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Sample records for scale prevention inhibitor

  1. Green chemistry applied to corrosion and scale inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Darling, D.; Rakshpal, R. [Environmental Protection Agency, Washington, DC (United States)

    1998-12-31

    Numerous breakthroughs in environmental protection and pollution prevention have been realized in recent years by both industry and academia through the application of green chemistry principles. Green chemistry, or pollution prevention at the molecular level, is chemistry designed to reduce or eliminate the use or generation of hazardous materials associated with the manufacture and application of chemicals. The application of the green chemistry principles to the areas of corrosion and scale inhibitors has resulted in the reduction/elimination of many of the more toxic inhibitors and the development of newer, more environmentally friendly ones.

  2. Prevention of Corrosion Rate by Natural Inhibitor Papaya Leaf Extract

    OpenAIRE

    Bow, Yohandri

    2012-01-01

    Corrosion is an event of damage or deterioration of a metal caused by reaction with the environtment. Corrosion process can be prevented by the addition of corrosion inhibitor. Papaya leaf extract is an organic material that could potentially be used as a corrosion inhibitor because it contains N-acetyl- glukosamida and amino acid. The purpose of this study is to determine the effects of brine concentration and surface area on the rate of corrosion of a metal plate that can be used as refere...

  3. Effect of the scale inhibitor on ion content in reverse osmosis system for seawater desalination

    Science.gov (United States)

    Gao, Yuhua; Liu, Zhenfa; Zhang, Lihui; Li, Haihua

    2017-09-01

    A scale inhibitor was synthesized from polysuccinimide with 2-aminoethanesulfonic acid and aspartic acid. The effect of scale inhibitor on ion content in reverse osmosis system for seawater desalination was studied. The results showed that the ion content of permeate water is lower with the scale inhibitor added in RO system for seawater desalination than without scale inhibitor. On the contrary, the ion content of concentrate water is higher when with scale inhibitor in RO system.

  4. Novel polymers as scale inhibitors for squeeze treatments

    Energy Technology Data Exchange (ETDEWEB)

    Duccini, Y.

    1996-12-31

    Squeeze treatments are increasingly important to recover oil from offshore platforms. During production deposition occurs and scale inhibitors are widely used. Different chemicals are already used to inhibit several scaling components, including BaSO{sub 4} which appears to be the major problem in wells of the North Sea. Phosphonates, polyacrylates, phosphinocarboxylates and polyvinylsulfonates are the leading products. All of them do not fulfill end users requirements, especially for harsh conditions such as low pHs, high barium and extreme temperatures and pressures. The paper describes new inhibitors both for standard conditions and harsh conditions which are overcoming most of the present drawbacks. In both sets of conditions, the results on performances, stability and absorption-desorption properties are presented. 7 refs., 9 figs., 4 tabs.

  5. The development and performance testing of a biodegradable scale inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, Julie; Fidoe, Steve; Jones, Chris

    2006-03-15

    The oil industry is currently facing severe restrictions concerning the discharge of oil field chemicals into the environment. Many commonly used materials in both topside and downhole applications are phased for substitution for use in the North Sea, and more will be identified. The development of biodegradable and low toxicity chemicals, which afford equal or improved efficacy, compared to conventional technology, available at a competitive price, is a current industry challenge. A range of biodegradable materials are increasingly available, however their limited performance can result in a restricted range of applications. This paper discusses the development and commercialization of a readily biodegradable scale inhibitor, ideal for use in topside applications. This material offers a broad spectrum of activity, notably efficiency against barium sulphate, calcium sulphate and calcium carbonate scales, in a range of water chemistries. A range of performance testing, compatibility, stability and OCNS dataset will be presented. Comparisons with commonly used chemicals have been made to identify the superior performance of this phosphate ester. This paper will discuss a scale inhibitor suitable for use in a variety of conditions which offers enhanced performance combined with a favourable biodegradation profile. This material is of great benefit to the industry, particularly in North Sea applications. (author) (tk)

  6. Surface modification to prevent oxide scale spallation

    Energy Technology Data Exchange (ETDEWEB)

    Stephens, Elizabeth V; Sun, Xin; Liu, Wenning; Stevenson, Jeffry W; Surdoval, Wayne; Khaleel, Mohammad A

    2013-07-16

    A surface modification to prevent oxide scale spallation is disclosed. The surface modification includes a ferritic stainless steel substrate having a modified surface. A cross-section of the modified surface exhibits a periodic morphology. The periodic morphology does not exceed a critical buckling length, which is equivalent to the length of a wave attribute observed in the cross section periodic morphology. The modified surface can be created using at least one of the following processes: shot peening, surface blasting and surface grinding. A coating can be applied to the modified surface.

  7. Topical application of entry inhibitors as "virustats" to prevent sexual transmission of HIV infection

    Directory of Open Access Journals (Sweden)

    Root Michael

    2008-12-01

    Full Text Available Abstract With the continuing march of the AIDS epidemic and little hope for an effective vaccine in the near future, work to develop a topical strategy to prevent HIV infection is increasingly important. This stated, the track record of large scale "microbicide" trials has been disappointing with nonspecific inhibitors either failing to protect women from infection or even increasing HIV acquisition. Newer strategies that target directly the elements needed for viral entry into cells have shown promise in non-human primate models of HIV transmission and as these agents have not yet been broadly introduced in regions of highest HIV prevalence, they are particularly attractive for prophylaxis. We review here the agents that can block HIV cellular entry and that show promise as topical strategies or "virustats" to prevent mucosal transmission of HIV infection

  8. Hepatocyte growth factor activator inhibitor-2 prevents shedding of matriptase

    DEFF Research Database (Denmark)

    Larsen, Brian R; Steffensen, Simon D R; Nielsen, Nis Valentin Ladefoged

    2013-01-01

    Hepatocyte growth factor activator inhibitor-2 (HAI-2) is an inhibitor of many proteases in vitro, including the membrane-bound serine protease, matriptase. Studies of knock-out mice have shown that HAI-2 is essential for placental development only in mice expressing matriptase, suggesting that HAI...

  9. Does Mineralocorticoid Receptor Antagonism Prevent Calcineurin Inhibitor-Induced Nephrotoxicity?

    Directory of Open Access Journals (Sweden)

    Line Aas Mortensen

    2017-11-01

    Full Text Available Calcineurin inhibitors have markedly reduced acute rejection rates in renal transplantation, thus significantly improved short-term outcome. The beneficial effects are, however, tampered by acute and chronic nephrotoxicity leading to interstitial fibrosis and tubular atrophy, which impairs long-term allograft survival. The mineralocorticoid hormone aldosterone induces fibrosis in numerous organs, including the kidney. Evidence from animal models suggests a beneficial effect of aldosterone antagonism in reducing calcineurin inhibitor-induced nephrotoxicity. This review summarizes current evidence of mineralocorticoid receptor antagonism in animal models of calcineurin inhibitor-induced nephrotoxicity and the results from studies of mineralocorticoid antagonism in renal transplant patients.

  10. Inhibitors

    Science.gov (United States)

    ... and exercise, immune tolerance therapy, and needs of older adults with hemophilia and an inhibitor. For more information, visit https://www.hemophilia.org/Events-Educational-Programs/Inhibitor-Education/Inhibitor-Education-Summits The NHF’s Inhibitor Education Summits ...

  11. Crizotinib, a MET inhibitor, prevents peritoneal dissemination in pancreatic cancer.

    Science.gov (United States)

    Takiguchi, Soichi; Inoue, Kazuko; Matsusue, Kimihiko; Furukawa, Masayuki; Teramoto, Norihiro; Iguchi, Haruo

    2017-07-01

    Peritoneal dissemination is a frequent occurrence in pancreatic cancer, which is associated with a poor prognosis. MET is associated with the progression of pancreatic cancer; therefore, we evaluated the effect of a MET inhibitor, crizotinib, on peritoneal dissemination of pancreatic cancer. Crizotinib inhibited the growth of 8 pancreatic cancer cell lines with the IC50 ranging from 1.4 to 4.3 µM. Invasion of the pancreatic cancer cell line Suit-2, was suppressed in vitro at a concentration of 1.0 µM, which is sufficient for the inhibition of MET phosphorylation. This effect on cell invasion was also recapitulated by the reduction of MET expression in Suit-2 with siRNA. Crizotinib also inhibited RhoA activation in addition to MET phosphorylation. We further evaluated the effect of crizotinib on peritoneal dissemination of pancreatic cancer in vivo. Crizotinib reduced tumor burden and ascites accumulation due to development of peritoneal dissemination after inoculation of Suit-2. Taken together, crizotinib may be a potent drug for treating peritoneal dissemination of pancreatic cancer by inhibiting cancer cell proliferation and invasion, at least in part through the suppression of HGF/MET signaling and RhoA activation.

  12. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis

    National Research Council Canada - National Science Library

    Healey, Jeff S; Baranchuk, Adrian; Crystal, Eugene; Morillo, Carlos A; Garfinkle, Michael; Yusuf, Salim; Connolly, Stuart J

    2005-01-01

    This study was designed to identify all randomized clinical trial data evaluating angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for the prevention of atrial fibrillation (AF...

  13. The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates.

    Science.gov (United States)

    McCann, Nicole C; Lynch, Terrie J; Kim, Soon Ok; Duffy, Diane M

    2013-12-01

    Cyclooxygenase-2 (COX-2) inhibitors reduce prostaglandin synthesis and disrupt essential reproductive processes. Ultrasound studies in women demonstrated that oral COX-2 inhibitors can delay or prevent follicle collapse associated with ovulation. The goal of this study was to determine if oral administration of a COX-2 inhibitor can inhibit reproductive function with sufficient efficacy to prevent pregnancy in primates. The COX-2 inhibitor meloxicam (or vehicle) was administered orally to proven fertile female cynomolgus macaques using one emergency contraceptive model and three monthly contraceptive models. In the emergency contraceptive model, females were bred with a proven fertile male once 2±1 days before ovulation, returned to the females' home cage, and then received 5 days of meloxicam treatment. In the monthly contraceptive models, females were co-caged for breeding with a proven fertile male for a total of 5 days beginning 2±1 days before ovulation. Animals received meloxicam treatment (1) cycle days 5-22, or (2) every day, or (3) each day of the 5-day breeding period. Female were then assessed for pregnancy. The pregnancy rate with meloxicam administration using the emergency contraception model was 6.5%, significantly lower than the pregnancy rate of 33.3% when vehicle without meloxicam was administered. Pregnancy rates with the three monthly contraceptive models (75%-100%) were not consistent with preventing pregnancy. Oral COX-2 inhibitor administration can prevent pregnancy after a single instance of breeding in primates. While meloxicam may be ineffective for regular contraception, pharmacological inhibition of COX-2 may be an effective method of emergency contraception for women. COX-2 inhibitors can interfere with ovulation, but the contraceptive efficacy of drugs of this class has not been directly tested. This study, conducted in nonhuman primates, is the first to suggest that a COX-2 inhibitor may be effective as an emergency contraceptive.

  14. Utility-scale system preventive and failure-related maintenance

    Energy Technology Data Exchange (ETDEWEB)

    Jennings, C.; Hutchinson, P.

    1995-11-01

    This paper describes the design and performance background on PVUSA utility-scale systems at Davis and Kerman, California, and reports on a preventative and failure-related maintenance approach and costs.

  15. Na(+)-H(+) exchanger inhibitor prevents early death in hereditary cardiomyopathy.

    Science.gov (United States)

    Bkaily, Ghassan; Chahine, Mirna; Al-Khoury, Johny; Avedanian, Levon; Beier, Norbert; Scholz, Wolfgang; Jacques, Danielle

    2015-11-01

    Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular Na(+) and Ca(2+) overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented Na(+) and Ca(2+) overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent Na(+) and Ca(2+) overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy.

  16. Rapid, high-temperature, field test method for evaluation of geothermal calcium carbonate scale inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Asperger, R.G.

    1986-09-01

    A new test method is described that allows the rapid field testing of calcium carbonate scale inhibitors at 500/sup 0/F (260/sup 0/C). The method evolved from use of a full-flow test loop on a well with a mass flow rate of about 1 x 10/sup 6/ lbm/hr (126 kg/s). It is a simple, effective way to evaluate the effectiveness of inhibitors under field conditions. Five commercial formulations were chosen for field evaluation on the basis of nonflowing, laboratory screening tests at 500/sup 0/F (260/sup 0/C). Four of these formulations from different suppliers controlled calcium carbonate scale deposition as measured by the test method. Two of these could dislodge recently deposited scale that had not age-hardened. Performance-profile diagrams, which were measured for these four effective inhibitors, show the concentration interrelationship between brine calcium and inhibitor concentrations at which the formulations will and will not stop scale formation in the test apparatus. With these diagrams, one formulation was chosen for testing on the full-flow brine line. The composition was tested for 6 weeks and showed a dramatic decrease in the scaling occurring at the flow-control valve. This scaling was about to force a shutdown of a major, long-term flow test being done for reservoir economic evaluations. The inhibitor stopped the scaling, and the test was performed without interruption.

  17. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

    Directory of Open Access Journals (Sweden)

    Chihiro Okuma

    2015-07-01

    Conclusion: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

  18. Novel polymeric phosphonate scale inhibitors for improved squeeze treatment lifetimes

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, G.E.; Poynton, N.; McLaughlin, K.; Clark, D.R.

    1996-12-31

    New patented chemistry has provided an exciting discovery which may be used to reduce costs in scale squeeze applications. Phosphomethylated polyamines (PMPAs) have been found to possess outstanding adsorption-desorption properties which generate long squeeze lifetimes. This paper describes the core-flood tests and modelling work, which highlight these properties, plus additional scale inhibition performance studies to demonstrate the all-round capabilities of this chemistry for squeeze treatments. An example of a PMPA is used to show the extremely viable adsorption and desorption isotherms. These illustrate the efficient way in which the desorption occurs to minimise the chemical in the returns with a benefit of reduced chemical content in the discharge. The PMPA also demonstrates that both polymer and phosphonate properties can be embraced in a single product (e.g. dual scale control mechanisms) confirming that this chemistry is a true polymeric phosphonate. 13 refs., 12 figs., 1 tab.

  19. Further developments and field deployment of phosphorus functionalized polymeric scale inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Todd, Malcolm J.; Thornton, Alex R.; Wylde, Jonathan J.; Strachan, Catherine J.; Moir, Gordon [Clariant Oil Services, Muttenz (Switzerland); Goulding, John [John Goulding Consultancy, York (United Kingdom)

    2012-07-01

    As the oil and gas industry strives to replace ageing, environmentally undesirable scale inhibitors there is an ever increasing use of polymeric inhibitors. The incorporation of phosphorous functionality into a polymer backbone has been shown to improve inhibition efficiency, enhance adsorption characteristics and allow the polymer concentration to be analyzed by elemental phosphorus. It is known that some phosphorus tagged polymers can be problematic to analyze in oil field brines as they typically have a low phosphorus content which is difficult to determine from the background. The development of novel phosphorus functionalized polymeric scale inhibitors was previously described (IBP3530-10). This paper follows the development of the inhibitor class. Utilizing extensive laboratory testing the interactive nature of the scale inhibitors and reservoir lithology was studied. These novel phosphorus functionalized inhibitors were compared to a number of other available scale inhibitors. The incorporation of phosphorus functionality into polymeric inhibitors can be expensive utilizing traditional methods as the phosphorus containing monomers are the financially limiting factor. These are typically vinyl phosphonic acid (VPA), or vinyl diphosphonic acid (VDPA). The novel phosphorus functionalized monomers utilized herein are simpler to manufacture allowing higher phosphorus content within the polymer backbone. The addition of phosphorus into a polymer backbone has previously been known to exacerbate analysis issues in some commercially available scale inhibitors. This is due to incomplete polymerization reactions leaving free and/or inorganic phosphorus containing moieties which can interfere with the analysis, or low levels of phosphorus within end-capped polymers can make it difficult to determine the active concentration accurately within field brines which contain many impuritie. Polymeric inhibitors are known to contain a range of molecular weights with varying

  20. Protein synthesis inhibitors prevent both spontaneous and hormone-dependent maturation of isolated mouse oocytes

    Energy Technology Data Exchange (ETDEWEB)

    Downs, S.M. (Marquette Univ., Milwaukee, WI (USA))

    1990-11-01

    The present study was carried out to examine the role of protein synthesis in mouse oocyte maturation in vitro. In the first part of this study, the effects of cycloheximide (CX) were tested on spontaneous meiotic maturation when oocytes were cultured in inhibitor-free medium. CX reversibly suppressed maturation of oocytes as long as maturation was either initially prevented by the phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), or delayed by follicle-stimulating hormone (FSH). In the second part of this study, the actions of protein synthesis inhibitors were tested on hormone-induced maturation. CEO were maintained in meiotic arrest for 21-22 h with hypoxanthine, and germinal vesicle breakdown (GVB) was induced with follicle-stimulating hormone (FSH). Three different protein synthesis inhibitors (CX, emetine (EM), and puromycin (PUR)) each prevented the stimulatory action of FSH on GVB in a dose-dependent fashion. This was accompanied by a dose-dependent suppression of 3H-leucine incorporation by oocyte-cumulus cell complexes. The action of these inhibitors on FSH- and epidermal growth factor (EGF)-induced GVB was next compared. All three drugs lowered the frequency of GVB in the FSH-treated groups, below even that of the controls (drug + hypoxanthine); the drugs maintained meiotic arrest at the control frequencies in the EGF-treated groups. Puromycin aminonucleoside, an analog of PUR with no inhibitory action on protein synthesis, had no effect. The three inhibitors also suppressed the stimulatory action of FSH on oocyte maturation when meiotic arrest was maintained with the cAMP analog, dbcAMP.

  1. Scaling up Prevention of Mother to Child Transmission of HIV ...

    African Journals Online (AJOL)

    Nigeria is scaling up prevention of mother-to-child transmission (PMTCT) of HIV interventions to primary health care centres (PHCs). This retrospective study of PMTCT was at two PHCs in Northwest Nigeria with the main outcome measure being HIV infection rate of exposed infants at 6 weeks of life. Of 10,289 women who ...

  2. Scaling up Prevention of Mother to Child Transmission of HIV ...

    African Journals Online (AJOL)

    AJRH Managing Editor

    Jigawa State, 3Federal Medical Centre Katsina, Katsina State.4Takai Comprehensive Health Centre, Takai, Kano State. 5Maternal ... Nigeria is scaling up prevention of mother-to-child transmission (PMTCT) of HIV interventions to primary health care centres. (PHCs). ..... stigma, inability to afford transport cost and long.

  3. ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

    Science.gov (United States)

    Moulder, J E; Fish, B L; Cohen, E P

    2003-01-01

    Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

  4. Rapid high temperature field test method for evaluation of geothermal calcite scale inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Asperger, R.G.

    1982-08-01

    A test method is described which allows the rapid field testing of calcite scale inhibitors in high- temperature geothermal brines. Five commercial formulations, chosen on the basis of laboratory screening tests, were tested in brines with low total dissolved solids at ca 500 F. Four were found to be effective; of these, 2 were found to be capable of removing recently deposited scale. One chemical was tested in the full-flow brine line for 6 wks. It was shown to stop a severe surface scaling problem at the well's control valve, thus proving the viability of the rapid test method. (12 refs.)

  5. Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

    Science.gov (United States)

    Franchini, Massimo; Lippi, Giuseppe

    2016-12-01

    Thanks to considerable progresses made over the last 30years, hemophilia benefits from the most efficacious and safe treatment among the many monogenic inherited disorders. The most challenging complication of replacement therapy in hemophilia A is the occurrence of alloantibodies against infused factor VIII (FVIII), thus predisposing the patients to increased morbidity and disability. Extensive research in this field has definitively unraveled that development of inhibitors in hemophilia A is a complex and multifactorial process, in which inherited and environmental factors dynamically interact. This narrative review, after providing a concise overview about the main genetic and non-genetic risk factors, is aimed to focus on prediction risk models and preventive strategies for minimizing the risk of developing inhibitors in hemophilia A patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. OPPORTUNITIES FOR APPLICATION OF THE NEURAMINIDASE INHIBITORS IN TREATMENT AND PREVENTION OF THE FLU

    Directory of Open Access Journals (Sweden)

    Yu.B. Belan

    2007-01-01

    Full Text Available Flu viruses cause yearly epidemics with the lesion of approximately 20% of population. during the increase of the flu sickness rate, it is necessary to take urgent anti epidemic and treatment steps aimed to reduce the spread of an infection as soon as possible and incorporating the application of the specific antiviral medications. The major aims for prescription of the specific antiviral medications in flu treatment are to reduce the duration and severity of the leading disease symptoms, risks of complications, as well as to prevent the lethal out comes. There were developed medications, effectively inhibiting the replication of B flu virus. At present, there are the 1st generation medications available — adamantane derivatives (amantadine and rimantadine and the 2nd generation medications — neuraminidase inhibitors (oseltamivir and zanamivir. The fast increase of the flu virus resistance towards adamantanes determine the necessity of a wider application of neuraminidase inhibitors, which are highly effective in respect flu viruses of A and B, as well as avian flu virus (h5n1.Key words: neuraminidase inhibitors, adamantanes, oseltamivir, zanamivir, h3n2, h5n1.

