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.

Distinguish metabolic profiles and defense enzymes in Alternaria leaf blight resistant and susceptible genotypes of groundnut.

Alternaria leaf blight is major fungal disease of summer groundnut, causes significant loss of haulm and pod yield. Aims of this study were to understand the role of metabolites and phenylpropanoid related enzymes in Alternaria leaf blight resistance and to find out metabolic marker for disease resistance. Alternaria leaf blight resistant (GPBD4 and CS186) and susceptible genotypes (GG2 and TPG41) of groundnut were grown in pots during rabi-summer 2015. Groundnut plants were infected with Alternaria alternata (Fr.) Keissler at 40 days after sowing. 5 days after infection, upper second leaves were collected from both control and infected plants for analysis. A total of 67 metabolites comprising sugars, sugar alcohols, amino acids, organic acids, fatty acids, sterols and phenolic were identified using gas chromatography-mass spectrometry (non-targeted metabolomics). Constitutive levels of alpha-d-galactoside, d-mannitol, d-erythropentitol, glycine, and hexadecanoic acid were observed higher in resistant genotypes compared to susceptible genotypes. Moreover, arabinofuranose, cinnamic acid, 2-butendioic acid, and linoleic acid were observed only in resistant genotypes at both control and infected stage. In susceptible genotypes myo-inositol, glucose and fructose content was increased after infection with pathogen while decreased in resistant genotypes. Resistant genotypes had higher constitutive level of cinnamic and salicylic acid compared to susceptible genotypes. Non-infected leaves of resistant genotypes also had higher activities of phenylalanine ammonia lyase and tyrosine ammonia lyase activities. Our results suggest that metabolites specifically present in resistant genotypes impart defense mechanism against Alternaria pathogen and can be used as bio-marker for screening of germplasm.

Transport properties and electroresistance of a manganite based heterostructure: role of the manganite-manganite interface.

In this paper, we report the results of the investigations on the transport properties performed across the manganite-manganite interface in the LaMnO3-δ/La0.7Ca0.3MnO3/LaAlO3 (LMO/LCMO/LAO) heterostructure. The bilayered heterostructure was synthesized by a low cost and simple chemical solution deposition (CSD) method by employing the acetate precursor route. The same LMO/LCMO/LAO heterostructure was also grown using the dry metal oxide chemical vapor deposition (CVD) method and the results of transport characterization have been compared on the basis of wet and dry chemical methods used. XRD Φ-scan measurements were carried out to verify the structural quality and crystallographic orientations of LMO and LCMO manganite layers, for both wet and dry chemical method grown heterostructures. For wet and dry chemical methods, the temperature dependent resistance of the LMO/LCMO interface suggests the metallic nature. The asymmetric I-V curves collected at different temperatures show normal diode characteristics which get transformed to backward diode characteristics at high temperatures under high applied voltages at Vtr for both the methods. The values of Vtr are strongly dependent on the chemical method used. I-V data have been fitted using the Simmons model at different temperatures and discussed in terms of the spin-flip scattering mechanism for both wet and dry chemical method grown heterostructures. The electric field dependent electroresistance (ER) behavior of the presently studied LMO/LCMO manganite-manganite interface, grown using wet and dry chemical methods, has been understood on the basis of complex mechanisms including charge injection, formation of the depletion region, the tunneling effect, thermal processes and junction breakdown and their dependence on the applied electric field, field polarity and temperature studied.

Vacancy-Engineered Nickel Ferrite Forming-Free Low-Voltage Resistive Switches for Neuromorphic Circuits.

