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MJN110 inhibits the enzyme monoacylglycerol lipase (MAGL) to increase levels of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG), an endogenous high-efficacy agonist of cannabinoid 1 and 2 receptors (CB1/2R). MAGL inhibitors are under consideration as candidate analgesics, and we reported previously that acute MJN110 produced partial antinociception in an assay of pain-related behavioral depression in mice. Given the need for repeated analgesic administration in many pain patients and the potential for analgesic tolerance during repeated treatment, this study examined antinociceptive effects of repeated MJN110 on pain-related behavioral depression and CB1R-mediated G-protein function. Male and female ICR mice were treated daily for 7 days in a 2x2 design with (a) 1.0 mg/kg/day MJN110or its vehicle followed by (b) intraperitoneal injection of dilute lactic acid (IP acid) or its vehicle as a visceral noxious stimulus to depress nesting behavior. After behavioral testing, G-protein activity was assessed in lumbar spinal cord andfive brain regions using an assay of CP55,940-stimulated [35S]GTPÉ£S activation. As reported previously, acute MJN110 produced partial but significant relief of IP acid-induced nesting depression on Day 1. After 7 days, MJN110 continued to produce significant but partial antinociception in males, while antinociceptive tolerance developed in females. Repeated MJN110 also produced modest decreases in maximum levels of CP55,940-induced [35S]GTPÉ£S binding in spinal cord and most brain regions. These results indicate that repeated treatment with a relatively low antinociceptive MJN110 dose produces only partial and sex-dependent transient antinociception associated with the emergence of CB1R desensitization in this model of IP acid-induced nesting depression. Significance Statement The drug MJN110 inhibits monoacylglycerol lipase (MAGL) to increase levels of the endogenous cannabinoid 2-arachidonoylglycerol and produce potentially useful therapeutic effects including analgesia. This study used an assay of pain-related behavioral depression in mice to show that repeated MJN110 treatment produced (1) weak but sustained antinociception in male mice, (2) antinociceptive tolerance in females, and (3) modest cannabinoid-receptor desensitization that varied by region and sex. Antinociceptive tolerance may limit the utility of MJN110 for treatment of pain.
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The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.
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Receptores Opioides mu , Animais , Relação Estrutura-Atividade , Camundongos , Receptores Opioides mu/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Humanos , Estrutura Molecular , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Tiofenos/uso terapêutico , Masculino , Relação Dose-Resposta a Droga , Analgésicos Opioides/farmacologia , Analgésicos Opioides/química , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/química , Morfina/farmacologiaRESUMO
BACKGROUND: This study examines the perceptions of the Australian public canvassed in 2021 during the COVID-19 pandemic about their health system compared to four previous surveys (2008, 2010, 2012 and 2018). METHODS: In 2021, a nationwide online survey was conducted with a representative sample of Australians (N = 5100) recruited via market research panels. The results were compared to previous nationwide Australian survey samples from 2018 (N = 1024), 2012 (N = 1200), 2010 (N = 1201) and 2008 (N = 1146). The survey included questions consistent with previous polls regarding self-reported health status and overall opinions of, and confidence in, the Australian health system. RESULTS: There was an increase in the proportion of respondents reporting positive perceptions at each survey between 2008 and 2021, with a significantly higher proportion of respondents expressing a more positive view of the Australian healthcare system in 2021 compared to previous years (χ2(8, N = 9645) = 487.63, p < 0.001). In 2021, over two-thirds of respondents (n = 3949/5100, 77.4%) reported that following the COVID-19 pandemic, their confidence in the Australian healthcare system had either remained the same (n = 2433/5100, 47.7%) or increased (n = 1516/5100, 29.7%). Overall, respondents living in regional or remote regions, younger Australians (< 45 years) and women held less positive views in relation to the system. In 2021, the most frequently identified area for urgent improvement was the need for more healthcare workers (n = 1350/3576, 37.8%), an area of concern particularly for Australians residing in regional or remote areas (n = 590/1385, 42.6%). CONCLUSIONS: Irrespective of disruptions to the Australian healthcare system caused by the COVID-19 pandemic, Australians' perceptions of their healthcare system were positive in 2021. However, concerns were raised about inadequate workforce capacity and the cost of healthcare, with differences identified by age groups and geographical location. PATIENT OR PUBLIC CONTRIBUTION: Health consumer representatives from the Consumers Health Forum of Australia contributed to the co-design, deployment, analysis and interpretation of the results of this survey. J.A. and L.W. from the Consumers Health Forum of Australia contributed to the development of the paper.
