbital. The reduction was proportional to the decreased drug plasma levels. There was a significant contribution of the metabolite to alprenolol effect. The estimation of relative potency of metabolite against parent compound was 0.9 before pentobarbital and 1.9 after pentobarbital.

Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension.

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagoinst of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metroprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 +/- 3.8 (SEM)/10 +/- 2.1 mm Hg in the lying position and 23 +/- 4.4/9 +/- 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady-state plasma concentrations of metoprolol varied 17-fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p less than 0.05) and decrease in exercise tachycardia (r = 0.65, p less than 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mg/kg. Metoprolol decreased PRA by 67 +/- 1.9 and 71 +/- 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p less than 0.05) but not to the plasma steady-state levels of metoprolol, the degree of beta receptor blockade, and the decrease in PRA.

Relationship between scholastic and health behaviors and reading level in adolescent females.

This was a study of 102 adolescent females, 12-20 years of age, presenting to a central city clinic for medical care. Participants completed an oral questionnaire that included demographics, and questions regarding scholastic history, sexual behavior, and substance use. Each subject completed the Accuracy Level Test (ALT), a reading test. The subject's reading test grade level was subtracted from her appropriate grade in school to give a reading delay level (RDL). The mean reading grade level for all subjects was 6.7 +/- 2.6 and the average reading delay was 4.5 +/- 2.5 grades. Poor school attenders had greater reading delays (5.8 +/- 3.4 grades behind vs. 4.3 +/- 2.2 for good attenders p < 0.04), and those who repeated grades were also significantly delayed (5.5 +/- 2.4 grades behind vs. 3.7 +/- 2.3, p < 0.0007). Previously pregnant students had a greater delay in reading level than their nonpregnant peers (5.2 +/- 2.3 vs. 3.9 +/- 2.5 respectively p < 0.01). Delayed reading levels appear to correlate with some risk behaviors. The ALT may serve as a tool to identify high-risk patients who need more intensive clinical intervention.

"It was just realizing ... that life isn't one big horror": a qualitative study of supported socialization.

This report describes the qualitative component of a large-scale study of supported socialization. Paralleling the recent advances made through supported housing, supported employment, and supported education, this approach seeks to increase the involvement of individuals with psychiatric disabilities in naturally occurring social and recreational activities in community settings of their choice. After a review of social relationships and psychiatric disability, we describe the Partnership Project and present findings from a series of qualitative interviews conducted with a subsample of participants. We then discuss the implications of these findings for the community integration of individuals with psychiatric disabilities.

Forced medication in psychiatric care: patient experiences and nurse perceptions.

The aims of this study were to describe: patient experiences of and nurse perceptions of patient experiences of forced medication before, during and after forced medication; patient and nurse perceptions of alternatives to forced medication; and whether patients, according to patients and nurses, retrospectively approved of forced medication. Eleven patients and nurses were interviewed about a certain situation of forced medication. Data were analysed by content analysis. The findings demonstrate that forced medication evokes a number of patient experiences according to patients and nurses. These are related to the disease, the situation of being forcibly medicated and the drug. Patients mentioned several alternatives to the forced medication, whereas nurses mentioned no alternatives. A minority of the patients, and not as many patients as the nurses' thought, retrospectively approved of the use of forced medication. It can be concluded that patients and nurses do not share the same perceptions about what patients experience when forcibly medicated.

Medication administration in inpatient psychiatric care--get control and leave control.

The aim of this mini-ethnographic study was to describe medication administration (MA) in short-time inpatient psychiatric care. MA was observed on two psychiatric wards. Field-notes were taken and interviews were conducted with 15 voluntarily admitted patients and nine nurses. The data analysis was conducted as a dialectical and interactive process. Two central categories were generated: get control and leave control, and two subcategories: interpersonal contact and nurses' knowledge. The patients left control over medication to the nurses and expressed gratefulness for the opportunity to do so. Interpersonal contact between patients and nurses and nurses' knowledge were of importance for the possibility for the nurses to get control and for the patients to leave control. MA is a complex task with an importance beyond giving the right pill to the right patient, and provides patients with an opportunity to communicate with the nurses.

Patients' experience of auricular acupuncture during protracted withdrawal.

