Aspartate-Histidine Interaction in the Retinal Schiff Base Counterion of the Light-Driven Proton Pump of Exiguobacterium sibiricum†

PubMed Central

Balashov, S.P.; Petrovskaya, L.E.; Lukashev, E.P.; Imasheva, E.S.; Dioumaev, A.K.; Wang, J.M.; Sychev, S.V.; Dolgikh, D.A.; Rubin, A.B.; Kirpichnikov, M.P.; Lanyi, J.K.

2012-01-01

One of the distinctive features of eubacterial retinal based proton pumps, proteorhodopsins, xanthorhodopsin and others, is hydrogen bonding of the key aspartate residue, the counterion to the retinal Schiff base, to a histidine. We describe properties of the recently found eubacterium proton pump from Exiguobacterium sibiricum (named ESR) expressed in E. coli, especially features that depend on Asp-His interaction, the protonation state of the key aspartate, Asp85, and its ability to accept proton from the Schiff base during the photocycle. Proton pumping by liposomes and E. coli cells containing ESR occurs in a broad pH range above pH 4.5. Large light-induced pH changes indicate that ESR is a potent proton pump. Replacement of His57 with methionine or asparagine strongly affects the pH dependent properties of ESR. In the H57M mutant a dramatic decrease in the quantum yield of chromophore fluorescence emission and a 45 nm blue shift of the absorption maximum upon raising the pH from 5 to 8 indicates deprotonation of the counterion with a pKa of 6.3, which is also the pKa at which the M intermediate is observed in the photocycle of the protein solubilized in detergent (DDM). This is in contrast with the wild type protein, in which the same experiments show that the major fraction of Asp85 is deprotonated at pH > 3 and that it protonates only at low pH, with a pKa of 2.3. The M intermediate in the wild type photocycle accumulates only at high pH, with an apparent pKa of 9 from deprotonation of a residue interacting with Asp85, presumably His57. In liposomes reconstituted with ESR the pKas for M formation and spectral shifts are 2–3 pH units lower than in DDM. The distinctively different pH dependencies of the protonation of Asp85 and the accumulation of the M intermediate in the wild type protein vs. the H57M mutant indicate that there is strong Asp-His interaction, which substantially lowers the pKa of Asp85 by stabilizing its deprotonated state. PMID:22738070

Biological proton pumping in an oscillating electric field.

PubMed

Kim, Young C; Furchtgott, Leon A; Hummer, Gerhard

2009-12-31

Time-dependent external perturbations provide powerful probes of the function of molecular machines. Here we study biological proton pumping in an oscillating electric field. The protein cytochrome c oxidase is the main energy transducer in aerobic life, converting chemical energy into an electric potential by pumping protons across a membrane. With the help of master-equation descriptions that recover the key thermodynamic and kinetic properties of this biological "fuel cell," we show that the proton pumping efficiency and the electronic currents in steady state depend significantly on the frequency and amplitude of the applied field, allowing us to distinguish between different microscopic mechanisms of the machine. A spectral analysis reveals dominant reaction steps consistent with an electron-gated pumping mechanism.

Heat driven pulse pump

NASA Technical Reports Server (NTRS)

Benner, Steve M (Inventor); Martins, Mario S. (Inventor)

2000-01-01

A heat driven pulse pump includes a chamber having an inlet port, an outlet port, two check valves, a wick, and a heater. The chamber may include a plurality of grooves inside wall of the chamber. When heated within the chamber, a liquid to be pumped vaporizes and creates pressure head that expels the liquid through the outlet port. As liquid separating means, the wick, disposed within the chamber, is to allow, when saturated with the liquid, the passage of only liquid being forced by the pressure head in the chamber, preventing the vapor from exiting from the chamber through the outlet port. A plurality of grooves along the inside surface wall of the chamber can sustain the liquid, which is amount enough to produce vapor for the pressure head in the chamber. With only two simple moving parts, two check valves, the heat driven pulse pump can effectively function over the long lifetimes without maintenance or replacement. For continuous flow of the liquid to be pumped a plurality of pumps may be connected in parallel.

Correlation between proton pump inhibitors and risk of pyogenic liver abscess.

PubMed

Lin, Hsien-Feng; Liao, Kuan-Fu; Chang, Ching-Mei; Lin, Cheng-Li; Lai, Shih-Wei

2017-08-01

Little is known about the relationship between proton pump inhibitors use and pyogenic liver abscess. The objective of this study was to evaluate the correlation between proton pump inhibitors use and pyogenic liver abscess in Taiwan. This was a population-based case-control study using the database of the Taiwan National Health Insurance Program since 2000 to 2011. Subjects aged 20 to 84 who experienced their first episode of pyogenic liver abscess were enrolled as the case group (n = 1372). Randomly selected subjects aged 20 to 84 without pyogenic liver abscess were enrolled as the control group (n = 1372). Current use, early use, and late use of proton pump inhibitors was defined as subjects whose last one tablet for proton pump inhibitors was noted ≤30 days, between 31 to 90 days and ≥91 days before the date of admission for pyogenic liver abscess. Subjects who never received a prescription for proton pump inhibitors were defined as nonusers of proton pump inhibitors. A multivariable unconditional logistic regression model was used to measure the odds ratio and 95% confidence interval to evaluate the correlation between proton pump inhibitors use and pyogenic liver abscess. After adjusting for confounders, the adjusted odds ratio of pyogenic liver abscess was 7.59 for subjects with current use of proton pump inhibitors (95% confidence interval 5.05, 11.4), when compared with nonusers. Current use of proton pump inhibitors is associated with a greater risk of pyogenic liver abscess.

Biological proton pumping in an oscillating electric field

PubMed Central

Kim, Young C.; Furchtgott, Leon A.; Hummer, Gerhard

2010-01-01

Time-dependent external perturbations provide powerful probes of the function of molecular machines. Here we study biological proton pumping in an oscillating electric field. The protein cytochrome c oxidase is the main energy transducer in aerobic life, converting chemical energy into an electric potential by pumping protons across a membrane. With the help of master-equation descriptions that recover the key thermodynamic and kinetic properties of this biological “fuel cell,” we show that the proton pumping efficiency and the electronic currents in steady state both depend significantly and distinctly on the frequency and amplitude of the applied field, allowing us to distinguish between different microscopic mechanisms of the machine. A spectral analysis reveals dominant kinetic modes that show reaction steps consistent with an electron-gated pumping mechanism. PMID:20366348

Multimorbidities and Overprescription of Proton Pump Inhibitors in Older Patients.

PubMed

Delcher, Anne; Hily, Sylvie; Boureau, Anne Sophie; Chapelet, Guillaume; Berrut, Gilles; de Decker, Laure

2015-01-01

To determine whether there is an association between overprescription of proton pump inhibitors (PPIs) and multimorbidities in older patients. Multicenter prospective study. Acute geriatric medicine at the University Hospital of Nantes and the Hospital of Saint-Nazaire. Older patients aged 75 and over hospitalized in acute geriatric medicine. Older patients in acute geriatric medicine who received proton pump inhibitors. Variables studied were individual multimorbidities, the burden of multimorbidity evaluated by the Cumulative Illness Rating Scale, age, sex, type of residence (living in nursing home or not), functional abilities (Lawton and Katz scales), nutritional status (Body Mass Index), and the type of concomitant medications (antiaggregant, corticosteroids', or anticoagulants). Overprescription of proton pump inhibitors was found in 73.9% older patients. In the full model, cardiac diseases (odds ratio [OR] = 4.17, p = 0.010), metabolic diseases (OR = 2.14, p = 0.042) and corticosteroids (OR = 5.39, p = 0.028) were significantly associated with overprescription of proton pump inhibitors. Esogastric diseases (OR = 0.49, p = 0.033) were negatively associated with overprescription of proton pump inhibitors. Cardiac diseases and metabolic diseases were significantly associated with overprescription of proton pump inhibitors.

Multimorbidities and Overprescription of Proton Pump Inhibitors in Older Patients

PubMed Central

Delcher, Anne; Hily, Sylvie; Boureau, Anne Sophie; Chapelet, Guillaume; Berrut, Gilles; de Decker, Laure

2015-01-01

Objectives To determine whether there is an association between overprescription of proton pump inhibitors (PPIs) and multimorbidities in older patients. Design Multicenter prospective study. Setting Acute geriatric medicine at the University Hospital of Nantes and the Hospital of Saint-Nazaire. Participants Older patients aged 75 and over hospitalized in acute geriatric medicine. Measurements Older patients in acute geriatric medicine who received proton pump inhibitors. Variables studied were individual multimorbidities, the burden of multimorbidity evaluated by the Cumulative Illness Rating Scale, age, sex, type of residence (living in nursing home or not), functional abilities (Lawton and Katz scales), nutritional status (Body Mass Index), and the type of concomitant medications (antiaggregant, corticosteroids’, or anticoagulants). Results Overprescription of proton pump inhibitors was found in 73.9% older patients. In the full model, cardiac diseases (odds ratio [OR] = 4.17, p = 0.010), metabolic diseases (OR = 2.14, p = 0.042) and corticosteroids (OR = 5.39, p = 0.028) were significantly associated with overprescription of proton pump inhibitors. Esogastric diseases (OR = 0.49, p = 0.033) were negatively associated with overprescription of proton pump inhibitors. Conclusion Cardiac diseases and metabolic diseases were significantly associated with overprescription of proton pump inhibitors. PMID:26535585

Respiratory Complex I in Bos taurus and Paracoccus denitrificans Pumps Four Protons across the Membrane for Every NADH Oxidized.

PubMed

Jones, Andrew J Y; Blaza, James N; Varghese, Febin; Hirst, Judy

2017-03-24

Respiratory complex I couples electron transfer between NADH and ubiquinone to proton translocation across an energy-transducing membrane to support the proton-motive force that drives ATP synthesis. The proton-pumping stoichiometry of complex I ( i.e. the number of protons pumped for each two electrons transferred) underpins all mechanistic proposals. However, it remains controversial and has not been determined for any of the bacterial enzymes that are exploited as model systems for the mammalian enzyme. Here, we describe a simple method for determining the proton-pumping stoichiometry of complex I in inverted membrane vesicles under steady-state ADP-phosphorylating conditions. Our method exploits the rate of ATP synthesis, driven by oxidation of NADH or succinate with different sections of the respiratory chain engaged in catalysis as a proxy for the rate of proton translocation and determines the stoichiometry of complex I by reference to the known stoichiometries of complexes III and IV. Using vesicles prepared from mammalian mitochondria (from Bos taurus ) and from the bacterium Paracoccus denitrificans , we show that four protons are pumped for every two electrons transferred in both cases. By confirming the four-proton stoichiometry for mammalian complex I and, for the first time, demonstrating the same value for a bacterial complex, we establish the utility of P. denitrificans complex I as a model system for the mammalian enzyme. P. denitrificans is the first system described in which mutagenesis in any complex I core subunit may be combined with quantitative proton-pumping measurements for mechanistic studies. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Performance of a vane driven-gear pump

NASA Technical Reports Server (NTRS)

Heald, R H

1921-01-01

Given here are the results of a test conducted in a wind tunnel on the performance of a vane-driven gear pump used to pump gasoline upward into a small tank located within the upper wing from which it flows by gravity to the engine carburetor. Information is given on the efficiency of the pump, the head resistance of the vanes, the performance and characteristics of the unit with and without housing about the vanes, the pump performance when motor driven, and resistance and power characteristics.

Enhancement of Survival and Electricity Production in an Engineered Bacterium by Light-Driven Proton Pumping▿ †

PubMed Central

Johnson, Ethan T.; Baron, Daniel B.; Naranjo, Belén; Bond, Daniel R.; Schmidt-Dannert, Claudia; Gralnick, Jeffrey A.

2010-01-01

Microorganisms can use complex photosystems or light-dependent proton pumps to generate membrane potential and/or reduce electron carriers to support growth. The discovery that proteorhodopsin is a light-dependent proton pump that can be expressed readily in recombinant bacteria enables development of new strategies to probe microbial physiology and to engineer microbes with new light-driven properties. Here, we describe functional expression of proteorhodopsin and light-induced changes in membrane potential in the bacterium Shewanella oneidensis strain MR-1. We report that there were significant increases in electrical current generation during illumination of electrochemical chambers containing S. oneidensis expressing proteorhodopsin. We present evidence that an engineered strain is able to consume lactate at an increased rate when it is illuminated, which is consistent with the hypothesis that proteorhodopsin activity enhances lactate uptake by increasing the proton motive force. Our results demonstrate that there is coupling of a light-driven process to electricity generation in a nonphotosynthetic engineered bacterium. Expression of proteorhodopsin also preserved the viability of the bacterium under nutrient-limited conditions, providing evidence that fulfillment of basic energy needs of organisms may explain the widespread distribution of proteorhodopsin in marine environments. PMID:20453141

Recent advances in chirally pure proton pump inhibitors.

PubMed

Pai, Vikas; Pai, Nitin

2007-08-01

Chirality is a ubiquitous natural phenomenon resulting because of a differential spatial orientation of molecules around its chiral centre. This leads to the existence of two or more spatially dissimilar forms, known as stereoisomers or enantiomers, which are non-superimposable images of each other and may significantly differ from each other with respect to pharmacokinetic and pharmacodynamic properties and molecular interaction. Thus one isomer may offer significant pharmacokinetic and therapeutic advantages as compared to the other isomer or the racemic mixture (mixture containing both enantiomers). Proton pump inhibitors are a class of drugs which have been very effective in the management of acid-related disorders. The proton pumps currently available in the market including omeprazole, pantoprazole, rabeprazole and lansoprazole are racemic mixtures of the S and R isomers. Chirally pure forms of proton pump inhibitors show a superior metabolic and pharmacokinetic profile as compared to their racemates. The therapeutic efficacy is also superior to the parent racemate. This has been clearly demonstrated with the development of esomeprazole- the S-isomer of omeprazole. S-pantoprazole and dexrabeprazole also offer therapeutic advantages as compared to racemic pantoprazole and racemic rabeprazole respectively. This article reviews the chiral developments in the proton pump inhibitors and their clinical applications.

Mammalian complex I pumps 4 protons per 2 electrons at high and physiological proton motive force in living cells.

PubMed

Ripple, Maureen O; Kim, Namjoon; Springett, Roger

2013-02-22

Mitochondrial complex I couples electron transfer between matrix NADH and inner-membrane ubiquinone to the pumping of protons against a proton motive force. The accepted proton pumping stoichiometry was 4 protons per 2 electrons transferred (4H(+)/2e(-)) but it has been suggested that stoichiometry may be 3H(+)/2e(-) based on the identification of only 3 proton pumping units in the crystal structure and a revision of the previous experimental data. Measurement of proton pumping stoichiometry is challenging because, even in isolated mitochondria, it is difficult to measure the proton motive force while simultaneously measuring the redox potentials of the NADH/NAD(+) and ubiquinol/ubiquinone pools. Here we employ a new method to quantify the proton motive force in living cells from the redox poise of the bc(1) complex measured using multiwavelength cell spectroscopy and show that the correct stoichiometry for complex I is 4H(+)/2e(-) in mouse and human cells at high and physiological proton motive force.

Mammalian Complex I Pumps 4 Protons per 2 Electrons at High and Physiological Proton Motive Force in Living Cells*

PubMed Central

Ripple, Maureen O.; Kim, Namjoon; Springett, Roger

2013-01-01

Mitochondrial complex I couples electron transfer between matrix NADH and inner-membrane ubiquinone to the pumping of protons against a proton motive force. The accepted proton pumping stoichiometry was 4 protons per 2 electrons transferred (4H+/2e−) but it has been suggested that stoichiometry may be 3H+/2e− based on the identification of only 3 proton pumping units in the crystal structure and a revision of the previous experimental data. Measurement of proton pumping stoichiometry is challenging because, even in isolated mitochondria, it is difficult to measure the proton motive force while simultaneously measuring the redox potentials of the NADH/NAD+ and ubiquinol/ubiquinone pools. Here we employ a new method to quantify the proton motive force in living cells from the redox poise of the bc1 complex measured using multiwavelength cell spectroscopy and show that the correct stoichiometry for complex I is 4H+/2e− in mouse and human cells at high and physiological proton motive force. PMID:23306206

The Evolution of Ion Pumps.

ERIC Educational Resources Information Center

Maloney, Peter C.; Wilson, T. Hastings

1985-01-01

Constructs an evolutionary sequence to account for the diversity of ion pumps found today. Explanations include primary ion pumps in bacteria, features and distribution of ATP-driven pumps, preference for cation transport, and proton pump reversal. The integrated evolutionary hypothesis should encourage new experimental approaches. (DH)

Proton-coupled electron transfer and the role of water molecules in proton pumping by cytochrome c oxidase

PubMed Central

Sharma, Vivek; Enkavi, Giray; Vattulainen, Ilpo; Róg, Tomasz; Wikström, Mårten

2015-01-01

Molecular oxygen acts as the terminal electron sink in the respiratory chains of aerobic organisms. Cytochrome c oxidase in the inner membrane of mitochondria and the plasma membrane of bacteria catalyzes the reduction of oxygen to water, and couples the free energy of the reaction to proton pumping across the membrane. The proton-pumping activity contributes to the proton electrochemical gradient, which drives the synthesis of ATP. Based on kinetic experiments on the O–O bond splitting transition of the catalytic cycle (A → PR), it has been proposed that the electron transfer to the binuclear iron–copper center of O2 reduction initiates the proton pump mechanism. This key electron transfer event is coupled to an internal proton transfer from a conserved glutamic acid to the proton-loading site of the pump. However, the proton may instead be transferred to the binuclear center to complete the oxygen reduction chemistry, which would constitute a short-circuit. Based on atomistic molecular dynamics simulations of cytochrome c oxidase in an explicit membrane–solvent environment, complemented by related free-energy calculations, we propose that this short-circuit is effectively prevented by a redox-state–dependent organization of water molecules within the protein structure that gates the proton transfer pathway. PMID:25646428

Proton-pumping rhodopsins are abundantly expressed by microbial eukaryotes in a high-Arctic fjord.

PubMed

Vader, Anna; Laughinghouse, Haywood D; Griffiths, Colin; Jakobsen, Kjetill S; Gabrielsen, Tove M

2018-02-01

Proton-pumping rhodopsins provide an alternative pathway to photosynthesis by which solar energy can enter the marine food web. Rhodopsin genes are widely found in marine bacteria, also in the Arctic, and were recently reported from several eukaryotic lineages. So far, little is known about rhodopsin expression in Arctic eukaryotes. In this study, we used metatranscriptomics and 18S rDNA tag sequencing to examine the mid-summer function and composition of marine protists (size 0.45-10 µm) in the high-Arctic Billefjorden (Spitsbergen), especially focussing on the expression of microbial proton-pumping rhodopsins. Rhodopsin transcripts were highly abundant, at a level similar to that of genes involved in photosynthesis. Phylogenetic analyses placed the environmental rhodopsins within disparate eukaryotic lineages, including dinoflagellates, stramenopiles, haptophytes and cryptophytes. Sequence comparison indicated the presence of several functional types, including xanthorhodopsins and a eukaryotic clade of proteorhodopsin. Transcripts belonging to the proteorhodopsin clade were also abundant in published metatranscriptomes from other oceanic regions, suggesting a global distribution. The diversity and abundance of rhodopsins show that these light-driven proton pumps play an important role in Arctic microbial eukaryotes. Understanding this role is imperative to predicting the future of the Arctic marine ecosystem faced by a changing light climate due to diminishing sea-ice. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

Endoscopic and histopathologic gastric changes in chronic users of proton-pump inhibitors.

PubMed

Camilo, Sílvia Maria Perrone; Almeida, Élia Cláudia de Souza; Miranzi, Benito André Silveira; Silva, Juliano Carvalho; Nomelini, Rosemary Simões; Etchebehere, Renata Margarida

2015-01-01

Proton-pump inhibitors have been used for at least two decades. They are among the most commonly sold drugs in the world. However, some controversy remains about the indications for their use and the consequences of their prolonged use. To evaluate and compare the endoscopic and histopathologic gastric changes in chronic users of proton-pump inhibitors to changes in non-users. A prospective study performed at a tertiary Public Hospital involving 105 patients undergoing upper-gastrointestinal endoscopy. Subjects included 81 proton-pump inhibitor users and 24 non-users (control group). Biopsies of the antral-type mucosa, the antral-fundic transition, and the fundus were evaluated by the Sydney System. The presence of erosion or ulceration, lymphatic follicles, reactive gastropathy, and polypoid or epithelial hyperplasia was also determined. Serum levels of gastrin were measured. We found two polyps, one in each group, both of which were negative for Helicobacter pylori. There were two cases of parietal cell hyperplasia in users of proton-pump inhibitors. Gastrin was elevated in 28 users of proton-pump inhibitors and in four members of the control group. We did not find statistically significant differences in the endoscopic or histopathologic findings between the two groups. Chronic use of proton-pump inhibitors for the duration examined was not associated with significant gastric changes. An interesting finding was that the 4 chronic users of proton-pump inhibitors who had serum gastrin levels above 500 pg/mL also had positive serology for Chagas disease.

Proton Pumps: Mechanism of Action and Applications

NASA Technical Reports Server (NTRS)

Lanyi, Janos K.; Pohorille, Andrew; DeVincenzi, Donald L. (Technical Monitor)

2001-01-01

Recent progress in understanding molecular structures and mechanisms of action of proton pumps has paved the way to their novel applications in biotechnology. Proton pumps, in particular bacteriorhodopsin and ATP synthases, are capable of continuous, renewable conversion of light to chemical, mechanical or electrical energy, which can be used in macro- or nano-scale devices. The capability of protein systems incorporated into liposomes to generate ATP, which can be further used to drive chemical reactions, and to act as molecular motors has been already demonstrated. Other possible applications of such biochemical devices include targeted drug delivery and biocatalytic re actors. All these devices might prove superior to their inorganic alternatives.

Proton-pumping mechanism of cytochrome c oxidase: A kinetic master-equation approach

PubMed Central

Kim, Young C.; Hummer, Gerhard

2011-01-01

Cytochrome c oxidase (CcO) is an efficient energy transducer that reduces oxygen to water and converts the released chemical energy into an electrochemical membrane potential. As a true proton pump, CcO translocates protons across the membrane against this potential. Based on a wealth of experiments and calculations, an increasingly detailed picture of the reaction intermediates in the redox cycle has emerged. However, the fundamental mechanism of proton pumping coupled to redox chemistry remains largely unresolved. Here we examine and extend a kinetic master-equation approach to gain insight into redox-coupled proton pumping in CcO. Basic principles of the CcO proton pump emerge from an analysis of the simplest kinetic models that retain essential elements of the experimentally determined structure, energetics, and kinetics, and that satisfy fundamental physical principles. The master-equation models allow us to address the question of how pumping can be achieved in a system in which all reaction steps are reversible. Whereas proton pumping does not require the direct modulation of microscopic reaction barriers, such kinetic gating greatly increases the pumping efficiency. Further efficiency gains can be achieved by partially decoupling the proton uptake pathway from the ative-site region. Such a mechanism is consistent with the proposed Glu valve, in which the side chain of a key glutamic acid shuttles between the D channel and the active-site region. We also show that the models predict only small proton leaks even in the absence of turnover. The design principles identified here for CcO provide a blueprint for novel biology-inspired fuel cells, and the master-equation formulation should prove useful also for other molecular machines. PMID:21946020

Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication.

PubMed

Sharara, Ala I

2005-12-01

Proton pump inhibitors have become one of the cornerstones in the treatment of Helicobacter pylori infection. Rabeprazole (Pariet) is a substituted benzimidazole proton pump inhibitor with potent gastric acid suppression properties. Its high acid-base dissociation constant allows activation over a broader pH range, resulting in quick, irreversible binding to the H+/K+-ATPase pump, and a more rapid onset of action compared with omeprazole, lansoprazole and pantoprazole. Unlike other proton pump inhibitors, the metabolism of rabeprazole is primarily via a nonenzymatic reduction to the thioether derivative, and the cytochrome P450 isoenzyme 2C19 is only partly involved in its metabolism. The effect of genetic polymorphism in cytochrome P450 isoenzyme 2C19 on the pharmacokinetics and pharmacodynamics of rabeprazole is therefore limited. In humans, once-daily dosing of 5-40 mg of rabeprazole inhibits gastric acid secretion in a dose-dependent manner. In vitro studies have shown that rabeprazole possesses more potent antibacterial properties against the growth of H. pylori than other proton pump inhibitors. Furthermore, its thioether derivative has more potent inhibitory in vitro activity against the growth and motility of clarithromycin-resistant H. pylori than other proton pump inhibitors or commonly used antimicrobials. Despite these inherent favorable characteristics of rabeprazole, randomized controlled trials have largely shown equivalence amongst proton pump inhibitors when used with two antibiotics in the eradication of H. pylori, with cure rates of 75-89% on an intent-to-treat basis. However, rabeprazole appears to consistently achieve such comparable eradication rates even when used at reduced doses (10 mg twice daily) as part of clarithromycin-based triple therapy.

[Influence of proton pump inhibitors on intestinal fermentative profile: a case-control study].

PubMed

Senderovky, Melisa; Lasa, Juan; Dima, Guillermo; Peralta, Daniel; Argüello, Mariano; Soifer, Luis

2014-01-01

Proton pump inhibitors could have an impact on the results of breath tests performed in patients with irritable bowel syndrome. This impact could be due to the development of small intestine bacterial overgrowth. To compare the prevalence of fermentative profile alterations of irritable bowel syndrome patients exposed and not-exposed to proton pump inhibitor therapy. Subjects with irritable bowel syndrome were enrolled. A validated questionnaire assessing symptom severity as well as proton pump inhibitor treatment was delivered. A lactulose breath test was undertaken by each enrolled subject. Fermentative profile (area under the curve of hydrogen excretion/time) was compared between proton pump inhibitors consumers and non-consumers. Furthermore, small intestine bacterial overgrowth prevalence was compared. Two hundred and twenty five patients were enrolled. No significant differences were found on the fermentative profile between groups [AUC mediana 3,776 (rango 2,124-5,571) vs 4,347 (rango 2,038-5,481), P = 0.3]. Small intestine bacterial overgrowth prevalence was similar as well [33% vs 27.5%]. These differences remained non-significant after adjusting for proton pump inhibitor dose and treatment time. Surprisingly, symptom score was significantly higher in those patients under proton pump inhibitor therapy [28.5 (23-26) vs 23 (15-29), P = 0.01]. Proton pump inhibitors have no significant influence on lactulose breath tests, regardless of the dosage and time of administration.

Analogies between respiration and a light-driven proton pump as sources of energy for active glutamate transport in Halobacterium halobium

NASA Technical Reports Server (NTRS)

Belliveau, J. W.; Lanyi, J. K.

1977-01-01

Halobacterium halobium is known to contain sheets of bacteriorhodopsin, a pigment which upon exposure to light undergoes cyclic protonation and deprotonation, resulting in net H(+) translocation. In this paper, experiments were conducted to test H. halobium cell envelope vesicles for respiration-induced glutamate uptake. It is shown that glutamate transport in H. halobium cell envelope vesicles can occur as a result of respiration, as well as light acting on bacteriorhodopsin. Glutamate transport can be energized by the oxidation of dimethyl phenylenediamine, and the properties of the transport system are entirely analogous to those observed with illumination as the source of energy. In the case of respiration-dependent glutamate transport, the transportation is also driven by a Na(+) gradient, thereby confirming the existence of a single glutamate transport system independent of the source of energy. The analogy observed is indirect evidence that the cytochrome oxidase of H. halobium functions as a H(+) pump.

Stable transport in proton driven fast ignition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bret, A.

2009-09-15

Proton beam transport in the context of proton driven fast ignition is usually assumed to be stable due to proton high inertia, but an analytical analysis of the process is still lacking. The stability of a charge and current neutralized proton beam passing through a plasma is therefore conducted here, for typical proton driven fast ignition parameters. In the cold regime, two fast growing modes are found, with an inverse growth rate much smaller than the beam time of flight to the target core. The stability issue is thus not so obvious, and kinetic effects are investigated. One unstable modemore » is found stabilized by the background plasma proton and electron temperatures. The second mode is also damped, providing the proton beam thermal spread is larger than {approx}10 keV. In fusion conditions, the beam propagation should therefore be stable.« less

[Pharmacogenic osteoporosis beyond cortisone. Proton pump inhibitors, glitazones and diuretics].

PubMed

Kann, P H; Hadji, P; Bergmann, R S

2014-05-01

[corrected] There are many drugs which can cause osteoporosis or at least favor its initiation. The effect of hormones and drugs with antihormonal activity, such as glucocorticoids and aromatase inhibitors, on initiation of osteoporosis is well known. In addition, proton pump inhibitors, glitazones and diuretics also influence the formation of osteoporosis. The results of currently available studies on the correlation between proton pump inhibitors, glitazones and diuretics on formation of osteoporosis were evaluated and summarized. Proton pump inhibitors and glitazones increase the risk for osteoporotic fractures. Loop diuretics may slightly increase fracture risk, whereas thiazides were shown to be osteoprotective by reducing fracture probability on a relevant scale. Proton pump inhibitors should not be prescribed without serious consideration and then only as long as necessary. Alternatively, the administration of the less effective H2 antagonists should be considered when possible due to the reduction of acid secretion. Because the long-term intake of thiazides is associated with a clinically relevant reduction in the risk of fractures and they are economic and well-tolerated, prescription can be thoroughly recommended within the framework of differential diagnostic considerations in an appropriate clinical context. The briefly increased risk of falling immediately after starting diuretic therapy is the only point which needs to be considered.

Voltage Dependence of Proton Pumping by Bacteriorhodopsin Mutants with Altered Lifetime of the M Intermediate

PubMed Central

Geibel, Sven; Lörinczi, Èva; Bamberg, Ernst; Friedrich, Thomas

2013-01-01

The light-driven proton pump bacteriorhodopsin (BR) from Halobacterium salinarum is tightly regulated by the [H+] gradient and transmembrane potential. BR exhibits optoelectric properties, since spectral changes during the photocycle are kinetically controlled by voltage, which predestines BR for optical storage or processing devices. BR mutants with prolonged lifetime of the blue-shifted M intermediate would be advantageous, but the optoelectric properties of such mutants are still elusive. Using expression in Xenopus oocytes and two-electrode voltage-clamping, we analyzed photocurrents of BR mutants with kinetically destabilized (F171C, F219L) or stabilized (D96N, D96G) M intermediate in response to green light (to probe H+ pumping) and blue laser flashes (to probe accumulation/decay of M). These mutants have divergent M lifetimes. As for BR-WT, this strictly correlates with the voltage dependence of H+ pumping. BR-F171C and BR-F219L showed photocurrents similar to BR-WT. Yet, BR-F171C showed a weaker voltage dependence of proton pumping. For both mutants, blue laser flashes applied during and after green-light illumination showed reduced M accumulation and shorter M lifetime. In contrast, BR-D96G and BR-D96N exhibited small photocurrents, with nonlinear current-voltage curves, which increased strongly in the presence of azide. Blue laser flashes showed heavy M accumulation and prolonged M lifetime, which accounts for the strongly reduced H+ pumping rate. Hyperpolarizing potentials augmented these effects. The combination of M-stabilizing and -destabilizing mutations in BR-D96G/F171C/F219L (BR-tri) shows that disruption of the primary proton donor Asp-96 is fatal for BR as a proton pump. Mechanistically, M destabilizing mutations cannot compensate for the disruption of Asp-96. Accordingly, BR-tri and BR-D96G photocurrents were similar. However, BR-tri showed negative blue laser flash-induced currents even without actinic green light, indicating that Schiff base

Pantoprazole: a new proton pump inhibitor.

PubMed

Jungnickel, P W

2000-11-01

This paper reviews the pharmacology, clinical efficacy, and tolerability of pantoprazole in comparison with those of other available proton pump inhibitors (PPIs). Relevant English-language research and review articles were identified by database searches of MEDLINE, International Pharmaceutical Abstracts, and UnCover, and by examining the reference lists of the articles so identified. In selecting data for inclusion, the author gave preference to full-length articles published in peer-reviewed journals. Like other PPIs, pantoprazole exerts its pharmacodynamic actions by binding to the proton pump (H+,K+ -adenosine triphosphatase) in the parietal cells, but, compared with other PPIs, its binding may be more specific for the proton pump. Pantoprazole is well absorbed when administered as an enteric-coated, delayed-release tablet, with an oral bioavailability of approximately 77%. It is hepatically metabolized via cytochrome P2C19 to hydroxypantoprazole, an inactive metabolite that subsequently undergoes sulfate conjugation. The elimination half-life ranges from 0.9 to 1.9 hours and is independent of dose. Pantoprazole has similar efficacy to other PPIs in the healing of gastric and duodenal ulcers, as well as erosive esophagitis, and as part of triple-drug regimens for the eradication of Helicobacter pylori from the gastric mucosa. It is well tolerated, with the most common adverse effects being headache, diarrhea, flatulence, and abdominal pain. In clinical studies, it has been shown to have no interactions with various other agents, including carbamazepine, cisapride, cyclosporine, digoxin, phenytoin, theophylline, and warfarin. Pantoprazole appears to be as effective as other PPIs. Its low potential for drug interactions may give it an advantage in patients taking other drugs.

Electrogenic steps of light-driven proton transport in ESR, a retinal protein from Exiguobacterium sibiricum.

PubMed

Siletsky, Sergey A; Mamedov, Mahir D; Lukashev, Evgeniy P; Balashov, Sergei P; Dolgikh, Dmitriy A; Rubin, Andrei B; Kirpichnikov, Mikhail P; Petrovskaya, Lada E

2016-11-01

A retinal protein from Exiguobacterium sibiricum (ESR) functions as a light-driven proton pump. Unlike other proton pumps, it contains Lys96 instead of a usual carboxylic residue in the internal proton donor site. Nevertheless, the reprotonation of the Schiff base occurs fast, indicating that Lys96 facilitates proton transfer from the bulk. In this study we examined kinetics of light-induced transmembrane electrical potential difference, ΔΨ, generated in proteoliposomes reconstituted with ESR. We show that total magnitude of ΔΨ is comparable to that produced by bacteriorhodopsin but its kinetic components and their pH dependence are substantially different. The results are in agreement with the earlier finding that proton uptake precedes reprotonation of the Schiff base in ESR, suggesting that Lys96 is unprotonated in the initial state and gains a proton transiently in the photocycle. The electrogenic phases and the photocycle transitions related to proton transfer from the bulk to the Schiff base are pH dependent. At neutral pH, they occur with τ 0.5ms and 4.5ms. At alkaline pH, the fast component ceases and Schiff base reprotonation slows. At pH8.4, a spectrally silent electrogenic component with τ 0.25ms is detected, which can be attributed to proton transfer from the bulk to Lys96. At pH5.1, the amplitude of ΔΨ decreases 10 fold, reflecting a decreased yield and rate of proton transfer, apparently from protonation of the acceptor (Asp85-His57 pair) in the initial state. The features of the photoelectric potential generation correlate with the ESR structure and proposed mechanism of proton transfer. Copyright © 2016 Elsevier B.V. All rights reserved.

Intrinsic uncoupling of mitochondrial proton pumps. 2. Modeling studies.

PubMed

Pietrobon, D; Zoratti, M; Azzone, G F; Caplan, S R

1986-02-25

The thermodynamic and kinetic properties associated with intrinsic uncoupling in a six-state model of a redox proton pump have been studied by computing the flow-force relations for different degrees of coupling. Analysis of these relations shows the regulatory influence of the thermodynamic forces on the extent and relative contributions of redox slip and proton slip. Inhibition has been introduced into the model in two different ways, corresponding to possible modes of action of experimental inhibitors. Experiments relating the rate of electron transfer to delta microH at static head upon progressive inhibition of the pumps have been simulated considering (1) the limiting case that the nonzero rate of electron transfer at static head is only due to intrinsic uncoupling (no leaks) and (2) the experimentally observed case that about 30% of the nonzero rate of electron transfer at static head is due to a constant proton leakage conductance in parallel with the pumps, the rest being due to intrinsic uncoupling. The same simulations have been performed for experiments in which the rate of electron transfer is varied by varying the substrate concentration rather than by using an inhibitor. The corresponding experimental results obtained by measuring delta microH and the rate of electron transfer at different succinate concentrations in rat liver mitochondria are presented. Comparison between simulated behavior and experimental results leads to the general conclusion that the typical relationship between rate of electron transfer and delta microH found in mitochondria at static head could certainly be a manifestation of some degree of intrinsic uncoupling in the redox proton pumps.(ABSTRACT TRUNCATED AT 250 WORDS)

Piston-assisted proton pumping in Complex I of mitochondria membranes

NASA Astrophysics Data System (ADS)

Mourokh, Lev; Filonenko, Ilan

2014-03-01

Proton-pumping mechanism of Complex I remains mysterious because its electron and proton paths are well separated and the direct Coulomb interaction seems to be negligible. The structure of this enzyme was resolved very recently and its functionality was connected the shift of the helix HL. We model the helix as a piston oscillating between the protons and electrons. We assume that positive charges are accumulated near the edges of the helix. In the oxidized state, the piston is attracted to electrons, so its distance to the proton sites increases, the energy of these sites decreases and the sites can be populated. When electrons proceed to the drain, elastic forces return the piston to the original position and the energies of populated proton sites increase, so the protons can be transferred to the positive site of the membrane. In this work, we explore a simplified model when the interaction of the piston with electrons is replaced by a periodic force. We derive quantum Heisenberg equations for the proton operators and solve them jointly with the Langevin equation for the piston position. We show that the proton pumping is possible in such structure with parameters closely resembling the real system. We also address the feasibility of using such mechanism in nanoelectronics.

Impact of a pharmacist-driven protocol to decrease proton pump inhibitor use in non-intensive care hospitalized adults.

PubMed

Michal, Jessica; Henry, Thomas; Street, Connie

2016-09-01

Results of a pharmacist-driven protocol to decrease proton pump inhibitor (PPI) use in non-intensive care unit (ICU) hospitalized adults are presented. This concurrent preintervention and postintervention study included subjects at least 18 years of age receiving PPIs while hospitalized in general medical or surgical beds. Patients were identified for inclusion in the postintervention group using a daily list of hospitalized patients with active PPI orders. A pharmacist evaluated these subjects for PPI appropriateness, and then recommended discontinuing or changing PPIs to histamine H2-receptor antagonists. Per protocol, the pharmacist could change PPIs to H2-antagonists if prescribers did not respond to recommendations. Preintervention group patients were gathered retrospectively and treated as the retrospective control group. Patients were excluded if they had cumulative ICU or ICU step-down stays of at least two days, had predefined appropriate indications for PPIs, or were not evaluated within one day of PPI orders. The primary outcome was the rate of PPI use. Secondary objectives included rates of prescriber acceptance of pharmacist recommendations and hospital-onset Clostridium difficile infections (HO-CDI). PPIs were discontinued in 66.0% (n = 62) of postintervention group patients compared to 41.1% (n = 39) of the preintervention group (absolute risk reduction, 24.9%; p = 0.001). In the postintervention group, 31.9% (n = 30) of recommendations were accepted, whereas 11.7% (n = 11) were rejected. No subjects in either group were diagnosed with HO-CDI during the study period. The pharmacist-driven protocol described in this study decreased PPI use in non-ICU hospitalized adults. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Infrared laser driven double proton transfer. An optimal control theory study

NASA Astrophysics Data System (ADS)

Abdel-Latif, Mahmoud K.; Kühn, Oliver

2010-02-01

Laser control of ultrafast double proton transfer is investigated for a two-dimensional model system describing stepwise and concerted transfer pathways. The pulse design has been done by employing optimal control theory in combination with the multiconfiguration time-dependent Hartree wave packet propagation. The obtained laser fields correspond to multiple pump-dump pulse sequences. Special emphasis is paid to the relative importance of stepwise and concerted transfer pathways for the driven wave packet and its dependence on the parameters of the model Hamiltonian as well as on the propagation time. While stepwise transfer is dominating in all cases considered, for high barrier systems concerted transfer proceeding via tunneling can make a contribution.

Proton transfer mediated by the vibronic coupling in oxygen core ionized states of glyoxalmonoxime studied by infrared-X-ray pump-probe spectroscopy.

PubMed

Felicíssimo, V C; Guimarães, F F; Cesar, A; Gel'mukhanov, F; Agren, H

2006-11-30

The theory of IR-X-ray pump-probe spectroscopy beyond the Born-Oppenheimer approximation is developed and applied to the study of the dynamics of intramolecular proton transfer in glyoxalmonoxime leading to the formation of the tautomer 2-nitrosoethenol. Due to the IR pump pulses the molecule gains sufficient energy to promote a proton to a weakly bound well. A femtosecond X-ray pulse snapshots the wave packet route and, hence, the dynamics of the proton transfer. The glyoxalmonoxime molecule contains two chemically nonequivalent oxygen atoms that possess distinct roles in the hydrogen bond, a hydrogen donor and an acceptor. Core ionizations of these form two intersecting core-ionized states, the vibronic coupling between which along the OH stretching mode partially delocalizes the core hole, resulting in a hopping of the core hole from one site to another. This, in turn, affects the dynamics of the proton transfer in the core-ionized state. The quantum dynamical simulations of X-ray photoelectron spectra of glyoxalmonoxime driven by strong IR pulses demonstrate the general applicability of the technique for studies of intramolecular proton transfer in systems with vibronic coupling.

Electrogenic active proton pump in Rana esculenta skin and its role in sodium ion transport.

PubMed

Ehrenfeld, J; Garcia-Romeu, F; Harvey, B J

1985-02-01

Kinetic and electrophysiological studies were carried out in the in vitro Rana esculenta skin, bathed in dilute sodium solution, to characterize the proton pump and coupling between sodium absorption (JNa+n) and proton excretion (JH+n). JNa+n and JH+n were both dependent on transepithelial potential (psi ms); hyperpolarizing the skin decreased JNa+n and increased JH+n; depolarization produced the opposite effects. Amiloride (5 X 10(-5) M) at a clamped psi ms of +50 mV inhibited JNa+n without affecting JH+n. Variations of psi ms or pH had identical effects on JH+n. Ethoxzolamide inhibited JH+n and simultaneously increased psi ms by 15-30 mV. These changes were accompanied by depolarization of the apical membrane potential psi mc from -47 to -25 mV and an increase in apical membrane resistance of 30%; no significant effects on basolateral membrane potential (psi cs) and resistance (Rb) nor on shunt resistance (Rj) were observed. The proton pump appears to be localized at the apical membrane. The proton pump was also inhibited by deoxygenation, oligomycin, dicyclohexylcarbodiimide and vanadate (100, 78, 83 and 100% inhibition respectively). The variations of JH+n and of the measured electrical currents were significantly correlated. These findings are supportive evidence of a primary active proton pump, electrogenic and strictly linked to aerobic metabolism. The current-voltage (I-V) relation of the proton pump was obtained as the difference in the I-V curves of the apical membrane extracted before and after proton-pump inhibition by ethoxzolamide during amiloride block of sodium transport. The proton-pump current (IP) was best described by a saturable exponential function of psi mc. Maximal pump current (ImaxP) was calculated to be 200 nequiv h-1 cm-2 at a psi mc of +50 mV and the pump reversal potential ERP was -130 mV. The effect of ethoxzolamide to depolarize psi mc was dependent on the relation between psi mc and ERP. Maximal induced depolarization occurred at a

Electrogenic active proton pump in Rana esculenta skin and its role in sodium ion transport.

PubMed Central

Ehrenfeld, J; Garcia-Romeu, F; Harvey, B J

1985-01-01

Kinetic and electrophysiological studies were carried out in the in vitro Rana esculenta skin, bathed in dilute sodium solution, to characterize the proton pump and coupling between sodium absorption (JNa+n) and proton excretion (JH+n). JNa+n and JH+n were both dependent on transepithelial potential (psi ms); hyperpolarizing the skin decreased JNa+n and increased JH+n; depolarization produced the opposite effects. Amiloride (5 X 10(-5) M) at a clamped psi ms of +50 mV inhibited JNa+n without affecting JH+n. Variations of psi ms or pH had identical effects on JH+n. Ethoxzolamide inhibited JH+n and simultaneously increased psi ms by 15-30 mV. These changes were accompanied by depolarization of the apical membrane potential psi mc from -47 to -25 mV and an increase in apical membrane resistance of 30%; no significant effects on basolateral membrane potential (psi cs) and resistance (Rb) nor on shunt resistance (Rj) were observed. The proton pump appears to be localized at the apical membrane. The proton pump was also inhibited by deoxygenation, oligomycin, dicyclohexylcarbodiimide and vanadate (100, 78, 83 and 100% inhibition respectively). The variations of JH+n and of the measured electrical currents were significantly correlated. These findings are supportive evidence of a primary active proton pump, electrogenic and strictly linked to aerobic metabolism. The current-voltage (I-V) relation of the proton pump was obtained as the difference in the I-V curves of the apical membrane extracted before and after proton-pump inhibition by ethoxzolamide during amiloride block of sodium transport. The proton-pump current (IP) was best described by a saturable exponential function of psi mc. Maximal pump current (ImaxP) was calculated to be 200 nequiv h-1 cm-2 at a psi mc of +50 mV and the pump reversal potential ERP was -130 mV. The effect of ethoxzolamide to depolarize psi mc was dependent on the relation between psi mc and ERP. Maximal induced depolarization occurred at a

A magnetically driven piston pump for ultra-clean applications

NASA Astrophysics Data System (ADS)

LePort, F.; Neilson, R.; Barbeau, P. S.; Barry, K.; Bartoszek, L.; Counts, I.; Davis, J.; deVoe, R.; Dolinski, M. J.; Gratta, G.; Green, M.; Díez, M. Montero; Müller, A. R.; O'Sullivan, K.; Rivas, A.; Twelker, K.; Aharmim, B.; Auger, M.; Belov, V.; Benitez-Medina, C.; Breidenbach, M.; Burenkov, A.; Cleveland, B.; Conley, R.; Cook, J.; Cook, S.; Craddock, W.; Daniels, T.; Dixit, M.; Dobi, A.; Donato, K.; Fairbank, W.; Farine, J.; Fierlinger, P.; Franco, D.; Giroux, G.; Gornea, R.; Graham, K.; Green, C.; Hägemann, C.; Hall, C.; Hall, K.; Hallman, D.; Hargrove, C.; Herrin, S.; Hughes, M.; Hodgson, J.; Juget, F.; Kaufman, L. J.; Karelin, A.; Ku, J.; Kuchenkov, A.; Kumar, K.; Leonard, D. S.; Lutter, G.; Mackay, D.; MacLellan, R.; Marino, M.; Mong, B.; Morgan, P.; Odian, A.; Piepke, A.; Pocar, A.; Prescott, C. Y.; Pushkin, K.; Rollin, E.; Rowson, P. C.; Schmoll, B.; Sinclair, D.; Skarpaas, K.; Slutsky, S.; Stekhanov, V.; Strickland, V.; Swift, M.; Vuilleumier, J.-L.; Vuilleumier, J.-M.; Wichoski, U.; Wodin, J.; Yang, L.; Yen, Y.-R.

2011-10-01

A magnetically driven piston pump for xenon gas recirculation is presented. The pump is designed to satisfy extreme purity and containment requirements, as is appropriate for the recirculation of isotopically enriched xenon through the purification system and large liquid xenon time projection chamber of EXO-200. The pump, using sprung polymer gaskets, is capable of pumping more than 16 standard liters per minute of xenon gas with 750 Torr differential pressure.

A magnetically driven piston pump for ultra-clean applications.

PubMed

LePort, F; Neilson, R; Barbeau, P S; Barry, K; Bartoszek, L; Counts, I; Davis, J; deVoe, R; Dolinski, M J; Gratta, G; Green, M; Montero Díez, M; Müller, A R; O'Sullivan, K; Rivas, A; Twelker, K; Aharmim, B; Auger, M; Belov, V; Benitez-Medina, C; Breidenbach, M; Burenkov, A; Cleveland, B; Conley, R; Cook, J; Cook, S; Craddock, W; Daniels, T; Dixit, M; Dobi, A; Donato, K; Fairbank, W; Farine, J; Fierlinger, P; Franco, D; Giroux, G; Gornea, R; Graham, K; Green, C; Hägemann, C; Hall, C; Hall, K; Hallman, D; Hargrove, C; Herrin, S; Hughes, M; Hodgson, J; Juget, F; Kaufman, L J; Karelin, A; Ku, J; Kuchenkov, A; Kumar, K; Leonard, D S; Lutter, G; Mackay, D; MacLellan, R; Marino, M; Mong, B; Morgan, P; Odian, A; Piepke, A; Pocar, A; Prescott, C Y; Pushkin, K; Rollin, E; Rowson, P C; Schmoll, B; Sinclair, D; Skarpaas, K; Slutsky, S; Stekhanov, V; Strickland, V; Swift, M; Vuilleumier, J-L; Vuilleumier, J-M; Wichoski, U; Wodin, J; Yang, L; Yen, Y-R

2011-10-01

A magnetically driven piston pump for xenon gas recirculation is presented. The pump is designed to satisfy extreme purity and containment requirements, as is appropriate for the recirculation of isotopically enriched xenon through the purification system and large liquid xenon time projection chamber of EXO-200. The pump, using sprung polymer gaskets, is capable of pumping more than 16 standard liters per minute of xenon gas with 750 Torr differential pressure.

Review article: relationship between the metabolism and efficacy of proton pump inhibitors--focus on rabeprazole.

PubMed

Horn, J

2004-11-01

Proton pump inhibitors are now considered the mainstay of treatment for acid-related disease. Although all proton pump inhibitors are highly effective, the antisecretory effects of different drugs in this class are not completely consistent across patients. One reason for this is the acid-suppressing effect of Helicobacter pylori infection, which may augment the actions of proton pump inhibitors. A second important reason for interpatient variability of the effects of proton pump inhibitors on acid secretion involves genetically determined differences in the metabolism of these drugs. This article focuses on the impact of genetic polymorphism of cytochrome P450 (CYP)2C19 on the pharmacokinetics and pharmacodynamics of proton pump inhibitors, particularly rabeprazole. Results reviewed indicate that the metabolism and pharmacokinetics of rabeprazole differ significantly from those of other proton pump inhibitors. Most importantly, the clearance of rabeprazole is largely nonenzymatic and less dependent on CYP2C19 than other drugs in its class. This results in greater consistency of pharmacokinetics for rabeprazole across a wide range of patients with acid-related disease, particularly those with different CYP2C19 genotypes. The pharmacodynamic profile for rabeprazole is also characterized by more rapid suppression of gastric acid secretion than with other proton pump inhibitors, which is also independent of CYP2C19 genotype. The favourable pharmacokinetic/pharmacodynamic profile for rabeprazole has been shown to result in high eradication rates for H. pylori in both normal and poor metabolizers. Pharmacodynamic results have also suggested that rabeprazole may be better suited than omeprazole as on-demand therapy for symptomatic gastro-oesophageal reflux disease. Finally, the use of rabeprazole is not complicated by clinically significant drug-drug interactions of the type that have been reported for omeprazole.

Exchangers man the pumps: Functional interplay between proton pumps and proton-coupled Ca exchangers.

PubMed

Barkla, Bronwyn J; Hirschi, Kendal D; Pittman, Jon K

2008-05-01

Tonoplast-localised proton-coupled Ca(2+) transporters encoded by cation/H(+)exchanger (CAX) genes play a critical role in sequestering Ca(2+) into the vacuole. These transporters may function in coordination with Ca(2+) release channels, to shape stimulus-induced cytosolic Ca(2+) elevations. Recent analysis of Arabidopsis CAX knockout mutants, particularly cax1 and cax3, identified a variety of phenotypes including sensitivity to abiotic stresses, which indicated that these transporters might play a role in mediating the plant's stress response. A common feature of these mutants was the perturbation of H(+)-ATPase activity at both the tonoplast and the plasma membrane, suggesting a tight interplay between the Ca(2+)/H(+) exchangers and H(+) pumps. We speculate that indirect regulation of proton flux by the exchangers may be as important as the direct regulation of Ca(2+) flux. These results suggest cautious interpretation of mutant Ca(2+)/H(+) exchanger phenotypes that may be due to either perturbed Ca(2+) or H(+) transport.

Low-dose or standard-dose proton pump inhibitors for maintenance therapy of gastro-oesophageal reflux disease: a cost-effectiveness analysis.

PubMed

You, J H S; Lee, A C M; Wong, S C Y; Chan, F K L

2003-03-15

Studies on the use of low-dose proton pump inhibitor for the maintenance therapy of gastro-oesophageal reflux disease have shown that it might be comparable with standard-dose proton pump inhibitor treatment and superior to standard-dose histamine-2 receptor antagonist therapy. To compare the impact of standard-dose histamine-2 receptor antagonist, low-dose proton pump inhibitor and standard-dose proton pump inhibitor treatment for the maintenance therapy of gastro-oesophageal reflux disease on symptom control and health care resource utilization from the perspective of a public health organization in Hong Kong. A Markov model was designed to simulate, over 12 months, the economic and clinical outcomes of gastro-oesophageal reflux disease patients treated with standard-dose histamine-2 receptor antagonist, low-dose proton pump inhibitor and standard-dose proton pump inhibitor. The transition probabilities were derived from the literature. Resource utilization was retrieved from a group of gastro-oesophageal reflux disease patients in Hong Kong. Sensitivity analysis was conducted to examine the robustness of the model. The standard-dose proton pump inhibitor strategy was associated with the highest numbers of symptom-free patient-years (0.954 years) and quality-adjusted life-years gained (0.999 years), followed by low-dose proton pump inhibitor and standard-dose histamine-2 receptor antagonist. The direct medical cost per patient in the standard-dose proton pump inhibitor group (904 US dollars) was lower than those of the low-dose proton pump inhibitor and standard-dose histamine-2 receptor antagonist groups. The standard-dose proton pump inhibitor strategy appears to be the most effective and least costly for the maintenance management of patients with gastro-oesophageal reflux disease in Hong Kong.

Radiobiological study by using laser-driven proton beams

NASA Astrophysics Data System (ADS)

Yogo, A.; Sato, K.; Nishikino, M.; Mori, M.; Teshima, T.; Numasaki, H.; Murakami, M.; Demizu, Y.; Akagi, S.; Nagayama, S.; Ogura, K.; Sagisaka, A.; Orimo, S.; Nishiuchi, M.; Pirozhkov, A. S.; Ikegami, M.; Tampo, M.; Sakaki, H.; Suzuki, M.; Daito, I.; Oishi, Y.; Sugiyama, H.; Kiriyama, H.; Okada, H.; Kanazawa, S.; Kondo, S.; Shimomura, T.; Nakai, Y.; Tanoue, M.; Sugiyama, H.; Sasao, H.; Wakai, D.; Kawachi, T.; Nishimura, H.; Bolton, P. R.; Daido, H.

2009-07-01

Particle acceleration driven by high-intensity laser systems is widely attracting interest as a potential alternative to conventional ion acceleration, including ion accelerator applications to tumor therapy. Recent works have shown that a high intensity laser pulse can produce single proton bunches of a high current and a short pulse duration. This unique feature of laser-ion acceleration can lead to progress in the development of novel ion sources. However, there has been no experimental study of the biological effects of laser-driven ion beams. We describe in this report the first demonstrated irradiation effect of laser-accelerated protons on human lung cancer cells. In-vitro A549 cells are irradiated with a proton dose of 20 Gy, resulting in a distinct formation of γ-H2AX foci as an indicator of DNA double-strand breaks. This is a pioneering result that points to future investigations of the radiobiological effects of laser-driven ion beams. The laser-driven ion beam is apotential excitation source for time-resolved determination of hydroxyl (OH) radical yield, which will explore relationship between the fundamental chemical reactions of radiation effects and consequent biological processes.

Protonation-state-Coupled Conformational Dynamics in Reaction Mechanisms of Channel and Pump Rhodopsins

DOE PAGES

Bondar, Ana-Nicoleta; Smith, Jeremy C.

2017-07-25

Channel and pump rhodopsins use energy from light absorbed by a covalently bound retinal chromophore to transport ions across membranes of microbial cells. Ion transfer steps, including proton transfer, can couple to changes in protein conformational dynamics and water positions. Although general principles of how microbial rhodopsins function are largely understood, key issues pertaining to reaction mechanisms remain unclear. Here, we compare the protonation-coupled dynamics of pump and channelrhodopsins, highlighting the roles that water dynamics, protein electrostatics and protein flexibility can have in ion transport mechanisms. We discuss observations supporting important functional roles of inter- and intra-helical carboxylate/hydroxyl hydrogen-bonding motifs.more » Specifically, we use the proton pump bacteriorhodopsin, the sodium pump KR2, channelrhodopsins and Anabaena sensory rhodopsin. We outline the usefulness of theoretic biophysics approaches to the study of retinal proteins, challenges in studying the hydrogen-bond dynamics of rhodopsin active sites, and implications for conformational coupling in membrane transporters.« less

Protonation-state-Coupled Conformational Dynamics in Reaction Mechanisms of Channel and Pump Rhodopsins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bondar, Ana-Nicoleta; Smith, Jeremy C.

Channel and pump rhodopsins use energy from light absorbed by a covalently bound retinal chromophore to transport ions across membranes of microbial cells. Ion transfer steps, including proton transfer, can couple to changes in protein conformational dynamics and water positions. Although general principles of how microbial rhodopsins function are largely understood, key issues pertaining to reaction mechanisms remain unclear. Here, we compare the protonation-coupled dynamics of pump and channelrhodopsins, highlighting the roles that water dynamics, protein electrostatics and protein flexibility can have in ion transport mechanisms. We discuss observations supporting important functional roles of inter- and intra-helical carboxylate/hydroxyl hydrogen-bonding motifs.more » Specifically, we use the proton pump bacteriorhodopsin, the sodium pump KR2, channelrhodopsins and Anabaena sensory rhodopsin. We outline the usefulness of theoretic biophysics approaches to the study of retinal proteins, challenges in studying the hydrogen-bond dynamics of rhodopsin active sites, and implications for conformational coupling in membrane transporters.« less

Surgery and proton pump inhibitors for treatment of vocal process granulomas.

PubMed

Hong-Gang, Duan; He-Juan, Jin; Chun-Quan, Zheng; Guo-Kang, Fan

2013-11-01

The aim of this study was to analyze the outcomes of vocal process granulomas treated with surgery and proton pump inhibitors and to specify related factors of recurrence. The medical records of patients with diagnosis of vocal process granuloma between 2000 and 2012 were reviewed. All patients were treated with surgery and proton pump inhibitors for at least 1 month. Forty-one patients were reviewed; mean follow-up time was 45 months. There was no recurrence among the patients who had a recent history of intubation. The recurrence rates of contact granuloma was 38.7 %, and significantly related to the frequency of surgery (P = 0.042), but was not significantly associated with the history of acid reflux (P = 0.676) and vocal abuse (P = 0.447), lesion size (P = 0.203) or surgical techniques (P = 0.331). Surgery combined with proton pump inhibitors was partially effective for the vocal process granulomas, especially with intubated patients. However, repeat surgery for recurrent contact granuloma should be preceded with caution due to high recurrence rates.

A charge-driven molecular water pump.