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COVID-19 , Opinião Pública , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , Austrália , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Inquéritos e Questionários , Idoso , Atenção à Saúde , Adolescente , Adulto Jovem , SARS-CoV-2 , Pandemias , PercepçãoRESUMO
Fusarium head blight (FHB), caused by the fungus Fusarium graminearum, is associated with grain contamination with mycotoxins such as deoxynivalenol (DON) and zearalenone (ZEA). Unlike DON, less is known about factors affecting ZEA production during FHB epidemics. The objective of this study was to quantify ZEA contamination of wheat grain as influenced by temperature, relative humidity, FHB index (IND), grain maturation, simulated late-season rainfall, and harvest timing. Mean ZEA concentrations were low (<1.1 ppm) during the early stages of grain development (25 to 31 days after anthesis [DAA]) but rapidly increased 35 to 51 DAA in field experiments, particularly under rainy conditions. Five or ten consecutive days with simulated rainfall shortly before harvest greatly increased ZEA contamination. Similarly, extremely high levels of ZEA (51.8 to 468.6 ppm) were observed in grain from spikes exposed to 100% relative humidity (RH) at all tested temperatures and mean IND levels under controlled conditions. Interestingly, at RH ≤ 90%, ZEA concentrations were very low (0.1 to 3.6 ppm) at all tested temperatures, even at IND above 90%. At 100% RH, mean ZEA contamination was significantly higher at 20 and 25°C (235.1 and 278.2 ppm) than at 30°C (104.7 ppm). Grain harvested early and not exposed to rainfall had lower mean ZEA than grain harvested late and/or subjected to preharvest rainfall. This study was the first to associate ZEA contamination of grain from FHB-affected wheat spikes with temperature and moisture and show through designed experiments that early harvest could be a useful strategy for reducing ZEA contamination.
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Fusarium , Micotoxinas , Tricotecenos , Zearalenona , Zearalenona/farmacologia , Triticum/microbiologia , Doenças das Plantas/microbiologia , Grão Comestível/microbiologiaRESUMO
Fusarium head blight (FHB) of wheat, caused by the fungus Fusarium graminearum, is associated with grain contamination with mycotoxins such as deoxynivalenol (DON). Although FHB is often positively correlated with DON, this relationship can break down under certain conditions. One possible explanation for this could be the conversion of DON to DON-3-glucoside (D3G), which is typically missed by common DON testing methods. The objective of this study was to quantify the effects of temperature, relative humidity (RH), and preharvest rainfall on DON, D3G, and the D3D/DON relationship. D3G levels were higher in grain from spikes exposed to 100% RH than to 70, 80, or 90% RH at 20 and 25°C across all tested levels of mean FHB index (percentage of diseased spikelets per spike). Mean D3G contamination was higher at 20°C than at 25 or 30°C. There were significantly positive linear relationships between DON and D3G. Rainfall treatments resulted in significantly higher mean D3G than the rain-free check and induced preharvest sprouting, as indicated by low falling numbers (FNs). There were significant positive relationships between the rate of increase in D3G per unit increase in DON (a measure of conversion) and sprouting. As FN decreased, the rate of D3G conversion increased, and this rate of conversion per unit decrease in FN was greater at relatively low than at high mean DON levels. These results provide strong evidence that moisture after FHB visual symptom development was associated with DON-to-D3G conversion and constitute valuable new information for understanding this complex disease-mycotoxin system.
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Fusarium , Micotoxinas , Triticum/microbiologia , Doenças das Plantas/microbiologia , Grão ComestívelRESUMO
OBJECTIVES: This paper compares the evolution of the psychosocial sector in two Australian regions pre and post introduction of the National Disability Insurance Scheme - a major reform to the financing, planning and provision of disability services in Australia, intended to create greater competition and efficiency in the market, and more choice for service users. METHODS: We used a standardised service classification instrument based on a health ecosystems approach to assess service availability and diversity of psychosocial services provided by non-government organisations in two Primary Health Network regions. RESULTS: We identified very different evolutionary pathways in the two regions. Service availability increased in Western Sydney but decreased in the Australian Capital Territory. The diversity of services available did not increase in either Primary Health Network 4 years after the reform. Many services were experiencing ongoing funding uncertainty. CONCLUSION: Assumptions of increased efficiency through organisational scaling up, and a greater diversity in range of service availability were not borne out. IMPLICATIONS: This study shows the urgent need for evaluation of the effects of the NDIS on the provision of psychosocial care in Australia. Four years after the implementation of the NDIS at vast expense key objectives not been met for consumers or for the system as a whole, and an environment of uncertainty has been created for providers. It demonstrates the importance of standardised service mapping to monitor the effects of major reforms on mental health care as well as the need for a focus at the local level.