Over the last decades interest in using auricular acupuncture for substance dependence care has increased. The specific auricular acupuncture protocol used follows the National Acupuncture Detoxification Association (NADA) definition. This paper describes patients' experiences of receiving auricular acupuncture during protracted withdrawal. Interviews were conducted with 15 patients treated at an outpatient clinic for substance dependence. Content analysis was used to analyse the interviews. The analysis resulted in seven categories of positive experiences and seven categories of negative experiences. The positive experiences were: Relaxation and well-being, Peacefulness and harmony, New behaviours, Positive physical impact, Importance of context, Anxiety reduction and Reduced drug and alcohol consumption. The negative experiences were: Nothing negative, Disturbing context, Short-term effect, Depending on someone else, Time-consuming, Physical distractions and Remaining cravings. The conclusion of this study is that all respondents appreciated NADA treatment. This study supports further research on using NADA in addiction treatment to reduce suffering during protracted withdrawal and in other contexts.

Alternariol induces abnormal nuclear morphology and cell cycle arrest in murine RAW 264.7 macrophages.

The mycotoxin alternariol (AOH), a frequent contaminant in fruit and cereal products, is known to induce DNA damage with subsequent cell cycle arrest. Here we elucidated the effects of AOH on stages of cell cycle progression using the RAW 264.7 macrophage model. AOH resulted in an accumulation of cells in the G2/M-phase (4N). Most cells exhibited a large G2 nucleus whereas numbers of true mitotic cells were reduced relative to control. Both cyclin B1 and p-cdc2 levels increased, while cyclin B1 remained in the cytoplasm; suggesting arrest in the G2/M transition point. Remarkably, after exposure to AOH for 24h, most of the cells exhibited abnormally shaped nuclei, as evidenced by partly divided nuclei, nuclear blebs, polyploidy and micronuclei (MN). AOH treatment also induced abnormal Aurora B bridges, suggesting that cytokinesis was interfered within cells undergoing karyokinesis. A minor part of the resultant G1 tetraploid (4N) cells re-entered the S-phase and progressed to 8N cells.

Door locking and exit security measures on acute psychiatric admission wards.

Locking the exit doors of psychiatric wards is believed to reduce the risk of patients absconding. The aims of the study were to investigate both the prevalence of door locking and other exit security measures on UK admission wards, as well as whether door locking appears to be effective in keeping inpatients in. A cross-sectional survey on 136 acute psychiatric wards in the UK was conducted, in which a range of data on patients, staff, and conflict and containment events, including door locking and absconding, were collected from shift to shift during a period of 6 months. About one-third of the participating wards (30%) operated with their ward exit door permanently locked, whereas another third (34%) never locked the ward door. Univariate analyses suggested little association between exit security measures and absconding. A more robust multilevel statistical analysis, however, did indicate a reduction of about 30% of absconding rates when the ward door was locked the entire shift. Although locking the ward door does seem to reduce absconding to a certain extent, it far from completely prevents it. As it may be unrealistic to strive for a 100% absconding-proof ward, alternative measures for door locking to prevent absconding are discussed.

Locked doors: a survey of patients, staff and visitors.

ACCESSIBLE SUMMARY: • Locking of psychiatric wards doors is more frequent, but the impact is unknown. • Staff patients and visitors returned a questionnaire about the issue. • Patients did not like the door being locked as much as staff, and being on a locked ward was associated with greater rejection of the practice. • Staff working on locked wards were more positive about it than those who did not. ABSTRACT: Locking the door of adult acute psychiatric wards has become increasingly common in the UK. There has been little investigation of its efficacy or acceptability in comparison to other containment methods. We surveyed the beliefs and attitudes of patients, staff and visitors to the practice of door locking in acute psychiatry. Wards that previously participated in a previous study were contacted and sent a questionnaire. A total of 1227 responses were obtained, with the highest number coming from staff, and the smallest from visitors. Analysis identified five factors (adverse effects, staff benefits, patient safety benefits, patient comforts and cold milieu). Patients were more negative about door locking than the staff, and more likely to express such negative judgments if they were residing in a locked ward. For staff, being on a locked ward was associated with more positive judgments about the practice. There were significant age, gender and ethnicity effects for staff only. Each group saw the issue of locked doors from their own perspective. Patients registered more anger, irritation and depression as a consequence of locked doors than staff or visitors thought they experienced. These differences were accentuated by the actual experience of the ward being locked.