The adenosine A1 receptor (AjR) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed ...because ofa lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that 2-amino-4-(3,5-bis(trifluoromethyl) phenyl)thiophen-3-yl)(4-chlorophenyl)methanone (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, M1PS521 and a Gi2 heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby M1PS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.
Cooking at home is likely to be associated with benefits to diet and health. However, the nuanced perceptions and practices linked to different types of cooking are not yet fully understood. This ...research aimed to explore the specific concept of 'home cooking', using qualitative research from the UK and US. Data from two previously completed studies exploring cooking at home were combined and a new secondary analysis was undertaken using the Framework Method. Data in the first study were drawn from participants in the North East of the UK who were interviewed. Data in the second study were drawn from participants in Baltimore, US, who took part in focus groups. Data from a total of 71 adults (18 UK and 53 US), with diverse sociodemographic characteristics and experiences of cooking, were analysed. In both countries, participants distinguished 'home cooking' as a distinct subtype of cooking at home. 'Home cooking' was defined in terms of preparing a meal from scratch, cooking with love and care, and nostalgia. Cooking at home had a range of dimensions, and perceptions of 'home cooking' tended to focus on social and emotional associations. In future, public health initiatives might, therefore, highlight the potential social and emotional benefits of 'home cooking', rather than emphasising implications for physical health.
Ready-to-eat meals (to eat in, to take away or to be delivered) sold by food outlets are often more energy dense and nutrient poor compared with meals prepared at home, making them a reasonable ...target for public health intervention. The aim of the research presented in this paper was to systematically identify and describe interventions to promote healthier ready-to-eat meals (to eat in, to take away, or to be delivered) sold by specific food outlets in England.
A systematic search and sift of the literature, followed by evidence mapping of relevant interventions, was conducted. Food outlets were included if they were located in England, were openly accessible to the public and, as their main business, sold ready-to-eat meals. Academic databases and grey literature were searched. Also, local authorities in England, topic experts, and key health professionals and workers were contacted. Two tiers of evidence synthesis took place: type, content and delivery of each intervention were summarised (Tier 1) and for those interventions that had been evaluated, a narrative synthesis was conducted (Tier 2).
A total of 75 interventions were identified, the most popular being awards. Businesses were more likely to engage with cost neutral interventions which offered imperceptible changes to price, palatability and portion size. Few interventions involved working upstream with suppliers of food, the generation of customer demand, the exploration of competition effects, and/or reducing portion sizes. Evaluations of interventions were generally limited in scope and of low methodological quality, and many were simple assessments of acceptability.
Many interventions promoting healthier ready-to-eat meals (to eat in, to take away, or to be delivered) sold by specific food outlets in England are taking place; award-type interventions are the most common. Proprietors of food outlets in England that, as their main business, sell ready-to-eat meals, can be engaged in implementing interventions to promote healthier ready-to-eat-food. These proprietors are generally positive about such interventions, particularly when they are cost neutral and use a health by stealth approach.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Phospholipase C (PLC) enzymes are an important family of regulatory proteins involved in numerous cellular functions, primarily through hydrolysis of the polar head group from inositol-containing ...membrane phospholipids. U73122 (1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione), one of only a few small molecules reported to inhibit the activity of these enzymes, has been broadly applied as a pharmacological tool to implicate PLCs in diverse experimental phenotypes. The purpose of this study was to develop a better understanding of molecular interactions between U73122 and PLCs. Hence, the effects of U73122 on human PLCβ3 (hPLCβ3) were evaluated in a cell-free micellar system. Surprisingly, U73122 increased the activity of hPLCβ3 in a concentration- and time-dependent manner; up to an 8-fold increase in enzyme activity was observed with an EC50 = 13.6 ± 5 μm. Activation of hPLCβ3 by U73122 required covalent modification of cysteines as evidenced by the observation that enzyme activation was attenuated by thiol-containing nucleophiles, l-cysteine and glutathione. Mass spectrometric analysis confirmed covalent reaction with U73122 at eight cysteines, although maximum activation was achieved without complete alkylation; the modified residues were identified by LC/MS/MS peptide sequencing. Interestingly, U73122 (10 μm) also activated hPLCγ1 (>10-fold) and hPLCβ2 (∼2-fold); PLCδ1 was neither activated nor inhibited. Therefore, in contrast to its reported inhibitory potential, U73122 failed to inhibit several purified PLCs. Most of these PLCs were directly activated by U73122, and a simple mechanism for the activation is proposed. These results strongly suggest a need to re-evaluate the use of U73122 as a general inhibitor of PLC isozymes.