  7. Statins and renin-angiotensin system inhibitor combination treatment to prevent cardiovascular disease.

    Science.gov (United States)

    Lee, Hae-Young; Sakuma, Ichiro; Ihm, Sang-Hyun; Goh, Choong-Won; Koh, Kwang Kon

    2014-01-01

    Hypercholesterolemia and hypertension are common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reductions of overall cardiovascular risks. Experimental studies have shown reciprocal relationships between insulin resistance (IR) and endothelial dysfunction. Hypercholesterolemia and hypertension have a synergistic deleterious effect on IR and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of atherosclerosis and hypertension. Various strategies with different classes of antihypertensive medications to reach target goals have failed to reduce residual CVD risk further. Of interest, treating moderate cholesterol elevations with low-dose statins in hypertensive patients reduced CVD risk by 35-40% further. Therefore, statins are important in reducing CVD risk. Unfortunately, statin therapy causes IR and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and IR. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of IR and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic effects on endothelial dysfunction and IR in addition to lowering cholesterol levels and blood pressure when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity to prevent CVD.  

  8. Isoflurane-induced spatial memory impairment in mice is prevented by the acetylcholinesterase inhibitor donepezil.

    Directory of Open Access Journals (Sweden)

    Diansan Su

    Full Text Available Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2% for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE, choline acetylase (ChAT and α7 nicotinic receptor (α7-nAChR were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or α7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.

  9. A randomized, controlled field trial for the prevention of jellyfish stings with a topical sting inhibitor.

    Science.gov (United States)

    Boulware, David R

    2006-01-01

    Jellyfish stings are a common occurrence among ocean goers worldwide with an estimated 150 million envenomations annually. Fatalities and hospitalizations occur annually, particularly in the Indo-Pacific regions. A new topical jellyfish sting inhibitor based on the mucous coating of the clown fish prevents 85% of jellyfish stings in laboratory settings. The field effectiveness is unknown. The objective is to evaluate the field efficacy of the jellyfish sting inhibitor, Safe Sea. A double-blind, randomized, placebo-controlled trial occurred at the Dry Tortugas National Park, FL, USA and Sapodilla Cayes, Belize. Participants were healthy volunteers planning to snorkel for 30 to 45 minutes. Ten minutes prior to swimming, each participant was directly observed applying a blinded sample of Safe Sea (Nidaria Technology Ltd, Jordan Valley, Israel) to one side of their body and a blinded sample of Coppertone (Schering-Plough, Kenilworth, NJ, USA) to the contralateral side as placebo control. Masked 26 g samples of both Safe Sea SPF15 and Coppertone SPF15 were provided in identical containers to achieve 2 mg/cm(2) coverage. Sides were randomly chosen by participants. The incidence of jellyfish stings was the main outcome measure. This was assessed by participant interview and examination as subjects exited the water. A total of 82 observed water exposures occurred. Thirteen jellyfish stings occurred during the study period for a 16% incidence. Eleven jellyfish stings occurred with placebo, two with the sting inhibitor, resulting in a relative risk reduction of 82% (95% confidence interval: 21%-96%; p= 0.02). No seabather's eruption or side effects occurred. Safe Sea is a topical barrier cream effective at preventing >80% jellyfish stings under real-world conditions.

  10. The role of selective serotonin reuptake inhibitors in preventing relapse of major depressive disorder.

    Science.gov (United States)

    Clevenger, Steven S; Malhotra, Devvrat; Dang, Jonathan; Vanle, Brigitte; IsHak, Waguih William

    2018-01-01

    The objective of this review was to evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) and SSRIs compared with other treatment modalities in preventing relapse after an episode of major depressive disorder (MDD). An Ovid MEDLINE and PsycINFO search (from 1987 to August 2017) was conducted using the following terms: selective serotonin reuptake inhibitors, antidepressants, depression, prevention, prophylaxis, relapse and MDD. Using predefined criteria, two authors independently selected and reached consensus on the included studies. Sixteen articles met the criteria: 10 compared the relapse rate of selective SSRIs with placebo or other SSRIs; one discussed the effectiveness of SSRIs plus psychotherapy, two compared SSRI versus tricyclic antidepressants (TCAs), two were mainly composed of TCAs plus psychotherapy, and one compared SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs). According to the included studies, the relapse risk in adults was lower when SSRIs were combined with psychotherapy. Results comparing SSRIs and SNRIs were inconclusive. TCAs may be equally as effective as SSRIs. Atypical antidepressants (mirtazapine and St John's Wort) had no significant difference in efficacy and remission rates compared with SSRIs. Escitalopram appeared to fare better in efficacy than other SSRIs, owing to a higher prophylactic efficacy and lower side effects; however, according to the current data, this difference was not significant. To conclude, this review provides evidence that continuing SSRIs for 1 year reduces risk of MDD and relapse. Furthermore, the combination of SSRIs and cognitive behavioural therapy may effectively reduce relapse. Escitalopram appeared to yield better results and fewer side effects than did other SSRIs or SNRIs. The effectiveness in reducing relapse of SSRIs was similar to that of TCAs and atypical antidepressants.

  11. Prevention of PCDD/F formation by chemical inhibitor injection into the flue gases in the incineration processes

    Energy Technology Data Exchange (ETDEWEB)

    Ruuskanen, J.; Halonen, I.; Ruokojaervi, P.; Tuppurainen, K.; Tarhanen, J. [Kuopio Univ. (Finland). Lab. of Environmental Chemistry

    1997-10-01

    Three series of inhibition tests were performed at the laboratory and the pilot scale plants during the years 1995-1996. In the laboratory tests chemical inhibitors were added to fly ash before the thermal treatment. Inhibitors were not found to have any effects on destruction of PCDD/Fs at the torment temperature of 160 and 300 deg C compared to the situation without inhibitors. The thermal treatment at 300 deg C alone reduced and dechlorinated PCDD/Fs effectively. In the pilot scale tests both gaseous and liquid inhibitors were injected to the flue gases at 700 deg C, and gaseous inhibitors also at 400 deg C. The total PCDD/F reductions were between 0-95 % depending on the inhibitor, injection temperature and the amount of inhibitors. In the gaseous inhibitor tests the PCDD/F reductions especially high in the particle phase, being even 98 % in dimethylamine injection. In the liquid inhibitor tests the PCDD/F reductions were also high in the gas phase being even 96 % in sodium ammonium hydrogen phosphate injection. (orig.)

  12. A selective cyclooxygenase-2 inhibitor (Etodolac) prevents spontaneous biliary tumorigenesis in a hamster bilioenterostomy model.

    Science.gov (United States)

    Kitasato, Amane; Kuroki, Tamotsu; Adachi, Tomohiko; Ono, Shinichiro; Tanaka, Takayuki; Tsuneoka, Noritsugu; Hirabaru, Masataka; Takatsuki, Mitsuhisa; Eguchi, Susumu

    2014-01-01

    Secondary biliary carcinomas are associated with persistent reflux cholangitis after bilioenterostomy. Cyclooxygenase-2 (COX-2) has been a target for cancer prevention. The aim of this study was to evaluate the chemopreventive efficacy of long-term treatment with a selective COX-2 inhibitor medication during the natural course after bilioenterostomy without chemical induction. Syrian golden hamsters which underwent choledochojejunostomy were randomly divided into two groups: the control group (n = 31), which was fed a normal diet, and the etodolac group (n = 33), which was fed 0.01% etodolac (a selective COX-2 inhibitor) mixed in the meal. The hamsters were killed at the postoperative weeks 20-39, 40-59, 60-79, or 80-100. Biliary neoplasms, cholangitis, proliferating cell nuclear antigen labeling index (PCNA-LI) of the biliary epithelium, and prostaglandin E2 (PGE2) production were evaluated. The occurrence rates of biliary neoplasm were 43.8 and 15.2% in the control and etodolac groups, respectively (p < 0.05). The incidence of biliary neoplasm increased as time progressed in the control group, whereas it remained at a low level throughout the experimental period in the etodolac group. PGE2 products tended to be lower in the etodolac group, and PCNA-LI was significantly lower in the etodolac group (p < 0.01). These results suggest that the medication etodolac suppresses cell proliferation of the biliary epithelium, thereby preventing biliary carcinogenesis. Etodolac is expected to prevent secondary biliary carcinogenesis caused by persistent reflux cholangitis after bilioenterostomy. © 2014 S. Karger AG, Basel.

  13. Investigation of some green compounds as corrosion and scale inhibitors for cooling systems

    Energy Technology Data Exchange (ETDEWEB)

    Quraishi, M.A.; Farooqi, I.H.; Saini, P.A. (Aligarh Muslim Univ. (India))

    1999-05-01

    The performance of an open-recirculating cooling system, an important component in most industries, is affected by corrosion and scale formation. Numerous additives have been used in the past for the control of corrosion and scale formation. Effects of the naturally occurring compounds azadirachta indica (leaves), punica granatum (shell), and momordica charantia (fruits), on corrosion of mild steel in 3% sodium chloride (NaCl) were assessed using weight loss, electrochemical polarization, and impedance techniques. Extracts of the compounds exhibited excellent inhibition efficiencies comparable to that of hydroxyethylidine diphosphonic acid (HEDP), the most preferred cooling water inhibitor. The compounds were found effective under static and flowing conditions. Extracts were quite effective in retarding formation of scales, and the maximum antiscaling efficiency was exhibited by the extract of azadirachta indica (98%). The blowdown of the cooling system possessed color and chemical oxygen demand (COD). Concentrations of these parameters were reduced by an adsorption process using activated carbon as an adsorbent.

  14. Crystal Growth Inhibitors for the Prevention of L-Cystine Kidney Stones Through Molecular Design

    Energy Technology Data Exchange (ETDEWEB)

    Rimer, Jeffrey D.; An, Zhihua; Zhu, Zina; Lee, Michael H.; Goldfarb, David S.; Wesson, Jeffrey A.; Ward, Michael D. (NY Univ.); (MCW)

    2010-11-12

    Crystallization of L-cystine is a critical step in the pathogenesis of cystine kidney stones. Treatments for this disease are somewhat effective but often lead to adverse side effects. Real-time in situ atomic force microscopy (AFM) reveals that L-cystine dimethylester (L-CDME) and L-cystine methylester (L-CME) dramatically reduce the growth velocity of the six symmetry-equivalent {l_brace}100{r_brace} steps because of specific binding at the crystal surface, which frustrates the attachment of L-cystine molecules. L-CDME and L-CME produce L-cystine crystals with different habits that reveal distinct binding modes at the crystal surfaces. The AFM observations are mirrored by reduced crystal yield and crystal size in the presence of L-CDME and L-CME, collectively suggesting a new pathway to the prevention of L-cystine stones by rational design of crystal growth inhibitors.

  15. Secondary prevention after acute myocardial infarction and coronary revascularisation: focus on Angiotensin converting enzyme inhibitors.

    Science.gov (United States)

    Kaski, Juan Carlos; Fernandez-Berges, Daniel

    2008-06-01

    Cardiovascular disease (CVD) is responsible for an estimated one third of all deaths worldwide. One group of patients who are at a particularly high risk of cardiovascular events and death are those with stable coronary artery disease (CAD), especially if they have had a previous myocardial infarction (MI) or revascularisation. Lifestyle changes (smoking, alcohol intake, diet, exercise) and cardiac rehabilitation play an important part in reducing risk of recurrent events. In patients with a history of MI and/or those who underwent myocardial revascularisation these have to be supplemented with medication. Several pharmacological agents are known to improve prognosis in these patients, i.e. beta-blockers, antiplatelet agents, statins, and angiotensin converting enzyme inhibitors (ACEi). The present article focuses mainly on the role of ACEi in the prevention of cardiovascular events in patients with a history of MI or myocardial revascularization.

  16. A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production

    DEFF Research Database (Denmark)

    Nachbur, Ueli; Stafford, Che A; Bankovacki, Aleksandra

    2015-01-01

    Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase 2...... (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation......, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD...

  17. Application of Polyelectrolyte Complex Nanoparticles in Increasing the Lifetime of Poly(Vinyl Sulfonate) Scale Inhibitor in Berea Sandstone Rock

    Science.gov (United States)

    Veisi, Masoumeh

    Water flooding is used extensively in oil fields to maintain reservoir pressure and displace oil. However, seawater containing high concentrations of sulfate ion may form scale precipitate when mixed with incompatible formation water containing barium and strontium ions. Formation of scales such as barium sulfate can pose costly operational problems by plugging the injection and production wells. Polymers such as poly(vinyl sulfonate) (PVS) are well-known scale inhibitors which can effectively prevent the formation of barium sulfate. Squeeze treatment is a common method which can be used to inject the PVS in the reservoir. In this process, PVS solution is injected into production wells and the inhibitor is adsorbed on reservoir rocks and released during subsequent production of reservoir fluids. Once inhibitor concentration decreases to its minimum effective concentration (MEC), the process needs to be repeated. However, the low adsorption of PVS onto the rock results in a very short squeeze lifetime rendering the treatment uneconomical. In this research, the application of polyelectrolyte complexes (PECs) to increase the squeeze treatment lifetime of PVS was examined. The objective of the project was to develop PEC nanoparticles (NPs) which would improve the PVS adsorption on the rock through charge alteration. The PECs entrapped the PVS in their structure and released the polymer gradually when pH or ionic strength of the surrounding brine increased. PVS adsorption followed by a slow release of the polymer can maintain the scale inhibitor concentration above MEC for longer, and therefore extend the squeeze treatment lifetime. Positively charged nanoparticles consisting of poly(ethyleneimine) and poly(vinyl sulfonate) (PEI-PVS) were prepared and optimized to maximize PVS entrapment in the PEC structure. The stability of the nanoparticles at different temperatures and over time was confirmed. Their stability in the presence of mono and divalent cations was also

  18. Prevention of aromatase inhibitor-induced bone loss with alendronate in postmenopausal women: The BATMAN Trial.

    Science.gov (United States)

    Lomax, Anna J; Yee Yap, Saw; White, Karen; Beith, Jane; Abdi, Ehtesham; Broad, Adam; Sewak, Sanjeev; Lee, Chooi; Sambrook, Philip; Pocock, Nicholas; Henry, Margaret J; Yeow, Elaine G; Bell, Richard

    2013-12-01

    Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures. In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70 mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1 mg daily), calcium and vitamin D. All osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm. At three years, lumbar spine mean BMD increased (15.6%, p<0.01) in the osteoporotic group. BMD in the osteopaenic group with early intervention significantly increased at three years (6.3%, p=0.02). No significant change was seen in the late intervention group. No change was observed in those with osteopaenia without alendronate. There was a significant drop in lumbar spine (-5.4%) and hip (-4.5%) mean BMD, in the normal BMD group, none of whom received alendronate. Fracture data will be presented. In postmenopausal women with endocrine-responsive EBC, BMD improved over time when a bisphosphonate is administered with anastrozole in osteoporotic patients using an osteoporosis schedule. Subjects with normal baseline BMD experienced the greatest BMD loss, although none became osteoporotic.

  19. The Tat Inhibitor Didehydro-Cortistatin A Prevents HIV-1 Reactivation from Latency.

    Science.gov (United States)

    Mousseau, Guillaume; Kessing, Cari F; Fromentin, Rémi; Trautmann, Lydie; Chomont, Nicolas; Valente, Susana T

    2015-07-07

    Antiretroviral therapy (ART) inhibits HIV-1 replication, but the virus persists in latently infected resting memory CD4(+) T cells susceptible to viral reactivation. The virus-encoded early gene product Tat activates transcription of the viral genome and promotes exponential viral production. Here we show that the Tat inhibitor didehydro-cortistatin A (dCA), unlike other antiretrovirals, reduces residual levels of viral transcription in several models of HIV latency, breaks the Tat-mediated transcriptional feedback loop, and establishes a nearly permanent state of latency, which greatly diminishes the capacity for virus reactivation. Importantly, treatment with dCA induces inactivation of viral transcription even after its removal, suggesting that the HIV promoter is epigenetically repressed. Critically, dCA inhibits viral reactivation upon CD3/CD28 or prostratin stimulation of latently infected CD4(+) T cells from HIV-infected subjects receiving suppressive ART. Our results suggest that inclusion of a Tat inhibitor in current ART regimens may contribute to a functional HIV-1 cure by reducing low-level viremia and preventing viral reactivation from latent reservoirs. Antiretroviral therapy (ART) reduces HIV-1 replication to very low levels, but the virus persists in latently infected memory CD4(+) T cells, representing a long-lasting source of resurgent virus upon ART interruption. Based on the mode of action of didehydro-cortistatin A (dCA), a Tat-dependent transcription inhibitor, our work highlights an alternative approach to current HIV-1 eradication strategies to decrease the latent reservoir. In our model, dCA blocks the Tat feedback loop initiated after low-level basal reactivation, blocking transcriptional elongation and hence viral production from latently infected cells. Therefore, dCA combined with ART would be aimed at delaying or halting ongoing viral replication, reactivation, and replenishment of the latent viral reservoir. Thus, the latent pool of

  20. Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases.

    Science.gov (United States)

    Silverman, Richard B

    2009-03-17

    a one-amino-acid difference between nNOS and eNOS in the second sphere of amino acids; this was the difference that we were searching for from the beginning of this project. With the aid of these crystal structures, we developed a new fragment-based de novo design method called "fragment hopping", which allowed the design of a new class of nonpeptide nNOS-selective inhibitors. These compounds were modified to give low nanomolar, highly dual-selective nNOS inhibitors, which we recently showed are active in a rabbit model for the prevention of neurobehavioral symptoms of cerebral palsy. These compounds could also have general application in other neurodegenerative diseases for which excess NO is responsible.

  1. The Class I Histone Deacetylase Inhibitor MS-275 Prevents Pancreatic Beta Cell Death Induced by Palmitate

    Directory of Open Access Journals (Sweden)

    Valérie Plaisance

    2014-01-01

    Full Text Available Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER stress markers including activating transcription factor 3 (Atf3 and CAAT/enhancer-binding protein homologous protein-10 (Chop. In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes.

  2. Etanercept, an inhibitor of TNF-a, prevents propofol-induced neurotoxicity in the developing brain.

    Science.gov (United States)

    Chen, Bo; Deng, Xiaoyuan; Wang, Bin; Liu, Hongliang

    2016-12-01

    Propofol can induce acute neuronal apoptosis, neuronal loss or long-term cognitive impairment when exposed in neonatal rodents, but the mechanisms by which propofol induces developmental neurotoxicity are unclear. Recent studies have demonstrated that propofol can increase the TNF-α level in the developing brain, but there is a lack of direct evidence to show whether TNF-α is partially or fully involved in propofol-induced neurotoxicity. The present study shows that propofol exposure in neonatal rats induces an increase of TNF-α in the cerebral spinal fluid, hippocampus and prefrontal cortex (PFC). Etanercept, a TNF-α inhibitor, prevents propofol-induced short- or long-term neuronal apoptosis, neuronal loss, synaptic loss and long-term cognitive impairment. Furthermore, mTNF-α (precursor of TNF-α) expression in microglia cells is increased after propofol anaesthesia in either the hippocampus or PFC, but mTNF-α expression in neurons is only increased in the PFC. These findings suggest that TNF-α may mediate propofol-induced developmental neurotoxicity, and etanercept can provide neural protection. Microglia are the main cellular source of TNF-α after propofol exposure, while the synthesis of TNF-α in neurons is brain-region selective. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

  3. Naringin prevents HIV-1 protease inhibitors-induced metabolic complications in vivo.

    Directory of Open Access Journals (Sweden)

    Sanelisiwe Nzuza

    Full Text Available Insulin resistance, glucose intolerance and overt diabetes are known metabolic complications associated with chronic use of HIV-Protease Inhibitors. Naringin is a grapefruit-derived flavonoid with anti-diabetic, anti-dyslipidemia, anti-inflammatory and anti-oxidant activities.The study investigated the protective effects of naringin on glucose intolerance and impaired insulin secretion and signaling in vivo.Male Wistar rats were divided into six groups (n = 6 and were daily orally treated with distilled water {3.0 ml/kg body weight (BW}, atazanavir (133 mg/kg BW, saquinavir (333 mg/kg BW with or without naringin (50 mg/kg BW, respectively for 56 days. Body weights and water consumption were recorded daily. Glucose tolerance tests were carried out on day 55 of the treatment and thereafter, the rats were sacrificed by halothane overdose.Atazanavir (ATV- or saquinavir (SQV-treated rats exhibited significant weight loss, polydipsia, elevated Fasting blood glucose (FBG, reduced Fasting Plasma Insulin (FPI and expression of phosphorylated, Insulin Receptor Substrate-1 (IRS-1 and Akt proteins, hepatic and pancreatic glucokinase levels, and also increasing pancreatic caspase-3 and -9 as well as UCP2 protein expressions compared to controls, respectively. These effects were completely reversed by naringin treatment.Naringin prevents PI-induced glucose intolerance and impairment of insulin signaling and as nutritional supplement it could therefore alleviate metabolic complications associated with antiretroviral therapy.

