Dopamine responsiveness is regulated by targeted sorting of D2 receptors

Abstract Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.

Responsiveness of the Effective Consumer Scale (EC-17)

Objective. The Effective Consumer Scale (EC-17) comprises 17 items measuring the main skills and behaviors people need to effectively manage their healthcare. We tested the responsiveness of the EC-17. Methods. Participants, in 2 waves of a 6-week Arthritis Self-Management Program (ASMP) from Arthritis Ireland, received a questionnaire at the first and last week of the weekly ASMP. The questionnaire included the EC-17 and 10 other measures for arthritis. Deficits, mean change, and standard deviations were calculated at baseline and Week 6. The EC-17 scores were compared to the Arthritis Self-Efficacy (ASE) and Patient Activation Measure (PAM) scales. Results were presented at OMERACT 9. Results. There is some overlap between the EC-17 and the ASE and PAM; however, most items of greatest deficit in the EC-17 are not covered by those scales. In 327 participants representing both intervention waves (2006 and 2007), the EC-17 was more efficient than the ASE but less efficient than the PAM for detecting improvements after the ASMP, and was moderately correlated with the PAM. Conclusion. The EC-17 appears to measure different skills and attributes than the ASE and PAM. Discussions with participants at OMERACT 9 agreed that it is worthwhile to measure the skills and attributes of an effective consumer, and supported the development of an intervention (such as proposed online decision aids) that would include education in the categories in the EC-17.

Validation of a new tool to measure responsiveness and structure in the feeding context : the Authoritative Feeding Practices Questionnaire

How mothers interact with their toddlers around food lays the foundations for healthy eating and healthy weight gain in later life. This research involving 467 Australian first-time mothers of 2-year-old children resulted in the development of a new self-report tool, the Authoritative Feeding Practices Questionnaire, assessing maternal responsive feeding and mealtime structure. Secondary analysis of the NOURISH randomised controlled trial included theory-driven item selection, confirmatory factor analysis, evaluation of psychometric properties and construct validation. The result is a brief, reliable and valid new tool for evaluating the maternal feeding practices that support children to become healthy, independent eaters.

Satiety responsiveness in toddlerhood predicts energy intake and weight status at four years of age

The aim of this study was to examine whether maternal-report of child eating behaviour at two years predicted self-regulation of energy intake and weight status at four years. Using an ‘eating in the absence of hunger’ paradigm, children’s energy intake (kJ) from a semi-standardized lunch meal and a standardized selection of snacks were measured. Participants were 37 mother-child dyads (16 boys, Median child age = 4.4 years, Inter-quartile range = 3.7-4.5 years) recruited from an existing longitudinal study (NOURISH randomised controlled trial). All participants were tested in their own home. Details of maternal characteristics, child eating behaviours (at age two years) reported by mothers on a validated questionnaire, and measured child height and weight (at age 3.5-4 years) were sourced from existing NOURISH trial data. Correlation and partial correlation analyses were used to examine longitudinal relationships. Satiety responsiveness and Slowness in eating were inversely associated with energy intake of the lunch meal (partial r = -.40, p =.023, and partial r = -.40, p = .023) and the former was also negatively associated with BMI-for-age Z score (partial r = -.42, p = .015). Food responsiveness and Enjoyment of food were not related to energy intake or BMI Z score. None of the eating behaviours were significantly associated with energy intake of the snacks (i.e., eating in the absence of hunger). The small and predominantly ‘healthy weight’ sample of children may have limited the ability to detect some hypothesized effects. Nevertheless, the study provides evidence for the predictive validity of two eating behaviours and future research with a larger and more diverse sample should be able to better evaluate the predictive validity of other children’s early eating behaviour styles.

Association between maternal depressive symptoms in the early postnatal period and responsiveness in feeding at child age 2 years