PubMed

Gong, Xiaojing; Li, Jingyuan; Lu, Hangjun; Wan, Rongzheng; Li, Jichen; Hu, Jun; Fang, Haiping

2007-11-01

Understanding and controlling the transport of water across nanochannels is of great importance for designing novel molecular devices, machines and sensors and has wide applications, including the desalination of seawater. Nanopumps driven by electric or magnetic fields can transport ions and magnetic quanta, but water is charge-neutral and has no magnetic moment. On the basis of molecular dynamics simulations, we propose a design for a molecular water pump. The design uses a combination of charges positioned adjacent to a nanopore and is inspired by the structure of channels in the cellular membrane that conduct water in and out of the cell (aquaporins). The remarkable pumping ability is attributed to the charge dipole-induced ordering of water confined in the nanochannels, where water can be easily driven by external fields in a concerted fashion. These findings may provide possibilities for developing water transport devices that function without osmotic pressure or a hydrostatic pressure gradient.

Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism.

PubMed

Fais, S

2010-05-01

This review presents a possible new approach against cancer, as represented by inhibition of proton pumps, a mechanism used by tumour cells to avoid intracellular accumulation of toxic substances. Proton pump inhibitors (PPIs) belong to a family of pro-drugs that are currently used in the treatment of peptic diseases needing acidity to be activated. PPIs target the acidic tumour mass, where they are metabolized, thus blocking proton traffic. Proton pump inhibition triggers a rapid cell death as a result of intracellular acidification, caspase activation and early accumulation of reactive oxygen species into tumour cells. As a whole, the devastating effect of PPIs on tumour cells suggest the triggering of a fatal cell toxification. Many human tumours, including melanoma, osteosarcoma, lymphomas and various adenocarcinomas are responsive to PPIs. This appears highly conceivable, in as much as almost all human tumours are acidic and express high levels of proton pumps. Paradoxically, metastatic tumours appear to be more responsive to PPIs being more acidic than the majority of primary tumours. However, two clinical trials test the effectiveness of PPIs in chemosensitizing melanoma and osteosarcoma patients. Indeed, tumour acidity represents a very potent mechanism of chemoresistance. A majority of cytotoxic agents, being weak bases, are quickly protonated outside and do not enter the cells, thus preventing drugs to reach specific cellular targets. Clinical data will provide the proof of concept on the use of PPIs as a new class of antitumour agent with a very low level of systemic toxicity as compared with standard chemotherapeutic agents.

Proton-driven electromagnetic instabilities in high-speed solar wind streams

NASA Technical Reports Server (NTRS)

Abraham-Shrauner, B.; Asbridge, J. R.; Bame, S. J.; Feldman, W. C.

1979-01-01

Electromagnetic instabilities of the field-aligned, right-hand circularly polarized magnetosonic wave and the left-hand circularly polarized Alfven wave driven by two drifted proton components are analyzed for model parameters determined from Imp 7 solar wind proton data measured during high-speed flow conditions. Growth rates calculated using bi-Lorentzian forms for the main and beam proton as well as core and halo electron velocity distributions do not differ significantly from those calculated using bi-Maxwellian forms. Using distribution parameters determined from 17 measured proton spectra, we show that considering the uncertainties the magnetosonic wave may be linearly stable and the Alfven wave is linearly unstable. Because proton velocity distribution function shapes are observed to persist for times long compared to the proton gyroperiod, the latter result suggests that linear stability theory fails for proton-driven ion cyclotron waves in the high-speed solar wind.

The role of the pharmacist in the selection and use of over-the-counter proton-pump inhibitors.

PubMed

Boardman, Helen F; Heeley, Gordon

2015-10-01

Heartburn and other symptoms of gastro-oesophageal reflux occur in ~30% of survey respondents in multiple countries worldwide. Heartburn and acid regurgitation are common complaints in the pharmacy, where patients frequently seek relief through medication and advice. The growing number of proton-pump inhibitors available in the over-the-counter setting provides an efficacious choice to patients experiencing frequent heartburn. Pharmacists can assist patients in their treatment decisions whilst inquiring about alarm symptoms that should prompt a physician referral. Aim of the review Provide pharmacists with a review of current clinical research and expert guidelines on use of over-the-counter proton-pump inhibitors. This narrative review was conducted to identify publications relevant to the following themes: overview of available treatments for frequent episodes of heartburn/acid regurgitation; treatment algorithms providing guidance on when to use over-the-counter proton-pump inhibitors; and the role of the pharmacist in the use of over-the-counter proton-pump inhibitors. Frequent symptoms of acid reflux, such as heartburn and acid regurgitation, can interfere substantially with daily life activities. Proton-pump inhibitors are the most efficacious treatment for frequent reflux symptoms and are recommended as an appropriate initial treatment in uncomplicated cases. Proton-pump inhibitors have varying pharmacokinetics and pharmacodynamics across the class; 20 mg esomeprazole has higher bioavailability and exposure than over-the-counter omeprazole, for example. However, differences in clinical efficacy for symptom relief have not been demonstrated. The safety and tolerability of proton-pump inhibitors have been well established in clinical trial and post-marketing settings, and use of a short regimen is associated with a very low likelihood of missing a more serious condition. Pharmacists can assist patients with accurate self-diagnosis by asking short, simple

Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy.

PubMed

Spugnini, Enrico P; Citro, Gennaro; Fais, Stefano

2010-05-08

The vacuolar ATPases are ATP-dependent proton pumps whose functions include the acidification of intracellular compartments and the extrusion of protons through the cell cytoplasmic membrane. These pumps play a pivotal role in the regulation of cell pH in normal cells and, to a much greater extent, in tumor cells. In fact, the glucose metabolism in hypoxic conditions by the neoplasms leads to an intercellular pH drift towards acidity. The acid microenvironment is modulated through the over-expression of H+ transporters that are also involved in tumor progression, invasiveness, distant spread and chemoresistance. Several strategies to block/downmodulate the efficiency of these transporters are currently being investigated. Among them, proton pump inhibitors have shown to successfully block the H+ transporters in vitro and in vivo, leading to apoptotic death. Furthermore, their action seems to synergize with conventional chemotherapy protocols, leading to chemosensitization and reversal of chemoresistance. Aim of this article is to critically revise the current knowledge of this cellular machinery and to summarize the therapeutic strategies developed to counter this mechanism.

Are higher doses of proton pump inhibitors better in acute peptic bleeding?

PubMed

Villalón, Alejandro; Olmos, Roberto; Rada, Gabriel

2016-06-24

Although there is broad consensus about the benefits of proton pump inhibitors in acute upper peptic bleeding, there is still controversy over their optimal dosing. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 27 randomized trials addressing this question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded high-dose proton pump inhibitors probably result in little or no difference in re-bleeding rate or mortality. The risk/benefit and cost/benefit balance probably favor use of low-doses.

Proton Pump Inhibitors: Risk for Myopathy?

PubMed

Colmenares, Evan W; Pappas, Ashley L

2017-01-01

The purpose of this article is to describe the relationship between proton pump inhibitors (PPIs) and symptoms of myopathy based on case reports. A literature search was conducted in PubMed (1946 to June 2016) using MeSH terms proton pump inhibitors, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, and muscular diseases. Additionally, a search was conducted in ToxNet and EMBASE using similar search criteria. The resulting articles were scanned to assess relevance to the review. Bibliographies of all relevant articles were evaluated for additional sources; 26 articles resulted from the search of PubMed, ToxNet, and EMBASE; articles that involved medications typically considered to have myalgia-like side effects (eg, statins), or included patients who presented with a confounding disease state (eg, Guillain-Barré) were excluded. In total, 11 case reports as well as a review of an adverse event reporting database that included 292 cases were evaluated. Association of PPI use and myopathy symptoms does not have a clear etiology. Overall, the available published data do not show a high risk of myopathy with PPI use but should be considered if a patient presents with myopathy symptoms and concurrent PPI use. A limited body of published data suggests that PPI use has been associated with myopathy-like symptoms without long-term effects following discontinuation. Although myopathy is a rare adverse effect observed with PPIs, it can be a serious side effect to be considered when starting a patient on acid suppression therapy.

Route, mechanism, and implications of proton import during Na+/K+ exchange by native Na+/K+-ATPase pumps

PubMed Central

Vedovato, Natascia

2014-01-01

A single Na+/K+-ATPase pumps three Na+ outwards and two K+ inwards by alternately exposing ion-binding sites to opposite sides of the membrane in a conformational sequence coupled to pump autophosphorylation from ATP and auto-dephosphorylation. The larger flow of Na+ than K+ generates outward current across the cell membrane. Less well understood is the ability of Na+/K+ pumps to generate an inward current of protons. Originally noted in pumps deprived of external K+ and Na+ ions, as inward current at negative membrane potentials that becomes amplified when external pH is lowered, this proton current is generally viewed as an artifact of those unnatural conditions. We demonstrate here that this inward current also flows at physiological K+ and Na+ concentrations. We show that protons exploit ready reversibility of conformational changes associated with extracellular Na+ release from phosphorylated Na+/K+ pumps. Reversal of a subset of these transitions allows an extracellular proton to bind an acidic side chain and to be subsequently released to the cytoplasm. This back-step of phosphorylated Na+/K+ pumps that enables proton import is not required for completion of the 3 Na+/2 K+ transport cycle. However, the back-step occurs readily during Na+/K+ transport when external K+ ion binding and occlusion are delayed, and it occurs more frequently when lowered extracellular pH raises the probability of protonation of the externally accessible carboxylate side chain. The proton route passes through the Na+-selective binding site III and is distinct from the principal pathway traversed by the majority of transported Na+ and K+ ions that passes through binding site II. The inferred occurrence of Na+/K+ exchange and H+ import during the same conformational cycle of a single molecule identifies the Na+/K+ pump as a hybrid transporter. Whether Na+/K+ pump–mediated proton inflow may have any physiological or pathophysiological significance remains to be clarified. PMID

[Proton pump inhibitors in gastro-oesophageal reflux disease: what is the further step?].

PubMed

Simon, Mireille; Zerbib, Frank

2013-01-01

Optimisation of proton pump inhibitors use may improve reflux symptoms in 20-25% of the patients. Pathological gastro-oesophageal reflux should be documented in a patient with refractory reflux symptoms using upper endoscopy and/or pH testing. While on proton pump inhibitors twice daily, persistent symptoms are not related to gastro-oesophageal refluxdisease(GERD) in 50% of the patients. The new anti-reflux compounds have yet a limited efficacy and side effects that currently limit their development. Copyright © 2012. Published by Elsevier Masson SAS.

1-Arylsulfonyl-2-(Pyridylmethylsulfinyl) Benzimidazoles as New Proton Pump Inhibitor Prodrugs

PubMed Central

Shin, Jai Moo; Sachs, George; Cho, Young-moon; Garst, Michael

2010-01-01

New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition. PMID:20032890

A population-based study of the drug interaction between proton pump inhibitors and clopidogrel

PubMed Central

Juurlink, David N.; Gomes, Tara; Ko, Dennis T.; Szmitko, Paul E.; Austin, Peter C.; Tu, Jack V.; Henry, David A.; Kopp, Alex; Mamdani, Muhammad M.

2009-01-01

Background Most proton pump inhibitors inhibit the bioactivation of clopidogrel to its active metabolite. The clinical significance of this drug interaction is unknown. Methods We conducted a population-based nested case–control study among patients aged 66 years or older who commenced clopidogrel between Apr. 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute myocardial infarction. The cases in our study were those readmitted with acute myocardial infarction within 90 days after discharge. We performed a secondary analysis considering events within 1 year. Event-free controls (at a ratio of 3:1) were matched to cases on age, percutaneous coronary intervention and a validated risk score. We categorized exposure to proton pump inhibitors before the index date as current (within 30 days), previous (31–90 days) or remote (91–180 days). Results Among 13 636 patients prescribed clopidogrel following acute myocardial infarction, we identified 734 cases readmitted with myocardial infarction and 2057 controls. After extensive multivariable adjustment, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03–1.57). We found no association with more distant exposure to proton pump inhibitors or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70–1.47). Interpretation Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopidogrel and an increased risk of reinfarction. PMID:19176635

Conjecture Regarding Posttranslational Modifications to the Arabidopsis Type I Proton-Pumping Pyrophosphatase (AVP1)

PubMed Central

Pizzio, Gaston A.; Hirschi, Kendal D.; Gaxiola, Roberto A.

2017-01-01

Agbiotechnology uses genetic engineering to improve the output and value of crops. Altering the expression of the plant Type I Proton-pumping Pyrophosphatase (H+-PPase) has already proven to be a useful tool to enhance crop productivity. Despite the effective use of this gene in translational research, information regarding the intracellular localization and functional plasticity of the pump remain largely enigmatic. Using computer modeling several putative phosphorylation, ubiquitination and sumoylation target sites were identified that may regulate Arabidopsis H+-PPase (AVP1- Arabidopsis Vacuolar Proton-pump 1) subcellular trafficking and activity. These putative regulatory sites will direct future research that specifically addresses the partitioning and transport characteristics of this pump. We posit that fine-tuning H+-PPases activity and cellular distribution will facilitate rationale strategies for further genetic improvements in crop productivity. PMID:28955362

Regulatory assembly of the vacuolar proton pump VoV1-ATPase in yeast cells by FLIM-FRET

NASA Astrophysics Data System (ADS)

Ernst, Stefan; Batisse, Claire; Zarrabi, Nawid; Böttcher, Bettina; Börsch, Michael

2010-02-01

We investigate the reversible disassembly of VOV1-ATPase in life yeast cells by time resolved confocal FRET imaging. VOV1-ATPase in the vacuolar membrane pumps protons from the cytosol into the vacuole. VOV1-ATPase is a rotary biological nanomotor driven by ATP hydrolysis. The emerging proton gradient is used for secondary transport processes as well as for pH and Ca2+ homoeostasis in the cell. The activity of the VOV1-ATPase is regulated through assembly / disassembly processes. During starvation the two parts of VOV1-ATPase start to disassemble. This process is reversed after addition of glucose. The exact mechanisms are unknown. To follow the disassembly / reassembly in vivo we tagged two subunits C and E with different fluorescent proteins. Cellular distributions of C and E were monitored using a duty cycle-optimized alternating laser excitation scheme (DCO-ALEX) for time resolved confocal FRET-FLIM measurements.

A quantum chemical study of the mechanism for proton-coupled electron transfer leading to proton pumping in cytochrome c oxidase

NASA Astrophysics Data System (ADS)

Blomberg, Margareta R. A.; Siegbahn, Per E. M.

2010-10-01

The proton pumping mechanism in cytochrome c oxidase, the terminal enzyme in the respiratory chain, has been investigated using hybrid DFT with large chemical models. In previous studies, a gating mechanism was suggested based on electrostatic interpretations of kinetic experiments. The predictions from that analysis are tested here. The main result is that the suggestion of a positively charged transition state for proton transfer is confirmed, while some other suggestions for the gating are not supported. It is shown that a few critical relative energy values from the earlier studies are reproduced with quite high accuracy using the present model calculations. Examples are the forward barrier for proton transfer from the N-side of the membrane to the pump-loading site when the heme a cofactor is reduced, and the corresponding back leakage barrier when heme a is oxidised. An interesting new finding is an unexpected double-well potential for proton transfer from the N-side to the pump-loading site. In the intermediate between the two transition states found, the proton is bound to PropD on heme a. A possible purpose of this type of potential surface is suggested here. The accuracy of the present values are discussed in terms of their sensitivity to the choice of dielectric constant. Only one energy value, which is not critical for the present mechanism, varies significantly with this choice and is therefore less certain.

An online, energy-resolving beam profile detector for laser-driven proton beams.

PubMed

Metzkes, J; Zeil, K; Kraft, S D; Karsch, L; Sobiella, M; Rehwald, M; Obst, L; Schlenvoigt, H-P; Schramm, U

2016-08-01

In this paper, a scintillator-based online beam profile detector for the characterization of laser-driven proton beams is presented. Using a pixelated matrix with varying absorber thicknesses, the proton beam is spatially resolved in two dimensions and simultaneously energy-resolved. A thin plastic scintillator placed behind the absorber and read out by a CCD camera is used as the active detector material. The spatial detector resolution reaches down to ∼4 mm and the detector can resolve proton beam profiles for up to 9 proton threshold energies. With these detector design parameters, the spatial characteristics of the proton distribution and its cut-off energy can be analyzed online and on-shot under vacuum conditions. The paper discusses the detector design, its characterization and calibration at a conventional proton source, as well as the first detector application at a laser-driven proton source.

Proton Pump Inhibition Increases Rapid Eye Movement Sleep in the Rat

PubMed Central

Jha, Sushil K.

2014-01-01

Increased bodily CO2 concentration alters cellular pH as well as sleep. The proton pump, which plays an important role in the homeostatic regulation of cellular pH, therefore, may modulate sleep. We investigated the effects of the proton pump inhibitor “lansoprazole” on sleep-wakefulness. Male Wistar rats were surgically prepared for chronic polysomnographic recordings. Two different doses of lansoprazole (low: 1 mg/kg; high: 10 mg/kg) were injected intraperitoneally in the same animal (n = 7) and sleep-wakefulness was recorded for 6 hrs. The changes in sleep-wakefulness were compared statistically. Percent REM sleep amount in the vehicle and lansoprazole low dose groups was 9.26 ± 1.03 and 9.09 ± 0.54, respectively, which increased significantly in the lansoprazole high dose group by 31.75% (from vehicle) and 34.21% (from low dose). Also, REM sleep episode numbers significantly increased in lansoprazole high dose group. Further, the sodium-hydrogen exchanger blocker “amiloride” (10 mg/kg; i.p.) (n = 5) did not alter sleep-wake architecture. Our results suggest that the proton pump plays an important role in REM sleep modulation and supports our view that REM sleep might act as a sentinel to help maintain normal CO2 level for unperturbed sleep. PMID:24701564

Natural Gas Engine-Driven Heat Pump Demonstration at DoD Installations: Performance and Reliability Summary

DTIC Science & Technology

2009-06-09

ER D C/ CE R L TR -0 9 -1 0 Natural Gas Engine-Driven Heat Pump Demonstration at DoD Installations Performance and Reliability Summary...L ab or at or y Approved for public release; distribution is unlimited. ERDC/CERL TR-09-10 June 2009 Natural Gas Engine-Driven Heat Pump ...CERL TR-09-10 ii Abstract: Results of field testing natural gas engine-driven heat pumps (GHP) at six southwestern U.S. Department of Defense (DoD

Effect of proton pump inhibitors on markers of risk for high-grade dysplasia and oesophageal cancer in Barrett's oesophagus.

PubMed

Hillman, L C; Chiragakis, L; Shadbolt, B; Kaye, G L; Clarke, A C

2008-02-15

It has been shown that the presence on diagnosis of endoscopic macroscopic markers indicates a high-risk group for Barrett's oesophagus. To determine whether proton pump inhibitor therapy prior to diagnosis of Barrett's oesophagus influences markers for risk development of subsequent high-grade dysplasia/adenocarcinoma. A review of all patients with Barrett's oesophagus entering a surveillance programme was undertaken. Five hundred and two patients diagnosed with Barrett's oesophagus were assessed on diagnosis for endoscopic macroscopic markers or low-grade dysplasia. Subsequent development of high-grade dysplasia/adenocarcinoma was documented. The relationship between the initiation of proton pump inhibitor therapy prior to the diagnosis of BE and the presence of macroscopic markers or low-grade dysplasia at entry was determined. Fourteen patients developed high-grade dysplasia/adenocarcinoma during surveillance. Patients who entered without prior proton pump inhibitor therapy were 3.4 times (95% CI: 1.98-5.85) more likely to have a macroscopic marker or low-grade dysplasia than those patients already on a proton pump inhibitor. Use of proton pump inhibitor therapy prior to diagnosis of Barrett's oesophagus significantly reduced the presence of markers used to stratify patient risk. Widespread use of proton pump inhibitors will confound surveillance strategies for patients with Barrett's oesophagus based on entry characteristics but is justified because of the lower risk of neoplastic progression.

An online, energy-resolving beam profile detector for laser-driven proton beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Metzkes, J.; Rehwald, M.; Obst, L.

In this paper, a scintillator-based online beam profile detector for the characterization of laser-driven proton beams is presented. Using a pixelated matrix with varying absorber thicknesses, the proton beam is spatially resolved in two dimensions and simultaneously energy-resolved. A thin plastic scintillator placed behind the absorber and read out by a CCD camera is used as the active detector material. The spatial detector resolution reaches down to ∼4 mm and the detector can resolve proton beam profiles for up to 9 proton threshold energies. With these detector design parameters, the spatial characteristics of the proton distribution and its cut-off energymore » can be analyzed online and on-shot under vacuum conditions. The paper discusses the detector design, its characterization and calibration at a conventional proton source, as well as the first detector application at a laser-driven proton source.« less

An analytical study of hybrid ejector/internal combustion engine-driven heat pumps

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murphy, R.W.

1988-01-01

Because ejectors can combine high reliability with low maintenance cost in a package requiring little capital investment, they may provide attractive heat pumping capability in situations where the importance of their inefficiencies is minimized. One such concept, a hybrid system in which an ejector driven by engine reject heat is used to increase the performance of an internal combustion engine-driven heat pump, was analyzed by modifying an existing ejector heat pump model and combining it with generic compressor and internal combustion engine models. Under the model assumptions for nominal cooling mode conditions, the results showed that hybrid systems could providemore » substantial performance augmentation/emdash/up to 17/percent/ increase in system coefficient of performance for a parallel arrangement of an enhanced ejector with the engine-driven compressor. 4 refs., 4 figs., 4 tabs.« less

Gas-driven pump for ground-water samples

USGS Publications Warehouse

Signor, Donald C.

1978-01-01

Observation wells installed for artificial-recharge research and other wells used in different ground-water programs are frequently cased with small-diameter steel pipe. To obtain samples from these small-diameter wells in order to monitor water quality, and to calibrate solute-transport models, a small-diameter pump with unique operating characteristics is required that causes a minimum alternation of samples during field sampling. A small-diameter gas-driven pump was designed and built to obtain water samples from wells of two-inch diameter or larger. The pump is a double-piston type with the following characteristics: (1) The water sample is isolated from the operating gas, (2) no source of electricity is ncessary, (3) operation is continuous, (4) use of compressed gas is efficient, and (5) operation is reliable over extended periods of time. Principles of operation, actual operation techniques, gas-use analyses and operating experience are described. Complete working drawings and a component list are included. Recent modifications and pump construction for high-pressure applications also are described. (Woodard-USGS)

Decrease in Switches to 'Unsafe' Proton Pump Inhibitors After Communications About Interactions with Clopidogrel.

PubMed

Kruik-Kollöffel, Willemien J; van der Palen, Job; van Herk-Sukel, Myrthe P P; Kruik, H Joost; Movig, Kris L L

2017-08-01

In 2009 and 2010 medicines regulatory agencies published official safety statements regarding the concomitant use of proton pump inhibitors and clopidogrel. We wanted to investigate a change in prescription behaviour in prevalent gastroprotective drug users (2008-2011). Data on drug use were retrieved from the Out-patient Pharmacy Database of the PHARMO Database Network. We used interrupted time series analyses (ITS) to estimate the impact of each safety statement on the number of gastroprotective drug switches around the start of clopidogrel and during clopidogrel use. After the first statement (June 2009), significantly fewer patients switched from another proton pump inhibitor to (es)omeprazole (-14.9%; 95% CI -22.6 to -7.3) at the moment they started clopidogrel compared to the period prior to this statement. After the adjusted statement in February 2010, the switch percentage to (es)omeprazole decreased further (-4.5%; 95% CI -8.1 to -0.9). We observed a temporary increase in switches from proton pump inhibitors to histamine 2-receptor antagonists after the first statement; the decrease in the reverse switch was statistically significant (-23.0%; 95% CI -43.1 to -2.9). With ITS, we were able to demonstrate a decrease in switches from other proton pump inhibitors to (es)omeprazole and an increase of the reverse switch to almost 100%. We observed a partial and temporary switch to histamine 2-receptor antagonists. This effect of safety statements was shown for gastroprotective drug switches around the start of clopidogrel treatment.

Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: A meta-analysis

PubMed Central

Wang, Wei-Hong; Huang, Jia-Qing; Zheng, Ge-Fan; Xia, Harry Hua-Xiang; Wong, Wai-Man; Lam, Shiu-Kum; Wong, Benjamin Chun-Yu

2005-01-01

AIM: To systematically evaluate the efficacy of H2-receptor antagonists (H2RAs) and proton pump inhibitors in healing erosive esophagitis (EE). METHODS: A meta-analysis was performed. A literature search was conducted in PubMed, Medline, Embase, and Cochrane databases to include randomized controlled head-to-head comparative trials evaluating the efficacy of H2RAs or proton pump inhibitors in healing EE. Relative risk (RR) and 95% confidence interval (CI) were calculated under a random-effects model. RESULTS: RRs of cumulative healing rates for each comparison at 8 wk were: high dose vs standard dose H2RAs, 1.17 (95%CI, 1.02-1.33); standard dose proton pump inhibitors vs standard dose H2RAs, 1.59 (95%CI, 1.44-1.75); standard dose other proton pump inhibitors vs standard dose omeprazole, 1.06 (95%CI, 0.98-1.06). Proton pump inhibitors produced consistently greater healing rates than H2RAs of all doses across all grades of esophagitis, including patients refractory to H2RAs. Healing rates achieved with standard dose omeprazole were similar to those with other proton pump inhibitors in all grades of esophagitis. CONCLUSION: H2RAs are less effective for treating patients with erosive esophagitis, especially in those with severe forms of esophagitis. Standard dose proton pump inhibitors are significantly more effective than H2RAs in healing esophagitis of all grades. Proton pump inhibitors given at the recommended dose are equally effective for healing esophagitis. PMID:15996033

A Conserved Asparagine in a P-type Proton Pump Is Required for Efficient Gating of Protons*

PubMed Central

Ekberg, Kira; Wielandt, Alex G.; Buch-Pedersen, Morten J.; Palmgren, Michael G.

2013-01-01

The minimal proton pumping machinery of the Arabidopsis thaliana P-type plasma membrane H+-ATPase isoform 2 (AHA2) consists of an aspartate residue serving as key proton donor/acceptor (Asp-684) and an arginine residue controlling the pKa of the aspartate. However, other important aspects of the proton transport mechanism such as gating, and the ability to occlude protons, are still unclear. An asparagine residue (Asn-106) in transmembrane segment 2 of AHA2 is conserved in all P-type plasma membrane H+-ATPases. In the crystal structure of the plant plasma membrane H+-ATPase, this residue is located in the putative ligand entrance pathway, in close proximity to the central proton donor/acceptor Asp-684. Substitution of Asn-106 resulted in mutant enzymes with significantly reduced ability to transport protons against a membrane potential. Sensitivity toward orthovanadate was increased when Asn-106 was substituted with an aspartate residue, but decreased in mutants with alanine, lysine, glutamine, or threonine replacement of Asn-106. The apparent proton affinity was decreased for all mutants, most likely due to a perturbation of the local environment of Asp-684. Altogether, our results demonstrate that Asn-106 is important for closure of the proton entrance pathway prior to proton translocation across the membrane. PMID:23420846

A conserved asparagine in a P-type proton pump is required for efficient gating of protons.

PubMed

Ekberg, Kira; Wielandt, Alex G; Buch-Pedersen, Morten J; Palmgren, Michael G

2013-04-05

The minimal proton pumping machinery of the Arabidopsis thaliana P-type plasma membrane H(+)-ATPase isoform 2 (AHA2) consists of an aspartate residue serving as key proton donor/acceptor (Asp-684) and an arginine residue controlling the pKa of the aspartate. However, other important aspects of the proton transport mechanism such as gating, and the ability to occlude protons, are still unclear. An asparagine residue (Asn-106) in transmembrane segment 2 of AHA2 is conserved in all P-type plasma membrane H(+)-ATPases. In the crystal structure of the plant plasma membrane H(+)-ATPase, this residue is located in the putative ligand entrance pathway, in close proximity to the central proton donor/acceptor Asp-684. Substitution of Asn-106 resulted in mutant enzymes with significantly reduced ability to transport protons against a membrane potential. Sensitivity toward orthovanadate was increased when Asn-106 was substituted with an aspartate residue, but decreased in mutants with alanine, lysine, glutamine, or threonine replacement of Asn-106. The apparent proton affinity was decreased for all mutants, most likely due to a perturbation of the local environment of Asp-684. Altogether, our results demonstrate that Asn-106 is important for closure of the proton entrance pathway prior to proton translocation across the membrane.

Design and optimization of a compact laser-driven proton beamline.

PubMed

Scisciò, M; Migliorati, M; Palumbo, L; Antici, P

2018-04-19

Laser-accelerated protons, generated by irradiating a solid target with a short, energetic laser pulse at high intensity (I > 10 18  W·cm -2 ), represent a complementary if not outperforming source compared to conventional accelerators, due  to their intrinsic features, such as high beam charge and short bunch duration. However, the broadband energy spectrum of these proton sources is a bottleneck that precludes their use in applications requiring a more reduced energy spread. Consequently, in recent times strong effort has been put to overcome these limits and to develop laser-driven proton beamlines with low energy spread. In this paper, we report on beam dynamics simulations aiming at optimizing a laser-driven beamline - i.e. a laser-based proton source coupled to conventional magnetic beam manipulation devices - producing protons with a reduced energy spread, usable for applications. The energy range of investigation goes from 2 to 20 MeV, i.e. the typical proton energies that can be routinely obtained using commercial TW-power class laser systems. Our beamline design is capable of reducing the energy spread below 20%, still keeping the overall transmission efficiency around 1% and producing a proton spot-size in the range of 10 mm 2 . We briefly discuss the results in the context of applications in the domain of Cultural Heritage.

Halorhodopsin pumps Cl– and bacteriorhodopsin pumps protons by a common mechanism that uses conserved electrostatic interactions

PubMed Central

Gunner, M. R.

2014-01-01

Key mutations differentiate the functions of homologous proteins. One example compares the inward ion pump halorhodopsin (HR) and the outward proton pump bacteriorhodopsin (BR). Of the nine essential buried ionizable residues in BR, six are conserved in HR. However, HR changes three BR acids, D85 in a central cluster of ionizable residues, D96, nearer the intracellular, and E204, nearer the extracellular side of the membrane to the small, neutral amino acids T111, V122, and T230, respectively. In BR, acidic amino acids are stationary anions whose proton affinity is modulated by conformational changes, establishing a sequence of directed binding and release of protons. Multiconformation continuum electrostatics calculations of chloride affinity and residue protonation show that, in reaction intermediates where an acid is ionized in BR, a Cl– is bound to HR in a position near the deleted acid. In the HR ground state, Cl– binds tightly to the central cluster T111 site and weakly to the extracellular T230 site, recovering the charges on ionized BR-D85 and neutral E204 in BR. Imposing key conformational changes from the BR M intermediate into the HR structure results in the loss of Cl– from the central T111 site and the tight binding of Cl– to the extracellular T230 site, mirroring the changes that protonate BR-D85 and ionize E204 in BR. The use of a mobile chloride in place of D85 and E204 makes HR more susceptible to the environmental pH and salt concentrations than BR. These studies shed light on how ion transfer mechanisms are controlled through the interplay of protein and ion electrostatics. PMID:25362051

New superconducting cyclotron driven scanning proton therapy systems

NASA Astrophysics Data System (ADS)

Klein, Hans-Udo; Baumgarten, Christian; Geisler, Andreas; Heese, Jürgen; Hobl, Achim; Krischel, Detlef; Schillo, Michael; Schmidt, Stefan; Timmer, Jan

2005-12-01

Since one and a half decades ACCEL is investing in development and engineering of state of the art particle-therapy systems. A new medical superconducting 250 MeV proton cyclotron with special focus on the present and future beam requirements of fast scanning treatment systems has been designed. The first new ACCEL medical proton cyclotron is under commissioning at PSI for their PROSCAN proton therapy facility having undergone successful factory tests especially of the closed loop cryomagnetic system. The second cyclotron is part of ACCEL's integrated proton therapy system for Europe's first clinical center, RPTC in Munich. The cyclotron, the energy selection system, the beamline as well as the four gantries and patient positioners have been installed. The scanning system and major parts of the control software have already been tested. We will report on the concept of ACCEL's superconducting cyclotron driven scanning proton therapy systems and the current status of the commissioning work at PSI and RPTC.

[Proton pump inhibitor - side effects and complications of long-term proton pump inhibitor administration].

PubMed

Ueberschaer, Hendrik; Allescher, Hans-Dieter

2017-01-01

Proton Pump Inhibitors are among the most common drugs taken. The indication is for treatment of heartburn, reflux disease, prophylaxis and treatment of peptic ulcers, in combination with NSAIDs and steroids as well as H. pylori-eradication. PPI's are widely used, even with non-specific symptoms. This certainly has to do with good tolerability and a previously considered low side effect profile. At the moment, there is growing evidence that the long-term intake of PPI's may not be as safe as assumed. In addition to interactions with some drugs, including platelet aggregation inhibitors, recent studies have shown an increased risk of myocardial infarction, interstitial nephritis, chronic renal injury, infections, vitamin deficiencies and electrolyte shifts as well developing dementia. © Georg Thieme Verlag KG Stuttgart · New York.

Centrifugal Force Based Magnetic Micro-Pump Driven by Rotating Magnetic Fields

NASA Astrophysics Data System (ADS)

Kim, S. H.; Hashi, S.; Ishiyama, K.

2011-01-01

This paper presents a centrifugal force based magnetic micro-pump for the pumping of blood. Most blood pumps are driven by an electrical motor with wired control. To develop a wireless and battery-free blood pump, the proposed pump is controlled by external rotating magnetic fields with a synchronized impeller. Synchronization occurs because the rotor is divided into multi-stage impeller parts and NdFeB permanent magnet. Finally, liquid is discharged by the centrifugal force of multi-stage impeller. The proposed pump length is 30 mm long and19 mm in diameter which much smaller than currently pumps; however, its pumping ability satisfies the requirement for a blood pump. The maximum pressure is 120 mmHg and the maximum flow rate is 5000ml/min at 100 Hz. The advantage of the proposed pump is that the general mechanical problems of a normal blood pump are eliminated by the proposed driving mechanism.

Identification of proton-pump inhibitor drugs that inhibit Trichomonas vaginalis uridine nucleoside ribohydrolase.

PubMed

Shea, Tara A; Burburan, Paola J; Matubia, Vivian N; Ramcharan, Sandy S; Rosario, Irving; Parkin, David W; Stockman, Brian J

2014-02-15

Trichomonas vaginalis continues to be a major health problem with drug-resistant strains increasing in prevalence. Novel antitrichomonal agents that are mechanistically distinct from current therapies are needed. The NIH Clinical Compound Collection was screened to find inhibitors of the uridine ribohydrolase enzyme required by the parasite to scavenge uracil for its growth. The proton-pump inhibitors omeprazole, pantoprazole, and rabeprazole were identified as inhibitors of this enzyme, with IC50 values ranging from 0.3 to 14.5 μM. This suggests a molecular mechanism for the in vitro antitrichomonal activity of these proton-pump inhibitors, and may provide important insights toward structure-based drug design. Copyright © 2014 Elsevier Ltd. All rights reserved.

A rationale for the use of proton pump inhibitors as antineoplastic agents.

PubMed

De Milito, Angelo; Marino, Maria Lucia; Fais, Stefano

2012-01-01

It is becoming increasingly acknowledged that tumorigenesis is not simply characterized by the accumulation of rapidly proliferating, genetically mutated cells. Microenvironmental biophysical factors like hypoxia and acidity dramatically condition cancer cells and act as selective forces for malignant cells, adapting through metabolic reprogramming towards aerobic glycolysis. Avoiding intracellular accumulation of lactic acid and protons, otherwise detrimental to cell survival is crucial for malignant cells to maintain cellular pH homeostasis. As a consequence of the upregulated expression and/or function of several pH-regulating systems, cancer cells display an alkaline intracellular pH (pHi) and an acidic extracellular pH (pHe). Among the pH-regulating proteins, proton pumps play an important role in both drug-resistance and metastatic spread, thus representing a suitable therapeutic target. Proton pump inhibitors (PPI) have been reported as cytotoxic drugs active against several human tumor cells and preclinical data have prompted the investigation of PPI as anticancer agents in humans. This review will update the current knowledge on the antitumor activities of PPI and their potential applications.

A thermo-physical analysis of the proton pump vacuolar-ATPase: the constructal approach.

PubMed

Lucia, Umberto; Ponzetto, Antonio; Deisboeck, Thomas S

2014-10-24

Pumping protons across a membrane was a critical step at the origin of life on earth, and it is still performed in all living organisms, including in human cells. Proton pumping is paramount to keep normal cells alive, e.g. for lysosomal digestion and for preparing peptides for immune recognition, but it goes awry in cancer cells. They acidify their microenvironment hence membrane voltage is lowered, which in turn induces cell proliferation, a hallmark of cancer. Proton pumping is achieved by means of rotary motors, namely vacuolar ATPases (V-ATPase), which are present at many of the multiple cellular interfaces. Therefore, we undertook an examination of the thermodynamic properties of V-ATPases. The principal result is that the V-ATPase-mediated control of the cell membrane potential and the related and consequent environmental pH can potentially represent a valuable support strategy for anticancer therapies. A constructal theory approach is used as a new viewpoint to study how V-ATPase can be modulated for therapeutic purposes. In particular, V-ATPase can be regulated by using external fields, such as electromagnetic fields, and a theoretical approach has been introduced to quantify the appropriate field strength and frequency for this new adjuvant therapeutic strategy.

Proton pump inhibitors and the risk of pneumonia: a comparison of cohort and self-controlled case series designs

PubMed Central

2013-01-01

Background To compare the results of a new-user cohort study design and the self-controlled case series (SCCS) design using the risk of hospitalisation for pneumonia in those dispensed proton pump inhibitors compared to those unexposed as a case study. Methods The Australian Government Department of Veterans’ Affairs administrative claims database was used. Exposure to proton pump inhibitors and hospitalisations for pneumonia were identified over a 4 year study period 01 Jul 2007 -30 Jun 2011. The same inclusion and exclusion criteria were applied to both studies, however, the SCCS study included subjects with a least one hospitalisation for pneumonia. Results There were 105,467 subjects included in the cohort study and 6775 in the SCCS. Both studies showed an increased risk of hospitalisations for pneumonia in the three defined risk periods following initiation of proton pump inhibitors compared to baseline. With the highest risk in the first 1 to 7 days (Cohort RR, 3.24; 95% CI (2.50, 4.19): SCCS: RR, 3.07; 95% CI (2.69, 3.50)). Conclusions This study has shown that the self-controlled case series method produces similar risk estimates to a new-users cohort study design when applied to the association of proton pump inhibitors and pneumonia. Exposure to a proton pump inhibitor increases the likelihood of being admitted to hospital for pneumonia, with the risk highest in the first week of treatment. PMID:23800078

Effects of membrane curvature and pH on proton pumping activity of single cytochrome bo3 enzymes.

PubMed

Li, Mengqiu; Khan, Sanobar; Rong, Honglin; Tuma, Roman; Hatzakis, Nikos S; Jeuken, Lars J C

2017-09-01

The molecular mechanism of proton pumping by heme-copper oxidases (HCO) has intrigued the scientific community since it was first proposed. We have recently reported a novel technology that enables the continuous characterisation of proton transport activity of a HCO and ubiquinol oxidase from Escherichia coli, cytochrome bo 3 , for hundreds of seconds on the single enzyme level (Li et al. J Am Chem Soc 137 (2015) 16055-16063). Here, we have extended these studies by additional experiments and analyses of the proton transfer rate as a function of proteoliposome size and pH at the N- and P-side of single HCOs. Proton transport activity of cytochrome bo 3 was found to decrease with increased curvature of the membrane. Furthermore, proton uptake at the N-side (proton entrance) was insensitive to pH between pH6.4-8.4, while proton release at the P-side had an optimum pH of ~7.4, suggesting that the pH optimum is related to proton release from the proton exit site. Our previous single-enzyme experiments identified rare, long-lived conformation states of cytochrome bo 3 where protons leak back under turn-over conditions. Here, we analyzed and found that ~23% of cytochrome bo 3 proteoliposomes show ΔpH half-lives below 50s after stopping turnover, while only ~5% of the proteoliposomes containing a non-pumping mutant, E286C cytochrome bo 3 exhibit such fast decays. These single-enzyme results confirm our model in which HCO exhibit heterogeneous pumping rates and can adopt rare leak states in which protons are able to rapidly flow back. Copyright © 2017 Elsevier B.V. All rights reserved.

HOW MAY PROTON PUMP INHIBITORS IMPAIR CARDIOVASCULAR HEALTH?

PubMed Central

Sukhovershin, Roman A.; Cooke, John P.

2016-01-01

Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastro-esophageal disorders and usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health. PMID:26817947

Carbon Nanotube-Based Membrane for Light-Driven, Simultaneous Proton and Electron Transport

DOE PAGES

Pilgrim, Gregory A.; Amori, Amanda R.; Hou, Zhentao; ...

2016-12-07

Here we discuss the photon driven transport of protons and electrons over hundreds of microns through a membrane based on vertically aligned single walled carbon nanotubes (SWNTs). Electrons are photogenerated in colloidal CdSe quantum dots that have been noncovalently attached to the carbon nanotube membrane and can be delivered at potentials capable of reducing earth-abundant molecular catalysts that perform proton reduction. Proton transport is driven by the electron photocurrent and is shown to be faster through the SWNT based membrane than through the commercial polymer Nafion. Furthermore, the potential utility of SWNT membranes for solar water splitting applications is demonstratedmore » through their excellent proton and electron transport properties as well as their ability to interact with other components of water splitting systems, such as small molecule electron acceptors.« less

Meta-analysis: comparative efficacy of different proton-pump inhibitors in triple therapy for Helicobacter pylori eradication.

PubMed

Vergara, M; Vallve, M; Gisbert, J P; Calvet, X

2003-09-15

It is not known whether certain proton-pump inhibitors are more efficacious than others when used in triple therapy for Helicobacter pylori eradication. To compare the efficacy of different proton-pump inhibitors in triple therapy by performing a meta-analysis. A MEDLINE search was performed. Abstracts of the European Helicobacter pylori Study Group and the American Gastroenterological Association congresses from 1996 to 2002 were also examined. Randomized studies with at least two branches of triple therapy that differed only in terms of type of proton-pump inhibitor were included in a meta-analysis using Review Manager 4.1. Fourteen studies were included. Intention-to-treat cure rates were similar for omeprazole and lansoprazole: 74.7% vs. 76%, odds ratio (OR) 0.91 [95% confidence interval (CI) 0.69-1.21] in a total of 1085 patients; for omeprazole and rabeprazole: 77.9% vs. 81.2%, OR 0.81 (95% CI 0.58-1.15) in a total of 825 patients; for omeprazole and esomeprazole: 87.7% vs. 89%, OR 0.89 (95% CI 0.58-1.35) in 833 patients; and for lansoprazole and rabeprazole: 81% vs. 85.7%, OR 0.77 (95% CI 0.48-1.22) in 550 patients. The efficacy of various proton-pump inhibitors seems to be similar when used for H. pylori eradication in standard triple therapy.

Nanoantioxidant-driven plasmon enhanced proton-coupled electron transfer

NASA Astrophysics Data System (ADS)

Sotiriou, Georgios A.; Blattmann, Christoph O.; Deligiannakis, Yiannis

2015-12-01

Proton-coupled electron transfer (PCET) reactions involve the transfer of a proton and an electron and play an important role in a number of chemical and biological processes. Here, we describe a novel phenomenon, plasmon-enhanced PCET, which is manifested using SiO2-coated Ag nanoparticles functionalized with gallic acid (GA), a natural antioxidant molecule that can perform PCET. These GA-functionalized nanoparticles show enhanced plasmonic response at near-IR wavelengths, due to particle agglomeration caused by the GA molecules. Near-IR laser irradiation induces strong local hot-spots on the SiO2-coated Ag nanoparticles, as evidenced by surface enhanced Raman scattering (SERS). This leads to plasmon energy transfer to the grafted GA molecules that lowers the GA-OH bond dissociation enthalpy by at least 2 kcal mol-1 and therefore facilitates PCET. The nanoparticle-driven plasmon-enhancement of PCET brings together the so far unrelated research domains of nanoplasmonics and electron/proton translocation with significant impact on applications based on interfacial electron/proton transfer.Proton-coupled electron transfer (PCET) reactions involve the transfer of a proton and an electron and play an important role in a number of chemical and biological processes. Here, we describe a novel phenomenon, plasmon-enhanced PCET, which is manifested using SiO2-coated Ag nanoparticles functionalized with gallic acid (GA), a natural antioxidant molecule that can perform PCET. These GA-functionalized nanoparticles show enhanced plasmonic response at near-IR wavelengths, due to particle agglomeration caused by the GA molecules. Near-IR laser irradiation induces strong local hot-spots on the SiO2-coated Ag nanoparticles, as evidenced by surface enhanced Raman scattering (SERS). This leads to plasmon energy transfer to the grafted GA molecules that lowers the GA-OH bond dissociation enthalpy by at least 2 kcal mol-1 and therefore facilitates PCET. The nanoparticle-driven plasmon

Proton-driven amide bond-cleavage pathways of gas-phase peptide ions lacking mobile protons.

PubMed

Bythell, Benjamin J; Suhai, Sándor; Somogyi, Arpád; Paizs, Béla

2009-10-07

The mobile proton model (Dongre, A. R., Jones, J. L., Somogyi, A. and Wysocki, V. H. J. Am. Chem. Soc. 1996, 118 , 8365-8374) of peptide fragmentation states that the ionizing protons play a critical role in the gas-phase fragmentation of protonated peptides upon collision-induced dissociation (CID). The model distinguishes two classes of peptide ions, those with or without easily mobilizable protons. For the former class mild excitation leads to proton transfer reactions which populate amide nitrogen protonation sites. This enables facile amide bond cleavage and thus the formation of b and y sequence ions. In contrast, the latter class of peptide ions contains strongly basic functionalities which sequester the ionizing protons, thereby often hindering formation of sequence ions. Here we describe the proton-driven amide bond cleavages necessary to produce b and y ions from peptide ions lacking easily mobilizable protons. We show that this important class of peptide ions fragments by different means from those with easily mobilizable protons. We present three new amide bond cleavage mechanisms which involve salt-bridge, anhydride, and imine enol intermediates, respectively. All three new mechanisms are less energetically demanding than the classical oxazolone b(n)-y(m) pathway. These mechanisms offer an explanation for the formation of b and y ions from peptide ions with sequestered ionizing protons which are routinely fragmented in large-scale proteomics experiments.

Effect of the Prophylactic Use of Proton-Pump Inhibitors on the Pattern of Gastrointestinal Symptoms in Patients Late After Kidney Transplant.

PubMed

Królikowski, Jerzy; Pawłowicz, Ewa; Budzisz, Ewa; Nowicki, Michał

2016-10-01

Although immunosuppressive drugs have been recognized as leading causes of gastrointestinal symptoms after kidney transplant, other widely used medications such as proton-pump inhibitors recently have been implicated. Our aim was to study the effects of chronic proton-pump inhibitor therapy on gastrointestinal symptoms in clinically stable patients late after kidney transplant. The study comprised 100 kidney transplant recipients (66 men and 34 women, mean age of 49 ± 12 y, mean time after transplant of 56 ± 46 mo). All patients completed the Gastrointestinal Symptoms Rating Scale and the Quality of Life Questionnaire SF-8 surveys. The most commonly reported symptoms included borborygmus (27%), flatulence (23%), abdominal distension (18%), urgent need of defecation (17%), and heartburn, acid reflux, and eructation (13%). Proton-pump inhibitors were chronically used by 50% of patients and sporadically by 33%. Gastrointestinal Symptoms Rating Scale scores were higher in patients who used proton-pump inhibitors (mean score of 7.8 ± 5.5 vs 4.6 ± 3.0; P = .013). Total score of items representing diarrhea in the Gastrointestinal Symptoms Rating Scale (increased passage of stools, loose stools, urgent need of defecation, incomplete evacuation) was higher in patients treated with proton-pump inhibitors than in those not treated (2.3 ± 2.2 vs 1.3 ± 1.9; P = .04). Chronic use of proton-pump inhibitors may increase the prevalence of gastrointestinal symptoms, particularly diarrhea, in patients late after kidney transplant.

Prescribing patterns and economic costs of proton pump inhibitors in Colombia

PubMed Central

Fernández, Alejandra; Castrillón, Juan Daniel; Campo, Carlos Felipe; Echeverri, Luis Felipe; Gaviria, Andrés; Londoño, Manuel José; Ochoa, Sergio Andrés; Ruíz, Joaquín Octavio

2013-01-01

Objective: To determine the prescribing patterns for proton pump inhibitors and to estimate the economic cost of their use in a group of patients affiliated with the Colombian Health System. Methods: This is a descriptive observational study. Data for analysis consisted of prescriptions dispensed between October 1st, 2010 and October 31st, 2010 and were collected from a systematic database of 4.2 million members. Socio-demographic variables were considered along with the defined daily dose,comedication, convenience of the indication for proton pump inhibitor use and costs. Results: In this study, 113,560 prescriptions were dispensed in 89 cities, mostly to women (57.6%) with a mean age of 54.4 ± 18.7 years; the drugs were omeprazole (n= 111.294; 97.81%),esomeprazole (n= 1.378; 1.2%), lansoprazole (n= 524; 0.4%), pantoprazole and rabeprazole. The indication for 87.349 of the formulas (76.9%) was justified and statistically associated with the use of NSAIDs, antithrombotics, corticosteroids, anti-ulcer, antibiotics and prokinetics. No justification was found for 26.211 (23.1%) of the prescriptions, which were associated with antidiabetics, antihypertensives, hypolipidemics and others (p <0.001).The annual justified cost was estimated to be US$ 1,654,701 and the unjustified cost was estimated to be U.S. $2,202,590, as calculated using the minimum reference prices. Discussion: Each month, the Colombian health system is overloaded by unjustified costs that include payments for non-approved indications of proton pump inhibitors and for drugs outside the list of essential medications. This issue is contributing to rising costs of healthcare in Colombia. PMID:24892316

Thermally driven microfluidic pumping via reversible shape memory polymers

NASA Astrophysics Data System (ADS)

Robertson, J. M.; Rodriguez, R. X.; Holmes, L. R., Jr.; Mather, P. T.; Wetzel, E. D.

2016-08-01

The need exists for autonomous microfluidic pumping systems that utilize environmental cues to transport fluid within a network of channels for such purposes as heat distribution, self-healing, or optical reconfiguration. Here, we report on reversible thermally driven microfluidic pumping enabled by two-way shape memory polymers. After developing a suitable shape memory polymer (SMP) through variation in the crosslink density, thin and flexible microfluidic devices were constructed by lamination of plastic films with channels defined by laser-cutting of double-sided adhesive film. SMP blisters integrated into the devices provide thermally driven pumping, while opposing elastic blisters are used to generate backpressure for reversible operation. Thermal cycling of the device was found to drive reversible fluid flow: upon heating to 60 °C, the SMP rapidly contracted to fill the surface channels with a transparent fluid, and upon cooling to 8 °C the flow reversed and the channel re-filled with black ink. Combined with a metallized backing layer, this device results in refection of incident light at high temperatures and absorption of light (at the portions covered with channels) at low temperatures. We discuss power-free, autonomous applications ranging from thermal regulation of structures to thermal indication via color change.

Proton pump inhibitors and the risk of severe adverse events - a cardiovascular bomb?

PubMed

Cunha, Nelson; Machado, António Pedro

2018-05-24

Proton pump inhibitors are currently one of the most prescribed pharmacological classes in developed countries, given their effectiveness and safety profile previously considered favourable. However, over the last few years, several papers have been published that associate prolonged use of these drugs with a wide range of adverse effects, posing doubts about their safety. Among the adverse effects described, one should emphasize the increased risk of cardiovascular events. This relationship was first described in subjects after acute coronary syndrome by the interference of proton pump inhibitors in cytochrome P450 2C19 and the conversion of clopidogrel to active metabolite. However, more recent studies describe this relationship also with the use of antiplatelet agents that do not depend on cytochrome P450 2C19 activation. The proposed mechanism is by inhibiting dimethylarginine dimethylaminohydrolase, a physiological inhibitor of asymmetric dimethylarginine, thus increasing the plasma concentrations of the latter enzyme and in turn translating into lower levels of nitric oxide. The authors reviewing in this article the relationship between the use of proton pump inhibitors and the increased risk of cardio and cerebrovascular events, are intended to alert the scientific community to the potentially harmful effects of these drugs and recommend the setting of a moratorium on their prolonged use. Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

The Mg2+-containing Water Cluster of Mammalian Cytochrome c Oxidase Collects Four Pumping Proton Equivalents in Each Catalytic Cycle*

PubMed Central

Yano, Naomine; Muramoto, Kazumasa; Shimada, Atsuhiro; Takemura, Shuhei; Baba, Junpei; Fujisawa, Hidenori; Mochizuki, Masao; Shinzawa-Itoh, Kyoko; Yamashita, Eiki; Tsukihara, Tomitake; Yoshikawa, Shinya

2016-01-01

Bovine heart cytochrome c oxidase (CcO) pumps four proton equivalents per catalytic cycle through the H-pathway, a proton-conducting pathway, which includes a hydrogen bond network and a water channel operating in tandem. Protons are transferred by H3O+ through the water channel from the N-side into the hydrogen bond network, where they are pumped to the P-side by electrostatic repulsion between protons and net positive charges created at heme a as a result of electron donation to O2 bound to heme a3. To block backward proton movement, the water channel remains closed after O2 binding until the sequential four-proton pumping process is complete. Thus, the hydrogen bond network must collect four proton equivalents before O2 binding. However, a region with the capacity to accept four proton equivalents was not discernable in the x-ray structures of the hydrogen bond network. The present x-ray structures of oxidized/reduced bovine CcO are improved from 1.8/1.9 to 1.5/1.6 Å resolution, increasing the structural information by 1.7/1.6 times and revealing that a large water cluster, which includes a Mg2+ ion, is linked to the H-pathway. The cluster contains enough proton acceptor groups to retain four proton equivalents. The redox-coupled x-ray structural changes in Glu198, which bridges the Mg2+ and CuA (the initial electron acceptor from cytochrome c) sites, suggest that the CuA-Glu198-Mg2+ system drives redox-coupled transfer of protons pooled in the water cluster to the H-pathway. Thus, these x-ray structures indicate that the Mg2+-containing water cluster is the crucial structural element providing the effective proton pumping in bovine CcO. PMID:27605664

The Mg2+-containing Water Cluster of Mammalian Cytochrome c Oxidase Collects Four Pumping Proton Equivalents in Each Catalytic Cycle.

PubMed

Yano, Naomine; Muramoto, Kazumasa; Shimada, Atsuhiro; Takemura, Shuhei; Baba, Junpei; Fujisawa, Hidenori; Mochizuki, Masao; Shinzawa-Itoh, Kyoko; Yamashita, Eiki; Tsukihara, Tomitake; Yoshikawa, Shinya

2016-11-11

Bovine heart cytochrome c oxidase (CcO) pumps four proton equivalents per catalytic cycle through the H-pathway, a proton-conducting pathway, which includes a hydrogen bond network and a water channel operating in tandem. Protons are transferred by H 3 O + through the water channel from the N-side into the hydrogen bond network, where they are pumped to the P-side by electrostatic repulsion between protons and net positive charges created at heme a as a result of electron donation to O 2 bound to heme a 3 To block backward proton movement, the water channel remains closed after O 2 binding until the sequential four-proton pumping process is complete. Thus, the hydrogen bond network must collect four proton equivalents before O 2 binding. However, a region with the capacity to accept four proton equivalents was not discernable in the x-ray structures of the hydrogen bond network. The present x-ray structures of oxidized/reduced bovine CcO are improved from 1.8/1.9 to 1.5/1.6 Å resolution, increasing the structural information by 1.7/1.6 times and revealing that a large water cluster, which includes a Mg 2+ ion, is linked to the H-pathway. The cluster contains enough proton acceptor groups to retain four proton equivalents. The redox-coupled x-ray structural changes in Glu 198 , which bridges the Mg 2+ and Cu A (the initial electron acceptor from cytochrome c) sites, suggest that the Cu A -Glu 198 -Mg 2+ system drives redox-coupled transfer of protons pooled in the water cluster to the H-pathway. Thus, these x-ray structures indicate that the Mg 2+ -containing water cluster is the crucial structural element providing the effective proton pumping in bovine CcO. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Association Between Proton Pump Inhibitors and Microscopic Colitis.

PubMed

Law, Ernest H; Badowski, Melissa; Hung, Yu-Ting; Weems, Kimberly; Sanchez, Angelica; Lee, Todd A

2017-03-01

Microscopic colitis (MC) is a chronic inflammatory disease of the colon that is characterized by chronic, watery, nonbloody diarrhea. Concern regarding a potential association between proton-pump inhibitors (PPIs) and MC has recently emerged. We sought to systematically review and summarize the evidence for the potential association between PPIs and MC. We systematically searched EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Google Scholar using the terms proton-pump inhibitors (omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, or esomeprazole), microscopic colitis, collagenous colitis, and lymphocytic colitis. Full-text, English-language reports of case reports/series, observational studies, experimental studies, and systematic reviews/meta-analyses published between January 2000 to August 2016 were included. Bibliographies from pertinent publications were reviewed for additional references. Outcome was defined as the development of biopsy-confirmed MC. A total of 19 publications were identified: 5 case control studies and 14 case reports/series (encompassing a total of 32 cases). All studies were limited by small sample sizes. Risk of MC by dose or specific PPI agent was not investigated in any of the studies. A review of the current body of evidence reveals a possible association between PPIs and MC. There is a need for large observational studies of high quality to examine the differential effect of specific PPIs and whether the magnitude of association is dose dependent. Given their widespread use, clinicians should routinely question whether patients are receiving unnecessary treatment with PPIs and discontinue therapy where appropriate.

Enhanced Component Performance Study: Motor-Driven Pumps 1998–2014

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schroeder, John Alton

2016-02-01

This report presents an enhanced performance evaluation of motor-driven pumps at U.S. commercial nuclear power plants. The data used in this study are based on the operating experience failure reports from fiscal year 1998 through 2014 for the component reliability as reported in the Institute of Nuclear Power Operations (INPO) Consolidated Events Database (ICES). The motor-driven pump failure modes considered for standby systems are failure to start, failure to run less than or equal to one hour, and failure to run more than one hour; for normally running systems, the failure modes considered are failure to start and failure tomore » run. An eight hour unreliability estimate is also calculated and trended. The component reliability estimates and the reliability data are trended for the most recent 10-year period while yearly estimates for reliability are provided for the entire active period. Statistically significant increasing trends were identified in pump run hours per reactor year. Statistically significant decreasing trends were identified for standby systems industry-wide frequency of start demands, and run hours per reactor year for runs of less than or equal to one hour.« less

Cost-effectiveness of histamine receptor-2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients*.

