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The objective of this study was to determine which adenosine receptor subtypes were involved in the modulation of norepinephrine release from cardiac nerve terminals. In addition, the persistence of adenosine-mediated effects was evaluated. Rat hearts attached to the stellate ganglion were isolated and perfused. The ganglion was electrically stimulated twice (S1 and S2), allowing 10 min between the stimulations. To determine adenosine receptor subtypes, selective and nonselective adenosine agonists and antagonists were infused following S1 and until the end of S2. To evaluate the persistence of adenosine-mediated effect on norepinephrine release, the stellate ganglion was stimulated a third (S3) and fourth (S4) time. Coronary effluents were collected to determine norepinephrine content. Adenosine and a selective A 1 receptor agonist, CCPA, inhibited norepinephrine release by 49% and 54%, respectively. This effect was reversed by simultaneous infusion of nonspecific (8-SPT) and specific (DPCPX) A 1 receptor antagonists. Selective A 2A (CGS 21680) and A 3 (AB-MECA) receptor agonists had no discernible effect on norepinephrine release. Similarly, adenosine A 2A receptor antagonists CSC and DMPX did not alter the dose-response relation between norepinephrine release and adenosine. Finally, the inhibitory effects of adenosine on norepinephrine release did not persist 10 min subsequent to the removal of adenosine. Adenosine inhibited norepinephrine release primarily via the adenosine A 1 receptor. This effect of adenosine was of short duration. Adenosine A 2A and A 3 receptors were either absent or functionally insignificant in the regulation of norepinephrine release in the rat heart.Key words: adenosine, norepinephrine, receptor, rat, neurotransmitters.

Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H 2 O 2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H 2 O 2 . In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.

The contribution of neuronal ATP to interstitial adenosine levels was investigated in isolated perfused rat hearts. Ventricular surface transudates, representing interstitial fluid, were analyzed for norepinephrine, ATP, and adenosine. Exocytotic release of norepinephrine was induced by electrical stimulation of cardiac efferents emanating from the stellate ganglion. Ganglion stimulation increased contractility, interstitial norepinephrine, ATP, and adenosine. Interstitial adenosine was 11- to 27-fold higher than interstitial ATP, suggesting that the released ATP is unlikely the only source of adenosine. In the presence of AOPCP ( α, β-methyleneadenosine 5'-diphosphate), an ecto-5'-nucleotidase inhibitor, the ganglion-stimulated increase in interstitial ATP and adenosine reached levels similar to those in the absence of AOPCP, also suggesting that adenosine does not derive from extracellular ATP. The perfusate Ca 2+ was raised from 1 to 4 mM to determine the importance of the enhanced contractile function on the levels of norepinephrine, ATP, and adenosine. The results were increases in contractility and interstitial norepinephrine, ATP, and adenosine, which were not suppressed with atenolol, indicating a norepinephrine-independent release of ATP and adenosine. Reserpine treatment and administration of guanethidine depleted the catecholamine stores and diminished the catecholamine release, respectively. However, neither agent altered Ca 2+ -induced increases in ATP and adenosine. It is concluded that the amount of neuronal-derived ATP is low and most likely does not contribute significantly to interstitial levels of adenosine. Furthermore, elevations in interstitial norepinephrine, ATP, and adenosine are associated with neuronal-independent increases in contractile function.Key words: perfused heart, stellate ganglion, co-transmission, calcium, and contractility.