The World Health Organization identified medication adherence as the greatest opportunity to improve outcomes related to chronic disease. Adherence rates of 80% or greater, or taking medication as ...prescribed at least 80% of the time, can positively impact health outcomes.
A prior study at two nurse practitioner (NP)-owned family practice clinics in New Hampshire measured medication adherence among adult type-2 diabetes mellitus (DM) patients at 77% and declining over a 4-year period. Patients' hemoglobin A1c rates were stagnant despite previous initiative to improve this biomarker.
Nurse practitioners were educated on provider-driven strategies to improve medication adherence in the older adult with DM, hypertension, and hyperlipidemia. A review of medical records was performed on patients for 52 weeks before seminar and 13 weeks after seminar to capture medication adherence rates and clinical biomarkers.
Pre- and postseminar data were analyzed to determine whether the seminar resulted in improved adherence and clinical outcomes.
Preseminar medication adherence rates exceeded evidence-based standards of 80% for each condition. Postseminar, statistically significant improved adherence rates were seen among DM patients with hypertension. Adherence worsened among hyperlipidemia patients, although this change was not statistically significant. Clinical biomarkers saw little change.
This quality improvement project found that educating NPs on strategies to improve medication adherence can improve adherence among DM and hypertension patients. Continued education and measurement of adherence and clinical biomarkers are encouraged to capture more postseminar visits. This project adds to the growing body of knowledge about patients managed by NPs and NP-owned practices.
Diabetes is a major health concern in the U.S. with increasing prevalence. There are limited data on nurse practitioner (NP) roles in diabetes management and clinical patient outcomes in relation to ...national standards of care. This project aimed to identify rates of American Diabetes Association (ADA) guideline adherence of two NP-owned and operated practices during an ongoing four-year quality improvement project.
Methods: Electronic health records of 83 - 112 patients (depending on the year) ages > 18 years with type 2 diabetes were reviewed. Mean A1C and rates of adherence to ADA standards were compared from 2013 to 2017 and to national and state data.
Findings demonstrated that diabetes management provided by NPs consistently adhered to national ADA standards of care and met or exceeded national data. This four-year ongoing quality improvement project has led to the implementation of practice modifications that continue to improve patient outcomes through increased adherence to ADA guidelines.
Strategies which improve adherence to ADA standards of care by NPs are essential. Identifying rates of adherence and implementing quality improvement strategies can significantly improve the quality of care provided to patients with diabetes.
Abstract Background Food choices have an important impact on health. Preparation methods, including home cooking, are associated with food choices, and evidence suggests that home cooking may be ...linked to dietary and health benefits. Little is known about how and why people choose to cook and their experience of cooking; previous qualitative research has often been limited in perspective. We aimed to develop an in-depth understanding of home cooking practices, experiences, and perceptions among adults in North East England. Methods A matrix including sociodemographic characteristics, cooking skills, and interest in cooking was used to purposively sample adult participants for semi-structured qualitative interviews. Participants took photographs of their interactions with food to develop photographic food diaries, which were used as prompts during photo-elicitation interviews. Transcripts were analysed with the framework method. Findings Interviews were conducted to data saturation with 18 adults (five men, 13 women), aged approximately 20–80 years. Practices varied widely, from complete reliance on pre-prepared foods to frequently producing complex meals prepared entirely from basic ingredients. Key themes emerged about identity (eg, roles), the process of cooking (eg, skills), and situational drivers (eg, necessity). Resources also affected home cooking behaviour, in terms of time, money, and facilities. Participants' cooking practices generally reflected compromises between varied competing demands and challenges in life. Both personal motivations to cook and the influence of others on cooking experiences and perceptions were important determinants. Most people seemed overall to be content with their home cooking behaviour, although they ideally aspired to cook more often and more extensively from basic ingredients. Interpretation Our findings indicate that home cooking is complex, with heterogeneous practices, experiences, and perceptions both between individuals and within the same individual over time, in response to shifting priorities and circumstances. Transferability of the results might be limited by the regional participant sample. Focusing interventions on life-transition points at which priorities and circumstances alter could prove to be an effective strategy to encourage home cooking. Interventions should be carefully targeted to stimulate personal motivation and social norms, to avoid complacency about changes in home cooking behaviour. Funding This report is independent research arising from a doctoral research fellowship (DRF-2014-07-020) for SDHM, supported by the National Institute for Health Research (NIHR). JA and MLW received funding from the Centre for Diet and Activity Research.