PubMed

MacLaren, Robert; Campbell, Jon

2014-04-01

To examine the cost-effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. Decision analysis model examining costs and effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. Costs were expressed in 2012 U.S. dollars from the perspective of the institution and included drug regimens and the following outcomes: clinically significant stress-related mucosal bleed, ventilator-associated pneumonia, and Clostridium difficile infection. Effectiveness was the mortality risk associated with these outcomes and represented by survival. Costs, occurrence rates, and mortality probabilities were extracted from published data. A simulation model. A mixed adult ICU population. Histamine receptor-2 antagonist or proton pump inhibitor for 9 days of stress ulcer prophylaxis therapy. Output variables were expected costs, expected survival rates, incremental cost, and incremental survival rate. Univariate sensitivity analyses were conducted to determine the drivers of incremental cost and incremental survival. Probabilistic sensitivity analysis was conducted using second-order Monte Carlo simulation. For the base case analysis, the expected cost of providing stress ulcer prophylaxis was $6,707 with histamine receptor-2 antagonist and $7,802 with proton pump inhibitor, resulting in a cost saving of $1,095 with histamine receptor-2 antagonist. The associated mortality probabilities were 3.819% and 3.825%, respectively, resulting in an absolute survival benefit of 0.006% with histamine receptor-2 antagonist. The primary drivers of incremental cost and survival were the assumptions surrounding ventilator-associated pneumonia and bleed. The probabilities that histamine receptor-2 antagonist was less costly and provided favorable survival were 89.4% and 55.7%, respectively. A secondary analysis assuming equal rates of C. difficile infection showed a cost saving of $908 with histamine

Development of a Compact, Efficient Cooling Pump for Space Suit Life Support Systems

NASA Technical Reports Server (NTRS)

van Boeyen, Roger; Reeh, Jonathan; Trevino, Luis

2009-01-01

A compact, low-power electrochemically-driven fluid cooling pump is currently being developed by Lynntech, Inc. With no electric motor and minimal lightweight components, the pump is significantly lighter than conventional rotodynamic and displacement pumps. Reliability and robustness is achieved with the absence of rotating or moving components (apart from the bellows). By employing sulfonated polystyrene-based proton exchange membranes, rather than conventional Nafion membranes, a significant reduction in the actuator power consumption was demonstrated. Lynntech also demonstrated that these membranes possess the necessary mechanical strength, durability, and temperature range for long life space operation. The preliminary design for a Phase II prototype pump compares very favorably to the fluid cooling pumps currently used in space suit primary life support systems (PLSSs). Characteristics of the electrochemically-driven pump are described and the benefits of the technology as a replacement for electric motor pumps in mechanically pumped single-phase fluid loops is discussed.

Development of a tritium monitor combined with an electrochemical tritium pump using a proton conducting oxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanaka, M.; Sugiyama, T.

2015-03-15

The detection of low level tritium is one of the key issues for tritium management in tritium handling facilities. Such a detection can be performed by tritium monitors based on proton conducting oxide technique. We tested a tritium monitoring system composed of a commercial proportional counter combined with an electrochemical hydrogen pump equipped with CaZr{sub 0.9}In{sub 0.1}O{sub 3-α} as proton conducting oxide. The hydrogen pump operated at 973 K under electrolysis conditions using tritiated water vapor (HTO). The proton conducting oxide extracts tritium molecules (HT) from HTO and tritium concentration is measured by the proportional counter. The advantage of themore » proposed tritium monitoring system is that it is able to convert HTO into molecular hydrogen.« less

Chimeric Proton-Pumping Rhodopsins Containing the Cytoplasmic Loop of Bovine Rhodopsin

PubMed Central

Sasaki, Kengo; Yamashita, Takahiro; Yoshida, Kazuho; Inoue, Keiichi; Shichida, Yoshinori; Kandori, Hideki

2014-01-01

G-protein-coupled receptors (GPCRs) transmit stimuli to intracellular signaling systems. Rhodopsin (Rh), which is a prototypical GPCR, possesses an 11-cis retinal. Photoisomerization of 11-cis to all-trans leads to structural changes in the protein of cytoplasmic loops, activating G-protein. Microbial rhodopsins are similar heptahelical membrane proteins that function as bacterial sensors, light-driven ion-pumps, or light-gated channels. They possess an all-trans retinal, and photoisomerization to 13-cis triggers structural changes in protein. Despite these similarities, there is no sequence homology between visual and microbial rhodopsins, and microbial rhodopsins do not activate G-proteins. In this study, new chimeric proton-pumping rhodopsins, proteorhodopsin (PR) and Gloeobacter rhodopsin (GR) were designed by replacing cytoplasmic loops with bovine Rh loops. Although G-protein was not activated by the PR chimeras, all 12 GR chimeras activated G-protein. The GR chimera containing the second cytoplasmic loop of bovine Rh did not activate G-protein. However, the chimera with a second and third double-loop further enhanced G-protein activation. Introduction of an E132Q mutation slowed the photocycle 30-fold and enhanced activation. The highest catalytic activity of the GR chimera was still 3,200 times lower than bovine Rh but only 64 times lower than amphioxus Go-rhodopsin. This GR chimera showed a strong absorption change of the amide-I band on a light-minus-dark difference FTIR spectrum which could represent a larger helical opening, important for G-protein activation. The light-dependent catalytic activity of this GR chimera makes it a potential optogenetic tool for enzymatic activation by light. PMID:24621599

Occupational Airborne Contact Dermatitis From Proton Pump Inhibitors.

PubMed

DeKoven, Joel G; Yu, Ashley M

2015-01-01

Few published reports have described occupational contact dermatitis from proton pump inhibitor (PPI) exposure in the literature. We present an additional case of a 58-year-old male pharmaceutical worker with an occupational airborne allergic contact dermatitis to PPIs confirmed by patch testing. This is a novel report of workplace exposure to dexlansoprazole and esomeprazole PPIs with resultant clinical contact allergy and relevant positive patch test results to these 2 agents. A literature review of all previously reported cases of occupational contact dermatitis to PPI is summarized. The case also emphasizes the importance of even minute exposures when considering workplace accommodation.

Laser-driven proton acceleration with nanostructured targets

NASA Astrophysics Data System (ADS)

Vallières, Simon; Morabito, Antonia; Veltri, Simona; Scisciò, Massimiliano; Barberio, Marianna; Antici, Patrizio

2017-05-01

Laser-driven particle acceleration has become a growing field of research, in particular for its numerous interesting applications. One of the most common proton acceleration mechanism that is obtained on typically available multi-hundred TW laser systems is based on the irradiation of thin solid metal foils by the intense laser, generating the proton acceleration on its rear target surface. The efficiency of this acceleration scheme strongly depends on the type of target used. Improving the acceleration mechanism, i.e. enhancing parameters such as maximum proton energy, laminarity, efficiency, monocromaticy, and number of accelerated particles, is heavily depending on the laser-to-target absorption, where obviously cheap and easy to implement targets are best candidates. In this work, we present nanostructured targets that are able to increase the absorption of light compared to what can be achieved with a classical solid (non-nanostructured) target and are produced with a method that is much simpler and cheaper than conventional lithographic processes. Several layers of gold nanoparticles were deposited on solid targets (aluminum, Mylar and multiwalled carbon nanotube buckypaper) and allow for an increased photon absorption. This ultimately permits to increase the laser-to-particle energy transfer, and thus to enhance the yield in proton production. Experimental characterization results on the nanostructured films are presented (UV-Vis spectroscopy and AFM), along with preliminary experimental proton spectra obtained at the JLF-TITAN laser facility at LLNL.

Charge Requirements for Proton Gradient-driven Translocation of Anthrax Toxin*

PubMed Central

Brown, Michael J.; Thoren, Katie L.; Krantz, Bryan A.

2011-01-01

Anthrax lethal toxin is used as a model system to study protein translocation. The toxin is composed of a translocase channel, called protective antigen (PA), and an enzyme, called lethal factor (LF). A proton gradient (ΔpH) can drive LF unfolding and translocation through PA channels; however, the mechanism of ΔpH-mediated force generation, substrate unfolding, and establishment of directionality are poorly understood. One recent hypothesis suggests that the ΔpH may act through changes in the protonation state of residues in the substrate. Here we report the charge requirements of LF's amino-terminal binding domain (LFN) using planar lipid bilayer electrophysiology. We found that acidic residues are required in LFN to utilize a proton gradient for translocation. Constructs lacking negative charges in the unstructured presequence of LFN translocate independently of the ΔpH driving force. Acidic residues markedly increase the rate of ΔpH-driven translocation, and the presequence is optimized in its natural acidic residue content for efficient ΔpH-driven unfolding and translocation. We discuss a ΔpH-driven charge state Brownian ratchet mechanism for translocation, where glutamic and aspartic acid residues in the substrate are the “molecular teeth” of the ratchet. Our Brownian ratchet model includes a mechanism for unfolding and a novel role for positive charges, which we propose chaperone negative charges through the PA channel during ΔpH translocation. PMID:21507946

Novel target design for enhanced laser driven proton acceleration

NASA Astrophysics Data System (ADS)

Dalui, Malay; Kundu, M.; Tata, Sheroy; Lad, Amit D.; Jha, J.; Ray, Krishanu; Krishnamurthy, M.

2017-09-01

We demonstrate a simple method of preparing structured target for enhanced laser-driven proton acceleration under target-normal-sheath-acceleration scheme. A few layers of genetically modified, clinically grown micron sized E. Coli bacteria cell coated on a thin metal foil has resulted in an increase in the maximum proton energy by about 1.5 times and the total proton yield is enhanced by approximately 25 times compared to an unstructured reference foil at a laser intensity of 1019 W/cm2. Particle-in-cell simulations on the system shows that the structures on the target-foil facilitates anharmonic resonance, contributing to enhanced hot electron production which leads to stronger accelerating field. The effect is observed to grow as the number of structures is increased in the focal area of the laser pulse.

Dynamic control of laser driven proton beams by exploiting self-generated, ultrashort electromagnetic pulses

NASA Astrophysics Data System (ADS)

Kar, S.; Ahmed, H.; Nersisyan, G.; Brauckmann, S.; Hanton, F.; Giesecke, A. L.; Naughton, K.; Willi, O.; Lewis, C. L. S.; Borghesi, M.

2016-05-01

As part of the ultrafast charge dynamics initiated by high intensity laser irradiations of solid targets, high amplitude EM pulses propagate away from the interaction point and are transported along any stalks and wires attached to the target. The propagation of these high amplitude pulses along a thin wire connected to a laser irradiated target was diagnosed via the proton radiography technique, measuring a pulse duration of ˜20 ps and a pulse velocity close to the speed of light. The strong electric field associated with the EM pulse can be exploited for controlling dynamically the proton beams produced from a laser-driven source. Chromatic divergence control of broadband laser driven protons (upto 75% reduction in divergence of >5 MeV protons) was obtained by winding the supporting wire around the proton beam axis to create a helical coil structure. In addition to providing focussing and energy selection, the technique has the potential to post-accelerate the transiting protons by the longitudinal component of the curved electric field lines produced by the helical coil lens.

Dynamic control of laser driven proton beams by exploiting self-generated, ultrashort electromagnetic pulses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kar, S., E-mail: s.kar@qub.ac.uk; Ahmed, H.; Nersisyan, G.

As part of the ultrafast charge dynamics initiated by high intensity laser irradiations of solid targets, high amplitude EM pulses propagate away from the interaction point and are transported along any stalks and wires attached to the target. The propagation of these high amplitude pulses along a thin wire connected to a laser irradiated target was diagnosed via the proton radiography technique, measuring a pulse duration of ∼20 ps and a pulse velocity close to the speed of light. The strong electric field associated with the EM pulse can be exploited for controlling dynamically the proton beams produced from amore » laser-driven source. Chromatic divergence control of broadband laser driven protons (upto 75% reduction in divergence of >5 MeV protons) was obtained by winding the supporting wire around the proton beam axis to create a helical coil structure. In addition to providing focussing and energy selection, the technique has the potential to post-accelerate the transiting protons by the longitudinal component of the curved electric field lines produced by the helical coil lens.« less

Pharmacokinetics and pharmacodynamics of the proton pump inhibitors.

PubMed

Shin, Jai Moo; Kim, Nayoung

2013-01-01

Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H(+), K(+)-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.

Systematic review: proton pump inhibitors (PPIs) for the healing of reflux oesophagitis - a comparison of esomeprazole with other PPIs.

PubMed

Edwards, S J; Lind, T; Lundell, L

2006-09-01

No randomized controlled trial has compared all the licensed standard dose proton pump inhibitors in the healing of reflux oesophagitis. To compare the effectiveness of esomeprazole with licensed standard dose proton pump inhibitors for healing of reflux oesophagitis (i.e. lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg). Systematic review of CENTRAL, BIOSIS, EMBASE and MEDLINE for randomized controlled trials in patients with reflux oesophagitis. Searching was completed in February 2005. Data on endoscopic healing rates at 4 and 8 weeks were extracted and re-analysed if not analysed by intention-to-treat. Meta-analysis was conducted using a fixed effects model. Of 133 papers identified in the literature search, six were of sufficient quality to be included in the analysis. No studies were identified comparing rabeprazole with esomeprazole. A meta-analysis of healing rates of esomeprazole 40 mg compared with standard dose proton pump inhibitors gave the following results: at 4 weeks [relative risk (RR) 0.92; 95% CI: 0.90, 0.94; P < 0.00001], and 8 weeks (RR 0.95; 95% CI: 0.94, 0.97; P < 0.00001). Publication bias did not have a significant impact on the results. The results were robust to changes in the inclusion/exclusion criteria and using a random effects model. Esomeprazole consistently demonstrates higher healing rates when compared with standard dose proton pump inhibitors.

Qualitative analysis of anatomopathological changes of gastric mucosa due to long term therapy with proton pump inhibitors: experimental studies x clinical studies.

PubMed

de Souza, Iure Kalinine Ferraz; da Silva, Alcino Lázaro; de Araújo, Alex; Santos, Fernanda Carolina Barbosa; Mendonça, Bernardo Pinto Coelho Keuffer

2013-01-01

For a few decades the long-term use of proton pump inhibitors has had wide application in the treatment of several gastrointestinal diseases. Since then, however, several studies have called attention to the possible development of anatomical and pathological changes of gastric mucosa, resulting from the long term use of this therapeutic modality. Recent experimental and clinical studies suggest that these changes have connection not only to the development of precancerous lesions, but also of gastric tumors. To present a qualitative analysis of anatomical and pathological changes of gastric mucosa resulting from the long-term use of proton pump inhibitors. The headings used were: proton pump inhibitors, precancerous lesions and gastric neoplasms for a non systematic review of the literature, based on Medline, Lillacs and Scielo. Twelve articles were selected from clinical (9) and experimental (3) studies, for qualitative analysis of the results. The gastric acid suppression by high doses of proton pump inhibitors induces hypergastrinemia and the consequent emergence of neuroendocrine tumors in animal models. Morphological changes most often found in these experimental studies were: enterochromaffin-like cell hyperplasia, neuroendocrine tumor, atrophy, metaplasia and adenocarcinoma. In the studies in humans, however, despite enterochromaffin-like cell hyperplasia, the other effects, neuroendocrine tumor and gastric atrophy, gastric metaplasia and or adenocarcinoma, were not identified. Although it is not possible to say that the long-term treatment with proton pump inhibitors induces the appearance or accelerates the development of gastric cancer in humans, several authors have suggested that prolonged administration of this drug could provoke the development of gastric cancer. Thus, the evidence demonstrated in the animal model as well as the large number of patients who do or will do a long-term treatment with proton pump inhibitors, justifies the maintenance of

Proton pump inhibitors are associated with accelerated development of cirrhosis, hepatic decompensation and hepatocellular carcinoma in noncirrhotic patients with chronic hepatitis C infection: results from ERCHIVES.

PubMed

Li, D K; Yan, P; Abou-Samra, A-B; Chung, R T; Butt, A A

2018-01-01

Proton pump inhibitors are among the most commonly prescribed medications in the United States. Their safety in cirrhosis has recently been questioned, but their overall effect on disease progression in noncirrhotic patients with chronic liver disease remains unclear. To determine the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus (HCV) infection. Using the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database, we identified all subjects who received HCV treatment and all incident cases of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Proton pump inhibitor use was measured using cumulative defined daily dose. Multivariate Cox regression analysis was performed after adjusting univariate predictors of cirrhosis and various indications for proton pump inhibitor use. Among 11 526 eligible individuals, we found that exposure to proton pump inhibitors was independently associated with an increased risk of developing cirrhosis (hazard ratio [HR]: 1.32; 95% confidence interval: [1.17, 1.49]). This association remained robust to sensitivity analysis in which only patients who achieved sustained virologic response were analysed as well as analysis excluding those with alcohol abuse/dependence. Proton pump inhibitor exposure was also independently associated with an increased risk of hepatic decompensation (HR: 3.79 [2.58, 5.57]) and hepatocellular carcinoma (HR: 2.01 [1.50, 2.70]). In patients with chronic HCV infection, increasing proton pump inhibitor use is associated with a dose-dependent risk of progression of chronic liver disease to cirrhosis, as well as an increased risk of hepatic decompensation and hepatocellular carcinoma. © 2017 John Wiley & Sons Ltd.

Solid hydrogen target for laser driven proton acceleration

NASA Astrophysics Data System (ADS)

Perin, J. P.; Garcia, S.; Chatain, D.; Margarone, D.

2015-05-01

The development of very high power lasers opens up new horizons in various fields, such as laser plasma acceleration in Physics and innovative approaches for proton therapy in Medicine. Laser driven proton acceleration is commonly based on the so-called Target Normal Sheath Acceleration (TNSA) mechanisms: a high power laser is focused onto a solid target (thin metallic or plastic foil) and interact with matter at very high intensity, thus generating a plasma; as a consequence "hot" electrons are produced and move into the forward direction through the target. Protons are generated at the target rear side, electrons try to escape from the target and an ultra-strong quasi-electrostatic field (~1TV/m) is generated. Such a field can accelerate protons with a wide energy spectrum (1-200 MeV) in a few tens of micrometers. The proton beam characteristics depend on the laser parameters and on the target geometry and nature. This technique has been validated experimentally in several high power laser facilities by accelerating protons coming from hydrogenated contaminant (mainly water) at the rear of metallic target, however, several research groups are investigating the possibility to perform experiments by using "pure" hydrogen targets. In this context, the low temperature laboratory at CEA-Grenoble has developed a cryostat able to continuously produce a thin hydrogen ribbon (from 40 to 100 microns thick). A new extrusion concept, without any moving part has been carried out, using only the thermodynamic properties of the fluid. First results and perspectives are presented in this paper.

Proton pump inhibitors and symptomatic hypomagnesemic hypoparathyroidism.

PubMed

Fatuzzo, P; Portale, G; Scollo, V; Zanoli, L; Granata, Antonio

2017-04-01

Hypomagnesemia is a common but often overlooked problem in hospitalized patients. Unrecognized hypomagnesemia can cause serious complications. The association of hypokalemia and hypocalcemia is strongly evocative of a magnesium deficiency. Research into the causes of hypomagnesemia is imperative, as it will definitely change the approach, treatment and prognosis. We report the case of a 65-year-old man with chronic hypocalcemia and hypokalemia associated with cerebellar syndrome, a solitary seizure and cerebellar hyperintensities on magnetic resonance imaging. After the detection and treatment of hypomagnesemia with oral supplements of magnesium and the replacement of pantoprazole with ranitidine, we observed immediate relief of the symptoms. In conclusion, in clinical practice, magnesium depletion should be investigated in elderly patients with hypocalcemia treated with proton pump inhibitors for many years, in particular in the presence of neurological disorders.

Deletion of a unique loop in the mycobacterial F-ATP synthase γ subunit sheds light on its inhibitory role in ATP hydrolysis-driven H(+) pumping.

PubMed

Hotra, Adam; Suter, Manuel; Biuković, Goran; Ragunathan, Priya; Kundu, Subhashri; Dick, Thomas; Grüber, Gerhard

2016-05-01

The F1 FO -ATP synthase is one of the enzymes that is essential to meet the energy requirement of both the proliferating aerobic and hypoxic dormant stages of the life cycle of mycobacteria. Most F-ATP synthases consume ATP in the α3 :β3 headpiece to drive the γ subunit, which couples ATP cleavage with proton pumping in the c ring of FO via the bottom of the γ subunit. ATPase-driven H(+) pumping is latent in mycobacteria. The presence of a unique 14 amino acid residue loop of the mycobacterial γ subunit has been described and aligned in close vicinity to the c-ring loop Priya R et al. (2013) J Bioenerg Biomembr 45, 121-129 Here, we used inverted membrane vesicles (IMVs) of fast-growing Mycobacterium smegmatis and a variety of covalent and non-covalent inhibitors to characterize the ATP hydrolysis activity of the F-ATP synthase inside IMVs. These vesicles formed a platform to investigate the function of the unique mycobaterial γ loop by deleting the respective loop-encoding sequence (γ166-179 ) in the genome of M. smegmatis. ATP hydrolysis-driven H(+) pumping was observed in IMVs containing the Δγ166-179 mutant protein but not for IMVs containing the wild-type F-ATP synthase. In addition, when compared to the wild-type enzyme, IMVs containing the Δγ166-179 mutant protein showed increased ATP cleavage and lower levels of ATP synthesis, demonstrating that the loop affects ATPase activity, ATPase-driven H(+) pumping and ATP synthesis. These results further indicate that the loop may affect coupling of ATP hydrolysis and synthesis in a different mode. © 2016 Federation of European Biochemical Societies.

How cytochrome c oxidase can pump four protons per oxygen molecule at high electrochemical gradient.

PubMed

Blomberg, Margareta R A; Siegbahn, Per E M

2015-03-01

Experiments have shown that the A-family cytochrome c oxidases pump four protons per oxygen molecule, also at a high electrochemical gradient. This has been considered a puzzle, since two of the reduction potentials involved, Cu(II) and Fe(III), were estimated from experiments to be too low to afford proton pumping at a high gradient. The present quantum mechanical study (using hybrid density functional theory) suggests a solution to this puzzle. First, the calculations show that the charge compensated Cu(II) potential for CuB is actually much higher than estimated from experiment, of the same order as the reduction potentials for the tyrosyl radical and the ferryl group, which are also involved in the catalytic cycle. The reason for the discrepancy between theory and experiment is the very large uncertainty in the experimental observations used to estimate the equilibrium potentials, mainly caused by the lack of methods for direct determination of reduced CuB. Second, the calculations show that a high energy metastable state, labeled EH, is involved during catalytic turnover. The EH state mixes the low reduction potential of Fe(III) in heme a3 with another, higher potential, here suggested to be that of the tyrosyl radical, resulting in enough exergonicity to allow proton pumping at a high gradient. In contrast, the corresponding metastable oxidized state, OH, is not significantly higher in energy than the resting state, O. Finally, to secure the involvement of the high energy EH state it is suggested that only one proton is taken up via the K-channel during catalytic turnover. Copyright © 2014 Elsevier B.V. All rights reserved.

Transient proton inflows during illumination of anaerobic Halobacterium halobium cells

NASA Technical Reports Server (NTRS)

Helgerson, S. L.; Stoeckenius, W.

1985-01-01

The roles of bacteriorhodopsin (bR), halorhodopsin (hR), and the H(+)-ATPase in the proton uptake in intact cells are examined. The Halobacterium halobium strains and solutions utilized in the experiment, and the techniques for measuring extracellular pH changes and intracellular K(+) concentrations are described. It is observed that in Halobacterium halobium strain R1, containing bR and hR, the light-driven proton uptake is divided into three transient inflows superimposed on the larger proton outflow. Under anaerobic conditions early proton uptake consists of an inflow which can be blocked with Dio-9 and a second inflow that can be eliminated by low concentrations (less than 125 nm) of triphenyltin chloride (TPT). The effects of Dio-9 and TPT on the passive proton-hydroxyl permeability of the cell membrane are investigated. A third transient light-driven proton flow observed at later times of illumination is studied. The data reveal that the first proton inflow correlates with proton dependent ATP synthesis; the second inflow is a passive uptake through an unidentified channel in response to electrogenic chloride pumping by bR and/or hR; and the third inflow correlates with the Na(+)/H(+) antiporter function.

The Chemically Elegant Proton Pump Inhibitors

PubMed Central

Roche, Victoria F.

2006-01-01

Medicinal chemistry instruction at Creighton University is designed to provide an in-depth scientifically grounded and clinically relevant learning experience for pharmacy students. Each topic covered in the 2-semester required course sequence is selected based on the general utility of the compounds in question and/or the therapeutic importance of the drugs in treating life-threatening diseases. All lessons provided to campus- and Web-based students by the author are in the form of a descriptive and conversational narrative and course requirements are in place to assure that students read the lesson prior to the class period in which it is discussed. Learning tools and aids are provided to help students more readily discern the most critical aspects of each lesson, to practice required critical thinking and structure analysis skills, and to self-assess competency in meeting specific learning objectives. This manuscript illustrates this approach by sharing a lesson on the chemistry and clinically relevant structure-activity relationships of proton pump inhibitors. PMID:17149430

Proton-pump inhibitors in patients requiring antiplatelet therapy: new FDA labeling.

PubMed

Johnson, David A; Chilton, Robert; Liker, Harley R

2014-05-01

Proton-pump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper gastrointestinal bleeding. Proton-pump inhibitors should also be considered for patients receiving antiplatelet therapy who have other risk factors for gastrointestinal bleeding, including use of aspirin. Thus, evidence of pharmacokinetic and pharmacodynamic interactions between PPIs and consequent impaired effectiveness of the antiplatelet agent clopidogrel has caused concern. Here, we discuss comparative studies suggesting that the extent to which a PPI reduces exposure to the active metabolite of clopidogrel and attenuates its antithrombotic effect differs among PPIs. Although a clinically meaningful effect of the interaction between PPIs and clopidogrel on cardiovascular outcomes has not been established, these studies provided the basis for recent changes in US Food and Drug Administration (FDA) labeling for several PPIs and clopidogrel. New labeling suggests that PPI use among patients taking clopidogrel be limited to pantoprazole, rabeprazole, lansoprazole, or dexlansoprazole. Because comparative studies indicate that omeprazole and esomeprazole have a greater effect on the CYP2C19-mediated conversion of clopidogrel to its active metabolite and, consequently, clopidogrel's effect on platelet reactivity, FDA labeling recommends avoiding omeprazole and esomeprazole in patients taking clopidogrel. Even a 12-hour separation of dosing does not appear to prevent drug interactions between omeprazole and clopidogrel.

Role of protons in the pump cycle of KdpFABC investigated by time-resolved kinetic experiments.

PubMed

Damnjanovic, Bojana; Apell, Hans-Jürgen

2014-05-20

The time-resolved kinetics of the KdpFABC complex solubilized in Aminoxide WS-35 was investigated by ATP concentration jump experiments. ATP was photoreleased from its inactive precursor, caged ATP, and charge movements in the membrane domain of the KdpFABC were detected by the electrochromic dye RH421. At low ATP concentrations, the ATP binding step became rate-limiting with an apparent, pH-independent ATP binding affinity of ~70 μM. At saturating ATP concentrations, the rate-limiting step is the conformational transition (E1-P → P-E2) with a rate constant of ~1.7 s(-1) at 20 °C that was independent of K(+) concentration. This observation together with the detected fluorescence decrease indicates that K(+) (or another positive ion) is bound in the membrane domain after enzyme phosphorylation and the conformational transition to the P-E2 state. pH dependence experiments revealed different roles of H(+) in the transport mechanism. Two different functions of protons for the ion pump must be distinguished. On one hand, there are electrogenically bound "functional" protons, which are not transported but prerequisite for the performance of the ATP-driven half-cycle. On the other hand, protons bind to the transport sites, acting as weak congeners of K(+). There possibly are noncompetitively bound protons, affecting the enzyme activity and/or coupling between KdpA and KdpB subunits. Finally, the recently proposed Post-Albers model for the KdpFABC complex was supplemented with stoichiometry factors of 2 for K(+) and 3 for H(+), and additional inhibitory side reactions controlled by H(+) were introduced, which are relevant at pH <6.5 and/or in the absence of K(+).

Fluoroquinolone resistance of Serratia marcescens: involvement of a proton gradient-dependent efflux pump.

PubMed

Kumar, Ayush; Worobec, Elizabeth A

2002-10-01

To determine the presence of a proton gradient-dependent efflux of fluoroquinolone drugs in Serratia marcescens. Thirteen clinical isolates of S. marcescens were screened for resistance to four fluoroquinolones: ofloxacin, ciprofloxacin, norfloxacin and nalidixic acid by determining MICs. The presence of a proton gradient-dependent efflux mechanism was assessed using ethidium bromide accumulation assays. Drug accumulation studies for norfloxacin, ciprofloxacin and ofloxacin were performed to determine the drug specificity of efflux. Western transfer of cellular proteins, followed by immunodetection using anti-AcrA (Escherichia coli) antibodies were used to demonstrate the presence of a resistance-nodulation-cell division (RND) pump protein. PCR was used to identify a RND pump-encoding gene using primers for two conserved motifs within inner membrane components of RND proteins. A mutant strain of S. marcescens, UOC-67WL, was isolated by culturing the wild-type strain in the presence of ciprofloxacin in T-soy media and was subjected to the same studies as described above for the clinical isolates. Ethidium bromide accumulation assays confirmed the presence of a proton gradient-dependent efflux mechanism in S. marcescens. One clinical isolate, T-861, and the mutant strain, UOC-67WL, were found to efflux ciprofloxacin and ofloxacin. Western immunoblot results confirmed overexpression of an AcrA-like protein in T-861 and UOC-67WL. Sequencing of the PCR product showed the presence of a mexF-like gene, which is overexpressed in nfxC mutants of Pseudomonas aeruginosa. This study reports the presence of a proton gradient-dependent efflux mechanism in S. marcescens.

Conjecture regarding posttranslational modifications to the arabidopsis type I proton-pumping pyrophosphatase (AVP1)

USDA-ARS?s Scientific Manuscript database

Agbiotechnology uses genetic engineering to improve the output and value of crops. Altering the expression of the plant Type I Proton-pumping Pyrophosphatase (H+-PPase) has already proven to be a useful tool to enhance crop productivity. Despite the effective use of this gene in translational resear...

Recent effectiveness of proton pump inhibitors for severe reflux esophagitis: the first multicenter prospective study in Japan.

PubMed

Mizuno, Hideki; Matsuhashi, Nobuyuki; Sakaguchi, Masahiro; Inoue, Syuji; Nakada, Koji; Higuchi, Kazuhide; Haruma, Ken; Joh, Takashi

2015-11-01

Proton pump inhibitors are the first-line treatment for reflux esophagitis. Because severe reflux esophagitis has very low prevalence in Japan, little is known about the effectiveness of proton pump inhibitors in these patients. This prospective multicenter study assessed the effectiveness of proton pump inhibitors for severe reflux esophagitis in Japan. Patients with modified Los Angeles grade C or D reflux esophagitis were treated with daily omeprazole (10 or 20 mg), lansoprazole (15 or 30 mg), or rabeprazole (10, 20, or 40 mg) for 8 weeks. Healing was assessed endoscopically, with questionnaires administered before and after treatment to measure the extent of reflux and dyspepsia symptoms. Factors affecting healing rates, including patient characteristics and endoscopic findings, were analyzed. Of the 115 patients enrolled, 64 with grade C and 19 with grade D reflux esophagitis completed the study. The healing rate was 67.5% (56/83), with 15 of the other 27 patients (55.6%) improving to grade A or B. No patient characteristic or endoscopic comorbidity was significantly associated with healing rate. Reflux and dyspepsia symptoms improved significantly with treatment. The low healing rate suggests the need of endoscopic examination to assess healing of reflux esophagitis at the end of therapy. (UMIN000005271).

Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.

PubMed

Arora, Pradeep; Gupta, Anu; Golzy, Mojgan; Patel, Nilang; Carter, Randolph L; Jalal, Kabir; Lohr, James W

2016-08-03

Acute interstitial nephritis secondary to proton pump inhibitors (PPIs) frequently goes undiagnosed due to its subacute clinical presentation, which may later present as chronic kidney disease (CKD). We investigated the association of PPI use with the development of CKD and death. Two separate retrospective case-control study designs were employed with a prospective logistic regression analysis of data to evaluate the association of development of CKD and death with PPI use. The population included 99,269 patients who were seen in primary care VISN2 clinics from 4/2001 until 4/2008. For evaluation of the CKD outcome, 22,807 with preexisting CKD at the first observation in Veterans Affairs Health Care Upstate New York (VISN2) network data system were excluded. Data obtained included use of PPI (Yes/No), demographics, laboratory data, pre-PPI comorbidity variables. A total of 19,311/76,462 patients developed CKD. Of those who developed CKD 24.4 % were on PPI. Patients receiving PPI were less likely to have vascular disease, COPD, cancer and diabetes. Of the total of 99,269 patients analyzed for mortality outcome, 11,758 died. A prospective logistic analysis of case-control data showed higher odds for development of CKD (OR 1.10 95 % CI 1.05-1.16) and mortality (OR 1.76, 95 % CI 1.67-1.84) among patients taking PPIs versus those not on PPIs. Use of proton pump inhibitors is associated with increased risk of development of CKD and death. With the large number of patients being treated with proton pump inhibitors, healthcare providers need to be better educated about the potential side effects of these medications.

The Proton Pump Inhibitor Non-Responder: A Clinical Conundrum

PubMed Central

Hussain, Zilla H; Henderson, Emily E; Maradey-Romerao, Carla; George, Nina; Fass, Ronnie; Lacy, Brian E

2015-01-01

Gastroesophageal reflux disease (GERD) is a highly prevalent chronic condition where in stomach contents reflux into the esophagus causing symptoms, esophageal injury, and subsequent complications. Proton pump inhibitors (PPI) remain the mainstay of therapy for acid suppression. Despite their efficacy, significant proportions of GERD patients are either partial or non-responders to PPI therapy. Patients should be assessed for mechanisms that can lead to PPI failure and may require further evaluation to investigate for alternative causes. This monograph will outline a diagnostic approach to the PPI non-responder, review mechanisms associated with PPI failure, and discuss therapeutic options for those who fail to respond to PPI therapy. PMID:26270485

Controlling laser driven protons acceleration using a deformable mirror at a high repetition rate

NASA Astrophysics Data System (ADS)

Noaman-ul-Haq, M.; Sokollik, T.; Ahmed, H.; Braenzel, J.; Ehrentraut, L.; Mirzaie, M.; Yu, L.-L.; Sheng, Z. M.; Chen, L. M.; Schnürer, M.; Zhang, J.

2018-03-01

We present results from a proof-of-principle experiment to optimize laser driven protons acceleration by directly feeding back its spectral information to a deformable mirror (DM) controlled by evolutionary algorithms (EAs). By irradiating a stable high-repetition rate tape driven target with ultra-intense pulses of intensities ∼1020 W/ cm2, we optimize the maximum energy of the accelerated protons with a stability of less than ∼5% fluctuations near optimum value. Moreover, due to spatio-temporal development of the sheath field, modulations in the spectrum are also observed. Particularly, a prominent narrow peak is observed with a spread of ∼15% (FWHM) at low energy part of the spectrum. These results are helpful to develop high repetition rate optimization techniques required for laser-driven ion accelerators.

High-quality electron beam generation in a proton-driven hollow plasma wakefield accelerator

NASA Astrophysics Data System (ADS)

Li, Y.; Xia, G.; Lotov, K. V.; Sosedkin, A. P.; Hanahoe, K.; Mete-Apsimon, O.

2017-10-01

Simulations of proton-driven plasma wakefield accelerators have demonstrated substantially higher accelerating gradients compared to conventional accelerators and the viability of accelerating electrons to the energy frontier in a single plasma stage. However, due to the strong intrinsic transverse fields varying both radially and in time, the witness beam quality is still far from suitable for practical application in future colliders. Here we demonstrate the efficient acceleration of electrons in proton-driven wakefields in a hollow plasma channel. In this regime, the witness bunch is positioned in the region with a strong accelerating field, free from plasma electrons and ions. We show that the electron beam carrying the charge of about 10% of 1 TeV proton driver charge can be accelerated to 0.6 TeV with a preserved normalized emittance in a single channel of 700 m. This high-quality and high-charge beam may pave the way for the development of future plasma-based energy frontier colliders.

The relationship between long-term proton pump inhibitor therapy and skeletal frailty.

PubMed

Lau, Arthur N; Tomizza, Michael; Wong-Pack, Matthew; Papaioannou, Alexandra; Adachi, Jonathan D

2015-08-01

Proton pump inhibitors (PPIs) are a commonly prescribed class of medications. Their use has been associated with an increased rate of fractures, most notably hip fractures. However, there does not seem to be a clear association between PPI use and bone mineral density measurements, assessed by dual X-ray absorptiometry. The mechanism by which PPI use increases the risk of fractures remains unclear. This review will summarize the current evidence on this topic.

Overutilization of proton pump inhibitors: a review of cost-effectiveness and risk [corrected].

PubMed

Heidelbaugh, Joel J; Goldberg, Kathleen L; Inadomi, John M

2009-03-01

Proton pump inhibitors (PPIs) are superior to histamine-2 receptor antagonists for the treatment of gastroesophageal reflux disease (GERD) and erosive esophagitis. Antisecretory therapy (AST), however, accounts for significant cost expenditure in the United States including over-the-counter and prescription formulations. Moreover, emerging data illustrate the potential risks associated with long-term PPI therapy including variations in bioavailability of common medications, vitamin B12 deficiency, Clostridium difficile-associated diarrhea, community-acquired pneumonia, and hip fracture. For these reasons, it is imperative to use the lowest dose of drug necessary to achieve desired therapeutic goals. This may entail the use of step-down, step-off, or on-demand PPI therapy for the treatment of GERD. In addition, PPIs are the most commonly used medications for stress ulcer prophylaxis (SUP), despite little evidence to support their use. Compounding this problem is evidence that patients erroneously administered SUP are often discharged on long-term PPI therapy. Pharmacy-driven step-down orders, limitation of the use of PPIs for SUP in non-ICU settings, and meticulous chart review to ensure that hospitalized patients are not discharged home on a PPI without an appropriate indication are interventions that can ensure proper PPI utilization with minimal of risk and optimization of cost-effectiveness.

Exciton Absorption in Semiconductor Quantum Wells Driven by a Strong Intersubband Pump Field

NASA Technical Reports Server (NTRS)

Liu, Ansheng; Ning, Cun-Zheng

1999-01-01

Optical interband excitonic absorption of semiconductor quantum wells (QW's) driven by a coherent pump field is investigated based on semiconductor Bloch equations. The pump field has a photon energy close to the intersubband spacing between the first two conduction subbands in the QW's. An external weak optical field probes the interband transition. The excitonic effects and pump-induced population redistribution within the conduction subbands in the QW system are included. When the density of the electron-hole pairs in the QW structure is low, the pump field induces an Autler-Townes splitting of the exciton absorption spectrum. The split size and the peak positions of the absorption doublet depend not only on the pump frequency and intensity but also on the carrier density. As the density of the electron-hole pairs is increased, the split contrast (the ratio between the maximum and minimum values) is decreased because the exciton effect is suppressed at higher densities due to the many-body screening.

Why are patients prescribed proton pump inhibitors? Retrospective analysis of link between morbidity and prescribing in the General Practice Research Database

PubMed Central

Bashford, James N R; Norwood, Jeff; Chapman, Stephen R

1998-01-01

Objectives: To establish the relation between new prescriptions for proton pump inhibitors and recorded upper gastrointestinal morbidity within a large computerised general practitioner database. Design: Retrospective survey of morbidity and prescribing data linked to new prescriptions for proton pump inhibitors and comparison with licensed indications between 1991 and 1995. Setting: General Practice Research Database and prescribing analysis and cost (PACT) data for the former West Midlands region. Subjects: Information for 612 700 patients in the General Practice Research Database. Anonymous PACT data for all general practitioners in West Midlands region. Main outcome measures: Diagnostic codes linked to the first prescriptions issued for proton pump inhibitors; relation between new prescriptions and licensed indications; yearly change in ratio of new to repeat prescriptions and prescribing volumes measured as defined daily doses. Results: Oesophagitis was the commonest recorded indication in 1991, accounting for 31% of new prescriptions, but was third in 1995 (14%). During the study new prescriptions increased substantially, especially for duodenal disease (780%) and non-ulcer dyspepsia (690%). In 1995 non-specific morbidity accounted for 46% of new prescriptions. The total volume of prescribing rose 10-fold between 1991 and 1995, when repeat prescribing accounted for 77% of the total. Conclusions: Changes in recorded morbidity associated with new prescriptions of proton pump inhibitors did not necessarily reflect changes in licensed indications. Although general practitioners seemed to respond to changes in licensing, particularly for duodenal and gastric disease, prescribing for unlicensed indications non-ulcer dyspepsia and non-specific abdominal pain increased. Key messages There has been much speculation about the reasons behind the substantial rise in prescribing of proton pump inhibitors, especially their use for minor symptoms. We used the General

A new hypothesis on the simultaneous direct and indirect proton pump mechanisms in NADH-quinone oxidoreductase (complex I)

PubMed Central

Ohnishi, Tomoko; Nakamaru-Ogiso, Eiko; Ohnishi, S. Tsuyoshi

2010-01-01

Recently, Sazanov’s group reported the X-ray structure of whole complex I [Nature, 465, 441 (2010)], which presented a strong clue for a “piston-like” structure as a key element in an “indirect” proton pump. We have studied the NuoL subunit which has a high sequence similarity to Na+/H+ antiporters, as do the NuoM and N subunits. We constructed 27 site-directed NuoL mutants. Our data suggest that the H+/e− stoichiometry seems to have decreased from (4H+/2e−) in the wild-type to approximately (3H+/2e−) in NuoL mutants. We propose a revised hypothesis that each of the “direct” and the “indirect” proton pumps transports 2H+ per 2e−. PMID:20816962

Long-term safety concerns with proton pump inhibitors.

PubMed

Ali, Tauseef; Roberts, David Neil; Tierney, William M

2009-10-01

Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide. Their use has resulted in dramatic improvements in treatment of peptic ulcer disease and gastroesophageal reflux disease. Despite an acceptable safety profile, mounting data demonstrate concerns about the long-term use of PPIs. To provide a comprehensive review regarding the concerns of long-term PPI use, a literature search was performed to identify pertinent original and review articles. Despite study shortcomings, the collective body of information overwhelmingly suggests an increased risk of infectious complications and nutritional deficiencies. Data regarding any increased risk in gastric or colon malignancy are less convincing. PPIs have revolutionized the management and complications of acid-related disorders with a high margin of safety; however, with the data available, efforts to reduce the dosing of or discontinue the use of PPIs must be reassessed frequently.

Structure of a prokaryotic virtual proton pump at 3.2 Å resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Yiling; Jayaram, Hariharan; Shane, Tania

2009-09-15

To reach the mammalian gut, enteric bacteria must pass through the stomach. Many such organisms survive exposure to the harsh gastric environment (pH 1.5-4) by mounting extreme acid-resistance responses, one of which, the arginine-dependent system of Escherichia coli, has been studied at levels of cellular physiology, molecular genetics and protein biochemistry. This multiprotein system keeps the cytoplasm above pH 5 during acid challenge by continually pumping protons out of the cell using the free energy of arginine decarboxylation. At the heart of the process is a 'virtual proton pump' in the inner membrane, called AdiC, that imports L-arginine from themore » gastric juice and exports its decarboxylation product agmatine. AdiC belongs to the APC superfamily of membrane proteins, which transports amino acids, polyamines and organic cations in a multitude of biological roles, including delivery of arginine for nitric oxide synthesis, facilitation of insulin release from pancreatic {beta}-cells, and, when inappropriately overexpressed, provisioning of certain fast-growing neoplastic cells with amino acids. High-resolution structures and detailed transport mechanisms of APC transporters are currently unknown. Here we describe a crystal structure of AdiC at 3.2 {angstrom} resolution. The protein is captured in an outward-open, substrate-free conformation with transmembrane architecture remarkably similar to that seen in four other families of apparently unrelated transport proteins.« less

Hypomagnesaemia associated with long-term use of proton pump inhibitors

PubMed Central

Toh, James Wei Tatt; Ong, Evonne; Wilson, Robert

2015-01-01

Hypomagnesaemia and associated hypocalcaemia and hypoparathyroidism have been increasingly recognised as rare long-term side-effects of proton pump inhibitors (PPIs). The PPIs may inhibit active magnesium (Mg) absorption by interfering with transcellular transient receptor potential melastatin-6 and -7 (TRPM 6 and 7) channels. More recent cell culture studies have suggested concomitant inhibition of passive Mg absorption by omeprazole. After being treated with a range of PPIs, the four patients in our case series developed hypomagnesaemia, which responded to withdrawal of therapy and initiation of Mg replacement. Their clinical course and management demonstrate key aspects of hypomagnesaemia associated with long-term use of PPIs. PMID:25138239

Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis.

PubMed

Alhazzani, Waleed; Alenezi, Farhan; Jaeschke, Roman Z; Moayyedi, Paul; Cook, Deborah J

2013-03-01

Critically ill patients may develop bleeding caused by stress ulceration. Acid suppression is commonly prescribed for patients at risk of stress ulcer bleeding. Whether proton pump inhibitors are more effective than histamine 2 receptor antagonists is unclear. To determine the efficacy and safety of proton pump inhibitors vs. histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in the ICU. We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, ACPJC, CINHAL, online trials registries (clinicaltrials.gov, ISRCTN Register, WHO ICTRP), conference proceedings databases, and reference lists of relevant articles. Randomized controlled parallel group trials comparing proton pump inhibitors to histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in critically ill patients, published before March 2012. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcomes were clinically important upper gastrointestinal bleeding and overt upper gastrointestinal bleeding; secondary outcomes were nosocomial pneumonia, ICU mortality, ICU length of stay, and Clostridium difficile infection. Trial authors were contacted for additional or clarifying information. Fourteen trials enrolling a total of 1,720 patients were included. Proton pump inhibitors were more effective than histamine 2 receptor antagonists at reducing clinically important upper gastrointestinal bleeding (relative risk 0.36; 95% confidence interval 0.19-0.68; p = 0.002; I = 0%) and overt upper gastrointestinal bleeding (relative risk 0.35; 95% confidence interval 0.21-0.59; p < 0.0001; I = 15%). There were no differences between proton pump inhibitors and histamine 2 receptor antagonists in the risk of nosocomial pneumonia (relative risk 1.06; 95% confidence interval 0.73-1.52; p = 0.76; I = 0%), ICU mortality (relative risk 1.01; 95% confidence interval 0.83-1.24; p = 0.91; I = 0

Development of a Compact Efficient Cooling Pump for Space Suit Life Support Systems

NASA Technical Reports Server (NTRS)

vanBoeyen, Roger W.; Reeh, Jonathan A.; Trevino, Luis

2008-01-01

With the increasing demands placed on extravehicular activity (EVA) for the International Space Station (ISS) assembly and maintenance, along with planned lunar and Martian missions, the need for increased human productivity and capability becomes ever more critical. This is most readily achieved by reduction in space suit weight and volume, and increased hardware reliability, durability, and operating lifetime. Considerable progress has been made with each successive generation of space suit design; from the Apollo A7L suit, to the current Shuttle Extravehicular Mobile Unit (EMU) suit, and the next generation Constellation Space Suit Element (CSSE). However, one area of space suit design which has continued to lag is the fluid pump used to drive the water cooling loop of the Primary Life Support System (PLSS). The two main types of fluid pumps typically used in space applications are rotodynamic pumps (pumping is achieved through a rotary vaned impeller) and displacement pumps (which includes rotary and diaphragm pumps). The rotating and moving parts found in the pumps and electric motor add significantly to the susceptibility to wear and friction, thermal mismatch, and complexity of the pumps. Electric motor-driven pumps capable of achieving high operational reliability are necessarily large, heavy, and energy inefficient. This report describes a development effort conducted for NASA by Lynntech, Inc., who recently demonstrated the feasibility of an electrochemically-driven fluid cooling pump. With no electric motor and minimal lightweight components, an electrochemically-driven pump is expected to be significantly smaller, lighter and achieve a longer life time than conventional rotodynamic and displacement pumps. By employing sulfonated polystyrene-based proton exchange membranes, rather than conventional Nafion membranes, a significant reduction in the actuator power consumption was demonstrated. It was also demonstrated that these membranes possess the

Characterization of a membrane-based, electrochemically driven pumping system using aqueous electrolyte solutions.

PubMed

Norman, Mya A; Evans, Christine E; Fuoco, Anthony R; Noble, Richard D; Koval, Carl A

2005-10-01

Electrokinetic flow provides a mechanism for a variety of fluid pumping schemes. The design and characterization of an electrochemically driven pump that utilizes porous carbon electrodes, iodide/triiodide redox electrolytes, and Nafion membranes is described. Fluid pumping by the cell is reversible and controlled by the cell current. Chronopotentiometry experiments indicate that the total available fluid that can be pumped in a single electrolysis without gas evolution is determined solely by the initial concentration of electrolyte and the applied current. The magnitude of the fluid flow at a given current is determined by the nature of the cation in the electrolyte and by the water absorption properties of the Nafion membrane. For 1 M aqueous electrolytes, pumping rates ranging from 1 to 14 microL/min were obtained for current densities of 10-30 mA/cm2 of membrane area. Molar volume changes for the I3-/I- redox couple and for the alkali cation migration contribute little to the observed volumetric flow rates; the magnitude of the flow is dominated by the migration-induced flow of water.

Defining Appropriate Use of Proton-Pump Inhibitors Among Medical Inpatients.

PubMed

Pappas, Matt; Jolly, Sanjay; Vijan, Sandeep

2016-04-01

Proton-pump inhibitors (PPIs) are commonly used among medical inpatients, both for prophylaxis against upper gastrointestinal bleeding (UGIB) and continuation of outpatient use. While PPIs reduce the risk of UGIB, they also appear to increase the risk of hospital-acquired pneumonia (HAP) and Clostridium difficile infection (CDI). Depending upon the underlying risks of these conditions and the changes in those risks with PPIs, use of proton-pump inhibitors may lead to a net benefit or net harm among medical inpatients. We aimed to determine the net impact of PPIs on hospital mortality among medical inpatients. A microsimulation model, using literature-derived estimates of the risks of UGIB, HAP, and CDI among medical inpatients, along with the changes in risk associated with PPI use for each of these outcomes. The primary outcome was change in inpatient mortality. Simulated general medical inpatients outside the intensive care unit (ICU). Change in overall mortality during hospitalization. New initiation of PPI therapy led to an increase in hospital mortality in about 90% of simulated patients. Continuation of outpatient PPI therapy on admission led to net increase in hospital mortality in 79% of simulated patients. Results were robust to both one-way and multivariate sensitivity analyses, with net harm occurring in at least two-thirds of patients in all scenarios. For the majority of medical inpatients outside the ICU, use of PPIs likely leads to a net increase in hospital mortality. Even in patients at particularly high risk of UGIB, only those at the very lowest risk of HCAP and CDI should be considered for prophylactic PPI use. Continuation of outpatient PPIs may also increase expected hospital mortality. Apart from patients with active UGIB, use of PPIs in hospitalized patients should be discouraged.

Comparison of p.o. or i.v. proton pump inhibitors on 72-h intragastric pH in bleeding peptic ulcer.

PubMed

Javid, Gul; Zargar, Showkat Ali; U-Saif, Riyaz-; Khan, Bashir Ahmad; Yatoo, Ghulam Nabi; Shah, Altaf Hussain; Gulzar, Ghulam Mohammad; Sodhi, Jaswinder Singh; Khan, Mushtaq Ahmad

2009-07-01

After successful endoscopic hemostasis in bleeding peptic ulcer, addition of proton pump inhibitors reduce the rate of recurrent bleeding by maintaining intragastric pH at neutral level. The aim of the present study was to evaluate the effect of various proton pump inhibitors given through different routes on intragastric pH over 72 h after endoscopic hemostasis in bleeding peptic ulcer. Ninety consecutive patients who had successful endoscopic therapy of bleeding peptic ulcer underwent 72-h continuous ambulatory intragastric pH study, were randomly assigned to receive p.o. omeprazole 80 mg bolus followed by 40 mg every 12 h for 72 h or i.v. 80 mg omeprazole followed by infusion 8 mg/h for 72 h. Oral pantoprazole 80 mg bolus followed by 80 mg every 12 h for 72 h or i.v. 80 mg pantoprazole followed by infusion of 8 mg/h for 72 h. Oral rabeprazole 80 mg bolus followed by 40 mg every 12 h for 72 h or i.v. 80 mg rabeprazole followed by infusion 8 mg/h for 72 h. Five patients received no treatment after successful endoscopic therapy and underwent 72-h pH study. Mean 72-h intragastric pH for p.o. omeprazole was 6.56 versus 6.93 for omeprazole infusion (P = 0.48). Mean 72-h intragastric pH for p.o. pantoprazole was 6.34 versus 6.32 for pantoprazole infusion (P = 0.62). Mean 72-h intragastric pH for rabeprazole p.o. was 6.11 versus 6.18 rabeprazole i.v. (P = 0.55). Mean 72-h pH for the no proton pump inhibitor group was 2.04. There was no significant difference among various proton pump inhibitors given through different routes on raising intragastric pH above 6 for 72 h after successful endoscopic hemostasis in bleeding peptic ulcer.

Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy

PubMed Central

Ang, Daphne; How, Choon How; Ang, Tiing Leong

2016-01-01

About one-third of patients with suspected gastro-oesophageal reflux disease (GERD) do not respond symptomatically to proton pump inhibitors (PPIs). Many of these patients do not suffer from GERD, but may have underlying functional heartburn or atypical chest pain. Other causes of failure to respond to PPIs include inadequate acid suppression, non-acid reflux, oesophageal hypersensitivity, oesophageal dysmotility and psychological comorbidities. Functional oesophageal tests can exclude cardiac and structural causes, as well as help to confi rm or exclude GERD. The use of PPIs should only be continued in the presence of acid reflux or oesophageal hypersensitivity for acid reflux-related events that is proven on functional oesophageal tests. PMID:27779277

Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy.

PubMed

Ang, Daphne; How, Choon How; Ang, Tiing Leong

2016-10-01

About one-third of patients with suspected gastro-oesophageal reflux disease (GERD) do not respond symptomatically to proton pump inhibitors (PPIs). Many of these patients do not suffer from GERD, but may have underlying functional heartburn or atypical chest pain. Other causes of failure to respond to PPIs include inadequate acid suppression, non-acid reflux, oesophageal hypersensitivity, oesophageal dysmotility and psychological comorbidities. Functional oesophageal tests can exclude cardiac and structural causes, as well as help to confi rm or exclude GERD. The use of PPIs should only be continued in the presence of acid reflux or oesophageal hypersensitivity for acid reflux-related events that is proven on functional oesophageal tests. Copyright: © Singapore Medical Association.

Prolonged utilization of proton pump inhibitors in patients with ischemic and valvular heart disease is associated with surgical treatments, weight loss and aggravates anemia.

PubMed

Boban, Marko; Zulj, Marinko; Persic, Viktor; Medved, Igor; Zekanovic, Drazen; Vcev, Aleksandar

2016-09-15

Proton pump inhibitors (PPIs) are among the commonest drugs used nowadays. The aim of our study was to analyze prolonged utilization of proton pump inhibitors in medical therapy of patients with ischemic and valvular heart disease. Secondly, profile of utilization was scrutinized to patient characteristics and type of cardiovascular treatments. The study included consecutive patients scheduled for cardiovascular rehabilitation 2-6months after index cardiovascular treatment. Two hundred ninety-four patients (n=294/604; 48.7%) have been using proton pump inhibitor in their therapy after index cardiovascular treatment. Cardiovascular treatments were powerfully connected with utilization of PPIs; surgery 5.77 (95%-confidence intervals [CI]: 4.05-8.22; p<0.001) and PCI 0.15 (CI: 0.10-0.22; p<0.001). The odds for having proton pump inhibitor in their chronic therapy were increased for atrial fibrillation 1.87 (CI: 1.08-3.23; p=0.025) and decreased for obesity 0.65 (CI: 0.45-0.96; p=0.035); surviving myocardial infarction 0.49 (CI: 0.29-0.83; p=0.035). Multinomial logistic regression controlled for existence of chronic renal disease found no significant association of renal dysfunction and PPI therapy. The existence of anemia was significantly increased in patients taking PPIs than controls; 6.00 (CI: 3.85-9.33; p<0.001). The use of PPI was also associated with worsening of metabolic profile, in part due to decreased utilization of ACE-inhibitors and statins. PPI consumption correlated with age of patients (Rho=0.216; p<0.001). High proportion of cardiovascular, particularly surgical patients with ischemic and valvular heart disease utilized proton pump inhibitor in prolonged courses. Prolonged courses of PPIs were connected with existence and worsening of red blood count indexes, older age, lesser weight of patients and underutilization of cardioprotective drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inward H+ pump xenorhodopsin: Mechanism and alternative optogenetic approach.

PubMed

Shevchenko, Vitaly; Mager, Thomas; Kovalev, Kirill; Polovinkin, Vitaly; Alekseev, Alexey; Juettner, Josephine; Chizhov, Igor; Bamann, Christian; Vavourakis, Charlotte; Ghai, Rohit; Gushchin, Ivan; Borshchevskiy, Valentin; Rogachev, Andrey; Melnikov, Igor; Popov, Alexander; Balandin, Taras; Rodriguez-Valera, Francisco; Manstein, Dietmar J; Bueldt, Georg; Bamberg, Ernst; Gordeliy, Valentin

2017-09-01

Generation of an electrochemical proton gradient is the first step of cell bioenergetics. In prokaryotes, the gradient is created by outward membrane protein proton pumps. Inward plasma membrane native proton pumps are yet unknown. We describe comprehensive functional studies of the representatives of the yet noncharacterized xenorhodopsins from Nanohaloarchaea family of microbial rhodopsins. They are inward proton pumps as we demonstrate in model membrane systems, Escherichia coli cells, human embryonic kidney cells, neuroblastoma cells, and rat hippocampal neuronal cells. We also solved the structure of a xenorhodopsin from the nanohalosarchaeon Nanosalina ( Ns XeR) and suggest a mechanism of inward proton pumping. We demonstrate that the Ns XeR is a powerful pump, which is able to elicit action potentials in rat hippocampal neuronal cells up to their maximal intrinsic firing frequency. Hence, inwardly directed proton pumps are suitable for light-induced remote control of neurons, and they are an alternative to the well-known cation-selective channelrhodopsins.

Electrostatic coupling of ion pumps.

PubMed

Nieto-Frausto, J; Lüger, P; Apell, H J

1992-01-01

In this paper the electrostatic interactions between membrane-embedded ion-pumps and their consequences for the kinetics of pump-mediated transport processes have been examined. We show that the time course of an intrinsically monomolecular transport reaction can become distinctly nonexponential, if the reaction is associated with charge translocation and takes place in an aggregate of pump molecules. First we consider the electrostatic coupling of a single dimer of ion-pumps embedded in the membrane. Then we apply the treatment to the kinetic analysis of light-driven proton transport by bacteriorhodopsin which forms two-dimensional hexagonal lattices. Finally, for the case of nonordered molecules, we also consider a model in which the pumps are randomly distributed over the nodes of a lattice. Here the average distance is equal to that deduced experimentally and the elemental size of the lattice is the effective diameter of one single pump. This latter model is applied to an aggregate of membrane-embedded Na, K- and Ca-pumps. In all these cases the electrostatic potential considered is the exact solution calculated from the method of electrical images for a plane membrane of finite thickness immersed in an infinite aqueous solution environment. The distributions of charges (ions or charged binding sites) are considered homogeneous or discrete in the membrane and/or in the external solution. In the case of discrete distributions we compare the results from a mean field approximation and a stochastic simulation.

Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits

PubMed Central

Gwee, Kok Ann; Goh, Vernadine; Lima, Graca

2018-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coadministered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (GI) adverse events. This coadministration is generally regarded as safe, and is included in many of the guidelines on NSAID prescription. However, recent evidence indicates that the GI risks associated with NSAIDs can be potentiated when they are combined with PPIs. This review discusses the GI effects and complications of NSAIDs and how PPIs may potentiate these effects, options for prevention of GI side effects, and appropriate use of PPIs in combination with NSAIDs. PMID:29491719

Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits.

PubMed

Gwee, Kok Ann; Goh, Vernadine; Lima, Graca; Setia, Sajita

2018-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coadministered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (GI) adverse events. This coadministration is generally regarded as safe, and is included in many of the guidelines on NSAID prescription. However, recent evidence indicates that the GI risks associated with NSAIDs can be potentiated when they are combined with PPIs. This review discusses the GI effects and complications of NSAIDs and how PPIs may potentiate these effects, options for prevention of GI side effects, and appropriate use of PPIs in combination with NSAIDs.

A new hypothesis on the simultaneous direct and indirect proton pump mechanisms in NADH-quinone oxidoreductase (complex I).

PubMed

Ohnishi, Tomoko; Nakamaru-Ogiso, Eiko; Ohnishi, S Tsuyoshi

2010-10-08

Recently, Sazanov's group reported the X-ray structure of whole complex I [Nature, 465, 441 (2010)], which presented a strong clue for a "piston-like" structure as a key element in an "indirect" proton pump. We have studied the NuoL subunit which has a high sequence similarity to Na(+)/H(+) antiporters, as do the NuoM and N subunits. We constructed 27 site-directed NuoL mutants. Our data suggest that the H(+)/e(-) stoichiometry seems to have decreased from (4H(+)/2e(-)) in the wild-type to approximately (3H(+)/2e(-)) in NuoL mutants. We propose a revised hypothesis that each of the "direct" and the "indirect" proton pumps transports 2H(+) per 2e(-). Copyright © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

EFFECT OF CYP2C19 GENETIC POLYMORPHISMS ON THE EFFICACY OF PROTON PUMP INHIBITOR-BASED TRIPLE ERADICATION THERAPY IN SLAVIC PATIENTS WITH PEPTIC ULCERS: A META-ANALYSIS.

PubMed

Denisenko, N P; Sychev, D A; Sizova, Zh M; Rozhkov, A V; Kondrashov, A V

Several meta-analyzes reported the effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication. Most of the studies which were included in these meta-analyzes were held on Asian population. Thus, there is lack of information about the effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple eradication therapy in Slavic patients with peptic ulcers. The aim of the study - to determine whether CYP2C19 affect the efficacy of proton pump inhibitor-based triple eradica- tion therapy in Slavic patients with peptic ulcers. Data search was performed using Russian index of scientific citation database, Google Scholar and MEDLINE PubMed. Statistics was held in Review Manager v 5.3. The odds ratio (OR) and 95% confidence interval (95% Cl) for eradication of H.pylori was estimated in a fixed-effect model when no heterogeneity across the studies was indicated. Four articles published between 2008 and 2015 were included in meta-analysis (three Russian studies, one Polish study). Eradication rates were significantly lower in CYP2C19 extensive metabolizers of proton pump inhibitors than in a combined group of intermediate and poor metabolizers (OR = 1,90, CI-95% 1,08-3,34, p = 0,03; heterogeneity: 12= 0%, p = 0,74). We also found that proton pump inhibitor-based triple eradication therapy achieved higher rates in poor metabolizers than in a combined group of intermediate and extensive metabolizers of CYP2C19 (OR= 5,48 CI-95% 1,51-19,93, p = 0,01; heterogeneity: F= 0%, p = 0,66). The impact of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple eradication therapy in Slavic patients appears significant.

The frequency of CYP2C19 genetic polymorphisms in Russian patients with peptic ulcers treated with proton pump inhibitors.

PubMed

Sychev, D A; Denisenko, N P; Sizova, Z M; Grachev, A V; Velikolug, K A

2015-01-01

Proton pump inhibitors, which are widely used as acid-inhibitory agents for the treatment of peptic ulcers, are mainly metabolized by 2C19 isoenzyme of cytochrome P450 (CYP2C19). CYP2C19 has genetic polymorphisms, associated with extensive, poor, intermediate or ultra-rapid metabolism of proton pump inhibitors. Genetic polymorphisms of CYP2C19 could be of clinical concern in the treatment of peptic ulcers with proton pump inhibitors. To investigate the frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles and genotypes in Russian patients with peptic ulcers. We retrospectively reviewed the cases of 971 patients of Caucasian origin with Russian nationality from Moscow region with endoscopically and histologically proven ulcers, 428 males (44%) and 543 females (56%). The mean age was 44.6±11.9 years (range: 15-88 years). DNA was extracted from ethylenediaminetetraacetic acid whole blood samples (10 mL). The polymorphisms CYP2C19 681G.A (CYP2C19*2, rs4244285), CYP2C19 636 G.A (CYP2C19*3, rs4986893) and CYP2C19 -806 C.T (CYP2C19*17, rs12248560) were evaluated using real-time polymerase chain reaction. Regarding CYP2C19 genotype, 317 patients (32.65%) out of 971 were CYP2C19*1/*1 carriers classified as extensive metabolizers. Three hundred and eighty-six (39.75%) with CYP2C19*1/*17 or CYP2C19*17/*17 genotype were ultra-rapid metabolizers. Two hundred and fifty-one people (25.85%) were intermediate metabolizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, CYP2C19*3/*17 genotypes. Seventeen patients (1.75%) with CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes were poor metabolizers. The allele frequencies were the following: CYP2C19*2 - 0.140, CYP2C19*3 - 0.006, CYP2C19*17 - 0.274. There is a high frequency of CYP2C19 genotypes associated with modified response to proton pump inhibitors in Russian patients with peptic ulcers. Genotyping for CYP2C19 polymorphisms is suggested to be a useful tool for personalized dosing of proton pump inhibitors.

Efficient laser-driven proton acceleration from cylindrical and planar cryogenic hydrogen jets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Obst, Lieselotte; Gode, Sebastian; Rehwald, Martin

We report on recent experimental results deploying a continuous cryogenic hydrogen jet as a debris-free, renewable laser-driven source of pure proton beams generated at the 150 TW ultrashort pulse laser Draco. Efficient proton acceleration reaching cut-off energies of up to 20 MeV with particle numbers exceeding 109 particles per MeV per steradian is demonstrated, showing for the first time that the acceleration performance is comparable to solid foil targets with thicknesses in the micrometer range. Two different target geometries are presented and their proton beam deliverance characterized: cylindrical (Ø 5 μm) and planar (20 μm × 2 μm). In bothmore » cases typical Target Normal Sheath Acceleration emission patterns with exponential proton energy spectra are detected. Significantly higher proton numbers in laser-forward direction are observed when deploying the planar jet as compared to the cylindrical jet case. As a result, this is confirmed by two-dimensional Particle-in-Cell (2D3V PIC) simulations, which demonstrate that the planar jet proves favorable as its geometry leads to more optimized acceleration conditions.« less

Efficient laser-driven proton acceleration from cylindrical and planar cryogenic hydrogen jets

DOE PAGES

Obst, Lieselotte; Gode, Sebastian; Rehwald, Martin; ...

2017-08-31

We report on recent experimental results deploying a continuous cryogenic hydrogen jet as a debris-free, renewable laser-driven source of pure proton beams generated at the 150 TW ultrashort pulse laser Draco. Efficient proton acceleration reaching cut-off energies of up to 20 MeV with particle numbers exceeding 109 particles per MeV per steradian is demonstrated, showing for the first time that the acceleration performance is comparable to solid foil targets with thicknesses in the micrometer range. Two different target geometries are presented and their proton beam deliverance characterized: cylindrical (Ø 5 μm) and planar (20 μm × 2 μm). In bothmore » cases typical Target Normal Sheath Acceleration emission patterns with exponential proton energy spectra are detected. Significantly higher proton numbers in laser-forward direction are observed when deploying the planar jet as compared to the cylindrical jet case. As a result, this is confirmed by two-dimensional Particle-in-Cell (2D3V PIC) simulations, which demonstrate that the planar jet proves favorable as its geometry leads to more optimized acceleration conditions.« less

Proton Pump Inhibitors Inhibit Pancreatic Secretion: Role of Gastric and Non-Gastric H+/K+-ATPases

PubMed Central

Tozzi, Marco; Giannuzzo, Andrea; Sørensen, Christiane E.; Novak, Ivana

2015-01-01

The mechanism by which pancreas secretes high HCO3 - has not been fully resolved. This alkaline secretion, formed in pancreatic ducts, can be achieved by transporting HCO3 - from serosa to mucosa or by moving H+ in the opposite direction. The aim of the present study was to determine whether H+/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3 -, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3 - secretion. We propose that proton transport is driving secretion, and that in addition it may provide a protective pH buffer zone and K+ recirculation. Furthermore, it seems relevant to re-evaluate whether PPIs should be used in treatment therapies where pancreatic functions are already compromised. PMID:25993003

Proton-pump inhibitors: understanding the complications and risks.

PubMed

Malfertheiner, Peter; Kandulski, Arne; Venerito, Marino

2017-12-01

Proton-pump inhibitors (PPIs) are the most effective therapy for the full spectrum of gastric-acid-related diseases. However, in the past decade, a steadily increasing list of complications following long-term use of PPIs has been reported. Their potent acid-suppressive action induces several structural and functional changes within the gastric mucosa, including fundic gland polyps, enterochromaffin-like cell hyperplasia and hypergastrinaemia, which can be exaggerated in the presence of Helicobacter pylori infection. As discussed in this Review, most associations of PPIs with severe adverse events are not based on sufficient evidence because of confounding factors and a lack of plausible mechanisms. Thus, a causal relationship remains unproven in most associations, and further studies are needed. Awareness of PPI-associated risks should not lead to anxiety in patients but rather should induce the physician to consider the appropriate dosing and duration of PPI therapy, including long-term monitoring strategies in selected groups of patients because of their individual comorbidities and risk factors.

An evaluation of a hubless inducer and a full flow hydraulic turbine driven inducer boost pump

NASA Technical Reports Server (NTRS)

Lindley, B. K.; Martinson, A. R.

1971-01-01

The purpose of the study was to compare the performance of several configurations of hubless inducers with a hydrodynamically similar conventional inducer and to demonstrate the performance of a full flow hydraulic turbine driven inducer boost pump using these inducers. A boost pump of this type consists of an inducer connected to a hydraulic turbine with a high speed rotor located in between. All the flow passes through the inducer, rotor, and hydraulic turbine, then into the main pump. The rotor, which is attached to the main pump shaft, provides the input power to drive the hydraulic turbine which, in turn, drives the inducer. The inducer, rotating at a lower speed, develops the necessary head to prevent rotor cavitation. The rotor speed is consistent with present main engine liquid hydrogen pump designs and the overall boost pump head rise is sufficient to provide adequate main pump suction head. This system would have the potential for operating at lower liquid hydrogen tank pressures.

Properties of the anion-binding site of pharaonis Halorhodopsin studied by ultrafast pump-probe spectroscopy and low-temperature FTIR spectroscopy.

PubMed

Nakashima, Keisuke; Nakamura, Takumi; Takeuchi, Satoshi; Shibata, Mikihiro; Demura, Makoto; Tahara, Tahei; Kandori, Hideki

2009-06-18

Halorhodopsin (HR) is a light-driven chloride pump. Cl(-) is bound in the Schiff base region of the retinal chromophore, and unidirectional Cl(-) transport is probably enforced by the specific hydrogen-bonding interaction with the protonated Schiff base and internal water molecules. It is known that HR from Natronobacterium pharaonis (pHR) also pumps NO(3)(-) with similar efficiency, suggesting that NO(3)(-) binds to the Cl(-)-binding site. In the present study, we investigated the properties of the anion-binding site by means of ultrafast pump-probe spectroscopy and low-temperature FTIR spectroscopy. The obtained data were surprisingly similar between pHR-NO(3)(-) and pHR-Cl(-), even though the shapes and sizes of the two anions are quite different. Femtosecond pump-probe spectroscopy showed very similar excited-state dynamics between pHR-NO(3)(-) and pHR-Cl(-). Low-temperature FTIR spectroscopy of unlabeled and [zeta-(15)N]Lys-labeled pHR revealed almost identical hydrogen-bonding strengths of the protonated retinal Schiff base between pHR-NO(3)(-) and pHR-Cl(-), which is similarly strengthened after retinal isomerization. There were spectral variations for water stretching vibrations between pHR-NO(3)(-) and pHR-Cl(-), suggesting that the water molecules hydrate each anion. Nevertheless, the overall spectral features were similar for the two species. These observations strongly suggest that the anion-binding site has a flexible structure and that the interaction between retinal and the anions is weak, despite the presence of an electrostatic interaction. Such a flexible hydrogen-bonding network in the Schiff base region in HR appears to be in remarkable contrast to that in light-driven proton-pumping proteins.

Proton-pump inhibitors and risk of fractures: an update meta-analysis.

PubMed

Zhou, B; Huang, Y; Li, H; Sun, W; Liu, J

2016-01-01

To identify the relationship between proton-pump inhibitors (PPIs) and the risk of fracture, we conducted an update meta-analysis of observational studies. Results showed that PPI use was associated with a modestly increased risk of hip, spine, and any-site fracture. Many studies have investigated the association of proton-pump inhibitors (PPIs) with fracture risk, but the results have been inconsistent. To evaluate this question, we performed a meta-analysis of relevant observational studies. A systematic literature search up to February 2015 was performed in PubMed. We combined relative risks (RRs) for fractures using random-effects models and conducted subgroup and stratified analyses. Eighteen studies involving a total of 244,109 fracture cases were included in this meta-analysis. Pooled analysis showed that PPI use could moderately increase the risk of hip fracture [RR = 1.26, 95 % confidence intervals (CIs) 1.16–1.36]. There was statistically significant heterogeneity among studies (p < 0.001; I 2 = 71.9 %). After limiting to cohort studies, there was also a moderate increase in hip fracture risk without evidence of study heterogeneity. Pooling revealed that short-term use (<1 year) and longer use (>1 year) were similarly associated with increased risk of hip fracture. Furthermore, a moderately increased risk of spine (RR = 1.58, 95 % CI 1.38–1.82) and any-site fracture (RR = 1.33, 95 % CI 1.15–1.54) was also found among PPI users. In this update meta-analysis of observational studies, PPI use modestly increased the risk of hip, spine, and any-site fracture, but no evidence of duration effect in subgroup analysis.

Clopidogrel and proton pump inhibitors - where do we stand in 2012?

PubMed Central

Drepper, Michael D; Spahr, Laurent; Frossard, Jean Louis

2012-01-01

Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events. Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines. Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19 (CYP2C19) and proton pump inhibitors (PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well. Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole, but not for pantoprazole. Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events, when under clopidogrel and PPI treatment at the same time. These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI (especially omeprazole) in the same year. In contrast, more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel. Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality, with high and moderate quality studies not reporting any association, rising concern about unmeasured confounders biasing the low quality studies. Thus, no definite evidence exists for an effect on mortality. Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding, combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended. PMID:22611308

Protonation of key acidic residues is critical for the K+-selectivity of the Na/K pump

PubMed Central

Yu, Haibo; Ratheal, Ian; Artigas, Pablo; Roux, Benoît

2011-01-01

The sodium-potassium (Na/K) pump is a P-type ATPase that generates Na+ and K+ concentration gradients across the cell membrane. For each ATP molecule, the pump extrudes three Na+ and imports two K+ by alternating between outward- and inward-facing conformations that preferentially bind K+ or Na+, respectively. Remarkably, the selective K+ and Na+ binding sites share several residues, and how the pump is able to achieve the selectivity required for the functional cycle is unclear. Here, free energy perturbation molecular dynamics (FEP/MD) simulations based on the crystal structures of the Na/K pump in a K+-loaded state (E2·Pi) reveal that protonation of the high-field acidic side-chains involved in the binding sites is critical to achieve the proper K+ selectivity. This prediction is tested with electrophysiological experiments showing that the selectivity of the E2P state for K+ over Na+ is affected by extracellular pH. PMID:21909093

[New-generation proton pump inhibitors: progress in the treatment of peptic acid diseases?].

PubMed

de Korwin, Jean-Dominique; Ducrotté, Philippe; Vallot, Thierry

2004-06-19

EFFECTS AND INCONVENIENCIES OF THE OLDER PRODUCTS: The proton pump inhibitors (PPIs) are now universally considered the treatment of choice for management of gastric-acid-related diseases, mainly gastro-oesophageal reflux disease (GERD). These drugs share similar properties: general structure, acid-activation step, covalent binding to the proton pump of the gastric parietal cell via the production of covalent disulphide bonds, relatively stable inhibition of H+,K+-ATPase. However, the older PPIs (omeprazole, lansoprazole et pantoprazole) have notable limitations. These drugs exhibit substantial interpatient variability and may have significant interactions with other drugs. These first-generation PPIs also do not achieve a rapid and sustained suppression of gastric acid, leading to the development of new acid-pump antagonists. The new-generation PPIs, esomeprazole and rabeprazole, offer several pharmacokinetic advantages: lower oxidative hepatic metabolism rate via the CYP 2C19 reducing the activity variations due to genetic polymorphisms and decreasing the risk of significant drug-drug interactions (advantages mainly for rabeprazole), lower metabolic clearance of esomeprazole (S-enantiomer of omeprazole) increasing plasma concentrations and acid suppression of this new PPI, higher accumulation of rabeprazole in the parietal cell due to its higher pKa. Gastric pH studies and therapeutic trials have demonstrated significant advantages of esomeprazole and rabeprazole compared with the older PPIs, which omeprazole is the prototype: a greater inhibition of acid secretion, a more rapid onset of action to provide reflux symptoms relief over 24 hours with lower GERD-related cost for rabeprazole, a sustained acid suppression, cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole, reduced potential for clinically significant drug-drug interactions with rabeprazole compared with omeprazole and

Preliminary study of a gas burner-driven and ground-coupled heat pump system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, P.F.

1995-12-31

To address the concerns for higher energy efficiency and the immediate phase out of the chlorofluorocarbons (CFCs), a new gas burner-driven, ground-coupled heat pump (GBGCHP) system is proposed for study. The new system is energy efficient and pose no environmental problem. There are three unique features in the proposed system: (1) a patented gas burner-driven compressor with a floating diaphragm piston-cylinder for energy efficiency and accommodating variable load, (2) the ground coupled water-to-air heat exchangers for high coefficient of performance (COPs), and (3) the new refrigerants based on fluoroiodocarbons (FICS) with very little ozone depletion and global warming potential. Amore » preliminary analysis of a prototype heat pump with 3 ton (10.55 kW) heating capacity is presented. The thermodynamics analysis of the system shows that the steady state COP rating higher than 7 is possible with the system operating in heating mode. Additional research work for the GBGCHP system, especially the FICs` thermodynamic properties in the superheated region, is also described.« less

The impact of proton pump inhibitors on the human gastrointestinal microbiome.

PubMed

Freedberg, Daniel E; Lebwohl, Benjamin; Abrams, Julian A

2014-12-01

Potent gastric acid suppression using proton pump inhibitors (PPIs) is common in clinical practice but may have important effects on human health that are mediated through changes in the gastrointestinal microbiome. In the esophagus, PPIs change the normal bacterial milieu to decrease distal esophageal exposure to inflammatory gram-negative bacteria. In the stomach, PPIs alter the abundance and location of gastric Helicobacter pylori and other bacteria. In the small bowel, PPIs cause polymicrobial small bowel bacterial overgrowth and have been associated with the diagnosis of celiac disease. In the colon, PPIs associate with incident but not recurrent Clostridium difficile infection. Copyright © 2014 Elsevier Inc. All rights reserved.

Micron-size hydrogen cluster target for laser-driven proton acceleration

NASA Astrophysics Data System (ADS)

Jinno, S.; Kanasaki, M.; Uno, M.; Matsui, R.; Uesaka, M.; Kishimoto, Y.; Fukuda, Y.

2018-04-01

As a new laser-driven ion acceleration technique, we proposed a way to produce impurity-free, highly reproducible, and robust proton beams exceeding 100 MeV using a Coulomb explosion of micron-size hydrogen clusters. In this study, micron-size hydrogen clusters were generated by expanding the cooled high-pressure hydrogen gas into a vacuum via a conical nozzle connected to a solenoid valve cooled by a mechanical cryostat. The size distributions of the hydrogen clusters were evaluated by measuring the angular distribution of laser light scattered from the clusters. The data were analyzed mathematically based on the Mie scattering theory combined with the Tikhonov regularization method. The maximum size of the hydrogen cluster at 25 K and 6 MPa in the stagnation state was recognized to be 2.15 ± 0.10 μm. The mean cluster size decreased with increasing temperature, and was found to be much larger than that given by Hagena’s formula. This discrepancy suggests that the micron-size hydrogen clusters were formed by the atomization (spallation) of the liquid or supercritical fluid phase of hydrogen. In addition, the density profiles of the gas phase were evaluated for 25 to 80 K at 6 MPa using a Nomarski interferometer. Based on the measurement results and the equation of state for hydrogen, the cluster mass fraction was obtained. 3D particles-in-cell (PIC) simulations concerning the interaction processes of micron-size hydrogen clusters with high power laser pulses predicted the generation of protons exceeding 100 MeV and accelerating in a laser propagation direction via an anisotropic Coulomb explosion mechanism, thus demonstrating a future candidate in laser-driven proton sources for upcoming multi-petawatt lasers.

Proton pumping in the bc1 complex: a new gating mechanism that prevents short circuits.

PubMed

Crofts, Antony R; Lhee, Sangmoon; Crofts, Stephanie B; Cheng, Jerry; Rose, Stuart

2006-08-01

The Q-cycle mechanism of the bc1 complex explains how the electron transfer from ubihydroquinone (quinol, QH2) to cytochrome (cyt) c (or c2 in bacteria) is coupled to the pumping of protons across the membrane. The efficiency of proton pumping depends on the effectiveness of the bifurcated reaction at the Q(o)-site of the complex. This directs the two electrons from QH2 down two different pathways, one to the high potential chain for delivery to an electron acceptor, and the other across the membrane through a chain containing heme bL and bH to the Qi-site, to provide the vectorial charge transfer contributing to the proton gradient. In this review, we discuss problems associated with the turnover of the bc1 complex that center around rates calculated for the normal forward and reverse reactions, and for bypass (or short-circuit) reactions. Based on rate constants given by distances between redox centers in known structures, these appeared to preclude conventional electron transfer mechanisms involving an intermediate semiquinone (SQ) in the Q(o)-site reaction. However, previous research has strongly suggested that SQ is the reductant for O2 in generation of superoxide at the Q(o)-site, introducing an apparent paradox. A simple gating mechanism, in which an intermediate SQ mobile in the volume of the Q(o)-site is a necessary component, can readily account for the observed data through a coulombic interaction that prevents SQ anion from close approach to heme bL when the latter is reduced. This allows rapid and reversible QH2 oxidation, but prevents rapid bypass reactions. The mechanism is quite natural, and is well supported by experiments in which the role of a key residue, Glu-295, which facilitates proton transfer from the site through a rotational displacement, has been tested by mutation.

FMR-driven spin pumping in Y3Fe5O12-based structures

NASA Astrophysics Data System (ADS)

Yang, Fengyuan; Hammel, P. Chris

2018-06-01

Ferromagnetic resonance driven spin pumping, a topic of steadily increasing interest since its emergence over two decades ago, remains one of the most exciting research fields in condensed matter physics. Among the many materials that have been explored for spin pumping, yttrium iron garnet (YIG) is one of the most extensively studied because of its exceptionally low magnetic damping and insulating nature. There is a great amount of literature in the spin pumping and related research fields, too broad for this review to cover. In this Topical Review, we focus on the YIG-based spin pumping results carried out by our groups, including: the mechanism and technical details of our off-axis sputtering technique for the growth of single-crystalline YIG epitaxial films with a high degree ordering, experimental evidence for the high quality of the YIG films, spin pumping results from YIG into various transition metals and their heterostructures, dynamic spin transport in YIG/antiferromagnet hybrid structures, intralayer spin pumping by localized spin wave modes confined by a micromagnetic probe, dynamic spin coupling between YIG and nitrogen-vacancy centers in diamond, parametric spin pumping from high-wavevector spin waves in YIG, and localized spin wave mode behavior in broadly tunable spatially complex magnetic configurations. These results build on the power and versatility of YIG spin pumping to improve our understanding of spin dynamics, spin currents, spin Hall physics, spin–orbit coupling, dynamic magnetic coupling, and the relationship between these phenomena in a broad range of materials, geometries, and settings.

Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study

PubMed Central

Grove, Erik L; Hansen, Peter Riis; Olesen, Jonas B; Ahlehoff, Ole; Selmer, Christian; Lindhardsen, Jesper; Madsen, Jan Kyst; Køber, Lars; Torp-Pedersen, Christian; Gislason, Gunnar H

2011-01-01

Objective To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction. Design Retrospective nationwide propensity score matched study based on administrative data. Setting All hospitals in Denmark. Participants All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded. Main outcome measures The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models. Results 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78). Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events. PMID:21562004

Delirium in the geriatric unit: proton-pump inhibitors and other risk factors.

PubMed

Otremba, Iwona; Wilczyński, Krzysztof; Szewieczek, Jan

2016-01-01

Delirium remains a major nosocomial complication of hospitalized elderly. Predictive models for delirium may be useful for identification of high-risk patients for implementation of preventive strategies. Evaluate specific factors for development of delirium in a geriatric ward setting. Prospective cross-sectional study comprised 675 consecutive patients aged 79.2±7.7 years (66% women and 34% men), admitted to the subacute geriatric ward of a multiprofile university hospital after exclusion of 113 patients treated with antipsychotic medication because of behavioral disorders before admission. Comprehensive geriatric assessments including a structured interview, physical examination, geriatric functional assessment, blood sampling, ECG, abdominal ultrasound, chest X-ray, Confusion Assessment Method for diagnosis of delirium, Delirium-O-Meter to assess delirium severity, Richmond Agitation-Sedation Scale to assess sedation or agitation, visual analog scale and Doloplus-2 scale to assess pain level were performed. Multivariate logistic regression analysis revealed five independent factors associated with development of delirium in geriatric inpatients: transfer between hospital wards (odds ratio [OR] =2.78; confidence interval [CI] =1.54-5.01; P=0.001), preexisting dementia (OR =2.29; CI =1.44-3.65; P<0.001), previous delirium incidents (OR =2.23; CI =1.47-3.38; P<0.001), previous fall incidents (OR =1.76; CI =1.17-2.64; P=0.006), and use of proton-pump inhibitors (OR =1.67; CI =1.11-2.53; P=0.014). Transfer between hospital wards, preexisting dementia, previous delirium incidents, previous fall incidents, and use of proton-pump inhibitors are predictive of development of delirium in the geriatric inpatient setting.

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease.

PubMed

Lazarus, Benjamin; Chen, Yuan; Wilson, Francis P; Sang, Yingying; Chang, Alex R; Coresh, Josef; Grams, Morgan E

2016-02-01

Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD). To quantify the association between PPI use and incident CKD in a population-based cohort. In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System. Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator. Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort. Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17-1.55). The association persisted when baseline PPI users were

Proton Pump Inhibitors and Risk of Rhabdomyolysis.

PubMed

Duncan, Scott J; Howden, Colin W

2017-01-01

Proton pump inhibitors (PPIs) have been associated with a variety of adverse events, although the level of evidence for many of these is weak at best. Recently, one national regulatory authority has mandated a change to the labeling of one PPI based on reports of possible associated rhabdomyolysis. Thus, in this review we summarize the available evidence linking PPI use with rhabdomyolysis. The level of evidence is insufficient to establish a causal relationship and is largely based on sporadic case reports. In general, patients with suspected PPI-associated rhabdomyolysis have not been re-challenged with a PPI after recovery. The mechanism whereby PPIs might have been associated with rhabdomyolysis is unclear but possibly related to interaction with concomitantly administered drugs such as HMG-CoA reductase inhibitors (statins). For patients with rhabdomyolysis, a careful search must be made for possible etiological factors. In patients who recover from an episode of possible PPI-related rhabdomyolysis but do not have a genuine requirement for PPI treatment, the PPI should not be re-introduced. For those with a definite indication for ongoing PPI treatment, the PPI can be re-introduced but should preferably not be administered with a statin.

Laser-driven proton and deuteron acceleration from a pure solid-density H2/D2 cryogenic jet

NASA Astrophysics Data System (ADS)

Kim, Jongjin; Gauthier, Maxence; Aurand, Bastian; Curry, Chandra; Goede, Sebastian; Goyon, Clement; Williams, Jackson; Kerr, Shaun; Ruby, John; Propp, Adrienne; Ramakrishna, Bhuvanesh; Pak, Art; Hazi, Andy; Glenzer, Siegfried; Roedel, Christian

2015-11-01

Laser-driven proton acceleration has become of tremendous interest for the fundamental science and the potential applications in tumor therapy and proton radiography. We have developed a cryogenic liquid hydrogen jet, which can deliver a self-replenishing target of pure solid-density hydrogen or deuterium. This allows for a target compatible with high-repetition-rate experiments and results in a pure hydrogen plasma, facilitating comparison with simulations. A new modification has allowed for the formation of jets with rectangular profiles, facilitating comparison with foil targets. This jet was installed at the Titan laser and driven by laser pulses of 40-60 J of 527 nm laser light in 1 ps. The resulting proton and deuteron spectra were measured in multiple directions with Thomson parabola spectrometers and RCF stacks. The spectral and angular information suggest contribution from both the TNSA and RPA acceleration mechanisms.

Light-driven, proton-controlled, catalytic aerobic C-H oxidation mediated by a Mn(III) porphyrinoid complex.

PubMed

Neu, Heather M; Jung, Jieun; Baglia, Regina A; Siegler, Maxime A; Ohkubo, Kei; Fukuzumi, Shunichi; Goldberg, David P

2015-04-15

The visible light-driven, catalytic aerobic oxidation of benzylic C-H bonds was mediated by a Mn(III) corrolazine complex. To achieve catalytic turnovers, a strict selective requirement for the addition of protons was established. The resting state of the catalyst was unambiguously characterized by X-ray diffraction as [Mn(III)(H2O)(TBP8Cz(H))](+), in which a single, remote site on the ligand is protonated. If two remote sites are protonated, however, reactivity with O2 is shut down. Spectroscopic methods revealed that the related Mn(V)(O) complex is also protonated at the same remote site at -60 °C, but undergoes valence tautomerization upon warming.

Proton pump inhibitors are associated with lower gastrointestinal tract bleeding in low-dose aspirin users with ischaemic heart disease.

PubMed

Miyake, Kazumasa; Akimoto, Teppei; Hanada, Yuriko; Nagoya, Hiroyuki; Kodaka, Yasuhiro; Ueki, Nobue; Kusunoki, Masafumi; Kawagoe, Tetsuro; Futagami, Seiji; Takahashi, Yasuhiro; Takano, Hitoshi; Sakamoto, Choitsu

2015-09-01

Impact of acid suppressants on lower gastrointestinal bleeding remains unclear in low-dose aspirin users; we aimed to investigate this relationship. Retrospective cohort study of low-dose aspirin users who underwent coronary angiography for ischaemic heart disease in our institution between October 2005 and December 2006; patients were evaluated for upper or lower gastrointestinal bleedings within 3 years post-angiography. 538 patients were enrolled (males, 74.4%; mean age 67.4±10.6 years). Risk for upper gastrointestinal bleeding decreased with concomitant use of statins (HR, 0.37; 95% CI, 0.15-0.89), calcium channel blockers (HR, 0.29; 95% CI, 0.10-0.85), and histamine-2 receptor antagonists (HR, 0.26; 95% CI, 0.08-0.89). Concomitant use of proton pump inhibitors tended to decrease risk of upper gastrointestinal bleeding (HR, 0.27; 95% CI, 0.06-1.18). Risk for lower gastrointestinal bleeding increased with both concomitant use of warfarin (HR, 15.68; 95% CI, 4.43-55.53) and proton pump inhibitors (HR, 6.55; 95% CI, 2.01-21.32), but not with histamine-2 receptor antagonists. Hyperuricemia lowered risk for lower gastrointestinal bleeding (HR, 0.12; 95% CI, 0.02-0.88). In low-dose aspirin users, concomitant use of proton pump inhibitors increased lower gastrointestinal bleeding risk, independent from effects on upper gastrointestinal bleeding. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

A randomized controlled trial of laparoscopic nissen fundoplication versus proton pump inhibitors for treatment of patients with chronic gastroesophageal reflux disease: One-year follow-up.

PubMed

Anvari, Mehran; Allen, Christopher; Marshall, John; Armstrong, David; Goeree, Ron; Ungar, Wendy; Goldsmith, Charles

2006-12-01

A randomized controlled trial conducted in patients with gastroesophageal reflux disease compared optimized medical therapy using proton pump inhibitor (n = 52) with laparoscopic Nissen fundoplication (n = 52). Patients were monitored for 1 year. The primary end point was frequency of gastroesophageal reflux dis-ease symptoms. Surgical patients had improved symptoms, pH control, and overall quality of life health index after surgery at 1 year compared with the medical group. The overall gastroesophageal reflux disease symptom score at 1 year was unchanged in the medical patients, but improved in the surgical patients. Fourteen patients in the medical arm experienced symptom relapse requiring titration of the proton pump inhibitor dose, but 6 had satisfactory symptom remission. No surgical patients required additional treatment for symptom control. Patients controlled on long-term proton pump inhibitor therapy for chronic gastroesophageal reflux disease are excellent surgical candidates and should experience improved symptom control after surgery at 1 year.

Gas-heat-pump development

NASA Astrophysics Data System (ADS)

Creswick, F. A.

Incentives for the development of gas heat pumps are discussed. Technical progress made on several promising technologies was reviewed. The status of development of gas-engine-driven heat pumps, the absorption cycle for the near- and long-term gas heat pump systems, the Stirling engine, the small Rankine-cycle engines, and gas-turbine-driven heat pump systems were briefly reviewed. Progress in the US, Japan, and Europe is noted.

46 CFR 56.50-55 - Bilge pumps.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) Each self-propelled vessel must be provided with a power-driven pump or pumps connected to the bilge... power-driven pump is required. (See Part 171 of this chapter for determination of criterion numeral.) 5... available, or where a suitable water supply is available from a power-driven pump of adequate pressure and...

Proton Pump Inhibitors and Risk of Mild Cognitive Impairment and Dementia.

PubMed

Goldstein, Felicia C; Steenland, Kyle; Zhao, Liping; Wharton, Whitney; Levey, Allan I; Hajjar, Ihab

2017-09-01

To examine the risk associated with the use of proton pump inhibitors (PPIs) of conversion to mild cognitive impairment (MCI), dementia, and specifically Alzheimer's disease (AD). Observational, longitudinal study. Tertiary academic Alzheimer's Disease Centers funded by the National Institute on Aging. Research volunteers aged 50 and older with two to six annual visits; 884 were taking PPIs at every visit, 1,925 took PPIs intermittently, and 7,677 never reported taking PPIs. All had baseline normal cognition or MCI. Multivariable Cox regression analyses evaluated the association between PPI use and annual conversion of baseline normal cognition to MCI or dementia or annual conversion of baseline MCI to dementia, controlling for demographic characteristics, vascular comorbidities, mood, and use of anticholinergics and histamine-2 receptor antagonists. Continuous (always vs never) PPI use was associated with lower risk of decline in cognitive function (hazard ratio (HR) = 0.78, 95% confidence interval (CI) =0.66-0.93, P = .005) and lower risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.69-0.98, P = .03). Intermittent use was also associated with lower risk of decline in cognitive function (HR = 0.84, 95% CI = 0.76-0.93, P = .001) and risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.74-0.91, P = .001). This lower risk was found for persons with normal cognition or MCI. Proton pump inhibitors were not associated with greater risk of dementia or of AD, in contrast to recent reports. Study limitations include reliance on self-reported PPI use and lack of dispensing data. Prospective studies are needed to confirm these results to guide empirically based clinical treatment recommendations. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Proton pump inhibitors and potential interactions with clopidogrel: an update.

PubMed

Gerson, Lauren B

2013-06-01

Clopidogrel, an antiplatelet agent, is increasingly prescribed for patients with recent stroke, myocardial infarction, acute coronary syndrome, and/or patients post-coronary stent insertion to prevent recurrent cardiovascular events. Since clopidogrel can increase the risk of gastrointestinal hemorrhage, co-administration of proton pump inhibitors (PPIs) has been recommended, particularly in patients at high risk. In 2009, the FDA issued warnings about potential interactions between clopidogrel and PPIs, given the fact that both drugs are metabolized via the cytochrome P450 pathway. Prior studies have demonstrated significant reduction in platelet inhibition when PPI therapy is administered to subjects on clopidogrel therapy. Two meta-analyses were published in 2010 and 2011, the first suggesting association of PPIs with adverse cardiovascular events when observational studies were examined, but noting that the results were limited by the presence of significant heterogeneity. The second meta-analysis did not find a significant increase in the risk of adverse primary events (which included all cause mortality, cardiovascular death, myocardial infarction, or stroke), and concluded that analysis of the data from two randomized controlled trials yielded a risk difference of zero. An updated literature search was performed to assess clinical studies describing interactions between PPIs and clopidogrel published from 2011-2012. The majority of these studies did not show significant interactions when primary cardiac outcomes were considered. More importantly, the newer data demonstrated that PPI usage independently was a risk factor for adverse CV outcomes, since most PPI users were older patients who were more likely to have concomitant co-morbid conditions. Two updated reviews also concluded that the presence of confounding factors likely explained differences in results between studies, and that there were no significant differences in effects on clopidogrel between

25 Years of Proton Pump Inhibitors: A Comprehensive Review.

PubMed

Strand, Daniel S; Kim, Daejin; Peura, David A

2017-01-15

Proton pump inhibitors (PPIs) were clinically introduced more than 25 years ago and have since proven to be invaluable, safe, and effective agents for the management of a variety of acid-related disorders. Although all members in this class act in a similar fashion, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism, and Food and Drug Administration (FDA)-approved clinical indications. Nevertheless, each is effective in managing gastroesophageal reflux disease and uncomplicated or complicated peptic ulcer disease. Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individuals, especially at night. Longer-acting PPIs and technology to prolong conventional PPI activity have been developed to specifically address these limitations and may improve clinical outcomes.

25 Years of Proton Pump Inhibitors: A Comprehensive Review

PubMed Central

Strand, Daniel S.; Kim, Daejin; Peura, David A.

2017-01-01

Proton pump inhibitors (PPIs) were clinically introduced more than 25 years ago and have since proven to be invaluable, safe, and effective agents for the management of a variety of acid-related disorders. Although all members in this class act in a similar fashion, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism, and Food and Drug Administration (FDA)-approved clinical indications. Nevertheless, each is effective in managing gastroesophageal reflux disease and uncomplicated or complicated peptic ulcer disease. Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individuals, especially at night. Longer-acting PPIs and technology to prolong conventional PPI activity have been developed to specifically address these limitations and may improve clinical outcomes. PMID:27840364

A treatment planning study to assess the feasibility of laser-driven proton therapy using a compact gantry design.

PubMed

Hofmann, Kerstin M; Masood, Umar; Pawelke, Joerg; Wilkens, Jan J

2015-09-01

Laser-driven proton acceleration is suggested as a cost- and space-efficient alternative for future radiation therapy centers, although the properties of these beams are fairly different compared to conventionally accelerated proton beams. The laser-driven proton beam is extremely pulsed containing a very high proton number within ultrashort bunches at low bunch repetition rates of few Hz and the energy spectrum of the protons per bunch is very broad. Moreover, these laser accelerated bunches are subject to shot-to-shot fluctuations. Therefore, the aim of this study was to investigate the feasibility of a compact gantry design for laser-driven proton therapy and to determine limitations to comply with. Based on a published gantry beam line design which can filter parabolic spectra from an exponentially decaying broad initial spectrum, a treatment planning study was performed on real patient data sets. All potential parabolic spectra were fed into a treatment planning system and numerous spot scanning proton plans were calculated. To investigate limitations in the fluence per bunch, the proton number of the initial spectrum and the beam width at patient entrance were varied. A scenario where only integer shots are delivered as well as an intensity modulation from shot to shot was studied. The resulting plans were evaluated depending on their dosimetric quality and in terms of required treatment time. In addition, the influence of random shot-to-shot fluctuations on the plan quality was analyzed. The study showed that clinically relevant dose distributions can be produced with the system under investigation even with integer shots. For small target volumes receiving high doses per fraction, the initial proton number per bunch must remain between 1.4 × 10(8) and 8.3 × 10(9) to achieve acceptable delivery times as well as plan qualities. For larger target volumes and standard doses per fraction, the initial proton number is even more restricted to stay between 1.4 �

A treatment planning study to assess the feasibility of laser-driven proton therapy using a compact gantry design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hofmann, Kerstin M., E-mail: kerstin.hofmann@lrz.tu-muenchen.de; Wilkens, Jan J.; Masood, Umar

Purpose: Laser-driven proton acceleration is suggested as a cost- and space-efficient alternative for future radiation therapy centers, although the properties of these beams are fairly different compared to conventionally accelerated proton beams. The laser-driven proton beam is extremely pulsed containing a very high proton number within ultrashort bunches at low bunch repetition rates of few Hz and the energy spectrum of the protons per bunch is very broad. Moreover, these laser accelerated bunches are subject to shot-to-shot fluctuations. Therefore, the aim of this study was to investigate the feasibility of a compact gantry design for laser-driven proton therapy and tomore » determine limitations to comply with. Methods: Based on a published gantry beam line design which can filter parabolic spectra from an exponentially decaying broad initial spectrum, a treatment planning study was performed on real patient data sets. All potential parabolic spectra were fed into a treatment planning system and numerous spot scanning proton plans were calculated. To investigate limitations in the fluence per bunch, the proton number of the initial spectrum and the beam width at patient entrance were varied. A scenario where only integer shots are delivered as well as an intensity modulation from shot to shot was studied. The resulting plans were evaluated depending on their dosimetric quality and in terms of required treatment time. In addition, the influence of random shot-to-shot fluctuations on the plan quality was analyzed. Results: The study showed that clinically relevant dose distributions can be produced with the system under investigation even with integer shots. For small target volumes receiving high doses per fraction, the initial proton number per bunch must remain between 1.4 × 10{sup 8} and 8.3 × 10{sup 9} to achieve acceptable delivery times as well as plan qualities. For larger target volumes and standard doses per fraction, the initial proton number is

Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions

PubMed Central

Mermelstein, Joseph; Chait Mermelstein, Alanna; Chait, Maxwell M

2018-01-01

A significant percentage of patients with gastroesophageal reflux disease (GERD) will not respond to proton pump inhibitor (PPI) therapy. The causes of PPI-refractory GERD are numerous and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety of pharmacologic and procedural interventions that should be selected based on the underlying mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundoplication and Stretta. Several alternative and complementary treatments of possible benefit also exist. PMID:29606884

46 CFR 132.120 - Fire pumps.

Code of Federal Regulations, 2012 CFR

2012-10-01

... vessel must be equipped with one self-priming power-driven fire pump capable of delivering a single... propulsion engines are installed, the pump required by paragraph (a) of this section may be driven by one of the engines. If only one propulsion engine is installed, the pump must be driven by a source of power...

46 CFR 132.120 - Fire pumps.

Code of Federal Regulations, 2014 CFR

2014-10-01

... vessel must be equipped with one self-priming power-driven fire pump capable of delivering a single... propulsion engines are installed, the pump required by paragraph (a) of this section may be driven by one of the engines. If only one propulsion engine is installed, the pump must be driven by a source of power...

46 CFR 132.120 - Fire pumps.

Code of Federal Regulations, 2013 CFR

2013-10-01

... vessel must be equipped with one self-priming power-driven fire pump capable of delivering a single... propulsion engines are installed, the pump required by paragraph (a) of this section may be driven by one of the engines. If only one propulsion engine is installed, the pump must be driven by a source of power...

Antitumor effect of combination of the inhibitors of two new oncotargets: proton pumps and reverse transcriptase.

PubMed

Lugini, Luana; Sciamanna, Ilaria; Federici, Cristina; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Fais, Stefano

2017-01-17

Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects. We thus pretreated human metastatic melanoma cells with LAN and then with EFV, both in 2D and 3D spheroid models. We evaluated the treatment effect by proliferation and cell death/apoptosis assays in classical and in pulse administration experiments. The action of EFV was negatively affected by the tumor microenvironmental acidity, and LAN pretreatment overcame the problem. LAN potentiated the cytotoxicity of EFV to melanoma cells and, when administered during the drug interruption period, prevented the replacement of tumor cell growth.This study supports the implementation of the current therapies with combination of Proton Pumps and Reverse Transcriptase inhibitors.

Antitumor effect of combination of the inhibitors of two new oncotargets: proton pumps and reverse transcriptase

PubMed Central

Lugini, Luana; Sciamanna, Ilaria; Federici, Cristina; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Fais, Stefano

2017-01-01

Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects. We thus pretreated human metastatic melanoma cells with LAN and then with EFV, both in 2D and 3D spheroid models. We evaluated the treatment effect by proliferation and cell death/apoptosis assays in classical and in pulse administration experiments. The action of EFV was negatively affected by the tumor microenvironmental acidity, and LAN pretreatment overcame the problem. LAN potentiated the cytotoxicity of EFV to melanoma cells and, when administered during the drug interruption period, prevented the replacement of tumor cell growth. This study supports the implementation of the current therapies with combination of Proton Pumps and Reverse Transcriptase inhibitors. PMID:27926505

Air swallowing can be responsible for non-response of heartburn to high-dose proton pump inhibitor.

PubMed

Zentilin, P; Accornero, L; Dulbecco, P; Savarino, E; Savarino, V

2005-06-01

Intraluminal electrical impedance is a novel technique, which is able for the first time to provide a qualitative assessment of refluxed material moving from the stomach to the oesophagus. In other words, the presence of air can be differentiated from that of liquid, because the former is characterised by high and the latter by low impedance compared with baseline. Moreover, the combined measurement of electrical impedance and pH-metry permits to distinguish acid from non-acid liquid reflux. One of the most important clinical applications of this method is to assess the reasons for poor response of GORD patients to high-dose proton pump inhibitors. This case report describes the results of impedance in the evaluation of a young woman, who did not respond to twice-daily doses of rabeprazole. She continued to complain of heartburn as major symptom and impedance allowed us to clarify that it was not related to acid or non-acid reflux, but to air swallowing. Therefore, this technique identified aerophagia to be responsible for persistent heartburn despite high-dose proton pump inhibitor and prevented the adoption of more aggressive, but probably unuseful therapies, such as the surgical one.

46 CFR 132.120 - Fire pumps.

Code of Federal Regulations, 2011 CFR

2011-10-01

... with one self-priming power-driven fire pump capable of delivering a single stream of water from the..., the pump required by paragraph (a) of this section may be driven by one of the engines. If only one propulsion engine is installed, the pump must be driven by a source of power independent of the engine. (e...

[Do opioids, sedatives and proton-pump inhibitors increase the risk of fractures?

PubMed

Thorsdottir, Gudlaug; Benedikz, Elisabet; Thorgeirsdottir, Sigridur A; Johannsson, Magnus

2017-01-01

A pharmacoepidemiological study was conducted to analyse the relationship between bone fracture and the use of certain drugs. The study includes patients 40 years and older, diagnosed with bone fractures in the Emergency Department of Landspitali University Hospital in Reykjavik, Iceland, during a 10-year period (2002-2011). Also were included those who picked up from a pharmacy 90 DDD or more per year of the drugs included in the study in the capital region of Iceland during same period. Opiates, benzodiazepines/hypnotics (sedatives) were compared with HMG-CoA reductase inhibitors (statins), non-steroid anti-inflammatory drugs (NSAID) and beta blockers. Proton-pump inhibitors (PPI) and histamine H2-antagonists were also examined. To examine the association between above drugs and fractures the data from electronic hospital database were matched to the prescription database run by the Directorate of Health. A total of 29,056 fractures in 22,891 individuals were identified. The females with fractures were significantly older and twice as many, compared to males. The odds ratio (OR) for fractures was not significantly different between the NSAID, statins and beta blockers. OR for opiates showed almost double increased risk of fractures, 40% increased risk for sedatives and 30% increased risk for PPIs compared to beta blockers. No increased fracture-risk was noted in patients taking H2 antagonists. This study shows a relationship between the use of opiates, sedatives and bone fractures. The incidence of fractures was also increased in patients taking PPIs which is interesting in the light of the wide-spread use of PPIs in the community. Key words: Opiates, sedatives, proton- pump inhibitors, fractures. Correspondence: Magnus Johannsson, magjoh@hi.is.

Proton Pump Inhibitor use in Hospitalized Patients: Is Overutilization Becoming a Problem?

PubMed Central

Durand, Cheryl; Willett, Kristine C.; Desilets, Alicia R.

2012-01-01

Proton pump inhibitors (PPIs) are among the most common classes of medications prescribed. Though they were previously thought of as safe, recent literature has shown risks associated with their use including increased risk for Clostridium difficile infection, pneumonia, and fractures. Due to these risks, it is important to determine if PPIs are being used appropriately. This review evaluates seven studies in hospitalized patients. Additionally, this review evaluates literature pertaining to recently discovered adverse reactions; all studies found PPIs are being overutilized. Findings highlight the importance of evaluating appropriate therapy with these agents and recommending discontinuation if a proper indication does not exist. PMID:24833936

TOPPITS: Trial Of Proton Pump Inhibitors in Throat Symptoms. Study protocol for a randomised controlled trial.

PubMed

Watson, Gillian; O'Hara, James; Carding, Paul; Lecouturier, Jan; Stocken, Deborah; Fouweather, Tony; Wilson, Janet

2016-04-01

Persistent throat symptoms and Extra Oesophageal Reflux (EOR) are among the commonest reasons for attendance at a secondary care throat or voice clinic. There is a growing trend to treat throat symptom patients with proton pump inhibitors (PPIs) to suppress stomach acid, but most controlled studies fail to demonstrate a significant benefit of PPI over placebo. In addition, patient views on PPI use vary widely. A UK multi-centre, randomised, controlled trial for adults with persistent throat symptoms to compare the effectiveness of treatment with the proton pump inhibitor (PPI) lansoprazole versus placebo. The trial includes a six-month internal pilot, during which three sites will recruit 30 participants in total, to assess the practicality of the trial and assess the study procedures and willingness of the patient population to participate. If the pilot is successful, three additional sites will be opened to recruitment, and a further 302 participants recruited across the six main trial sites. Further trial sites may be opened, as necessary. The main trial will continue for a further 18 months. Participants will be followed up for 12 months from randomisation, throughout which both primary and secondary outcome data will be collected. The primary outcome is change in Reflux Symptom Index (RSI) score, the 'area standard' for this type of assessment, after 16 weeks (four months) of treatment. Secondary outcomes are RSI changes at 12 months after randomisation, Quality of Life assessment at four and 12 months, laryngeal mucosal changes, assessments of compliance and side effects, and patient-reported satisfaction. TOPPITS is designed to evaluate the relative effectiveness of treatment with a proton pump inhibitor versus placebo in patients with persistent throat symptoms. This will provide valuable information to clinicians and GPs regarding the treatment and management of care for these patients, on changes in symptoms, and in Quality of Life, over time. ISRCTN

Transforming in-situ observations of CME-driven shock accelerated protons into the shock's reference frame.

NASA Astrophysics Data System (ADS)

Robinson, I. M.; Simnett, G. M.

2005-07-01

We examine the solar energetic particle event following solar activity from 14, 15 April 2001 which includes a "bump-on-the-tail" in the proton energy spectra at 0.99 AU from the Sun. We find this population was generated by a CME-driven shock which arrived at 0.99 AU around midnight 18 April. As such this population represents an excellent opportunity to study in isolation, the effects of proton acceleration by the shock. The peak energy of the bump-on-the-tail evolves to progressively lower energies as the shock approaches the observing spacecraft at the inner Lagrange point. Focusing on the evolution of this peak energy we demonstrate a technique which transforms these in-situ spectral observations into a frame of reference co-moving with the shock whilst making allowance for the effects of pitch angle scattering and focusing. The results of this transform suggest the bump-on-the-tail population was not driven by the 15 April activity but was generated or at least modulated by a CME-driven shock which left the Sun on 14 April. The existence of a bump-on-the-tail population is predicted by models in Rice et al. (2003) and Li et al. (2003) which we compare with observations and the results of our analysis in the context of both the 14 April and 15 April CMEs. We find an origin of the bump-on-the-tail at the 14 April CME-driven shock provides better agreement with these modelled predictions although some discrepancy exists as to the shock's ability to accelerate 100 MeV protons. Keywords. Solar physics, astrophysics and astronomy (Energetic particles; Flares and mass ejections) Space plasma physics (Transport processes)

Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer

PubMed Central

Chu, Michael P.; Hecht, J. Randolph; Slamon, Dennis; Wainberg, Zev A.; Bang, Yung-Jue; Hoff, Paulo M.; Sobrero, Alberto; Qin, Shukui; Afenjar, Karen; Houe, Vincent; King, Karen; Koski, Sheryl; Mulder, Karen; Hiller, Julie Price; Scarfe, Andrew; Spratlin, Jennifer; Huang, Yingjie J.; Khan-Wasti, Saba; Chua, Neil

2016-01-01

Importance Capecitabine is an oral cytotoxic chemotherapeutic commonly used across cancer subtypes. As with other oral medications though, it may suffer from drug interactions that could impair its absorption. Objective To determine if gastric acid suppressants such as proton pump inhibitors (PPIs) may impair capecitabine efficacy. Design, Setting, and Participants This secondary analysis of TRIO-013, a phase III randomized trial, compares capecitabine and oxaliplatin (CapeOx) with or without lapatinib in 545 patients with ERBB2/HER2-positive metastatic gastroesophageal cancer (GEC); patients were randomized 1:1 between CapeOx with or without lapatinib. Proton pump inhibitor use was identified by medication records. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with PPIs vs patients who were not. Specific subgroups were accounted for, such as younger age (<60 years), Asian ethnicity, female sex, and disease stage (metastatic/advanced) in multivariate Cox proportional hazards modeling. The TRIO-013 trial accrued and randomized patients between June 2008 and January 2012; this analysis took place in January 2014. Interventions Patients were divided based on PPI exposure. Main Outcomes and Measures Primary study outcome was PFS and OS between patients treated with PPIs vs patients who were not. Secondary outcomes included disease response rates and toxicities. Results Of the 545 patients with GEC (median age, 60 years; 406 men [74%]) included in the study, 229 received PPIs (42.0%) and were evenly distributed between arms. In the placebo arm, PPI-treated patients had poorer median PFS, 4.2 vs 5.7 months (hazard ratio [HR], 1.55; 95% CI, 1.29-1.81, P < .001); OS, 9.2 vs 11.3 months (HR, 1.34; 95% CI, 1.06-1.62; P = .04); and disease control rate (72% vs 83%; P = .02) vs patients not treated with PPIs. In multivariate analysis considering age, race, disease stage, and sex, PPI-treated patients had poorer PFS

Teaching the Fundamentals of Biological Research with Primary Literature: Learning from the Discovery of the Gastric Proton Pump

ERIC Educational Resources Information Center

Zhu, Lixin

2011-01-01

For the purpose of teaching collegians the fundamentals of biological research, literature explaining the discovery of the gastric proton pump was presented in a 50-min lecture. The presentation included detailed information pertaining to the discovery process. This study was chosen because it demonstrates the importance of having a broad range of…

Nafion-coating of the electrodes improves the flow-stability of the Ag/SiO2/Ag2O electroosmotic pump.

PubMed

Shin, Woonsup; Zhu, Enhua; Nagarale, Rajaram Krishna; Kim, Chang Hwan; Lee, Jong Myung; Shin, Samuel Jaeho; Heller, Adam

2011-06-15

When a current or a voltage is applied across the ceramic membrane of the nongassing Ag/Ag(2)O-SiO(2)-Ag/Ag(2)O pump, protons produced in the anodic reaction 2Ag(s) + H(2)O → Ag(2)O(s) + 2H(+) + 2e(-) are driven to the cathode, where they are consumed by the reaction Ag(2)O(s) + H(2)O + 2e(-) → 2Ag(s) + 2 OH(-). The flow of water is induced by momentum transfer from the electric field-driven proton-sheet at the surface of the ceramic membrane. About 10(4) water molecules flowed per reacted electron. Because dissolved ions decrease the field at the membrane surface, the flow decreases upon increasing the ionic strength. For this reason Ag(+) ions introduced through the anodic reaction and by dissolution of Ag(2)O decrease the flow. Their accumulation is reduced by applying Nafion-films to the electrodes. The 20 μL min(-1) flow rate of 6 mm i.d. pumps with Nafion coated electrodes operate daily for 5 min at 1 V for 1 month, for 70 h when the pump is pulsed for 30 s every 30 min, and for 2 h when operating continuously.

Dynamically balanced, hydraulically driven compressor/pump apparatus for resonant free piston Stirling engines

DOEpatents

Corey, John A.

1984-05-29

A compressor, pump, or alternator apparatus is designed for use with a resonant free piston Stirling engine so as to isolate apparatus fluid from the periodically pressurized working fluid of the Stirling engine. The apparatus housing has a first side closed by a power coupling flexible diaphragm (the engine working member) and a second side closed by a flexible diaphragm gas spring. A reciprocally movable piston is disposed in a transverse cylinder in the housing and moves substantially at right angles relative to the flexible diaphragms. An incompressible fluid fills the housing which is divided into two separate chambers by suitable ports. One chamber provides fluid coupling between the power diaphragm of the RFPSE and the piston and the second chamber provides fluid coupling between the gas spring diaphragm and the opposite side of the piston. The working members of a gas compressor, pump, or alternator are driven by the piston. Sealing and wearing parts of the apparatus are mounted at the external ends of the transverse cylinder in a double acting arrangement for accessibility. An annular counterweight is mounted externally of the reciprocally movable piston and is driven by incompressible fluid coupling in a direction opposite to the piston so as to damp out transverse vibrations.

Device and method to relieve cordelle action in a chain driven pump

DOEpatents

Dysarz, Edward D.

1994-01-01

A cordelle action relief apparatus or device for use in sucker rod pumps in a petroleum or water well. The device is incorporated in a chain driven pump to prevent the chain from forming a bow or archlike configuration as the chain rolls off of the sprocket and down into the well. When the chain is allowed to form this bow or arch it could damage the well and well casing. The device includes a first rod on the side of the chain and a second rod on the second side of the chain that will allow the rollers of the chain to roll on the rod and further prevent the chain from bowing or arching and will further allow the rollers on the chain to roll on the rods which will further prevent damage to the well casing, the well, and the chain.