Innovations in resistive switching devices constitute a core objective for the development of ultralow-power computing devices. Forming-free resistive switching is a type of resistive switching that eliminates the need for an initial high voltage for the formation of conductive filaments and offers promising opportunities to overcome the limitations of traditional resistive switching devices. Here, we demonstrate mixed charge state oxygen vacancy-engineered electroforming-free resistive switching in NiFe2O4 (NFO) thin films, fabricated as asymmetric Ti/NFO/Pt heterostructures, for the first time. Using pulsed laser deposition in a controlled oxygen atmosphere, we tune the oxygen vacancies together with the cationic valence state in the nickel ferrite phase, with the latter directly affecting the charge state of the oxygen vacancies. The structural integrity and chemical composition of the films are confirmed by X-ray diffraction and hard X-ray photoelectron spectroscopy, respectively. Electrical transport studies reveal that resistive switching characteristics in the films can be significantly altered by tuning the amount and charge state of the oxygen vacancy concentration during the deposition of the films. The resistive switching mechanism is seen to depend upon the migration of both singly and doubly charged oxygen vacancies formed as a result of changes in the nickel valence state and the consequent formation/rupture of conducting filaments in the switching layer. This is supported by the existence of an optimum oxygen vacancy concentration for efficient low-voltage resistive switching, below or above which the switching process is inhibited. Along with the filamentary switching mechanism, the Ti top electrode also enhances the resistive switching performance due to interfacial effects. Time-resolved measurements on the devices display both long- and short-term potentiation in the optimized vacancy-engineered NFO resistive switches, ideal for solid-state synapses achieved in a single system. Our work on correlated oxide forming-free resistive switches holds significant potential for CMOS-compatible low-power, nonvolatile resistive memory and neuromorphic circuits.

Natural mutations of human XDH promote the nitrite (NO2-)-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?

Several rare genetic variations of human XDH have been shown to alter xanthine oxidoreductase (XOR) activity leading to impaired purine catabolism. However, XOR is a multi-functional enzyme that depending upon the environmental conditions also expresses oxidase activity leading to both O2·- and H2O2 and nitrite (NO2-) reductase activity leading to nitric oxide (·NO). Since these products express important, and often diametrically opposite, biological activity, consideration of the impact of XOR mutations in the context of each aspect of the biochemical activity of the enzyme is needed to determine the potential full impact of these variants. Herein, we show that known naturally occurring hXDH mutations do not have a uniform impact upon the biochemical activity of the enzyme in terms of uric acid (UA), reactive oxygen species (ROS) and nitric oxide ·NO formation. We show that the His1221Arg mutant, in the presence of xanthine, increases UA, O2·- and NO generation compared to the WT, whilst the Ile703Val increases UA and ·NO formation, but not O2·-. We speculate that this change in the balance of activity of the enzyme is likely to endow those carrying these mutations with a harmful or protective influence over health that may explain the current equipoise underlying the perceived importance of XDH mutations. We also show that, in presence of inorganic NO2-, XOR-driven O2·- production is substantially reduced. We suggest that targeting enzyme activity to enhance the NO2--reductase profile in those carrying such mutations may provide novel therapeutic options, particularly in cardiovascular disease.

A novel variant of esophageal atresia with tracheo-esophageal fistula with a crossed-over proximal esophageal pouch: a diagnostic dilemma.

Diagnosis of esophageal atresia (EA) with tracheo-esophageal fistula (TEF) can be easily done in newborns with symptoms of excessive salivation and failure to pass infant-feeding tube (IFT) into the stomach. There are many reports in the literature which describe the diagnostic pitfall of this IFT test. We describe a case of a neonate with EA with TEF in which the upper atretic esophageal pouch had grown long enough to reach up to the level of diaphragm, thus allowing the IFT to go up to significant distance from the alveolus giving the radiograph as if the tube is in the upper part of stomach, thus creating a diagnostic dilemma.

Health care delivery practices in the rural part of the Yavatmal district regarding IUD insertion.

A cross-sectional survey of Cu T users in a rural area of the Yavatmal district was carried out using stratified sampling, to identify interventions that can improve intrauterine device (IUD) service provision processes and their acceptance. The average age at Cu T insertion was 23.8 years. Cu T acceptance with one child was 55.5%. 80.8% of Cu Ts were inserted within 10 days of menstruation, while there were no post-partum Cu T insertions. 51.8% Cu Ts were inserted in PHC's. At the time of the survey, 48.2% users already have their Cu T removed. Only 22.7% couples utilized some alternate contraception after Cu T removal. Post-discontinuation contraceptive use was lower in a tribal area. 30% Cu T acceptors received less than two health checkups. 78.8% (58.1% in a tribal area and 84.9% in a non-tribal area) beneficiaries received information about Cu T from health workers. Only 6.6% Cu T acceptors received specific advice of checking the Cu T string. Utilization of private facility was more common among tribals. Reach of health service regarding Cu T need to be improved in tribal areas. Health service providers need to be more proactive, especially about utilization of the immediate post-partum period for Cu T insertion, clients counseling, and follow up of users.

