Opportunities for fundamental physics research with radioactive molecules.

Molecules containing short-lived, radioactive nuclei are uniquely positioned to enable a wide range of scientific discoveries in the areas of fundamental symmetries, astrophysics, nuclear structure, and chemistry. Recent advances in the ability to create, cool, and control complex molecules down to the quantum level, along with recent and upcoming advances in radioactive species production at several facilities around the world, create a compelling opportunity to coordinate and combine these efforts to bring precision measurement and control to molecules containing extreme nuclei. In this manuscript, we review the scientific case for studying radioactive molecules, discuss recent atomic, molecular, nuclear, astrophysical, and chemical advances which provide the foundation for their study, describe the facilities where these species are and will be produced, and provide an outlook for the future of this nascent field.

Haemodynamic, hormonal and renal actions of osteocrin in normal sheep.

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B-type (BNP) and C-type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR-C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle-controlled incremental infusions of ovine proOSTN (83-133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose-dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR-C in regulating plasma concentrations of NPs and associated cGMP-mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.

Lived experience of burnout and fatigue in perioperative healthcare professionals in Rwanda: a qualitative study.

BACKGROUND: There is a lack of qualitative data on the negative effects of workplace stressors on the well-being of healthcare professionals in hospitals in Africa. It is unclear how well research methods developed for high-income country contexts apply to different cultural, social, and economic contexts in the global south. METHODS: We conducted a qualitative interview-based study including 64 perioperative healthcare professionals across all provinces of Rwanda. We used an iterative thematic analysis and aimed to explore the lived experience of Rwandan healthcare professionals and to consider to what extent the Maslach model aligns with these experiences. RESULTS: We found mixed responses of the effects on individuals, including the denial of burnout and fatigue to the points of physical exhaustion. Responses aligned with Maslach's three-factor model of emotional exhaustion, decreased personal accomplishment, and depersonalisation, with downstream effects on the healthcare system. Other factors included strongly patriotic culture, goals framed by narratives of Rwanda's recovery after the genocide, and personal and collective investment in developing the Rwandan healthcare system. CONCLUSIONS: The Rwandan healthcare system presents many challenges which can become profoundly stressful for the workforce. Consideration of reduced personal and collective accomplishment, of moral injury, and its diverse downstream effects on the whole healthcare system may better represent the costs of burnout Rwanda. It is likely that improving the causes of work-based stress will require a significant investment in improving staffing and working conditions.

Nursing vaccine mandates: Ethically justified, an infringement on autonomy, or both?

After almost a year and a half of the COVID-19 pandemic, many healthcare institutions in the United States announced that they would mandate COVID-19 vaccination, with medical and religious exceptions, as a term of employment. The mandates resulted in widely publicized protests from hospital staff, including some nurses, who argued that these medical institutions violated the ethical principle of autonomy. As the world enters the "post-pandemic period," decisions such as these, made during times of crisis, must be reviewed to provide clarity for when the next pandemic occurs. In this paper, we support the argument that such mandates are ethically justifiable. We explore the framework of objections that were brought forward by dissenters of this vaccine mandate. Next, we provide an analysis of conflicting ethical principles present when such mandates were deployed. Utilizing the American Nurses Association's Code of Ethics for Nurses, notably provisions 2, 3, and 6 we argue that it is an ethical duty of the nurse to be vaccinated. Specifically, we turn to provision two, which most explicitly underscores the necessity of vaccination as a function of the nurse's primary commitment to the patient. Next, we highlight the International Council of Nurses Code of Ethics which provides similar guidance internationally. Finally, we examine the applicability of the principles of public health, care ethics, and the nursing role as frameworks to underpin such mandates both for the current and for potential future pandemics, arguing that the nurse's ethical duty to be vaccinated spans these contexts.

Interrogating the Role of miR-125b and Its 3'isomiRs in Protection against Hypoxia.

MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5' or 3' addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are few. In this study, we discovered using NGS, four 3'isomiRs of miR-125b, i.e., addition of A (adenosine), along with deletions of A, AG (guanosine) and AGU (uridine) from rat and sheep heart. These findings were validated using RT-qPCR. Comprehensive functional studies were carried out in the H9C2 hypoxia model. After miR-125b, isomiRs of Plus A, Trim A, AG and AGU mimic transfection, the H9C2 cells were subjected to hypoxic challenge. As assessed using cell viability, apoptosis, CCK-8 and LDH release, miR-125b and isomiRs were all protective against hypoxia. However, Plus A and Trim A were more effective than miR-125b, whilst Trim AG and Trim AGU had far weaker effects than miR-125b. Interestingly, both the gene regulation profile and apoptotic gene validation indicated a major overlap among miR-125b, Plus A and Trim A, whilst Trims AG and AGU revealed a different profile compared to miR-125b. Conclusions: miR-125b and its 3' isomiRs are expressed stably in the heart. miR-125b and isomiRs with addition or deletion of A might function concurrently and concordantly under specific physiological and pathophysiological conditions. In-depth understanding of isomiRs' metabolism and function will contribute to better miRNA therapeutic drug design.