Effect of long-term proton pump inhibitor administration on gastric mucosal atrophy: A meta-analysis

PubMed Central

Li, Zhong; Wu, Cong; Li, Ling; Wang, Zhaoming; Xie, Haibin; He, Xiaozhou; Feng, Jin

2017-01-01

Background/Aims: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related gastrointestinal diseases. Recently, some studies have reported that PPIs can alter the gastric mucosal architecture; however, the relationship remains controversial. This meta-analysis study was designed to quantify the association between long-term PPI administration and gastric atrophy. Materials and Methods: A PubMed search was conducted to identify studies using the keywords proton pump inhibitors or PPI and gastric atrophy or atrophic gastritis; the timeframe of publication searched was up to May 2016. Heterogeneity among studies was tested with the Q test; odds ratios (OR) and 95% confidence intervals (CI) were calculated. P values were calculated by I2 tests and regarded as statistically significant when <0.05. Results: We identified 13 studies that included 1465 patients under long-term PPI therapy and 1603 controls, with a total gastric atrophy rate of 14.50%. There was a higher presence of gastric atrophy (15.84%; statistically significant) in PPI group compared to the control group (13.29%) (OR: 1.55, 95% CI: 1.00–2.41). Conclusions: The pooled data suggest that long-term PPI use is associated with increased rates of gastric atrophy. Large-scale multicenter studies should be conducted to further investigate the relationship between acid suppressants and precancerous diseases. PMID:28721975

Water exit pathways and proton pumping mechanism in B-type cytochrome c oxidase from molecular dynamics simulations.

PubMed

Yang, Longhua; Skjevik, Åge A; Han Du, Wen-Ge; Noodleman, Louis; Walker, Ross C; Götz, Andreas W

2016-09-01

Cytochrome c oxidase (CcO) is a vital enzyme that catalyzes the reduction of molecular oxygen to water and pumps protons across mitochondrial and bacterial membranes. While proton uptake channels as well as water exit channels have been identified for A-type CcOs, the means by which water and protons exit B-type CcOs remain unclear. In this work, we investigate potential mechanisms for proton transport above the dinuclear center (DNC) in ba3-type CcO of Thermus thermophilus. Using long-time scale, all-atom molecular dynamics (MD) simulations for several relevant protonation states, we identify a potential mechanism for proton transport that involves propionate A of the active site heme a3 and residues Asp372, His376 and Glu126(II), with residue His376 acting as the proton-loading site. The proposed proton transport process involves a rotation of residue His376 and is in line with experimental findings. We also demonstrate how the strength of the salt bridge between residues Arg225 and Asp287 depends on the protonation state and that this salt bridge is unlikely to act as a simple electrostatic gate that prevents proton backflow. We identify two water exit pathways that connect the water pool above the DNC to the outer P-side of the membrane, which can potentially also act as proton exit transport pathways. Importantly, these water exit pathways can be blocked by narrowing the entrance channel between residues Gln151(II) and Arg449/Arg450 or by obstructing the entrance through a conformational change of residue Tyr136, respectively, both of which seem to be affected by protonation of residue His376. Copyright © 2016 Elsevier B.V. All rights reserved.

Lactobacillus paracasei F19 versus placebo for the prevention of proton pump inhibitor-induced bowel symptoms: a randomized clinical trial.

PubMed

Compare, Debora; Rocco, Alba; Sgamato, Costantino; Coccoli, Pietro; Campo, Salvatore Maria Antonio; Nazionale, Immacolata; Larussa, Tiziana; Luzza, Francesco; Chiodini, Paolo; Nardone, Gerardo

2015-04-01

Proton pump inhibitors may foster intestinal dysbiosis and related bowel symptoms. To evaluate the effect of Lactobacillus paracasei F19 on bowel symptom onset in patients on long-term proton pump inhibitors. In this randomized, double-blind, placebo-controlled study, patients with typical gastroesophageal reflux disease symptoms receiving pantoprazole 40 mg/d for six months were randomly assigned to receive: (A) Lactobacillus paracasei F19 bid for three days/week for six months; (B) placebo bid for three days/week for six months; (C) Lactobacillus paracasei F19 bid for three days/week for three months and placebo bid for three days/week for the following three months; (D) placebo bid for three days/week for three months and Lactobacillus paracasei F19 bid for three days/week for the following three months. Bloating, flatulence, abdominal pain and bowel habit were assessed monthly. 100/312 patients were enrolled. In the parallel groups, the treatment-by-time interaction affected bloating (p = 0.015), while Lactobacillus paracasei F19 treatment alone affected flatulence (p = 0.011). Moreover, the treatment-by-time interaction significantly affected the mean score of bloating (p = 0.01) and flatulence (p < 0.0001), the mean stool form (p = 0.03) and mean stool frequency/week (p = 0.016). Analysis of the cross-over groups, limited to the first three months because of carry-over effect, confirmed these results. Lactobacillus paracasei F19 supplementation prevents bowel symptom onset in patients on long-term proton pump inhibitors. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Proton Pump Inhibitors in Gastroesophageal Reflux Disease: Friend or Foe.

PubMed

Gyawali, C Prakash

2017-09-01

Proton pump inhibitor (PPI) use in gastroesophageal reflux disease (GERD) has been redefined, in light of recent advances highlighting GERD phenotypes that respond to PPIs, and fresh revelations of potential risks of long-term PPI therapy. Erosive esophagitis predicts excellent response to PPI therapy, but non-erosive reflux disease (NERD) with abnormal reflux parameters on ambulatory reflux monitoring also demonstrates a similar response. In contrast, response is suboptimal in the absence of abnormal reflux parameters. In this setting, if an alternate appropriate indication for PPI therapy does not coexist, risks may outweigh benefits of PPI therapy. Adverse events from long-term PPI therapy continue to be reported, most based on association rather than cause-and-effect. Appropriate indications need to be established before embarking on long-term PPI therapy. Future research will define true risks of long-term PPI therapy, and develop alternate management options for acid peptic diseases.

Performance Analysis of a Wind Turbine Driven Swash Plate Pump for Large Scale Offshore Applications

NASA Astrophysics Data System (ADS)

Buhagiar, D.; Sant, T.

2014-12-01

This paper deals with the performance modelling and analysis of offshore wind turbine-driven hydraulic pumps. The concept consists of an open loop hydraulic system with the rotor main shaft directly coupled to a swash plate pump to supply pressurised sea water. A mathematical model is derived to cater for the steady state behaviour of entire system. A simplified model for the pump is implemented together with different control scheme options for regulating the rotor shaft power. A new control scheme is investigated, based on the combined use of hydraulic pressure and pitch control. Using a steady-state analysis, the study shows how the adoption of alternative control schemes in a the wind turbine-hydraulic pump system may result in higher energy yields than those from a conventional system with an electrical generator and standard pitch control for power regulation. This is in particular the case with the new control scheme investigated in this study that is based on the combined use of pressure and rotor blade pitch control.

Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use.

PubMed

Cheng, Hsiu-Chi; Yang, Er-Hsiang; Wu, Chung-Tai; Wang, Wen-Lun; Chen, Po-Jun; Lin, Meng-Ying; Sheu, Bor-Shyang

2018-04-01

Peptic ulcer bleeding remains a deadly disease, and a simple indicator of long-term outcomes is crucial. This study validated whether hypoalbuminemia and its related factors in patients with peptic ulcer bleeding can indicate long-term mortality and rebleeding under proton pump inhibitor use. The prospective cohort study enrolled 426 patients with peptic ulcer bleeding who had high risk stigmata at endoscopy and had received endoscopic hemostasis. They were divided into 79 patients in the hypoalbuminemia group (Hypo-AG, serum albumin <28 g/L), 135 in the marginal hypoalbuminemia group (Margin-AG, serum albumin 28-34.9 g/L), and 212 in the normal albuminemia group (Normal-AG, serum albumin ≥35 g/L). Each subject received 72-h of intravenous infusion and then the oral form of proton pump inhibitors and were monitored for 84 days to assess all-cause mortality and recurrent bleeding. The primary outcome of all-cause mortality rates were increased in a stepwise fashion in a trend from Normal-AG, Margin-AG, to Hypo-AG (0-28th day: 1.9%, 2.2%, 12.8%, p < 0.001; 29th-84th day: 2.5%, 8.0%, 10.6%, p < 0.01). The secondary outcome of recurrent bleeding rates were also increased in the same fashion (0-28th day: 6.4%, 15.4%, 24.6%, p < 0.001; 29th-84th day: 0%, 3.0%, 4.2%, p = 0.01). Abnormal albuminemia was <30 g/L related to hemoglobin levels <70 g/L, nosocomial bleeding, cirrhosis, age ≥70 years, shock, and ulcer size ≥1.0 cm independently (p < 0.05). Hypoalbuminemia in patients with peptic ulcer bleeding can be an alarm indicator of all-cause mortality and recurrent bleeding in a long-term follow-up situation under proton pump inhibitor use (NCT01591083). Copyright © 2017. Published by Elsevier B.V.

Antiplatelet drug interactions with proton pump inhibitors

PubMed Central

Scott, Stuart A; Obeng, Aniwaa Owusu; Hulot, Jean-Sébastien

2014-01-01

Introduction Non-aspirin antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are commonly prescribed for the prevention of recurrent cardiovascular events among patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI). In addition, combination therapy with proton pump inhibitors (PPIs) is often recommended to attenuate gastrointestinal bleeding risk, particularly during dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Importantly, a pharmacological interaction between clopidogrel and some PPIs has been proposed based on mutual CYP450-dependent metabolism, but available evidence is inconsistent. Areas covered This article provides an overview of the currently approved antiplatelet agents and PPIs, including their metabolic pathways. Additionally, the CYP450 isoenzyme at the center of the drug interaction, CYP2C19, is described in detail, and the available evidence on both the potential pharmacological interaction and influence on clinical outcomes are summarized and evaluated. Expert opinion Although concomitant DAPT and PPI use reduces clopidogrel active metabolite levels and ex vivo-measured platelet inhibition, the influence of the drug interaction on clinical outcomes has been conflicting and largely reported from non-randomized observational studies. Despite this inconsistency, a clinically important interaction cannot be definitively excluded, particularly among patient subgroups with higher overall cardiovascular risk and potentially among CYP2C19 loss-of-function allele carriers. PMID:24205916

Transient Resonance Raman Spectroscopy of a Light-Driven Sodium-Ion-Pump Rhodopsin from Indibacter alkaliphilus.

PubMed

Kajimoto, Kousuke; Kikukawa, Takashi; Nakashima, Hiroki; Yamaryo, Haruki; Saito, Yuta; Fujisawa, Tomotsumi; Demura, Makoto; Unno, Masashi

2017-05-04

Sodium-ion-pump rhodopsin (NaR) is a microbial rhodopsin that transports Na + during its photocycle. Here we explore the photocycle mechanism of NaR from Indibacter alkaliphilus with transient absorption and transient resonance Raman spectroscopy. The transient absorption data indicate that the photocycle of NaR is K (545 nm) → L (490 nm)/M (420 nm) → O 1 (590 nm) → O 2 (560 nm) → NaR, where the L and M are formed as equilibrium states. The presence of K, L, M, and O intermediates was confirmed by the resonance Raman spectra with 442 and 532 nm excitation. The main component of the transient resonance Raman spectra was due to L which contains a 13-cis retinal protonated Schiff base. The presence of an enhanced hydrogen out-of-plane band as well as its sensitivity to the H/D exchange indicate that the retinal chromophore is distorted near the Schiff base region in L. Moreover, the retinal Schiff base of the L state forms a hydrogen bond that is stronger than that of the dark state. These observations are consistent with a Na + pumping mechanism that involves a proton transfer from the retinal Schiff base to a key aspartate residue (Asp116 in Krokinobacter eikastus rhodopsin 2) in the L/M states.

[Effects of exogenous spermidine on lipid peroxidation and membrane proton pump activity of cucumber seedling leaves under high temperature stress].

PubMed

Tian, Jing; Guo, Shi-Rong; Sun, Jin; Wang, Li-Ping; Yang, Yan-Juan; Li, Bin

2011-12-01

Taking a relatively heat-resistant cucumber (Cucumis sativus) cultivar 'Jinchun No. 4' as test material, a sand culture experiment was conducted in growth chamber to investigate the effects of foliar spraying spermidine (Spd) on the lipid peroxidation, membrane proton pump activity, and corresponding gene expression of cucumber seedling leaves under high temperature stress. Compared with the control, foliar spraying Spd increased the plant height, stem diameter, dry and fresh mass, and leaf area significantly, and inhibited the increase of leaf relative conductivity, malondialdehyde (MDA) content, and lipoxygenase (LOX) activity effectively. Foliar spraying Spd also helped to the increase of leaf plasma membrane- and tonoplast H(+)-ATPase activity, but no significant difference was observed in the gene expression levels. These results suggested that exogenous Spd could significantly decrease the leaf lipid peroxidation and increase the proton pump activity, and thus, stabilize the leaf membrane structure and function, alleviate the damage induced by high temperature stress, and enhance the heat tolerance of cucumber seedlings.

Practical considerations in the management of proton-pump inhibitors.

PubMed

Aguilera-Castro, Lara; Martín-de-Argila-dePrados, Carlos; Albillos-Martínez, Agustín

2016-03-01

Proton-pump inhibitors (PPIs) are one of the most active ingredients prescribed in Spain. In recent decades there has been an overuse of these drugs in both outpatient clinics and hospitals that has lead to a significant increase in healthcare spending and to an increase in the risk of possible side effects. It is important for health professionals to know the accepted indications and the correct doses for the use of these drugs. On the market there are different types of PPI: omeprazole, pantoprazole, lansoprazole, rabeprazole and esomeprazole. Omeprazole is the oldest and most used PPI, being also the cheapest. Although there are no important differences between PPIs in curing diseases, esomeprazole, a new-generation PPI, has proved to be more effective in eradicating H. pylori and in healing severe esophagitis compared to other PPIs. In recent years the use of generic drugs has spread; these drugs have the same bioavailability than the original drugs. In the case of PPIs, the few comparative studies available in the literature between original and generic drugs have shown no significant differences in clinical efficacy.

Pancreatic bicarbonate secretion involves two proton pumps.

PubMed

Novak, Ivana; Wang, Jing; Henriksen, Katrine L; Haanes, Kristian A; Krabbe, Simon; Nitschke, Roland; Hede, Susanne E

2011-01-07

Pancreas secretes fluid rich in digestive enzymes and bicarbonate. The alkaline secretion is important in buffering of acid chyme entering duodenum and for activation of enzymes. This secretion is formed in pancreatic ducts, and studies to date show that plasma membranes of duct epithelium express H(+)/HCO(3)(-) transporters, which depend on gradients created by the Na(+)/K(+)-ATPase. However, the model cannot fully account for high-bicarbonate concentrations, and other active transporters, i.e. pumps, have not been explored. Here we show that pancreatic ducts express functional gastric and non-gastric H(+)-K(+)-ATPases. We measured intracellular pH and secretion in small ducts isolated from rat pancreas and showed their sensitivity to H(+)-K(+) pump inhibitors and ion substitutions. Gastric and non-gastric H(+)-K(+) pumps were demonstrated on RNA and protein levels, and pumps were localized to the plasma membranes of pancreatic ducts. Quantitative analysis of H(+)/HCO(3)(-) and fluid transport shows that the H(+)-K(+) pumps can contribute to pancreatic secretion in several species. Our results call for revision of the bicarbonate transport physiology in pancreas, and most likely other epithelia. Furthermore, because pancreatic ducts play a central role in several pancreatic diseases, it is of high relevance to understand the role of H(+)-K(+) pumps in pathophysiology.

Linking Chemical Electron–Proton Transfer to Proton Pumping in Cytochrome c Oxidase: Broken-Symmetry DFT Exploration of Intermediates along the Catalytic Reaction Pathway of the Iron–Copper Dinuclear Complex

PubMed Central

2015-01-01

After a summary of the problem of coupling electron and proton transfer to proton pumping in cytochrome c oxidase, we present the results of our earlier and recent density functional theory calculations for the dinuclear Fe-a3–CuB reaction center in this enzyme. A specific catalytic reaction wheel diagram is constructed from the calculations, based on the structures and relative energies of the intermediate states of the reaction cycle. A larger family of tautomers/protonation states is generated compared to our earlier work, and a new lowest-energy pathway is proposed. The entire reaction cycle is calculated for the new smaller model (about 185–190 atoms), and two selected arcs of the wheel are chosen for calculations using a larger model (about 205 atoms). We compare the structural and redox energetics and protonation calculations with available experimental data. The reaction cycle map that we have built is positioned for further improvement and testing against experiment. PMID:24960612

A rapid Fourier transform infrared spectroscopic method for analysis of certain proton pump inhibitors in binary and ternary mixtures

NASA Astrophysics Data System (ADS)

Khashaba, Pakinaz Y.; Ali, Hassan Refat H.; El-Wekil, Mohamed M.

2018-02-01

A simple and non-destructive FTIR method was used to determine certain proton pump inhibitors (PPIs) in binary and ternary mixtures. Proton pump inhibitors (PPIs); omeprazole (OMZ), esomeprazole (EZM), lansoprazole (LAN), pantoprazole sodium (PAN sodium) and rabeprazole sodium (RAB sodium) in binary mixture with domperidone (DOM) and ternary mixture of OMZ, clarithromycin (CLM) and tinidazole (TNZ) were determined in the solid-state by FTIR spectroscopy for the first time. The method was validated according to ICH-guidelines where linearity was ranged from 20 to 850 μg/g and 20-360 μg/g for PPIs and DOM, respectively in binary mixtures and 10-400, 100-8000 and 150-14,000 μg/g for OMZ, CLM and TNZ, respectively. Limits of detection were found to be 6-100 and 9-100 μg/g for PPIs and DOM, respectively and 4, 40 and 50 μg/g for OMZ, CLM and TNZ, respectively. The method was applied successfully for determination of the cited drugs in their respective pharmaceutical dosage forms.

Direct measurement of kilo-tesla level magnetic field generated with laser-driven capacitor-coil target by proton deflectometry

NASA Astrophysics Data System (ADS)

Law, K. F. F.; Bailly-Grandvaux, M.; Morace, A.; Sakata, S.; Matsuo, K.; Kojima, S.; Lee, S.; Vaisseau, X.; Arikawa, Y.; Yogo, A.; Kondo, K.; Zhang, Z.; Bellei, C.; Santos, J. J.; Fujioka, S.; Azechi, H.

2016-02-01

A kilo-tesla level, quasi-static magnetic field (B-field), which is generated with an intense laser-driven capacitor-coil target, was measured by proton deflectometry with a proper plasma shielding. Proton deflectometry is a direct and reliable method to diagnose strong, mm3-scale laser-produced B-field; however, this was not successful in the previous experiment. A target-normal-sheath-accelerated proton beam is deflected by Lorentz force in the laser-produced magnetic field with the resulting deflection pattern recorded on a radiochromic film stack. A 610 ± 30 T of B-field amplitude was inferred by comparing the experimental proton pattern with Monte-Carlo calculations. The amplitude and temporal evolutions of the laser-generated B-field were also measured by a differential magnetic probe, independently confirming the proton deflectometry measurement results.

Evidence-based assessment of proton-pump inhibitors in Helicobacter pylori eradication: a systematic review.

PubMed

Nagaraja, Vinayak; Eslick, Guy D

2014-10-28

Peptic ulcer disease continues to be issue especially due to its high prevalence in the developing world. Helicobacter pylori (H. pylori) infection associated duodenal ulcers should undergo eradication therapy. There are many regimens offered for H. pylori eradication which include triple, quadruple, or sequential therapy regimens. The central aim of this systematic review is to evaluate the evidence for H. pylori therapy from a meta-analytical outlook. The consequence of the dose, type of proton-pump inhibitor, and the length of the treatment will be debated. The most important risk factor for eradication failure is resistance to clarithromycin and metronidazole.

ATP4A gene regulatory network for fine-tuning of proton pump and ion channels.

PubMed

Singh, Vijai; Mani, Indra; Chaudhary, Dharmendra Kumar

2013-06-01

The ATP4A encodes α subunit of H(+), K(+)-ATPase that contains catalytic sites of the enzyme forming pores through cell membrane which allows the ion transport. H(+), K(+)-ATPase is a membrane bound P-type ATPase enzyme which is found on the surface of parietal cells and uses the energy derived from each cycle of ATP hydrolysis that can help in exchanging ions (H(+), K(+) and Cl(-)) across the cell membrane secreting acid into the gastric lumen. The 3-D model of α-subunit of H(+), K(+)-ATPase was generated by homology modeling. It was evaluated and validated on the basis of free energies and amino acid residues. The inhibitor binding amino acid active pockets were identified in the 3-D model by molecular docking. The two drugs Omeprazole and Rabeprazole were found more potent interactions with generated model of α-subunit of H(+), K(+)-ATPase on the basis of their affinity between drug-protein interactions. We have generated ATP4A gene regulatory networks for interactions with other proteins which involved in regulation that can help in fine-tuning of proton pump and ion channels. These findings provide a new dimension for discovery and development of proton pump inhibitors and gene regulation of the ATPase. It can be helpful in better understanding of human physiology and also using synthetic biology strategy for reprogramming of parietal cells for control of gastric ulcers.

Repositioning of proton pump inhibitors in cancer therapy.

PubMed

Lu, Zhen-Ning; Tian, Bing; Guo, Xiu-Li

2017-11-01

Drug repositioning, as a smart way to exploit new molecular targets of a known drug, has been gaining increasing attention in the discovery of anti-cancer drugs. Proton pump inhibitors (PPIs) as benzimidazole derivatives, which are essentially H + -K + -ATPases inhibitors, are commonly used in the treatment of acid-related diseases such as gastric ulcer. In recent years, exploring the new application of PPIs in anti-cancer field has become a hot research topic. Interestingly, cancer cells display an alkaline intracellular pH and an acidic extracellular pH. The extracellular acidity of tumors can be corrected by PPIs that are selectively activated in an acid milieu. It is generally believed that PPIs might provoke disruption of pH homeostasis by targeting V-ATPase on cancer cells, which is the theoretical basis for PPIs to play an anti-cancer role. Numerous studies have shown specialized effects of the PPIs on tumor cell growth, metastasis, chemoresistance, and autophagy. PPIs may really represent new anti-cancer drugs due to better safety and tolerance, the potential selectivity in targeting tumor acidity, and the ability to inhibit mechanism pivotal for cancer homeostasis. In this review, we focus on the new therapeutic applications of PPIs in multiple cancers, explaining the rationale behind this approach and providing practical evidence.

Association between proton pump inhibitors and hepatic encephalopathy

PubMed Central

Bian, Jin; Wang, Anqiang; Lin, Jianzhen; Wu, Liangcai; Huang, Hanchun; Wang, Shanshan; Yang, Xiaobo; Lu, Xin; Xu, Yiyao; Zhao, Haitao

2017-01-01

Abstract Background & aims: Several studies have shown that proton pump inhibitors (PPIs) use can increase the risk of developing hepatic encephalopathy (HE) in patients with liver dysfunction. However, no definite conclusion is drawn because of study design limitations. Therefore, we conducted a meta-analysis to explore the association between PPIs and HE. Methods: We searched PubMed, EMBASE, and the Cochrane Library from inception until November 2016. Data from the identified studies were combined using a random effects model, and odds ratios (ORs) were calculated. Results: Three case-control studies were included. Compared with nonusers, hepatic insufficiency patients receiving PPIs therapy had a significantly increased risk of developing HE (OR = 1.76, 95% CI: 1.15–2.69), with notable heterogeneity (I2 = 61.4%, P = .075) and publication bias. No relevance was found between PPIs and HE after using the trim and fill method (OR = 1.360, 95%CI: 0.909–2.035, P = .135). Conclusions: PPIs are associated with a higher risk of HE among patients with chronic and acute liver dysfunction. A final conclusion cannot be drawn because of the limited number of studies and a lack of prospective studies. PMID:28445288

Self-generated surface magnetic fields inhibit laser-driven sheath acceleration of high-energy protons.

PubMed

Nakatsutsumi, M; Sentoku, Y; Korzhimanov, A; Chen, S N; Buffechoux, S; Kon, A; Atherton, B; Audebert, P; Geissel, M; Hurd, L; Kimmel, M; Rambo, P; Schollmeier, M; Schwarz, J; Starodubtsev, M; Gremillet, L; Kodama, R; Fuchs, J

2018-01-18

High-intensity lasers interacting with solid foils produce copious numbers of relativistic electrons, which in turn create strong sheath electric fields around the target. The proton beams accelerated in such fields have remarkable properties, enabling ultrafast radiography of plasma phenomena or isochoric heating of dense materials. In view of longer-term multidisciplinary purposes (e.g., spallation neutron sources or cancer therapy), the current challenge is to achieve proton energies well in excess of 100 MeV, which is commonly thought to be possible by raising the on-target laser intensity. Here we present experimental and numerical results demonstrating that magnetostatic fields self-generated on the target surface may pose a fundamental limit to sheath-driven ion acceleration for high enough laser intensities. Those fields can be strong enough (~10 5  T at laser intensities ~10 21  W cm -2 ) to magnetize the sheath electrons and deflect protons off the accelerating region, hence degrading the maximum energy the latter can acquire.

Self-generated surface magnetic fields inhibit laser-driven sheath acceleration of high-energy protons

DOE PAGES

Nakatsutsumi, M.; Sentoku, Y.; Korzhimanov, A.; ...

2018-01-18

High-intensity lasers interacting with solid foils produce copious numbers of relativistic electrons, which in turn create strong sheath electric fields around the target. The proton beams accelerated in such fields have remarkable properties, enabling ultrafast radiography of plasma phenomena or isochoric heating of dense materials. In view of longer-term multidisciplinary purposes (e.g., spallation neutron sources or cancer therapy), the current challenge is to achieve proton energies well in excess of 100 MeV, which is commonly thought to be possible by raising the on-target laser intensity. Here we present experimental and numerical results demonstrating that magnetostatic fields self-generated on the targetmore » surface may pose a fundamental limit to sheath-driven ion acceleration for high enough laser intensities. Those fields can be strong enough (~10 5 T at laser intensities ~10 21 W cm –2) to magnetize the sheath electrons and deflect protons off the accelerating region, hence degrading the maximum energy the latter can acquire.« less

Self-generated surface magnetic fields inhibit laser-driven sheath acceleration of high-energy protons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakatsutsumi, M.; Sentoku, Y.; Korzhimanov, A.

High-intensity lasers interacting with solid foils produce copious numbers of relativistic electrons, which in turn create strong sheath electric fields around the target. The proton beams accelerated in such fields have remarkable properties, enabling ultrafast radiography of plasma phenomena or isochoric heating of dense materials. In view of longer-term multidisciplinary purposes (e.g., spallation neutron sources or cancer therapy), the current challenge is to achieve proton energies well in excess of 100 MeV, which is commonly thought to be possible by raising the on-target laser intensity. Here we present experimental and numerical results demonstrating that magnetostatic fields self-generated on the targetmore » surface may pose a fundamental limit to sheath-driven ion acceleration for high enough laser intensities. Those fields can be strong enough (~10 5 T at laser intensities ~10 21 W cm –2) to magnetize the sheath electrons and deflect protons off the accelerating region, hence degrading the maximum energy the latter can acquire.« less

Optical silencing of body wall muscles induces pumping inhibition in Caenorhabditis elegans

PubMed Central

Takahashi, Megumi

2017-01-01

Feeding, a vital behavior in animals, is modulated depending on internal and external factors. In the nematode Caenorhabditis elegans, the feeding organ called the pharynx ingests food by pumping driven by the pharyngeal muscles. Here we report that optical silencing of the body wall muscles, which drive the locomotory movement of worms, affects pumping. In worms expressing the Arch proton pump or the ACR2 anion channel in the body wall muscle cells, the pumping rate decreases after activation of Arch or ACR2 with light illumination, and recovers gradually after terminating illumination. Pumping was similarly inhibited by illumination in locomotion-defective mutants carrying Arch, suggesting that perturbation of locomotory movement is not critical for pumping inhibition. Analysis of mutants and cell ablation experiments showed that the signals mediating the pumping inhibition response triggered by activation of Arch with weak light are transferred mainly through two pathways: one involving gap junction-dependent mechanisms through pharyngeal I1 neurons, which mediate fast signals, and the other involving dense-core vesicle-dependent mechanisms, which mediate slow signals. Activation of Arch with strong light inhibited pumping strongly in a manner that does not rely on either gap junction-dependent or dense-core vesicle-dependent mechanisms. Our study revealed a new aspect of the neural and neuroendocrine controls of pumping initiated from the body wall muscles. PMID:29281635

FTIR spectroscopic study on individual amino acid residues in the proton pumping process of bacteriorhodopsin

NASA Astrophysics Data System (ADS)

Liu, Xiaomei

1998-05-01

My thesis project has concentrated on clarifying the role of individual amino acids such as tyrosine, arginine and threonine in the active proton transferring process of Bacteriorhodopsin(bR). BR is a protein found in the purple membrane of Halobacteria salinarium. The main function of bR is to transfer a proton from the interior side of the cell to the external medium upon illumination by visible light. BR belongs to a family of retinal- containing membrane proteins which includes rhodopsin, a visual receptor found in the eye, and sensory rhodopsin I, a light receptor for phototaxis found in H. salinarium. Complete understanding of the proton transferring mechanism of bR can help explain the energy transduction and active ion transport in biological systems. This information also provides insight into other members of the retinal-containing protein family. To study the behavior of a single amino acid in a protein which consists of 248 amino acids, I employed the Fourier transform infrared (FTIR) difference spectroscopy technique. This was combined with the recently developed genetic engineering method of site directed isotope labeling (SDIL). As complementary work, I also characterized the vibrational properties of individual amino acids in various environments. Because of the high resolution and sensitivity of FTIR difference spectroscopy, along with the ability of SDIL to detect structural changes at the single amino acid level, we are able to determine changes in the structure of specific amino acids at different steps in bR photocycle. My research results provide strong evidence for a proton pump model. This model predicts the participation of tyrosine 185 and one or more threonines in a hydrogen bonded chain which can transfer proton across the membrane. My data also suggest a more accurate model for the proton release step which involves arginine 82.

Exergy analysis of electrically- and thermally-driven engines to drive heat pumps: An exhaustive comparative study

DOE PAGES

Ally, Moonis R.; Sharma, Vishaldeep; Abdelaziz, Omar

2017-02-21

The choice of driving a heat pump with an electrically$-$or a thermally-driven engine is a vexing question complicated by the carbon footprint and environmental impact of using electricity versus natural gas (or waste heat) as the main driver for the respective engines. The amount of useful work generated by these two distinct engines is the focal point of this paper, which addresses a key question: which engine presents a better choice for a given heat pumping application within the constraints of energy and environmental stewardship? Extensive use of energy, exergy, and availability analysis is necessary to quantify the useful workmore » and to examine the issue holistically for both types of engines. The methodology explains why the output of work from these two distinct engines to satisfy a given load is vastly different, a direct consequence of their inherent Irreversibility. Thermodynamic consistency is guaranteed by satisfaction of the First and Second Laws applied to closed systems and their subsystems. The general conclusion is that thermally-driven engines are not industrious converters of heat to mechanical work.« less

Exergy analysis of electrically- and thermally-driven engines to drive heat pumps: An exhaustive comparative study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ally, Moonis R.; Sharma, Vishaldeep; Abdelaziz, Omar

The choice of driving a heat pump with an electrically$-$or a thermally-driven engine is a vexing question complicated by the carbon footprint and environmental impact of using electricity versus natural gas (or waste heat) as the main driver for the respective engines. The amount of useful work generated by these two distinct engines is the focal point of this paper, which addresses a key question: which engine presents a better choice for a given heat pumping application within the constraints of energy and environmental stewardship? Extensive use of energy, exergy, and availability analysis is necessary to quantify the useful workmore » and to examine the issue holistically for both types of engines. The methodology explains why the output of work from these two distinct engines to satisfy a given load is vastly different, a direct consequence of their inherent Irreversibility. Thermodynamic consistency is guaranteed by satisfaction of the First and Second Laws applied to closed systems and their subsystems. The general conclusion is that thermally-driven engines are not industrious converters of heat to mechanical work.« less

Proton pump inhibitors for functional dyspepsia.

PubMed

Pinto-Sanchez, Maria Ines; Yuan, Yuhong; Bercik, Premysl; Moayyedi, Paul

2017-03-08

Functional dyspepsia (FD or non-ulcer dyspepsia) is defined as continuous or frequently recurring epigastric pain or discomfort for which no organic cause can be found. Acid suppressive therapy, including proton pump inhibitors (PPIs), has been proposed as a therapeutic option in FD, but its efficacy remains controversial. While PPIs are generally considered safe and well tolerated, they have been associated with adverse events, especially in the long term. For this reason, decisions on whether to initiate or continue PPI therapy should be made based on an appropriate clinical indication. Therefore, we conducted a systematic review to evaluate whether PPI therapy provides symptomatic relief in FD. To determine the efficacy of proton pump inhibitors in the improvement of global symptoms of dyspepsia and quality of life compared to placebo, H2 receptor antagonists or prokinetics, in people with functional dyspepsia. We searched in the following electronic databases: the Cochrane Library (to January 2016), MEDLINE (OvidSP; to February 2016), Embase (OvidSP; to February 2016), and SIGLE grey literature (up to February 2016) and clinical trial registries; we handsearched abstracts from conferences up to February 2016. We screened non-systematic reviews, systematic reviews and guidelines to identify any additional trials. We contacted trialists to obtain missing information. All randomized controlled trials (RCTs) comparing any PPI with placebo, H2 receptor antagonists (H2RAs) or prokinetics for the treatment of FD. Participants were adults (aged 16 years or greater) with an adequate diagnosis of FD (any validated criteria such as Rome I, II, III or Lancet Working Group). Two review authors independently assessed eligibility, trial quality and extracted data. We collected data on dyspeptic symptoms, quality of life and number of overall adverse events. Specific adverse events were beyond the scope of this review. We identified 23 RCTs from 22 papers (with 8759

Evaluation of potential interactions between mycophenolic acid derivatives and proton pump inhibitors.

PubMed

Gabardi, Steven; Olyaei, Ali

2012-01-01

To evaluate the incidence of gastrointestinal (GI) complications in solid organ transplant (SOT) recipients, impact of the complications on transplant outcomes, and the potential interactions between mycophenolic acid (MPA) derivatives and proton pump inhibitors (PPIs). An unrestricted literature search (1980-January 2012) was performed with MEDLINE and EMBASE using the following key words: drug-drug interaction, enteric-coated mycophenolic acid, GI complications, mycophenolate mofetil, solid organ transplant, and proton pump inhibitor, including individual agents within the class. Abstracts from scientific meetings were also evaluated. Additionally, reference citations from identified publications were reviewed. Relevant English-language, original research articles and review articles were evaluated if they focused on any of the topics identified in the search or included substantial content addressing GI complications in SOT recipients or drug interactions. GI complications are frequent among SOT recipients, with some studies showing prevalence rates as high as 70%. Transplant outcomes among renal transplant recipients are significantly impacted by GI complications, especially in patients requiring immunosuppressant dosage reductions or premature discontinuation. To this end, PPI use among patients receiving transplants is common. Recent data demonstrate that PPIs significantly reduce the overall exposure to MPA after oral administration of mycophenolate mofetil. Similar studies show this interaction does not exist between PPIs and enteric-coated mycophenolic acid (EC-MPA). Unfortunately, most of the available data evaluating this interaction are pharmacokinetic analyses that do not investigate the clinical impact of this interaction. A significant interaction exists between PPIs and mycophenolate mofetil secondary to reduced dissolution of mycophenolate mofetil in higher pH environments. EC-MPA is not absorbed in the stomach; therefore, low intragastric acidity

PROTON HEATING BY PICK-UP ION DRIVEN CYCLOTRON WAVES IN THE OUTER HELIOSPHERE: HYBRID EXPANDING BOX SIMULATIONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hellinger, Petr; Trávníček, Pavel M., E-mail: petr.hellinger@asu.cas.cz

Using a one-dimensional hybrid expanding box model, we investigate properties of the solar wind in the outer heliosphere. We assume a proton–electron plasma with a strictly transverse ambient magnetic field and, aside from the expansion, we take into account the influence of a continuous injection of cold pick-up protons through the charge-exchange process between the solar wind protons and hydrogen of interstellar origin. The injected cold pick-up protons form a ring distribution function, which rapidly becomes unstable, and generate Alfvén cyclotron waves. The Alfvén cyclotron waves scatter pick-up protons to a spherical shell distribution function that thickens over that timemore » owing to the expansion-driven cooling. The Alfvén cyclotron waves heat solar wind protons in the perpendicular direction (with respect to the ambient magnetic field) through cyclotron resonance. At later times, the Alfvén cyclotron waves become parametrically unstable and the generated ion-acoustic waves heat protons in the parallel direction through Landau resonance. The resulting heating of the solar wind protons is efficient on the expansion timescale.« less

Proton pump inhibitor medication is associated with colonisation of gut flora in the oropharynx.

PubMed

Tranberg, A; Thorarinsdottir, H R; Holmberg, A; Schött, U; Klarin, B

2018-03-08

The normal body exists in mutualistic balance with a large range of microbiota. The primary goal of this study was to establish whether there is an imbalance in the oropharyngeal flora early after hospital or ICU admittance, and whether flora differs between control, ward and critically ill patients. The secondary goal was to explore whether there are patient characteristics that can be associated with a disturbed oropharyngeal flora. Oropharyngeal cultures were obtained from three different study groups: (1) controls from the community, (2) ward patients and (3) critically ill patients, the two latter within 24 h after admittance. Cultures were obtained from 487 individuals: 77 controls, 193 ward patients and 217 critically ill patients. Abnormal pharyngeal flora was more frequent in critically ill and ward patients compared with controls (62.2% and 10.4% vs. 1.3%, P < 0.001 and P = 0.010, respectively). Colonisation of gut flora in the oropharynx was more frequent in critically ill patients compared with ward patients or controls (26.3% vs. 4.7% and 1.3%, P < 0.001 and P < 0.001, respectively). Proton pump inhibitor medication was the strongest independent factor associated with the presence of gut flora in the oropharynx in both ward and critically ill patients (P = 0.030 and P = 0.044, respectively). This study indicates that abnormal oropharyngeal flora is an early and frequent event in hospitalised patients and more so in the critically ill, compared to controls. Proton pump inhibitor medication is associated with colonisation of gut flora in the oropharynx. © 2018 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Simulation of Solar Heat Pump Dryer Directly Driven by Photovoltaic Panels

NASA Astrophysics Data System (ADS)

Houhou, H.; Yuan, W.; Wang, G.

2017-05-01

This paper investigates a new type of solar heat pump dryer directly driven by photovoltaic panels. In order to design this system, a mathematical model has been established describing the whole drying process, including models of key components and phenomena of heat and mass transfer at the product layer and the air. The results of simulation at different drying air temperatures and velocities have been calculated and it indicate that the temperature of drying air is crucial external parameter compared to the velocity, with the increase of drying temperature from 45°C to 55°C, the product moisture content (Kg water/Kg dry product) decreased from 0.75 Kg/Kg to 0.3 Kg/Kg.

Voltage-Driven Magnetization Switching and Spin Pumping in Weyl Semimetals

NASA Astrophysics Data System (ADS)

Kurebayashi, Daichi; Nomura, Kentaro

2016-10-01

We demonstrate electrical magnetization switching and spin pumping in magnetically doped Weyl semimetals. The Weyl semimetal is a three-dimensional gapless topological material, known to have nontrivial coupling between the charge and the magnetization due to the chiral anomaly. By solving the Landau-Lifshitz-Gilbert equation for a multilayer structure of a Weyl semimetal, an insulator and a metal while taking the charge-magnetization coupling into account, magnetization dynamics is analyzed. It is shown that the magnetization dynamics can be driven by the electric voltage. Consequently, switching of the magnetization with a pulsed electric voltage can be achieved, as well as precession motion with an applied oscillating electric voltage. The effect requires only a short voltage pulse and may therefore be energetically favorable for us in spintronics devices compared to conventional spin-transfer torque switching.

Generation of quasi-monoenergetic protons from a double-species target driven by the radiation pressure of an ultraintense laser pulse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pae, Ki Hong; Kim, Chul Min, E-mail: chulmin@gist.ac.kr; Advanced Photonics Research Institute, Gwangju Institute of Science and Technology, Gwangju 61005

In laser-driven proton acceleration, generation of quasi-monoenergetic proton beams has been considered a crucial feature of the radiation pressure acceleration (RPA) scheme, but the required difficult physical conditions have hampered its experimental realization. As a method to generate quasi-monoenergetic protons under experimentally viable conditions, we investigated using double-species targets of controlled composition ratio in order to make protons bunched in the phase space in the RPA scheme. From a modified optimum condition and three-dimensional particle-in-cell simulations, we showed by varying the ion composition ratio of proton and carbon that quasi-monoenergetic protons could be generated from ultrathin plane targets irradiated withmore » a circularly polarized Gaussian laser pulse. The proposed scheme should facilitate the experimental realization of ultrashort quasi-monoenergetic proton beams for unique applications in high field science.« less

The selectivity of the Na+/K+-pump is controlled by binding site protonation and self-correcting occlusion

PubMed Central

Rui, Huan; Artigas, Pablo; Roux, Benoît

2016-01-01

The Na+/K+-pump maintains the physiological K+ and Na+ electrochemical gradients across the cell membrane. It operates via an 'alternating-access' mechanism, making iterative transitions between inward-facing (E1) and outward-facing (E2) conformations. Although the general features of the transport cycle are known, the detailed physicochemical factors governing the binding site selectivity remain mysterious. Free energy molecular dynamics simulations show that the ion binding sites switch their binding specificity in E1 and E2. This is accompanied by small structural arrangements and changes in protonation states of the coordinating residues. Additional computations on structural models of the intermediate states along the conformational transition pathway reveal that the free energy barrier toward the occlusion step is considerably increased when the wrong type of ion is loaded into the binding pocket, prohibiting the pump cycle from proceeding forward. This self-correcting mechanism strengthens the overall transport selectivity and protects the stoichiometry of the pump cycle. DOI: http://dx.doi.org/10.7554/eLife.16616.001 PMID:27490484

Reaction pathways of photoexcited retinal in proteorhodopsin studied by pump-dump-probe spectroscopy.

PubMed

Rupenyan, Alisa; van Stokkum, Ivo H M; Arents, Jos C; van Grondelle, Rienk; Hellingwerf, Klaas J; Groot, Marie Louise

2009-12-17

Proteorhodopsin (pR) is a membrane-embedded proton pump from the microbial rhodopsin family. Light absorption by its retinal chromophore initiates a photocycle, driven by trans/cis isomerization on the femtosecond to picosecond time scales. Here, we report a study on the photoisomerization dynamics of the retinal chromophore of pR, using dispersed ultrafast pump-dump-probe spectroscopy. The application of a pump pulse initiates the photocycle, and with an appropriately tuned dump pulse applied at a time delay after the dump, the molecules in the initial stages of the photochemical process can be de-excited and driven back to the ground state. In this way, we were able to resolve an intermediate on the electronic ground state that represents chromophores that are unsuccessful in isomerization. In particular, the fractions of molecules that undergo slow isomerization (20 ps) have a high probability to enter this state rather than the isomerized K-state. On the ground state reaction surface, return to the stable ground state conformation via a structural or vibrational relaxation occurs in 2-3 ps. Inclusion of this intermediate in the kinetic scheme led to more consistent spectra of the retinal-excited state, and to a more accurate estimation of the quantum yield of isomerization (Phi = 0.4 at pH 6).

Patient acceptability and experiences of therapeutic switching of proton pump inhibitors within the National Preferred Drugs initiative in Ireland.

PubMed

O'Connor, G; O'Keeffe, D; Darker, C; O'Shea, B

2017-08-01

A 'Preferred Drugs' initiative was introduced into Ireland in 2013. This identified a single recommended drug to be prescribed to patients requiring treatment from a particular class of drugs. This study investigates how patients on established proton pump inhibitor (PPI) therapy experienced the therapeutic switching of their medication to the 'preferred drug', and the extent to which they regarded it as an acceptable practice. The experiences of 61 patients on established proton pump inhibitor (PPI) therapy were sought before and after their drug was switched to the 'preferred drug'. Eighty per cent of patients were happy to switch medications. When asked for their opinions on medications in general, 71% felt doctors should prescribe the least expensive medication, 84% agreed that all licensed medications were safe while 67% felt their GP changing medication for cost reasons was safe. After 8 weeks, 20% of patients had switched back to their old PPI. When asked how they felt about their medication change, 74% felt happy or pleased. The majority of patients in our study were satisfied to have their medication switched. However, prescribers should be mindful that 1 in 5 patients encountered problems as a result of the switching process.

TOR complex 1 regulates the yeast plasma membrane proton pump and pH and potassium homeostasis.

PubMed

Mahmoud, Shima; Planes, María Dolores; Cabedo, Marc; Trujillo, Cristina; Rienzo, Alessandro; Caballero-Molada, Marcos; Sharma, Sukesh C; Montesinos, Consuelo; Mulet, José Miguel; Serrano, Ramón

2017-07-01

We have identified in yeast a connection between two master regulators of cell growth: a biochemical connection involving the TORC1 protein kinase (which activates protein synthesis, nutrient uptake, and anabolism) and a biophysical connection involving the plasma membrane proton-pumping H + -ATPase Pma1 (which drives nutrient and K + uptake and regulates pH homeostasis). Raising the temperature to nonpermissive values in a TOR thermosensitive mutant decreases Pma1 activity. Rapamycin, a TORC1 inhibitor, inhibits Pma1 dependent on its receptor Fpr1 and on the protein phosphatase Sit4, a TORC1 effector. Mutation of either Sit4 or Tco89, a nonessential subunit of TORC1, decreases proton efflux, K + uptake, intracellular pH, cell growth, and tolerance to weak organic acids. Tco89 does not affect Pma1 activity but activates K + transport. © 2017 Federation of European Biochemical Societies.

Formation of M-Like Intermediates in Proteorhodopsin in Alkali Solutions (pH ≥ ∼8.5) Where the Proton Release Occurs First in Contrast to the Sequence at Lower pH.

PubMed

Tamogami, Jun; Sato, Keitaro; Kurokawa, Sukuna; Yamada, Takumi; Nara, Toshifumi; Demura, Makoto; Miyauchi, Seiji; Kikukawa, Takashi; Muneyuki, Eiro; Kamo, Naoki

2016-02-23

Proteorhodopsin (PR) is an outward light-driven proton pump observed in marine eubacteria. Despite many structural and functional similarities to bacteriorhodopsin (BR) in archaea, which also acts as an outward proton pump, the mechanism of the photoinduced proton release and uptake is different between two H(+)-pumps. In this study, we investigated the pH dependence of the photocycle and proton transfer in PR reconstituted with the phospholipid membrane under alkaline conditions. Under these conditions, as the medium pH increased, a blue-shifted photoproduct (defined as Ma), which is different from M, with a pKa of ca. 9.2 was produced. The sequence of the photoinduced proton uptake and release during the photocycle was inverted with the increase in pH. A pKa value of ca. 9.5 was estimated for this inversion and was in good agreement with the pKa value of the formation of Ma (∼ 9.2). In addition, we measured the photoelectric current generated by PRs attached to a thin polymer film at varying pH. Interestingly, increases in the medium pH evoked bidirectional photocurrents, which may imply a possible reversal of the direction of the proton movement at alkaline pH. On the basis of these findings, a putative photocycle and proton transfer scheme in PR under alkaline pH conditions was proposed.

Squeezing at Entrance of Proton Transport Pathway in Proton-translocating Pyrophosphatase upon Substrate Binding*

PubMed Central

Huang, Yun-Tzu; Liu, Tseng-Huang; Lin, Shih-Ming; Chen, Yen-Wei; Pan, Yih-Jiuan; Lee, Ching-Hung; Sun, Yuh-Ju; Tseng, Fan-Gang; Pan, Rong-Long

2013-01-01

Homodimeric proton-translocating pyrophosphatase (H+-PPase; EC 3.6.1.1) is indispensable for many organisms in maintaining organellar pH homeostasis. This unique proton pump couples the hydrolysis of PPi to proton translocation across the membrane. H+-PPase consists of 14–16 relatively hydrophobic transmembrane domains presumably for proton translocation and hydrophilic loops primarily embedding a catalytic site. Several highly conserved polar residues located at or near the entrance of the transport pathway in H+-PPase are essential for proton pumping activity. In this investigation single molecule FRET was employed to dissect the action at the pathway entrance in homodimeric Clostridium tetani H+-PPase upon ligand binding. The presence of the substrate analog, imidodiphosphate mediated two sites at the pathway entrance moving toward each other. Moreover, single molecule FRET analyses after the mutation at the first proton-carrying residue (Arg-169) demonstrated that conformational changes at the entrance are conceivably essential for the initial step of H+-PPase proton translocation. A working model is accordingly proposed to illustrate the squeeze at the entrance of the transport pathway in H+-PPase upon substrate binding. PMID:23720778

Flushing of a polluted lagoon in Canc'un, using a SIBEO wave-driven seawater pump

NASA Astrophysics Data System (ADS)

Czitrom, Steven; Carbajal, Noel

2006-11-01

The coastal lagoon which adorns the seaside resort at Canc'un, Mexico, is heavily polluted as a result of decades of intense tourist activity development and overwhelmed inadequate planning. The natural flushing time of the lagoon, estimated at 2 to 4 years, is insufficient to cope with the waste that is being dumped and a thick layer of organic matter has accumulated on the lagoon bed. Appropriate legal and sewage treatment measures are imperative to curb further dumping and thus attack the root cause of the problem. This aside, however, the existing situation requires additional technical solutions to restore the ecosystem to a less altered state. A wave and tide driven seawater pump, invented and developed at the National University of Mexico, has been proposed to flush the lagoon with an average 0.2 m^3/s of clean and oxygen rich seawater from the neighboring ocean. This flow would reduce the residence time of the lagoon to around 6 months, promoting long term recovery of the ecosystem. The effect and distribution of the pumped water is being studied using a wind and tide driven 3D numerical model of the lagoon hydrodynamics. Some results from this study are presented here.

The Proton Pump Inhibitor Nonresponder: a Behavioral Approach to Improvement and Wellness.

PubMed

Riehl, Megan E; Chen, Joan W

2018-06-09

Gastroesophageal reflux disease (GERD) is a difficult to treat medical condition, where nearly 40% of patients are refractory to standard medical intervention, which typically begins with a proton pump inhibitor (PPI). These PPI nonresponders represent a population of patients, where treatment planning must be individualized; multidisciplinary and psychiatric comorbidities should be considered. This review highlights treatment options that include neuromodulators, lifestyle, and psychological interventions for the PPI nonresponder. Mental health specialists in the field of psychogastroenterology can aid in the management of esophageal hypersensitivity, which can drive the symptom experience of a PPI nonresponder. Considerations for comorbid anxiety and depression in this population require careful assessment and treatment. Physicians are encouraged to create realistic expectations for symptom management and offer multidisciplinary options for treatment early in care. Patients will frequently benefit from working with a GI psychologist and find value in behavioral interventions.

Characterization of the ELIMED Permanent Magnets Quadrupole system prototype with laser-driven proton beams

NASA Astrophysics Data System (ADS)

Schillaci, F.; Pommarel, L.; Romano, F.; Cuttone, G.; Costa, M.; Giove, D.; Maggiore, M.; Russo, A. D.; Scuderi, V.; Malka, V.; Vauzour, B.; Flacco, A.; Cirrone, G. A. P.

2016-07-01

Laser-based accelerators are gaining interest in recent years as an alternative to conventional machines [1]. In the actual ion acceleration scheme, energy and angular spread of the laser-driven beams are the main limiting factors for beam applications and different solutions for dedicated beam-transport lines have been proposed [2,3]. In this context a system of Permanent Magnet Quadrupoles (PMQs) has been realized [2] by INFN-LNS (Laboratori Nazionali del Sud of the Instituto Nazionale di Fisica Nucleare) researchers, in collaboration with SIGMAPHI company in France, to be used as a collection and pre-selection system for laser driven proton beams. This system is meant to be a prototype to a more performing one [3] to be installed at ELI-Beamlines for the collection of ions. The final system is designed for protons and carbons up to 60 MeV/u. In order to validate the design and the performances of this large bore, compact, high gradient magnetic system prototype an experimental campaign have been carried out, in collaboration with the group of the SAPHIR experimental facility at LOA (Laboratoire d'Optique Appliquée) in Paris using a 200 TW Ti:Sapphire laser system. During this campaign a deep study of the quadrupole system optics has been performed, comparing the results with the simulation codes used to determine the setup of the PMQ system and to track protons with realistic TNSA-like divergence and spectrum. Experimental and simulation results are good agreement, demonstrating the possibility to have a good control on the magnet optics. The procedure used during the experimental campaign and the most relevant results are reported here.

Control of a rotary pulsatile cardiac assist pump driven by an electric motor without a pressure sensor to avoid collapse of the pump inlet.

PubMed

Trinkl, J; Havlik, P; Mesana, T; Mitsui, N; Morita, S; Demunck, J L; Tourres, J L; Monties, J R

1993-01-01

Our ventricular assist device uses a valveless volumetric pump operating on the Maillard-Wankel rotary principle. It is driven by an electric motor and provides a semi pulsatile flow. At each cycle, blood is actively aspirated into the device, and overpumping results in collapse at the pump inlet. To prevent overpumping, it is necessary to ensure that pump intake does not exceed venous return. Poor long-term reliability rules out the use of current implantable pressure sensors for this purpose. To resolve this problem, we have developed a method of control based on monitoring of the intensity of electric current consumed by the motor. The method consists of real time monitoring of current intensity at the beginning of each pump cycle. A sudden change in intensity indicates underfilling, and motor speed is reduced to prevent collapse. The current consumed by the motor also depends on the afterload, but the form of the signal remains the same when afterload changes. After demonstrating the feasibility of this technique in a simulator, we are now testing it in animals. We were able to detect and prevent collapse due to overpumping by the cardiac assist device. This system also enables us to know the maximum possible assistance and to thus adapt assistance to the user.

Status of intense permanent magnet proton source for China-accelerator driven sub-critical system Linac.

PubMed

Wu, Q; Ma, H Y; Yang, Y; Sun, L T; Zhang, X Z; Zhang, Z M; Zhao, H Y; He, Y; Zhao, H W

2016-02-01

Two compact intense 2.45 GHz permanent magnet proton sources and their corresponding low energy beam transport (LEBT) system were developed successfully for China accelerator driven sub-critical system in 2014. Both the proton sources operate at 35 kV potential. The beams extracted from the ion source are transported by the LEBT, which is composed of two identical solenoids, to the 2.1 MeV Radio-Frequency Quadrupole (RFQ). In order to ensure the safety of the superconducting cavities during commissioning, an electrostatic-chopper has been designed and installed in the LEBT line that can chop the continuous wave beam into a pulsed one. The minimum width of the pulse is less than 10 μs and the fall/rise time of the chopper is about 20 ns. The performance of the proton source and the LEBT, such as beam current, beam profile, emittance and the impact to RFQ injection will be presented.

Status of intense permanent magnet proton source for China-accelerator driven sub-critical system Linac

NASA Astrophysics Data System (ADS)

Wu, Q.; Ma, H. Y.; Yang, Y.; Sun, L. T.; Zhang, X. Z.; Zhang, Z. M.; Zhao, H. Y.; He, Y.; Zhao, H. W.

2016-02-01

Two compact intense 2.45 GHz permanent magnet proton sources and their corresponding low energy beam transport (LEBT) system were developed successfully for China accelerator driven sub-critical system in 2014. Both the proton sources operate at 35 kV potential. The beams extracted from the ion source are transported by the LEBT, which is composed of two identical solenoids, to the 2.1 MeV Radio-Frequency Quadrupole (RFQ). In order to ensure the safety of the superconducting cavities during commissioning, an electrostatic-chopper has been designed and installed in the LEBT line that can chop the continuous wave beam into a pulsed one. The minimum width of the pulse is less than 10 μs and the fall/rise time of the chopper is about 20 ns. The performance of the proton source and the LEBT, such as beam current, beam profile, emittance and the impact to RFQ injection will be presented.

Characterizing the proton loading site in cytochrome c oxidase.

PubMed

Lu, Jianxun; Gunner, M R

2014-08-26

Cytochrome c oxidase (CcO) uses the energy released by reduction of O2 to H2O to drive eight charges from the high pH to low pH side of the membrane, increasing the electrochemical gradient. Four electrons and protons are used for chemistry, while four more protons are pumped. Proton pumping requires that residues on a pathway change proton affinity through the reaction cycle to load and then release protons. The protonation states of all residues in CcO are determined in MultiConformational Continuum Electrostatics simulations with the protonation and redox states of heme a, a3, Cu(B), Y288, and E286 used to define the catalytic cycle. One proton is found to be loaded and released from residues identified as the proton loading site (PLS) on the P-side of the protein in each of the four CcO redox states. Thus, the same proton pumping mechanism can be used each time CcO is reduced. Calculations with structures of Rhodobacter sphaeroides, Paracoccus denitrificans, and bovine CcO derived by crystallography and molecular dynamics show the PLS functions similarly in different CcO species. The PLS is a cluster rather than a single residue, as different structures show 1-4 residues load and release protons. However, the proton affinity of the heme a3 propionic acids primarily determines the number of protons loaded into the PLS; if their proton affinity is too low, less than one proton is loaded.

Use of proton pump inhibitors and mortality after hip fracture in a nationwide study.

PubMed

Brozek, W; Reichardt, B; Zwerina, J; Dimai, H P; Klaushofer, K; Zwettler, E

2017-05-01

We analyzed the association of proton pump inhibitors (PPIs) with mortality after osteoporosis-related hip fracture in Austria. PPIs were associated with reduced 90-day mortality but elevated mortality after half a year when initiated pre-fracture. Inpatients and discharged patients on PPIs showed lowered in-hospital and 90-day mortality, respectively. We herein investigated use of proton pump inhibitors (PPIs) and mortality among hip fracture patients in a nationwide study in Austria. In this retrospective cohort study, data on use of PPIs were obtained from 31,668 Austrian patients ≥50 years with a hip fracture between July 2008 and December 2010. All-cause mortality in patients without anti-osteoporotic drug treatment who had received their first recorded PPI prescription in the study period either before or after fracture was compared with hip fracture patients on neither PPIs nor anti-osteoporotic medication using logistic and Cox regression analysis. With PPI use, 90-day mortality was significantly reduced, both at initiation before (OR 0.66; p < 0.0001) and after hip fracture (OR 0.23; p < 0.0001). 90-day mortality was also reduced when PPIs were prescribed not until after discharge from the last recorded hip fracture-related hospital stay (OR 0.49; p < 0.0001) except for patients aged <70 years. In a sub-cohort of patients beginning PPIs during hospital stay, in-hospital mortality (0.2%) was substantially reduced relative to matched control patients (3.5%) (p < 0.0001). Longer-term mortality significantly increased after half a year post-fracture only among those who started PPI prescription before fracture. PPI use during and after hospital stay due to hip fracture is associated with a considerable decrease in mortality. These findings could have implications for hip fracture treatment.

Timing of electron and proton transfer in the ba(3) cytochrome c oxidase from Thermus thermophilus.