  4. 5-α reductase inhibitors and prostate cancer prevention: where do we turn now?

    Directory of Open Access Journals (Sweden)

    Hamilton Robert J

    2011-09-01

    Full Text Available Abstract With the lifetime risk of being diagnosed with prostate cancer so great, an effective chemopreventive agent could have a profound impact on the lives of men. Despite decades of searching for such an agent, physicians still do not have an approved drug to offer their patients. In this article, we outline current strategies for preventing prostate cancer in general, with a focus on the 5-α-reductase inhibitors (5-ARIs finasteride and dutasteride. We discuss the two landmark randomized, controlled trials of finasteride and dutasteride, highlighting the controversies stemming from the results, and address the issue of 5-ARI use, including reasons why providers may be hesitant to use these agents for chemoprevention. We further discuss the recent US Food and Drug Administration ruling against the proposed new indication for dutasteride and the change to the labeling of finasteride, both of which were intended to permit physicians to use the drugs for chemoprevention. Finally, we discuss future directions for 5-ARI research.

  5. Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice.

    Science.gov (United States)

    Chiasson, Valorie L; Pakanati, Abhinandan R; Hernandez, Marcos; Young, Kristina J; Bounds, Kelsey R; Mitchell, Brett M

    2017-07-01

    The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4 + /FoxP3 + regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice. © 2017 American Heart Association, Inc.

  6. The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation

    DEFF Research Database (Denmark)

    Schaller, Sophie; Henriksen, Kim; Sveigaard, Christina

    2004-01-01

    formation. This study indicates that chloride channel inhibitors are highly promising for treatment of osteoporosis. INTRODUCTION: The chloride channel inhibitor, NS3736, blocked osteoclastic acidification and resorption in vitro with an IC50 value of 30 microM. When tested in the rat ovariectomy model...... for osteoporosis, daily treatment with 30 mg/kg orally protected bone strength and BMD by approximately 50% 6 weeks after surgery. Most interestingly, bone formation assessed by osteocalcin, mineral apposition rate, and mineralized surface index was not inhibited. MATERIALS AND METHODS: Analysis of chloride......: In conclusion, we show for the first time that chloride channel inhibitors can be used for prevention of ovariectomy-induced bone loss without impeding bone formation. We speculate that the coupling of bone resorption to bone formation is linked to the acidification of the resorption lacunae, thereby enabling...

  7. Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice

    NARCIS (Netherlands)

    Hess, M.W.; Baaij, J.H.F. de; Gommers, L.M.; Hoenderop, J.G.J.; Bindels, R.J.M.

    2015-01-01

    BACKGROUND: Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the

  8. Developing a Small Scale Preventive Maintenance Program: Part 1.

    Science.gov (United States)

    Morris, John M.

    1981-01-01

    The first of two articles outlines how the director of the physical plant at Monroe County Community College (Michigan) developed a preventive maintenance program. The first step, assembling a set of up-to-date records, is detailed. (MLF)

  9. Specific MAPK inhibitors prevent hyperglycemia-induced renal diseases in type 1 diabetic mouse model.

    Science.gov (United States)

    Hong, Zhe; Hong, Zongyuan; Wu, Denglong; Nie, Hezhongrong

    2016-08-01

    Mitogen-activated protein kinase (MAPK) and renin-angiotensin system (RAS) play critical roles in the process of renal diseases, but their interaction has not been comprehensively discussed. In the present studies, we investigated the renoprotective effects of MPAK inhibitors on renal diseases in type 1 diabetic mouse model, and clarify the crosstalk among MAPK signaling. Type 1 diabetic mouse model was established in male C57BL/6 J mice, and treated with or without 10 mg/kg MAPK blockers, including ERK inhibitor PD98059, p38 inhibitor SB203850, and JNK inhibitor SP600125 for four weeks. Hyperglycemia induced renal injuries, but treating them with MAPK inhibitors significantly decreased glomerular volume and glycogen in renal tissues. Although slightly changed body weight and fasting blood glucose levels, MAPK inhibitors attenuated blood urea nitrogen, urea protein, and microalbuminuria. Administration also reduced the diabetes-induced RAS activation, including angiotensin II converting enzyme (c) and Ang II, which contributed to its renal protective effects in the diabetic mice. In addition, the anti-RAS of MAPK inhibitor treatment markedly reduced gene expression of tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase, fibrotic accumulation, and transforming growth factor-β1 levels in renal tissues. Furthermore, chemical inhibitors and genetic siRNA results identified the crosstalk among the three MAPK signaling, and proved JNK signaling played a critical role in MAPK-mediated ACE pathway in hyperglycemia state. Collectively, these results support the therapeutic effects of MAPK-specific inhibitors, especially JNK inactivation, on hyperglycemia-induced renal damages.

  10. Estimating unbiased economies of scale of HIV prevention projects: a case study of Avahan.

    Science.gov (United States)

    Lépine, Aurélia; Vassall, Anna; Chandrashekar, Sudha; Blanc, Elodie; Le Nestour, Alexis

    2015-04-01

    Governments and donors are investing considerable resources on HIV prevention in order to scale up these services rapidly. Given the current economic climate, providers of HIV prevention services increasingly need to demonstrate that these investments offer good 'value for money'. One of the primary routes to achieve efficiency is to take advantage of economies of scale (a reduction in the average cost of a health service as provision scales-up), yet empirical evidence on economies of scale is scarce. Methodologically, the estimation of economies of scale is hampered by several statistical issues preventing causal inference and thus making the estimation of economies of scale complex. In order to estimate unbiased economies of scale when scaling up HIV prevention services, we apply our analysis to one of the few HIV prevention programmes globally delivered at a large scale: the Indian Avahan initiative. We costed the project by collecting data from the 138 Avahan NGOs and the supporting partners in the first four years of its scale-up, between 2004 and 2007. We develop a parsimonious empirical model and apply a system Generalized Method of Moments (GMM) and fixed-effects Instrumental Variable (IV) estimators to estimate unbiased economies of scale. At the programme level, we find that, after controlling for the endogeneity of scale, the scale-up of Avahan has generated high economies of scale. Our findings suggest that average cost reductions per person reached are achievable when scaling-up HIV prevention in low and middle income countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Pipeline corrosion prevention by pH stabilization or corrosion inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Nyborg, Rolf [Institute for Energy Technology, Oslo (Norway)

    2009-07-01

    In many offshore oil and gas projects the pipeline costs are a considerable part of the investment and can become prohibitively high if the corrosivity of the fluid necessitates the use of corrosion resistant alloys instead of carbon steel. Development of more robust and reliable methods for internal corrosion control can increase the application range of carbon steel and therefore have a large economic impact. Corrosion control of carbon steel pipelines has traditionally often been managed by the use of corrosion inhibitors. The pH stabilization technique has been successfully used for corrosion control of several large wet gas pipelines in the last years. This method has advantages over film forming corrosion inhibitors when no or little formation water is produced. The use of corrosion inhibitors in multiphase pipelines implies several challenges which are not fully accounted for in traditional corrosion inhibitor testing procedures. Specialized test procedures have been developed to take account for the presence of emulsions dispersions and sand and clay particles in corrosion inhibitor testing. (author)

  12. Causes and preventive management of scale formation in oilfield ...

    African Journals Online (AJOL)

    Scale formation in oilfield operations causes lot problems. In the reservoir, it reduces near wellbore permeability, resulting in high skin and lower inflow. In wells it causes flow restriction resulting in higher pressure losses or lower throughput. Moreover, in flow lines and surface facilities, it causes loss of equipment ...

  13. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

    Directory of Open Access Journals (Sweden)

    Tom Jefferson

    Full Text Available BACKGROUND:Neuraminidase inhibitors (NIs are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.OBJECTIVE:To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments.METHODSSearch methods: We searched trial registries, electronic databases (to 22 July 2013 and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL, MEDLINE, MEDLINE (Ovid, EMBASE, Embase.com, PubMed (not MEDLINE, the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database.Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT population. All trials were sponsored by the manufacturers.MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA, GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA, EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design and 46 in Stage 2 (formal analysis, including 20

  14. Converting Hangar High Expansion Foam Systems to Prevent Cockpit Damage: Full-Scale Validation Tests

    Science.gov (United States)

    2017-09-01

    AFCEC-CO-TY-TR-2018-0001 CONVERTING HANGAR HIGH EXPANSION FOAM SYSTEMS TO PREVENT COCKPIT DAMAGE: FULL-SCALE VALIDATION TESTS Gerard G...09-2017 Final Test Report May 2017 Converting Hangar High Expansion Foam Systems to Prevent Cockpit Damage: Full-Scale Validation Tests N00173-15-D...images. The fire protection systems currently installed in U.S. Air Force (USAF) aircraft hangars consist of High Expansion (Hi-Ex) foam generators located

  15. Clove extract functions as a natural fatty acid synthesis inhibitor and prevents obesity in a mouse model.

    Science.gov (United States)

    Ding, Yiran; Gu, Zhennan; Wang, Yihe; Wang, Shunhe; Chen, Haiqin; Zhang, Hao; Chen, Wei; Chen, Yong Q

    2017-08-01

    Numerous medicinal plants have been reported to prevent various chronic diseases. In this study, we screened a new FASN inhibitor-alcohol extract of clove (AEC) using a fast microplate method developed in our laboratory. The major components of AEC were: eugenol (42.27%), acetyl eugenol (29.12%), caryophyllene (15.40%), and humulene (3.22%). Fatty acid synthase (FASN) is a key enzyme for de novo lipogenesis, and it has been suggested as a potential therapeutic target in cancer and obesity. We have tested the ability of AEC to inhibit FASN in mammalian cells and tissues. Furthermore, we found that AEC as a FASN inhibitor could inhibit the S-phase DNA replication of HepG2 cells and adipocyte differentiation of OP9 cells. AEC also limited the development of high fat diet (HFD) induced obesity. AEC supplementation significantly reduced body weight and abdominal adipose tissue weight, lowered lipid accumulation in the liver and epididymal adipose tissue compared with the HFD control group. The serum lipid profiles showed that AEC could regulate the content of total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C). Collectively, our data suggest that FASN inhibitor AEC is a potential therapeutic agent for obesity.

  16. Next-generation calcineurin inhibitors in development for the prevention of organ rejection

    Directory of Open Access Journals (Sweden)

    Gheith O

    2014-03-01

    Full Text Available Osama Gheith, Torki Al-Otaibi, Hany MansourDepartment of Nephrology, Hamed Al-Essa Organ Transplant Center, Ibn Sina Hospital, Shuwaikh, KuwaitAbstract: Calcineurin inhibitors (CNIs remain the cornerstone of immunosuppression after renal transplantation despite their adverse effects. Some CNIs have well known negative impacts on the cardiovascular system, including hypertension, hyperlipidemia, new onset diabetes after transplantation (NODAT, neurotoxicity, hypertrichosis, and nephrotoxicity. Many clinical trials dealing with CNI avoidance or elimination were associated with higher risk of rejection of the transplanted organ. New generation CNIs are concerned with modifying CNI molecules so that they become more potent and are suitable for patients with suboptimal adherence with less adverse effects. In this review, we address these issues.Keywords: calcineurin inhibitors, organ transplant, rejection

  17. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis.

    Science.gov (United States)

    Okuma, Chihiro; Ohta, Takeshi; Tadaki, Hironobu; Ishigure, Tatsuya; Sakata, Shohei; Taniuchi, Hideyuki; Sano, Ryuhei; Hamada, Hiromi; Kume, Shinichi; Nishiu, Jun; Kakutani, Makoto

    2015-07-01

    Monoacyglycerol acyltransferases (MGATs) are known to play important roles in intestinal TG absorption. In contrast, the role of MGATs in the liver is still unclear. We investigated the effects of JTP-103237, a novel MGAT inhibitor, on hepatic MGAT activity and hepatic lipid metabolism. JTP-103237 reduced hepatic triglyceride content and hepatic MGAT activity in a high sucrose very low fat (HSVLF) diet induced fatty liver model. Interestingly, JTP-103237 suppressed not only triglyceride (TG) and diacylglycerol (DG) synthesis, but also fatty acid (FA) synthesis (de novo lipogenesis) in this model. JTP-103237 also suppressed lipogenesis-related gene expression, such as sterol regulatory element-binding protein 1-c. Moreover, JTP-103237 decreased plasma glucose levels and total cholesterol and reduced the accumulation of epididymal fats in HSVLF diet fed mice. In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  18. Inhibitors of endocytosis prevent Wnt/Wingless signalling by reducing the level of basal β-catenin/Armadillo.

    Science.gov (United States)

    Gagliardi, Maria; Hernandez, Ana; McGough, Ian J; Vincent, Jean-Paul

    2014-11-15

    A key step in the canonical Wnt signalling pathway is the inhibition of GSK3β, which results in the accumulation of nuclear β-catenin (also known as CTNNB1), and hence regulation of target genes. Evidence suggests that endocytosis is required for signalling, yet its role and the molecular understanding remains unclear. A recent and controversial model suggests that endocytosis contributes to Wnt signalling by causing the sequestration of the ligand-receptor complex, including LRP6 and GSK3 to multivesicular bodies (MVBs), thus preventing GSK3β from accessing β-catenin. Here, we use specific inhibitors (Dynasore and Dyngo-4a) to confirm the essential role of endocytosis in Wnt/Wingless signalling in human and Drosophila cells. However, we find no evidence that, in Drosophila cells or wing imaginal discs, LRP6/Arrow traffics to MVBs or that MVBs are required for Wnt/Wingless signalling. Moreover, we show that activation of signalling through chemical blockade of GSK3β is prevented by endocytosis inhibitors, suggesting that endocytosis impacts on Wnt/Wingless signalling downstream of the ligand-receptor complex. We propose that, through an unknown mechanism, endocytosis boosts the resting pool of β-catenin upon which GSK3β normally acts. © 2014. Published by The Company of Biologists Ltd.

  19. Salvianolic acid A, a novel matrix metalloproteinase-9 inhibitor, prevents cardiac remodeling in spontaneously hypertensive rats.

    Science.gov (United States)

    Jiang, Baohong; Li, Defang; Deng, Yanping; Teng, Fukang; Chen, Jing; Xue, Song; Kong, Xiangqian; Luo, Cheng; Shen, Xu; Jiang, Hualiang; Xu, Feng; Yang, Wengang; Yin, Jun; Wang, Yanhui; Chen, Hui; Wu, Wanying; Liu, Xuan; Guo, De-an

    2013-01-01

    Cardiac fibrosis is a deleterious consequence of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9) contributes to the underlying mechanism. Therefore, new therapeutic strategies to attenuate the effects of MMP-9 are urgently needed. In the present study, we characterize salvianolic acid A (SalA) as a novel MMP-9 inhibitor at molecular, cellular and animal level. We expressed a truncated form of MMP-9 which contains only the catalytic domain (MMP-9 CD), and used this active protein for enzymatic kinetic analysis and Biacore detection. Data generated from these assays indicated that SalA functioned as the strongest competitive inhibitor of MMP-9 among 7 phenolic acids from Salvia miltiorrhiza. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM), interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as collagen induced by MMP-9 CD. Functional effects of SalA inhibition on MMP-9 was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR) in vivo. Moreover, SalA treatment in SHR resulted in decreased heart fibrosis and attenuated heart hypertrophy. These results indicated that SalA is a novel inhibitor of MMP-9, thus playing an inhibitory role in hypertensive fibrosis. Further studies to develop SalA and its analogues for their potential clinical application of cardioprotection are warranted.

  20. Preventing Mycobacterium avium complex in patients who are using protease inhibitors: a cost-effectiveness analysis.

    Science.gov (United States)

    Bayoumi, A M; Redelmeier, D A

    1998-08-20

    Practice guidelines recommending Mycobacterium avium complex (MAC) prophylaxis for patients with HIV disease were based on clinical trials in which individuals did not receive protease inhibitors. To estimate the cost-effectiveness of strategies for MAC prophylaxis in patients whose treatment regimen includes protease inhibitors. Decision analysis with Markov modelling of the natural history of advanced HIV disease. Five strategies were evaluated: no prophylaxis, azithromycin, rifabutin, clarithromycin and a combination of azithromycin plus rifabutin. Survival, quality of life, quality-adjusted survival, health care costs and marginal cost-effectiveness ratios. Compared with no prophylaxis, rifabutin increased life expectancy from 78 to 80 months, increased quality-adjusted life expectancy from 50 to 52 quality-adjusted months and increased health care costs from $233000 to $239800. Ignoring time discounting and quality of life, the cost-effectiveness of rifabutin relative to no prophylaxis was $44300 per life year. Adjusting for time discounting and quality of life, the cost-effectiveness of rifabutin relative to no prophylaxis was $41500 per quality-adjusted life year (QALY). In comparison with rifabutin, azithromycin was associated with increased survival, increased costs and an incremental cost-effectiveness ratio of $54300 per QALY. In sensitivity analyses, prophylaxis remained economically attractive unless the lifetime chance of being diagnosed with MAC was less than 20%, the rate of CD4 count decline was less than 10 x 10(6) cells/l per year, or the CD4 count was greater than 50 x 10(6) cells/l. MAC prophylaxis increases quality-adjusted survival at a reasonable cost, even in patients using protease inhibitors. When not contraindicated, starting azithromycin or rifabutin when the patient's CD4 count is between 50 and 75 x 10(6) cells/l is the most cost-effective strategy. The main determinants of cost-effectiveness are CD4 count, viral load, place of

  1. Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus.

    Science.gov (United States)

    Ebert, Gregor; Preston, Simon; Allison, Cody; Cooney, James; Toe, Jesse G; Stutz, Michael D; Ojaimi, Samar; Scott, Hamish W; Baschuk, Nikola; Nachbur, Ueli; Torresi, Joseph; Chin, Ruth; Colledge, Danielle; Li, Xin; Warner, Nadia; Revill, Peter; Bowden, Scott; Silke, John; Begley, C Glenn; Pellegrini, Marc

    2015-05-05

    Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes. Here, we show that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF signaling during hepatitis B infection, and they restrict the death of infected hepatocytes, thus allowing viral persistence. Animals with a liver-specific cIAP1 and total cIAP2 deficiency efficiently control HBV infection compared with WT mice. This phenotype was partly recapitulated in mice that were deficient in cIAP2 alone. These results indicate that antagonizing the function of cIAPs may promote the clearance of HBV infection.

  2. Novel gaseous ethylene binding inhibitor prevents ethylene effects in potted flowering plants

    Energy Technology Data Exchange (ETDEWEB)

    Serek, M.; Reid, M.S. (Univ. of California, Davis, CA (United States). Dept. of Environmental Horticulture); Sisler, E.C. (North Carolina State Univ., Raleigh, NC (United States). Dept. of Biochemistry)

    1994-11-01

    A 6-hour fumigation of flowering Begonia xelatior hybrida Fotsch. Najada' and Rosa', B. xtuberhybrida Voss. Non-Stop', Kalanchoe blossfeldiana Poelln. Tropicana', and Rosa hybrida L. Victory Parade' plants with 1-MCP, (formerly designated as SIS-X), a gaseous nonreversible ethylene binding inhibitor, strongly inhibited exogenous ethylene effects such as bud and flower drop, leaf abscission, and accelerated flower senescence. The inhibitory effects of 1-MCP increased linearly with concentration, and at 20 nl-liter[sup [minus]1] this compound gave equal protection to that afforded by spraying the plants with a 0.5 STS mM solution. Chemical names used: 1-methylcyclopropene (1-MCP), silver thiosulfate (STS).

