Sildenafil Citrate-Restored eNOS and PDE5 Regulation in Sickle Cell Mouse Penis Prevents Priapism Via Control of Oxidative/Nitrosative Stress

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders. © 2013 Bivalacqua et al

Structuring an integrated water-energy-food nexus assessment of a local wind energy desalination system for irrigation

Unidad de excelencia María de Maeztu MdM-2015-0552Desalination is increasingly put forward as a sustainable local solution to water scarcity in combination with the exploitation of renewable energy sources. However, the complexity of the resource nexus entails the unavoidable existence of pros and cons across its various dimensions that can only be assessed at different scales of analysis. In turn, these pros and cons entail different winners and losers among the different social actors linked through the nexus. To address these challenges, a novel approach to resource nexus assessment is put forward, based on multi-scale integrated analysis of societal and ecosystem metabolism (MuSIASEM) and recognizing the resource nexus as a wicked problem. The integrated representation identifies the existence of biophysical constraints determined by processes both under human control (in the technosphere) and beyond human control (in the biosphere). The approach is illustrated with a local case study of desalination in the Canary Islands, Spain. The material presented has been generated in the context of the project "Moving towards adaptive governance in complexity: Informing nexus security" (MAGIC) for use in participatory processes of co-production of knowledge claims about desalination, a prerequisite for informed policy deliberation

A realisation of Lorentz algebra in Lorentz violating theory

A Lorentz non-invariant higher derivative effective action in flat spacetime, characterised by a constant vector, can be made invariant under infinitesimal Lorentz transformations by restricting the allowed field configurations. These restricted fields are defined as functions of the background vector in such a way that background dependance of the dynamics of the physical system is no longer manifest. We show here that they also provide a field basis for the realisation of Lorentz algebra and allow the construction of a Poincar\'e invariant symplectic two form on the covariant phase space of the theory.Comment: text body edited, reference adde

Role of Neural NO Synthase (nNOS) Uncoupling in the Dysfunctional Nitrergic Vasorelaxation of Penile Arteries from Insulin-Resistant Obese Zucker Rats

Objective: Erectile dysfunction (ED) is considered as an early sign of vascular disease due to its high prevalence in patients with cardiovascular risk factors. Endothelial and neural dysfunction involving nitric oxide (NO) are usually implicated in the pathophysiology of the diabetic ED, but the underlying mechanisms are unclear. The present study assessed the role of oxidative stress in the dysfunctional neural vasodilator responses of penile arteries in the obese Zucker rat (OZR), an experimental model of metabolic syndrome/prediabetes. Methods and Results: Electrical field stimulation (EFS) under non-adrenergic non-cholinergic (NANC) conditions evoked relaxations that were significantly reduced in penile arteries of OZR compared with those of lean Zucker rats (LZR). Blockade of NO synthase (NOS) inhibited neural relaxations in both LZR and OZR, while saturating concentrations of the NOS substrate L-arginine reversed the inhibition and restored relaxations in OZR to levels in arteries from LZR. nNOS expression was unchanged in arteries from OZR compared to LZR and nNOS selective inhibition decreased the EFS relaxations in LZR but not in OZR, while endothelium removal did not alter these responses in either strain. Superoxide anion production and nitro-tyrosine immunostaining were elevated in the erectile tissue from OZR. Treatment with the NADPH oxidase inhibitor apocynin or acute incubation with the NOS cofactor tetrahydrobiopterin (BH4) restored neural relaxations in OZR to levels in control arteries, while inhibition of the enzyme of BH4 synthesis GTP-cyclohydrolase (GCH) reduced neural relaxations i

Vasculogenesis and Diabetic Erectile Dysfunction: How Relevant Is Glycemic Control?