Background Accelerometer measures of physical behaviours (physical activity, sedentary behaviour and sleep) in observational studies offer detailed insight into associations with health and disease. Maximising recruitment and accelerometer wear, and minimising data loss remain key challenges. How varying methods used to collect accelerometer data influence data collection outcomes is poorly understood. We examined the influence of accelerometer placement and other methodological factors on participant recruitment, adherence and data loss in observational studies of adult physical behaviours. Methods The review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). Observational studies of adults including accelerometer measurement of physical behaviours were identified using database (MEDLINE (Ovid), Embase, PsychINFO, Health Management Information Consortium, Web of Science, SPORTDiscus and Cumulative Index to Nursing & Allied Health Literature) and supplementary searches to May 2022. Information regarding study design, accelerometer data collection methods and outcomes were extracted for each accelerometer measurement (study wave). Random effects meta-analyses and narrative syntheses were used to examine associations of methodological factors with participant recruitment, adherence and data loss. Results 123 accelerometer data collection waves were identified from 95 studies (92.5% from high-income countries). In-person distribution of accelerometers was associated with a greater proportion of invited participants consenting to wear an accelerometer (+ 30% [95% CI 18%, 42%] compared to postal distribution), and adhering to minimum wear criteria (+ 15% [4%, 25%]). The proportion of participants meeting minimum wear criteria was higher when accelerometers were worn at the wrist (+ 14% [ 5%, 23%]) compared to waist. Daily wear-time tended to be higher in studies using wrist-worn accelerometers compared to other wear locations. Reporting of information regarding data collection was inconsistent. Conclusion Methodological decisions including accelerometer wear-location and method of distribution may influence important data collection outcomes including recruitment and accelerometer wear-time. Consistent and comprehensive reporting of accelerometer data collection methods and outcomes is needed to support development of future studies and international consortia. Review supported by the British Heart Foundation (SP/F/20/150002) and registered (Prospero CRD42020213465).

Achieving a malaria-free world presents exciting scientific challenges as well as overwhelming health, equity, and economic benefits. WHO and countries are setting ambitious goals for reducing the burden and eliminating malaria through the \"Global Technical Strategy\" and 21 countries are aiming to eliminate malaria by 2020. The commitment to achieve these targets should be celebrated. However, the need for innovation to achieve these goals, sustain elimination, and free the world of malaria is greater than ever. Over 180 experts across multiple disciplines are engaged in the Malaria Eradication Research Agenda (malERA) Refresh process to address problems that need to be solved. The result is a research and development agenda to accelerate malaria elimination and, in the longer term, transform the malaria community's ability to eradicate it globally.

Consumption of low dietary potassium, common with ultraprocessed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the with no (K) lysine kinase/STE20/SPS1-related proline-alanine-rich protein kinase (WNK/SPAK) pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high-potassium \"DASH-like\" diets (dietary approaches to stop hypertension) inactivate the cotransporter and whether this decreases BP. A transcriptomics screen identified Ppp1Ca, encoding PP1A, as a potassium-upregulated gene, and its negative regulator Ppp1r1a, as a potassium-suppressed gene in the kidney. PP1A directly binds to and dephosphorylates NCC when extracellular potassium is elevated. Using mice genetically engineered to constitutively activate the NCC-regulatory kinase SPAK and thereby eliminate the effects of the WNK/SPAK kinase cascade, we confirmed that PP1A dephosphorylated NCC directly in a potassium-regulated manner. Prior adaptation to a high-potassium diet was required to maximally dephosphorylate NCC and lower BP in constitutively active SPAK mice, and this was associated with potassium-dependent suppression of Ppp1r1a and dephosphorylation of its cognate protein, inhibitory subunit 1 (I1). In conclusion, potassium-dependent activation of PP1A and inhibition of I1 drove NCC dephosphorylation, providing a mechanism to explain how high dietary K+ lowers BP. Shifting signaling of PP1A in favor of activation of WNK/SPAK may provide an improved therapeutic approach for treating salt-sensitive hypertension.

Richard Houlston and colleagues report a genome-wide association study of multiple myeloma and identify four loci associated with susceptibility to this malignancy. To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10 −14 ), 6p21.33 (rs2285803, PSORS1C2 , P = 9.67 × 10 −11 ), 17p11.2 (rs4273077, TNFRSF13B , P = 7.67 × 10 −9 ) and 22q13.1 (rs877529, CBX7 , P = 7.63 × 10 −16 ). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.