  3. Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice

    Science.gov (United States)

    Hess, Mark W.; de Baaij, Jeroen H. F.; Gommers, Lisanne M. M.; Hoenderop, Joost G. J.; Bindels, René J. M.

    2015-01-01

    Background Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH. Methods Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR. Results Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake. Conclusions This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies. PMID:26397986

  4. Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI-Induced Hypocalcemia in Mice.

    Directory of Open Access Journals (Sweden)

    Mark W Hess

    Full Text Available Proton-pump inhibitor-induced hypomagnesemia (PPIH is the most recognized side effect of proton-pump inhibitors (PPIs. Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH.Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR.Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake.This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies.

  5. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.

    Science.gov (United States)

    Phillips, Margaret A; Lotharius, Julie; Marsh, Kennan; White, John; Dayan, Anthony; White, Karen L; Njoroge, Jacqueline W; El Mazouni, Farah; Lao, Yanbin; Kokkonda, Sreekanth; Tomchick, Diana R; Deng, Xiaoyi; Laird, Trevor; Bhatia, Sangeeta N; March, Sandra; Ng, Caroline L; Fidock, David A; Wittlin, Sergio; Lafuente-Monasterio, Maria; Benito, Francisco Javier Gamo; Alonso, Laura Maria Sanz; Martinez, Maria Santos; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Haselden, John N; Louttit, James; Cui, Yi; Sridhar, Arun; Zeeman, Anna-Marie; Kocken, Clemens; Sauerwein, Robert; Dechering, Koen; Avery, Vicky M; Duffy, Sandra; Delves, Michael; Sinden, Robert; Ruecker, Andrea; Wickham, Kristina S; Rochford, Rosemary; Gahagen, Janet; Iyer, Lalitha; Riccio, Ed; Mirsalis, Jon; Bathhurst, Ian; Rueckle, Thomas; Ding, Xavier; Campo, Brice; Leroy, Didier; Rogers, M John; Rathod, Pradipsinh K; Burrows, Jeremy N; Charman, Susan A

    2015-07-15

    Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage. Copyright © 2015, American Association for the Advancement of Science.

  6. Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice.

    Science.gov (United States)

    Hess, Mark W; de Baaij, Jeroen H F; Gommers, Lisanne M M; Hoenderop, Joost G J; Bindels, René J M

    2015-01-01

    Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH. Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR. Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake. This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies.

  7. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.

    Science.gov (United States)

    Jefferson, Tom; Jones, Mark A; Doshi, Peter; Del Mar, Chris B; Hama, Rokuro; Thompson, Matthew J; Spencer, Elizabeth A; Onakpoya, Igho; Mahtani, Kamal R; Nunan, David; Howick, Jeremy; Heneghan, Carl J

    2014-04-10

    Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the

  8. Utilization of Preventive Dental Services Before and After Health Insurance Covered Dental Scaling in Korea.

    Science.gov (United States)

    Jang, Young-Eun; Kim, Chun-Bae; Kim, Nam-Hee

    2017-01-01

    Health insurance reduces the economic burden of diseases and enhances access to medical services. This study compared, among social classes, the utilization of preventive dental service before and after health insurance covered dental scaling. We analyzed time-series secondary data for 3  175  584 participants from 253 survey areas nationwide in the Community Health Survey (2009-2014) in Korea. The weighted proportion of participants who underwent dental scaling was defined as the scaling rate. Data regarding demographic and socioeconomic characteristics were collected. Scaling rates continuously increased over the 6-year period, particularly in 2014. College graduates had significantly higher scaling rates. Monthly income and scaling rate were positively related. Differences by education decreased over time. Differences by income were particularly high between 2012 and 2014. For women, the temporal rate was 2 times higher for professionals than for the unemployed. Despite increased dental scaling rates since the health coverage change in 2013, socioeconomic differences persist.

  9. A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection.

    Science.gov (United States)

    Niu, Xin; Brahmbhatt, Hetal; Mergenthaler, Philipp; Zhang, Zhi; Sang, Jing; Daude, Michael; Ehlert, Fabian G R; Diederich, Wibke E; Wong, Eve; Zhu, Weijia; Pogmore, Justin; Nandy, Jyoti P; Satyanarayana, Maragani; Jimmidi, Ravi K; Arya, Prabhat; Leber, Brian; Lin, Jialing; Culmsee, Carsten; Yi, Jing; Andrews, David W

    2017-04-20

    Aberrant apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 family proteins Bax/Bak is an irreversible step leading to execution of apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM. Small-molecule inhibition of Bax/Bak oligomerization allowed cells to evade apoptotic stimuli and rescued neurons from death after excitotoxicity, demonstrating that oligomerization of Bax is essential for MOMP. Our discovery of small-molecule Bax/Bak inhibitors provides novel tools for the investigation of the mechanisms leading to MOMP and will ultimately facilitate development of compounds inhibiting Bax/Bak in acute and chronic degenerative diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. The implications of HP/HT reservoir conditions on the selection and application of scale inhibitors - some preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Jordan, M.M; Sorbie, K.S.; Graham, G.M.; Hennessey, S.; Hill, P.

    1996-12-31

    This paper presents some of the obtained initial results on the thermal stability of scale inhibitor chemicals under HP/HT conditions offshore. Very little information is available on this topic in the open literature, with only a few references to the treatment of geothermal systems. This topic will be a very important issue especially as squeeze treatments are carried out in the new HP/HT reservoirs, such as ETAP (Eastern Trough Area Project) due for first oil in early 1999, and in reservoirs of the new central fields which contain very high salinity brines. 6 refs., 17 figs., 1 tab.

  11. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.

    Science.gov (United States)

    De Nicola, Luca; Gabbai, Francis B; Liberti, Maria Elena; Sagliocca, Adelia; Conte, Giuseppe; Minutolo, Roberto

    2014-07-01

    Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose-dependent and -independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data. Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  12. Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

    Energy Technology Data Exchange (ETDEWEB)

    Rancourt, Raymond C., E-mail: raymond.rancourt@ucdenver.edu; Veress, Livia A., E-mail: livia.veress@ucdenver.edu; Ahmad, Aftab, E-mail: aftab.ahmad@ucdenver.edu; Hendry-Hofer, Tara B., E-mail: tara.hendry-hofer@ucdenver.edu; Rioux, Jacqueline S., E-mail: jacqueline.rioux@ucdenver.edu; Garlick, Rhonda B., E-mail: rhonda.garlick@ucdenver.edu; White, Carl W., E-mail: carl.w.white@ucdenver.edu

    2013-10-01

    Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O{sub 2} saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin–antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. - Highlights: • TFPI administration to rats after mustard inhalation reduces airway cast formation. • Inhibition of thrombin activation is the likely mechanism for limiting casts. • Rats given TFPI

  13. The preventive services use self-efficacy (PRESS) scale in older women: development and psychometric properties.

    Science.gov (United States)

    Jacob, Mini E; Lo-Ciganic, Wei-Hsuan; Simkin-Silverman, Laurey R; Albert, Steven M; Newman, Anne B; Terhorst, Lauren; Bilt, Joni Vander; Zgibor, Janice C; Schlenk, Elizabeth A

    2016-02-20

    Preventive services offered to older Americans are currently under-utilized despite considerable evidence regarding their health and economic benefits. Individuals with low self-efficacy in accessing these services need to be identified and provided self-efficacy enhancing interventions. Scales measuring self-efficacy in the management of chronic diseases exist, but do not cover the broad spectrum of preventive services and behaviors that can improve the health of older adults, particularly older women who are vulnerable to poorer health and lesser utilization of preventive services. This study aimed to evaluate the psychometric properties of a new preventive services use self-efficacy scale, by measuring its internal consistency reliability, assessing internal construct validity by exploring factor structure, and examining differences in self-efficacy scores according to participant characteristics. The Preventive Services Use Self-Efficacy (PRESS) Scale was developed by an expert panel at the University of Pittsburgh Center for Aging and Population Health - Prevention Research Center. It was administered to 242 women participating in an ongoing trial and the data were analyzed to assess its psychometric properties. An exploratory factor analysis with a principal axis factoring approach and orthogonal varimax rotation was used to explore the underlying structure of the items in the scale. The internal consistency of the subscales was assessed using Cronbach's alpha coefficient. The exploratory factor analysis defined five self-efficacy factors (self-efficacy for exercise, communication with physicians, self-management of chronic disease, obtaining screening tests, and getting vaccinations regularly) formed by 16 items from the scale. The internal consistency of the subscales ranged from .81 to .94. Participants who accessed a preventive service had higher self-efficacy scores in the corresponding sub-scale than those who did not. The 16-item PRESS scale

  14. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Takemasa, Akihiro; Ishii, Yoshiki; Fukuda, Takeshi

    2012-12-01

    Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-β1, in this study. To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation. In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.

  15. Scaling Up a Multifaceted Violence Prevention Package: County-Level Impact of the North Carolina Youth Violence Prevention Center.

    Science.gov (United States)

    Smokowski, Paul R; Cotter, Katie L; Guo, Shenyang; Evans, Caroline Bill Robertson

    2017-01-01

    Multifaceted approaches to youth-violence prevention package evidence-based programs into initiatives that yield large-scale impact. This study assessed the impact of a package of evidence-based violence prevention programs, implemented as part of the North Carolina Youth Violence Prevention Center, on county-level violence indicators. Using growth-curve modeling, the target county was compared to all other counties in North Carolina and a comparison county. Results reveal downward trends on several county-level indicators (i.e., undisciplined/delinquent complaints, total delinquent complaints, juvenile arrests-aggravated assaults, and short-term suspensions) throughout the intervention period. However, statistical tests were unable to confirm that intervention-period scores on youth-violence indicators were significantly different than expected scores given the relationship between pretest and intervention-period scores in other North Carolina counties. Although additional administrative data points are needed to support the hypotheses, this study provides preliminary evidence of the effectiveness of North Carolina Youth Violence Prevention Center interventions.

  16. RAF265, a dual BRAF and VEGFR2 inhibitor, prevents osteoclast formation and resorption. Therapeutic implications.

    Science.gov (United States)

    Garcia-Gomez, Antonio; Ocio, Enrique M; Pandiella, Atanasio; San Miguel, Jesús F; Garayoa, Mercedes

    2013-02-01

    The RAS/RAF/MEK/ERK signaling pathway plays an important role in osteoclast (OC) differentiation and survival mediated by macrophage-colony stimulating factor (M-CSF). Also, vascular endothelial growth factor (VEGF) may greatly influence OC formation and resorption through VEGFR1 and VEGFR2. RAF265 is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2. Effect of RAF265 on osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) and OC resorption on calcium-coated wells was assessed by appropriate in vitro assays. Immunoblotting, real-time RT-PCR and flow cytometry were used to evaluate RAF265 mechanism of action. RAF265 significantly impaired in vitro differentiation of PBMCs to OCs induced by receptor activator of NF-kB ligand (RANKL) and M-CSF (IC(50) ≅ 160 nM). In parallel, RAF265 exerted a potent inhibition of OC resorptive capacity (IC(50) ≅ 20 nM). RAF265 treatment led to ERK inhibition and diminished expression of c-fos and NFATc1 (nuclear factor of activated T cells, calcineurin-dependent 1), which would likely account for inhibition of osteoclastogenesis. The reduced gene expression of aVb3 integrin, CCR1, cathepsin K, carbonic anhydrase II, matrix metalloproteinase 9, urokinase and tissue-type plasminogen activators, vacuolar H(+)-ATPase subunit (ATP6V1A) and Rab7 GTPase would probably mediate RAF265 hindered resorption. RAF265 inhibitory effect on VEGFR2 (noticeable at 10-50 nM) was also found to be implicated in the potent inhibition of this agent on OC function. We have found a new therapeutic application for RAF265 as an inhibitory agent of osteoclastogenesis and OC function, which might be useful for the treatment of skeletal disorders associated with increased bone resorption.

  17. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model.

    Science.gov (United States)

    Capell, Brian C; Olive, Michelle; Erdos, Michael R; Cao, Kan; Faddah, Dina A; Tavarez, Urraca L; Conneely, Karen N; Qu, Xuan; San, Hong; Ganesh, Santhi K; Chen, Xiaoyan; Avallone, Hedwig; Kolodgie, Frank D; Virmani, Renu; Nabel, Elizabeth G; Collins, Francis S

    2008-10-14

    Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form of human premature aging. Death occurs at a mean age of 13 years, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A (LMNA) gene that results in production of a mutant lamin A protein termed progerin. This protein is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has been shown to prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. We have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. Here we show that the dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease.

  18. Insights into the broad cellular effects of nelfinavir and the HIV protease inhibitors supporting their role in cancer treatment and prevention.

    Science.gov (United States)

    Gantt, Soren; Casper, Corey; Ambinder, Richard F

    2013-09-01

    The development of HIV protease inhibitors more than two decades ago heralded a new era in HIV care, changing the infection from universally fatal to chronic but controllable. With the widespread use of protease inhibitors, there was a reduction in the incidence and mortality of HIV-associated malignancies. Studies later found these drugs to have promising direct antitumor effects. Protease inhibitors have a wide range of effects on several cellular pathways that are important for tumorigenesis and independent of inhibition of the HIV protease, including reducing angiogenesis and cell invasion, inhibition of the Akt pathway, induction of autophagy, and promotion of apoptosis. Among protease inhibitors, nelfinavir appears to have the most potent and broad antineoplastic activities, and also affects replication of the oncogenic herpesviruses Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus. Nelfinavir is being studied for the prevention and treatment of a wide range of malignancies in persons with and without HIV infection. Nelfinavir and other protease inhibitors are well tolerated, oral drugs that have promising antitumor properties, and may prove to play an important role in the prevention and treatment of several cancers. Additional insights into protease inhibitors' mechanisms of action may lead to the development of novel cancer chemotherapy agents.

  19. Relationship between the enzymatic browning and phenylalanine ammonia-lyase activity of cut lettuce, and the prevention of browning by inhibitors of polyphenol biosynthesis.

    Science.gov (United States)

    Hisaminato, H; Murata, M; Homma, S

    2001-05-01

    Cut lettuce stored at 4 degrees C gradually turned brown on the cut section after several days of storage. Three factors for enzymatic browning, the polyphenol content, polyphenol oxidase activity, and phenylalanine ammonia-lyase (PAL) activity, were examined during the cold storage of cut lettuce. A relationship between the browning and PAL activity was apparent. We tried to prevent this browning by using the two enzyme inhibitors, 2-aminoindane-2-phosphonic acid (AIP), an inhibitor of the phenylpropanoid pathway, and glyphosate, an inhibitor of the shikimate pathway. AIP and glyphosate significantly inhibited the browning of cut lettuce. The polyphenol content and PAL activity were both reduced by the treatment with AIP. These results show that regulating the biosynthesis of polyphenols is essential to prevent the browning of cut lettuce.

  20. Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation.

    Science.gov (United States)

    Rancourt, Raymond C; Veress, Livia A; Ahmad, Aftab; Hendry-Hofer, Tara B; Rioux, Jacqueline S; Garlick, Rhonda B; White, Carl W

    2013-10-01

    Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin-antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Neuraminidase inhibitors in the treatment and post exposure prevention of influenza

    Directory of Open Access Journals (Sweden)

    von der Schulenburg, Johann-Matthias

    2006-01-01

    Full Text Available Introduction: Influenza is a viral respiratory infection which presents itself as an acute febrile disease. It is contracted by virus-laden respiratory secretions from infected individuals. Symptoms usually last three to seven days and are accompanied by severely limited activities during this time. A definite diagnosis, however, can only be made by laboratory analysis. Every year, about 20% of children and 5% of adults develop symptomatic influenza of the serotypes A or B worldwide. Typical complications of influenza include viral or bacterial infections, as well as deterioration of an existing cardio-vascular or respiratory disease which may lead to hospitalization and death. Current policy recommends that individuals, who are at-risk of developing serious complications (patients over sixty years of age or patients with concomitant chronic diseases, as well as people in direct contact with high risk patients (i.e. nursing staff in living and care facilities, should be annually vaccinated with inactivated influenza strains. Various pharmaceutical agents for the treatment and prophylaxis of influenza have been approved. Amantadine, which inhibits the viral M2-ion channel, is only effective in influenza-serotype A. Neuraminidase inhibitors (NI represent a new class of antivirals for prophylaxis and treatment of influenza A and B. NI interrupt various central functions that are vital for the life cycle and spreading of the virus. Two drugs of this substance class, Zanamivir (RelenzaTM and Oseltamivir (Tamiflu®, are licensed for the treatment of influenza. For adults and teenagers over thirteen years of age Oseltamivir is also approved for the prophylaxis of influenza. Zanamivir is a powder which needs to be inhaled, whereas Oseltamivir is licensed as a capsule for oral administration. M2-inhibitors and NI are only effective at an early stage of the influenza infection, i.e. during the first 36 to 48 hours after symptom onset, before replication

  2. A randomised controlled trial of meloxicam, a Cox-2 inhibitor, to prevent hepatocellular carcinoma recurrence after initial curative treatment.

    Science.gov (United States)

    Takami, Yuko; Eguchi, Susumu; Tateishi, Masaki; Ryu, Tomoki; Mikagi, Kazuhiro; Wada, Yoshiyuki; Saitsu, Hideki

    2016-09-01

    Because the recurrence rate of hepatocellular carcinoma (HCC) is high, even after curative treatments such as hepatic resection and microwave ablation, chemopreventive agents that can effectively suppress HCC recurrence are required. Cyclooxygenase-2 (Cox-2) was recently found to be overexpressed in HCC. Therefore, Cox-2 inhibitors may offer a chemopreventive therapy for HCC. This randomised controlled trial (RCT) investigated the potential for meloxicam, a clinically used Cox-2 inhibitor, to prevent HCC recurrence after initial curative treatment. A total of 232 consecutive patients underwent hepatic resection and/or microwave ablation as initial therapy for HCC at our institute between July 2008 and April 2011. Eight patients were excluded because of poor renal function, history of non-steroidal anti-inflammatory drug-related ulceration, or multiple cancers. The remaining 224 patients were randomised to a control group (n = 113) or a meloxicam group (n = 111). To patients in the meloxicam group, meloxicam was administered at 15 mg daily (5 mg three times a day) as long as possible. The overall survival (OS) and disease-free survival (DFS) rates were determined. The 1-, 3-, and 5-year OS rates of the meloxicam group were 95.4, 82.4, and 70.1 %, respectively. Those of the control group were 98.2, 85.1, and 71.5 %, respectively (p = 0.9549). The corresponding DFS rates of the meloxicam group were 89.2, 53.9, and 44.0 % and those of control group were 86.5, 57.0, and 43.4 %, respectively (p = 0.6722). In the OS and DFS of subsets including patients with hepatitis B or C virus infection, we could not find significant differences between the meloxicam and control groups. However, in the subgroup of analysis of patients without viral hepatitis (NBNC-HCC), significant differences were observed in the DFS between the meloxicam group (1-year DFS, 92.3 %; 3-year DFS, 75.8 %; 5-year DFS, 70.4 %) and control group (1-year DFS, 83.3 %; 3-year DFS, 48.1 %; 5

  3. NoScale - Characterisation of thermal deep groundwater for the prevention of scaling and corrosion in geothermal plants

    Science.gov (United States)

    Haslinger, Edith; Goldbrunner, Johann; Dietzel, Martin; Leis, Albrecht; Boch, Ronny; Knauss, Ralf; Hippler, Dorothee; Shirbaz, Andrea; Fröschl, Heinz; Wyhlidal, Stefan; Plank, Otmar; Gold, Marlies; Elster, Daniel

    2017-04-01

    During the exploitation of thermal water for the use in a geothermal plant a series of hydrochemical reactions such as solution and precipitation processes (scaling) or corrosion processes can be caused by pressure and temperature changes and degassing of the thermal water. Operators of hydrogeothermal plants are often confronted with precipitations in water-bearing parts of their plant, such as heat exchangers and pipes, which result in considerable costs for cleaning or remediation or the use of inhibitors. In the worst case, scaling and corrosion can lead to the abandonment of the system. The effects of the fluids on the technical facilities of hydrogeothermal plants are usually difficult to predict. This applies in particular to the long-term effects in the exploitation and use as well as the aspect of the reinjection of the fluids. In publications and guides for thermal water use in Austria, it is emphasized that the hydrochemical conditions have to be checked during the operation of geothermal plants, but precise directives and thus guidance for operators as well as a scientific investigations on this topic are almost completely missing today. The aim of the research project NoScale was the assessment of deep thermal water bodies in different geological reservoirs in Austria and Bavaria and therefore different hydrochemical compositions with regard to their scaling and corrosion potential in geothermal use. In the course of parallel chemical and mineralogical laboratory investigations, conclusions were drawn about the effects of thermal water on different technical components of hydrogeothermal plants and on the other hand a data basis for the model simulation of the relevant hydrochemical processes was developed. Subsequently, on the basis of detailed hydrochemical model calculations, possible effects of the use of the thermal waters on the technical components of the geothermal plants were shown. This approach of complex process modeling, detailed

  4. Edivoxetine compared to placebo as adjunctive therapy to selective serotonin reuptake inhibitors in the prevention of symptom re-emergence in major depressive disorder.