Maternal depression is a known risk factor for poor outcomes for children. Pathways to these poor outcomes relate to reduced maternal responsiveness or sensitivity to the child. Impaired responsiveness potentially impacts the feeding relationship and thus may be a risk factor for inappropriate feeding practices. The aim of this study was to examine the longitudinal relationships between self-reported maternal post-natal depressive symptoms at child age 4 months and feeding practices at child age 2 years in a community sample. Participants were Australian first-time mothers allocated to the control group of the NOURISH randomized controlled trial when infants were 4 months old. Complete data from 211 mothers (of 346 allocated) followed up when their children were 2 years of age (51% girls) were available for analysis. The relationship between Edinburgh Postnatal Depression Scale (EPDS) score (child age 4 months) and child feeding practices (child age 2 years) was tested using hierarchical linear regression analysis adjusted for maternal and child characteristics. Higher EPDS score was associated with less responsive feeding practices at child age 2 years: greater pressure [β = 0.18, 95% confidence interval (CI): 0.04–0.32, P = 0.01], restriction (β = 0.14, 95% CI: 0.001–0.28, P = 0.05), instrumental (β = 0.14, 95% CI: 0.005–0.27, P = 0.04) and emotional (β = 0.15, 95% CI: 0.01–0.29, P = 0.03) feeding practices (ΔR2 values: 0.02–0.03, P < 0.05). This study provides evidence for the proposed link between maternal post-natal depressive symptoms and lower responsiveness in child feeding. These findings suggest that the provision of support to mothers experiencing some levels of depressive symptomatology in the early post-natal period may improve responsiveness in the child feeding relationship.

Developing cultural responsiveness in environmental design students through digital storytelling and photovoice

As the Latino population in the United States grows, it will become increasingly important for undergraduate students in environmental design and related disciplines to become more culturally responsive and learn how to understand and address challenges faced by population groups, such as Latino youth. To this end, we involved environmental design undergraduate students at the University of Colorado in a service-learning class to mentor Latino youth in the creation of multimedia narratives using photovoice and digital storytelling techniques. The introduction of technology was used as a bridge between the two groups and to provide a platform for the Latino youth to reveal their community experiences. Based on focus group results, we describe the impact on the undergraduate students and provide recommendations for similar programs that can promote cultural responsiveness through the use of digital technology and prepare environmental design students to work successfully in increasingly diverse communities.

Evaluating the responsiveness of accelerometry to detect change in physical activity

The responsiveness to change of the Actical and ActiGraph accelerometers was assessed in children and adolescents. Participants (n=208) aged 6-16 years completed two simulated free-living protocols, one with primarily light-to-moderate physical activities (PA) and one with mostly moderate-to-vigorous PA. Time in sedentary, light, moderate, and vigorous PA was estimated using 8 previously developed cut-points (4 for Actical and 4 for ActiGraph) and 15-s and 30-s epochs. Accelerometer responsiveness for detecting differences in PA between protocols was assessed using standardized response means (SRM). SRM values >/=0.8 represented high responsiveness to change. Both accelerometers showed high responsiveness for all PA intensities (SRMs = 1.2-4.7 for Actical and 1.1-3.3 for ActiGraph). All cut-points and epoch lengths yielded high responsiveness, and choice of cut-points and epoch length had little effect on responsiveness. Thus, both the Actical and ActiGraph can detect change in PA in a simulated free-living setting, irrespective of cut-point selection or epoch length.

A preliminary investigation into adrenal responsiveness and outcomes in patients with cardiogenic shock after acute myocardial infarction

PURPOSE: This study investigated the significance of baseline cortisol levels and adrenal response to corticotropin in shocked patients after acute myocardial infarction (AMI). METHODS: A short corticotropin stimulation test was performed in 35 patients with cardiogenic shock after AMI by intravenously injecting of 250 μg of tetracosactrin (Synacthen). Blood samples were obtained at baseline (T0) before and at 30 (T30) and 60 (T60) minutes after the test to determine plasma total cortisol (TC) and free cortisol concentrations. The main outcome measure was in-hospital mortality and its association with T0 TC and maximum response to corticotropin (maximum difference [Δ max] in cortisol levels between T0 and the highest value between T30 and T60). RESULTS: The in-hospital mortality was 37%, and the median time to death was 4 days (interquartile range, 3-9 days). There was some evidence of an increased mortality in patients with T0 TC concentrations greater than 34 μg/dL (P=.07). Maximum difference by itself was not an independent predictor of death. Patients with a T0 TC 34 μg/dL or less and Δ max greater than 9 μg/dL appeared to have the most favorable survival (91%) when compared with the other 2 groups: T0 34 μg/dL or less and Δ max 9 μg/dL or less or T0 34 μg/dL or higher and Δ max greater than 9 μg/dL (75%; P=.8) and T0 greater than 34 μg/dL and Δ max 9 μg/dL or less (60%; P=.02). Corticosteroid therapy was associated with an increased mortality (P=.03). There was a strong correlation between plasma TC and free cortisol (r=0.85). CONCLUSIONS: A high baseline plasma TC was associated with a trend toward increased mortality in patients with cardiogenic shock post-AMI. Patients with lower baseline TC, but with an inducible adrenal response, appeared to have a survival benefit. A prognostic system based on basal TC and Δ max similar to that described in septic shock appears feasible in this cohort. Corticosteroid therapy was associated with adverse outcomes. These findings require further validation in larger studies.