This extended essay seeks to unpack some of the key aspects of philosophy which are applicable to medical thought and practice. It proceeds via an analytical discussion of the contemporary debate in three key areas of medical ethics: euthanasia, concepts of health & disease and psychiatry. The main claims are as follows: The case for legalising euthanasia is strong on philosophical grounds but there are numerous practical obstacles. Elements from the normative and naturalistic definitions of disease are necessary for a thorough definition that dodges common objections to either. Mental health cannot be subsumed under a purely physicalist model of health rendering it distinctly different from other fields in Medicine. Through a detailed discussion of three salient issues in the philosophy of medicine, it is argued that the application of profound philosophical thought to medicine and its practices reveals a depth that necessitates exploration before simply following the aims of curing all. Philosophical rigour matched with modern medicine has the potential to engage patients and help them make independent, informed decisions and assist physicians to think more clearly, analytically and empathetically.

Aim Detection of rare species is limited by their intrinsic nature and by the constraints associated with traditional field surveys. Remote sensing (RS) provides a powerful alternative to traditional detection methods through the increasing availability of RS products. Here, we assess the capacity of RS at high and medium resolution to detect rare plants with direct and indirect approaches, and how the performance of RS can be influenced by the characteristics of species. Methods An extensive literature review was conducted to synthesize the use of RS to detect or predict rare plant occurrence at high and medium resolution (<30 m and 30–300 m, respectively). The concept of “rarity” was based on Rabinowitz's rare species classification. The literature review was performed in Scopus for the period 1990–2020. Results While direct detection is often limited, it is possible with high and very high spatial resolution data for rare plants with distinctive traits. RS is also able to capture biophysical conditions driving rare plant distributions, which can indirectly provide accurate predictions for them. Both approaches have the potential to discover new populations of rare plants. RS can also feed SAMs of rare plants, which combined with SDMs can provide a valuable approach for rare plant detection. While direct detection is limited by the space occupied by a species within its habitat and its morphological, phenological and physiological characteristics, the predictive performance of RS‐based SDMs (indirect detection) can be influenced by habitat size, habitat specificity and phenological features of rare plants. Similarly, model predictive performance can be influenced by the rarity form of the target species according to the rarity classification criteria. Main conclusions. With this synthesis, the strong potential of RS for the purposes of detection and prediction of rare plant has been highlighted, with practical applications for conservation and management.

The objective of this systematic review and meta-analysis is to evaluate the effectiveness of exercise programs to reduce falls in older people with dementia who are living in the community. Peer-reviewed articles (randomized controlled trials [RCTs] and quasi-experimental trials) published in English between January 2000 and February 2014, retrieved from six electronic databases - Medline (ProQuest), CINAHL, PubMed, PsycInfo, EMBASE and Scopus - according to predefined inclusion criteria were included. Where possible, results were pooled and meta-analysis was conducted. Four articles (three RCT and one single-group pre- and post-test pilot study) were included. The study quality of the three RCTs was high; however, measurement outcomes, interventions, and follow-up time periods differed across studies. On completion of the intervention period, the mean number of falls was lower in the exercise group compared to the control group (mean difference [MD] [95% confidence interval {CI}] =-1.06 [-1.67 to -0.46] falls). Importantly, the exercise intervention reduced the risk of being a faller by 32% (risk ratio [95% CI] =0.68 [0.55-0.85]). Only two other outcomes were reported in two or more of the studies (step test and physiological profile assessment). No between-group differences were observed in the results of the step test (number of steps) (MD [95% CI] =0.51 [-1.77 to 2.78]) or the physiological profile assessment (MD [95% CI] =-0.10 [-0.62 to 0.42]). Findings from this review suggest that an exercise program may potentially assist in preventing falls of older people with dementia living in the community. However, further research is needed with studies using larger sample sizes, standardized measurement outcomes, and longer follow-up periods, to inform evidence-based recommendations.