    Science.gov (United States)

    Oakes, Tina M; Dellva, Mary Anne; Waterman, Karen; Greenbaum, Michael; Poppe, Christopher; Goldberger, Celine; Ahl, Jonna; Perahia, David G

    2015-06-01

    When patients with major depressive disorder (MDD) are partial responders to antidepressant therapy, adjunctive treatment with an agent that has a different mode of action may provide additional benefit. We investigated the efficacy of edivoxetine, a highly selective norepinephrine reuptake inhibitor (NRI), as adjunctive treatment to selective serotonin reuptake inhibitors (SSRIs) in the prevention of re-emergence of depressive symptoms in patients with MDD (ClinicalTrials.gov identifier: NCT01299272). Adult outpatients with MDD who were partial responders to SSRI treatment (N = 1249) entered an open-label 8 week flexibly dosed (12-18 mg/day) adjunctive edivoxetine period. Patients who achieved remission (Montgomery-Åsberg Depression Rating Scale total score ≤10 at week 8) entered a 12 week open-label fixed-dose (12 mg or 18 mg/day) stabilization period, and those still in remission at each of weeks 18, 19, and 20 were randomized to continue treatment at the same dose of edivoxetine or switch to placebo for a 24 week double-blind withdrawal period. All patients remained on SSRI therapy throughout the study. The primary outcome was time to re-emergence of depressive symptoms during double-blind withdrawal. Two hundred and ninety-four patients were randomized to continue adjunctive edivoxetine and 292 were switched to adjunctive placebo. Comparing adjunctive edivoxetine with adjunctive placebo, differences were not significant for time to re-emergence of symptoms (Kaplan-Meier log-rank p = 0.485), rates of symptom re-emergence (9.9% vs 8.2%, p = 0.565) or rates of sustained remission (75.4% vs 76.7%, p = 0.771). Treatment-emergent adverse events were consistent with the noradrenergic mechanism of action. Edivoxetine failed to demonstrate superiority vs placebo as adjunctive treatment in the prevention of symptom re-emergence during maintenance treatment in SSRI partial responders with MDD. While no selective NRIs are approved for adjunctive

  5. Large scale purification of the SERCA inhibitor thapsigargin from Thapsia garganica L. roots using centrifugal partition chromatography.

    Science.gov (United States)

    Ollivier, Anthony; Grougnet, Raphaël; Cachet, Xavier; Meriane, Djamila; Ardisson, Janick; Boutefnouchet, Sabrina; Deguin, Brigitte

    2013-05-01

    Thapsigargin (Tg) is a selective and irreversible inhibitor of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-dependent pump at subnanomolecular concentrations. As such, it has become a powerful tool in the study of Ca(2+) signaling pathway. Purification of Tg from Thapsia species requires repeated chromatographic steps with normal-phase alumina or silica and reverse phase chromatography. We thus developed an innovative procedure coupling high pressure automatized extraction with centrifugal partition chromatography allowing a fast and safe large-scale isolation of highly pure Tg, in two steps from Thapsia garganica L. roots. Comparison of influence of extraction procedures, storage conditions and harvesting areas on Tg content in different Algerian specimens of Thapsia garganica L. roots has been precised by mean of HPLC quantification procedure. Highest Tg content were found in the fresh material of the sample from Setif area. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Early Treatment with Fumagillin, an Inhibitor of Methionine Aminopeptidase-2, Prevents Pulmonary Hypertension in Monocrotaline-Injured Rats

    Science.gov (United States)

    Kass, Daniel J.; Rattigan, Eileen; Kahloon, Rehan; Loh, Katrina; Yu, Liyang; Savir, Asaf; Markowski, Mark; Saqi, Anjali; Rajkumar, Revathi; Ahmad, Ferhaan; Champion, Hunter C.

    2012-01-01

    Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients. PMID:22509410

  7. Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents Pulmonary Hypertension in monocrotaline-injured rats.

    Directory of Open Access Journals (Sweden)

    Daniel J Kass

    Full Text Available Pulmonary Hypertension (PH is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2 regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients.

  8. Implementation of Global Strategies to Prevent Hospital-Onset Clostridium difficile Infection: Targeting Proton Pump Inhibitors and Probiotics.

    Science.gov (United States)

    Lewis, Paul O; Lundberg, Timothy S; Tharp, Jennifer L; Runnels, Clay W

    2017-10-01

    Proton pump inhibitors (PPIs) have been identified as a significant risk factor for the development of Clostridium difficile infection (CDI). Probiotics given concurrently with antibiotics have been shown to have a moderate impact on preventing CDI. To evaluate the effectiveness of hospital-wide interventions designed to reduce PPI use and increase probiotics and whether these interventions were associated with a change in the incidence of hospital onset (HO)-CDI. This retrospective cohort study compared 2 fiscal years: July 2013 to June 2014 (FY14) and July 2014 to June 2015 (FY15). In July of FY15, global educational initiatives were launched targeting PPIs. Additionally, a HO-CDI prevention bundle was added to antibiotic-containing order sets targeting probiotics. Overall PPI use, probiotic use, and incidence of HO-CDI were recorded and compared for each cohort. Charts were also reviewed for patients who developed HO-CDI for the presence and appropriateness of a PPI and presence of probiotics. The interventions resulted in a decrease in PPI use by 14% or 96 doses/1000 patient days (TPD; P = 0.0002) and a reduction in IV PPI use by 31% or 71 doses/TPD ( P = 0.0008). Probiotic use increased by 130% or 126 doses/TPD ( P = 0.0006). The incidence of HO-CDI decreased by 20% or 0.1 cases/TPD ( P = 0.04). A collaborative, multifaceted educational initiative directed at highlighting the risks associated with PPI use was effective in reducing PPI prescribing. The implementation of a probiotic bundle added to antibiotic order sets was effective in increasing probiotic use. These interventions were associated with a decrease in incidence of HO-CDI.

  9. A Selective Irreversible Inhibitor of Furin Does Not Prevent Pseudomonas Aeruginosa Exotoxin A-Induced Airway Epithelial Cytotoxicity.

    Directory of Open Access Journals (Sweden)

    Timothy E G Ferguson

    Full Text Available Many bacterial and viral pathogens (or their toxins, including Pseudomonas aeruginosa exotoxin A, require processing by host pro-protein convertases such as furin to cause disease. We report the development of a novel irreversible inhibitor of furin (QUB-F1 consisting of a diphenyl phosphonate electrophilic warhead coupled with a substrate-like peptide (RVKR, that also includes a biotin tag, to facilitate activity-based profiling/visualisation. QUB-F1 displays greater selectivity for furin, in comparison to a widely used exemplar compound (furin I which has a chloromethylketone warhead coupled to RVKR, when tested against the serine trypsin-like proteases (trypsin, prostasin and matriptase, factor Xa and the cysteine protease cathepsin B. We demonstrate QUB-F1 does not prevent P. aeruginosa exotoxin A-induced airway epithelial cell toxicity; in contrast to furin I, despite inhibiting cell surface furin-like activity to a similar degree. This finding indicates additional proteases, which are sensitive to the more broad-spectrum furin I compound, may be involved in this process.

  10. Centers for Disease Control and Prevention (CDC) Radiation Hazard Scale Data Product Review Feedback Report

    Energy Technology Data Exchange (ETDEWEB)

    Askin, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Buddemeier, B. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Alai, M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Yu, K. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2017-09-20

    In support of the Department of Energy (DOE) National nuclear Security Administration (NNSA) and the Centers for Disease Control and Prevention (CDC), Lawrence Livermore National Laboratory (LLNL) assisted in the development of new data templates for disseminating and communicating FRMAC1 data products using the CDC Radiation Hazard Scale communication tool. To ensure these data products will be useful to stakeholders during a radiological emergency, LLNL facilitated opportunities for product socialization and review.

  11. What Determines HIV Prevention Costs at Scale? Evidence from the Avahan Programme in India.

    Science.gov (United States)

    Lépine, Aurélia; Chandrashekar, Sudhashree; Shetty, Govindraj; Vickerman, Peter; Bradley, Janet; Alary, Michel; Moses, Stephen; Vassall, Anna

    2016-02-01

    Expanding essential health services through non-government organisations (NGOs) is a central strategy for achieving universal health coverage in many low-income and middle-income countries. Human immunodeficiency virus (HIV) prevention services for key populations are commonly delivered through NGOs and have been demonstrated to be cost-effective and of substantial global public health importance. However, funding for HIV prevention remains scarce, and there are growing calls internationally to improve the efficiency of HIV prevention programmes as a key strategy to reach global HIV targets. To date, there is limited evidence on the determinants of costs of HIV prevention delivered through NGOs; and thus, policymakers have little guidance in how best to design programmes that are both effective and efficient. We collected economic costs from the Indian Avahan initiative, the largest HIV prevention project conducted globally, during the first 4 years of its implementation. We use a fixed-effect panel estimator and a random-intercept model to investigate the determinants of average cost. We find that programme design choices such as NGO scale, the extent of community involvement, the way in which support is offered to NGOs and how clinical services are organised substantially impact average cost in a grant-based payment setting. © 2016 The Authors. Health Economics published by John Wiley & Sons Ltd.

  12. Telomerase inhibitor PinX1 provides a link between TRF1 and telomerase to prevent telomere elongation.

    Science.gov (United States)

    Soohoo, Christina Y; Shi, Rong; Lee, Tae Ho; Huang, Pengyu; Lu, Kun Ping; Zhou, Xiao Zhen

    2011-02-04

    Telomere maintenance is essential for protecting chromosome ends. Aberrations in telomere length have been implicated in cancer and aging. Telomere elongation by human telomerase is inhibited in cis by the telomeric protein TRF1 and its associated proteins. However, the link between TRF1 and inhibition of telomerase elongation of telomeres remains elusive because TRF1 has no direct effect on telomerase activity. We have previously identified one Pin2/TRF1-interacting protein, PinX1, that has the unique property of directly binding and inhibiting telomerase catalytic activity (Zhou, X. Z., and Lu, K. P. (2001) Cell 107, 347-359). However, nothing is known about the role of the PinX1-TRF1 interaction in the regulation of telomere maintenance. By identifying functional domains and key amino acid residues in PinX1 and TRF1 responsible for the PinX1-TRF1 interaction, we show that the TRF homology domain of TRF1 interacts with a minimal 20-amino acid sequence of PinX1 via hydrophilic and hydrophobic interactions. Significantly, either disrupting this interaction by mutating the critical Leu-291 residue in PinX1 or knocking down endogenous TRF1 by RNAi abolishes the ability of PinX1 to localize to telomeres and to inhibit telomere elongation in cells even though neither has any effect on telomerase activity per se. Thus, the telomerase inhibitor PinX1 is recruited to telomeres by TRF1 and provides a critical link between TRF1 and telomerase inhibition to prevent telomere elongation and help maintain telomere homeostasis.

  13. Salivary secretory leukocyte protease inhibitor (SLPI) and head and neck cancer: The Cancer Prevention Study II Nutrition Cohort

    Science.gov (United States)

    Campbell, Christine M. Pierce; Giuliano, Anna R.; Torres, B. Nelson; O'Keefe, Michael T.; Ingles, Donna J.; Anderson, Rebecca L.; Teras, Lauren R.; Gapstur, Susan M.

    2016-01-01

    Objectives Secretory leukocyte protease inhibitor (SLPI) is an innate-immunity protein displaying antimicrobial and anti-inflammatory properties that is found in high concentrations in saliva. The role of extracellular salivary SLPI in head and neck squamous cell carcinoma (HNSCC) remains unclear. Thus, we aimed to evaluate the association between SLPI and HNSCC risk in the Cancer Prevention Study II Nutrition Cohort. Materials and Methods Among 53,180 men and women with no history of cancer who provided an oral rinse between 2001 and 2002, 60 were subsequently diagnosed with incident HNSCC between specimen collection and June 2009. In this nested case-control study, archived oral supernatants were evaluated using the Human SLPI Quantikine ELISA Kit for all 60 cases and 180 controls individually matched on gender, race, date of birth, and date of oral rinse collection. Conditional logistic regression was used to estimate HNSCC risk. Results Overall, pre-diagnostic salivary SLPI was associated with a non-statistically significant higher risk of HNSCC (OR=1.6, 95% CI=0.9–3.0). Among never smokers, high SLPI was associated with a non-statistically significant lower risk (OR=0.5, 95% CI=0.1–1.9), whereas among ever smokers, high SLPI was associated with a statistically significant higher risk (OR=2.1, 95% CI=1.0–4.3) of HNSCC, compared to low SLPI. Conclusion While results from this study suggest that higher concentrations of salivary SLPI might increase the risk of HNSCC among ever smokers, more research is needed to verify these findings and define the mechanisms by which SLPI and smoking influence the etiology of HNSCC. PMID:27016010

  14. Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells from damage by atherogenic LDL.

    Science.gov (United States)

    Kapiotis, S; Hermann, M; Held, I; Seelos, C; Ehringer, H; Gmeiner, B M

    1997-11-01

    There is now growing evidence that the oxidative modification of LDL plays a potential role in atherosclerosis. In this study, genistein, a compound derived from a soy diet with a flavonoid chemical structure (4',5,7-trihydroxyisoflavone), which was found to inhibit angiogenesis, has been evaluated for its ability to act as an LDL antioxidant and a vascular cell protective agent against oxidized LDL. The results showed that genistein was able to inhibit the oxidation of LDL in the presence of copper ions or superoxide/nitric oxide radicals as measured by thiobarbituric acid-reactive substance formation, alteration in electrophoretic mobility, and lipid hydroperoxides. Bovine aortic endothelial cell- and human endothelial cell-mediated LDL oxidation was also inhibited in the presence of genistein. The 7-O-glucoside of genistein, genistin, was much less effective in inhibiting LDL oxidation in the cell-free and cell-mediated lipoprotein-oxidating systems. Incubating human endothelial cells in the absence or presence of genistein and challenging the cells with already oxidized lipoprotein revealed that in addition to its antioxidative potential during LDL oxidating processes, genistein effectively protected the vascular cells from damage by oxidized lipoproteins. The tyrosine kinase inhibitor genistein was found to block upregulation of two tyrosine-phosphorylated proteins of 132 and 69 kDa in endothelial cells induced by oxidized LDL. Parallel experiments with the inactive analogue daidzein, however, showed that the cytoprotective effect of the isoflavones seems not to be dependent on tyrosine phosphorylation. Our findings will support the suggested and documented beneficial action of a soy diet in preventing chronic vascular diseases and early atherogenic events.

  15. Inhibitors of cysteine cathepsin and calpain do not prevent ultraviolet-B-induced apoptosis in human keratinocytes and HeLa cells

    DEFF Research Database (Denmark)

    Bang, Bo; Baadsgaard, Ole; Skov, Lone

    2004-01-01

    been demonstrated to play a role in the execution of programmed cell death induced by other stimuli, e.g. TNF-alpha. The purpose of the present study was therefore to investigate whether inhibitors of cysteine cathepsins and calpains could prevent UVB-induced apoptosis in HeLa cells and keratinocytes....... This was done by investigating the effect of the irreversible cysteine protease inhibitor zFA-fmk, the cathepsin B inhibitor CA-074-Me and the calpain inhibitor ALLN on the viability of UVB-irradiated human keratinocytes and HeLa cells. At concentrations of 10 microM and above zVAD-fmk conferred partial dose......-dependent protection against UVB-induced apoptosis in HeLa cells and keratinocytes. Moreover, caspase-3 activity was completely blocked at zVAD-fmk concentrations of 1 microM in HeLa cells. This indicates that caspase-independent mechanisms could be involved in UVB-induced apoptosis. However, the protease inhibitors z...

  16. Producing a problem? Effects of produced water contaminants (PAHs, radium-226, barium and scale inhibitor) on the copepod Calanus finmarchicus

    Energy Technology Data Exchange (ETDEWEB)

    Kiel Jensen, Louise [Norwegian Radiation Protection Authority, Fram Centre, 9296 Tromsoe (Norway); Halvorsen, Elisabeth; Gammelsaeter Hallanger, Ingeborg [UiT The Arctic University of Norway, Department of Arctic and Marine Biology, P.O. box 6050 Langnes, 9037 Tromsoe (Norway); Tollefsen, Knut Erik; Brooks, Steven [Norwegian Institute for Water Research, Gaustadalleen 21, 0349 Oslo (Norway); Hansen, Bjoern Henrik [SINTEF Materials and Chemistry, Marine Environmental Technology, Brattoerkaia 17B, 7010 Trondheim (Norway)

    2014-07-01

    In the Barents Sea region new petroleum fields are discovered yearly and the extraction of petroleum products are expected to increase in the upcoming years. Despite enhanced technology and stricter governmental legislation, establishing the petroleum industry in the Barents Sea will introduce a new source of Naturally Occurring Radioactive Material (NORM) to the area as some discharges of produced water will be allowed. Whether the presence of produced water poses a risk to the Arctic marine life remains to be examined. We examined effects on the copepod species Calanus finmarchicus after exposure to several compounds found in produced water. A mixture of polycyclic aromatic hydrocarbons and alkyl phenols commonly found in produced water was used as a proxy of the organic fraction of the produced water (hereafter termed APW (Artificial Produced Water)). In addition, exposures were done using radium-226 (proxy for NORM), barium (proxy for metals) and a scale inhibitor (SI -4470, M-I SWACO, Schlumberger Norge AS). Short-term screening tests on a range of concentrations of all compounds were run to assess the hatchability of the eggs and early survival of the nauplii. Long-term experiments were carried out with exposure concentrations at realistic levels found in the vicinity of known discharge points. The copepod C. finmarchicus is considered a keystone species in the Barents Sea ecosystem as it represents the major pathway of energy transfer from lower to higher trophic levels. We have examined sub-lethal effects on early life stages and on adult females. The hatchability of the eggs was not affected by concentrations well above realistic environmental levels. However, the instant mortality of the hatched larvae increased with higher concentrations of barium, scale inhibitor and APW, though not with higher radium-226 concentration. When examining the long-term growth of the nauplii, we found that the survival was poor in the APW treatment, and in the barium

  17. Scaling up diarrhea prevention and treatment interventions: a Lives Saved Tool analysis.

    Science.gov (United States)

    Fischer Walker, Christa L; Friberg, Ingrid K; Binkin, Nancy; Young, Mark; Walker, Neff; Fontaine, Olivier; Weissman, Eva; Gupta, Akanksha; Black, Robert E

    2011-03-01

    Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated. We use the Lives Saved Tool (LiST) to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding) were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions) and universal (assumes near 100% coverage of all interventions) scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions. Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations' Millennium Development Goal 4 (MDG4) by 2015.

  18. Scaling up diarrhea prevention and treatment interventions: a Lives Saved Tool analysis.

    Directory of Open Access Journals (Sweden)

    Christa L Fischer Walker

    2011-03-01

    Full Text Available BACKGROUND: Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated. METHODS AND FINDINGS: We use the Lives Saved Tool (LiST to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions and universal (assumes near 100% coverage of all interventions scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions. CONCLUSION: Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations' Millennium Development Goal 4 (MDG4 by 2015.

  19. Scaling Up Diarrhea Prevention and Treatment Interventions: A Lives Saved Tool Analysis

    Science.gov (United States)

    Walker, Christa L. Fischer; Friberg, Ingrid K.; Binkin, Nancy; Young, Mark; Walker, Neff; Fontaine, Olivier; Weissman, Eva; Gupta, Akanksha; Black, Robert E.