PubMed

von Ballmoos, Christoph; Lachmann, Peter; Gennis, Robert B; Ädelroth, Pia; Brzezinski, Peter

2012-06-05

Heme-copper oxidases are membrane-bound proteins that catalyze the reduction of O(2) to H(2)O, a highly exergonic reaction. Part of the free energy of this reaction is used for pumping of protons across the membrane. The ba(3) oxidase from Thermus thermophilus presumably uses a single proton pathway for the transfer of substrate protons used during O(2) reduction as well as for the transfer of the protons that are pumped across the membrane. The pumping stoichiometry (0.5 H(+)/electron) is lower than that of most other (mitochondrial-like) oxidases characterized to date (1 H(+)/electron). We studied the pH dependence and deuterium isotope effect of the kinetics of electron and proton transfer reactions in the ba(3) oxidase. The results from these studies suggest that the movement of protons to the catalytic site and movement to a site located some distance from the catalytic site [proposed to be a "proton-loading site" (PLS) for pumped protons] are separated in time, which allows individual investigation of these reactions. A scenario in which the uptake and release of a pumped proton occurs upon every second transfer of an electron to the catalytic site would explain the decreased proton pumping stoichiometry compared to that of mitochondrial-like oxidases.

Review of pharmacokinetic and pharmacodynamic modeling and safety of proton pump inhibitors and aspirin.

PubMed

Gesheff, Martin G; Franzese, Christopher J; Bliden, Kevin P; Contino, Chase J; Rafeedheen, Rahil; Tantry, Udaya S; Gurbel, Paul A

2014-09-01

The efficacy of aspirin in primary and secondary prevention of cardiovascular diseases has been convincingly demonstrated. Gastrointestinal (GI) adverse effects with aspirin may lead to poor adherence and/or discontinuation of treatment. Proton pump inhibitors (PPIs) have been used for more than 20 years as the first choice for treating peptic ulcers and their bleeding complications, gastroesophageal reflux disease, non-steroidal anti-inflammatory drug-induced GI lesions and dyspepsia. Adherence becomes a major concern when aspirin is co-prescribed with PPIs to prevent GI adverse effects. Combining aspirin and PPIs into one tablet is an effective approach to address aspirin-related GI adverse effects and increase adherence to aspirin therapy for the prevention of cardiovascular diseases.

Thermal and Spectroscopic Characterization of a Proton Pumping Rhodopsin from an Extreme Thermophile*

PubMed Central

Tsukamoto, Takashi; Inoue, Keiichi; Kandori, Hideki; Sudo, Yuki

2013-01-01

So far retinylidene proteins (∼rhodopsin) have not been discovered in thermophilic organisms. In this study we investigated and characterized a microbial rhodopsin derived from the extreme thermophilic bacterium Thermus thermophilus, which lives in a hot spring at around 75 °C. The gene for the retinylidene protein, named thermophilic rhodopsin (TR), was chemically synthesized with codon optimization. The codon optimized TR protein was functionally expressed in the cell membranes of Escherichia coli cells and showed active proton transport upon photoillumination. Spectroscopic measurements revealed that the purified TR bound only all-trans-retinal as a chromophore and showed an absorption maximum at 530 nm. In addition, TR exhibited both photocycle kinetics and pH-dependent absorption changes, which are characteristic of rhodopsins. Of note, time-dependent thermal denaturation experiments revealed that TR maintained its absorption even at 75 °C, and the denaturation rate constant of TR was much lower than those of other proton pumping rhodopsins such as archaerhodopsin-3 (200 ×), Haloquadratum walsbyi bacteriorhodopsin (by 10-times), and Gloeobacter rhodopsin (100 ×). Thus, these results suggest that microbial rhodopsins are also distributed among thermophilic organisms and have high stability. TR should allow the investigation of the molecular mechanisms of ion transport and protein folding. PMID:23740255

Thermal and spectroscopic characterization of a proton pumping rhodopsin from an extreme thermophile.

PubMed

Tsukamoto, Takashi; Inoue, Keiichi; Kandori, Hideki; Sudo, Yuki

2013-07-26

So far retinylidene proteins (∼rhodopsin) have not been discovered in thermophilic organisms. In this study we investigated and characterized a microbial rhodopsin derived from the extreme thermophilic bacterium Thermus thermophilus, which lives in a hot spring at around 75 °C. The gene for the retinylidene protein, named thermophilic rhodopsin (TR), was chemically synthesized with codon optimization. The codon optimized TR protein was functionally expressed in the cell membranes of Escherichia coli cells and showed active proton transport upon photoillumination. Spectroscopic measurements revealed that the purified TR bound only all-trans-retinal as a chromophore and showed an absorption maximum at 530 nm. In addition, TR exhibited both photocycle kinetics and pH-dependent absorption changes, which are characteristic of rhodopsins. Of note, time-dependent thermal denaturation experiments revealed that TR maintained its absorption even at 75 °C, and the denaturation rate constant of TR was much lower than those of other proton pumping rhodopsins such as archaerhodopsin-3 (200 ×), Haloquadratum walsbyi bacteriorhodopsin (by 10-times), and Gloeobacter rhodopsin (100 ×). Thus, these results suggest that microbial rhodopsins are also distributed among thermophilic organisms and have high stability. TR should allow the investigation of the molecular mechanisms of ion transport and protein folding.

Evidence-based support for the use of proton pump inhibitors in cancer therapy.

PubMed

Fais, Stefano

2015-11-24

'We can only cure what we can understand first', said Otto H. Warburg, the 1931 Nobel laureate for his discovery on tumor metabolism. Unfortunately, we still don't know too much the mechanisms underlying of cancer development and progression. One of the unsolved mystery includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg's discovery, that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. One of the most mechanism to survive to the acidic tumor microenvironment are proton exchangers not allowing intracellular acidification through a continuous elimination of H(+) either outside the cells or within the internal vacuoles. This article wants to comment a translational process through which from the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed chemosensitizers as well, we have got to the clinical proof of concept that PPI may well be included in new anti-cancer strategies, and with a solid background and rationale.

Small Bowel Bacterial Overgrowth Associated with Persistence of Abdominal Symptoms in Children Treated with a Proton Pump Inhibitor.

PubMed

Sieczkowska, Agnieszka; Landowski, Piotr; Zagozdzon, Pawel; Kaminska, Barbara; Lifschitz, Carlos

2015-05-01

Small bowel bacterial overgrowth (SBBO) was diagnosed in 22.5% of 40 children treated for 3 months with a proton pump inhibitor (PPI). Compared with those without SBBO, children with SBBO had higher frequency of abdominal pain, bloating, eructation, and flatulence. Patients with gastrointestinal symptoms after PPI treatment should be evaluated for SBBO rather than empirically prolonging PPI therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Gas Engine-Driven Heat Pump with Desiccant Dehumidification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Bo; Abu-Heiba, Ahmad

About 40% of total U.S. energy consumption was consumed in residential and commercial buildings. Improved air-conditioning technology has by far the greatest potential impact on the electric industry compared to any other technology that uses electricity. This paper describes the development of an innovative natural gas, propane, LNG or bio-gas IC engine-driven heat pump (GHP) with desiccant dehumidification (GHP/DD). This integrated system has higher overall efficiencies than conventional equipment for space cooling, addresses both new and existing commercial buildings, and more effectively controls humidity in humid areas. Waste heat is recovered from the GHP to provide energy for regenerating themore » desiccant wheel and to augment heating capacity and efficiency. By combining the two technologies, an overall source COP of greater that 1.5 (hot, humid case) can be achieved by utilizing waste heat from the engine to reduce the overall energy required to regenerate the desiccant. Moreover, system modeling results show that the sensible heat ratio (SHR- sensible heat ratio) can be lowered to less 60% in a dedicated outdoor air system application with hot, humid cases.« less

Blood Pressure-Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor.

PubMed

Montenegro, Marcelo F; Sundqvist, Michaela L; Larsen, Filip J; Zhuge, Zhengbing; Carlström, Mattias; Weitzberg, Eddie; Lundberg, Jon O

2017-01-01

Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg -1 ), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg -1 min -1 ) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascular relaxation to nitroprusside and acetylcholine, demonstrating an intact downstream NO-signaling pathway. We conclude that the acute blood pressure-lowering effect of nitrite requires an acidic gastric environment. Future studies will reveal if the cardiovascular complications associated with the use of proton pump inhibitors are linked to interference with the nitrate-nitrite-NO pathway. © 2016 American Heart Association, Inc.

Characterizing the proton loading site in cytochrome c oxidase

PubMed Central

Lu, Jianxun; Gunner, M. R.

2014-01-01

Cytochrome c oxidase (CcO) uses the energy released by reduction of O2 to H2O to drive eight charges from the high pH to low pH side of the membrane, increasing the electrochemical gradient. Four electrons and protons are used for chemistry, while four more protons are pumped. Proton pumping requires that residues on a pathway change proton affinity through the reaction cycle to load and then release protons. The protonation states of all residues in CcO are determined in MultiConformational Continuum Electrostatics simulations with the protonation and redox states of heme a, a3, CuB, Y288, and E286 used to define the catalytic cycle. One proton is found to be loaded and released from residues identified as the proton loading site (PLS) on the P-side of the protein in each of the four CcO redox states. Thus, the same proton pumping mechanism can be used each time CcO is reduced. Calculations with structures of Rhodobacter sphaeroides, Paracoccus denitrificans, and bovine CcO derived by crystallography and molecular dynamics show the PLS functions similarly in different CcO species. The PLS is a cluster rather than a single residue, as different structures show 1–4 residues load and release protons. However, the proton affinity of the heme a3 propionic acids primarily determines the number of protons loaded into the PLS; if their proton affinity is too low, less than one proton is loaded. PMID:25114210

Pressure charged airlift pump

DOEpatents

Campbell, Gene K.

1983-01-01

A pumping system is described for pumping fluids, such as water with entrained mud and small rocks, out of underground cavities such as drilled wells, which can effectively remove fluids down to a level very close to the bottom of the cavity and which can operate solely by compressed air pumped down through the cavity. The system utilizes a subassembly having a pair of parallel conduit sections (44, 46) adapted to be connected onto the bottom of a drill string utilized for drilling the cavity, the drill string also having a pair of coaxially extending conduits. The subassembly includes an upper portion which has means for connection onto the drill string and terminates the first conduit of the drill string in a plenum (55). A compressed air-driven pump (62) is suspended from the upper portion. The pump sucks fluids from the bottom of the cavity and discharges them into the second conduit. Compressed air pumped down through the first conduit (46) to the plenum powers the compressed air-driven pump and aerates the fluid in the second conduit to lift it to the earth's surface.

Light-driven Na + pump from Gillisia limnaea: A high-affinity Na + binding site is formed transiently in the photocycle

DOE PAGES

Balashov, Sergei P.; Imasheva, Eleonora S.; Dioumaev, Andrei K.; ...

2014-11-06

A group of microbial retinal proteins most closely related to the proton pump xanthorhodopsin has a novel sequence motif and a novel function. Instead of, or in addition to, proton transport, they perform light-driven sodium ion transport, as reported for one representative of this group (KR2) from Krokinobacter. In this paper, we examine a similar protein, GLR from Gillisia limnaea, expressed in Escherichia coli, which shares some properties with KR2 but transports only Na +. The absorption spectrum of GLR is insensitive to Na + at concentrations of ≤3 M. However, very low concentrations of Na + cause profound differencesmore » in the decay and rise time of photocycle intermediates, consistent with a switch from a “Na +-independent” to a “Na +-dependent” photocycle (or photocycle branch) at ~60 μM Na +. The rates of photocycle steps in the latter, but not the former, are linearly dependent on Na + concentration. This suggests that a high-affinity Na + binding site is created transiently after photoexcitation, and entry of Na + from the bulk to this site redirects the course of events in the remainder of the cycle. A greater concentration of Na + is needed for switching the reaction path at lower pH. The data suggest therefore competition between H + and Na + to determine the two alternative pathways. The idea that a Na + binding site can be created at the Schiff base counterion is supported by the finding that upon perturbation of this region in the D251E mutant, Na + binds without photoexcitation. Furthermore, binding of Na+ to the mutant shifts the chromophore maximum to the red like that of H +, which occurs in the photocycle of the wild type.« less

Exchangers man the pumps: Functional interplay between proton pumps and proton-coupled Ca(2+) exchangers

USDA-ARS?s Scientific Manuscript database

Tonoplast-localised proton-coupled Ca(2+) transporters encoded by cation/H(+) exchanger (CAX) genes play a critical role in sequestering Ca(2+) into the vacuole. These transporters may function in coordination with Ca(2+) release channels, to shape stimulus-induced cytosolic Ca(2+) elevations. Recen...

Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma.

PubMed

Furney, Simon J; Turajlic, Samra; Stamp, Gordon; Nohadani, Mahrokh; Carlisle, Anna; Thomas, J Meirion; Hayes, Andrew; Strauss, Dirk; Gore, Martin; van den Oord, Joost; Larkin, James; Marais, Richard

2013-07-01

Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular, the mutation signatures are not indicative of ultraviolet light- or tobacco smoke-induced DNA damage. Genes previously reported as mutated in other cancers were also mutated in mucosal melanoma. Notably, there were substantially more copy number and structural variations in mucosal melanoma than have been reported in cutaneous melanoma. Thus, mucosal and cutaneous melanomas are distinct diseases with discrete genetic features. Our data suggest that different mechanisms underlie the genesis of these diseases and that structural variations play a more important role in mucosal than in cutaneous melanomagenesis. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors

PubMed Central

Bellone, Matteo; Calcinotto, Arianna; Filipazzi, Paola; De Milito, Angelo; Fais, Stefano; Rivoltini, Licia

2013-01-01

We have recently reported that lowering the pH to values that are frequently detected in tumors causes reversible anergy in both human and mouse CD8+ T lymphocytes in vitro. The same occurs in vivo, in the tumor microenvironment and the administration of proton pump inhibitors, which buffer tumor acidity, can revert T-cell anergy and increase the efficacy of immunotherapy. PMID:23483769

Proton velocity ring-driven instabilities and their dependence on the ring speed: Linear theory

NASA Astrophysics Data System (ADS)

Min, Kyungguk; Liu, Kaijun; Gary, S. Peter

2017-08-01

Linear dispersion theory is used to study the Alfvén-cyclotron, mirror and ion Bernstein instabilities driven by a tenuous (1%) warm proton ring velocity distribution with a ring speed, vr, varying between 2vA and 10vA, where vA is the Alfvén speed. Relatively cool background protons and electrons are assumed. The modeled ring velocity distributions are unstable to both the Alfvén-cyclotron and ion Bernstein instabilities whose maximum growth rates are roughly a linear function of the ring speed. The mirror mode, which has real frequency ωr=0, becomes the fastest growing mode for sufficiently large vr/vA. The mirror and Bernstein instabilities have maximum growth at propagation oblique to the background magnetic field and become more field-aligned with an increasing ring speed. Considering its largest growth rate, the mirror mode, in addition to the Alfvén-cyclotron mode, can cause pitch angle diffusion of the ring protons when the ring speed becomes sufficiently large. Moreover, because the parallel phase speed, v∥ph, becomes sufficiently small relative to vr, the low-frequency Bernstein waves can also aid the pitch angle scattering of the ring protons for large vr. Potential implications of including these two instabilities at oblique propagation on heliospheric pickup ion dynamics are discussed.

Metal-Organic Frameworks in Adsorption-Driven Heat Pumps: The Potential of Alcohols as Working Fluids.

PubMed

de Lange, Martijn F; van Velzen, Benjamin L; Ottevanger, Coen P; Verouden, Karlijn J F M; Lin, Li-Chiang; Vlugt, Thijs J H; Gascon, Jorge; Kapteijn, Freek

2015-11-24

A large fraction of global energy is consumed for heating and cooling. Adsorption-driven heat pumps and chillers could be employed to reduce this consumption. MOFs are often considered to be ideal adsorbents for heat pumps and chillers. While most published works to date on this topic have focused on the use of water as a working fluid, the instability of many MOFs to water and the fact that water cannot be used at subzero temperatures pose certain drawbacks. The potential of using alcohol-MOF pairs in adsorption-driven heat pumps and chillers is investigated. To this end, 18 different selected MOF structures in combination with either methanol or ethanol as a working fluid are considered, and their potential is assessed on the basis of adsorption measurements and thermodynamic efficiencies. If alcohols are used instead of water, then (1) adsorption occurs at lower relative pressures for methanol and even lower pressure for ethanol, (2) larger pores can be utilized efficiently, as hysteresis is absent for pores smaller than 3.4 nm (2 nm for water), (3) larger pore sizes need to be employed to ensure the desired stepwise adsorption, (4) the effect of (polar/apolar) functional groups in the MOF is far less pronounced, (5) the energy released or taken up per cycle is lower, but heat and mass transfer may be enhanced, (6) stability of MOFs seems to be less of an issue, and (7) cryogenic applications (e.g., ice making) become feasible. From a thermodynamic perspective, UiO-67, CAU-3, and ZIF-8 seem to be the most promising MOFs for both methanol and ethanol as working fluids. Although UiO-67 might not be completely stable, both CAU-3 and ZIF-8 have the potential to be applied, especially in subzero-temperature adsorption chillers (AC).

Proton pump inhibitors affect the gut microbiome

PubMed Central

Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Tigchelaar, Ettje F; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

2016-01-01

Background and aims Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. Methods The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. Results 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10−38). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. Conclusions The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs. PMID:26657899

A Novel Skin and Fascia Opening for Subfascial Inserting of Intrathecal Baclofen Pump.

PubMed

Fiaschi, Pietro; Cama, Armando; Piatelli, Gianluca; Moretti, Paolo; Pavanello, Marco

2018-02-01

The aim of this article is to introduce a new skin and fascia opening for intrathecal baclofen pump implantation in the abdomen, with the purpose of reducing complications related to wound breakdown. We introduce a novel way of cutaneous and fascial opening that leads two opposed "L shaped" incisions. This method entails numerous advantages. The first advantage is avoiding the direct alignment of overlapped sutures, which creates a locus minoris resistentiae that can weaken and break under the push of the pump. Another advantage consists of an increased obstruction against deep extension of infective processes from cutaneous origin. The wide opening of the subfascial pocket permits the implantation of any type of pump available, and it reduces complexities in reopening the pouch for pump replacement. It also permits the fastening of all anchoring systems usually present in pumps. Another advantage is the improved possibility of careful muscle cauterization thanks to the wide fascia opening, with reduced risk of postsurgical hematoma. Our results showed a reduction of wound complications with this method. This method could contribute to reducing the rate of wound complications and patient discomfort. Copyright © 2017 Elsevier Inc. All rights reserved.

A miniature, nongassing electroosmotic pump operating at 0.5 V.

PubMed

Shin, Woonsup; Lee, Jong Myung; Nagarale, Rajaram Krishna; Shin, Samuel Jaeho; Heller, Adam

2011-03-02

Electroosmotic pumps are arguably the simplest of all pumps, consisting merely of two flow-through electrodes separated by a porous membrane. Most use platinum electrodes and operate at high voltages, electrolyzing water. Because evolved gas bubbles adhere and block parts of the electrodes and the membrane, steady pumping rates are difficult to sustain. Here we show that when the platinum electrodes are replaced by consumed Ag/Ag(2)O electrodes, the pumps operate well below 1.23 V, the thermodynamic threshold for electrolysis of water at 25 °C, where neither H(2) nor O(2) is produced. The pumping of water is efficient: 13 000 water molecules are pumped per reacted electron and 4.8 mL of water are pumped per joule at a flow rate of 0.13 mL min(-1) V(-1) cm(-2), and a flow rate per unit of power is 290 mL min(-1) W(-1). The water is driven by protons produced in the anode reaction 2Ag(s) + H(2)O → Ag(2)O(s) + 2H(+) + 2e(-), traveling through the porous membrane, consumed by hydroxide ions generated in the cathode reaction Ag(2)O(s) + 2 H(2)O + 2e(-) → 2Ag(s) + 2 OH(-). A pump of 2 mm thickness and 0.3 cm(2) cross-sectional area produces flow of 5-30 μL min(-1) when operating at 0.2-0.8 V and 0.04-0.2 mA. Its flow rate can be either voltage or current controlled. The flow rate suffices for the delivery of drugs, such as a meal-associated boli of insulin.

Proton pump inhibitor-responsive esophageal eosinophilia: a historical perspective on a novel and evolving entity.

PubMed

Molina-Infante, Javier; Katzka, David A; Dellon, Evan S

2015-01-01

Eosinophilic esophagitis (EoE) is an emerging chronic esophageal disease, first described in 1993, with a steadily increasing incidence and prevalence in western countries. Over the 80's and early 90's, dense esophageal eosinophilia was mostly associated gastroesophageal reflux disease (GERD). For the next 15 years, EoE and GERD were rigidly considered separate entities: Esophageal eosinophilia with pathological acid exposure on pH monitoring or response to proton pump inhibitor (PPI) therapy was GERD, whereas normal pH monitoring or absence of response to PPIs was EoE. Updated guidelines in 2011 described a novel phenotype, proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), referring to patients who appear to have EoE clinically, but who achieve complete remission after PPI therapy. Currently, PPI-REE must be formally excluded before diagnosing EoE, since 30-40% of patients with suspected EoE are eventually diagnosed with PPI-REE.Interestingly, PPI-REE and EoE remain undistinguishable based on clinical, endoscopic, and histological findings, pH monitoring, and measurement of tissue markers and cytokines related to eosinophilic inflammation.This review article aims to revisit the relatively novel concept of PPI-REE from a historical perspective, given the strong belief that only GERD, as an acid peptic disorder, could respond to the acid suppressing ability of PPI therapy, is becoming outdated. Evolving evidence suggests that PPI-REE is genetically and phenotypically undistinguishable from EoE and PPI therapy alone can almost completely reverse allergic inflammation. As such, PPI-REE might constitute a subphenotype of EoE and PPI therapy may be the first therapeutic step and diet/ steroids may represent step up therapy. Possibly, the term PPI-REE will be soon replaced by PPI-responsive EoE. The mechanism as to why some patients respond to PPI therapy (PPI-REE) while others do not (EoE), remains to be elucidated.

Pharmacokinetics and Pharmacodynamics of Azeloprazole Sodium, a Novel Proton Pump Inhibitor, in Healthy Japanese Volunteers.

PubMed

Toda, Ryoko; Shiramoto, Masanari; Komai, Emi; Yoshii, Kazuyoshi; Hirayama, Masamichi; Kawabata, Yoshihiro

2018-04-01

The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z-215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD of azeloprazole sodium have not been evaluated in Japanese subjects. We conducted an open-label, crossover study in healthy Japanese male volunteers to evaluate the plasma concentration and intragastric pH with respect to CYP2C19 genotype after repeated administration of 10, 20, and 40 mg azeloprazole sodium and 10 and 20 mg rabeprazole sodium (rabeprazole). The plasma concentration profile of azeloprazole sodium was similar among genotypes, whereas that of rabeprazole differed. The 24-hour intragastric pH ≥ 4 holding time ratio (pH ≥ 4 HTR) of azeloprazole sodium was similar among genotypes. The pH ≥ 4 HTR was 52.5%-60.3%, 55.1%-65.8%, and 69.4%-77.1% after administration of 10, 20, and 40 mg azeloprazole sodium, respectively, and 59.2%-72.3% and 64.4%-91.2% after administration of 10 and 20 mg rabeprazole, respectively, on the fifth day of dosing. The maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC), and pH ≥ 4 HTR of azeloprazole sodium were proportional to dose. The C max , AUC, and pH ≥ 4 HTR on day 5 were slightly higher following administration of 20 mg azeloprazole sodium before comparison with after a meal. No serious adverse events were observed. These results suggest that azeloprazole sodium is useful for treating gastroesophageal reflux disease in all CYP2C19 genotypes. © 2017, The American College of Clinical Pharmacology.

The impact of proton pump inhibitors on the human gastrointestinal microbiome

PubMed Central

Freedberg, Daniel E.; Lebwohl, Benjamin; Abrams, Julian A.

2014-01-01

Potent gastric acid suppression using proton pump inhibitors (PPIs) is common in clinical practice yet may have important effects on human health that are mediated through changes in the gastrointestinal microbiome. Acting through pH-dependent or pH-independent mechanisms, PPIs have the potential to alter the normal microbiota throughout the human gastrointestinal lumen. In the esophagus, PPIs change the normal bacterial milieu to decrease distal esophageal exposure to inflammatory Gram-negative bacteria which may lower the risk of Barrett's esophagus. In the stomach, PPIs alter the abundance and location of gastric Helicobacter pylori and other bacteria, which has implications for peptic ulcer disease and gastric malignancy. In the small bowel, PPIs cause polymicrobial small bowel bacterial overgrowth and have been associated with the diagnosis of celiac disease. In the colon, PPIs associate with incident but not recurrent Clostridium difficile infection, putatively through alterations in commensal colonic anaerobes. Our understanding of the effect of gastric acid suppression on the human gastrointestinal microbiome is incomplete but is rapidly advancing. PMID:25439276

Engine having multiple pumps driven by a single shaft

DOEpatents

Blass, James R.

2001-01-01

An engine comprises an engine housing. A first engine fluid sub-system that includes a first pump and the engine housing defining a first fluid passage is also included in the engine. The engine also includes at least one additional engine fluid sub-system that includes a second pump and the engine housing defining a second fluid passage. A rotating shaft is at least partially positioned in the engine housing, the first pump and the second pump.

What are the effects of proton pump inhibitors on the small intestine?

PubMed Central

Fujimori, Shunji

2015-01-01

Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, non-alcoholic fatty liver disease, and autoimmune diseases. When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked. PMID:26078557

What are the effects of proton pump inhibitors on the small intestine?

PubMed

Fujimori, Shunji

2015-06-14

Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, non-alcoholic fatty liver disease, and autoimmune diseases. When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked.

Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease.

PubMed

Cicala, Michele; Emerenziani, Sara; Guarino, Michele Pier Luca; Ribolsi, Mentore

2013-10-21

Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH-impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery.

In silico design of novel proton-pump inhibitors with reduced adverse effects.

PubMed

Li, Xiaoyi; Kang, Hong; Liu, Wensheng; Singhal, Sarita; Jiao, Na; Wang, Yong; Zhu, Lixin; Zhu, Ruixin

2018-05-30

The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features: (1) number of ring II = number of ring I + 1; (2) preferably five, six, or seven-membered heteroatomic ring for stability; and (3) 1 < pKa1 < 4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.

Single mutations that redirect internal proton transfer in the ba3 oxidase from Thermus thermophilus

PubMed Central

Smirnova, Irina; Chang, Hsin-Yang; von Ballmoos, Christoph; Ädelroth, Pia; Gennis, Robert B.; Brzezinski, Peter

2014-01-01

The ba3-type cytochrome c oxidase from Thermus thermophilus is a membrane-bound proton pump. Results from earlier studies have shown that with the aa3-type oxidases proton uptake to the catalytic site and “pump site” occur simultaneously. However, with the ba3 oxidase the pump site is loaded before proton transfer to the catalytic site because the proton transfer to the latter is slower than with the aa3 oxidases. In addition, the timing of formation and decay of catalytic intermediates is different in the two types of oxidases. In the present study, we have investigated two mutant ba3 CytcOs in which residues of the proton pathway leading to the catalytic site as well as the pump site were exchanged, Thr312Val and Tyr244Phe. Even though the ba3 CytcO uses only a single proton pathway for transfer of the substrate and “pumped” protons, the amino-acid residue substitutions had distinctly different effects on the kinetics of proton transfer to the catalytic site and the pump site, respectively. The results indicate that the rates of these reactions can be modified independently by replacement of single residues within the proton pathway. Furthermore, the data suggest that the Thr312Val and Tyr244Phe mutations interfere with a structural rearrangement in the proton pathway that is rate limiting for proton transfer to the catalytic site. PMID:24004023

Proton pump inhibitors affect the gut microbiome.

PubMed

Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Tigchelaar, Ettje F; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

2016-05-01

Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Atypical Cutaneous Presentations of Sarcoidosis: Two Case Reports and Review of the Literature.

PubMed

Leverenz, David L; Henderson, Christopher; Shah, Ankoor

2018-06-14

The goal of this review is to provide the reader with an updated summary of the cutaneous manifestations of systemic sarcoidosis, with a particular emphasis on the predilection of sarcoidosis for scars, tattoos, and other areas of traumatized skin. While the mechanism underlying the propensity for traumatized skin to develop sarcoidosis lesions remains unclear, several theories have been proposed including the idea that cutaneous sarcoidosis represents an exuberant, antigen-driven foreign-body response, as well as the theory that traumatized skin represents an immunocompromised district with altered local immune trafficking and neural signaling. In this review, we present two cases in which the development of cutaneous lesions in scars and tattoos was integral to the diagnosis of systemic sarcoidosis. We then review the various cutaneous manifestations of systemic sarcoidosis, the clinical characteristics and differential diagnosis of scar and tattoo sarcoidosis, the proposed mechanism by which traumatized skin is prone to developing sarcoidosis lesions, and current treatments for cutaneous sarcoidosis.

Advantages and Disadvantages of Long-term Proton Pump Inhibitor Use

PubMed Central

Kinoshita, Yoshikazu; Ishimura, Norihisa; Ishihara, Shunji

2018-01-01

Proton pump inhibitors (PPIs) potently inhibit gastric acid secretion and are widely used for treatment of acid-related diseases including gastroesophageal reflux disease and secondary prevention of aspirin/NSAID-induced ulcers. Although clinically important adverse effects of PPIs can occur, just as with other drugs, those are not frequently observed during or after administration. Thus, PPIs are regarded as relatively safe and considered to be clinically beneficial. Recently, PPIs have become frequently administered to patients with functional gastrointestinal diseases or primary prevention of drug-related gastroduodenal damage, even though their beneficial effects for those conditions have not been fully confirmed. PPIs tend to be given for conditions in which the necessity of the drug has not been clarified, thus otherwise rare adverse effects are presented as clinically relevant. Although several PPI-related adverse effects have been reported, their clinical relevance is not yet clear, since the evidence reported in those studies is not at a high enough level, as the majority are based on retrospective observational studies and the reported hazard ratios are low. It is important to administer PPIs only for patients who will gain a substantial clinical benefit and to continue to investigate their adverse effects with high quality prospective studies. PMID:29605975

Advantages and Disadvantages of Long-term Proton Pump Inhibitor Use.

PubMed

Kinoshita, Yoshikazu; Ishimura, Norihisa; Ishihara, Shunji

2018-04-30

Proton pump inhibitors (PPIs) potently inhibit gastric acid secretion and are widely used for treatment of acid-related diseases including gastroesophageal reflux disease and secondary prevention of aspirin/NSAID-induced ulcers. Although clinically important adverse effects of PPIs can occur, just as with other drugs, those are not frequently observed during or after administration. Thus, PPIs are regarded as relatively safe and considered to be clinically beneficial. Recently, PPIs have become frequently administered to patients with functional gastrointestinal diseases or primary prevention of drug-related gastroduodenal damage, even though their beneficial effects for those conditions have not been fully confirmed. PPIs tend to be given for conditions in which the necessity of the drug has not been clarified, thus otherwise rare adverse effects are presented as clinically relevant. Although several PPI-related adverse effects have been reported, their clinical relevance is not yet clear, since the evidence reported in those studies is not at a high enough level, as the majority are based on retrospective observational studies and the reported hazard ratios are low. It is important to administer PPIs only for patients who will gain a substantial clinical benefit and to continue to investigate their adverse effects with high quality prospective studies.

46 CFR 32.50-35 - Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels-TB/ALL.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 1 2011-10-01 2011-10-01 false Remote manual shutdown for internal combustion engine... for Cargo Handling § 32.50-35 Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels—TB/ALL. (a) Any tank vessel which is equipped with an internal combustion engine...

46 CFR 32.50-35 - Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels-TB/ALL.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 1 2013-10-01 2013-10-01 false Remote manual shutdown for internal combustion engine... for Cargo Handling § 32.50-35 Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels—TB/ALL. (a) Any tank vessel which is equipped with an internal combustion engine...

46 CFR 32.50-35 - Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels-TB/ALL.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 1 2010-10-01 2010-10-01 false Remote manual shutdown for internal combustion engine... for Cargo Handling § 32.50-35 Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels—TB/ALL. (a) Any tank vessel which is equipped with an internal combustion engine...

46 CFR 32.50-35 - Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels-TB/ALL.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 1 2012-10-01 2012-10-01 false Remote manual shutdown for internal combustion engine... for Cargo Handling § 32.50-35 Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels—TB/ALL. (a) Any tank vessel which is equipped with an internal combustion engine...

46 CFR 32.50-35 - Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels-TB/ALL.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 1 2014-10-01 2014-10-01 false Remote manual shutdown for internal combustion engine... for Cargo Handling § 32.50-35 Remote manual shutdown for internal combustion engine driven cargo pump on tank vessels—TB/ALL. (a) Any tank vessel which is equipped with an internal combustion engine...

Cutaneous sarcoidosis.

PubMed

Noe, Megan H; Rosenbach, Misha

2017-09-01

Cutaneous sarcoidosis occurs in up to 30% of patients with sarcoidosis and skin findings are often the initial presenting symptom. Cutaneous sarcoidosis is a rare skin disease and many aspects of the disease presentation and treatment are not well understood. This review will highlight developments in the epidemiology, clinical presentation, diagnosis and treatment of cutaneous sarcoidosis over the past several years. Epidemiological studies from several different populations reaffirm that cutaneous sarcoidosis is more common in women and is often the presenting symptom of systemic sarcoidosis. Recently, more cases are being reported in association with oncologic immune modulators, which will be of great interest as use of those agents increases. Also, ultrasound has shown promise for the imaging of cutaneous granulomas for disease assessment and measuring response to treatment. Finally, the treatment of cutaneous sarcoidosis remains difficult and is based largely on retrospective data with a paucity of large, prospective trials. There have been recently introduced and validated cutaneous scoring tools which show promise and may lead to more high-quality studies going forward. The recent developments in cutaneous sarcoidosis have identified many new pharmacologic and physical triggers of disease, but the evidence for effective treatment is still lacking. Further research is necessary to improve the care of patients with cutaneous sarcoidosis.

Trypanosoma cruzi H+-ATPase 1 (TcHA1) and 2 (TcHA2) genes complement yeast mutants defective in H+ pumps and encode plasma membrane P-type H+-ATPases with different enzymatic properties.

PubMed

Luo, Shuhong; Scott, David A; Docampo, Roberto

2002-11-15

Previous studies in Trypanosoma cruzi have shown that intracellular pH homeostasis requires ATP and is affected by H(+)-ATPase inhibitors, indicating a major role for ATP-driven proton pumps in intracellular pH control. In the present study, we report the cloning and sequencing of a pair of genes linked in tandem (TcHA1 and TcHA2) in T. cruzi which encode proteins with homology to fungal and plant P-type proton-pumping ATPases. The genes are expressed at the mRNA level in different developmental stages of T. cruzi: TcHA1 is expressed maximally in epimastigotes, whereas TcHA2 is expressed predominantly in trypomastigotes. The proteins predicted from the nucleotide sequence of the genes have 875 and 917 amino acids and molecular masses of 96.3 and 101.2 kDa, respectively. Full-length TcHA1 and an N-terminal truncated version of TcHA2 complemented a Saccharomyces cerevisiae strain deficient in P-type H(+)-ATPase activity, the proteins localized to the yeast plasma membrane, and ATP-driven proton pumping could be detected in proteoliposomes reconstituted from plasma membrane purified from transfected yeast. The reconstituted proton transport activity was reduced by inhibitors of P-type H(+)-ATPases. C-terminal truncation did not affect complementation of mutant yeast, suggesting the lack of C-terminal autoinhibitory domains in these proteins. ATPase activity in plasma membrane from TcHA1- and (N-terminal truncated) TcHA2-transfected yeast was inhibited to different extents by vanadate, whereas the latter yeast strain was more resistant to extremes of pH, suggesting that the native proteins may serve different functions at different stages in the T. cruzi life cycle.

Gating of proton and water transfer in the respiratory enzyme cytochrome c oxidase.

PubMed

Wikström, Mårten; Ribacka, Camilla; Molin, Mika; Laakkonen, Liisa; Verkhovsky, Michael; Puustinen, Anne

2005-07-26

The membrane-bound enzyme cytochrome c oxidase is responsible for cell respiration in aerobic organisms and conserves free energy from O2 reduction into an electrochemical proton gradient by coupling the redox reaction to proton-pumping across the membrane. O2 reduction produces water at the bimetallic heme a3/CuB active site next to a hydrophobic cavity deep within the membrane. Water molecules in this cavity have been suggested to play an important role in the proton-pumping mechanism. Here, we show by molecular dynamics simulations that the conserved arginine/heme a3 delta-propionate ion pair provides a gate, which exhibits reversible thermal opening that is governed by the redox state and the water molecules in the cavity. An important role of this gate in the proton-pumping mechanism is supported by site-directed mutagenesis experiments. Transport of the product water out of the enzyme must be rigidly controlled to prevent water-mediated proton leaks that could compromise the proton-pumping function. Exit of product water is observed through the same arginine/propionate gate, which provides an explanation for the observed extraordinary spatial specificity of water expulsion from the enzyme.

SU-E-T-182: Feasibility of Dose Painting by Numbers in Proton Therapy with Contour-Driven Plan Optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montero, A Barragan; Differding, S; Lee, J

Purpose: The work aims to 1) prove the feasibility of dose painting by numbers (DPBN) in proton therapy with usual contour-driven plan optimization and 2) compare the achieved plan quality to that of rotational IMRT. Methods: For two patients with head and neck cancers, voxel-by-voxel prescription to the target volume (PTV-PET) was calculated from {sup 18} FDG-PET images and converted to contour-based prescription by defining several sub-contours. Treatments were planned with RayStation (RaySearch Laboratories, Sweden) and proton pencil beam scanning modality. In order to determine the optimal plan parameters to approach the DPBN prescription, the effect of the number ofmore » fields, number of sub-contours and use of range shifter were tested separately on each patient. The number of sub-contours were increased from 3 to 11 while the number of fields were set to 3, 5, 7 and 9. Treatment plans were also optimized on two rotational IMRT systems (TomoTherapy and Varian RapidArc) using previously published guidelines. Results: For both patients, more than 99% of the PTV-PET received at least 95% of the prescribed dose while less than 1% of the PTV-PET received more than 105%, which demonstrates the feasibility of the treatment. Neither the use of a range shifter nor the increase of the number of fields had a significant influence on PTV coverage. Plan quality increased when increasing number of fields up to 7 or 9 and slightly decreased for a bigger number of sub-contours. Good OAR sparing is achieved while keeping high plan quality. Finally, proton therapy achieved significantly better plan quality than rotational IMRT. Conclusion: Voxel-by-voxel prescriptions can be approximated accurately in proton therapy using a contour-driven optimization. Target coverage is nearly insensitive to the number of fields and the use of a range shifter. Finally, plan quality assessment confirmed the superiority of proton therapy compared to rotational IMRT.« less

Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial.

PubMed

Krag, Mette; Perner, Anders; Wetterslev, Jørn; Wise, Matt P; Borthwick, Mark; Bendel, Stepani; Pelosi, Paolo; Keus, Frederik; Guttormsen, Anne Berit; Schefold, Joerg C; Møller, Morten Hylander

2016-04-19

Critically ill patients in the intensive care unit (ICU) are at risk of clinically important gastrointestinal bleeding, and acid suppressants are frequently used prophylactically. However, stress ulcer prophylaxis may increase the risk of serious adverse events and, additionally, the quantity and quality of evidence supporting the use of stress ulcer prophylaxis is low. The aim of the SUP-ICU trial is to assess the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the ICU. We hypothesise that stress ulcer prophylaxis reduces the rate of gastrointestinal bleeding, but increases rates of nosocomial infections and myocardial ischaemia. The overall effect on mortality is unpredictable. The SUP-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomised, blinded, parallel-group trial of stress ulcer prophylaxis with a proton pump inhibitor versus placebo (saline) in 3350 acutely ill ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support in the 90-day period, serious adverse reactions, 1-year mortality, and health economic analyses. The sample size will enable us to detect a 20 % relative risk difference (5 % absolute risk difference) in 90-day mortality assuming a 25 % event rate with a risk of type I error of 5 % and power of 90 %. The trial will be externally monitored according to Good Clinical Practice standards. Interim analyses will be performed after 1650 and 2500 patients. The SUP-ICU trial will provide high-quality data on the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in critically ill adult patients admitted in the ICU. ClinicalTrials.gov Identifier: NCT02467621 .

Jet pump assisted artery

NASA Technical Reports Server (NTRS)

1975-01-01

A procedure for priming an arterial heat pump is reported; the procedure also has a means for maintaining the pump in a primed state. This concept utilizes a capillary driven jet pump to create the necessary suction to fill the artery. Basically, the jet pump consists of a venturi or nozzle-diffuser type constriction in the vapor passage. The throat of this venturi is connected to the artery. Thus vapor, gas, liquid, or a combination of the above is pumped continuously out of the artery. As a result, the artery is always filled with liquid and an adequate supply of working fluid is provided to the evaporator of the heat pipe.

46 CFR 181.300 - Fire pumps.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Fire pumps. 181.300 Section 181.300 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS (UNDER 100 GROSS TONS) FIRE PROTECTION EQUIPMENT Fire Main System § 181.300 Fire pumps. (a) A self priming, power driven fire pump must be...

46 CFR 181.300 - Fire pumps.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Fire pumps. 181.300 Section 181.300 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS (UNDER 100 GROSS TONS) FIRE PROTECTION EQUIPMENT Fire Main System § 181.300 Fire pumps. (a) A self priming, power driven fire pump must be...

Temporally resolved proton radiography of rapidly varying electric and magnetic fields in laser-driven capacitor coil targets

NASA Astrophysics Data System (ADS)

Morace, A.; Santos, J. J.; Bailly-Grandvaux, M.; Ehret, M.; Alpinaniz, J.; Brabetz, C.; Schaumann, G.; Volpe, L.

2017-02-01

Understanding the dynamics of rapidly varying electromagnetic fields in intense short pulse laser plasma interactions is of key importance to understand the mechanisms at the basis of a wide variety of physical processes, from high energy density physics and fusion science to the development of ultrafast laser plasma devices to control laser-generated particle beams. Target normal sheath accelerated (TNSA) proton radiography represents an ideal tool to diagnose ultrafast electromagnetic phenomena, providing 2D spatially and temporally resolved radiographs with temporal resolution varying from 2-3 ps to few tens of ps. In this work we introduce the proton radiography technique and its application to diagnose the spatial and temporal evolution of electromagnetic fields in laser-driven capacitor coil targets.

The energetics of the primary proton transfer in bacteriorhodopsin revisited: it is a sequential light-induced charge separation after all.

PubMed

Braun-Sand, Sonja; Sharma, Pankaz K; Chu, Zhen T; Pisliakov, Andrei V; Warshel, Arieh

2008-05-01

The light-induced proton transport in bacteriorhodopsin has been considered as a model for other light-induced proton pumps. However, the exact nature of this process is still unclear. For example, it is not entirely clear what the driving force of the initial proton transfer is and, in particular, whether it reflects electrostatic forces or other effects. The present work simulates the primary proton transfer (PT) by a specialized combination of the EVB and the QCFF/PI methods. This combination allows us to obtain sufficient sampling and a quantitative free energy profile for the PT at different protein configurations. The calculated profiles provide new insight about energetics of the primary PT and its coupling to the protein conformational changes. Our finding confirms the tentative analysis of an earlier work (A. Warshel, Conversion of light energy to electrostatic energy in the proton pump of Halobacterium halobium, Photochem. Photobiol. 30 (1979) 285-290) and determines that the overall PT process is driven by the energetics of the charge separation between the Schiff base and its counterion Asp85. Apparently, the light-induced relaxation of the steric energy of the chromophore leads to an increase in the ion-pair distance, and this drives the PT process. Our use of the linear response approximation allows us to estimate the change in the protein conformational energy and provides the first computational description of the coupling between the protein structural changes and the PT process. It is also found that the PT is not driven by twist-modulated changes of the Schiff base's pKa, changes in the hydrogen bond directionality, or other non-electrostatic effects. Overall, based on a consistent use of structural information as the starting point for converging free energy calculations, we conclude that the primary event should be described as a light-induced formation of an unstable ground state, whose relaxation leads to charge separation and to the

46 CFR 118.300 - Fire pumps.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Fire pumps. 118.300 Section 118.300 Shipping COAST GUARD... OVERNIGHT ACCOMMODATIONS FOR MORE THAN 49 PASSENGERS FIRE PROTECTION EQUIPMENT Fire Main System § 118.300 Fire pumps. (a) A self priming, power driven fire pump must be installed on each vessel. (b) On a...

Chimeric microbial rhodopsins for optical activation of Gs-proteins

PubMed Central

Yoshida, Kazuho; Yamashita, Takahiro; Sasaki, Kengo; Inoue, Keiichi; Shichida, Yoshinori; Kandori, Hideki

2017-01-01

We previously showed that the chimeric proteins of microbial rhodopsins, such as light-driven proton pump bacteriorhodopsin (BR) and Gloeobacter rhodopsin (GR) that contain cytoplasmic loops of bovine rhodopsin, are able to activate Gt protein upon light absorption. These facts suggest similar protein structural changes in both the light-driven proton pump and animal rhodopsin. Here we report two trials to engineer chimeric rhodopsins, one for the inserted loop, and another for the microbial rhodopsin template. For the former, we successfully activated Gs protein by light through the incorporation of the cytoplasmic loop of β2-adrenergic receptor (β2AR). For the latter, we did not observe any G-protein activation for the light-driven sodium pump from Indibacter alkaliphilus (IndiR2) or a light-driven chloride pump halorhodopsin from Natronomonas pharaonis (NpHR), whereas the light-driven proton pump GR showed light-dependent G-protein activation. This fact suggests that a helix opening motion is common to G protein coupled receptor (GPCR) and GR, but not to IndiR2 and NpHR. Light-induced difference FTIR spectroscopy revealed similar structural changes between WT and the third loop chimera for each light-driven pump. A helical structural perturbation, which was largest for GR, was further enhanced in the chimera. We conclude that similar structural dynamics that occur on the cytoplasmic side of GPCR are needed to design chimeric microbial rhodopsins. PMID:29362703

Molecular mechanisms for generating transmembrane proton gradients

PubMed Central

Gunner, M.R.; Amin, Muhamed; Zhu, Xuyu; Lu, Jianxun

2013-01-01

Membrane proteins use the energy of light or high energy substrates to build a transmembrane proton gradient through a series of reactions leading to proton release into the lower pH compartment (P-side) and proton uptake from the higher pH compartment (N-side). This review considers how the proton affinity of the substrates, cofactors and amino acids are modified in four proteins to drive proton transfers. Bacterial reaction centers (RCs) and photosystem II (PSII) carry out redox chemistry with the species to be oxidized on the P-side while reduction occurs on the N-side of the membrane. Terminal redox cofactors are used which have pKas that are strongly dependent on their redox state, so that protons are lost on oxidation and gained on reduction. Bacteriorhodopsin is a true proton pump. Light activation triggers trans to cis isomerization of a bound retinal. Strong electrostatic interactions within clusters of amino acids are modified by the conformational changes initiated by retinal motion leading to changes in proton affinity, driving transmembrane proton transfer. Cytochrome c oxidase (CcO) catalyzes the reduction of O2 to water. The protons needed for chemistry are bound from the N-side. The reduction chemistry also drives proton pumping from N- to P-side. Overall, in CcO the uptake of 4 electrons to reduce O2 transports 8 charges across the membrane, with each reduction fully coupled to removal of two protons from the N-side, the delivery of one for chemistry and transport of the other to the P-side. PMID:23507617

PV Array Driven Adjustable Speed Drive for a Lunar Base Heat Pump

NASA Technical Reports Server (NTRS)

Domijan, Alexander, Jr.; Buchh, Tariq Aslam

1995-01-01

A study of various aspects of Adjustable Speed Drives (ASD) is presented. A summary of the relative merits of different ASD systems presently in vogue is discussed. The advantages of using microcomputer based ASDs is now widely understood and accepted. Of the three most popular drive systems, namely the Induction Motor Drive, Switched Reluctance Motor Drive and Brushless DC Motor Drive, any one may be chosen. The choice would depend on the nature of the application and its requirements. The suitability of the above mentioned drive systems for a photovoltaic array driven ASD for an aerospace application are discussed. The discussion is based on the experience of the authors, various researchers and industry. In chapter 2 a PV array power supply scheme has been proposed, this scheme will have an enhanced reliability in addition to the other known advantages of the case where a stand alone PV array is feeding the heat pump. In chapter 3 the results of computer simulation of PV array driven induction motor drive system have been included. A discussion on these preliminary simulation results have also been included in this chapter. Chapter 4 includes a brief discussion on various control techniques for three phase induction motors. A discussion on different power devices and their various performance characteristics is given in Chapter 5.

Fuel system for rotary distributor fuel injection pump

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klopfer, K.H.; Kelly, W.W.

1993-06-01

In a fuel injection pump having a drive shaft, a pump rotor driven by the drive shaft, reciprocating pumping means with periodic intake and pumping strokes to periodically receive an intake charge of fuel and deliver fuel at high pressure for fuel injection is described; a distributor head with a plurality of angularly spaced distributor outlets, the pump rotor providing a distributor rotor with a distributor port connected to the pumping means, the distributor rotor being rotatably mounted in the distributor head for sequential registration of the distributor port with the distributor outlets for distributing said high pressure delivery ofmore » fuel thereto; a fuel system for supplying fuel to the pumping means, having an end chamber at one end of the pump rotor and a fuel supply pump driven by the drive shaft and having an inlet and outlet, the supply pump outlet being connected to the end chamber for supplying fuel thereto, and a pressure regulator for regulating the fuel pressure in the end chamber; and a control valve connected between the pumping means and the end chamber and selectively opened during the intake strokes to supply fuel to the pumping means from the end chamber and during the pumping strokes to spill fuel from the pumping means into the end chamber to terminate said high pressure delivery of fuel; the improvement wherein the fuel system comprises a fuel return passage connected in series with the end chamber downstream thereof, wherein the pressure regulator is mounted in the return passage for regulating the upstream fuel pressure, including the upstream fuel pressure within the end chamber, and is connected for conducting excess fuel for return to the supply pump inlet, and wherein the supply pump is driven by the drive shaft to supply fuel at a rate exceeding the rate of said high pressure delivery of fuel for fuel injection and to provide excess fuel flow continuously through the end chamber and return passage to the pressure regulator.« less

Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus.

PubMed

Zahn, Sabine; Graef, Medina; Patsinakidis, Nikolaos; Landmann, Aysche; Surber, Christian; Wenzel, Joerg; Kuhn, Annegret

2014-07-01

Irradiation with ultraviolet (UV) light is an important exacerbating factor in cutaneous lupus erythematosus (CLE) and induces various effects in the skin of patients with the disease, such as cell death and inflammation. Recently, we demonstrated the ability of a broad-spectrum sunscreen to prevent UV-induced damage both in patients with CLE and healthy controls (HCs). The aim of this study was to evaluate whether the UV-dependent activation of interferon (IFN)-driven inflammation in CLE can also be prevented by application of the sunscreen. In 20 patients with different subtypes of CLE and 10 HCs, defined areas on the upper back were treated with a broad-spectrum liposomal sunscreen 20 min prior to a combined standardized UVA/UVB irradiation. Immunohistological analyses using antibodies directed against MxA, CD11c, CD123 and CD68 were performed from skin biopsies taken from areas before UV irradiation as well as from sunscreen-treated and sunscreen-untreated areas 24 and 72 h after UV irradiation. The expression of MxA was completely prevented by the sunscreen applied prior to UV irradiation in CLE patients and HCs. Additionally, sunscreen protection significantly diminished the number of the CD11c- and CD123-positive dendritic cells, which are suggested to be a major source of type I/III IFNs, in UV-irradiated skin of patients with CLE. Moreover, the application of the sunscreen prevented the increase in CD68-positive macrophages in both groups 72 h after UV irradiation. The data of this study demonstrate that UV protection reduces lesional tissue damage and inhibits the typical IFN-driven inflammatory response in CLE. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Constant-Pressure Hydraulic Pump

NASA Technical Reports Server (NTRS)

Galloway, C. W.

1982-01-01

Constant output pressure in gas-driven hydraulic pump would be assured in new design for gas-to-hydraulic power converter. With a force-multiplying ring attached to gas piston, expanding gas would apply constant force on hydraulic piston even though gas pressure drops. As a result, pressure of hydraulic fluid remains steady, and power output of the pump does not vary.

Proton pump inhibition and cancer therapeutics: A specific tumor targeting or it is a phenomenon secondary to a systemic buffering?

PubMed

Spugnini, Enrico; Fais, Stefano

2017-04-01

One of the unsolved mysteries in oncology includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg's discovery that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to the development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. In the last decades a primordial role for proton exchangers has been supported as a key tumor advantage in facing off the acidic milieu. Proton exchangers do not allow intracellular acidification through a continuous elimination of H+ either outside the cells or within the internal vacuoles. This article wants to comment a translational process through that led to the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed powerful chemosensitizers as well. In this process we achieved the clinical proof of concept that PPI may well be included in new anti-cancer strategies with a solid background and rationale. Copyright © 2017 Elsevier Ltd. All rights reserved.

46 CFR 76.10-5 - Fire pumps.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 3 2010-10-01 2010-10-01 false Fire pumps. 76.10-5 Section 76.10-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) PASSENGER VESSELS FIRE PROTECTION EQUIPMENT Fire Main System, Details § 76.10-5 Fire pumps. (a) Vessels shall be equipped with independently driven fire pumps in...

Appropriate proton pump inhibitors use in elderly outpatients according to recommendations.

PubMed

Schonheit, Claire; Le Petitcorps, Hélène; Pautas, Éric

2016-12-01

Proton pump inhibitors (PPI) are widely prescribed, particularly in elderly patients, and their side effects are underestimated. Recommendations of the french health authorities, some specific to the elderly, specify their indications. The main objective of this descriptive and prospective study was to assess in elderly patients the adequacy of PPI prescriptions to these recommendations and to the marketing authorization. Analysis of all patients hospitalized in an acute geriatric unit over a period of 2 years for which the drug prescription on admission included a PPI. For the 125 patients included (mean age 84 years), the PPI treatment period exceeded one year in 68% of cases and 49.6% of PPI prescriptions were not consistent with the recommendations; not recommended indications are mainly prevention of gastroduodenal lesions in case of antiplatelet, VKA or corticosteroid treatment (24%), anemia (12%) or epigastric pain (8.5%) without prior endoscopic exploration. Only 50.4% of patients treated with PPI had an upper gastro-intestinal endoscopy, which should be systematically performed in patients over 65 years according to the recommendations. Our study confirms the low appropriateness of PPI prescriptions, particularly in elderly patients. This can be explained by controversial issues or by difficulties in adapting these recommendations in geriatric practice.

Effect of Timing of Proton Pump Inhibitor Administration on Acid Suppression.

PubMed

Furuta, Kenji; Adachi, Kyoichi; Aimi, Masahito; Shimura, Shino; Mikami, Hironobu; Nishimura, Nobuhiro; Ishimura, Norihisa; Ishihara, Shunji; Naora, Kohji; Kinoshita, Yoshikazu

2016-01-01

Esomeprazole has been reported to show a strong acid suppression following preprandial as compared to postprandial administration, though no known study has compared the acid suppressing effects of other proton pump inhibitors between those administrations. The aim of this study was to compare intragastric pH levels following pre- and postprandial administrations of rabeprazole and esomeprazole. In 15 Helicobacter pylori-negative healthy volunteers, we measured intragastric pH after 7 days of pre- and postprandial administrations of rabeprazole (10 mg) or esomeprazole (20 mg) using a 5-way crossover design. Preprandial administration of esomeprazole showed stronger acid suppression than postprandial administration. The values for percent time at pH >4.0 over a 24-hour period increased from 45.3% with postprandial administration of esomeprazole to 54.4% with preprandial administration, while the percent time at pH >4.0 during daytime was increased to a greater extent from 51.4 to 66.5% with preprandial administration (p = 0.05). On the other hand, the acid suppressing effect of rabeprazole was not influenced by the timing of administration. The acid suppressing effect of esomeprazole is influenced by administration timing. In contrast, the acid suppressing effect of rabeprazole is not augmented by preprandial administration. © 2015 S. Karger AG, Basel.

Comparison Between Individually and Group-Based Insulin Pump Initiation by Time-Driven Activity-Based Costing

PubMed Central

Ridderstråle, Martin

2017-01-01

Background: Depending on available resources, competencies, and pedagogic preference, initiation of insulin pump therapy can be performed on either an individual or a group basis. Here we compared the two models with respect to resources used. Methods: Time-driven activity-based costing (TDABC) was used to compare initiating insulin pump treatment in groups (GT) to individual treatment (IT). Activities and cost drivers were identified, timed, or estimated at location. Medical quality and patient satisfaction were assumed to be noninferior and were not measured. Results: GT was about 30% less time-consuming and 17% less cost driving per patient and activity compared to IT. As a batch driver (16 patients in one group) GT produced an upward jigsaw-shaped accumulative cost curve compared to the incremental increase incurred by IT. Taking the alternate cost for those not attending into account, and realizing the cost of opportunity gained, suggested that GT was cost neutral already when 5 of 16 patients attended, and that a second group could be initiated at no additional cost as the attendance rate reached 15:1. Conclusions: We found TDABC to be effective in comparing treatment alternatives, improving cost control and decision making. Everything else being equal, if the setup is available, our data suggest that initiating insulin pump treatment in groups is far more cost effective than on an individual basis and that TDABC may be used to find the balance point. PMID:28366085

Enhanced Component Performance Study: Turbine-Driven Pumps 1998–2014

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schroeder, John Alton

2015-11-01

This report presents an enhanced performance evaluation of turbine-driven pumps (TDPs) at U.S. commercial nuclear power plants. The data used in this study are based on the operating experience failure reports from fiscal year 1998 through 2014 for the component reliability as reported in the Institute of Nuclear Power Operations (INPO) Consolidated Events Database (ICES). The TDP failure modes considered are failure to start (FTS), failure to run less than or equal to one hour (FTR=1H), failure to run more than one hour (FTR>1H), and normally running systems FTS and failure to run (FTR). The component reliability estimates and themore » reliability data are trended for the most recent 10-year period while yearly estimates for reliability are provided for the entire active period. Statistically significant increasing trends were identified for TDP unavailability, for frequency of start demands for standby TDPs, and for run hours in the first hour after start. Statistically significant decreasing trends were identified for start demands for normally running TDPs, and for run hours per reactor critical year for normally running TDPs.« less

Pumping approximately integrable systems

PubMed Central

Lange, Florian; Lenarčič, Zala; Rosch, Achim

2017-01-01

Weak perturbations can drive an interacting many-particle system far from its initial equilibrium state if one is able to pump into degrees of freedom approximately protected by conservation laws. This concept has for example been used to realize Bose–Einstein condensates of photons, magnons and excitons. Integrable quantum systems, like the one-dimensional Heisenberg model, are characterized by an infinite set of conservation laws. Here, we develop a theory of weakly driven integrable systems and show that pumping can induce large spin or heat currents even in the presence of integrability breaking perturbations, since it activates local and quasi-local approximate conserved quantities. The resulting steady state is qualitatively captured by a truncated generalized Gibbs ensemble with Lagrange parameters that depend on the structure but not on the overall amplitude of perturbations nor the initial state. We suggest to use spin-chain materials driven by terahertz radiation to realize integrability-based spin and heat pumps. PMID:28598444

A proton pump ATPase with testis-specific E1-subunit isoform required for acrosome acidification.