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Pessoas com Deficiência , Seguro por Deficiência , Reabilitação Psiquiátrica , Humanos , Austrália , EcossistemaRESUMO
Electrostatic attraction between two groups of opposite charge, typically known as ion-pairing, offers unique opportunities for the design of systems to enable selectivity control in chemical reactions. Catalysis using noncovalent interactions is an established and vibrant research area, but it is noticeable that hydrogen bonding interactions are still the main interaction of choice in system design. Opposite charges experience the powerful force of Coulombic attraction and have the ability to exert fundamental influence on the outcome of reactions that involve charged reagents, intermediates or catalysts. In this Perspective, we will examine how ion-pairing interactions have been used to control selectivity in C-H bond functionalization processes. This broad class of reactions provides an interesting and thought-provoking lens through which to examine the application of ion-pairing design strategies because it is one that encompasses great mechanistic diversity, poses significant selectivity challenges, and perhaps most importantly is of immense interest to synthetic chemists in both industry and academia. We survey reactions that proceed via radical and ionic mechanisms alongside those that involve transition metal catalysis and will deal with control of site-selectivity and enantioselectivity. We anticipate that as this emerging area develops, it will become an ever-more important design strategy for selectivity control.
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Elementos de Transição , Catálise , Ligação de Hidrogênio , Indicadores e Reagentes , Íons , Elementos de Transição/químicaRESUMO
Ortho-sulfonyl anilines are important building blocks for a range of applications. We report the discovery of an aromatic rearrangement reaction of O-(arenesulfonyl)hydroxylamines which leads directly to ortho-sulfonyl anilines through formation of a new C-N bond with excellent levels of regiocontrol for the ortho position(s) over all others. We establish that the rearrangement is proceeding through an intermolecular mechanism and propose that the regiocontrol observed is the result of attractive non-covalent interactions occurring during the C-N bond-forming step. Importantly, this method is complementary to classical aniline sulfonation in terms of the variously substituted regioisomers that can be obtained and it is also applicable to O-(benzylsulfonyl) hydroxylamines.
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The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactive N-centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the arene ortho position. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly to ortho-phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuable ortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.
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In the present work, we reported the application of a nitrogen-walk approach on developing a series of novel opioid ligands containing an azaindole moiety at the C6-position of the epoxymorphinan skeleton. In vitro study results showed that introducing a nitrogen atom around the indole moiety not only retained excellent binding affinity, but also led to significant functional switch at the mu opioid receptor (MOR). Further computational investigations provided corroborative evidence and plausible explanations of the results of the in vitro studies. Overall, our current work implemented a series of novel MOR ligands with high binding affinity and considerably low efficacy, which may shed light on rational design of low efficacy MOR ligands for opioid use disorder therapeutics.
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Naltrexona/análogos & derivados , Nitrogênio/química , Receptores Opioides mu/efeitos dos fármacos , Sítios de Ligação , Humanos , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Naltrexona/síntese química , Naltrexona/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Conformação ProteicaRESUMO
In the present study, the role of 3-hydroxy group of a series of epoxymorphinan derivatives in their binding affinity and selectivity profiles toward the opioid receptors (ORs) has been investigated. It was found that the 3-hydroxy group was crucial for the binding affinity of these derivatives for all three ORs due to the fact that all the analogues 1a-e exhibited significantly higher binding affinities compared to their counterpart 3-dehydroxy ones 6a-e. Meanwhile most compounds carrying the 3-hydroxy group possessed similar selectivity profiles for the kappa opioid receptor over the mu opioid receptor as their corresponding 3-dehydroxy derivatives. [35S]-GTPγS functional assay results indicated that the 3-hydroxy group of these epoxymorphinan derivatives was important for maintaining their potency on the ORs with various effects. Further molecular modeling studies helped comprehend the remarkably different binding affinity and functional profiles between compound 1c (NCP) and its 3-dehydroxy analogue 6c.