    2011-01-01

    Background Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated. Methods and Findings We use the Lives Saved Tool (LiST) to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding) were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions) and universal (assumes near 100% coverage of all interventions) scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions. Conclusion Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations' Millennium Development Goal 4 (MDG4) by 2015. Please see later in the article for the Editors' Summary PMID:21445330

  20. Role of proton pump inhibitors in preventing hypergastrinemia-associated carcinogenesis and in antagonizing the trophic effect of gastrin.

    Science.gov (United States)

    Han, Y-M; Park, J-M; Kangwan, N; Jeong, M; Lee, S; Cho, J Y; Ko, W J; Hahm, K B

    2015-04-01

    Gastrin is the main hormone stimulating gastric acid secretion, but it exerts proliferative and anti-apoptotic actions on various cancer cell types, in addition to its well-known trophic effect on enterochromaffin-like cells. As treatment with proton pump inhibitors (PPIs) increases the biosynthesis and secretion of gastrin, it has been postulated that treatment with PPIs could increase the risk of cancer, especially in Barrett's esophagus, gastric carcinoids, and colorectal cancer (CRC). Some tumors produce gastrin of their own, which can act in an autocrine manner to promote tumor growth. In addition, gastrin is known to foster the tumor microenvironment. However, in spite of these potentially increased cancer risks due to PPI-induced hypergastrinemia, prospective, large-scale cohort studies did not show an increase in CRC prevalence. The question as to why the long-term use of PPIs was not associated with an increased cancer risk of CRC might be answered by the fact that the PPIs antagonized the trophic effects of hypergastrinemia. Furthermore, the blockade of proton pumps or potassium channels in cancer cells could limit the abnormal glycolytic energy metabolism of cancer cells. Apart from their suppressive effect on gastric acids, PPIs exert an anti-tumor effect through the selective induction of apoptosis as well as an anti-inflammatory effect, and they protect cells from developing chemo- or radiotherapeutic resistance. Moreover, the anti-carcinogenic actions of PPIs were augmented with PPI-induced hypergastrinemia. Together with their potential targeted killing of cancer stem cells, these effects demonstrate their potential anti-cancer actions.

  1. Fusarium graminearum produces different xylanases causing host cell death that is prevented by the xylanase inhibitors XIP-I and TAXI-III in wheat.

    Science.gov (United States)

    Tundo, Silvio; Moscetti, Ilaria; Faoro, Franco; Lafond, Mickaël; Giardina, Thierry; Favaron, Francesco; Sella, Luca; D'Ovidio, Renato

    2015-11-01

    To shed light on the role of Xylanase Inhibitors (XIs) during Fusarium graminearum infection, we first demonstrated that three out of four F. graminearum xylanases, in addition to their xylan degrading activity, have also the capacity to cause host cell death both in cell suspensions and wheat spike tissue. Subsequently, we demonstrated that TAXI-III and XIP-I prevented both the enzyme and host cell death activities of F. graminearum xylanases. In particular, we showed that the enzymatic inhibition by TAXI-III and XIP-I was competitive and only FGSG_11487 escaped inhibition. The finding that TAXI-III and XIP-I prevented cell death activity of heat inactivated xylanases and that XIP-I precluded the cell death activity of FGSG_11487 - even if XIP-I does not inhibit its enzyme activity - suggests that the catalytic and the cell death activities are separated features of these xylanases. Finally, the efficacy of TAXI-III or XIP-I to prevent host cell death caused by xylanases was confirmed in transgenic plants expressing separately these inhibitors, suggesting that the XIs could limit F. graminearum infection via direct inhibition of xylanase activity and/or by preventing host cell death. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Evidence for the prevention of bone loss in elderly and old early non-metastatic breast cancer patients treated with aromatase inhibitors

    DEFF Research Database (Denmark)

    Gunmalm, V.; Jørgensen, N. R.; Abrahamsen, B.

    2017-01-01

    Breast cancer (BC) is the most common cancer amongst women worldwide. Bone health is emerging as an important issue for BC survivors. In this literature study, we focus on agents for preventing bone loss in early non-metastatic estrogen receptor positive BC in treatment with aromatase inhibitors...... (AI) and to assess the evidence for antiresorptive treatment of bone loss in early non-metastatic breast cancer. We included randomized controlled trials (RCT's) comparing: (a) bisphosphonates and control; (b) different bisphosphonates; (c) denosumab and control and (d) bisphosphonates vs. denosumab...... in early non-metastatic BC women in AI treatment. Among antiresorptives, zoledronic acid currently has the highest evidence for prevention of AI associated bone loss in early non-metastatic BC. Data on fracture prevention among all patients, elderly and old is sparse. More randomized controlled studies...

  3. Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure

    Directory of Open Access Journals (Sweden)

    M. Klein

    2008-06-01

    Full Text Available Inhibition of tyrosine kinases can reverse pulmonary hypertension but little is known about the role of serine-/threonine kinases in vascular and myocardial remodeling. We investigated the effects of sorafenib, an inhibitor of the tyrosine kinases VEGFR, PDGFR and c-kit as well as the serine-/threonine kinase Raf-1, in pulmonary hypertension and right ventricular (RV pressure overload. In monocrotaline treated rats, sorafenib (10 mg·kg–1·d–1 p.o. reduced pulmonary arterial pressure, pulmonary artery muscularization and RV hypertrophy, and improved systemic hemodynamics (table 1. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of downstream signaling pathways (Erk 1/2. After pulmonary banding, sorafenib, but not the PDGFR/c-KIT/ABL-inhibitor imatinib reduced RV mass and RV filling pressure significantly. Congruent with these results, sorafenib only prevented ERK phosphorylation and vasopressin induced hypertrophy of the cardiomyocyte cell line H9c2 dose dependently (IC50 = 300 nM. Combined inhibition of tyrosine and serine-/threonine kinases by sorafenib prevents vascular and cardiac remodeling in pulmonary hypertension, which is partly mediated via inhibition of the Raf kinase pathway.

  4. Calpain inhibitors and antioxidants act synergistically to prevent cell necrosis: effects of the novel dual inhibitors (cysteine protease inhibitor and antioxidant) BN 82204 and its pro-drug BN 82270.

    Science.gov (United States)

    Pignol, Bernadette; Auvin, Serge; Carré, Denis; Marin, Jean-Grégoire; Chabrier, Pierre-Etienne

    2006-08-01

    Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in combination to protect cells against necrosis. Maitotoxin (MTX), which induces a massive influx of calcium, was used to provoke neuronal cell death. This toxin increased, in a concentration-dependent manner, both calpain activity and ROS formation. Calpain inhibitors or antioxidants inhibited MTX-induced necrosis only marginally (below 20%), whereas their association protected against cell death by 40-66% in a synergistic manner. BN 82204, which possesses both calpain-cathepsin L inhibitory and antioxidant properties, and its acetylated pro-drug BN 82270, totally protected cells at 100 microm. The pro-drug BN 82270, which had better cell penetration, was twice as effective as the active principle BN 82204 in protecting glioma C6 or neuroblastoma SHSY5Y cells against death. These results suggest the potential therapeutic relevance of using a single molecule with multiple activities (cysteine protease inhibitor/antioxidant), and warrant further in vivo investigations in models of neuronal disorders.

  5. Sexual life of Japanese patients with erectile dysfunction taking phosphodiesterase type 5 inhibitors: an Internet survey using the Psychological and Interpersonal Relationship Scales-Short Form questionnaire.

    Science.gov (United States)

    Tsujimura, Akira; Kiuchi, Hiroshi; Soda, Tetsuji; Takezawa, Kentaro; Okuda, Hidenobu; Fukuhara, Shinichiro; Takao, Tetsuya; Nonomura, Norio; Miyagawa, Yasushi

    2014-08-01

    To investigate details of sexual function of erectile dysfunction in Japanese patients taking phosphodiesterase type 5 inhibitors. A Japanese version of the Psychological and Interpersonal Relationship Scales-Short Form was used to carry out a nationwide survey using the Internet. A total of 556 erectile dysfunction patients (age 30-70 years) who had been prescribed a phosphodiesterase type 5 inhibitor and had attempted sexual intercourse within the past 6 months were included in this survey. Scores were compared in relation to the phosphodiesterase type 5 inhibitors most frequently taken within the past 6 months. In the subdomains of self-confidence and spontaneity of the Psychological and Interpersonal Relationship Scales-Short Form, scores for vardenafil and tadalafil were significantly higher than those for sildenafil. In the subdomain of time concern of the Psychological and Interpersonal Relationship Scales-Short Form, the score for tadalafil was significantly lower than that for others. Our findings support the hypothesis that Japanese patients with erectile dysfunction have high sexual self-confidence, spontaneity and low time concerns when taking tadalafil. These characteristics of tadalafil could be associated with high patient satisfaction and high preference. © 2014 The Japanese Urological Association.

  6. A Synergistic Combination of Advanced Separation and Chemical Scale Inhibitor Technologies for Efficient Use of Imparied Water As Cooling Water in Coal-based Power Plants

    Energy Technology Data Exchange (ETDEWEB)

    Jasbir Gill

    2010-08-30

    Nalco Company is partnering with Argonne National Laboratory (ANL) in this project to jointly develop advanced scale control technologies that will provide cost-effective solutions for coal-based power plants to operate recirculating cooling water systems at high cycles using impaired waters. The overall approach is to use combinations of novel membrane separations and scale inhibitor technologies that will work synergistically, with membrane separations reducing the scaling potential of the cooling water and scale inhibitors extending the safe operating range of the cooling water system. The project started on March 31, 2006 and ended in August 30, 2010. The project was a multiyear, multi-phase project with laboratory research and development as well as a small pilot-scale field demonstration. In Phase 1 (Technical Targets and Proof of Concept), the objectives were to establish quantitative technical targets and develop calcite and silica scale inhibitor chemistries for high stress conditions. Additional Phase I work included bench-scale testing to determine the feasibility of two membrane separation technologies (electrodialysis ED and electrode-ionization EDI) for scale minimization. In Phase 2 (Technology Development and Integration), the objectives were to develop additional novel scale inhibitor chemistries, develop selected separation processes, and optimize the integration of the technology components at the laboratory scale. Phase 3 (Technology Validation) validated the integrated system's performance with a pilot-scale demonstration. During Phase 1, Initial evaluations of impaired water characteristics focused on produced waters and reclaimed municipal wastewater effluents. Literature and new data were collected and evaluated. Characteristics of produced waters vary significantly from one site to another, whereas reclaimed municipal wastewater effluents have relatively more uniform characteristics. Assessment to date confirmed that calcite and silica

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

    Science.gov (United States)

    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 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.

  8. Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption.

    Directory of Open Access Journals (Sweden)

    An Qin

    Full Text Available Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis.

  9. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance

    Directory of Open Access Journals (Sweden)

    Aghel N

    2017-08-01

    Full Text Available Nazanin Aghel,1 Diego Hernan Delgado,1 Jeffrey Howard Lipton2 1Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network,University of Toronto, 2Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada Abstract: Tyrosine kinase inhibitors (TKIs have revolutionized the treatment and outcomes of chronic myeloid leukemia (CML. Despite their significant impact on the management of CML, there is growing evidence that TKIs may cause cardiovascular and/or metabolic complications. In this review, we present the current evidence regarding the cardiovascular safety profiles of BCR-ABL TKIs. Methodological challenges of studies that reported the cardiovascular safety of TKIs are discussed. We also propose management strategies for cardiovascular surveillance and risk factor modification during treatment with these agents. Keywords: BCR-ABL, tyrosine kinase inhibitor, peripheral arterial disease, cardiovascular disease, adverse event 

  10. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

    OpenAIRE

    Okuma, Chihiro; Ohta, Takeshi; Tadaki, Hironobu; Ishigure, Tatsuya; Sakata, Shohei; Taniuchi, Hideyuki; Sano, Ryuhei; Hamada, Hiromi; Kume, Shinichi; Nishiu, Jun; Kakutani, Makoto

    2015-01-01

    Aim: Monoacyglycerol acyltransferases (MGATs) are known to play important roles in intestinal TG absorption. In contrast, the role of MGATs in the liver is still unclear. We investigated the effects of JTP-103237, a novel MGAT inhibitor, on hepatic MGAT activity and hepatic lipid metabolism. Results: JTP-103237 reduced hepatic triglyceride content and hepatic MGAT activity in a high sucrose very low fat (HSVLF) diet induced fatty liver model. Interestingly, JTP-103237 suppressed not only t...

  11. Neurokinin-1 inhibitors in the prevention of nausea and vomiting from highly emetogenic chemotherapy: a network meta-analysis.

    Science.gov (United States)

    Abdel-Rahman, Omar

    2016-09-01

    A network meta-analysis of the comparative effectiveness of neurokinin 1 (NK-1) inhibitors in the prophylaxis of highly emetogenic chemotherapy induced nausea and vomiting has been conducted. Eligible studies included randomized trials evaluating aprepitant, fosaprepitant, netupitant (NEPA), casopitant and rolapitant containing regimens in the setting of highly emetogenic chemotherapy. Primary outcomes of interest include complete response (CR) and rate of no significant nausea. After preclusion of ineligible studies, 19 studies were included in the final analysis. The majority of the regimens containing NK-1 inhibitors (including NEPA, aprepitant/palonosetron (palono)/dexamethasone (dexa), casopitant/granisetron (grani) or ondansetron (ondan)/dexa, aprepitant/ondan/dexa) are better than regimens not containing them (palono/dexa, ondan/dexa, grani/dexa) in terms of achieving a CR in the overall phase. Moreover, casopitant/grani or ondan/dexa and aprepitant/grani or ondan/dexa are better than rolapitant/ondan or grani/dexa in terms of CR achievement [odds ratio (OR) 1.62, 95% credible interval (CrI) 1.14-2.23, and OR 1.28, 95% CrI 1.01-1.59, respectively]. Taking into consideration the limitations of cross-trial comparisons, regimens containing neurokinin inhibitors are associated with higher CR rates than regimens not containing them. Moreover, casopitant and aprepitant regimens seem to be more effective than rolapitant regimens.

  12. Irrelevant water-management scales for flood prevention, water harvesting and eutrophication control.

    Science.gov (United States)

    Andersson, Jafet; Arheimer, Berit

    2017-04-01

    This poster will give three examples of popular water-management methods, which we discovered had very little effect in practice because they were applied on irrelevant scales. They all use small scale solutions to large scale problems, and did not provide expected results due to neglecting the magnitude of components in the large-scale water budget. 1) Flood prevention: ponds are considered to be able to buffer water discharge in catchments and was suggested as a measure to reduce the 20-years return floods in an exposed areas in Sweden. However, when experimenting with several ponds allocation and size in a computational model, we found out that ponds had to cover 5-10% of the catchment to convert the 20-yr flood into an average flood. Most effective was to allocate one single water body at the catchment outlet, but this would correspond to 95 km2 which is by far too big to be called a pond. 2) Water Harvesting: At small-scale it is designed to increase water availability and agricultural productivity in smallholder agriculture. On field scale, we show that water harvesting decreases runoff by 55% on average in 62 investigated field-scale trials of drainage area ≤ 1ha in sub-Saharan Africa (Andersson et al., 2011). When upscaling, to river basin scale in South Africa (8-1.8×106 km2), using a scenario approach and the SWAT hydrological model we found that all smallholder fields would not significantly alter downstream river discharge (Sweden during the years 1996-2006 as a measure to reduce coastal eutrophication. From our detailed calculations, the gross removal was estimated at 140 tonnes Nitrogen per year and 12 tonnes Phosphorus per year in these wetlands. However, this only reduced the load to the sea by 0.2% for nitrogen and 0.5% for phosphorus (Arheimer and Pers, 2016). The wetland area was minor compared to the total area and load (41 km2 vs. 164,000 km2). For the eventual effect in the coast, additional consideration must be taken to the coastal

  13. Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain.

    Science.gov (United States)

    Masocha, Willias; Parvathy, Subramanian S

    2016-01-01

    There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. The reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711's antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and

  14. Delphinidin, a specific inhibitor of histone acetyltransferase, suppresses inflammatory signaling via prevention of NF-{kappa}B acetylation in fibroblast-like synoviocyte MH7A cells

    Energy Technology Data Exchange (ETDEWEB)

    Seong, Ah-Reum; Yoo, Jung-Yoon; Choi, KyungChul [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Lee, Mee-Hee [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University, College of Medicine, Seoul (Korea, Republic of); Lee, Yoo-Hyun [Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do (Korea, Republic of); Lee, Jeongmin [Department of Medical Nutrition, Kyung Hee University, Kyunggi-do (Korea, Republic of); Jun, Woojin [Department of Food and Nutrition, Chonnam National University, Gwangju (Korea, Republic of); Kim, Sunoh, E-mail: sunoh@korea.ac.kr [Jeollanamdo Institute of Natural Resources Research, Jeonnam (Korea, Republic of); Yoon, Ho-Geun, E-mail: yhgeun@yuhs.ac [Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University, College of Medicine, Seoul (Korea, Republic of)

    2011-07-08

    Highlights: {yields} Delphinidin is a novel inhibitor of p300/CBP histone acetyltransferase. {yields} Delphinidin prevents the hyperacetylation of p65 by inhibiting the HAT activity of p300/CBP. {yields} Delphinidin efficiently suppresses the expression of inflammatory cytokines in MH7A cells via hypoacetylation of NF-{kappa}B. {yields} Delphinidin inhibits cytokine release in the Jurkat T lymphocyte cell line. -- Abstract: Histone acetyltransferase (HAT) inhibitors (HATi) isolated from dietary compounds have been shown to suppress inflammatory signaling, which contributes to rheumatoid arthritis. Here, we identified a novel HATi in Punica granatum L. known as delphinidin (DP). DP did not affect the activity of other epigenetic enzymes (histone deacetylase, histone methyltransferase, or sirtuin1). DP specifically inhibited the HAT activities of p300/CBP. It also inhibited p65 acetylation in MH7A cells, a human rheumatoid arthritis synovial cell line. DP-induced hypoacetylation was accompanied by cytosolic accumulation of p65 and nuclear localization of IKB{alpha}. Accordingly, DP treatment inhibited TNF{alpha}-stimulated increases in NF-{kappa}B function and expression of NF-{kappa}B target genes in these cells. Importantly, DP suppressed lipopolysaccharide-induced pro-inflammatory cytokine expression in Jurkat T lymphocytes, demonstrating that HATi efficiently suppresses cytokine-mediated immune responses. Together, these results show that the HATi activity of DP counters anti-inflammatory signaling by blocking p65 acetylation and that this compound may be useful in preventing inflammatory arthritis.

  15. Chymase inhibitor prevents the development and progression of non-alcoholic steatohepatitis in rats fed a high-fat and high-cholesterol diet

    Directory of Open Access Journals (Sweden)

    Yuta Miyaoka

    2017-07-01

    Full Text Available The effect of the chymase inhibitor TY-51469 on the development and progression of non-alcoholic steatohepatitis (NASH was evaluated in rats fed a high-fat and high-cholesterol (HFC diet. To evaluate the preventive effect of TY-51469 on the development of NASH, stroke-prone spontaneously hypertensive rat 5 (SHRSP5/Dmcr rats were fed either a normal or HFC diet for 8 weeks, and concurrently administered either placebo or TY-51469 (1 mg/kg per day. To evaluate the effect of TY-51469 on the survival rate, TY-51469 was administered either concurrently with HFC diet (pretreated group or 8 weeks after HFC diet at which point NASH had developed (posttreated group. Eight weeks after HFC diet, significant increases of steatosis, fibrosis and chymase-positive cells were observed in liver from the placebo-treated rats. Significant increases of myeloperoxidase, transforming growth factor-β, matrix metalloproteinase-9, and collagen I mRNA levels were also observed. However, all parameters were significantly attenuated in the TY-51469-treated group. A survival rate of the placebo-treated group fed the HFC diet was 0% at 14 weeks. In comparison, the rates of TY-51469-pretreated and TY-51469-posttreated groups were 100% and 50% at 14 weeks, respectively. Chymase inhibitor may be applicable to preventing the development and progression of NASH.

  16. Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers

    Science.gov (United States)

    2015-12-01

    signifying loss of fork protection. Co-treatment with Mirin , an Mre11 inhibitor, prevents this shortening, demonstrating this degradation following ATRi... Mirin , an MRE11 inhibitor, in the parental UWB1, and resistant SYr12 and SYr14 cell lines.   19   Figure 8: A small scale DNA damage drug

  17. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance.