Erectile dysfunction (ED) is a complication of diabetes, condition responsible for causing endothelial dysfunction (EDys) and hampering repair mechanisms. However, scarce information is available linking vasculogenesis mediated by Endothelial Progenitor Cells (EPCs) and diabetes-associated ED. Furthermore, it remains to be elucidated if glycemic control plays a role on EPCs functions, EPCs modulators, and penile vascular health. We evaluated the effects of diabetes and insulin therapy on bone marrow (BM) and circulating EPCs, testosterone, and systemic/penile Stromal Derived Factor-1 alpha (SDF-1) expression. Male Wistar rats were divided into groups: age-matched controls, 8-weeks streptozotocin-induced type 1 diabetics, and insulin-treated 8-weeks diabetics. EPCs were identified by flow cytometry for CD34/CD133/VEGFR2/CXCR4 antigens. Systemic SDF-1 and testosterone levels were evaluated by ELISA. Penile SDF-1 protein expression was assessed, in experimental and human diabetic cavernosal samples, by immunohistochemical techniques. Diabetic animals presented a reduction of BM-derived EPCs and an increase in putative circulating endothelial cells (CECs) sloughed from vessels wall. These alterations were rescued by insulin therapy. In addition, glycemic control promoted an increase in systemic testosterone and SDF-1 levels, which were significantly decreased in animals with diabetes. SDF-1 protein expression was reduced in experimental and human cavernosal diabetic samples, an effect prevented by insulin in treated animals. Insulin administration rescued the effects of diabetes on BM function, CECs levels, testosterone, and plasmatic/penile SDF-1 protein expression. This emphasizes the importance of glycemic control in the prevention of diabetes-induced systemic and penile EDys, by the amelioration of endothelial damage, and increase in protective pathways.European Society for Sexual Medicine (ESSM Award for Medical Research 2011), and by the Portuguese Society of Andrology (Professor Alexandre Moreira Award “Research in Sexual Medicine 2013”)info:eu-repo/semantics/publishedVersio

Level 1 probabilistic risk assessment of low power and shutdown operations at a PWR: Phase 2 results

As a result of the Chernobyl accident and other precursor events (e.g., Diablo Canyon), the US Nuclear Regulatory Commission`s (NRC`s) Office of Nuclear Regulatory Research (RES) initiated an extensive project during 1989 to carefully examine the potential risks during Low Power and Shutdown (LP&S) operations. Shortly after the program began, an event occurred at the Vogtle plant during shutdown, which further intensified the effort of the LP&S program. In the LP&S program, one pressurized water reactor (PWR), Surry, and one boiling water reactor (BWR), Grand Gulf, were selected, mainly because they were previously analyzed in the NUREG-1150 Study. The Level-1 Program is being performed in two phases. Phase 1 was dedicated to performing a coarse screening level-1 analysis including internal fire and flood. A draft report was completed in November, 1991. In the phase 2 study, mid-loop operations at the Surry plant were analyzed in detail. The objective of this paper is to present the approach of the phase 2 study and the preliminary results and insights

Anti-UVC Irradiation and Metal Chelation Properties of 6-Benzoyl-5,7-dihydroxy-4-phenyl-chromen-2-one: An Implications for Anti-Cataract Agent

Coumarin derivative 1, 5,7-dihydroxy-6-(3-methyl-1-butyryl)-4-phenyl-chromen- 2-one, has been reported to possess radical scavenging activity and DNA protection. We have synthesized a series of coumarins with structural modifications at positions C4, C5, C6 and C7 and evaluated them for their anti-UVC properties. Coumarin 7, 6-benzoyl-5,6-dihydroxy-4-phenyl-chromen-2-one, was found to have the most potent activity in protecting porcine γ-crystallin against UVC insults. Results of fluorescence assays indicated that compound 7 was capable of decreasing the loss of intensity while lens crystallins and DNA PUC19 were irradiated with UVC. Presence of compound 7 decreased hydroxyl radical levels determined by probe 1b and the free iron concentrations determined by Ferrozine reagent. The chelation assay showed that compound 7 was chelated to metal via 6-CO and 5-OH on the benzopyrone ring. The observed protective effects of compound 7 towards crystallins from insults of UVC and free radicals may be due to its iron-chelating activity and its peak absorption at 254 nm