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Morfinanos/química , Morfinanos/farmacologia , Receptores Opioides/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Receptores Opioides/químicaRESUMO
BACKGROUND: With 50% of Australians having chronic disease, health consumer views are an important barometer of the 'health' of the healthcare system for system improvement and sustainability. AIMS: To describe the views of Australian health consumers with and without chronic conditions when accessing healthcare. METHODS: A survey of a representative sample of 1024 Australians aged over 18 years, distributed electronically and incorporating standardised questions and questions co-designed with consumers. RESULTS: Respondents were aged 18-88 years (432 males, 592 females) representing all states and territories, and rural and urban locations. General practices (84.6%), pharmacies (62.1%) and public hospitals (32.9%) were the most frequently accessed services. Most care was received through face-to-face consultations; only 16.5% of respondents accessed care via telehealth. The 605 (59.0%) respondents with chronic conditions were less likely to have private health insurance (50.3% vs 57.9%), more likely to skip doses of prescribed medicines (53.6% vs 28.6%), and miss appointments with doctors (15.3% vs 10.1%) or dentists (52.8% vs 40.4%) because of cost. Among 480 respondents without private health insurance, unaffordability (73.5%) or poor value for money (35.3%) were the most common reasons. Most respondents (87.7%) were confident that they would receive high quality and safe care. However, only 57% of people with chronic conditions were confident that they could afford needed healthcare compared with 71.3% without. CONCLUSIONS: Health consumers, especially those with chronic conditions, identified significant cost barriers to access of healthcare. Equitable access to healthcare must be at the centre of health reform.
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Reforma dos Serviços de Saúde , Acessibilidade aos Serviços de Saúde , Adulto , Austrália/epidemiologia , Doença Crônica , Custos e Análise de Custo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The views and experiences of the Australian public are an important barometer of the health system. This study provides key findings about the changing views held by Australians over time regarding their individual experiences and perceptions of the overall performance of the health system. METHODS: A population-based online survey was conducted in 2018 (N = 1024). Participants were recruited through market research panels. The results were compared with previous Australian population survey data sets from 2008 (N = 1146), 2010 (N = 1201) and 2012 (N = 1200), each of which used different population samples. The survey included questions consistent with previous surveys regarding self-reported health status, and questions about use, opinions and experiences of the health system. RESULTS: Overall, there has been a shift in views from 2008 to 2018, with a higher proportion of respondents now viewing the Australian health-care system more positively (X2 (2, N = 4543) = 96.59, P < .001). In 2018, areas for attention continued to include the following: the need for more doctors, nurses and other health workers (29.0%); lower costs for care or Orion medicines (27.8%); more access to care (13.1%); and enhancements in residential aged care (17.3% rated these services as 'bad' or 'very bad'). CONCLUSIONS: This research suggests that Australians' perceptions of their health-care system have significantly improved over the last decade; however, concerns have emerged over access to medicines, inadequate workforce capacity and the quality of aged care facilities. Our study highlights the value of periodically conducting public sentiment surveys to identify potential emerging health system problems.
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Atenção à Saúde , Opinião Pública , Idoso , Austrália , Pessoal de Saúde , Humanos , Inquéritos e QuestionáriosRESUMO
The increased use of sensor technology has been crucial in releasing the potential for remote rehabilitation. However, it is vital that human factors, that have potential to affect real-world use, are fully considered before sensors are adopted into remote rehabilitation practice. The smart sensor devices for rehabilitation and connected health (SENDoc) project assesses the human factors associated with sensors for remote rehabilitation of elders in the Northern Periphery of Europe. This article conducts a literature review of human factors and puts forward an objective scoring system to evaluate the feasibility of balance assessment technology for adaption into remote rehabilitation settings. The main factors that must be considered are: Deployment constraints, usability, comfort and accuracy. This article shows that improving accuracy, reliability and validity is the main goal of research focusing on developing novel balance assessment technology. However, other aspects of usability related to human factors such as practicality, comfort and ease of use need further consideration by researchers to help advance the technology to a state where it can be applied in remote rehabilitation settings.
