The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway.

In contrast to nitric oxide, which has well established and important roles in the regulation of blood flow and thrombosis, neurotransmission, the normal functioning of the genitourinary system, and the inflammation response and host defense, its oxidized metabolites nitrite and nitrate have, until recently, been considered to be relatively inactive. However, this view has been radically revised over the past decade and more. Much evidence has now accumulated demonstrating that nitrite serves as a storage form of nitric oxide, releasing nitric oxide preferentially under acidic and/or hypoxic conditions but also occurring under physiologic conditions: a phenomenon that is catalyzed by a number of distinct mammalian nitrite reductases. Importantly, preclinical studies demonstrate that reduction of nitrite to nitric oxide results in a number of beneficial effects, including vasodilatation of blood vessels and lowering of blood pressure, as well as cytoprotective effects that limit the extent of damage caused by an ischemia/reperfusion insult, with this latter issue having been translated more recently to the clinical setting. In addition, research has demonstrated that the other main metabolite of the oxidation of nitric oxide (i.e., nitrate) can also be sequentially reduced through processing in vivo to nitrite and then nitrite to nitric oxide to exert a range of beneficial effects-most notably lowering of blood pressure, a phenomenon that has also been confirmed recently to be an effective method for blood pressure lowering in patients with hypertension. This review will provide a detailed description of the pathways involved in the bioactivation of both nitrate and nitrite in vivo, their functional effects in preclinical models, and their mechanisms of action, as well as a discussion of translational exploration of this pathway in diverse disease states characterized by deficiencies in bioavailable nitric oxide. SIGNIFICANCE STATEMENT: The past 15 years has seen a major revision in our understanding of the pathways for nitric oxide synthesis in the body with the discovery of the noncanonical pathway for nitric oxide generation known as the nitrate-nitrite-nitric oxide pathway. This review describes the molecular components of this pathway, its role in physiology, potential therapeutics of targeting this pathway, and their impact in experimental models, as well as the clinical translation (past and future) and potential side effects.

Dislocation resistance of ProRoot Endo Sealer, a calcium silicate-based root canal sealer, from radicular dentine.

AIM: To examine the dislocation resistance of three root canal sealers from radicular dentine with and without immersion in a simulated body fluid (SBF), using a modified push-out test design that produced simulated canal spaces of uniform dimensions under identical cleaning and shaping conditions. METHODOLOGY: Sixty single-rooted caries-free human canine teeth were used. Standardized simulated canal spaces were created using 0.04 taper ProFile instruments along the coronal, middle and apical thirds of longitudinal tooth slabs. Following NaOCl/ethylenediamine tetra-acetic acid cleaning, the cavities were filled with ProRoot Endo Sealer, AH Plus Jet or Pulp Canal Sealer. After setting, half of the cavities were tested with a fibre-optic light-illuminated push-out testing device. The rest were immersed in SBF for 4 weeks before push-out evaluation. Failure modes were examined with stereomicroscopy and field emission (FE)-scanning electron microscopy. RESULTS: Location of the sealer-filled cavities did not affect push-out strengths. ProRoot Endo Sealer exhibited higher push-out strengths than the other two sealers particularly after SBF storage (P < 0.001). Failure modes were predominantly adhesive and mixed for Pulp Canal Sealer and AH Plus Jet, and predominantly cohesive for ProRoot Endo Sealer. Spherical amorphous calcium phosphate-like phases that spontaneously transformed into apatite-like phases were seen in the fractured specimens of ProRoot Endo Sealer after SBF storage. CONCLUSIONS: When tested in bulk without a main core, both 'sealer type' and 'SBF storage' were significant in affecting push-out results. The ProRoot Endo Sealer demonstrated the presence of spherical amorphous calcium phosphate-like phases and apatite-like phases (i.e. ex vivo bioactivity) after SBF storage.

Microscopic appearance and apical seal of root canals filled with gutta-percha and ProRoot Endo Sealer after immersion in a phosphate-containing fluid.