Comparison of SPEED, S-Trap, and In-Solution-Based Sample Preparation Methods for Mass Spectrometry in Kidney Tissue and Plasma.

Mass spectrometry is a powerful technique for investigating renal pathologies and identifying biomarkers, and efficient protein extraction from kidney tissue is essential for bottom-up proteomic analyses. Detergent-based strategies aid cell lysis and protein solubilization but are poorly compatible with downstream protein digestion and liquid chromatography-coupled mass spectrometry, requiring additional purification and buffer-exchange steps. This study compares two well-established detergent-based methods for protein extraction (in-solution sodium deoxycholate (SDC); suspension trapping (S-Trap)) with the recently developed sample preparation by easy extraction and digestion (SPEED) method, which uses strong acid for denaturation. We compared the quantitative performance of each method using label-free mass spectrometry in both sheep kidney cortical tissue and plasma. In kidney tissue, SPEED quantified the most unique proteins (SPEED 1250; S-Trap 1202; SDC 1197). In plasma, S-Trap produced the most unique protein quantifications (S-Trap 150; SDC 148; SPEED 137). Protein quantifications were reproducible across biological replicates in both tissue (R2 = 0.85-0.90) and plasma (SPEED R2 = 0.84; SDC R2 = 0.76, S-Trap R2 = 0.65). Our data suggest SPEED as the optimal method for proteomic preparation in kidney tissue and S-Trap or SPEED as the optimal method for plasma, depending on whether a higher number of protein quantifications or greater reproducibility is desired.

Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure.

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)-an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra-mass spectrometry (SWATH-MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2-2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.

Towards improved health service quality in Tanzania: contribution of a supportive supervision approach to increased quality of primary healthcare.

BACKGROUND: Universal Health Coverage only leads to the desired health outcomes if quality of health services is ensured. In Tanzania, quality has been a major concern for many years, including the problem of ineffective and inadequate routine supportive supervision of healthcare providers by council health management teams. To address this, we developed and assessed an approach to improve quality of primary healthcare through enhanced routine supportive supervision. METHODS: Mixed methods were used, combining trends of quantitative quality of care measurements with qualitative data mainly collected through in-depth interviews. The former allowed for identification of drivers of quality improvements and the latter investigated the perceived contribution of the new supportive supervision approach to these improvements. RESULTS: The results showed that the new approach managed to address quality issues that could be solved either solely by the healthcare provider, or in collaboration with the council. The new approach was able to improve and maintain crucial primary healthcare quality standards across different health facility level and owner categories in various contexts. CONCLUSION: Together with other findings reported in companion papers, we could show that the new supportive supervision approach not only served to assess quality of primary healthcare, but also to improve and maintain crucial primary healthcare quality standards. The new approach therefore presents a powerful tool to support, guide and drive quality improvement measures within council. It can thus be considered a suitable option to make routine supportive supervision more effective and adequate.

Towards improved health service quality in Tanzania: appropriateness of an electronic tool to assess quality of primary healthcare.

BACKGROUND: Progress in health service quality is vital to reach the target of Universal Health Coverage. However, in order to improve quality, it must be measured, and the assessment results must be actionable. We analyzed an electronic tool, which was developed to assess and monitor the quality of primary healthcare in Tanzania in the context of routine supportive supervision. The electronic assessment tool focused on areas in which improvements are most effective in order to suit its purpose of routinely steering improvement measures at local level. METHODS: Due to the lack of standards regarding how to best measure quality of care, we used a range of different quantitative and qualitative methods to investigate the appropriateness of the quality assessment tool. The quantitative methods included descriptive statistics, linear regression models, and factor analysis; the qualitative methods in-depth interviews and observations. RESULTS: Quantitative and qualitative results were overlapping and consistent. Robustness checks confirmed the tool's ability to assign scores to health facilities and revealed the usefulness of grouping indicators into different quality dimensions. Focusing the quality assessment on processes and structural adequacy of healthcare was an appropriate approach for the assessment's intended purpose, and a unique key feature of the electronic assessment tool. The findings underpinned the accuracy of the assessment tool to measure and monitor quality of primary healthcare for the purpose of routinely steering improvement measures at local level. This was true for different level and owner categories of primary healthcare facilities in Tanzania. CONCLUSION: The electronic assessment tool demonstrated a feasible option for routine quality measures of primary healthcare in Tanzania. The findings, combined with the more operational results of companion papers, created a solid foundation for an approach that could lastingly improve services for patients attending primary healthcare. However, the results also revealed that the use of the electronic assessment tool outside its intended purpose, for example for performance-based payment schemes, accreditation and other systematic evaluations of healthcare quality, should be considered carefully because of the risk of bias, adverse effects and corruption.