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Tecnologia de Sensoriamento Remoto , Tecnologia , Idoso , Europa (Continente) , Estudos de Viabilidade , Humanos , Reprodutibilidade dos TestesRESUMO
PURPOSE: This systematic review aims to explore patient satisfaction (PS) among patients who used Ministry of Health (MoH) primary care centres in Saudi Arabia, with a focus on their communication with physicians. DATA SOURCES: Medline, CINAHL, Embase, Global Health, the Saudi Medical Journal, Annals of Saudi Medicine, the Journal of Family and Community Medicine and Google Scholar. STUDY SELECTION/DATA EXTRACTION: The review focused on studies concerning PS in Saudi MoH primary care centres published between 2005 and 2017. Two independent reviewers confirmed that the included studies met the selection criteria, assessed the quality of the selected studies and extracted their significant characteristics. All of the articles were examined in terms of the five main domains that determine the patient-physician communication identified by Boquiren, Hack, Beaver et al. (What do measures of patient satisfaction with the doctor tell us? Patient Educ Couns 2015;98:1465-73). RESULTS: The literature search retrieved a total of 846 studies. Only 10 studies met the selection criteria. All of the studies reported at least one domain of PS. There was a strong relationship between the level of education, income and satisfaction rate. Most of the studies reported PS in terms of the domains of availability and accessibility, and communication. Few of the studies covered the other domains, such as relational conduct, views on the physician's technical skills/knowledge and the personal qualities of physicians. CONCLUSION: There was a contradiction between the patients' responses to the surveys on the domains of PS and their actual experience. While the patients reported that they were satisfied with primary care centres, they frequently attended the emergency department directly. This indicated that they were unlikely to be fully satisfied with the primary healthcare centre.
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Satisfação do Paciente , Relações Médico-Paciente , Atenção Primária à Saúde/normas , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Qualidade da Assistência à Saúde , Arábia SauditaRESUMO
In view of the increasing global importance of women as consumers/patients, employees, employers, and leaders, we discuss 10 best practices for the global health care organizations to attain greater gender parity: (1) make diversity and inclusion (D&I) an essential element of global strategy, (2), tailor global D&I to fit local needs, (3) embed D&I throughout organizations, (4) multiply D&I impact via external partnerships, (5) maximize the role of employee resource groups, (6) maximize the role of diversity councils, (7) leverage D&I for innovation, (8) leverage D&I for business development, (9) engage CEO, and (10) make sharing of D&I best practices a meta best practice. These are practical approaches that can be used in both overall strategic planning and in day-to-day management of health care institutions. We examine this in the context of what we call Gender Diversity 5.0, which will be an increasingly important part of today's health care environment as the business imperative grows for diversity, inclusion, and engagement at the patient, employee, and executive levels.
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Atenção à Saúde , Saúde Global , Guias de Prática Clínica como Assunto , HumanosRESUMO
AIMS: To study bladder sensation during a forced diuresis protocol and to assess differences in sensation perceived by different ethnic groups and after drinking artificially sweetened water. METHODS: Female Caucasian and south Indian Asian volunteers performed the diuresis protocol drinking water, or water sweetened with saccharin (5 mg/kg body weight). Participants recorded filling sensation every 5 min while drinking 250-350 mL/15 min. They were asked to record the strongest sensation before voiding as maximum sensation, before voiding. The void was measured and sensation immediately recorded as minimum. The process was repeated. Voided volume and time required to achieve maximum sensation during cycle 2 were compared by water and sweetener, ethnic group, and age. RESULTS: Twenty Asian and 20 Caucasian volunteers participated. No differences in maximum voided volume or diuresis rate was seen by ethnicity. Median diuresis with sweetener was 16.7 mL/min (8.6-35) compared to 13.2 (7.1-25) with water (P = 0.008), a difference accounted for by 16 women with >5 mL/min difference in diuresis rate. These were excluded to leave 24 women with similar diuresis rates with both sweetener and water (14.8 mL/min (8.6-28.0) and 13.2 mL/min (7.1-25.0). In these women, time to achieve maximum sensation was lower with sweetener than water: 37.5 min (20-85) versus 50.0 min (20-80), P = 0.002, with no difference in voided volume. CONCLUSIONS: Water sweetened with saccharin produced an increased diuresis rate in some women. After controlling for this, time to recording maximum sensation was decreased with sweetened water, suggesting saccharin has an effect upon perceived sensation.
