The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis.
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We have identified the Drosophila transmembrane molecule kekkon 1 (kek1) as an inhibitor of the epidermal growth factor receptor (EGFR) and demonstrate that it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase. During oogenesis, kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling. Consistent with our loss-of-function studies, we demonstrate that ectopic overexpression of kek1 mimics a loss of EGFR activity. We show that the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR, suggesting potential models for this inhibitory mechanism. (+info)
In Saccharomyces cerevisae, feedback inhibition of homocitrate synthase isoenzymes by lysine modulates the activation of LYS gene expression by Lys14p.
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Expression of the structural genes for lysine biosynthesis responds to an induction mechanism mediated by the transcriptional activator Lys14p in the presence of alpha-aminoadipate semialdehyde (alphaAASA), an intermediate of the pathway acting as a coinducer. This activation is reduced by the presence of lysine in the growth medium, leading to apparent repression. In this report we demonstrate that Saccharomyces cerevisiae possesses two genes, LYS20 and LYS21, encoding two homocitrate synthase isoenzymes which are located in the nucleus. Each isoform is inhibited by lysine with a different sensitivity. Lysine-overproducing mutants were isolated as resistant to aminoethylcysteine, a toxic lysine analog. Mutations, LYS20fbr and LYS21fbr, are allelic to LYS20 and LYS21, and lead to desensitization of homocitrate synthase activity towards lysine and to a loss of apparent repression by this amino acid. There is a fair correlation between the I0.5 of homocitrate synthase for lysine, the intracellular lysine pool and the levels of Lys enzymes, confirming the importance of the activity control of the first step of the pathway for the expression of LYS genes. The data are consistent with the conclusion that inhibition by lysine of Lys14p activation results from the control of alphaAASA production through the feedback inhibition of homocitrate synthase activity. (+info)
Feasibility of monitoring patient based health outcomes in a routine hospital setting.
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OBJECTIVE: To assess the feasibility of monitoring health outcomes in a routine hospital setting and the value of feedback of outcomes data to clinicians by using the SF 36 health survey questionnaire. DESIGN: Administration of the questionnaire at baseline and three months, with analysis and interpretation of health status data after adjustments for sociodemographic variables and in conjunction with clinical data. Exploration of usefulness of outcomes data to clinicians through feedback discussion sessions and by an evaluation questionnaire. SETTING: One gastroenterology outpatient department in Aberdeen Royal Hospitals Trust, Scotland. PATIENTS: All (573) patients attending the department during one month (April 1993). MAIN MEASURES: Ability to obtain patient based outcomes data and requisite clinical information and feed it back to the clinicians in a useful and accessible form. RESULTS: Questionnaires were completed by 542 (95%) patients at baseline and 450 (87%) patients at follow up. Baseline health status data and health outcomes data for the eight different aspects of health were analysed for individual patients, key groups of patients, and the total recruited patient population. Significant differences were shown between patients and the general population and between different groups of patients, and in health status over time. After adjustment for differences in sociodemography and main diagnosis patients with particularly poor scores were identified and discussed. Clinicians judged that this type of assessment could be useful for individual patients if the results were available at the time of consultation or for a well defined group of patients if used as part of a clinical trial. CONCLUSIONS: Monitoring routine outcomes is feasible and instruments to achieve this, such as the SF 36 questionnaire, have potential value in an outpatient setting. IMPLICATIONS: If data on outcomes are to provide a basis for clinical and managerial decision making, information systems will be required to collect, analyse, interpret, and feed it back regularly and in good time. (+info)
Do tailored behavior change messages enhance the effectiveness of health risk appraisal? Results from a randomized trial.
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Health risk appraisal (HRA) remains one of the most widely used health promotion tools despite only equivocal evidence for its effectiveness. Theories of behavior change predict conventional HRA's ineffectiveness because risk information alone is seldom sufficient to change complex behaviors. In this study, a randomized trial compared the effects of feedback from an enhanced HRA with a typical HRA and a control group among adult patients from eight family medicine practices. The enhanced HRA assessed behavior-specific psychosocial factors and provided patients with computer-generated, individually-tailored behavior change information in addition to typical HRA risk feedback. Changes in seven behaviors were assessed at a 6 month follow-up. Overall, patients receiving enhanced HRA feedback were 18% more likely to change at least one risk behavior than were patients receiving typical HRA feedback or no feedback (OR = 1.18, 95% CI = 1.00, 1.39). The enhanced HRA feedback appeared to promote changes in cholesterol screening, dietary fat consumption and physical activity, but not in smoking, seat belt use, mammography and Pap smears. We conclude that the addition of theory-based, individually-tailored behavior change information may improve the effectiveness of HRA. (+info)
Changing preventive practice: a controlled trial on the effects of outreach visits to organise prevention of cardiovascular disease.