Responsiveness of human male volunteers to immunization with ovine follicle stimulating hormone vaccine: Results of a pilot study

A study of 140 days duration was performed to examine if human male volunteers (n = 5) respond to ovine follicle stimulating hormone (oFSH) immunization (administered adsorbed on Alugel on days 1, 20, 40 and 70) by producing antibodies capable of both binding and neutralizing bioactivity of human FSH. The kinetics of antibody production for both the immunogen (oFSH) and the cross-reactive antigen (hFSH) were essentially similar, The volunteers responded only to the first two immunizations, The boosters given on days 40 and 70 were ineffective, probably because of the presence of substantial amounts of circulating antibody to oFSH. Of the antibodies generated to oFSH, 25-45% bound hFSH with a mean binding affinity of 0.65 x 10(9) +/- 0.53 M(-1). The binding capacities at the time of high (30-80 days of immunization) and low (>110 days) titres were 346 +/- 185 and 10.5 +/- 5.8 ng hFSH/ml respectively, During the period of high titre, free serum FSH (value in normal males 1-5 ng/ml) was not monitorable, A 50 mu l aliquot of the antiserum obtained from different volunteers between days 30 and 80 and on day 140 blocked binding of I-125-labelled hFSH to its receptor by 82 +/- 9.7 and 53 +/- 12.2% respectively, The antibody produced was specific for FSH, and no significant change in the values of related glycoprotein hormones (luteinizing hormone/testosterone and thyroid stimulating hormone/thyroxine) were recorded, Seminal plasma transferrin, a marker of Sertoli cell as well as of seminiferous tubular function, showed marked reduction (30-90%) following immunization with oFSH. Considering that endogenous FSH remained neutralized for approximately one sperm cycle only (65 days), the reduction in sperm counts (30-74%) exhibited by some volunteers is encouraging, Immunization with oFSH did not result in any significant changes in haematology, serum biochemistry or hormonal profiles, There was no production of antibodies capable of interacting with non-specific tissues, It is concluded that it should be possible to obtain a sustained long-term blockade of endogenous FSH action in men by using oFSH as an immunogen, This is a prerequisite for obtaining significant reduction in the quality and quantity of spermatozoa produced, thus leading to infertility.

DNA STRUCTURAL FEATURES AND ARCHITECTURE OF PROMOTER REGIONS PLAY A ROLE IN GENE RESPONSIVENESS OF S. CEREVISIAE

Gene expression is the most fundamental biological process, which is essential for phenotypic variation. It is regulated by various external (environment and evolution) and internal (genetic) factors. The level of gene expression depends on promoter architecture, along with other external factors. Presence of sequence motifs, such as transcription factor binding sites (TFBSs) and TATA-box, or DNA methylation in vertebrates has been implicated in the regulation of expression of some genes in eukaryotes, but a large number of genes lack these sequences. On the other hand, several experimental and computational studies have shown that promoter sequences possess some special structural properties, such as low stability, less bendability, low nucleosome occupancy, and more curvature, which are prevalent across all organisms. These structural features may play role in transcription initiation and regulation of gene expression. We have studied the relationship between the structural features of promoter DNA, promoter directionality and gene expression variability in S. cerevisiae. This relationship has been analyzed for seven different measures of gene expression variability, along with two different regulatory effect measures. We find that a few of the variability measures of gene expression are linked to DNA structural properties, nucleosome occupancy, TATA-box presence, and bidirectionality of promoter regions. Interestingly, gene responsiveness is most intimately correlated with DNA structural features and promoter architecture.

Immigrants Responsiveness to Labor Market Conditions

Using data from the Spanish Labor Force Survey (Encuesta de Población Activa) from 1999 through 2004, we explore the role of regional employment opportunities in explaining the increasing immigrant flows of recent years despite the limited internal mobility on the part of natives. Subsequently, we investigate the policy question of whether immigration has helped reduced unemployment rate disparities across Spanish regions by attracting immigrant flows to regions offering better employment opportunities. Our results indicate that immigrants choose to reside in regions with larger employment rates and where their probability of finding a job is higher. In particular, and despite some differences depending on their origin, immigrants appear generally more responsive than their native counterparts to a higher likelihood of informal, self, or indefinite employment. More importantly, insofar the vast majority of immigrants locate in regions characterized by higher employment rates, immigration contributes to greasing the wheels of the Spanish labor market by narrowing regional unemployment rate disparities.