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Diurese/efeitos dos fármacos , Percepção/efeitos dos fármacos , Sacarina/farmacologia , Edulcorantes/farmacologia , Bexiga Urinária/efeitos dos fármacos , Adulto , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensação , Método Simples-Cego , Micção/efeitos dos fármacos , Água , Adulto JovemRESUMO
AIMS: To identify in the human bladder the structures which express the Beta-3 adrenoceptor (ß3AR). METHODS: Human bladders from cadaveric organ donors (equally balanced in sex and age) were collected. Bladders were immediately fixed in paraformaldehyde and further processed for cryostat sectioning. Single and double immunohistochemistry was performed using antibodies against ß3AR C-terminal, ß3AR N-terminal, a pan-neuronal marker (ß3-Tubulin) and markers of cholinergic (Vesicular Acetylcholine Transporter), adrenergic (Tyrosine Hidroxylase), and peptidergic (Calcitonin Gene-Related Peptide) nerve fibers. RESULTS: Nerve fibers expressing immunoreactivity for ß3AR were abundantly found in the mucosa and muscular layers of the human bladder. No ß3AR-IR was detected on urothelial or smooth muscle cells. The presence of ß3AR-IR in nerve fibers was confirmed by co-expression with ß3-Tubulin. Nerve fibers expressing ß3AR-IR were cholinergic, VAChT+ , and abundantly observed in the suburothelium. The cholinergic fibers were in close proximity and intermingled with adrenergic TH+ and peptidergic CGRP+ fibers. CONCLUSIONS: We demonstrated that ß3AR is abundantly located in acetylcholine-containing nerve fibers. These findings have important consequences to understand the mechanism of action of ß3AR agonists currently used for the treatment of OAB.
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Fibras Colinérgicas/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Bexiga Urinária/inervação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeo Relacionado com Gene de Calcitonina , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Músculo Liso/inervação , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Adulto JovemRESUMO
AIMS: To establish a new approach to cystometry using telemetry in conscious rats and to use this technique to determine the role of conscious decision making processes with respect to the initiation of voiding in physiological, inflammatory, and painful conditions. METHODS: The pressure transducer of a telemetric transmitter was implanted in the dome of the urinary bladder. After a recovery period of at least 1 month, several investigations of urodynamic parameters were performed after diuresis activation by a pulse of furosemide. The model was characterized by tolterodine and mirabegron under physiological conditions and same animals were reused to evaluate the modification of the voiding pattern under bladder inflammation induced by cyclophosphamide. RESULTS: The quality of traces and measurement of parameters recorded telemetrically were comparable to those with conventional cystometry. Furosemide induced a reproducible transient increase of urine production and a series of voids that persisted for 60 min. Tolterodine reduced the amplitude of micturition contractions although mirabegron was devoid of any effect. Seven hours after injection of CYP, voiding frequency increased significantly and the micturition amplitude contraction was not altered. However, the mean volume voided during individual micturitions and the total voided volume decreased. During a second exposure to furosemide 24H after CYP injection, the micturition pattern returned to control, however, the micturition volume was still lower than in control. CONCLUSION: This telemetric model appears to be as accurate as previously described in conscious conventional cystometry, and allows the repeated evaluation of compounds which may modulate the voiding patterns. Neurourol. Urodynam. 36:308-315, 2017. © 2016 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.
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Telemetria/métodos , Bexiga Urinária/fisiologia , Micção/fisiologia , Urodinâmica/fisiologia , Acetanilidas/farmacologia , Animais , Diuréticos/farmacologia , Feminino , Furosemida/farmacologia , Ratos , Ratos Sprague-Dawley , Tiazóis/farmacologia , Tartarato de Tolterodina/farmacologia , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Agentes Urológicos/farmacologiaRESUMO
Objective The Partners in Recovery (PIR) program is an Australian government initiative designed to make the mental health and social care sectors work in more coordinated ways to meet the needs of those with severe and complex mental illness. Herein we reflect on demographic data collected during evaluation of PIR implementation in two Western Sydney sites. The aims of the present study were to: (1) explore whether two Sydney-based PIR programs had recruited their intended population, namely people living with severe and persistent mental illness; and (2) learn more about this relatively unknown population and their self-identified need priorities. Methods Routinely collected initial client assessment data were analysed descriptively. Results The data suggest that the two programs are engaging the intended population. The highest unmet needs identified included psychological distress, lack of daytime activities and company, poor physical health and inadequate accommodation. Some groups remain hard to connect, including people from Aboriginal and other culturally diverse communities. Conclusions The data confirm that the PIR program, at least in the two regions evaluated, is mostly reaching its intended audience. Some data were being collected inconsistently, limiting the usefulness of the data and the ability to build on PIR findings to develop ongoing support for this population. What is known about the topic? PIR is a unique national program funded to engage with and address the needs of Australians living with severe and persistent mental illness by facilitating service access. What does this paper add? This paper reports on recruitment of people living with severe and persistent mental illness, their need priorities and data collection. These are three central elements to successful roll-out of the much anticipated mental health component of the National Disability Insurance Scheme, as well as ongoing PIR operation. What are the implications for practitioners? Active recruitment, exploration of self-reported need priorities and routine outcome measurement are essential yet challenging work practices when working with people living with severe and persistent mental illness.