Extracellular Vesicles in Cardiovascular Diseases: Alternative Biomarker Sources, Therapeutic Agents, and Drug Delivery Carriers.

Cardiovascular diseases (CVD) represent the leading cause of morbidity and mortality globally. The emerging role of extracellular vesicles (EVs) in intercellular communication has stimulated renewed interest in exploring the potential application of EVs as tools for diagnosis, prognosis, and therapy in CVD. The ubiquitous nature of EVs in biological fluids presents a technological advantage compared to current diagnostic tools by virtue of their notable stability. EV contents, such as proteins and microRNAs, represent specific signatures of cellular activation or injury. This feature positions EVs as an alternative source of biomarkers. Furthermore, their intrinsic activity and immunomodulatory properties offer EVs unique opportunities to act as therapeutic agents per se or to serve as drug delivery carriers by acting as miniaturized vehicles incorporating bioactive molecules. In this article, we aim to review the recent advances and applications of EV-based biomarkers and therapeutics. In addition, the potential of EVs as a drug delivery and theranostic platform for CVD will also be discussed.

Enhancement of Ce/Cr Codopant Solubility and Chemical Homogeneity in TiO2 Nanoparticles through Sol-Gel versus Pechini Syntheses.

Ce/Cr codoped TiO2 nanoparticles were synthesized using sol-gel and Pechini methods with heat treatment at 400 °C for 4 h. A conventional sol-gel process produced well-crystallized anatase, while Pechini synthesis yielded less-ordered mixed-phase anatase + rutile; this suggests that the latter method enhances Ce solubility and increases chemical homogeneity but destabilizes the TiO2 lattice. Greater structural disruption from the decomposition of the Pechini precursor formed more open agglomerated morphologies, while the lower levels of structural disruption from pyrolysis of the dried sol-gel precursor resulted in denser agglomerates of lower surface areas. Codoping and associated destabilization of the lattice reduced the binding energies in both powders. Cr4+ formation in sol-gel powders and Cr6+ formation in Pechini powders suggest that these valence changes derive from synergistic electron exchange from intervalence and/or multivalence charge transfer. Since Ce is too large to allow either substitutional or interstitial solid solubility, the concept of integrated solubility is introduced, in which the Ti site and an adjacent interstice are occupied by the large Ce ion. The photocatalytic performance data show that codoping was detrimental owing to the effects of reduced crystallinity from lattice destabilization and surface area. Two regimes of mechanistic behavior are seen, which are attributed to the unsaturated solid solutions at lower codopant levels and supersaturated solid solutions at higher levels. The present work demonstrates that the Pechini method offers a processing technique that is superior to sol-gel because the former facilitates solid solubility and consequent chemical homogeneity.

The Use of a Magnetic Port Finder in the Retrieval of Air Rifle BBs to the Upper Extremity.

Air-powered rifles shoot ball bearings with enough kinetic energy to penetrate skin and fracture underlying bones. In addition, there are reports of these ball bearings embolizing within the vascular network, causing serious injuries such as ischemic stroke with resultant blindness. The severity of these complications warrants occasional removal of these foreign bodies; however, they can be difficult to localize. In this case report, we describe the use of a magnetic port finder, a sterilizable tool used in breast reconstruction, to localize the foreign body in situ. We believe that this tool is effective at locating ferrous foreign bodies precisely, allowing for surgical retrieval while minimizing damage to surrounding tissue.

Optical properties of zirconia ceramics for esthetic dental restorations: A systematic review.