Use of enhanced stent visualisation compared to angiography alone to guide percutaneous coronary intervention.

OBJECTIVE: We aimed to assess the use of enhanced stent visualisation (ESV) on outcomes, after PCI with overlapping stents, specifically using CLEARstent technology. BACKGROUND: Stent underexpansion and overlap are both significant risk factors for restenosis and stent thrombosis. Enhanced stent visualisation (e.g. CLEARstent) systems could provide important data to reduce under-expansion and stent overlap. METHODS: This was a cohort study based on this institution's percutaneous coronary intervention (PCI) registry. A total of 2614 patients who had PCI for stable angina or acute coronary syndromes (ACS, excluding cardiogenic shock) with overlapping 2nd generation drug eluting stents (DES) in the same vessel between May 2015 and January 2018 were included in the analysis. Patients were divided into ESV (n = 1354) and no ESV guided intervention (n = 1260). The primary end-point was major adverse cardiovascular events (MACE: target vessel revascularisation, target vessel myocardial infarction and all-cause mortality) recorded at a median follow up of 2.4 years. RESULTS: Groups were comparable for patient characteristics (age, diabetes mellitus, ACS presentation). A significant difference in MACE was observed between patients who underwent ESV-guided PCI (9.5%) compared with patients who underwent Standard PCI (14.4%, p = .018). This difference was mainly driven by reduced rates of target vessel revascularisation and recurrent myocardial infarction. Overall this difference persisted after multivariate Cox analysis (HR 0.86, 95% CI: 0.73-0.98) and propensity matching (HR = 0.88, 95% CI: 0.69-0.99). CONCLUSION: We suggest that routine clinical use of ESV technology during PCI can be useful, and is associated with better medium-term angiographic and clinical outcomes. Further study is required to build on this promising signal.

Transjugular liver biopsy using Tru-cut biopsy needle: KEM experience.

BACKGROUND AND AIM: Transjugular liver biopsy is accepted procedure in patients in whom percutaneous liver biopsy is contraindicated. We report our experience with this procedure, its indications, efficacy and safety in Indian population over 5 years. MATERIAL & METHODS: A retrospective study of 145 consecutive patients who had undergone transjugular liver biopsy from May 2002 to Nov. 2007 was done from the database maintained in our department. We evaluated the indications, technical success, complication and impact of histological diagnosis on the management of those patients. RESULTS: 145 Transjugular liver biopsies were performed of which 74 were males and 71 were females aged between 5 and 74 years. Two procedures were abandoned due to failed hepatic vein cannulation because of venous occlusion. Out of 143 biopsies, 4 were inadequate while 139 yielded adequate tissue for histopathological diagnosis. Histopathological examination in our study showed cirrhotic changes in 56, hepatitis including both acute and chronic in 48, periportal fibrosis in 9, Wilson's disease in 5 and obstructive cholangiopathy in 2 patients. The remaining 19 were normal. Minor complications occurred in 2 patients. CONCLUSION: Transjugular liver biopsy is a safe procedure in the trained hands and provides adequate tissue for diagnosis when percutaneous liver biopsy is contraindicated.

Sonochemical synthesis, characterization, thermal and semiconducting behavior of nano-sized azidopentaamminecobalt(III) complexes containing anion, CrO42- or Cr2O72.

New nano-sized cobalt(III) coordination complexes, [Co(NH3)5N3]CrO4 (1N) and [Co(NH3)5N3]Cr2O7 (2N) were synthesized using an innovative sonochemical methodology based on reaction between [Co(NH3)5N3]Cl2 and potassium salt of CrO42- or Cr2O72- in aqueous medium. These complexes were also compared with their respective bulks which were synthesized under identical conditions in the absence of sonicaion. All the complexes were characterized by elemental analysis and spectroscopic techniques (UV-visible and IR). Morphology and particle size of nano-sized complexes was determined by SEM and Zeta-sizer respectively. TGA was used for comparative thermal stability and XRD to identify the phase difference between nano structures and bulk complexes. Furthermore, the electrical property was investigated and all complexes were found to be electrical semiconducting materials and 2N shows better result than others. The single crystals X-ray structure study of new [Co(NH3)5N3]Cr2O7 revealed the presence of discrete ions, [Co(NH3)5N3]2+ and Cr2O72-, crystallizes in monoclinic, space group Pc, with R=0.0636 in the solid state.