AIM: To investigate the sealing quality of ProRoot Endo Sealer, a calcium silicate-based sealer and its morphologic characteristics after immersion in a phosphate-containing fluid (PCF). METHODOLOGY: Single-rooted canals were filled with gutta-percha and either ProRoot Endo Sealer or two commercially available zinc oxide eugenol (ZOE)-based and epoxy resin-based sealers. The sealers were allowed to set for 6 days and the filled teeth were immersed in PCF for 24 h before fluid leakage evaluation. After initial leakage evaluation at the 7th day, each filled root was restored and reimmersed in PCF for 28 days before the second phase of leakage evaluation at 35 days. Cryofractured specimens of additional teeth filled with the three sealers were examined using scanning electron microscopy after immersion in PCF for the two periods. RESULTS: One-way repeated measures anova and Tukey test revealed significant differences between the ZOE-based sealer at 35 days and the calcium silicate-based sealer at 35 days (P < 0.001), and between the ZOE-based sealer at 7 days and the calcium silicate-based sealer at 35 days (P = 0.001). No difference was found between the epoxy resin-based sealer and the calcium silicate-based sealer after both storage periods. Cryofractured calcium silicate-based sealer specimens demonstrated apatite-like crystalline deposits along the apical and middle thirds of the canal walls via transformation from amorphous calcium phosphate-like precursors. CONCLUSIONS: ProRoot Endo Sealer is comparable in sealing quality to the epoxy resin-based sealer and seals better than the ZOE-based sealer after immersion in PCF. The calcium silicate-based sealer also demonstrates ex vivo bioactivity when it comes into contact with phosphate ions.

Malaria and helminth co-infection in children living in a malaria endemic setting of mount Cameroon and predictors of anemia.

A study was carried out with 425 children aged 0-14 yr residing in Bolifamba, Cameroon, to investigate the effect of Plasmodium falciparum malaria and intestinal helminth coinfection on anemia and to identify significant predictors of anemia in the community. Blood was collected by finger prick to determine malaria parasitemia and packed cell volume (PCV). The Kato-Katz technique was used to assess the prevalence and egg load of intestinal helminths. The prevalence of P. falciparum malaria, intestinal helminth infections, and coinfection was 64.2%, 38.3%, and 24.7%, respectively. Coinfections in which heavy helminth loads were detected had corresponding high mean P. falciparum parasite loads >5,000/microl compared with coinfections involving light helminth burden. The overall prevalence of anemia was 30.8%. Anemia prevalence increased significantly with P. falciparum parasite load >5,000/microl compared with lower densities (chi2 = 6.734, P = 0.034). Anemia prevalence was significantly higher in febrile children compared with nonfebrile children (chi2 = 6.041, P = 0.014). Children infected exclusively with P. falciparum recorded the highest prevalence of anemia compared with uninfected children, those with coinfections, and those harboring only helminths. This difference in prevalence was significant (chi2 = 6.734, P = 0.031). Multiple regression analysis exposed fever (P > 0.001) and age (P = 0.004) as significant predictors of anemia.

Quantifying distraction and interruption in urological surgery.

BACKGROUND: To enhance safety in surgery, it is necessary to develop a variety of tools for measuring and evaluating the system of work. One important consideration for safety in any high-risk work is the frequency and effect of distraction and interruption. AIM: To quantify distraction and interruption to the sterile surgical team in urology. METHODS: Observation of the behaviour of the surgical team and their task activity determined distraction and interruption recorded. Using an ordinal scale, an observer rated each salient distraction or interruption observed in relation to the team's involvement. RESULTS: The frequency of events and their attached ratings were high, deriving from varying degrees of equipment, procedure and environment problems, telephones, bleepers and conversations. DISCUSSION: With further refinement and testing, this method may be useful for distinguishing ordinal levels of work interference in surgery and helpful in raising awareness of its origin for postoperative surgical team debriefing.