STATEMENT OF PROBLEM: Yttria-stabilized tetragonal zirconia polycrystal has been used as a dental biomaterial for several decades because the fracture toughness and bend strength are increased by a stress-induced transformation-toughening mechanism. However, its esthetics are compromised by its poor translucency and grayish-white appearance. PURPOSE: The purpose of the present systematic review was to assess information on the mechanical, chemical, and optical requirements of monolithic zirconia dental restorations. MATERIAL AND METHODS: The following databases (2010 to 2015) were electronically searched: ProQuest, EMBASE, SciFinder, MRS Online Proceedings Library, Medline, Compendex, and Journal of the American Ceramic Society. The search was limited to English-language publications, in vitro studies, experimental reports, and modeling studies. RESULTS: The data from 57 studies were considered in order to review the intrinsic and extrinsic characteristics of zirconia and their effects on the optical properties. CONCLUSIONS: The materials and microstructural issues relevant to the esthetics and long-term stability of zirconia have been considered in terms of monolithic restorations, while there also are restorations specifically for esthetic applications. Although zirconia-toughened lithium silicate offers the best esthetic outcomes, transformation-toughened zirconia offers the best mechanical properties and long-term stability; cubic stabilized zirconia offers a potential compromise. The properties of these materials can be altered to some extent through the appropriate application of intrinsic (such as, annealing) and extrinsic (such as, shade-matching) parameters.

(Pro)renin Receptor Blockade Ameliorates Cardiac Injury and Remodeling and Improves Function After Myocardial Infarction.

BACKGROUND: The (pro)renin receptor [(P)RR] is implicated in the pathogenesis of cardiovascular disease. We investigated the effects of (P)RR blockade after myocardial infarction (MI) in a mouse coronary-ligation model. METHODS AND RESULTS: Mice underwent sham control surgeries (n = 8) or induction of MI followed by 28 days' treatment with a vehicle control (n = 8) or (P)RR antagonist (n = 8). Compared with sham control subjects, MI + vehicle mice demonstrated reduced left ventricular (LV) ejection fraction (LVEF: P < .001) and fractional shortening (P < .001), and increased LV end-systolic and -diastolic volumes (LVESV: P < .001; LVEDV: P < .001) 28 days after MI. In addition, MI decreased LV posterior wall and septal diameters (both P < .001), increased heart weight-body weight ratios (P < .05), LV collagen deposition, and cardiomyocyte diameter (both P < .001), and up-regulated collagen 1 (P < .01) and ß-myosin heavy chain (ß-MHC: P < .05) mRNA. Compared with MI + vehicle mice, (P)RR antagonism after MI reduced infarct size (P < .01), improved LVEF (P < .001), fractional shortening (P < .001), and stroke volume (P < .05), and decreased LVESV (P < .001) and LVEDV (P < .001). (P)RR antagonism also reversed MI-induced transmural thinning (P < .001) and reduced LV fibrosis (P < .01), cardiomyocyte size (P < .001), and ventricular collagen 1 (P < .01), ß-MHC (P = .06), transforming growth factor ß1 (P < .01), and angiotensin-converting enzyme (P < .05) expression. CONCLUSIONS: The present study found that (P)RR blockade after MI in mice ameliorates infarct size, cardiac fibrosis/hypertrophy, and cardiac dysfunction and identifies the receptor as a potential therapeutic target in this setting.

Multivalence Charge Transfer in Doped and Codoped Photocatalytic TiO2.

The present work reports data for the mineralogical and chemical properties of anatase thin films individually doped or codoped with chromium and vanadium, fabricated by sol-gel spin coating on glass substrates and annealing at 450 °C for 2 h. X-ray photoelectron spectroscopy data indicated the presence of Ti(4+), Ti(3+), Cr(3+), and possibly Cr(4+) in the Cr-doped thin films; Ti(4+), Ti(3+), V(3+), V(4+), and possibly V(5+) in the V-doped thin films; and Ti(4+), Ti(3+), Cr(3+), Cr(4+), V(3+), V(4+), and possibly V(5+) in the codoped thin films. While the thermodynamically stable valences Ti(4+), Cr(3+), and V(5+) would be expected to have formed, the presence of the nonequilibrium valences Ti(3+), Cr(4+), V(3+), and V(4+) is considered to have resulted from intervalence charge transfer for the Cr-doped and V-doped systems but from multivalence charge transfer (MVCT) for the codoped system. The latter phenomenon, which is introduced as a new conceptual term, describes the nature of the mutual exchange of electrons during valence changes of both dopant (Cr, V) and matrix (Ti) ions during annealing. In the present case, MVCT appears to be a transient metastable condition that acts during annealing, but subsequent UV irradiation can alter its effects.

Human muscle sympathetic nerve responses to urocortin-2 in health and stable heart failure.