Safety and effectiveness of transjugular renal biopsy: A single center study.

Although percutaneous renal biopsy remains the preferred method, there are several scenarios where transjugular approach is more suitable. We hereby describe our technique of transjugular renal biopsy (TJRB) and evaluate its safety and efficacy. We retrospectively collected data regarding indication for the transjugular route of biopsy, its complications, clinical and laboratory data, and adequacy of samples from patients' records. TJRB was performed when the patients were at a high risk for bleeding from percutaneous renal biopsy. Tissue samples were assessed by a pathologist for adequacy. All patients were followed up with ultrasonographic scan 3 h after the procedure and on day 3. Nine patients (age 41.5 ± 15.4 years; 8 men) underwent 9 TJRB procedures. The procedure was technically successful in all patients. Six patients (66.67%) had a platelet count of <50,000/mcL, 2 (33.3%) had an elevated International Normalized Ratio of more than 1.4, and 1 had both. 3.2 ± 0.4 cores were obtained, with median (range) number of glomeruli being ten (7-11). Adequate renal tissue sample was obtained in all the patients. Though capsular perforation developed in 5 patients, none had major complication requiring management (endovascular treatment or blood transfusion). TJRB is a safe and effective in patients with contraindications to percutaneous biopsy.

Eptifibatide is associated with significant cost savings and similar clinical outcomes to abciximab when used during primary percutaneous coronary intervention for ST-elevation myocardial infarction: An observational cohort study of 3863 patients.

INTRODUCTION: Glycoprotein IIb/IIIa inhibitors are recommended by guidelines in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. There are few studies directly comparing these agents. The aim of this study was to assess whether eptifibatide is a safe and cost-effective alternative to abciximab in the treatment of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. METHODS: This was an observational cohort study of 3863 patients who received a GPIIb/IIIa inhibitor whilst undergoing primary percutaneous coronary intervention from 2007 to 2014. Patients who did not receive a GPIIb/IIIa inhibitor were excluded. Time to first major adverse cardiac event defined as death, non-fatal myocardial infarction, stroke or target vessel revascularization, and total hospital costs were compared between the groups. RESULTS: In all, 1741 patients received abciximab with 2122 receiving eptifibatide. Patients who received eptifibatide had higher rates of previous MI/percutaneous coronary intervention and were more likely to undergo a procedure from the radial route. Unadjusted Kaplan-Meier analysis revealed no significant difference in the 1-year event rates between patients given eptifibatide versus abciximab (p = 0.201). Age-adjusted Cox analysis demonstrated no difference in 1-year outcome between abciximab and eptifibatide (hazard ratio: 0.83; 95% confidence interval: 0.73-1.39), which persisted after multivariate adjustment (hazard ratio: 0.92; 95% confidence interval: 0.79-1.56) including the incorporation of a propensity score (hazard ratio: 0.88; 95% confidence interval: 0.71-1.44). Eptifbatide was associated with significant cost savings being 87% cheaper overall compared to abciximab (on average £650 cheaper per patient and saving approximately £950,000). CONCLUSION: This observational data suggest that eptifibatide is associated with similar outcomes and significant cost savings compared to abciximab when used in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Optical control of filamentation-induced damage to DNA by intense, ultrashort, near-infrared laser pulses.

We report on damage to DNA in an aqueous medium induced by ultrashort pulses of intense laser light of 800 nm wavelength. Focusing of such pulses, using lenses of various focal lengths, induces plasma formation within the aqueous medium. Such plasma can have a spatial extent that is far in excess of the Rayleigh range. In the case of water, the resulting ionization and dissociation gives rise to in situ generation of low-energy electrons and OH-radicals. Interactions of these with plasmid DNA produce nicks in the DNA backbone: single strand breaks (SSBs) are induced as are, at higher laser intensities, double strand breaks (DSBs). Under physiological conditions, the latter are not readily amenable to repair. Systematic quantification of SSBs and DSBs at different values of incident laser energy and under different external focusing conditions reveals that damage occurs in two distinct regimes. Numerical aperture is the experimental handle that delineates the two regimes, permitting simple optical control over the extent of DNA damage.

Female genital tuberculosis: hysterosalpingographic appearances.