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OBJECTIVES: To assess the effects of outreach visits by trained nurse facilitators on the organisation of services used to prevent cardiovascular disease. To identify the characteristics of general practices that determined success. DESIGN: A non-randomised controlled trial of two methods of implementing guidelines to organise prevention of cardiovascular disease: an innovative outreach visit method compared with a feedback method. The results in both groups were compared with data from a control group. SETTING AND SUBJECTS: 95 general practices in two regions in The Netherlands. INTERVENTIONS: Trained nurse facilitators visited practices, focusing on solving problems in the organisation of prevention. They applied a four step model in each practice. The number of visits depended on the needs of the practice team. The feedback method consisted of the provision of a feedback report with advice specific to each practice and standardised instructions. MAIN OUTCOME MEASURES: The proportion of practices adhering to 10 different guidelines. Guidelines were on the detection of patients at risk, their follow up, the registration of preventive activities, and teamwork within the practice. RESULTS: Outreach visits were more effective than feedback in implementing guidelines to organise prevention. Within the group with outreach visits, the increase in the number of practices adhering to the guidelines was significant for six out of 10 guidelines. Within the feedback group, a comparison of data before and after intervention showed no significant differences. Partnerships and practices with a computer changed more. CONCLUSION: Outreach visits by trained nurse facilitators proved to be effective in implementing guidelines within general practices, probably because their help was practical and designed for the individual practice, guided by the wishes and capabilities of the practice team. (+info)
Staff and patient feedback in mental health services for older people.
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OBJECTIVES: To compare the views of patients and staff on the quality of care provided on a psychogeriatric assessment ward over a five year period. To describe the quality improvements which were made as a result of their respective comments. DESIGN: Structured interviews were conducted with both patients and staff to obtain qualitative feedback and suggestions for improvement. An analysis of the percentage of positive and negative comments made by both patients and staff was used to compare the levels of satisfaction on a variety of aspects of the service provided. SETTING: Psychogeriatric inpatient assessment ward. SUBJECTS: 75 patients and 85 staff interviews were conducted. MAIN MEASURES: Structured interviews covering various aspects of service quality. RESULTS: Staff and patients picked up on different aspects of service quality as important. Quality improvements which arose from the interviews were clearly different. Generally patients were more positive about the physical environment and standards of professional care than staff, but less positive about issues of privacy, social interaction, and empowerment. CONCLUSIONS: The perspectives of patients and staff in this area are not interchangeable. Both series of interviews led to several positive changes in the quality of care. Interviews with staff seem to have been valuable in a low morale situation. A structured interview format provided patients with an opportunity to feedback openly and led to changes in service quality which would not otherwise have occurred. (+info)
Inhibition of phospholipase A2-mediated arachidonic acid release by cyclic AMP defines a negative feedback loop for P2Y receptor activation in Madin-Darby canine kidney D1 cells.
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In Madin-Darby canine kidney D1 cells extracellular nucleotides activate P2Y receptors that couple to several signal transduction pathways, including stimulation of multiple phospholipases and adenylyl cyclase. For one class of P2Y receptors, P2Y2 receptors, this stimulation of adenylyl cyclase and increase in cAMP occurs via the conversion of phospholipase A2 (PLA2)-generated arachidonic acid (AA) to prostaglandins (e.g. PGE2). These prostaglandins then stimulate adenylyl cyclase activity, presumably via activation of prostanoid receptors. In the current study we show that agents that increase cellular cAMP levels (including PGE2, forskolin, and the beta-adrenergic agonist isoproterenol) can inhibit P2Y receptor-promoted AA release. The protein kinase A (PKA) inhibitor H89 blocks this effect, suggesting that this feedback inhibition occurs via activation of PKA. Studies with PGE2 indicate that inhibition of AA release is attributable to inhibition of mitogen-activated protein kinase activity and in turn of P2Y receptor stimulated PLA2 activity. Although cAMP/PKA-mediated inhibition occurs for P2Y receptor-promoted AA release, we did not find such inhibition for epinephrine (alpha1-adrenergic) or bradykinin-mediated AA release. Taken together, these results indicate that negative feedback regulation via cAMP/PKA-mediated inhibition of mitogen-activated protein kinase occurs for some, but not all, classes of receptors that promote PLA2 activation and AA release. We speculate that receptor-selective feedback inhibition occurs because PLA2 activation by different receptors in Madin-Darby canine kidney D1 cells involves the utilization of different signaling components that are differentially sensitive to increases in cAMP or, alternatively, because of compartmentation of signaling components. (+info)
Inhibition of the Ca2+/calmodulin-dependent protein kinase I cascade by cAMP-dependent protein kinase.
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Several recent studies have shown that Ca2+/calmodulin-dependent protein kinase I (CaMKI) is phosphorylated and activated by a protein kinase (CaMKK) that is itself subject to regulation by Ca2+/calmodulin. In the present study, we demonstrate that this enzyme cascade is regulated by cAMP-mediated activation of cAMP-dependent protein kinase (PKA). In vitro, CaMKK is phosphorylated by PKA and this is associated with inhibition of enzyme activity. The major site of phosphorylation is threonine 108, although additional sites are phosphorylated with lower efficiency. In vitro, CaMKK is also phosphorylated by CaMKI at the same sites as PKA, suggesting that this regulatory phosphorylation might play a role as a negative-feedback mechanism. In intact PC12 cells, activation of PKA with forskolin resulted in a rapid inhibition of both CaMKK and CaMKI activity. In hippocampal slices CaMKK was phosphorylated under basal conditions, and activation of PKA led to an increase in phosphorylation. Two-dimensional phosphopeptide mapping indicated that activation of PKA led to increased phosphorylation of multiple sites including threonine 108. These results indicate that in vitro and in intact cells the CaMKK/CaMKI cascade is subject to inhibition by PKA-mediated phosphorylation of CaMKK. The phosphorylation and inhibition of CaMKK by PKA is likely to be involved in modulating the balance between cAMP- and Ca2+-dependent signal transduction pathways. (+info)