Sympatholytic and vasodilator drugs have been of major therapeutic benefit in patients with heart failure (HF). Urocortin-2 (Ucn2) is a small corticotrophin-related peptide distributed throughout the cardiovascular system which inhibits cardiac sympathetic nerve activity (CSNA) and is also a powerful vasodilator. This study analysed the effects of a 60-min infusion of Ucn2 (25 µg) on muscle sympathetic nerve activity (MSNA) recorded from the lower limb in eight healthy men and four men with stable HF. During Ucn2 infusion, mean arterial pressure fell to a nadir of 84 ± 2 compared to 95 ± 2 mmHg during placebo (P = 0.001) and heart rate increased to a maximum of 74 ± 1 compared to 64 ± 1 b.p.m. (P < 0.001). Total peripheral resistance fell by 23 ± 4% compared with an increase of 23 ± 4% (P < 0.001) and cardiac output increased by 22 ± 4 compared to 4 ± 4% (P = 0.001). The MSNA burst frequency increased by 9 ± 2 compared to 1 ± 2 burst/min (P = 0.005) and burst area/min by 133 ± 7 vs 107 ± 7% (P = 0.01). Burst incidence and baroreflex sensitivity were not significantly altered. Qualitatively similar changes were observed in stable HF patients. Ucn2-induced vasodilatation increased MSNA in humans, as opposed to the decrease in CSNA we observed in sheep. Therefore, if Ucn2 has a central inhibitory effect on MSNA, it was over-run by off-loading the cardiovagal baroreflex. Alternatively, CSNA may be less responsive to baroreflex off-loading than MSNA.

Thoracic impedance measures tissue characteristics in the vicinity of the electrodes, not intervening lung water: implications for heart failure monitoring.

The rationale for intrathoracic impedance (Z) detection of worsening heart failure (HF) presupposes that changes in Z reflect changes in pulmonary congestion, but is confounded by poor specificity in clinical trials. We therefore tested the hypothesis that Z is primarily affected by tissue/water content in proximity to electrodes rather than by lung water distribution between electrodes through the use of a new computational model for deriving the near-field impedance contributions from the various electrodes. Six sheep were implanted with a left atrial pressure (LAP) monitor and a cardiac resynchronization therapy device which measured Z from six vectors comprising of five electrodes. The vector-based Z was modelled as the summation of the near-field impedances of the two electrodes forming the vector. During volume expansion an acute increase in LAP resulted in simultaneous reductions in the near-field impedances of the intra-cardiac electrodes, while the subcutaneous electrode showed several hours of lag (all p<0.001). In contrast, during the simulated formation of device-pocket edema (induced by fluid injection) the near-field impedance of the subcutaneous electrode had an instantaneous response, while the intra-cardiac electrodes had a minimal inconsistent response. This study suggests that the primary contribution to the vector based Z is from the tissue/water in proximity to the individual electrodes. This novel finding may help explain the limited utility of Z for detecting worsening HF.

Low-dose B-type natriuretic peptide raises cardiac sympathetic nerve activity in sheep.

The reported effects of atrial natriuretic peptide (ANP) on sympathetic nerve activity (SNA) are variable, dependent on concomitant hemodynamic actions, and likely to be regionally differentiated. There are few reports of the effect of B-type natriuretic peptide (BNP) on SNA and none have measured cardiac SNA (CSNA) by direct microneurography. We measured the effects of low-dose ANP and BNP (2.4 pmol·kg(-1)·min(-1) infused for 120 min) on CSNA and hemodynamics in conscious sheep (n = 8). While there was a trend for mean arterial pressure and cardiac output to fall with both ANP and BNP, changes were not significant compared with vehicle control. However, BNP did significantly reduce systolic arterial (97 ± 4.2 vs. 107 ± 6.8 mmHg during control; P = 0.043) and pulse pressures (0.047) and increase heart rate (110 ± 6.7 vs. 96 ± 7.3 beats/min; P = 0.044). Trends for these hemodynamic parameters to change with ANP did not achieve statistical significance. ANP also had no significant effect on any CSNA parameters measured. In contrast, BNP induced a rise in both CSNA burst frequency (∼20 bursts/min higher than control, P = 0.011) and burst area (∼40% higher than control, P = 0.013). BNP-induced rises in burst incidence (bursts/100 beats), and burst area per 100 beats, however, were not significant. In conclusion, BNP infused at low doses that only had subtle effects on hemodynamics increased CSNA burst frequency and burst are per minute. This increase in CSNA may in large part be secondary to an increase in heart rate as CSNA burst incidence and burst area per 100 beats were not significantly increased. This study provides no evidence for inhibition of CSNA by natriuretic peptides.