PubMed

Sun-Wada, Ge-Hong; Imai-Senga, Yoko; Yamamoto, Akitsugu; Murata, Yoshiko; Hirata, Tomoyuki; Wada, Yoh; Futai, Masamitsu

2002-05-17

The vacuolar-type H(+)-ATPases (V-ATPases) are a family of multimeric proton pumps involved in a wide variety of physiological processes. We have identified two novel mouse genes, Atp6e1 and Atp6e2, encoding testis-specific (E1) and ubiquitous (E2) V-ATPase subunit E isoforms, respectively. The E1 transcript appears about 3 weeks after birth, corresponding to the start of meiosis, and is expressed specifically in round spermatids in seminiferous tubules. Immunohistochemistry with isoform-specific antibodies revealed that the V-ATPase with E1 and a2 isoforms is located specifically in developing acrosomes of spermatids and acrosomes in mature sperm. In contrast, the E2 isoform was expressed in all tissues examined and present in the perinuclear compartments of spermatocytes. The E1 isoform exhibits 70% identity with the E2, and both isoforms functionally complemented a null mutation of the yeast counterpart VMA4, indicating that they are bona fide V-ATPase subunits. The chimeric enzymes showed slightly lower K(m)(ATP) than yeast V-ATPase. Consistent with the temperature-sensitive growth of Deltavma4-expressing E1 isoform, vacuolar membrane vesicles exhibited temperature-sensitive coupling between ATP hydrolysis and proton transport. These results suggest that E1 isoform is essential for energy coupling involved in acidification of acrosome.

Proton Pump Inhibitors Decrease Phlebotomy Need in HFE Hemochromatosis: Double-Blind Randomized Placebo-Controlled Trial.

PubMed

Vanclooster, Annick; van Deursen, Cees; Jaspers, Reggy; Cassiman, David; Koek, Ger

2017-09-01

Phlebotomy constitutes the established treatment for HFE-related hemochromatosis. Retrospective studies have suggested proton pump inhibitors (PPIs) reduce the need for phlebotomy in this population. We conducted a randomized controlled trial to prove this. Thirty p.C282Y homozygous patients were randomly allocated to PPI (pantoprazole 40 mg/day) or placebo for 12 months. Phlebotomies were performed when serum ferritin was > 100 μg/L. Phlebotomy need turned out to be significantly lower in patients taking PPI (P = .0052). PPI treatment significantly reduces the need for phlebotomies in p.C282Y homozygous patients. In view of the known long-term safety profile of PPI, they can be a valuable addition to standard therapy. Clinicaltrials.gov: NCT01524757. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study

PubMed Central

Vonkeman, Harald E; Fernandes, Robert W; van der Palen, Job; van Roon, Eric N; van de Laar, Mart AFJ

2007-01-01

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 ± 16.7 years (mean ± SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications. PMID:17521422

Characterization of an induced pressure pumping force for microfluidics

NASA Astrophysics Data System (ADS)

Jiang, Hai; Fan, Na; Peng, Bei; Weng, Xuan

2017-05-01

The electro-osmotic pumping and pressure-driven manipulation of fluids are considered as the most common strategies in microfluidic devices. However, both of them exhibit major disadvantages such as hard integration and high reagent consumption, and they are destructive methods for detection and photo bleaching. In this paper, an electric field-effect flow control approach, combining the electro-osmotic pumping force and the pressure-driven pumping force, was developed to generate the induced pressure-driven flow in a T-shaped microfluidic chip. Electro-osmotic flow between the T-intersection and two reservoirs was demonstrated, and it provided a stable, continuous, and electric field-free flow in the section of the microchannel without the electrodes. The velocity of the induced pressure-driven flow was linearly proportional to the applied voltages. Both numerical and experimental investigations were conducted to prove the concept, and the experimental results showed good agreement with the numerical simulations. In comparison to other induced pressure pumping methods, this approach can induce a high and controllable pressure drop in the electric field-free segment, subsequently causing an induced pressure-driven flow for transporting particles or biological cells. In addition, the generation of bubbles and the blocking of the microchannel are avoided.

Use of proton pump inhibitors is associated with fractures in young adults: a population-based study.

PubMed

Freedberg, D E; Haynes, K; Denburg, M R; Zemel, B S; Leonard, M B; Abrams, J A; Yang, Y-X

2015-10-01

Proton pump inhibitors (PPIs) are associated with risk for fracture in osteoporotic adults. In this population-based study, we found a significant association between PPIs and fracture in young adults, with evidence of a dose-response effect. Young adults who use PPIs should be cautioned regarding risk for fracture. Proton pump inhibitors (PPIs) are associated with fracture in adults with osteoporosis. Because PPI therapy may interfere with bone accrual and attainment of peak bone mineral density, we studied the association between use of PPIs and fracture in children and young adults. We conducted a population-based, case-control study nested within records from general medical practices from 1994 to 2013. Participants were 4-29 years old with ≥ 1 year of follow-up who lacked chronic conditions associated with use of long-term acid suppression. Cases of fracture were defined as the first incident fracture at any site. Using incidence density sampling, cases were matched with up to five controls by age, sex, medical practice, and start of follow-up. PPI exposure was defined as 180 or more cumulative doses of PPIs. Conditional logistic regression was used to estimate the odds ratio and confidence interval for use of PPIs and fracture. We identified 124,799 cases and 605,643 controls. The adjusted odds ratio for the risk of fracture associated with PPI exposure was 1.13 (95% CI 0.92 to 1.39) among children aged < 18 years old and 1.39 (95% CI 1.26 to 1.53) among young adults aged 18-29 years old. In young adults but not children, we observed a dose-response effect with increased total exposure to PPIs (p for trend <0.001). PPI use was associated with fracture in young adults, but overall evidence did not support a PPI-fracture relationship in children. Young adults who use PPIs should be cautioned regarding potentially increased risk for fracture, even if they lack traditional fracture risk factors.

Ligand protons in a frozen solution of copper histidine relax via a T1e-driven three-spin mechanism

NASA Astrophysics Data System (ADS)

Stoll, S.; Epel, B.; Vega, S.; Goldfarb, D.

2007-10-01

Davies electron-nuclear double resonance spectra can exhibit strong asymmetries for long mixing times, short repetition times, and large thermal polarizations. These asymmetries can be used to determine nuclear relaxation rates in paramagnetic systems. Measurements of frozen solutions of copper(L-histidine)2 reveal a strong field dependence of the relaxation rates of the protons in the histidine ligand, increasing from low (g‖) to high (g⊥) field. It is shown that this can be attributed to a concentration-dependent T1e-driven relaxation process involving strongly mixed states of three spins: the histidine proton, the Cu(II) electron spin of the same complex, and another distant electron spin with a resonance frequency differing from the spectrometer frequency approximately by the proton Larmor frequency. The protons relax more efficiently in the g⊥ region, since the number of distant electrons able to participate in this relaxation mechanism is higher than in the g‖ region. Analytical expressions for the associated nuclear polarization decay rate Teen-1 are developed and Monte Carlo simulations are carried out, reproducing both the field and the concentration dependences of the nuclear relaxation.

Excited state proton transfer in strongly enhanced GFP (sGFP2).

PubMed

van Oort, Bart; ter Veer, Mirelle J T; Groot, Marie Louise; van Stokkum, Ivo H M

2012-07-07

Proton transfer is an elementary process in biology. Green fluorescent protein (GFP) has served as an important model system to elucidate the mechanistic details of this reaction, because in GFP proton transfer can be induced by light absorption. We have used pump-dump-probe spectroscopy to study how proton transfer through the 'proton-wire' around the chromophore is affected by a combination of mutations in a modern GFP variety (sGFP2). The results indicate that in H(2)O, after absorption of a photon, a proton is transferred (A* → I*) in 5 ps, and back-transferred from a ground state intermediate (I → A) in 0.3 ns, similar to time constants found with GFPuv, although sGFP2 shows less heterogeneous proton transfer. This suggests that the mutations left the proton-transfer largely unchanged, indicating the robustness of the proton-wire. We used pump-dump-probe spectroscopy in combination with target analysis to probe suitability of the sGFP2 fluorophore for super-resolution microscopy.

Accelerator driven sub-critical core

DOEpatents

McIntyre, Peter M; Sattarov, Akhdiyor

2015-03-17

Systems and methods for operating an accelerator driven sub-critical core. In one embodiment, a fission power generator includes a sub-critical core and a plurality of proton beam generators. Each of the proton beam generators is configured to concurrently provide a proton beam into a different area of the sub-critical core. Each proton beam scatters neutrons within the sub-critical core. The plurality of proton beam generators provides aggregate power to the sub-critical core, via the proton beams, to scatter neutrons sufficient to initiate fission in the sub-critical core.

Chemiosmotic Energy Conservation in Dinoroseobacter shibae: Proton Translocation Driven by Aerobic Respiration, Denitrification, and Photosynthetic Light Reaction.

PubMed

Kirchhoff, Christian; Ebert, Matthias; Jahn, Dieter; Cypionka, Heribert

2018-01-01

Dinoroseobacter shibae is an aerobic anoxygenic phototroph and able to utilize light energy to support its aerobic energy metabolism. Since the cells can also grow anaerobically with nitrate and nitrite as terminal electron acceptor, we were interested in how the cells profit from photosynthesis during denitrification and what the steps of chemiosmotic energy conservation are. Therefore, we conducted proton translocation experiments and compared O 2 - , NO 3 - , and NO 2 - respiration during different light regimes and in the dark. We used wild type cells and transposon mutants with knocked-out nitrate- and nitrite- reductase genes ( napA and nirS ), as well as a mutant ( ppsR ) impaired in bacteriochlorophyll a synthesis. Light had a positive impact on proton translocation, independent of the type of terminal electron acceptor present. In the absence of an electron acceptor, however, light did not stimulate proton translocation. The light-driven add-on to proton translocation was about 1.4 H + /e - for O 2 respiration and about 1.1 H + /e - for NO 3 - and NO 2 - . We could see that the chemiosmotic energy conservation during aerobic respiration involved proton translocation, mediated by the NADH dehydrogenase, the cytochrome bc 1 complex, and the cytochrome c oxidase. During denitrification the last proton translocation step of the electron transport was missing, resulting in a lower H + /e - ratio during anoxia. Furthermore, we studied the type of light-harvesting and found that the cells were able to channel light from the green-blue spectrum most efficiently, while red light has only minor impact. This fits well with the depth profiles for D. shibae abundance in the ocean and the penetration depth of light with different wavelengths into the water column.

Vanadium-pumped titanium x-ray laser

DOEpatents

Nilsen, J.

1992-05-26

A resonantly photo-pumped x-ray laser is formed of a vanadium and titanium foil combination that is driven by two beams of intense line focused optical laser radiation. Ground state neon-like titanium ions are resonantly photo-pumped by line emission from fluorine-like vanadium ions. 4 figs.

The Indications, Applications, and Risks of Proton Pump Inhibitors.

PubMed

Mössner, Joachim

2016-07-11

Proton pump inhibitors (PPI) are the most effective drugs for inhibiting gastric acid secretion. They have been in clinical use for more than 25 years, In 2014, 3.475 billion daily defined doses (DDD) of PPI were prescribed in Germany. This high number alone calls for a critical analysis of the spectrum of indications for PPI and their potential adverse effects. This review is based on pertinent publications retrieved by a selective search in the PubMed and Cochrane Library databases, with particular emphasis on randomized, prospective multicenter trials, cohort studies, case-control studies, and meta-analyses. The inhibition of gastric acid secretion with PPI is successfully used for the treatment of gastroesophageal reflux disease and of gastric and duodenal ulcers, for the secondary prevention of gastroduodenal lesions that have arisen under treatment with nonsteroidal anti-inflammatory drugs and acetylsalicylic acid, and for the prevention of recurrent hemorrhage from ulcers after successful endoscopic hemostasis. PPI are given along with practically all antibiotic regimens for the eradication of Helicobacter pylori infection. The number of prescriptions for PPI has risen linearly over the past 25 years. As there has been no broadening of indications, one may well ask whether the current, extensive use of PPI is justified. There is evidence that patients taking PPI are at greater risk for fractures. Moreover, the vitamin B12 level should be checked occasionally in all patients taking PPI. PPI are among the more effective drugs for the treatment of diseases associated with gastric acid. In view of their cost and potential adverse effects, they should only be prescribed for scientifically validated indications.

Enhanced proton acceleration in an applied longitudinal magnetic field

DOE PAGES

Arefiev, A.; Toncian, T.; Fiksel, G.

2016-10-31

Using two-dimensional particle-in-cell simulations, we examine how an externally applied strong magnetic field impacts proton acceleration in laser-irradiated solid-density targets. We find that a kT-level external magnetic field can sufficiently inhibit transverse transport of hot electrons in a flat laser-irradiated target. While the electron heating by the laser remains mostly unaffected, the reduced electron transport during proton acceleration leads to an enhancement of maximum proton energies and the overall number of energetic protons. The resulting proton beam is much better collimated compared to a beam generated without applying a kT-level magnetic field. A factor of three enhancement of the lasermore » energy conversion efficiency into multi-MeV protons is another effect of the magnetic field. The required kT-level magnetic fields are becoming feasible due to a significant progress that has been made in generating magnetic fields with laser-driven coils using ns-long laser pulses. The possibility of improving characteristics of laser-driven proton beams using such fields is a strong motivation for further development of laser-driven magnetic field capabilities.« less

Enhanced proton acceleration in an applied longitudinal magnetic field

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arefiev, A.; Toncian, T.; Fiksel, G.

Using two-dimensional particle-in-cell simulations, we examine how an externally applied strong magnetic field impacts proton acceleration in laser-irradiated solid-density targets. We find that a kT-level external magnetic field can sufficiently inhibit transverse transport of hot electrons in a flat laser-irradiated target. While the electron heating by the laser remains mostly unaffected, the reduced electron transport during proton acceleration leads to an enhancement of maximum proton energies and the overall number of energetic protons. The resulting proton beam is much better collimated compared to a beam generated without applying a kT-level magnetic field. A factor of three enhancement of the lasermore » energy conversion efficiency into multi-MeV protons is another effect of the magnetic field. The required kT-level magnetic fields are becoming feasible due to a significant progress that has been made in generating magnetic fields with laser-driven coils using ns-long laser pulses. The possibility of improving characteristics of laser-driven proton beams using such fields is a strong motivation for further development of laser-driven magnetic field capabilities.« less

Proton pump inhibitor failure in gastro-oesophageal reflux disease: a perspective aided by the Gartner hype cycle.

PubMed

Heading, Robert C

2017-04-01

Some patients with gastro-oesophageal reflux disease (GORD) experience symptoms despite proton pump inhibitor (PPI) treatment. In the early years of their availability, these drugs were thought to be a highly effective treatment for GORD and realisation that symptom relief was often incomplete came as a disappointment. This review considers the evolution of thinking with the aid of the Gartner hype cycle - a graphical depiction of the process of innovation, evolution and adoption of new technologies. Acknowledging that over-simplistic concepts of GORD have been largely responsible for inflated expectations of PPI therapy is an important step forward in establishing how patients with persistent symptoms, despite PPIs, should be assessed and treated. © Royal College of Physicians 2017. All rights reserved.

Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach.

PubMed

Taylor, Sophie; Spugnini, Enrico Pierluigi; Assaraf, Yehuda G; Azzarito, Tommaso; Rauch, Cyril; Fais, Stefano

2015-11-01

Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis. The fast efflux of anticancer drugs mediated by multidrug efflux pumps and the partial or complete reversibility of chemoresistance combined with the absence of genetic mutations suggests a multifactorial process. However, a growing body of recent evidence suggests that chemoresistance is often triggered by the highly acidic microenvironment of tumors. The vast majority of drugs, including conventional chemotherapeutics and more recent biological agents, are weak bases that are quickly protonated and neutralized in acidic environments, such as the extracellular microenvironment and the acidic organelles of tumor cells. It is therefore essential to develop new strategies to overcome the entrapment and neutralization of weak base drugs. One such strategy is the use of proton pump inhibitors which can enhance tumor chemosensitivity by increasing the pH of the tumor microenvironment. Recent clinical trials in animals with spontaneous tumors have indicated that patient alkalization is capable of reversing acquired chemoresistance in a large percentage of tumors that are refractory to chemotherapy. Of particular interest was the benefit of alkalization for patients undergoing metronomic regimens which are becoming more widely used in veterinary medicine. Overall, these results provide

AN ONLINE, RADIATION HARD PROTON ENERGY-RESOLVING SCINTILLATOR STACK FOR LASER-DRIVEN PROTON BUNCHES.

PubMed

Englbrecht, Franz Siegfried; Würl, Matthias; Olivari, Francesco; Ficorella, Andrea; Kreuzer, Christian; Lindner, Florian H; Palma, Matteo Dalla; Pancheri, Lucio; Betta, Gian-Franco Dalla; Schreiber, Jörg; Quaranta, Alberto; Parodi, Katia

2018-02-03

We report on a scintillator-based online detection system for the spectral characterization of polychromatic proton bunches. Using up to nine stacked layers of radiation hard polysiloxane scintillators, coupled to and readout edge-on by a large area pixelated CMOS detector, impinging polychromatic proton bunches were characterized. The energy spectra were reconstructed using calibration data and simulated using Monte-Carlo simulations. Despite the scintillator stack showed some problems like thickness inhomogeneities and unequal layer coupling, the prototype allows to obtain a first estimate of the energy spectrum of proton beams. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Flow pumping system for physiological waveforms.

PubMed

Tsai, William; Savaş, Omer

2010-02-01

A pulsatile flow pumping system is developed to replicate flow waveforms with reasonable accuracy for experiments simulating physiological blood flows at numerous points in the body. The system divides the task of flow waveform generation between two pumps: a gear pump generates the mean component and a piston pump generates the oscillatory component. The system is driven by two programmable servo controllers. The frequency response of the system is used to characterize its operation. The system has been successfully tested in vascular flow experiments where sinusoidal, carotid, and coronary flow waveforms are replicated.

The Contribution of Compressional Magnetic Pumping to the Energization of the Earth's Outer Electron Radiation Belt During High-Speed Stream-Driven Storms

NASA Astrophysics Data System (ADS)

Borovsky, Joseph E.; Horne, Richard B.; Meredith, Nigel P.

2017-12-01

Compressional magnetic pumping is an interaction between cyclic magnetic compressions and pitch angle scattering with the scattering acting as a catalyst to allow the cyclic compressions to energize particles. Compressional magnetic pumping of the outer electron radiation belt at geosynchronous orbit in the dayside magnetosphere is analyzed by means of computer simulations, wherein solar wind compressions of the dayside magnetosphere energize electrons with electron pitch angle scattering by chorus waves and by electromagnetic ion cyclotron (EMIC) waves. The magnetic pumping is found to produce a weak bulk heating of the electron radiation belt, and it also produces an energetic tail on the electron energy distribution. The amount of energization depends on the robustness of the solar wind compressions and on the amplitude of the chorus and/or EMIC waves. Chorus-catalyzed pumping is better at energizing medium-energy (50-200 keV) electrons than it is at energizing higher-energy electrons; at high energies (500 keV-2 MeV) EMIC-catalyzed pumping is a stronger energizer. The magnetic pumping simulation results are compared with energy diffusion calculations for chorus waves in the dayside magnetosphere; in general, compressional magnetic pumping is found to be weaker at accelerating electrons than is chorus-driven energy diffusion. In circumstances when solar wind compressions are robust and when EMIC waves are present in the dayside magnetosphere without the presence of chorus, EMIC-catalyzed magnetic pumping could be the dominant energization mechanism in the dayside magnetosphere, but at such times loss cone losses will be strong.

Pharmacoepidemiology for nephrologists: do proton pump inhibitors cause chronic kidney disease?

PubMed Central

Tomlinson, Laurie A.; Fogarty, Damian G.; Douglas, Ian; Nitsch, Dorothea

2017-01-01

Abstract Pharmacoepidemiology studies are increasingly used for research into safe prescribing in chronic kidney disease (CKD). Typically, patients prescribed a drug are compared with patients who are not on the drug and outcomes are compared to draw conclusions about the drug effects. This review article aims to provide the reader with a framework to critically appraise such research. A key concern in pharmacoepidemiology studies is confounding, in that patients who have worse health status are prescribed more drugs or different agents and their worse outcomes are attributed to the drugs not the health status. It may be challenging to adjust for this using statistical methods unless a comparison group with a similar health status but who are prescribed a different (comparison) drug(s) is identified. Another challenge in pharmacoepidemiology is outcome misclassification, as people who are more ill engage more often with the health service, leading to earlier diagnosis in people who are frequent attenders. Finally, using replication cohorts with the same methodology in the same type of health system does not ensure that findings are more robust. We use two recent papers that investigated the association of proton pump inhibitor drugs with CKD as a device to review the main pitfalls of pharmacoepidemiology studies and how to attempt to mitigate against potential biases that can occur. PMID:28201528

Proton Pump Inhibitors and Kidney Disease - GI Upset for the Nephrologist?

PubMed

Toth-Manikowski, Stephanie; Grams, Morgan E

2017-05-01

Widely regarded as safe and effective, proton pump inhibitors (PPIs) are among the most commonly used medications in the world today. However, a spate of observational studies suggest an association between PPI use and adverse events, including infection, bone fracture, and dementia. This review details evidence linking the use of PPI therapy to the development of kidney disease, including early case reports of acute interstitial nephritis and subsequent large observational studies of acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD). The majority of studies showed higher risk of kidney outcomes among persons prescribed PPI medications, with effect sizes that were slightly higher for AKI (∼2-3-fold) compared to CKD and ESRD (1.2-1.8-fold). Although observational pharmaco-epidemiology studies are limited by the possibility of residual confounding and confounding by indication, many of the described studies conducted rigorous sensitivity analyses aimed at minimizing these biases, including new-user design, comparison to similar agents (e.g., histamine 2 receptor antagonists), and evaluation for a dose-response, with robust results. Given the widespread use of PPIs, even a small effect on kidney outcomes could result in large public health burden. Timely cessation of PPI therapy when there is no clear indication for use might reduce the population burden of kidney disease.

Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole.

PubMed

Qi, Fang; Zhu, Liqin; Li, Na; Ge, Tingyue; Xu, Gaoqi; Liao, Shasha

2017-04-01

This study aimed to determine the influence of proton pump inhibitors (PPIs) on the pharmacokinetics of voriconazole and to characterise potential drug-drug interactions (DDIs) between voriconazole and various PPIs (omeprazole, esomeprazole, lansoprazole and rabeprazole). Using adjusted physicochemical data and the pharmacokinetic (PK) parameters of voriconazole and PPIs, physiologically based pharmacokinetic (PBPK) models were built and were verified in healthy subjects using GastroPlus TM to predict the plasma concentration-time profiles of voriconazole and PPIs. These models were then used to assess potential DDIs for voriconazole when administered with PPIs. The results indicated the PBPK model-simulated plasma concentration-time profiles of both voriconazole and PPIs were consistent with the observed profiles. In addition, the DDI simulations suggested that the PK values of voriconazole increased to various degrees when combined with several PPIs. The area under the plasma concentration-time curve for the time of the simulation (AUC 0- t ) of voriconazole was increased by 39%, 18%, 12% and 1% when co-administered with omeprazole, esomeprazole, lansoprazole and rabeprazole, respectively. Omeprazole was the most potent CYP2C19 inhibitor tested, whereas rabeprazole had no influence on voriconazole (omeprazole > esomeprazole > lansoprazole > rabeprazole). However, in consideration of the therapeutic concentration range, dosage adjustment of voriconazole is unnecessary regardless of which PPI was co-administered. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Proton-pump inhibitor use is associated with low serum magnesium concentrations

PubMed Central

Danziger, John; William, Jeffrey H.; Scott, Daniel J.; Lee, Joon; Lehman, Li-wei; Mark, Roger G.; Howell, Michael D.; Celi, Leo A.; Mukamal, Kenneth J.

2017-01-01

Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (< 1.6 mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012 mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028 mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy. PMID:23325090

Field Performance of Inverter-Driven Heat Pumps in Cold Climates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williamson, James; Aldrich, Robb

2015-08-19

Traditionally, air-source heat pumps (ASHPs) have been used more often in warmer climates; however, some new ASHPs are gaining ground in colder areas. These systems operate at subzero (Fahrenheit) temperatures and many do not include backup electric resistance elements. There are still uncertainties, however, about capacity and efficiency in cold weather. Also, questions such as “how cold is too cold?” do not have clear answers. These uncertainties could lead to skepticism among homeowners; poor energy savings estimates; suboptimal system selection by heating, ventilating, and air-conditioning contractors; and inconsistent energy modeling. In an effort to better understand and characterize the heatingmore » performance of these units in cold climates, the U.S. Department of Energy Building America team, Consortium for Advanced Residential Buildings (CARB), monitored seven inverter-driven, ductless ASHPs across the Northeast. Operating data were collected for three Mitsubishi FE18 units, three Mitsubishi FE12 units, and one Fujitsu 15RLS2 unit. The intent of this research was to assess heat output, electricity consumption, and coefficients of performance (COPs) at various temperatures and load conditions. This assessment was accomplished with long- and short-term tests that measured power consumption; supply, return, and outdoor air temperatures; and airflow through the indoor fan coil.« less

Cutaneous Collagenous Vasculopathy

PubMed Central

Ortleb, Melanie; Boyd, Alan S.; Powers, Jennifer

2015-01-01

Cutaneous collagenous vasculopathy is a rare microangiopathy of dermal blood vessels. Clinically indistinguishable from generalized essential telangiectasia, this condition is diagnosed by its unique histological appearance. In contrast to other primary telangiectatic processes, cutaneous collagenous vasculopathy has dilated vascular structures that contain deposits of eosinophilic hyaline material within the vessel walls. To date, cutaneous collagenous vasculopathy has been described in a total of 19 cases in the medical literature. The first several cases were described exclusively in middle-aged to elderly men. Though it has now been described in both men and women, cutaneous collagenous vasculopathy is still most often described in middle-aged to older adults. No particular disease or medication has been linked to the development of cutaneous collagenous vasculopathy, and the etiology remains unknown. In this case series, the authors present three additional patients diagnosed with cutaneous collagenous vasculopathy and discuss their clinical and histopathologic features. PMID:26705441

Molecular basis of proton uptake in single and double mutants of cytochrome c oxidase

NASA Astrophysics Data System (ADS)

Henry, Rowan M.; Caplan, David; Fadda, Elisa; Pomès, Régis

2011-06-01

Cytochrome c oxidase, the terminal enzyme of the respiratory chain, utilizes the reduction of dioxygen into water to pump protons across the mitochondrial inner membrane. The principal pathway of proton uptake into the enzyme, the D channel, is a 2.5 nm long channel-like cavity named after a conserved, negatively charged aspartic acid (D) residue thought to help recruiting protons to its entrance (D132 in the first subunit of the S. sphaeroides enzyme). The single-point mutation of D132 to asparagine (N), a neutral residue, abolishes enzyme activity. Conversely, replacing conserved N139, one-third into the D channel, by D, induces a decoupled phenotype, whereby oxygen reduction proceeds but not proton pumping. Intriguingly, the double mutant D132N/N139D, which conserves the charge of the D channel, restores the wild-type phenotype. We use molecular dynamics simulations and electrostatic calculations to examine the structural and physical basis for the coupling of proton pumping and oxygen chemistry in single and double N139D mutants. The potential of mean force for the conformational isomerization of N139 and N139D side chains reveals the presence of three rotamers, one of which faces the channel entrance. This out-facing conformer is metastable in the wild-type and in the N139D single mutant, but predominant in the double mutant thanks to the loss of electrostatic repulsion with the carboxylate group of D132. The effects of mutations and conformational isomerization on the pKa of E286, an essential proton-shuttling residue located at the top of the D channel, are shown to be consistent with the electrostatic control of proton pumping proposed recently (Fadda et al 2008 Biochim. Biophys. Acta 1777 277-84). Taken together, these results suggest that preserving the spatial distribution of charges at the entrance of the D channel is necessary to guarantee both the uptake and the relay of protons to the active site of the enzyme. These findings highlight the interplay

An improved design of axially driven permanent maglev centrifugal pump with streamlined impeller.

PubMed

Qian, K X; Zeng, P; Ru, W M; Yuan, H Y

2007-01-01

In 1839, Earnshaw proved theoretically that it is impossible to achieve a stable equilibrium with a pure permanent maglev. Furthermore, in 1939, Braunbeck deduced that it is only possible to stabilize a super conductive or an electric maglev. In 2000, however, the present authors discovered that stable levitation is achievable by a combination of permanent magnetic and nonmagnetic forces, and its stability can be maintained even with mere passive magnetic forces by use of the gyro-effect. An improved design of permanent maglev impeller pump has been developed. Passive magnetic (PM) bearings support the rotor radially; on its right side, an impeller is fixed and on its left side a motor magnets-assemble is mounted. Unlike a previous prototype design, in which the rotor magnets were driven by a motor via magnetic coupling, a motor coil is installed opposite to the motor magnets disc, producing a rotating magnetic field. At standstill or if the rotating speed is lower than 4000 rpm, the rotor has one axial point contact with the motor coil. The contact point is located at the centre of the rotor. As the rotating speed increases gradually to higher than 4000 rpm, the rotor will be drawn off from the contact point by the hydrodynamic force of the fluid. Then the rotor becomes fully suspended. For radial and peripheral stabilization, a gyro-effect is important, which is realized by designing the motor magnets disc to have large diameter, short length and high rotating speed; for axial stability, an axial rehabilitating force is necessary, which is produced by PM bearings. The rotor demonstrated a full levitation by rotation over 4000 rpm. As a left ventricular assist device, the rotation of the pump has a speed range from 5000 to 8000 rpm. The relation between pressure head and flow rate indicates that there is neither mechanical friction nor hydrodynamic turbulence inside the pump; the former is due to the frictionless maglev and the latter is a result of the

Randomized controlled trial of transoral incisionless fundoplication vs. proton pump inhibitors for treatment of gastroesophageal reflux disease.

PubMed

Witteman, Bart P L; Conchillo, Jose M; Rinsma, Nicolaas F; Betzel, Bark; Peeters, Andrea; Koek, Ger H; Stassen, Laurents P S; Bouvy, Nicole D

2015-04-01

Transoral incisionless fundoplication (TIF) was developed in an attempt to create a minimally invasive endoscopic procedure that mimics antireflux surgery. The objective of this trial was to evaluate effectiveness of TIF compared with proton pump inhibition in a population consisting of gastroesophageal reflux disease (GERD) patients controlled with proton pump inhibitors (PPIs) who opted for an endoscopic intervention over lifelong drug dependence. Patients with chronic GERD were randomized (2:1) for TIF or continuation of PPI therapy. American Society of Anesthesiologists >2, body mass index >35 kg/m(2), hiatal hernia >2 cm, and esophageal motility disorders were exclusion criteria. Primary outcome measure was GERD-related quality of life. Secondary outcome measures were esophageal acid exposure, number of reflux episodes, PPI usage, appearance of the gastroesophageal valve, and healing of reflux esophagitis. Crossover for the PPI group was allowed after 6 months. A total of 60 patients (TIF n=40, PPI n=20, mean body mass index 26 kg/m(2), 37 male) were included. At 6 months, GERD symptoms were more improved in the TIF group compared with the PPI group (P<0.001), with a similar improvement of distal esophageal acid exposure (P=0.228) compared with baseline. The pH normalization for TIF group and PPI group was 50% and 63%, respectively. All patients allocated for PPI treatment opted for crossover. At 12 months, quality of life remained improved after TIF compared with baseline (P<0.05), but no improvement in esophageal acid exposure compared with baseline was found (P=0.171) and normalization of pH was accomplished in only 29% in conjunction with deteriorated valve appearances at endoscopy and resumption of PPIs in 61%. Although TIF resulted in an improved GERD-related quality of life and produced a short-term improvement of the antireflux barrier in a selected group of GERD patients, no long-term objective reflux control was achieved.

Transepithelial leak in Barrett's esophagus patients: The role of proton pump inhibitors

PubMed Central

Farrell, Christopher; Morgan, Melissa; Tully, Owen; Wolov, Kevin; Kearney, Keith; Ngo, Benjamin; Mercogliano, Giancarlo; Thornton, James J; Valenzano, Mary Carmen; Mullin, James M

2012-01-01

AIM: To determine if the observed paracellular sucrose leak in Barrett’s esophagus patients is due to their proton pump inhibitor (PPI) use. METHODS: The in vivo sucrose permeability test was administered to healthy controls, to Barrett’s patients and to non-Barrett’s patients on continuous PPI therapy. Degree of leak was tested for correlation with presence of Barrett’s, use of PPIs, and length of Barrett’s segment and duration of PPI use. RESULTS: Barrett’s patients manifested a near 3-fold greater, upper gastrointestinal sucrose leak than healthy controls. A decrease of sucrose leak was observed in Barrett’s patients who ceased PPI use for 7 d. Although initial introduction of PPI use (in a PPI-naïve population) results in dramatic increase in sucrose leak, long-term, continuous PPI use manifested a slow spontaneous decline in leak. The sucrose leak observed in Barrett’s patients showed no correlation to the amount of Barrett’s tissue present in the esophagus. CONCLUSION: Although future research is needed to determine the degree of paracellular leak in actual Barrett’s mucosa, the relatively high degree of leak observed with in vivo sucrose permeability measurement of Barrett’s patients reflects their PPI use and not their Barrett’s tissue per se. PMID:22719187

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine.

PubMed

El Rouby, Nihal; Lima, John J; Johnson, Julie A

2018-04-01

Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.

Protons pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits.

PubMed

Lué, Alberto; Lanas, Angel

2016-12-28

Proton pump inhibitors (PPIs) represent a milestone in the treatment of acid-related diseases, and are the mainstay in preventing upper gastrointestinal bleeding in high-risk patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin. However, this beneficial effect does not extend to the lower gastrointestinal tract. PPIs do not prevent NSAID or aspirin-associated lower gastrointestinal bleeding (LGB). PPIs may increase both small bowel injury related to NSAIDs and low-dose aspirin treatment and the risk of LGB. Recent studies suggested that altering intestinal microbiota by PPIs may be involved in the pathogenesis of NSAID-enteropathy. An increase in LGB hospitalization rates may occur more frequently in older patients with more comorbidities and are associated with high hospital resource utilization, longer hospitalization, and increased mortality. Preventive strategies for NSAID and aspirin-associated gastrointestinal bleeding should be directed toward preventing both upper and lower gastrointestinal damage. Future research should be directed toward identifying patients at low-risk for gastrointestinal events associated with the use of NSAIDs or aspirin to avoid inappropriate PPI prescribing. Alternatively, the efficacy of new pharmacologic strategies should be evaluated in high-risk groups, with the aim of reducing the risk of both upper and lower gastrointestinal bleeding in these patients.

Proton pump inhibitors alter the composition of the gut microbiota.

PubMed

Jackson, Matthew A; Goodrich, Julia K; Maxan, Maria-Emanuela; Freedberg, Daniel E; Abrams, Julian A; Poole, Angela C; Sutter, Jessica L; Welter, Daphne; Ley, Ruth E; Bell, Jordana T; Spector, Tim D; Steves, Claire J

2016-05-01

Proton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort. We investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study. We identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut. Our findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Obesity does not affect treatment outcomes with proton pump inhibitors.

PubMed

Sharma, Prateek; Vakil, Nimish; Monyak, John T; Silberg, Debra G

2013-09-01

Obesity is associated with increased risk of gastroesophageal reflux disease (GERD). To evaluate the effect of obesity on symptom resolution in patients with nonerosive reflux disease (NERD) and healing rates in patients with erosive esophagitis (EE). Two post hoc analyses were performed. Analyses included pooled data from randomized, double-blind, multicenter studies of proton pump inhibitors (PPIs) in GERD patients. Analysis 1 included 704 patients with NERD receiving esomeprazole 20 mg, esomeprazole 40 mg, or placebo. Analysis 2 included 11,027 patients with EE receiving esomeprazole 40 mg, omeprazole 20 mg, or lansoprazole 30 mg. For NERD patients, no significant association between baseline heartburn severity and body mass index (BMI) was observed. In EE patients, overweight (BMI 25 to <35 kg/m) and obese (BMI ≥35 kg/m) patients had significantly higher rates of Los Angeles (LA) grade C or D EE than patients with BMI <25 kg/m (P<0.0001). Percentages of PPI-treated patients who achieved heartburn resolution or EE healing within a given LA grade were similar across BMI categories. Heartburn resolution was significantly associated with treatment (esomeprazole vs. placebo), increasing age, and for men versus women (all P≤0.0284). EE healing was significantly associated with PPI treatment (esomeprazole and lansoprazole vs. omeprazole), increasing age, race, presence of a hiatal hernia, and lower LA grade at baseline (all P≤0.0183). In patients with GERD, high BMI was associated with more severe EE at baseline. However, during PPI treatment, BMI is not a significant independent predictor of heartburn resolution or EE healing.

Strategies for discontinuation of proton pump inhibitors: a systematic review.

PubMed

Haastrup, Peter; Paulsen, Maja S; Begtrup, Luise M; Hansen, Jane M; Jarbøl, Dorte E

2014-12-01

Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. Systematic review based on clinical studies investigating discontinuation strategies and discontinuation rates for users of antisecretory medication judged eligible for withdrawal. The databases Medline, Embase and Cochrane Library were searched to December 2013 using the terms antisecretory, anti-ulcer, PPI, acid suppressant, discontinuation, step-down, step down, cessation, tapering, withdrawal and withhold. Search terms were used either singularly or in combination. Papers written in English or Scandinavian were included. Concurrent hand searching was undertaken to pursue references of references. The website ClinicalTrials.gov was searched for unpublished results and ongoing studies. A total of 371 abstracts were scrutinized to determine relevancy. The thorough search resulted in six clinical studies on strategies for discontinuation of PPIs. All discontinuation regimens used in the studies differed, and several interventions have been tested in order to decrease use of PPIs. Discontinuations were reported across all studies ranging from 14% to 64% without deteriorating symptom control. Tapering seems to be a more effective discontinuation strategy than abrupt discontinuation. Discontinuation of PPIs is feasible in a clinical setting, and a substantial number of the patients treated without a clear indication can safely reduce or discontinue treatment. Tapering seems to be the most effective way of doing this. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Safe use of proton pump inhibitors in patients with cirrhosis.

PubMed

Weersink, Rianne A; Bouma, Margriet; Burger, David M; Drenth, Joost P H; Froukje Harkes-Idzinga, S; Hunfeld, Nicole G M; Metselaar, Herold J; Monster-Simons, Margje H; van Putten, Sandra A W; Taxis, Katja; Borgsteede, Sander D

2018-04-24

Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in cirrhosis. A systematic literature search identified studies about the safety (i.e. adverse events) and pharmacokinetics of PPIs in cirrhotic patients. This evidence and data from the product information was reviewed by an expert panel who classified drugs as safe; no additional risks known; additional risks known; unsafe; or unknown. Guidance was aimed at the oral use of PPIs and categorized by the severity of cirrhosis, using the Child-Turcotte-Pugh (CTP) classification. A total of 69 studies were included. Esomeprazole, omeprazole and rabeprazole were classified as having 'no additional risks known'. A reduction in maximum dose of omeprazole and rabeprazole is recommended for CTP A and B patients. For patients with CTP C cirrhosis, the only PPI advised is esomeprazole in a maximum dosage of 20 mg per day. Pantoprazole and lansoprazole were classified as unsafe, because of 4- to 8-fold increased exposure. The use of PPIs in cirrhotic patients has been associated with the development of infections and hepatic encephalopathy and should be carefully considered. We suggest using esomeprazole, omeprazole or rabeprazole in patients with CTP A or B cirrhosis and only esomeprazole in patients with CTP C. Pharmacokinetic changes are also important to consider when prescribing PPIs to vulnerable, cirrhotic patients. This article is protected by copyright. All rights reserved.

The influence of proton pump inhibitors and other commonly used medication on the gut microbiota.

PubMed

Imhann, Floris; Vich Vila, Arnau; Bonder, Marc Jan; Lopez Manosalva, Ailine G; Koonen, Debby P Y; Fu, Jingyuan; Wijmenga, Cisca; Zhernakova, Alexandra; Weersma, Rinse K

2017-07-04

Proton pump inhibitors (PPIs), used to treat gastro-esophageal reflux and prevent gastric ulcers, are among the most widely used drugs in the world. The use of PPIs is associated with an increased risk of enteric infections. Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI-use on the gut microbiota. We discovered profound differences in the gut microbiota of PPI users: 20% of their bacterial taxa were statistically significantly altered compared with those of non-users. Moreover, we found that it is not only PPIs, but also antibiotics, antidepressants, statins and other commonly used medication were associated with distinct gut microbiota signatures. As a consequence, commonly used medications could affect how the gut microbiota resist enteric infections, promote or ameliorate gut inflammation, or change the host's metabolism. More studies are clearly needed to understand the role of commonly used medication in altering the gut microbiota as well as the subsequent health consequences.

Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling.

PubMed

Zeng, Wei-Zheng; Liu, Di-Shi; Liu, Lu; She, Liang; Wu, Long-Jun; Xu, Tian-Le

2015-09-15

Extracellular transients of pH alterations likely mediate signal transduction in the nervous system. Neuronal acid-sensing ion channels (ASICs) act as sensors for extracellular protons, but the mechanism underlying ASIC activation remains largely unknown. Here, we show that, following activation of a light-activated proton pump, Archaerhodopsin-3 (Arch), proton transients induced ASIC currents in both neurons and HEK293T cells co-expressing ASIC1a channels. Using chimera proteins that bridge Arch and ASIC1a by a glycine/serine linker, we found that successful coupling occurred within 15 nm distance. Furthermore, two-cell sniffer patch recording revealed that regulated release of protons through either Arch or voltage-gated proton channel Hv1 activated neighbouring cells expressing ASIC1a channels. Finally, computational modelling predicted the peak proton concentration at the intercellular interface to be at pH 6.7, which is acidic enough to activate ASICs in vivo. Our results highlight the pathophysiological role of proton signalling in the nervous system.

Vanadium-pumped titanium x-ray laser

DOEpatents

Nilsen, Joseph

1992-01-01

A resonantly photo-pumped x-ray laser (10) is formed of a vanadium (12) and titanium (14) foil combination (16) that is driven by two beams (18, 20) of intense line focused (22, 24) optical laser radiation. Ground state neon-like titanium ions (34) are resonantly photo-pumped by line emission from fluorine-like vanadium ions (32).

Cutaneous metastasis of cholangiocarcinoma.

PubMed

Liu, Min; Liu, Bai-Long; Liu, Bin; Guo, Liang; Wang, Qiang; Song, Yan-Qiu; Dong, Li-Hua

2015-03-14

To investigate the clinical characteristics and prognostic factors of cutaneous metastasis of cholangiocarcinoma by a retrospective analysis of published cases. An extensive search was conducted in the English literature within the PubMed database using the following keywords: cutaneous metastasis or skin metastasis and cholangiocarcinoma or bile duct. The data of 30 patients from 21 articles from 1978 to 2014 were analyzed. Patient data retrieved from the articles included the following: age, gender, time cutaneous metastasis occurred, number of cutaneous metastases throughout life, sites of initial cutaneous metastasis, anatomic site, pathology and differentiation of cholangiocarcinoma, and immunohistochemical results of the cutaneous metastasis. The assessment of overall survival after cutaneous metastasis (OSCM) was the primary endpoint. The median age at diagnosis of cutaneous metastasis of cholangiocarcinoma was 60.0 years (range: 35-77). This metastasis showed a predilection towards males, with a male to female ratio of 3.29. In 8 cases (27.6%), skin metastasis was the first sign of cholangiocarcinoma. Additionally, 18 cases (60.0%) manifested single cutaneous metastasis, while 12 cases (40.0%) demonstrated multiple skin metastases. In 50.0% of patients, the metastasis occurred in the drainage region, while 50.0% of patients had distant cutaneous metastases. The scalp was the most frequently involved region of distant skin metastasis, occurring in 36.7% of patients. The median OSCM of cholangiocarcinoma was 4.0 mo. Patient age and cutaneous metastatic sites showed no significant relation with OSCM, while male gender and single metastasis of the skin were associated with a poorer OSCM (hazard ratio: 0.168; P = 0.005, and hazard ratio: 0.296; P = 0.011, respectively). The prognosis of cutaneous metastasis of cholangiocarcinoma is dismal. Both male gender and single skin metastasis are associated with a poorer OSCM.

46 CFR 28.840 - Means for stopping pumps, ventilation, and machinery.

Code of Federal Regulations, 2014 CFR

2014-10-01

... pumps, ventilation, and machinery. All electrically driven fuel oil transfer pumps, fuel oil unit and service pumps, and ventilation fans shall be fitted with remote controls from a readily accessible... 46 Shipping 1 2014-10-01 2014-10-01 false Means for stopping pumps, ventilation, and machinery. 28...

46 CFR 28.840 - Means for stopping pumps, ventilation, and machinery.

Code of Federal Regulations, 2010 CFR

2010-10-01

... pumps, ventilation, and machinery. All electrically driven fuel oil transfer pumps, fuel oil unit and service pumps, and ventilation fans shall be fitted with remote controls from a readily accessible... 46 Shipping 1 2010-10-01 2010-10-01 false Means for stopping pumps, ventilation, and machinery. 28...

46 CFR 28.840 - Means for stopping pumps, ventilation, and machinery.

Code of Federal Regulations, 2013 CFR

2013-10-01

... pumps, ventilation, and machinery. All electrically driven fuel oil transfer pumps, fuel oil unit and service pumps, and ventilation fans shall be fitted with remote controls from a readily accessible... 46 Shipping 1 2013-10-01 2013-10-01 false Means for stopping pumps, ventilation, and machinery. 28...

46 CFR 28.840 - Means for stopping pumps, ventilation, and machinery.

Code of Federal Regulations, 2012 CFR

2012-10-01

... pumps, ventilation, and machinery. All electrically driven fuel oil transfer pumps, fuel oil unit and service pumps, and ventilation fans shall be fitted with remote controls from a readily accessible... 46 Shipping 1 2012-10-01 2012-10-01 false Means for stopping pumps, ventilation, and machinery. 28...

46 CFR 28.840 - Means for stopping pumps, ventilation, and machinery.

Code of Federal Regulations, 2011 CFR

2011-10-01

... pumps, ventilation, and machinery. All electrically driven fuel oil transfer pumps, fuel oil unit and service pumps, and ventilation fans shall be fitted with remote controls from a readily accessible... 46 Shipping 1 2011-10-01 2011-10-01 false Means for stopping pumps, ventilation, and machinery. 28...

Gas Fride Heat Pumps : The Present and Future

NASA Astrophysics Data System (ADS)

Kurosawa, Shigekichi; Ogura, Masao

In japan techniques for saving energy is an important goal since energy resources such as oil and nuclear power are limited. Recently gas fired absorption heat pumps and gas engine driven heat pumps have been installed in facilifies such as hotels, swimming pools and offices.
In this article recent techniques, applications and future aspects for gas fired heat pumps are explained.

Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed.

PubMed

Ferrari, Stefano; Perut, Francesca; Fagioli, Franca; Brach Del Prever, Adalberto; Meazza, Cristina; Parafioriti, Antonina; Picci, Piero; Gambarotti, Marco; Avnet, Sofia; Baldini, Nicola; Fais, Stefano

2013-10-24

Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H +-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.

Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species.

PubMed

De Milito, Angelo; Iessi, Elisabetta; Logozzi, Mariantonia; Lozupone, Francesco; Spada, Massimo; Marino, Maria Lucia; Federici, Cristina; Perdicchio, Maurizio; Matarrese, Paola; Lugini, Luana; Nilsson, Anna; Fais, Stefano

2007-06-01

Proton pumps like the vacuolar-type H+ ATPase (V-ATPase) are involved in the control of cellular pH in normal and tumor cells. Treatment with proton pump inhibitors (PPI) induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients. It is also known that low pH is the most suitable condition for a full PPI activation. Here, we tested whether PPI treatment in unbuffered culture conditions could affect survival and proliferation of human B-cell tumors. First, we showed that PPI treatment increased the sensitivity to vinblastine of a pre-B acute lymphoblastic leukemia (ALL) cell line. PPI, per se, induced a dose-dependent inhibition of proliferation of tumor B cells, which was associated with a dose- and time-dependent apoptotic-like cytotoxicity in B-cell lines and leukemic cells from patients with pre-B ALL. The effect of PPI was mediated by a very early production of reactive oxygen species (ROS), that preceded alkalinization of lysosomal pH, lysosomal membrane permeabilization, and cytosol acidification, suggesting an early destabilization of the acidic vesicular compartment. Lysosomal alterations were followed by mitochondrial membrane depolarization, release of cytochrome c, chromatin condensation, and caspase activation. However, inhibition of caspase activity did not affect PPI-induced cell death, whereas specific inhibition of ROS by an antioxidant (N-acetylcysteine) significantly delayed cell death and protected both lysosomal and mitochondrial membranes. The proapoptotic activity of PPI was consistent with a clear inhibition of tumor growth following PPI treatment of B-cell lymphoma in severe combined immunodeficient mice. This study further supports the importance of acidity and pH gradients in tumor cell homeostasis and suggests new therapeutic approaches for human B-cell tumors based on PPI.

Proton pump inhibitors therapy vs H2 receptor antagonists therapy for upper gastrointestinal bleeding after endoscopy: A meta-analysis.

PubMed

Zhang, Ying-Shi; Li, Qing; He, Bo-Sai; Liu, Ran; Li, Zuo-Jing

2015-05-28

To compare the therapeutic effects of proton pump inhibitors vs H₂ receptor antagonists for upper gastrointestinal bleeding in patients after successful endoscopy. We searched the Cochrane library, MEDLINE, EMBASE and PubMed for randomized controlled trials until July 2014 for this study. The risk of bias was evaluated by the Cochrane Collaboration's tool and all of the studies had acceptable quality. The main outcomes included mortality, re-bleeding, received surgery rate, blood transfusion units and hospital stay time. These outcomes were estimated using odds ratios (OR) and mean difference with 95% confidence interval (CI). RevMan 5.3.3 software and Stata 12.0 software were used for data analyses. Ten randomized controlled trials involving 1283 patients were included in this review; 678 subjects were in the proton pump inhibitors (PPI) group and the remaining 605 subjects were in the H₂ receptor antagonists (H₂RA) group. The meta-analysis results revealed that after successful endoscopic therapy, compared with H₂RA, PPI therapy had statistically significantly decreased the recurrent bleeding rate (OR = 0.36; 95%CI: 0.25-0.51) and receiving surgery rate (OR = 0.29; 95%CI: 0.09-0.96). There were no statistically significant differences in mortality (OR = 0.46; 95%CI: 0.17-1.23). However, significant heterogeneity was present in both the numbers of patients requiring blood transfusion after treatment [weighted mean difference (WMD), -0.70 unit; 95%CI: -1.64 - 0.25] and the time that patients remained hospitalized [WMD, -0.77 d; 95%CI: -1.87 - 0.34]. The Begg's test (P = 0.283) and Egger's test (P = 0.339) demonstrated that there was no publication bias in our meta-analysis. In patients with upper gastrointestinal bleeding after successful endoscopic therapy, compared with H₂RA, PPI may be a more effective therapy.

Nitric oxide contributes to minerals absorption, proton pumps and hormone equilibrium under cadmium excess in Trifolium repens L. plants.

PubMed

Liu, Shiliang; Yang, Rongjie; Pan, Yuanzhi; Ma, Mingdong; Pan, Jiang; Zhao, Yan; Cheng, Qingsu; Wu, Mengxi; Wang, Maohua; Zhang, Lin

2015-09-01

Nitric oxide (NO) is a stress-signaling molecule in plants that mediates a wide range of physiological processes and responses to metal toxicity. In this work, various NO modulators (NO donor: SNP; NO scavenger: cPTIO; NO synthase inhibitor: l-NAME; and SNP analogs: sodium nitrite/nitrate and sodium ferrocyanide) were investigated to determine the role of NO in Trifolium repens L. plants exposed to Cd. Cd (100μM) markedly reduced biomass, NO production and chlorophyll (Chl a, Chl b and total Chl) concentration but stimulated reactive oxygen species (ROS) and Cd accumulation in plants. SNP (50μM) substantially attenuated growth inhibition, reduced hydrogen peroxide (H2O2) and malonyldialdehyde (MDA) levels, stimulated ROS-scavenging enzymes/agents, and mitigated the H(+)-ATPase inhibition in proton pumps. Interestingly, SNP considerably up-regulated the levels of jasmonic acid (JA) and proline in plant tissues but down-regulated the levels of ethylene (ET) in both shoots and roots and the level of salicylic acid (SA) in roots only, which might be related to the elevated NO synthesis. Additionally, SNP (25-200μM) regulated mineral absorption and, particularly at 50μM, significantly enhanced the uptake of shoot magnesium (Mg) and copper (Cu) and of root calcium (Ca), Mg and iron (Fe). Nevertheless, the effects of SNP on plant growth were reversed by cPTIO and l-NAME, suggesting that the protective effect of SNP might be associated with NO synthesis in vivo. Moreover, SNP analogs did not display roles similar to that of SNP. These results indicated that NO depleted Cd toxicity by eliminating oxidative damage, enhancing minerals absorption, regulating proton pumps, and maintaining hormone equilibrium. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical value of wireless pH-monitoring of gastro-esophageal reflux in children before and after proton pump inhibitors.

PubMed

Boström, Michaela; Thorsson, Ola; Toth, Ervin; Agardh, Daniel

2014-12-24

Wireless pH-monitoring is an accurate method for diagnosing adults with gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the use of the Bravo capsule on children investigated for GERD in terms of safety, tolerability and feasibility before and after administration of proton pump inhibitors. A Bravo capsule was inserted during upper endoscopy under general anaesthesia or deep sedation with propofol. 48-hour pH-metry was performed in 106 children (50 males, 56 females) at the median age of 11 years (range 17 months-18 years). On the second day of investigation, proton pump inhibitor (PPI) was given at a mean dose of 1.6 mg/kg (SD ±0.6 mg). The definition of GERD was set to a reflux index (RI) of ≥5% and DeMeester score (DMS) ≥14.7. Application of the capsule was successful in 103 of the 106 children (97.2%) and interpretable in 99 of these 103 (96.1%). 49 of the children with interpretable results (49.5%) had GERD according to RI, while 51 (56.7%) had GERD according to DMS. After PPI was given on day 2, RI decreased from a median of 4.9% (range 0.3-63.4%) to 2.2% (0-58.0%), while DMS decreased from a median of 17.6 (range 2.2-207.6) to 8.2 (0.3-178.6), respectively (p < 0.0001). No severe adverse events were reported. Wireless pH-metry is a safe and tolerable method when investigating children for GERD. PPI given on the second day of assessment provides additional information on response to treatment suggesting that pH-metry preferably should be extended to 48 hours.

The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis.

PubMed

Park, Chan Hyuk; Kim, Eun Hye; Roh, Yun Ho; Kim, Ha Yan; Lee, Sang Kil

2014-01-01

Although many case reports have described patients with proton pump inhibitor (PPI)-induced hypomagnesemia, the impact of PPI use on hypomagnesemia has not been fully clarified through comparative studies. We aimed to evaluate the association between the use of PPI and the risk of developing hypomagnesemia by conducting a systematic review with meta-analysis. We conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Library using the primary keywords "proton pump," "dexlansoprazole," "esomeprazole," "ilaprazole," "lansoprazole," "omeprazole," "pantoprazole," "rabeprazole," "hypomagnesemia," "hypomagnesaemia," and "magnesium." Studies were included if they evaluated the association between PPI use and hypomagnesemia and reported relative risks or odds ratios or provided data for their estimation. Pooled odds ratios with 95% confidence intervals were calculated using the random effects model. Statistical heterogeneity was assessed with Cochran's Q test and I2 statistics. Nine studies including 115,455 patients were analyzed. The median Newcastle-Ottawa quality score for the included studies was seven (range, 6-9). Among patients taking PPIs, the median proportion of patients with hypomagnesemia was 27.1% (range, 11.3-55.2%) across all included studies. Among patients not taking PPIs, the median proportion of patients with hypomagnesemia was 18.4% (range, 4.3-52.7%). On meta-analysis, pooled odds ratio for PPI use was found to be 1.775 (95% confidence interval 1.077-2.924). Significant heterogeneity was identified using Cochran's Q test (df = 7, P<0.001, I2 = 98.0%). PPI use may increase the risk of hypomagnesemia. However, significant heterogeneity among the included studies prevented us from reaching a definitive conclusion.

Proton transfer events in GFP.

PubMed

Di Donato, Mariangela; van Wilderen, Luuk J G W; Van Stokkum, Ivo H M; Stuart, Thomas Cohen; Kennis, John T M; Hellingwerf, Klaas J; van Grondelle, Rienk; Groot, Marie Louise

2011-09-28

Proton transfer is one of the most important elementary processes in biology. Green fluorescent protein (GFP) serves as an important model system to elucidate the mechanistic details of this reaction, because in GFP proton transfer can be induced by light absorption. Illumination initiates proton transfer through a 'proton-wire', formed by the chromophore (the proton donor), water molecule W22, Ser205 and Glu222 (the acceptor), on a picosecond time scale. To obtain a more refined view of this process, we have used a combined approach of time resolved mid-infrared spectroscopy and visible pump-dump-probe spectroscopy to resolve with atomic resolution how and how fast protons move through this wire. Our results indicate that absorption of light by GFP induces in 3 ps (10 ps in D(2)O) a shift of the equilibrium positions of all protons in the H-bonded network, leading to a partial protonation of Glu222 and to a so-called low barrier hydrogen bond (LBHB) for the chromophore's proton, giving rise to dual emission at 475 and 508 nm. This state is followed by a repositioning of the protons on the wire in 10 ps (80 ps in D(2)O), ultimately forming the fully deprotonated chromophore and protonated Glu222.

Insights into proton translocation in cbb3 oxidase from MD simulations.

PubMed

Carvalheda, Catarina A; Pisliakov, Andrei V

2017-05-01

Heme-copper oxidases are membrane protein complexes that catalyse the final step of the aerobic respiration, namely the reduction of oxygen to water. The energy released during catalysis is coupled to the active translocation of protons across the membrane, which contributes to the establishment of an electrochemical gradient that is used for ATP synthesis. The distinctive C-type (or cbb 3 ) cytochrome c oxidases, which are mostly present in proteobacteria, exhibit a number of unique structural and functional features, including high catalytic activity at low oxygen concentrations. At the moment, the functioning mechanism of C-type oxidases, in particular the proton transfer/pumping mechanism presumably via a single proton channel, is still poorly understood. In this work we used all-atom molecular dynamics simulations and continuum electrostatics calculations to obtain atomic-level insights into the hydration and dynamics of a cbb 3 oxidase. We provide the details of the water dynamics and proton transfer pathways for both the "chemical" and "pumped" protons, and show that formation of protonic connections is strongly affected by the protonation state of key residues, namely H243, E323 and H337. Copyright © 2017 Elsevier B.V. All rights reserved.

Cutaneous applications of lasers.

PubMed

Ries, W R; Speyer, M T

1996-12-01

The cutaneous application of lasers today includes more selective and less damaging devices. Carbon dioxide, neodymium:yttrium-aluminum-garnet, potassium titanyl phosphate, argon, and yellow lasers are most prevalent in treating cutaneous lesions. Specific techniques in skin resurfacing, keloid excision, rhinophyma, actinic cheilitis ablation, and excision of superficial cutaneous tumors are discussed. Proper management of cutaneous vascular lesions is also presented.