    Science.gov (United States)

    Aghel, Nazanin; Delgado, Diego Hernan; Lipton, Jeffrey Howard

    2017-01-01

    Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment and outcomes of chronic myeloid leukemia (CML). Despite their significant impact on the management of CML, there is growing evidence that TKIs may cause cardiovascular and/or metabolic complications. In this review, we present the current evidence regarding the cardiovascular safety profiles of BCR-ABL TKIs. Methodological challenges of studies that reported the cardiovascular safety of TKIs are discussed. We also propose management strategies for cardiovascular surveillance and risk factor modification during treatment with these agents.

  18. Evidence for Janus kinase (JAK) inhibitors for the prevention of major morbid events in patients with myeloproliferative neoplasms (MPNs).

    Science.gov (United States)

    Pemmaraju, Naveen; Mesa, Ruben

    2015-01-01

    A 69-year-old man presents with a Dynamic International Prognostic Scoring System (DIPSS) intermediate-risk 2 post polycythemia vera myelofibrosis with significant splenomegaly, 30 pound weight loss, constitutional symptoms, and 2% peripheral blood blasts. He has no other significant past medical history and no other major comorbid conditions. You are asked by the hematology fellow you are supervising whether or not treating this patient with a Janus kinase (JAK) inhibitor will decrease major morbid events. © 2015 by The American Society of Hematology. All rights reserved.

  19. Prevention

    Science.gov (United States)

    Kerry Britton; Barbara Illman; Gary Man

    2010-01-01

    Prevention is considered the most cost-effective element of the Forest Service Invasive Species Strategy (USDA Forest Service 2004). What makes prevention difficult is the desire to maximize free trade and the resulting benefits to society while, at the same time, protecting natural resources. The role of science is to first identify which commodities pose an...

  20. Prevention

    DEFF Research Database (Denmark)

    Halken, S; Høst, A

    2001-01-01

    , breastfeeding should be encouraged for 4-6 months. In high-risk infants a documented extensively hydrolysed formula is recommended if exclusive breastfeeding is not possible for the first 4 months of life. There is no evidence for preventive dietary intervention neither during pregnancy nor lactation....... Preventive dietary restrictions after the age of 4-6 months are not scientifically documented....

  1. Calcineurin inhibitor-associated early renal insufficiency in cardiac transplant recipients: risk factors and strategies for prevention and treatment.

    Science.gov (United States)

    Baran, David A; Galin, Ira D; Gass, Alan L

    2004-01-01

    Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiac failure. Techniques have evolved to reduce surgical mortality to under 5%. Immediate and subsequent long-term survival is more dependent on acute and chronic rejection and the complications of immunosuppressive therapy. Ten-year survival is greater than 50%.The success of transplantation over the last 20 years has been largely due to the advances in immunosuppression. The most notable and dramatic milestone was the introduction of cyclosporine in the early 1980s, which resulted in a significant improvement in allograft and patient survival. Cyclosporine is a peptide that inhibits the immune system by suppressing T-helper cell activation via inhibition of calcineurin, a critical intracellular enzyme. Tacrolimus has a similar (but not identical) mechanism of action, and was introduced in the 1990s. Drugs such as cyclosporine and tacrolimus, generically referred to as calcineurin inhibitors, have become the cornerstones of immunosuppressive protocols. As a group, calcineurin inhibitors have adverse effects, including neurotoxicity, hypertension, and nephrotoxicity, which complicate their use. Early renal insufficiency manifests as postoperative oliguria (cardiac output, and mechanical obstruction to urine flow. Given that there is no highly efficacious treatment for this syndrome, ways to avoid its occurrence are desirable. One paper is referenced that suggests that avoidance of rapid changes in tacrolimus level during the first three days of therapy is associated with a low occurrence of early renal insufficiency.

  2. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

    Science.gov (United States)

    Lucas, C M; Harris, R J; Holcroft, A K; Scott, L J; Carmell, N; McDonald, E; Polydoros, F; Clark, R E

    2015-07-01

    High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.

  3. New TNF-alpha releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with EGCG and sulindac or tamoxifen.

    Science.gov (United States)

    Fujiki, Hirota; Suganuma, Masami; Kurusu, Miki; Okabe, Sachiko; Imayoshi, Yoko; Taniguchi, Shoko; Yoshida, Takashi

    2003-01-01

    Herbal medicines are now attracting attention as potential sources of cancer preventive agents. Using inhibition of tumor necrosis factor-alpha (TNF-alpha) release assay, we studied Acer nikoense, Megusurino-ki in Japanese. Inhibitory potential was found in the leaf extract, and the main active principles were identified as geraniin and corilagin. The IC(50) values for TNF-alpha release inhibition were 43 microM for geraniin and 76 microM for corilagin, whereas that for (-)-epigallocatechin gallate (EGCG), the green tea polyphenol, as control was 26 microM. Furthermore, treatment with geraniin inhibited okadaic acid tumor promotion in a two-stage carcinogenesis experiment on mouse skin. Geraniin and corilagin are present in another well-known Japanese traditional herb, Geranium thunbergii, Genno-shoko in Japanese. Considering seasonal variations of the agents and sites of cultivation of herbs, this paper reviews the significance of geraniin as a new cancer preventive agent. In addition, based on accumulated results of green tea as a cancer preventive, we review two important results with EGCG: the synergistic effects of EGCG with sulindac or tamoxifen on cancer preventive activity in PC-9 cells, and cancer prevention of intestinal tumor development in multiple intestinal neoplasia (Min) mice by cotreatment using EGCG with sulindac. We report here new findings on additional gene expression resulting from cotreatment with EGCG and sulindac in PC-9 cells compared with gene expression by EGCG alone or sulindac alone. Overall, our results indicate that, with the continuing spread of cancer chemoprevention as a fundamental medical strategy, both clinicians and researchers should take a closer look at herbal medicine. Copyright 2002 Elsevier Science B.V.

  4. Blockade of the MEK/ERK pathway with a raf inhibitor prevents activation of pro-inflammatory mediators in cerebral arteries and reduction in cerebral blood flow after subarachnoid hemorrhage in a rat model

    DEFF Research Database (Denmark)

    Maddahi, Aida; Ansar, Saema; Chen, Qingwen

    2011-01-01

    hours, cerebral arteries were harvested, and iNOS, interleukin (IL)-6, IL-1β, matrix metalloproteinase (MMP)-9, tissue inhibitors of metalloproteinase (TIMP)-1, and phosphorylated ERK1/2 were investigated by immunofluorescence, real-time polymerase chain reaction (PCR), and Western blot analysis....../ERK (MEK)/extracellular signal-regulated kinase (ERK) pathway upstream with a specific raf inhibitor would prevent SAH-induced activation of the cerebrovascular inflammatory response. The raf inhibitor SB-386023-b was injected intracisternally in our rat model at 0, 6, or 12 hours after the SAH. After 48...... normalized CBF and prevented SAH-induced upregulation of MMPs, pro-inflammatory cytokines, and pERK1/2 proteins. These results suggested that inhibition of MEK/ERK signal transduction by a specific raf inhibitor administered up to 6 hours after SAH normalized the expression of pro-inflammatory mediators...

  5. New oral antithrombotics: focus on dabigatran, an oral, reversible direct thrombin inhibitor for the prevention and treatment of venous and arterial thromboembolic disorders

    Directory of Open Access Journals (Sweden)

    Dahl OE

    2012-01-01

    Full Text Available Ola E Dahl1,21Department of Orthopaedics, Innlandet Hospital Trust, Elverum Central Hospital, Elverum, Norway; 2Thrombosis Research Institute, London, UKAbstract: Venous thromboembolism, presenting as deep vein thrombosis or pulmonary embolism, is a major challenge for health care systems. It is the third most common vascular disease after coronary heart disease and stroke, and many hospitalized patients have at least one risk factor. In particular, patients undergoing hip or knee replacement are at risk, with an incidence of asymptomatic deep vein thrombosis of 40%–60% without thromboprophylaxis. Venous thromboembolism is associated with significant mortality and morbidity, with patients being at risk of recurrence, post-thrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Arterial thromboembolism is even more frequent, and atrial fibrillation, the most common embolic source (cardiac arrhythmia, is associated with a five-fold increase in the risk of stroke. Strokes due to atrial fibrillation tend to be more severe and disabling and are more often fatal than strokes due to other causes. Currently, recommended management of both venous and arterial thromboembolism involves the use of anticoagulants such as coumarin and heparin derivatives. These agents are effective, although have characteristics that prevent them from providing optimal anticoagulation and convenience. Hence, new improved oral anticoagulants are being investigated. Dabigatran is a reversible, direct thrombin inhibitor, which is administered as dabigatran etexilate, the oral prodrug. Because it is the first new oral anticoagulant that has been licensed in many countries worldwide for thromboprophylaxis following orthopedic surgery and for stroke prevention in patients with atrial fibrillation, this compound will be the main focus of this review. Dabigatran has been investigated for the treatment of established venous thromboembolism and prevention of

  6. Prevention

    Science.gov (United States)

    ... Tips Latest Research Getting More Help Related Topics Cancer COPD Dementia Depression Diabetes Drug and Substance Abuse Falls Prevention Hearing Loss Heart Attack High Blood Pressure Nutrition Osteoporosis Shingles Skin Cancer Related News Quitting Smoking, ...

  7. Thermodynamic inhibitor performance extender that, effectively and economically prevent hydrate formation in the oil field production systems

    Energy Technology Data Exchange (ETDEWEB)

    Allenson, Stephen; Johnston, Angela [Nalco Energy Services, Sugar Land, TX (United States)

    2008-07-01

    This paper presents the development of a new additive that was developed to improve the effectiveness of the treatment two to four fold when added to the thermodynamic hydrate inhibitor (THI). Consequently, the THI/additive treatment can now enable the system to handle two to four times the amount of water production or can allow treatment of the same amount of water at half to quarter the dosage of THI. This new additive extends the performance of the THI and allows for a significant increase in production or a significant drop in the amount of THI usage with a corresponding drop in cost. This paper will further discuss the overall process of THI enhancement and will present several case studies where the enhanced THI has been successfully applied. (author)

  8. A multi-scale approach to cost/benefit analyses of landslide prevention vs. post-event actions

    Science.gov (United States)

    Salbego, G.; Floris, M.; Busnardo, E.; Toaldo, M.

    2015-02-01

    The main aim of this paper is to test economic benefits of landslide prevention measures vs. post-event emergency actions. To this end, small and large scale analyses were performed in a training area located in the North-Eastern Italian pre-Alps that was hit by an exceptional rainfall event occurred in November 2010. At the small-scale, landslide susceptibility was initially assessed using a simple probabilistic analysis, which allowed to highlight the main landslide conditioning factors and the most hazardous areas. However, this approach revealed to be quite insufficient to reach planned goals, so a large-scale case-by-case analysis was performed: a study case was defined, according to landslide occurrence frequency and assessment of elements at risk. Numerical modeling demonstrated that remedial works carried out after the landslide - water-removal intervention such as a drainage trench - could have improved slope stability if applied before its occurrence. Then, a cost-benefit analysis was finally employed. It defined that prevention would have been economically convenient compared to a non-preventive and passive attitude, allowing a 30% saving relative to total costs. Therefore, this kind of approach could be actually used as a mean toward preventive soil protection not only within the investigated case study, but also in all those hazardous areas where preventive measures are needed.

  9. Public knowledge and Preventive Behavior During a Large-Scale Salmonella Outbreak: Results from an Online Survey in the Netherlands

    NARCIS (Netherlands)

    van Velsen, Lex Stefan; Beaujean, Desirée; van Gemert-Pijnen, Julia E.W.C.; van Steenbergen, Jim; Timen, aura

    2014-01-01

    Background Food-borne Salmonella infections are a worldwide concern. During a large-scale outbreak, it is important that the public follows preventive advice. To increase compliance, insight in how the public gathers its knowledge and which factors determine whether or not an individual complies

  10. Taking School-Based Substance Abuse Prevention to Scale: District-Wide Implementation of Keep a Clear Mind

    Science.gov (United States)

    Jowers, Keri L.; Bradshaw, Catherine P.; Gately, Sherry

    2007-01-01

    Public schools are under increased pressure to implement evidence-based substance abuse prevention programs. A number of model programs have been identified, but little research has examined the effectiveness of these programs when "brought to scale" or implemented district-wide. The current paper summarizes the application of the Adelman and…

  11. Detailed and large-scale cost/benefit analyses of landslide prevention vs. post-event actions

    Science.gov (United States)

    Salbego, G.; Floris, M.; Busnardo, E.; Toaldo, M.; Genevois, R.

    2015-11-01

    The main aim of this paper is to test economic benefits of landslide prevention measures vs. post-event emergency actions. To this end, detailed- and large-scale analyses were performed in a training area located in the northeastern Italian pre-Alps that was hit by an exceptional rainfall event occurred in November 2010. On the detailed scale, a landslide reactivated after 2010 event was investigated. Numerical modeling demonstrated that remedial works carried out after the landslide - water-removal intervention such as a drainage trench - could have improved slope stability if applied before its occurrence. Then, a cost/benefit analysis was employed. It defined that prevention would have been economically convenient compared to a non-preventive and passive attitude, allowing a 30 % saving relative to total costs. On the large scale, one of the most affected areas after 2010 event was considered. A susceptibility analysis was performed using a simple probabilistic model, which allowed to highlight the main landslide conditioning factors and the most hazardous and vulnerable sectors. In particular, such low-cost analysis demonstrated that almost 50 % of landslides occurred after 2010 event could be foreseen and allowed to roughly quantify benefits from regional landslide prevention. However, a large-scale approach is insufficient to carry out a quantitative cost/benefit analysis, for which a detailed case-by-case risk assessment is needed. The here proposed approaches could be used as a means of preventive soil protection in not only the investigated case study but also all those hazardous areas where preventive measures are needed.

  12. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors

    Science.gov (United States)

    Rostom, Alaa; Muir, Katherine; Dube, Catherine; Lanas, Angel; Jolicoeur, Emilie; Tugwell, Peter

    2009-01-01

    Background: Traditional NSAIDs (tNSAIDs) and COX-2 inhibitors (COX-2s) are important agents for the treatment of a variety or arthritic conditions. The purpose of this study was to systematically review the effectiveness of misoprostol, H2-receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) for the prevention of tNSAID related upper gastrointestinal (GI) toxicity, and to review the upper gastrointestinal (GI) safety of COX-2s. Methods: An extensive literature search was performed to identify randomized controlled trials (RCTs) of prophylactic agents used for the prevention of upper GI toxicity, and RCTs that assessed the GI safety of the newer COX-2s. Meta-analysis was performed in accordance with accepted techniques. Results: 39 gastroprotection and 69 COX-2 RCTs met inclusion criteria. Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of both endoscopic gastric and duodenal tNSAID-induced ulcers. Standard doses of H2RAs are not effective at reducing the risk of tNSAID-induced gastric ulcers, but reduce the risk of duodenal ulcers. Misoprostol is associated with greater adverse effects than the other agents, particularly at higher doses. COX-2s are associated with fewer endoscopic ulcers and clinically important ulcer complications, and have fewer treatment withdrawals due to GI symptoms than tNSAIDS. Acetylsalicylic acid appears to diminish the benefit of COX-2s over tNSAIDs. In high risk GI patients, tNSAID with a PPI or a COX-2 alone appear to offer similar GI safety, but a strategy of a COX-2 with a PPI appears to offer the greatest GI safety. Conclusion: Several strategies are available to reduce the risk of upper GI toxicity with tNSAIDs. The choice between these strategies needs to consider patients’ underlying GI and cardiovascular risk. PMID:21701610

  13. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria.

    Science.gov (United States)

    Phillips, Margaret A; White, Karen L; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N; Marfurt, Jutta; Shackleford, David M; Chiu, Francis C K; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N; Waterson, David; Palmer, Michael J; Rathod, Pradipsinh K; Charman, Susan A

    2016-12-09

    The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

  14. Bowman-Birk inhibitor concentrate prevents atrophy, weakness, and oxidative stress in soleus muscle of hindlimb-unloaded mice.

    Science.gov (United States)

    Arbogast, Sandrine; Smith, Jacqueline; Matuszczak, Yves; Hardin, Brian J; Moylan, Jennifer S; Smith, Jeffrey D; Ware, Jeffrey; Kennedy, Ann R; Reid, Michael B

    2007-03-01

    Antigravity muscles atrophy and weaken during prolonged mechanical unloading caused by bed rest or spaceflight. Unloading also induces oxidative stress in muscle, a putative cause of weakness. We tested the hypothesis that dietary supplementation with Bowman-Birk inhibitor concentrate (BBIC), a soy protein extract, would oppose these changes. Adult mice were fed a diet supplemented with 1% BBIC during hindlimb unloading for up to 12 days. Soleus muscles of mice fed the BBIC-supplemented diet weighed less, developed less force per cross-sectional area, and developed less total force after unloading than controls. BBIC supplementation was protective, blunting decrements in soleus muscle weight and force. Cytosolic oxidant activity was assessed using 2',7'-dichlorofluorescin diacetate. Oxidant activity increased in unloaded muscle, peaking at 3 days and remaining elevated through 12 days of unloading. Increases in oxidant activity correlated directly with loss of muscle mass and were abolished by BBIC supplementation. In vitro assays established that BBIC directly buffers reactive oxygen species and also inhibits serine protease activity. We conclude that dietary supplementation with BBIC protects skeletal muscle during prolonged unloading, promoting redox homeostasis in muscle fibers and blunting atrophy-induced weakness.

  15. The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence.

    Science.gov (United States)

    Wall, Meaghan; Poortinga, Gretchen; Stanley, Kym L; Lindemann, Ralph K; Bots, Michael; Chan, Christopher J; Bywater, Megan J; Kinross, Kathryn M; Astle, Megan V; Waldeck, Kelly; Hannan, Katherine M; Shortt, Jake; Smyth, Mark J; Lowe, Scott W; Hannan, Ross D; Pearson, Richard B; Johnstone, Ricky W; McArthur, Grant A

    2013-01-01

    MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established Eμ-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes. This work provides novel insights into the requirements for MYC-induced oncogenesis by showing that mTORC1 activity is necessary to bypass senescence during transformation of B lymphocytes. Furthermore, tumor eradication through senescence elicited by targeted inhibition of mTORC1 identifies a previously uncharacterized mechanism responsible for significant anticancer activity of rapamycin analogues and serves as proof-of-concept that senescence can be harnessed for therapeutic benefit

  16. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors

    Directory of Open Access Journals (Sweden)

    Alaa Rostom

    2009-10-01

    Full Text Available Alaa Rostom1, Katherine Muir2, Catherine Dube3, Angel Lanas4, Emilie Jolicoeur3, Peter Tugwell31University of Calgary, Calgary, Alberta, Canada; 2University of Toronto, Toronto, Ontario, Canada; 3University of Ottawa, Ottawa, Ontario, Canada; 4University Hospital Lozano Blesa, Instituto Aragones de Ciencias de la Salud, Zaragoza, SpainBackground: Traditional NSAIDs (tNSAIDs and COX-2 inhibitors (COX-2s are important agents for the treatment of a variety or arthritic conditions. The purpose of this study was to systematically review the effectiveness of misoprostol, H2-receptor antagonists (H2RAs, and proton pump inhibitors (PPIs for the prevention of tNSAID related upper gastrointestinal (GI toxicity, and to review the upper gastrointestinal (GI safety of COX-2s.Methods: An extensive literature search was performed to identify randomized controlled trials (RCTs of prophylactic agents used for the prevention of upper GI toxicity, and RCTs that assessed the GI safety of the newer COX-2s. Meta-analysis was performed in accordance with accepted techniques.Results: 39 gastroprotection and 69 COX-2 RCTs met inclusion criteria. Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of both endoscopic gastric and duodenal tNSAID-induced ulcers. Standard doses of H2RAs are not effective at reducing the risk of tNSAID-induced gastric ulcers, but reduce the risk of duodenal ulcers. Misoprostol is associated with greater adverse effects than the other agents, particularly at higher doses. COX-2s are associated with fewer endoscopic ulcers and clinically important ulcer complications, and have fewer treatment withdrawals due to GI symptoms than tNSAIDS. Acetylsalicylic acid appears to diminish the benefit of COX-2s over tNSAIDs. In high risk GI patients, tNSAID with a PPI or a COX-2 alone appear to offer similar GI safety, but a strategy of a COX-2 with a PPI appears to offer the greatest GI safety.Conclusion: Several strategies are

  17. The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus.

    Science.gov (United States)

    García-Rojo, Gonzalo; Fresno, Cristóbal; Vilches, Natalia; Díaz-Véliz, Gabriela; Mora, Sergio; Aguayo, Felipe; Pacheco, Aníbal; Parra-Fiedler, Nicolás; Parra, Claudio S; Rojas, Paulina S; Tejos, Macarena; Aliaga, Esteban; Fiedler, Jenny L

    2017-04-01

    Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss. Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed. Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration. Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.

