In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of Agonists

GPCRs regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Stimulation of a GPCR by an extracellular ligand triggers receptor signaling via G proteins, and this process is highly regulated. Receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process of which receptor internalization is postulated as a key event. The in vivo significance of GPCR internalization is poorly understood. In fact, the majority of studies have been performed in transfected cell systems, which do not adequately model physiological environments and the complexity of integrated responses observed in the whole animal.In this study, we used knock-in mice expressing functional fluorescent delta opioid receptors (DOR-eGFP) in place of the native receptor to correlate receptor localization in neurons with behavioral responses. We analyzed the pain-relieving effects of two delta receptor agonists with similar signaling potencies and efficacies, but distinct internalizing properties. An initial treatment with the high (SNC80) or low (AR-M100390) internalizing agonist equally reduced CFA-induced inflammatory pain. However, subsequent drug treatment produced highly distinct responses. Animals initially treated with SNC80 showed no analgesic response to a second dose of either delta receptor agonist. Concomitant receptor internalization and G-protein uncoupling were observed throughout the nervous system. This loss of function was temporary, since full DOR-eGFP receptor responses were restored 24 hours after SNC80 administration. In contrast, treatment with AR-M100390 resulted in retained analgesic response to a subsequent agonist injection, and ex vivo analysis showed that DOR-eGFP receptor remained G protein-coupled on the cell surface. Finally SNC80 but not AR-M100390 produced DOR-eGFP phosphorylation, suggesting that the two agonists produce distinct active receptor conformations in vivo which likely lead to differential receptor trafficking.Together our data show that delta agonists retain full analgesic efficacy when receptors remain on the cell surface. In contrast, delta agonist-induced analgesia is abolished following receptor internalization, and complete behavioral desensitization is observed. Overall these results establish that, in the context of pain control, receptor localization fully controls receptor function in vivo. This finding has both fundamental and therapeutic implications for slow-recycling GPCRs

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Model of Functioning of Water-Management System With One Water Basin of Complex Function

The model of calculation for the balance of water-management beneath a water basin has been created. The model enables calculating water balance not only at the separate river sites, but also at the whole territory of water-management system

May measurement month 2019: blood pressure screening results in Georgia, Europe

May Measurement Month is a global campaign aimed at raising public awareness of hypertension and to improve the management of hypertension—the main risk factor for cardiovascular diseases in the population. Screening was carried out at 400 sites on a national scale. More than 500 volunteers, including physicians (80%) and students of medical universities (20%) participated in the screening. To familiarize them with the research tools and standard blood pressure (BP) measurement method, they were trained by the members of the Georgian Society of Hypertension and the National Center for Disease Control and Public Health’s staff. Medical societies, health-care professionals, public health workers, social mass media, and other stakeholders were actively involved in the recruitment process. A total of 13 267 (38.5% males and 61.5% females) individuals were screened. The mean age of participants was 54.7 years (SD 15.9). All participants were Caucasian. After imputation of missing BP readings, 8510 (64.1%) were found to have hypertension, out of whom 7269 (85.4%) were aware of their condition, 7232 (85.0%) were on medication, and 1278 (15.0%) were not taking any medication. Of those taking antihypertensive medication, 34.8% had their BP controlled (<140/90 mmHg). May Measurement Month detected a high proportion of participants with hypertension, with results indicating low rates of control in Georgia

May measurement month 2018: an analysis of blood pressure screening results in Georgia.

May Measurement Month (MMM) is aimed at raising public awareness about arterial hypertension-the main risk factor for cardiovascular diseases in the population. Screening was carried out at 200 sites on a national scale. More than 500 volunteers, including doctors (80%) and medical students (20%) participated in the screening. To familiarize them with the research tools and standard blood pressure (BP) measurement method, their training was conducted by the Georgian Society of Hypertension in Tbilisi and other large cities. Social and mass media, medical societies, and other stakeholders were actively involved in the recruitment process. A total of 10 756 people were screened. The mean age of participants was 53.1 years (SD 16.1). Males-67.9%, females-32.1%. One hundred percent were White. After multiple imputation, the number of hypertensive patients was 6.037 (56.1%) and out of them 4950 were aware and 4701 (77.9%) were on medication, 1336 (22.1%) were not taking a medication. Of those taking antihypertensive medication, 38.2% had controlled BP. In spite of non-randomized selection and certain restrictions with respect to extrapolation of the results, MMM comprehensively reflects an urgent problem and major gaps in the health system. Based on the above, its importance is extremely valuable for identifying public health policy priorities