Adults ages ≥65 years are at increased risk for infectious diseases. Ensuring these individuals are fully vaccinated is imperative. The purpose of this study was to assess the immunization rates of ...adults ages ≥65 years managed by nurse practitioners (NPs) and compare the results with national immunization rates and Healthy People 2020 goals.
A convenience sample of adults ages ≥65 years was obtained from two NP-managed clinics. The vaccine records of each subject were reviewed for documentation of having received five vaccines (tetanus, diphtheria, and pertussis; influenza; pneumococcal polysaccharide vaccine 23; pneumococcal conjugate vaccine 13; and herpes zoster vaccine).
One hundred and fifty females (70.8%) and 62 males (29.2%) met inclusion criteria. NP-managed patients had higher immunization rates than the national averages across all five major vaccines. The herpes zoster vaccination rates exceeded the recommendations from Healthy People 2020 whereas pneumococcal and influenza rates were below.
The stocking of vaccines within the NP-managed clinics, direct billing to Medicare for Part D vaccines, and previsit care planning likely contributed to the high vaccination rates. These high immunization rates in patients managed by NPs provide support for the important role that NPs play in the care of older adults.
New Findings
What is the central question of this study?
This study evaluated the following central question: does N‐acetylcysteine (N‐AC), an antioxidant that readily penetrates the blood–brain ...barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia?
What is the main finding and its importance?
We demonstrate that N‐AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N‐AC, have therapeutic potential in obstructive sleep apnoea.
This investigation tested the following hypotheses: that (i) N‐acetylcysteine (N‐AC) attenuates hyperacute intermittent hypoxia‐induced sympathoexcitation, (ii) without elevating superoxide measured in peripheral venous blood. Twenty‐eight healthy human subjects were recruited to the study. One hour before experimentation, each subject randomly ingested either 70 mg kg−1 of N‐AC (n = 16) or vehicle placebo (n = 12). Three‐lead ECG and arterial blood pressure, muscle sympathetic nerve activity (n = 17) and whole‐blood superoxide concentration (using electron paramagnetic resonance spectroscopy; n = 12) were measured. Subjects underwent a 20 min hyperacute intermittent hypoxia training (hAIHT) protocol that consisted of cyclical end‐expiratory apnoeas with 100% nitrogen. N‐AC decreased muscle sympathetic nerve activity after hAIHT compared with placebo (P < 0.02). However, N‐AC did not alter superoxide concentrations in venous blood compared with placebo (P > 0.05). Moreover, hAIHT did not increase superoxide concentrations in the peripheral circulation as measured by electron paramagnetic resonance (P > 0.05). Based on these findings, we contend that (i) hAIHT and (ii) the actions of N‐AC in hAIHT are primarily mediated centrally rather than peripherally, although central measurements of reactive oxygen species are difficult to obtain in human subjects, thus making this assertion difficult to verify. This investigation suggests the possibility of developing a pharmaceutical therapy to inhibit the sympathoexcitation associated with obstructive sleep apnoea.
Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the ...acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
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