Optically pure, structural and fluorescent analogues of a dimeric Y4 receptor agonist derived by an olefin metathesis approach

The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective Neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors, and as a lead compound for anti-obesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labelled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)- diaminosuberoyl containing peptide, (R,R)-1 had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore the sulfo-Cy5 labelled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors

Race, Ethnicity, Psychosocial Factors, and Telomere Length in a Multicenter Setting

Background Leukocyte telomere length(LTL) has been associated with age, self-reported race/ethnicity, gender, education, and psychosocial factors, including perceived stress, and depression. However, inconsistencies in associations of LTL with disease and other phenotypes exist across studies. Population characteristics, including race/ethnicity, laboratory methods, and statistical approaches in LTL have not been comprehensively studied and could explain inconsistent LTL associations. Methods LTL was measured using Southern Blot in 1510 participants from a multi-ethnic, multi-center study combining data from 3 centers with different population characteristics and laboratory processing methods. Main associations between LTL and psychosocial factors and LTL and race/ethnicity were evaluated and then compared across generalized estimating equations(GEE) and linear regression models. Statistical models were adjusted for factors typically associated with LTL(age, gender, cancer status) and also accounted for factors related to center differences, including laboratory methods(i.e., DNA extraction). Associations between LTL and psychosocial factors were also evaluated within race/ethnicity subgroups (Non-hispanic Whites, African Americans, and Hispanics). Results Beyond adjustment for age, gender, and cancer status, additional adjustments for DNA extraction and clustering by center were needed given their effects on LTL measurements. In adjusted GEE models, longer LTL was associated with African American race (Beta(beta) (standard error(SE)) = 0.09(0.04), p-value = 0.04) and Hispanic ethnicity (beta(SE) = 0.06 (0.01), p-value = 0.02) compared to Non-Hispanic Whites. Longer LTL was also associated with less than a high school education compared to having greater than a high school education (a(SE) = 0.06(0.02), p-value = 0.04). LTL was inversely related to perceived stress (a (SE) = -0.02(0.003), p \u3c 0.001). In subgroup analyses, there was a negative association with LTL in African Americans with a high school education versus those with greater than a high school education(beta(SE) = -0.11(0.03), p-value \u3c 0.001). Conclusions Laboratory methods and population characteristics that differ by center can influence telomere length associations in multicenter settings, but these effects could be addressed through statistical adjustments. Proper evaluation of potential sources of bias can allow for combined multicenter analyses and may resolve some inconsistencies in reporting of LTL associations. Further, biologic effects on LTL may differ under certain psychosocial and racial/ethnic circumstances and could impact future health disparity studies

Autoradiographic localization of [delta] opioid receptors in the rat brain using a highly selective bis-penicillamine cyclic enkephalin analog

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25669/1/0000221.pd

Improving breast cancer services for African-American women living in St. Louis

A mixed methods, community-based research study was conducted to understand how provider-level factors contribute to the African-American and white disparity in breast cancer mortality in a lower socioeconomic status area of North St. Louis. This study used mixed methods including: (1) secondary analysis of Missouri Cancer Registry data on all 885 African-American women diagnosed with breast cancer from 2000 to 2008 while living in the geographic area of focus; (2) qualitative interviews with a subset of these women; (3) analysis of data from electronic medical records of the women interviewed; and (4) focus group interviews with community residents, patient navigators, and other health care professionals. 565 women diagnosed with breast cancer from 2000 to 2008 in the geographic area were alive at the time of secondary data analysis; we interviewed (n = 96; 17 %) of these women. Provider-level obstacles to completion of prescribed treatment included fragmented navigation (separate navigators at Federally Qualified Health Centers, surgical oncology, and medical oncology, and no navigation services in surgical oncology). Perhaps related to the latter, women described radiation as optional, often in the same words as they described breast reconstruction. Discontinuous and fragmented patient navigation leads to failure to associate radiation therapy with vital treatment recommendations. Better integrated navigation that continues throughout treatment will increase treatment completion with the potential to improve outcomes in African Americans and decrease the disparity in mortality

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

The general social survey-national death index: an innovative new dataset for the social sciences