Common gastrointestinal symptoms: risks of long-term proton pump inhibitor therapy.

PubMed

Fashner, Julia; Gitu, Alfred Chege

2013-10-01

More than 11 million individuals receive proton pump inhibitor (PPI) prescriptions each year in the United States. Although PPIs are effective treatment for peptic ulcers and esophagitis and provide symptom relief for many other conditions, their use carries risks. They decrease gastric acid and can lower blood levels of drugs whose absorption is acid dependent, including several antiretroviral and cancer therapy drugs. Other drugs, such as digoxin, may be absorbed more extensively when gastric acid is reduced; thus, digoxin toxicity may occur with PPI use. Warfarin's effect also is increased in patients taking PPIs. Decreased gastric acid can lower absorption of vitamin B12, calcium, iron, and magnesium; deficiencies in these nutrients are a concern. Several medical conditions, including Clostridium difficile infection, osteoporotic fractures, and community-acquired pneumonia, are more likely to occur among PPI users. Interstitial nephritis also has been reported. Because of these risks, clinicians should try to use the lowest possible dose of PPI and to discontinue PPI therapy if it is not essential. Step-down regimens can be used to decrease/discontinue treatment; these regimens may prevent or minimize the rebound acid hypersecretion that can occur with abrupt discontinuation. For some patients, occasional treatment with intermittent or on-demand regimens may be sufficient to control symptoms. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Development of a miniature motor-driven pulsatile LVAD driven by a fuzzy controller.

PubMed

Okamoto, Eiji; Makino, Tsutomu; Tanaka, Shuji; Yasuda, Takahiko; Akasaka, Yuta; Tani, Makiko; Inoue, Yusuke; Mitoh, Ayumu; Mitamura, Yoshinori

2007-01-01

We have been developing a small, lightweight motor-driven pulsatile left ventricular assist device (LVAD) with a ball screw. The motor-driven LVAD consists of a brushless DC motor and a ball screw. The attractive magnetic force between Nd-Fe-B magnets (with a diameter of 5 mm and a thickness of 1.5 mm) mounted in holes in a silicone rubber sheet (thickness 2 mm) and an iron plate adhered onto the a diaphragm of the blood pump can provide optimum active blood filling during the pump filling phase. The LVAD has a stroke volume of 55 ml and an overall volume of 285 ml; it weighs 360 g. The controller mainly consists of a fuzzy logic position and velocity controller to apply doctors' and engineers' knowledge to control the LVAD. Each unit of the controller consists of a functionally independent program module for easy improvement of the controller's performance. The LVAD was evaluated in in vitro experiments using a mock circulation. A maximum pump outflow of 5.1 l/min was obtained at a drive rate of 95 bpm against an afterload of 95 mmHg, and active filling using the attractive magnetic force provided a pump output of 3.6 l/min at a drive rate of 75 bpm under a preload of 0 mmHg. The operating efficiency of the LVAD was measured at between 8% and 10.5%. While the LVAD can provide adequate pump outflow for cardiac assistance, further upgrading of the software and improvement of the blood pump are required to improve pump performance and efficiency.

Fluid driven reciprocating apparatus

DOEpatents

Whitehead, J.C.

1997-04-01

An apparatus is described comprising a pair of fluid driven pump assemblies in a back-to-back configuration to yield a bi-directional pump. Each of the pump assemblies includes a piston or diaphragm which divides a chamber therein to define a power section and a pumping section. An intake-exhaust valve is connected to each of the power sections of the pump chambers, and function to direct fluid, such as compressed air, into the power section and exhaust fluid therefrom. At least one of the pistons or diaphragms is connected by a rod assembly which is constructed to define a signal valve, whereby the intake-exhaust valve of one pump assembly is controlled by the position or location of the piston or diaphragm in the other pump assembly through the operation of the rod assembly signal valve. Each of the pumping sections of the pump assemblies are provided with intake and exhaust valves to enable filling of the pumping section with fluid and discharging fluid therefrom when a desired pressure has been reached. 13 figs.

Fluid driven recipricating apparatus

DOEpatents

Whitehead, John C.

1997-01-01

An apparatus comprising a pair of fluid driven pump assemblies in a back-to-back configuration to yield a bi-directional pump. Each of the pump assemblies includes a piston or diaphragm which divides a chamber therein to define a power section and a pumping section. An intake-exhaust valve is connected to each of the power sections of the pump chambers, and function to direct fluid, such as compressed air, into the power section and exhaust fluid therefrom. At least one of the pistons or diaphragms is connected by a rod assembly which is constructed to define a signal valve, whereby the intake-exhaust valve of one pump assembly is controlled by the position or location of the piston or diaphragm in the other pump assembly through the operation of the rod assembly signal valve. Each of the pumping sections of the pump assemblies are provided with intake and exhaust valves to enable filling of the pumping section with fluid and discharging fluid therefrom when a desired pressure has been reached.

Magnetic Heat Pump Containing Flow Diverters

NASA Technical Reports Server (NTRS)

Howard, Frank S.

1995-01-01

Proposed magnetic heat pump contains flow diverters for suppression of undesired flows. If left unchecked, undesired flows mix substantial amounts of partially heated and partially cooled portions of working fluid, effectively causing leakage of heat from heated side to cooled side. By reducing leakage of heat, flow diverters increase energy efficiency of magnetic heat pump, potentially offering efficiency greater than compressor-driven refrigerator.

Water Pump Development for the EVA PLSS

NASA Technical Reports Server (NTRS)

Schuller, Michael; Kurwitz, Cable; Goldman, Jeff; Morris, Kim; Trevino, Luis

2009-01-01

This paper describes the effort by the Texas Engineering Experiment Station (TEES) and Honeywell for NASA to design, fabricate, and test a preflight prototype pump for use in the Extravehicular activity (EVA) portable life support subsystem (PLSS). Major design decisions were driven by the need to reduce the pump s mass, power, and volume compared to the existing PLSS pump. In addition, the pump will accommodate a much wider range of abnormal conditions than the existing pump, including vapor/gas bubbles and increased pressure drop when employed to cool two suits simultaneously. A positive displacement, external gear type pump was selected because it offers the most compact and highest efficiency solution over the required range of flow rates and pressure drops. An additional benefit of selecting a gear pump design is that it is self priming and capable of ingesting noncondensable gas without becoming "air locked." The chosen pump design consists of a 28 V DC, brushless, sealless, permanent magnet motor driven, external gear pump that utilizes a Honeywell development that eliminates the need for magnetic coupling. Although the planned flight unit will use a sensorless motor with custom designed controller, the preflight prototype to be provided for this project incorporates Hall effect sensors, allowing an interface with a readily available commercial motor controller. This design approach reduced the cost of this project and gives NASA more flexibility in future PLSS laboratory testing. The pump design was based on existing Honeywell designs, but incorporated features specifically for the PLSS application, including all of the key features of the flight pump. Testing at TEES will simulate the vacuum environment in which the flight pump will operate. Testing will verify that the pump meets design requirements for range of flow rates, pressure rise, power consumption, working fluid temperature, operating time, and restart capability. Pump testing is currently

The nitric-oxide reductase from Paracoccus denitrificans uses a single specific proton pathway.

PubMed

ter Beek, Josy; Krause, Nils; Reimann, Joachim; Lachmann, Peter; Ädelroth, Pia

2013-10-18

The NO reductase from Paracoccus denitrificans reduces NO to N2O (2NO + 2H(+) + 2e(-) → N2O + H2O) with electrons donated by periplasmic cytochrome c (cytochrome c-dependent NO reductase; cNOR). cNORs are members of the heme-copper oxidase superfamily of integral membrane proteins, comprising the O2-reducing, proton-pumping respiratory enzymes. In contrast, although NO reduction is as exergonic as O2 reduction, there are no protons pumped in cNOR, and in addition, protons needed for NO reduction are derived from the periplasmic solution (no contribution to the electrochemical gradient is made). cNOR thus only needs to transport protons from the periplasm into the active site without the requirement to control the timing of opening and closing (gating) of proton pathways as is needed in a proton pump. Based on the crystal structure of a closely related cNOR and molecular dynamics simulations, several proton transfer pathways were suggested, and in principle, these could all be functional. In this work, we show that residues in one of the suggested pathways (denoted pathway 1) are sensitive to site-directed mutation, whereas residues in the other proposed pathways (pathways 2 and 3) could be exchanged without severe effects on turnover activity with either NO or O2. We further show that electron transfer during single-turnover reduction of O2 is limited by proton transfer and can thus be used to study alterations in proton transfer rates. The exchange of residues along pathway 1 showed specific slowing of this proton-coupled electron transfer as well as changes in its pH dependence. Our results indicate that only pathway 1 is used to transfer protons in cNOR.

Satellite Propellant Pump Research

NASA Technical Reports Server (NTRS)

Schneider, Steven J.; Veres, Joseph P.; Hah, Chunill; Nerone, Anthony L.; Cunningham, Cameron C.; Kraft, Thomas G.; Tavernelli, Paul F.; Fraser, Bryan

2005-01-01

NASA Glenn initiated a satellite propellant pump technology demonstration program. The goal was to demonstrate the technologies for a 60 percent efficient pump at 1 gpm flow rate and 500 psia pressure rise. The pump design and analysis used the in-house developed computer codes named PUMPA and HPUMP3D. The requirements lead to a 4-stage impeller type pump design with a tip diameter of 0.54 inches and a rotational speed of 57,000 rpm. Analyses indicated that flow cavitation was not a problem in the design. Since the flow was incompressible, the stages were identical. Only the 2-stage pump was designed, fabricated, assembled, and tested for demonstration. Water was selected as the surrogate fluid for hydrazine in this program. Complete mechanical design including stress and dynamic analyses were conducted. The pump was driven by an electric motor directly coupled to the impellers. Runs up to 57,000 rpm were conducted, where a pressure rise of 200 psia at a flow rate of 0.8 gpm was measured to validate the design effort.

46 CFR 95.10-5 - Fire pumps.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Fire pumps. 95.10-5 Section 95.10-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS FIRE PROTECTION EQUIPMENT Fire Main System, Details § 95.10-5 Fire pumps. (a) Vessels shall be equipped with independently driven fire...

Development of a compact, sealless, tripod supported, magnetically driven centrifugal blood pump.

PubMed

Yuhki, A; Nogawa, M; Takatani, S

2000-06-01

In this study, a tripod supported sealless centrifugal blood pump was designed and fabricated for implantable application using a specially designed DC brushless motor. The tripod structure consists of 3 ceramic balls mounted at the bottom surface of the impeller moving in a polyethylene groove incorporated at the bottom pump casing. The follower magnet inside the impeller is coupled to the driver magnet of the motor outside the bottom pump casing, thus allowing the impeller to slide-rotate in the polyethylene groove as the motor turns. The pump driver has a weight of 230 g and a diameter of 60 mm. The acrylic pump housing has a weight of 220 g with the priming volume of 25 ml. At the pump rpm of 1,000 to 2,200, the generated head pressure ranged from 30 to 150 mm Hg with the maximum system efficiency being 12%. When the prototype pump was used in the pulsatile mock loop to assist the ventricle from its apex to the aorta, a strong correlation was obtained between the motor current and bypass flow waveforms. The waveform deformation index (WDI), defined as the ratio of the fundamental to the higher order harmonics of the motor current power spectral density, was computed to possibly detect the suction occurring inside the ventricle due to the prototype centrifugal pump. When the WDI was kept under the value of 0.20 by adjusting the motor rpm, it was successful in suppressing the suction due to the centrifugal pump in the ventricle. The prototype sealless, centrifugal pump together with the control method based on the motor current waveform analysis may offer an intermediate support of the failing left or right ventricle bridging to heart transplantation.

Gyro-effect stabilizes unstable permanent maglev centrifugal pump.

PubMed

Qian, Kun-Xi

2007-03-01

According to Earnshaw's Theorem (1839), the passive maglev cannot achieve stable equilibrium and thus an extra coil is needed to make the rotor electrically levitated in a heart pump. The author had developed a permanent maglev centrifugal pump utilizing only passive magnetic bearings, to keep the advantages but to avoid the disadvantages of the electric maglev pumps. The equilibrium stability was achieved by use of so-called "gyro-effect": a rotating body with certain high speed can maintain its rotation stably. This pump consisted of a rotor (driven magnets and an impeller), and a stator with motor coil and pump housing. Two passive magnetic bearings between rotor and stator were devised to counteract the attractive force between the motor coil iron core and the rotor driven magnets. Bench testing with saline demonstrated a levitated rotor under preconditions of higher than 3,250 rpm rotation and more than 1 l/min pumping flow. Rotor levitation was demonstrated by 4 Hall sensors on the stator, with evidence of reduced maximal eccentric distance from 0.15 mm to 0.07 mm. The maximal rotor vibration amplitude was 0.06 mm in a gap of 0.15 mm between rotor and stator. It concluded that Gyro-effect can help passive maglev bearings to achieve stabilization of permanent maglev pump; and that high flow rate indicates good hydraulic property of the pump, which helps also the stability of passive maglev pump.

Inappropriate use of proton pump inhibitors in a local setting

PubMed Central

Chia, Christopher Tze Wei; Lim, Wan Peng; Vu, Charles Kien Fong

2014-01-01

INTRODUCTION There are growing concerns that the use of proton pump inhibitors (PPIs) may be inappropriate in instances that do not conform to evidence-based indications. This point-prevalence study aimed to investigate the frequency, indications and appropriateness of use of PPIs in hospitalised patients on a randomly chosen day. METHODS On a randomly chosen day, all inpatients were documented, and those on any form of PPIs on that day were determined. Indications for maintaining these patients on PPIs were obtained from the electronic medical records, which were then recorded and cross-referenced against a list of accepted indications adapted from the US Food and Drug Administration (FDA)-approved list. RESULTS In all, 1,025 inpatients were documented. Of the 477 (46.5%) inpatients using PPIs, only 219 (45.9%) fulfilled the FDA-approved indications, while the majority (n = 258, 54.1%) did not. Overall, PPIs were not strictly indicated for use in 206 (43.2%) inpatients, according to FDA criteria. Of the 477 inpatients on PPIs, 52 (10.9%) had borderline indications based on expert consensus/guidelines other than FDA criteria. CONCLUSION Although the use of PPIs is prevalent in hospitals, less than half of the hospitalised patients using PPIs in our study had evidence-based indications that supported such use. The overuse of PPIs has a negative impact on healthcare costs and may lead to adverse effects. Steps to curb the inappropriate use of PPIs should address factors such as indications for the initiation of PPIs, and reassessment of the need for ongoing PPI use in inpatients upon discharge and during outpatient reviews. PMID:25091884

The Gastric and Intestinal Microbiome: Role of Proton Pump Inhibitors.

PubMed

Minalyan, Artem; Gabrielyan, Lilit; Scott, David; Jacobs, Jonathan; Pisegna, Joseph R

2017-08-01

The discovery of Helicobacter pylori and other organisms colonizing the stomach and the intestines has shed some light on the importance of microbiome in maintaining overall health and developing pathological conditions when alterations in biodiversity are present. The gastric acidity plays a crucial role in filtering out bacteria and preventing development of enteric infections. In this article, we discuss the physiology of gastric acid secretion and bacterial contribution to the composition of gastric and intestinal barriers and review the current literature on the role of proton pump inhibitors (PPIs) in the microbial biodiversity of the gastrointestinal tract. Culture-independent techniques, such as 16S rRNA sequencing, have revolutionized our understanding of the microbial biodiversity in the gastrointestinal tract. Luminal and mucosa-associated microbial populations are not identical. Streptococcus is overrepresented in the biopsies of patients with antral gastritis and may also be responsible for the development of peptic ulcer disease. The use of PPIs favors relative streptococcal abundance irrespective of H. pylori status and may explain the persistence of dyspeptic symptoms in patients on PPI therapy. Increased risk of enteric infections has also been seen in patients taking PPIs. The overuse of PPIs leads to significant shift of the gastrointestinal microbiome towards a less healthy state. With the advent of PPIs, many studies have demonstrated the significant changes in the microbial composition of both gastric and intestinal microbiota. Although they are considered relatively safe over-the-counter medications, PPIs in many cases are over- and even inappropriately used. Future studies assessing the safety of PPIs and their role in the development of microbiome changes should be encouraged.

Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

PubMed

Lugini, Luana; Federici, Cristina; Borghi, Martina; Azzarito, Tommaso; Marino, Maria Lucia; Cesolini, Albino; Spugnini, Enrico Pierluigi; Fais, Stefano

2016-08-01

Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

Geothermal down well pumping system

NASA Technical Reports Server (NTRS)

Matthews, H. B.; Mcbee, W. D.

1974-01-01

A key technical problem in the exploitation of hot water geothermal energy resources is down-well pumping to inhibit mineral precipitation, improve thermal efficiency, and enhance flow. A novel approach to this problem involves the use of a small fraction of the thermal energy of the well water to boil and super-heat a clean feedwater flow in a down-hole exchanger adjacent to the pump. This steam powers a high-speed turbine-driven pump. The exhaust steam is brought to the surface through an exhaust pipe, condensed, and recirculated. A small fraction of the high-pressure clean feedwater is diverted to lubricate the turbine pump bearings and prevent leakage of brine into the turbine-pump unit. A project demonstrating the feasibility of this approach by means of both laboratory and down-well tests is discussed.

Cutaneous Pseudolymphomas.

PubMed

Romero-Pérez, D; Blanes Martínez, M; Encabo-Durán, B

2016-10-01

The term cutaneous pseudolymphoma refers to benign reactive lymphoid proliferations in the skin that simulate cutaneous lymphomas. It is a purely descriptive term that encompasses various reactive conditions with a varied etiology, pathogenesis, clinical presentation, histology, and behavior. We present a review of the different types of cutaneous pseudolymphoma. To reach a correct diagnosis, it is necessary to contrast clinical, histologic, immunophenotypic, and molecular findings. Even with these data, in some cases only the clinical course will confirm the diagnosis, making follow-up essential. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Optical Silencing of C. elegans Cells with Arch Proton Pump

PubMed Central

Okazaki, Ayako; Sudo, Yuki; Takagi, Shin

2012-01-01

Background Optogenetic techniques using light-driven ion channels or ion pumps for controlling excitable cells have greatly facilitated the investigation of nervous systems in vivo. A model organism, C. elegans, with its small transparent body and well-characterized neural circuits, is especially suitable for optogenetic analyses. Methodology/Principal Findings We describe the application of archaerhodopsin-3 (Arch), a recently reported optical neuronal silencer, to C. elegans. Arch::GFP expressed either in all neurons or body wall muscles of the entire body by means of transgenes were localized, at least partially, to the cell membrane without adverse effects, and caused locomotory paralysis of worms when illuminated by green light (550 nm). Pan-neuronal expression of Arch endowed worms with quick and sustained responsiveness to such light. Worms reliably responded to repeated periods of illumination and non-illumination, and remained paralyzed under continuous illumination for 30 seconds. Worms expressing Arch in different subsets of motor neurons exhibited distinct defects in the locomotory behavior under green light: selective silencing of A-type motor neurons affected backward movement while silencing of B-type motor neurons affected forward movement more severely. Our experiments using a heat-shock-mediated induction system also indicate that Arch becomes fully functional only 12 hours after induction and remains functional for more than 24 hour. Conclusions/Sgnificance Arch can be used for silencing neurons and muscles, and may be a useful alternative to currently widely used halorhodopsin (NpHR) in optogenetic studies of C. elegans. PMID:22629299

Velocity pump reaction turbine

DOEpatents

House, Palmer A.

1982-01-01

An expanding hydraulic/two-phase velocity pump reaction turbine including a dual concentric rotor configuration with an inter-rotor annular flow channel in which the inner rotor is mechanically driven by the outer rotor. In another embodiment, the inner rotor is immobilized and provided with gas recovery ports on its outer surface by means of which gas in solution may be recovered. This velocity pump reaction turbine configuration is capable of potential energy conversion efficiencies of up to 70%, and is particularly suited for geothermal applications.

Velocity pump reaction turbine

DOEpatents

House, Palmer A.

1984-01-01

An expanding hydraulic/two-phase velocity pump reaction turbine including a dual concentric rotor configuration with an inter-rotor annular flow channel in which the inner rotor is mechanically driven by the outer rotor. In another embodiment, the inner rotor is immobilized and provided with gas recovery ports on its outer surface by means of which gas in solution may be recovered. This velocity pump reaction turbine configuration is capable of potential energy conversion efficiencies of up to 70%, and is particularly suited for geothermal applications.

Velocity pump reaction turbine

DOEpatents

House, P.A.

An expanding hydraulic/two-phase velocity pump reaction turbine including a dual concentric rotor configuration with an inter-rotor annular flow channel in which the inner rotor is mechanically driven by the outer rotor. In another embodiment, the inner rotor is immobilized and provided with gas recovery ports on its outer surface by means of which gas in solution may be recovered. This velocity pump reaction turbine configuration is capable of potential energy conversion efficiencies of up to 70%, and is particularly suited for geothermal applications.

Hourly simulation of a Ground-Coupled Heat Pump system

NASA Astrophysics Data System (ADS)

Naldi, C.; Zanchini, E.

2017-01-01

In this paper, we present a MATLAB code for the hourly simulation of a whole Ground-Coupled Heat Pump (GCHP) system, based on the g-functions previously obtained by Zanchini and Lazzari. The code applies both to on-off heat pumps and to inverter-driven ones. It is employed to analyse the effects of the inverter and of the total length of the Borehole Heat Exchanger (BHE) field on the mean seasonal COP (SCOP) and on the mean seasonal EER (SEER) of a GCHP system designed for a residential house with 6 apartments in Bologna, North-Center Italy, with dominant heating loads. A BHE field with 3 in line boreholes is considered, with length of each BHE either 75 m or 105 m. The results show that the increase of the BHE length yields a SCOP enhancement of about 7%, while the SEER remains nearly unchanged. The replacement of the on-off heat pump by an inverter-driven one yields a SCOP enhancement of about 30% and a SEER enhancement of about 50%. The results demonstrate the importance of employing inverter-driven heat pumps for GCHP systems.

Electromagnetically driven peristaltic pump

DOEpatents

Marshall, Douglas W.

2000-01-01

An electromagnetic peristaltic pump apparatus may comprise a main body section having an inlet end and an outlet end and a flexible membrane which divides the main body section into a first cavity and a second cavity. The first cavity is in fluid communication with the inlet and outlet ends of the main body section. The second cavity is not in fluid communication with the first cavity and contains an electrically conductive fluid. The second cavity includes a plurality of electrodes which are positioned within the second cavity generally adjacent the flexible membrane. A magnetic field generator produces a magnetic field having a plurality of flux lines at least some of which are contained within the second cavity of the main body section and which are oriented generally parallel to a flow direction in which a material flows between the inlet and outlet ends of the main body section. A control system selectively places a voltage potential across selected ones of the plurality of electrodes to deflect the flexible membrane in a wave-like manner to move material contained in the first cavity between the inlet and outlet ends of the main body section.

Proton-pump inhibitor use does not affect semen quality in subfertile men.

PubMed

Keihani, Sorena; Craig, James R; Zhang, Chong; Presson, Angela P; Myers, Jeremy B; Brant, William O; Aston, Kenneth I; Emery, Benjamin R; Jenkins, Timothy G; Carrell, Douglas T; Hotaling, James M

2018-01-01

Proton-pump inhibitors (PPIs) are among the most widely used drugs worldwide. PPI use has recently been linked to adverse changes in semen quality in healthy men; however, the effects of PPI use on semen parameters remain largely unknown specifically in cases with male factor infertility. We examined whether PPI use was associated with detrimental effects on semen parameters in a large population of subfertile men. We retrospectively reviewed data from 12 257 subfertile men who had visited our fertility clinic from 2003 to 2013. Patients who reported using any PPIs for >3 months before semen sample collection were included; 7698 subfertile men taking no medication served as controls. Data were gathered on patient age, medication use, and conventional semen parameters; patients taking any known spermatotoxic medication were excluded. Linear mixed-effect regression models were used to test the effect of PPI use on semen parameters adjusting for age. A total of 248 patients (258 samples) used PPIs for at least 3 months before semen collection. In regression models, PPI use (either as the only medication or when used in combination with other nonspermatotoxic medications) was not associated with statistically significant changes in semen parameters. To our knowledge, this is the largest study to compare PPI use with semen parameters in subfertile men. Using PPIs was not associated with detrimental effects on semen quality in this retrospective study.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

PubMed Central

El Rouby, Nihal; Lima, John J.; Johnson, Julie A.

2018-01-01

ABSTRACT Introduction: Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs. PMID:29620484

Nuclear-Pumped Lasers. [efficient conversion of energy liberated in nuclear reactions to coherent radiation

NASA Technical Reports Server (NTRS)

1979-01-01

The state of the art in nuclear pumped lasers is reviewed. Nuclear pumped laser modeling, nuclear volume and foil excitation of laser plasmas, proton beam simulations, nuclear flashlamp excitation, and reactor laser systems studies are covered.

Fuel savings with conventional hot water space heating systems by incorporating a natural gas powered heat pump. Preliminary project: Development of heat pump technology

NASA Astrophysics Data System (ADS)

Vanheyden, L.; Evertz, E.

1980-12-01

Compression type air/water heat pumps were developed for domestic heating systems rated at 20 to 150 kW. The heat pump is driven either by a reciprocating piston or rotary piston engine modified to operate on natural gas. Particular features of natural gas engines as prime movers, such as waste heat recovery and variable speed, are stressed. Two systems suitable for heat pump operation were selected from among five different mass produced car engines and were modified to incorporate reciprocating piston compressor pairs. The refrigerants used are R 12 and R 22. Test rig data transferred to field conditions show that the fuel consumption of conventional boilers can be reduced by 50% and more by the installation of engine driven heat pumps. Pilot heat pumps based on a 1,600 cc reciprocating piston engine were built for heating four two-family houses. Pilot pump operation confirms test rig findings. The service life of rotary piston and reciprocating piston engines was investigated. The tests reveal characteristic curves for reciprocating piston engines and include exhaust composition measurements.

Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling

PubMed Central

Zeng, Wei-Zheng; Liu, Di-Shi; Liu, Lu; She, Liang; Wu, Long-Jun; Xu, Tian-Le

2015-01-01

Extracellular transients of pH alterations likely mediate signal transduction in the nervous system. Neuronal acid-sensing ion channels (ASICs) act as sensors for extracellular protons, but the mechanism underlying ASIC activation remains largely unknown. Here, we show that, following activation of a light-activated proton pump, Archaerhodopsin-3 (Arch), proton transients induced ASIC currents in both neurons and HEK293T cells co-expressing ASIC1a channels. Using chimera proteins that bridge Arch and ASIC1a by a glycine/serine linker, we found that successful coupling occurred within 15 nm distance. Furthermore, two-cell sniffer patch recording revealed that regulated release of protons through either Arch or voltage-gated proton channel Hv1 activated neighbouring cells expressing ASIC1a channels. Finally, computational modelling predicted the peak proton concentration at the intercellular interface to be at pH 6.7, which is acidic enough to activate ASICs in vivo. Our results highlight the pathophysiological role of proton signalling in the nervous system. PMID:26370138

Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed

PubMed Central

2013-01-01

Background Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H + −rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. Method MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. Results Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. Conclusion This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy. PMID

Association Between Proton Pump Inhibitors and Metronomic Capecitabine as Salvage Treatment for Patients With Advanced Gastrointestinal Tumors: A Randomized Phase II Trial.

PubMed

Marchetti, Paolo; Milano, Annalisa; D'Antonio, Chiara; Romiti, Adriana; Falcone, Rosa; Roberto, Michela; Fais, Stefano

2016-12-01

The acidification of extracellular compartment represents a conceivable mechanism of drug resistance in malignant cells. In addition, it has been reported to drive proliferation and promote invasion and metastasis. Experimental evidence has shown that proton pump inhibitors can counteract tumor acidification and restore sensitivity to anticancer drugs. Moreover, early clinical data have supported the role of proton pump inhibitors in anticancer treatments. Metronomic capecitabine has demonstrated beneficial effects as salvage chemotherapy for heavily pretreated or frail patients with gastrointestinal cancer. The present study (EudraCT Number: 2013-001096-20) was aimed at investigating the activity and safety of high-dose rabeprazole in combination with metronomic capecitabine in patients with advanced gastrointestinal cancer refractory to standard treatment. A total of 66 patients will be randomized 1:1 to receive capecitabine 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg twice a day, 3 days a week until disease progression, undue toxicity, or withdrawal of informed consent. The primary endpoint is progression-free survival. The secondary endpoints are clinical benefit, which reflects the proportion of patients with complete response, partial response, and stable disease, and overall survival. Progression-free and overall survival will be evaluated using a log-rank test to determine the effect of rabeprazole independently at the 2-sided α-level of 0.05. Other assessments will include the frequency and severity of adverse events and changes in laboratory parameters to measure the safety, and the pharmacokinetics of capecitabine. The results are expected in 2016. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessment of Proton Deflectometry for Exploding Wire Experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beg, Farhat Nadeem

2013-09-25

This project provides the first demonstration of the application of proton deflectometry for the diagnosis of electromagnetic field topology and current-carrying regions in Z-pinch plasma experiments. Over the course of this project several milestones were achieved. High-energy proton beam generation was demonstrated on the short-pulse high-intensity Leopard laser, (10 Joules in ~350 femtoseconds, and the proton beam generation was shown to be reproducible. Next, protons were used to probe the electromagnetic field structure of short circuit loads in order to benchmark the two numerical codes, the resistive-magnetohydrodynamics (MHD) code, Gorgon, and the hybrid particle-in-cell code, LSP for the interpretation ofmore » results. Lastly, the proton deflectometry technique was used to map the magnetic field structure of pulsed-power-driven plasma loads including wires and supersonic jets formed with metallic foils. Good agreement between the modeling and experiments has been obtained. The demonstrated technique holds great promise to significantly improve the understanding of current flow and electromagnetic field topology in pulsed power driven high energy density plasmas. Proton probing with a high intensity laser was for the first time implemented in the presence of the harsh debris and x-ray producing z-pinch environment driven by a mega-ampere-scale pulsed-power machine. The intellectual merit of the program was that it investigated strongly driven MHD systems and the influence of magnetic field topology on plasma evolution in pulsed power driven plasmas. The experimental program involved intense field-matter interaction in the generation of the proton probe, as well as the generation of plasma subjected to 1 MegaGauss scale magnetic fields. The computational aspect included two well-documented codes, in combination for the first time to provide accurate interpretation of the experimental results. The broader impact included the support of 2 graduate students

49 CFR 178.338-17 - Pumps and compressors.

Code of Federal Regulations, 2010 CFR

2010-10-01

... PACKAGINGS Specifications for Containers for Motor Vehicle Transportation § 178.338-17 Pumps and compressors. (a) Liquid pumps and gas compressors, if used, must be of suitable design, adequately protected against breakage by collision, and kept in good condition. They may be driven by motor vehicle power take...

49 CFR 178.337-15 - Pumps and compressors.

Code of Federal Regulations, 2010 CFR

2010-10-01

... PACKAGINGS Specifications for Containers for Motor Vehicle Transportation § 178.337-15 Pumps and compressors. (a) Liquid pumps or gas compressors, if used, must be of suitable design, adequately protected against breakage by collision, and kept in good condition. They may be driven by motor vehicle power take...

Beyond gastric acid reduction: Proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Becker, Jan C.; Grosser, Nina; Waltke, Christian

2006-07-07

Proton pump inhibitors (PPIs) have been demonstrated to prevent gastric mucosal injury by mechanisms independent of acid inhibition. Here we demonstrate that both omeprazole and lansoprazole protect human gastric epithelial and endothelial cells against oxidative stress. This effect was abrogated in the presence of the heme oxygenase-1 (HO-1) inhibitor ZnBG. Exposure to either PPI resulted in a strong induction of HO-1 expression on mRNA and protein level, and led to an increased activity of this enzyme. Expression of cyclooxygenase isoforms 1 and 2 remained unaffected, and COX-inhibitors did not antagonize HO-1 induction by PPIs. Our results suggest that the antioxidantmore » defense protein HO-1 is a target of PPIs in both endothelial and gastric epithelial cells. HO-1 induction might account for the gastroprotective effects of PPIs independently of acid inhibition, especially in NSAID gastropathy. Moreover, our findings provide additional perspectives for a possible but yet unexplored use of PPIs in vasoprotection.« less

The Association between the Use of Proton Pump Inhibitors and the Risk of Hypomagnesemia: A Systematic Review and Meta-Analysis

PubMed Central

Park, Chan Hyuk; Kim, Eun Hye; Roh, Yun Ho; Kim, Ha Yan; Lee, Sang Kil

2014-01-01

Background Although many case reports have described patients with proton pump inhibitor (PPI)-induced hypomagnesemia, the impact of PPI use on hypomagnesemia has not been fully clarified through comparative studies. We aimed to evaluate the association between the use of PPI and the risk of developing hypomagnesemia by conducting a systematic review with meta-analysis. Methods We conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Library using the primary keywords “proton pump,” “dexlansoprazole,” “esomeprazole,” “ilaprazole,” “lansoprazole,” “omeprazole,” “pantoprazole,” “rabeprazole,” “hypomagnesemia,” “hypomagnesaemia,” and “magnesium.” Studies were included if they evaluated the association between PPI use and hypomagnesemia and reported relative risks or odds ratios or provided data for their estimation. Pooled odds ratios with 95% confidence intervals were calculated using the random effects model. Statistical heterogeneity was assessed with Cochran’s Q test and I 2 statistics. Results Nine studies including 115,455 patients were analyzed. The median Newcastle-Ottawa quality score for the included studies was seven (range, 6–9). Among patients taking PPIs, the median proportion of patients with hypomagnesemia was 27.1% (range, 11.3–55.2%) across all included studies. Among patients not taking PPIs, the median proportion of patients with hypomagnesemia was 18.4% (range, 4.3–52.7%). On meta-analysis, pooled odds ratio for PPI use was found to be 1.775 (95% confidence interval 1.077–2.924). Significant heterogeneity was identified using Cochran’s Q test (df = 7, P<0.001, I 2 = 98.0%). Conclusions PPI use may increase the risk of hypomagnesemia. However, significant heterogeneity among the included studies prevented us from reaching a definitive conclusion. PMID:25394217

Taple-top imaging of the non-adiabatically driven isomerization in the acetylene cation

NASA Astrophysics Data System (ADS)

Beaulieu, Samuel; Ibrahim, Heide; Wales, Benji; Schmidt, Bruno E.; Thiré, Nicolas; Bisson, Éric; Hebeisen, Christoph T.; Wanie, Vincent; Giguere, Mathieu; Kieffer, Jean-Claude; Sanderson, Joe; Schuurman, Michael S.; Légaré, François

2014-05-01

One of the primary goals of modern ultrafast science is to follow nuclear and electronic evolution of molecules as they undergo a photo-chemical reaction. Most of the interesting dynamics phenomena in molecules occur when an electronically excited state is populated. When the energy difference between electronic ground and excited states is large, Free Electron Laser (FEL) and HHG-based VUV sources were, up to date, the only light sources able to efficiently initiate those non-adiabatic dynamics. We have developed a simple table-top approach to initiate those rich dynamics via multiphoton absorption. As a proof of principle, we studied the ultrafast isomerization of the acetylene cation. We have chosen this model system for isomerization since the internal conversion mechanism which leads to proton migration is still under debate since decades. Using 266 nm multiphoton absorption as a pump and 800 nm induced Coulomb Explosion as a probe, we have shoot the first high-resolution molecular movie of the non-adiabatically driven proton migration in the acetylene cation. The experimental results are in excellent agreement with high level ab initio trajectory simulations.

Optimal moderator materials at various proton energies considering photon dose rate after irradiation for an accelerator-driven ⁹Be(p, n) boron neutron capture therapy neutron source.

PubMed

Hashimoto, Y; Hiraga, F; Kiyanagi, Y

2015-12-01

We evaluated the accelerator beam power and the neutron-induced radioactivity of (9)Be(p, n) boron neutron capture therapy (BNCT) neutron sources having a MgF2, CaF2, or AlF3 moderator and driven by protons with energy from 8 MeV to 30 MeV. The optimal moderator materials were found to be MgF2 for proton energies less than 10 MeV because of lower required accelerator beam power and CaF2 for higher proton energies because of lower photon dose rate at the treatment position after neutron irradiation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Positive Darwinian Selection in the Piston That Powers Proton Pumps in Complex I of the Mitochondria of Pacific Salmon

PubMed Central

Garvin, Michael R.; Bielawski, Joseph P.; Gharrett, Anthony J.

2011-01-01

The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm. PMID:21969854

Positive Darwinian selection in the piston that powers proton pumps in complex I of the mitochondria of Pacific salmon.

PubMed

Garvin, Michael R; Bielawski, Joseph P; Gharrett, Anthony J

2011-01-01

The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm.

Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma.

PubMed

Canitano, Andrea; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Federici, Cristina; Fais, Stefano

2016-07-01

Multiple Myeloma (MM) is the second most common hematological malignancy and is responsive to a limited number of drugs. Unfortunately, to date, despite the introduction of novel drugs, no relevant increase in survival rates has been obtained. Proton pump inhibitors (PPIs) have been shown to have significant antitumor action as single agents as well as in combination with chemotherapy. This study investigates the potential anti-tumor effectiveness of two PPIs, Lansoprazole and Omeprazole, against human MM cells. We found that Lansoprazole exerts straightforward efficacy against myeloma cells, even at suboptimal concentrations (50 µM), while Omeprazole has limited cytotoxic action. The Lansoprazole anti-MM effect was mostly mediated by a caspase-independent apoptotic-like cytotoxicity, with only a secondary anti-proliferative action. This study provides clear evidence supporting the use of Lansoprazole in the strive against MM with an efficacy proven much higher than current therapeutical approaches and without reported side effects. It is however conceivable that, consistent with the results obtained in other human tumors, Lansoprazole may well be combined with existing anti-myeloma therapies with the aim to improve the low level of efficacy of the current strategies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cutaneous Tuberculosis

PubMed Central

Frankel, Amylynne; Penrose, Carolin

2009-01-01

Cutaneous tuberculosis occurs rarely, despite a high and increasing prevalence of tuberculosis worldwide. Mycobacterium tuberculosis, Mycobacterrium bovis, and the Bacille Calmette-Guérin vaccine can cause tuberculosis involving the skin. Cutaneous tuberculosis can be acquired exogenously or endogenously and present as a multitude of differing clinical morphologies. Diagnosis of these lesions can be difficult, as they resemble many other dermatological conditions that are often primarily considered. Further, microbiological confirmation is poor, despite scientific advances, such as the more frequent use of polymerase chain reaction. The authors report a case that illustrates the challenges faced by dermatologists when considering a diagnosis of cutaneous tuberculosis. PMID:20725570

A seal-less centrifugal pump (Baylor Gyro Pump) for application to long-term circulatory support.

PubMed

Minato, N; Sakuma, I; Sasaki, T; Shiono, M; Ohara, Y; Takatani, S; Noon, G P; Nosé, Y

1993-01-01

We are developing a new centrifugal pump, the Baylor Gyro Centrifugal Pump (Gyro Pump), which can function for more than 2 weeks. The concept of the Gyro Pump is that a one-piece rotor-impeller with embedded permanent magnets, driven directly by a brushless direct current motor stator placed outside, rotates like a "gyroscope," and the rotor-impeller is supported by one pivot bearing at the bottom in accordance with the gyroscopic principle. This concept enables us to eliminate a driving shaft and a seal between the driving shaft and the blood chamber, which results in extending the life of the centrifugal pump. The blood passes through the space between the motor stator and the rotor to the impeller portion. In this preliminary phase, two pivot bearings were applied to support the rotor-impeller at the top and the bottom inside the blood chamber. Both pivot bearings showed less blood trauma and less thrombogenicity in in vitro and in vivo studies. The Gyro Pump is a promising second-generation centrifugal pump for long-term circulatory support in the near future.

Custom Unit Pump Development for the EVA PLSS

NASA Technical Reports Server (NTRS)

Schuller, Michael; Kurwitz, Cable; Little, Frank; Oinuma, Ryoji; Larsen, Ben; Goldman, Jeff; Reinis, Filip; Trevino, Luis

2010-01-01

This paper describes the effort by the Texas Engineering Experiment Station (TEES) and Honeywell for NASA to design and test a pre-flight prototype pump for use in the Extra-vehicular activity (EVA) portable life support subsystem (PLSS). Major design decisions were driven by the need to reduce the pump s mass, power, and volume compared to the existing PLSS pump. In addition, the pump must accommodate a much wider range of abnormal conditions than the existing pump, including vapor/gas bubbles and increased pressure drop when employed to cool two suits simultaneously. A positive displacement, external gear type pump was selected because it offers the most compact and highest efficiency solution over the required range of flow rates and pressure drops. An additional benefit of selecting a gear pump design is that it is self priming and capable of ingesting non-condensable gas without becoming air locked. The chosen pump design consists of a 28 V DC, brushless, seal-less, permanent magnet motor driven, external gear pump that utilizes a Honeywell development that eliminates the need for magnetic coupling. The pump design was based on existing Honeywell designs, but incorporated features specifically for the PLSS application, including all of the key features of the flight pump. Testing at TEES verified that the pump meets the design requirements for range of flow rates, pressure drop, power consumption, working fluid temperature, operating time, gas ingestion, and restart capability under both ambient and vacuum conditions. The pump operated at 40 to 240 lbm/hr flow rate, 35 to 100 oF pump temperature, and 5 to 10 psid pressure rise. Power consumption of the pump controller at the nominal operating point in both ambient and vacuum conditions was 9.5 W, which was less than the 12 W predicted. Gas ingestion capabilities were tested by injecting 100 cc of air into the fluid line; the pump operated normally throughout this test.

The influence of proton pump inhibitors and other commonly used medication on the gut microbiota

PubMed Central

Imhann, Floris; Vich Vila, Arnau; Bonder, Marc Jan; Koonen, Debby P.Y.; Fu, Jingyuan; Zhernakova, Alexandra; Weersma, Rinse K.

2017-01-01

ABSTRACT Proton pump inhibitors (PPIs), used to treat gastro-esophageal reflux and prevent gastric ulcers, are among the most widely used drugs in the world. The use of PPIs is associated with an increased risk of enteric infections. Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI-use on the gut microbiota. We discovered profound differences in the gut microbiota of PPI users: 20% of their bacterial taxa were statistically significantly altered compared with those of non-users. Moreover, we found that it is not only PPIs, but also antibiotics, antidepressants, statins and other commonly used medication were associated with distinct gut microbiota signatures. As a consequence, commonly used medications could affect how the gut microbiota resist enteric infections, promote or ameliorate gut inflammation, or change the host's metabolism. More studies are clearly needed to understand the role of commonly used medication in altering the gut microbiota as well as the subsequent health consequences. PMID:28118083

A Benzimidazole Proton Pump Inhibitor Increases Growth and Tolerance to Salt Stress in Tomato.

PubMed

Van Oosten, Michael J; Silletti, Silvia; Guida, Gianpiero; Cirillo, Valerio; Di Stasio, Emilio; Carillo, Petronia; Woodrow, Pasqualina; Maggio, Albino; Raimondi, Giampaolo

2017-01-01

Pre-treatment of tomato plants with micromolar concentrations of omeprazole (OP), a benzimidazole proton pump inhibitor in mammalian systems, improves plant growth in terms of fresh weight of shoot and roots by 49 and 55% and dry weight by 54 and 105% under salt stress conditions (200 mM NaCl), respectively. Assessment of gas exchange, ion distribution, and gene expression profile in different organs strongly indicates that OP interferes with key components of the stress adaptation machinery, including hormonal control of root development (improving length and branching), protection of the photosynthetic system (improving quantum yield of photosystem II) and regulation of ion homeostasis (improving the K + :Na + ratio in leaves and roots). To our knowledge OP is one of the few known molecules that at micromolar concentrations manifests a dual function as growth enhancer and salt stress protectant. Therefore, OP can be used as new inducer of stress tolerance to better understand molecular and physiological stress adaptation paths in plants and to design new products to improve crop performance under suboptimal growth conditions. Highlight: Omeprazole enhances growth of tomato and increases tolerance to salinity stress through alterations of gene expression and ion uptake and transport.

One year treatment of Barrett's oesophagus with proton pump inhibitors (a multi-center study).

PubMed

Babic, Z; Bogdanovic, Z; Dorosulic, Z; Petrovic, Z; Kujundzic, M; Banic, M; Marusic, M; Heinzl, R; Bilić, B; Andabak, M

2015-12-01

Aim of the study was to investigate the effects of 1-year therapy by different proton pump inhibitors (PPIs) on epithelial tissue and surrounding inflammatory changes in Barrett's oesophagus, in patients who have abandoned invasive therapy. A group of 120 patients (sampled in 60-month period, from 61201 upper gastrointestinal endoscopies) who were diagnosed both, endoscopically and pathohistologically with Barrett's oesophagus, and who have abandoned invasive therapeutic approach were enrolled in study. Treatment with different PPIs was initiated and continued for a year. At the end of treatment, patients were reassessed by endoscopy with tissue biopsy and pathohistological analysis. No difference in regenerating squamous epithelium or degree of dysplasia was seen between different treatment groups. Interestingly, most patients receiving pantoprazole (94%) ended up with thinner squamous epithel (P<0.0001). The squamous epithel was consider thinner only if its total thickness, measured on histological specimen, was smaller for more than 50% of the thickness before therapy. Significantly less of difference (P<0.0014) was seen with patients receiving lansoprazole (65%) and (P<0.003) omeprazole (50%). Regeneration of the squamous epithel was the same for all PPIs but not good enough to stop the progression of the disease.

A Benzimidazole Proton Pump Inhibitor Increases Growth and Tolerance to Salt Stress in Tomato

PubMed Central

Van Oosten, Michael J.; Silletti, Silvia; Guida, Gianpiero; Cirillo, Valerio; Di Stasio, Emilio; Carillo, Petronia; Woodrow, Pasqualina; Maggio, Albino; Raimondi, Giampaolo

2017-01-01

Pre-treatment of tomato plants with micromolar concentrations of omeprazole (OP), a benzimidazole proton pump inhibitor in mammalian systems, improves plant growth in terms of fresh weight of shoot and roots by 49 and 55% and dry weight by 54 and 105% under salt stress conditions (200 mM NaCl), respectively. Assessment of gas exchange, ion distribution, and gene expression profile in different organs strongly indicates that OP interferes with key components of the stress adaptation machinery, including hormonal control of root development (improving length and branching), protection of the photosynthetic system (improving quantum yield of photosystem II) and regulation of ion homeostasis (improving the K+:Na+ ratio in leaves and roots). To our knowledge OP is one of the few known molecules that at micromolar concentrations manifests a dual function as growth enhancer and salt stress protectant. Therefore, OP can be used as new inducer of stress tolerance to better understand molecular and physiological stress adaptation paths in plants and to design new products to improve crop performance under suboptimal growth conditions. Highlight: Omeprazole enhances growth of tomato and increases tolerance to salinity stress through alterations of gene expression and ion uptake and transport. PMID:28769943

Proton pump inhibitors suppress iNOS-dependent DNA damage in Barrett's esophagus by increasing Mn-SOD expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thanan, Raynoo; Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507; Ma, Ning

2012-05-04

Highlights: Black-Right-Pointing-Pointer Inflammation by Barrett's esophagus (BE) is a risk factor of its adenocarcinoma (BEA). Black-Right-Pointing-Pointer 8-Nitroguanine and 8-oxodG are inflammation-related DNA lesions. Black-Right-Pointing-Pointer DNA lesions and iNOS expression were higher in the order, BEA > BE > normal tissues. Black-Right-Pointing-Pointer Proton pump inhibitors suppress DNA damage by increasing Mn-SOD via Nrf2 activation. Black-Right-Pointing-Pointer DNA lesions can be useful biomarkers to predict risk of BEA in BE patients. -- Abstract: Barrett's esophagus (BE), an inflammatory disease, is a risk factor for Barrett's esophageal adenocarcinoma (BEA). Treatment of BE patients with proton pump inhibitors (PPIs) is expected to reduce the riskmore » of BEA. We performed an immunohistochemical study to examine the formation of nitrative and oxidative DNA lesions, 8-nitroguanine and 8-oxo-7,8-dihydro-2 Prime -deoxygaunosine (8-oxodG), in normal esophageal, BE with pre- and post-treatment by PPIs and BEA tissues. We also observed the expression of an oxidant-generating enzyme (iNOS) and its transcription factor NF-{kappa}B, an antioxidant enzyme (Mn-SOD), its transcription factor (Nrf2) and an Nrf2 inhibitor (Keap1). The immunoreactivity of DNA lesions was significantly higher in the order of BEA > BE > normal tissues. iNOS expression was significantly higher in the order of BEA > BE > normal tissues, while Mn-SOD expression was significantly lower in the order of BEA < BE < normal tissues. Interestingly, Mn-SOD expression and the nuclear localization of Nrf2 were significantly increased, and the formation of DNA lesions was significantly decreased in BE tissues after PPIs treatment for 3-6 months. Keap1 and iNOS expression was not significantly changed by the PPIs treatment in BE tissues. These results indicate that 8-nitroguanine and 8-oxodG play a role in BE-derived BEA. Additionally, PPIs treatment may trigger the activation and nuclear

Pantoprazole, a proton pump inhibitor, increases orthodontic tooth movement in rats.

PubMed

Shirazi, Mohsen; Alimoradi, Houman; Kheirandish, Yasaman; Etemad-Moghadam, Shahroo; Alaeddini, Mojgan; Meysamie, Alipasha; Fatahi Meybodi, Seyed Amir Reza; Dehpour, Ahmad Reza

2014-06-01

Pantoprazole, is a proton pump inhibitor (PPI) prescribed for the treatment of upper gastrointestinal disorders, which in high doses has been suggested to decrease calcium absorption leading to hypocalcaemia and therefore osteoporosis. The aim of this study was to assess whether pantoprazol, could alter the rate of orthodontic tooth movement (OTM) in rats. A time course study was established using 72 rats which were divided into six groups of 12 samples each (four: vehicle; eight: pantoprazole + vehicle). Pantoprazole at a dose of 200 mg/kg suspended in carboxymethyl cellulose (0.25 percent) was administered by a gastric tube. The upper incisors and first molars were ligated by a 5 mm nickel-titanium closed-coil spring to deliver an initial force of 60 g. Animals were euthanized two weeks after orthodontic treatment followed by assessment of tooth movement and histomorphometric evaluation of the detached maxillae. Lateral skull radiographs were obtained once a week, starting from the first day to the 6(th) week of the study. OTM and bone density data were analyzed using independent sample t-test and repeated measures ANOVA. No significant changes in OTM measurements and optical density were observed in vehicle-receiving animals during the study (P=0.994). OTM was significantly increased after six weeks pantoprazole therapy which continued until the 7(th) week of the experiment (P=0.007). Optical density significantly increased in the pantoprazole-treated rats after six weeks. Long term PPI therapy at high doses could lead to osteoporosis and enhanced OTM.

Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

PubMed Central

Nies, Anne T.; Hofmann, Ute; Resch, Claudia; Schaeffeler, Elke; Rius, Maria; Schwab, Matthias

2011-01-01

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy. PMID:21779389

Cutaneous manifestations of lupus erythematosus.

PubMed

Parodi, A; Cozzani, E

2014-10-01

Cutaneous involvement in case of lupus erythematosus (LE) is very frequent and can present both specific or non-specific manifestations. LE specific lesions can be classified in acute, subacute and chronic cutaneous LE lesions. All of them can be localized and generalized. The LE non specific lesions are not exclusive to LE disease but are often seen in patients with active systemic LE. All the cutaneous lesions are often induced or aggravated by ultraviolet light, in fact they are usually localized in sun-exposed areas. Acute cutaneous LE is associated with systemic disease, subacute cutaneous LE has been considered a subset of its own since 1979 when it was first described, chronic cutaneous LE is the most common subtype of LE. Although less frequently also the chronic cutaneous lesions can be an aspect of systemic LE (25%).

Fast neutron production from lithium converters and laser driven protons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Storm, M.; Jiang, S.; Wertepny, D.

2013-05-15

Experiments to generate neutrons from the {sup 7}Li(p,n){sup 7}Be reaction with 60 J, 180 fs laser pulses have been performed at the Texas Petawatt Laser Facility at the University of Texas at Austin. The protons were accelerated from the rear surface of a thin target membrane using the target-normal-sheath-acceleration mechanism. The neutrons were generated in nuclear reactions caused by the subsequent proton bombardment of a pure lithium foil of natural isotopic abundance. The neutron energy ranged up to 2.9 MeV. The total yield was estimated to be 1.6 × 10{sup 7} neutrons per steradian. An extreme ultra-violet light camera, usedmore » to image the target rear surface, correlated variations in the proton yield and peak energy to target rear surface ablation. Calculations using the hydrodynamics code FLASH indicated that the ablation resulted from a laser pre-pulse of prolonged intensity. The ablation severely limited the proton acceleration and neutron yield.« less

Applications of High Intensity Proton Accelerators

NASA Astrophysics Data System (ADS)

Raja, Rajendran; Mishra, Shekhar

2010-06-01

Superconducting radiofrequency linac development at Fermilab / S. D. Holmes -- Rare muon decay experiments / Y. Kuno -- Rare kaon decays / D. Bryman -- Muon collider / R. B. Palmer -- Neutrino factories / S. Geer -- ADS and its potential / J.-P. Revol -- ADS history in the USA / R. L. Sheffield and E. J. Pitcher -- Accelerator driven transmutation of waste: high power accelerator for the European ADS demonstrator / J. L. Biarrotte and T. Junquera -- Myrrha, technology development for the realisation of ADS in EU: current status & prospects for realisation / R. Fernandez ... [et al.] -- High intensity proton beam production with cyclotrons / J. Grillenberger and M. Seidel -- FFAG for high intensity proton accelerator / Y. Mori -- Kaon yields for 2 to 8 GeV proton beams / K. K. Gudima, N. V. Mokhov and S. I. Striganov -- Pion yield studies for proton driver beams of 2-8 GeV kinetic energy for stopped muon and low-energy muon decay experiments / S. I. Striganov -- J-Parc accelerator status and future plans / H. Kobayashi -- Simulation and verification of DPA in materials / N. V. Mokhov, I. L. Rakhno and S. I. Striganov -- Performance and operational experience of the CNGS facility / E. Gschwendtner -- Particle physics enabled with super-conducting RF technology - summary of working group 1 / D. Jaffe and R. Tschirhart -- Proton beam requirements for a neutrino factory and muon collider / M. S. Zisman -- Proton bunching options / R. B. Palmer -- CW SRF H linac as a proton driver for muon colliders and neutrino factories / M. Popovic, C. M. Ankenbrandt and R. P. Johnson -- Rapid cycling synchrotron option for Project X / W. Chou -- Linac-based proton driver for a neutrino factory / R. Garoby ... [et al.] -- Pion production for neutrino factories and muon colliders / N. V. Mokhov ... [et al.] -- Proton bunch compression strategies / V. Lebedev -- Accelerator test facility for muon collider and neutrino factory R&D / V. Shiltsev -- The superconducting RF linac for muon

Diffusion-driven proton exchange membrane fuel cell for converting fermenting biomass to electricity.

PubMed

Malati, P; Mehrotra, P; Minoofar, P; Mackie, D M; Sumner, J J; Ganguli, R

2015-10-01

A membrane-integrated proton exchange membrane fuel cell that enables in situ fermentation of sugar to ethanol, diffusion-driven separation of ethanol, and its catalytic oxidation in a single continuous process is reported. The fuel cell consists of a fermentation chamber coupled to a direct ethanol fuel cell. The anode and fermentation chambers are separated by a reverse osmosis (RO) membrane. Ethanol generated from fermented biomass in the fermentation chamber diffuses through the RO membrane into a glucose solution contained in the DEFC anode chamber. The glucose solution is osmotically neutral to the biomass solution in the fermentation chamber preventing the anode chamber from drying out. The fuel cell sustains >1.3 mW cm(-2) at 47°C with high discharge capacity. No separate purification or dilution is necessary, resulting in an efficient and portable system for direct conversion of fermenting biomass to electricity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Proton transfer in the K-channel analog of B-type Cytochrome c oxidase from Thermus thermophilus.

PubMed

Woelke, Anna Lena; Wagner, Anke; Galstyan, Gegham; Meyer, Tim; Knapp, Ernst-Walter

2014-11-04

A key enzyme in aerobic metabolism is cytochrome c oxidase (CcO), which catalyzes the reduction of molecular oxygen to water in the mitochondrial and bacterial membranes. Substrate electrons and protons are taken up from different sides of the membrane and protons are pumped across the membrane, thereby generating an electrochemical gradient. The well-studied A-type CcO uses two different entry channels for protons: the D-channel for all pumped and two consumed protons, and the K-channel for the other two consumed protons. In contrast, the B-type CcO uses only a single proton input channel for all consumed and pumped protons. It has the same location as the A-type K-channel (and thus is named the K-channel analog) without sharing any significant sequence homology. In this study, we performed molecular-dynamics simulations and electrostatic calculations to characterize the K-channel analog in terms of its energetic requirements and functionalities. The function of Glu-15B as a proton sink at the channel entrance is demonstrated by its rotational movement out of the channel when it is deprotonated and by its high pKA value when it points inside the channel. Tyr-244 in the middle of the channel is identified as the valve that ensures unidirectional proton transfer, as it moves inside the hydrogen-bond gap of the K-channel analog only while being deprotonated. The electrostatic energy landscape was calculated for all proton-transfer steps in the K-channel analog, which functions via proton-hole transfer. Overall, the K-channel analog has a very stable geometry without large energy barriers.

Proton Transfer in the K-Channel Analog of B-Type Cytochrome c Oxidase from Thermus thermophilus

PubMed Central

Woelke, Anna Lena; Wagner, Anke; Galstyan, Gegham; Meyer, Tim; Knapp, Ernst-Walter

2014-01-01

A key enzyme in aerobic metabolism is cytochrome c oxidase (CcO), which catalyzes the reduction of molecular oxygen to water in the mitochondrial and bacterial membranes. Substrate electrons and protons are taken up from different sides of the membrane and protons are pumped across the membrane, thereby generating an electrochemical gradient. The well-studied A-type CcO uses two different entry channels for protons: the D-channel for all pumped and two consumed protons, and the K-channel for the other two consumed protons. In contrast, the B-type CcO uses only a single proton input channel for all consumed and pumped protons. It has the same location as the A-type K-channel (and thus is named the K-channel analog) without sharing any significant sequence homology. In this study, we performed molecular-dynamics simulations and electrostatic calculations to characterize the K-channel analog in terms of its energetic requirements and functionalities. The function of Glu-15B as a proton sink at the channel entrance is demonstrated by its rotational movement out of the channel when it is deprotonated and by its high pKA value when it points inside the channel. Tyr-244 in the middle of the channel is identified as the valve that ensures unidirectional proton transfer, as it moves inside the hydrogen-bond gap of the K-channel analog only while being deprotonated. The electrostatic energy landscape was calculated for all proton-transfer steps in the K-channel analog, which functions via proton-hole transfer. Overall, the K-channel analog has a very stable geometry without large energy barriers. PMID:25418102