Genital tuberculosis is an important cause of infertility in developing countries and hysterosalpingography (HSG) is the initial procedure performed for the evaluation. Reviewing 37 cases of female genital tuberculosis, we encountered various appearances on HSG. Of 579 HSGs performed over a period of 4 years, 492 (85%) were performed as part of infertility work up. Genital tuberculosis was found in 6.3% of all the patients who underwent HSGs and 7.5% of all patients investigated for infertility. The various features of proven tuberculosis cases are illustrated in this pictorial review. We briefly discuss the pathology and these appearances along with radiopathological correlation.

Mandibular haemophilic pseudotumour containing a fluid-fluid level.

Osseous haemophilic pseudotumours are uncommon. Mandibular haemophilic pseudotumours are rare, with only approximately 12 cases reported in the literature to date. We present imaging findings of a histopathologically proven mandibular haemophilic pseudotumour. A fluid-fluid level, hitherto not associated with this condition, is also described.

Glycoprotein IIb/IIIa inhibitors use and outcome after percutaneous coronary intervention for non-ST elevation myocardial infarction.

AIMS: We investigate the effect of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors on long-term outcomes following percutaneous coronary intervention (PCI) after non-ST elevation myocardial infarction (NSTEMI). Meta-analyses indicate that these agents are associated with improved short-term outcomes. However, many trials were undertaken before the routine use of P2Y12 inhibitors. Recent studies yield conflicting results and registry data have suggested that GP IIb/IIIa inhibitors may cause more bleeding than what trials indicate. METHODS AND RESULTS: This retrospective observational study involves 3047 patients receiving dual-antiplatelet therapy who underwent PCI for NSTEMI. Primary outcome was all-cause mortality. Major adverse cardiac events (MACE) were a secondary outcome. Mean follow-up was 4.6 years. Patients treated with GP IIb/IIIa inhibitors were younger with fewer comorbidities. Although the unadjusted Kaplan-Meier analysis suggested that GP IIb/IIIa inhibitor use was associated with improved outcomes, multivariate analysis (including propensity scoring) showed no benefit for either survival (P = 0.136) or MACE (P = 0.614). GP IIb/IIIa inhibitor use was associated with an increased risk of major bleeding (P = 0.021). CONCLUSION: Although GP IIb/IIIa inhibitor use appeared to improve outcomes after PCI for NSTEMI, patients who received GP IIb/IIIa inhibitors tended to be at lower risk. After multivariate adjustment we observed no improvement in MACE or survival and an increased risk of major bleeding.

Case fatality rates for South Asian and Caucasian patients show no difference 2.5 years after percutaneous coronary intervention.

OBJECTIVE: To compare short and medium-term prognosis in South Asian and Caucasian patients undergoing percutaneous coronary intervention (PCI) to determine if there are ethnic differences in case death rates. DESIGN: Retrospective cohort study. SETTING: A cardiology referral centre in east London. PATIENTS: 9771 patients who underwent PCI from October 2003 to December 2007 of whom 7966 (81.5%) were Caucasian and 1805 (18.5%) were South Asian. MAIN OUTCOME MEASURES: In-hospital major adverse cardiac events (MACE; death, myocardial infarction, stroke and target vessel revascularisation), subsequent revascularisation rates (PCI and coronary artery bypass grafting; CABG) and all-cause mortality during a median follow-up of 2.5 years (range 1.5-3.6 years). RESULTS: South Asian patients were younger than Caucasian patients (59.69±0.27 vs 64.69±0.13 years, p<0.0001), and more burdened by cardiovascular risk factors, particularly type II diabetes mellitus (45.9%±1.2% vs 15.7%±0.4%, p<0.0001). The in-hospital rates of MACE were similar for South Asians and Caucasians (3.5% vs 2.8%, p=0.40). South Asians had higher rates of clinically driven PCI for restenosis and subsequent CABG, although Kaplan-Meier estimates of all-cause mortality showed no significant differences; this was regardless of whether PCI was performed post-acute coronary syndrome or as an elective procedure. The adjusted hazard of death for South Asians compared with Caucasians was 1.00 (95% CI 0.81 to 1.23). CONCLUSION: In this large PCI cohort, the in-hospital and longer-term mortality of South Asians appeared no worse than that of Caucasians. South Asians had higher rates of restenosis and CABG during follow-up. Data suggest that the excess coronary mortality for South Asians compared with Caucasians is not explained by differences in case-fatality rates.