<p>Abstract</p> <p>Background</p> <p>Social epidemiology seeks in part to understand how social factors--ideas, beliefs, attitudes, actions, and social connections--influence health. However, national health datasets have not kept up with the evolving needs of this cutting-edge area in public health. Sociological datasets that do contain such information, in turn, provide limited health information.</p> <p>Findings</p> <p>Our team has prospectively linked three decades of General Social Survey data to mortality information through 2008 via the National Death Index. In this paper, we describe the sample, the core elements of the dataset, and analytical considerations.</p> <p>Conclusions</p> <p>The General Social Survey-National Death Index (GSS-NDI), to be released publicly in October 2011, will help shape the future of social epidemiology and other frontier areas of public health research.</p

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation.

RATIONALE: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. OBJECTIVES: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. METHODS: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. RESULTS: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. CONCLUSIONS: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders

Collaborative planning approach to inform the implementation of a healthcare manager intervention for hispanics with serious mental illness: a study protocol

Background: This study describes a collaborative planning approach that blends principles of community-based participatory research (CBPR) and intervention mapping to modify a healthcare manager intervention to a new patient population and provider group and to assess the feasibility and acceptability of this modified intervention to improve the physical health of Hispanics with serious mental illness (SMI) and at risk for cardiovascular disease (CVD). Methods: The proposed study uses a multiphase approach that applies CBPR principles and intervention-mapping steps--an intervention-planning approach--to move from intervention planning to pilot testing. In phase I, a community advisory board composed of researchers and stakeholders will be assembled to learn and review the intervention and make initial modifications. Phase II uses a combination of qualitative methods--patient focus groups and stakeholder interviews--to ensure that the modifications are acceptable to all stakeholders. Phase III uses results from phase II to further modify the intervention, develop an implementation plan, and train two care managers on the modified intervention. Phase IV consists of a 12-month open pilot study (N = 30) to assess the feasibility and acceptability of the modified intervention and explore its initial effects. Lastly, phase V consists of analysis of pilot study data and preparation for future funding to develop a more rigorous evaluation of the modified intervention. Discussion: The proposed study is one of the few projects to date to focus on improving the physical health of Hispanics with SMI and at risk for CVD by using a collaborative planning approach to enhance the transportability and use of a promising healthcare manager intervention. This study illustrates how blending health-disparities research and implementation science can help reduce the disproportionate burden of medical illness in a vulnerable population

Urocortin-1 within the Centrally-Projecting Edinger-Westphal Nucleus Is Critical for Ethanol Preference

Converging lines of evidence point to the involvement of neurons of the centrally projecting Edinger-Westphal nucleus (EWcp) containing the neuropeptide Urocortin-1 (Ucn1) in excessive ethanol (EtOH) intake and EtOH sensitivity. Here, we expanded these previous findings by using a continuous-access, two-bottle choice drinking paradigm (3%, 6%, and 10% EtOH vs. tap water) to compare EtOH intake and EtOH preference in Ucn1 genetic knockout (KO) and wild-type (WT) mice. Based on previous studies demonstrating that electrolytic lesion of the EWcp attenuated EtOH intake and preference in high-drinking C57BL/6J mice, we also set out to determine whether EWcp lesion would differentially alter EtOH consumption in Ucn1 KO and WT mice. Finally, we implemented well-established place conditioning procedures in KO and WT mice to determine whether Ucn1 and the corticotropin-releasing factor type-2 receptor (CRF-R2) were involved in the rewarding and aversive effects of EtOH (2 g/kg, i.p.). Results from these studies revealed that (1) genetic deletion of Ucn1 dampened EtOH preference only in mice with an intact EWcp, but not in mice that received lesion of the EWcp, (2) lesion of the EWcp dampened EtOH intake in Ucn1 KO and WT mice, but dampened EtOH preference only in WT mice expressing Ucn1, and (3) genetic deletion of Ucn1 or CRF-R2 abolished the conditioned rewarding effects of EtOH, but deletion of Ucn1 had no effect on the conditioned aversive effects of EtOH. The current findings provide strong support for the hypothesis that EWcp-Ucn1 neurons play an important role in EtOH intake, preference, and reward