  18. Prevention

    Science.gov (United States)

    ... Protection Equipment (PPE) Sequence for Putting on Personal Protection Equipment (PPE) [PDF – 2.85MB] Select Your PPE Equipment Combination Guidance ... PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word ... last updated: May 11, 2015 Content Source: Centers for Disease Control and Prevention National Center ...

  19. Plasminogen activator inhibitor-1 5G/5G genotype is a protecting factor preventing posttransplant diabetes mellitus.

    Science.gov (United States)

    Chang, Horng-Rong; Yang, Shun-Fa; Tsai, Jen-Pi; Hsieh, Ming-Chia; Wu, Sheng-Wen; Tsai, Hui-Ching; Hung, Tung-Wei; Huang, Jun-Huang; Lian, Jong-Da

    2011-01-30

    Plasminogen activator inhibitor 1 (PAI-1) is thought to play a role in the pathogenesis of obesity and insulin resistance. A connection between gestational diabetes mellitus and the functional -675 PAI-1 genotype has been reported. Therefore, we examined the role of the PAI-1 gene polymorphism in kidney transplant recipients. A total of 376 kidney transplant recipients were prospectively screened for posttransplant diabetes mellitus (PTDM). Eighty-one (21.5%) patients were diagnosed with PTDM and the other 295 patients were non-diabetic following kidney transplantation. DNA samples were isolated from the sera and analyzed for the functional -675 4G/5G promoter polymorphisms of the PAI-1 gene. Kidney transplant recipients with PTDM were significantly associated with tacrolimus use (p=0.03), older age (p=0.036), and higher body mass index (p=0.001). The genotype distribution was significantly different between the patients with PTDM (genotype 4G/4G:4G/5G:5G/5G=33.3%:60.5%:6.2%) and those without PTDM (genotype 4G/4G:4G/5G:5G/5G=36.9%:44.1%:19.0%) (p=0.018). Patients with homozygosity for 5G had a significantly lower rate of PTDM (aOR, 0.286, p=0.022) and higher cumulative event-free probability of time to PTDM (log rank test, p=0.0058). Homozygosity for the 5G allele of the PAI-1 gene constitutes a protecting factor for the development of PTDM. Our findings are similar to a previous study on gestational diabetes mellitus, and strongly support a possible genetic role of PAI-1 in the development of PTDM. Copyright © 2010 Elsevier B.V. All rights reserved.

  20. Renin-Angiotensin-Aldosterone Signaling Inhibitors-Losartan, Enalapril, and Cardosten-Prevent Infarction-induced Heart Failure Development in Rats.

    Science.gov (United States)

    Kiss, Krisztina; Fekete, Veronika; Pálóczi, János; Sárközy, Márta; Murlasits, Zsolt; Pipis, Judit; Kheyfets, Irina A; Dugina, Julia L; Sergeeva, Svetlana A; Epstein, Oleg I; Csonka, Csaba; Csont, Tamás; Ferdinandy, Péter; Bencsik, Péter

    2016-01-01

    The activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of congestive heart failure, which is the reason that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin 2 receptor blockers (ARBs) have become established therapies for heart failure. However, it is still not known whether preventive treatment with losartan or enalapril can reduce symptoms of infarction-induced heart failure. Ultra-low dose (ULD) drug therapy is thought to exert specific activity, with a lower chance of side effects. OBJECTIVES • The research team had hypothesized that preventive treatment with inhibitors of RAAS signaling-losartan, enalapril, and a preparation of a ULD antibody (ie, cardosten), which target the angiotensin type 1 (AT1) receptor-might alleviate pathological hypertrophy and/or functional decline in infarction-induced heart failure. The research team treated male Wistar rats orally for 30 d with 20 mg/kg of losartan, 10 mg/kg enalapril, 5 or 7.5 mL/kg of cardosten, or a control solution, started 1 d prior to permanent coronary occlusion. A sham-operated group functioned as a second control group. The study was conducted at the Department of Biochemistry of the Faculty of Medicine at the University of Szeged in Szeged, Hungary, in cooperation with the Pharmahungary Group, also in Szeged, Hungary, and with OOO "NPF" Materia Medica Holding Ltd in Moscow, Russia. To determine cardiac functional parameters in vivo, the research team inserted a catheter into the left ventricle of the rats and measured the parameters of ventricular pressure, and cardiac output was determined by thermodilution. Morphological parameters were measured after heart isolation in transverse sections by a digital caliper. A total of 30 d after permanent coronary ligation, both losartan and enalapril, significantly decreased mean arterial blood pressure (MABP), attenuated the development of the left-ventricular anterior-wall and septum

  1. Development of a community’s self-efficacy scale for preventing social isolation among community-dwelling older people (Mimamori Scale

    Directory of Open Access Journals (Sweden)

    Etsuko Tadaka

    2016-11-01

    Full Text Available Abstract Background Among older people in developed countries, social isolation leading to solitary death has become a public health issue of vital importance. Such isolation could be prevented by monitoring at-risk individuals at the neighborhood level and by implementing supportive networks at the community level. However, a means of measuring community confidence in these measures has not been established. This study is aimed at developing the Community’s Self-Efficacy Scale (CSES; Mimamori scale in Japanese for community members preventing social isolation among older people. Methods The CSES is a self-administered questionnaire developed on the basis of Bandura’s self-efficacy theory. The survey was given to a general population (GEN sample (n = 6,000 and community volunteer (CVOL sample (n = 1,297. Construct validity was determined using confirmatory factor analysis. Internal consistency was calculated using Cronbach’s alpha. The Generative Concern Scale (GCS-R and Brief Sense of Community Scale (BSCS were also administered to assess criterion-related validity of the CSES. Results In total, 3,484 and 859 valid responses were received in the GEN and CVOL groups, respectively. The confirmatory factor analysis identified eight items from two domains—community network and neighborhood watch—with goodness of fit index = 0.984, adjusted goodness of fit index = 0.970, comparative fit index = 0.988, and root mean square error of approximation = 0.047. Cronbach’s alpha for the entire CSES was 0.87 and for the subscales was 0.80 and higher. The score of the entire CSES was positively correlated with the GCS-R in both the GEN (r = 0.80, p < 0.001 and CVOL (r = 0.86, p < 0.001 samples. Conclusions The CSES demonstrated adequate reliability and validity for assessing a community’s self-efficacy to aid in its preventing social isolation among older people. The scale is potentially useful for

  2. Can EGFR-Tyrosine Kinase Inhibitors (TKI) Alone Without Talc Pleurodesis Prevent Recurrence of Malignant Pleural Effusion (MPE) in Lung Adenocarcinoma.

    Science.gov (United States)

    Verma, Akash; Chopra, Akhil; Lee, Yeo W; Bharwani, Lavina D; Asmat, Atasha B; Aneez, Dokeu B A; Akbar, Fazuludeen A; Lim, Albert Y H; Chotirmall, Sanjay H; Abisheganaden, John

    2016-01-01

    Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are effective against lung adenocarcinoma. However, limited data is available assessing the effectiveness of EGFR-TKI use in preventing re-accumulation of MPE. To our knowledge, there is no literature on comparison of talc pleurodesis with EGFR-TKIs alone on re-accumulation of MPE in Asian population. We investigated if EGFR-TKI therapy for advanced lung adenocarcinoma with malignant pleural effusion (MPE) is also successful in preventing pleural fluid re-accumulation following initial drainage. An observational cohort study of patients with lung adenocarcinoma and MPE in the year 2012 was conducted. 70 patients presented with MPE from lung adenocarcinoma. Fifty six underwent EGFR mutation testing of which 39 (69.6%) had activating EGFR mutation and 34 (87.1%) received TKI. 20 were managed by pleural fluid drainage only whereas 14 underwent talc pleurodesis following pleural fluid drainage. Time taken for the pleural effusion to re-accumulate in those with and without pleurodesis was 9.9 vs. 11.7 months, p=0.59 respectively. More patients (n=10, 25.6%) with activating EGFR mutation presented with complete opacification (white-out) of the hemithorax compared to none without activating EGFR mutation (p=0.02). In TKI eligible patients, early talc pleurodesis may not confer additional benefit in preventing re-accumulation of pleural effusion and may be reserved for non-adenocarcinoma histology, or EGFR negative adenocarcinoma. Complete opacification of the hemithorax on presentation may serve as an early radiographic signal of positive EGFR mutation status.

  3. Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT

    Directory of Open Access Journals (Sweden)

    Alejandro Morales-Bayuelo

    2013-01-01

    Full Text Available Molecular quantum similarity descriptors and Density Functional Theory (DFT based reactivity descriptors were studied for a series of cholinesterase/monoamine oxidase inhibitors used for the Alzheimer's disease treatment (AD. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these molecules with acetylcholinesterase (AChE and butyrylcholinesterase (BuChE, as well as with monoamine oxidase (MAO A and B. The Topogeometrical Superposition Algorithm to handle flexible molecules (TGSA-Flex alignment method was used to solve the problem of the relative orientation in the quantum similarity (QS field. Using the molecular quantum similarity (MQS field and reactivity descriptors supported in the DFT was possible the quantification of the steric and electrostatic effects through of the Coulomb and Overlap quantitative convergence scales (alpha and beta. In addition, an analysis of reactivity indexes is development, using global and local descriptors, identifying the binding sites and selectivity in the (cholinesterase/monoamine oxidase inhibitors, understanding the retrodonor process, and showing new insight for drugs design in a disease of difficult control as Alzheimer.

  4. Preventing large-scale controlled substance diversion from within the pharmacy.

    Science.gov (United States)

    Martin, Emory S; Dzierba, Steven H; Jones, David M

    2013-05-01

    Large-scale diversion of controlled substances (CS) from within a hospital or heath system pharmacy is a rare but growing problem. It is the responsibility of pharmacy leadership to scrutinize control processes to expose weaknesses. This article reviews examples of large-scale diversion incidents and diversion techniques and provides practical strategies to stimulate enhanced CS security within the pharmacy staff. Large-scale diversion from within a pharmacy department can be averted by a pharmacist-in-charge who is informed and proactive in taking effective countermeasures.

  5. Vortex-Concept for Radioactivity Release Prevention at NPP: Development of Computational Model of Lab-Scale Experimental Setup

    Energy Technology Data Exchange (ETDEWEB)

    Ullah, Sana; Sung, Yim Man; Park, Jin Soo; Sung Hyung Jin [KAERI, Daejeon (Korea, Republic of)

    2016-05-15

    The experimental validation of the vortex-like air curtain concept and use of an appropriate CFD modelling approach for analyzing the problem becomes crucial. A lab-scale experimental setup is designed to validate the proposed concept and CFD modeling approach as a part of validation process. In this study, a computational model of this lab-scale experiment setup is developed using open source CFD code OpenFOAM. The computational results will be compared with experimental data for validation purposes in future, when experimental data is available. 1) A computation model of a lab-scale experimental setup, designed to validate the concept of artificial vortex-like airflow generation for application to radioactivity dispersion prevention in the event of severe accident, was developed. 2) The mesh sensitivity study was performed and a mesh of about 2 million cells was found to be sufficient for this setup.

  6. Assessment of functional outcomes by Sheehan Disability Scale in patients with major depressive disorder treated with duloxetine versus selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Sheehan, David V; Mancini, Michele; Wang, Jianing; Berggren, Lovisa; Cao, Haijun; Dueñas, Héctor José; Yue, Li

    2016-01-01

    We compared functional impairment outcomes assessed with Sheehan Disability Scale (SDS) after treatment with duloxetine versus selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder. Data were pooled from four randomized studies comparing treatment with duloxetine and SSRIs (three double blind and one open label). Analysis of covariance, with last-observation-carried-forward approach for missing data, explored treatment differences between duloxetine and SSRIs on SDS changes during 8 to 12 weeks of acute treatment for the intent-to-treat population. Logistic regression analysis examined the predictive capacity of baseline patient characteristics for remission in functional impairment (SDS total score ≤ 6 and SDS item scores ≤ 2) at endpoint. Included were 2193 patients (duloxetine n = 1029; SSRIs n = 835; placebo n = 329). Treatment with duloxetine and SSRIs resulted in significantly (p Depression Rating Scale baseline scores (p depressive disorder. Higher SDS or 17-item Hamilton Depression Rating Scale baseline scores predicted less probability of SDS improvement; female gender predicted better improvement in functional impairment at endpoint. © 2015 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.

  7. Development of a Canine Care and Welfare Knowledge Scale: Implications for Welfare and Preventing Dogfighting.

    Science.gov (United States)

    Iliopoulou, Maria A; Rosenbaum, Rene P; Carleton, Carla L

    2017-01-01

    The objective of this study was to develop a Canine Care and Welfare Knowledge (CCWK) Scale for use in educational intervention development and evaluation and validate the instrument. The study population was 504 children, aged 11 to 19 years old, from Detroit, MI. In this cross-sectional study, exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used for scale development. The EFA and CFA of the CCWK Scale revealed a 2nd-order model with 6 factors to be a good fit of the data (chi-square [df = 269] = 433, p < .05, Comparative Fit Index = .94, Tucker-Lewis Index = .93, root mean square error of approximation = .05) with a Cronbach's alpha of .78. The scale is valid and reliable to assess the study population's CCWK.

  8. A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis.

    Science.gov (United States)

    Kanak, Mazhar A; Shahbazov, Rauf; Yoshimatsu, Gumpei; Levy, Marlon F; Lawrence, Michael C; Naziruddin, Bashoo

    2017-03-01

    The underlying molecular mechanism that leads to development of chronic pancreatitis remains elusive. The aim of this study is to understand the downstream inflammatory signaling involved in progression of chronic pancreatitis, and to use withaferin A (WA), a small molecule inhibitor of nuclear factor κB (NFκB), to prevent progression of chronic pancreatitis. Two different protocols were used to induce pancreatitis in mice: standard and stringent administration of cerulein. The severity of pancreatitis was assessed by means of pancreatic histology and serum amylase levels. Immunohistochemistry and flow-cytometric analysis was performed to visualize immune cell infiltration into the pancreas. Real-time PCR and Western blot were used to analyze the downstream signaling mechanism involved in the development of chronic pancreatitis. The severity of cerulein-induced pancreatitis was reduced significantly by WA, used as either preventive or curative treatment. Immune cell infiltration into the pancreas and acinar cell death were efficiently reduced by WA treatment. Expression of proinflammatory and proapoptotic genes regulated by NFκB activation was increased by cerulein treatment, and WA suppressed these genes significantly. Sustained endoplasmic reticulum stress activation by cerulein administration was reduced. NLRP3 inflammasome activation in cerulein-induced pancreatitis was identified, and this was also potently blocked by WA. The human pancreatitis tissue gene signature correlated with the mouse model. Our data provide evidence for the role of NFκB in the pathogenesis of chronic pancreatitis, and strongly suggest that WA could be used as a potential therapeutic drug to alleviate some forms of chronic pancreatitis.

  9. The effectiveness of prophylactic proton pump inhibitors for prevention of non-steroidal anti inflammatory drugs associated gastric and duodenal ulcers in elderly.

    Science.gov (United States)

    Kheiri, Babikir; Mabrouk, Ahmed; Ahmed, Imran; Khan, Hashim; Sheikh, Azeem S

    2014-01-01

    Aims was undertaken to ensure concomitant usage of proton pump inhibitors (PPIs) with Non-Steroidal Anti-inflammatory Drugs (NSAIDs) in Elderly, in order to avoid upper gastrointestinal (GI) symptoms and ulcers. Reviewing of 386 patients' prescription on the EMIS (Egton Medical Information Systems) Web, on April 2014. Checking who have not been prescribed PPIs with NSAIDs, offering them appointment for prescription and discussion about risks and benefits of PPIs. Re-audit of 390 patients' prescription on the EMIS Web, on July 2014. Exclusion criteria in the audit and re-audit were; NSAIDs usage for more than 3 years, contra-indications for PPIs, and patients who declined inclusion in the audit. In the first audit cycle, a total of 386 patients' prescription reviewed, 23 (6%) patients were not prescribed PPIs with NSAIDs and were eligible for PPIs prescription. Those patients were contacted by post, an appointment arranged for them and prescribed the PPIs. 12 weeks later a re-audit was done, showed that all patients (100%) who are prescribed NSAIDs are prescribed prophylactic PPIs. None of the patients who are prescribed NSAIDs and PPIs concomitantly developed upper GI symptoms or ulcers. The audit increased the awareness of the junior doctors of the importance of concomitant prescription of PPIs with NSAIDs, in accordance with the electronic Medical Compendium (eMC) guidelines, to prevent upper GI symptoms and ulcers. That was reflected in the re-audit having 100% of the patients prescribed NSAIDs and PPIs concomitantly.

  10. The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice.

    Science.gov (United States)

    Sun, Lifeng; Ren, Xiaomeng; Wang, I-Ching; Pradhan, Arun; Zhang, Yufang; Flood, Hannah M; Han, Bo; Whitsett, Jeffrey A; Kalin, Tanya V; Kalinichenko, Vladimir V

    2017-04-18

    Goblet cell metaplasia and excessive mucus secretion associated with asthma, cystic fibrosis, and chronic obstructive pulmonary disease contribute to morbidity and mortality worldwide. We performed a high-throughput screen to identify small molecules targeting a transcriptional network critical for the differentiation of goblet cells in response to allergens. We identified RCM-1, a nontoxic small molecule that inhibited goblet cell metaplasia and excessive mucus production in mice after exposure to allergens. RCM-1 blocked the nuclear localization and increased the proteasomal degradation of Forkhead box M1 (FOXM1), a transcription factor critical for the differentiation of goblet cells from airway progenitor cells. RCM-1 reduced airway resistance, increased lung compliance, and decreased proinflammatory cytokine production in mice exposed to the house dust mite and interleukin-13 (IL-13), which triggers goblet cell metaplasia. In cultured airway epithelial cells and in mice, RCM-1 reduced IL-13 and STAT6 (signal transducer and activator of transcription 6) signaling and prevented the expression of the STAT6 target genes Spdef and Foxa3, which are key transcriptional regulators of goblet cell differentiation. These results suggest that RCM-1 is an inhibitor of goblet cell metaplasia and IL-13 signaling, providing a new therapeutic candidate to treat patients with asthma and other chronic airway diseases. Copyright © 2017, American Association for the Advancement of Science.

  11. Treatment of erythrocytes with the 2-cys peroxiredoxin inhibitor, Conoidin A, prevents the growth of Plasmodium falciparum and enhances parasite sensitivity to chloroquine.

    Directory of Open Access Journals (Sweden)

    Mariana Brizuela

    Full Text Available The human erythrocyte contains an abundance of the thiol-dependant peroxidase Peroxiredoxin-2 (Prx2, which protects the cell from the pro-oxidant environment it encounters during its 120 days of life in the blood stream. In malarial infections, the Plasmodium parasite invades red cells and imports Prx2 during intraerythrocytic development, presumably to supplement in its own degradation of peroxides generated during cell metabolism, especially hemoglobin (Hb digestion. Here we demonstrate that an irreversible Prx2 inhibitor, Conoidin A (2,3-bis(bromomethyl-1,4-dioxide-quinoxaline; BBMQ, has potent cytocidal activity against cultured P. falciparum. Parasite growth was also inhibited in red cells that were treated with BBMQ and then washed prior to parasite infection. These cells remained susceptible to merozoite invasion, but failed to support normal intraerythrocytic development. In addition the potency of chloroquine (CQ, an antimalarial drug that prevents the detoxification of Hb-derived heme, was significantly enhanced in the presence of BBMQ. CQ IC50 values decreased an order of magnitude when parasites were either co-incubated with BBMQ, or introduced into BBMQ-pretreated cells; these effects were equivalent for both drug-resistant and drug-sensitive parasite lines. Together these results indicate that treatment of red cells with BBMQ renders them incapable of supporting parasite growth and increases parasite sensitivity to CQ. We also propose that molecules such as BBMQ that target host cell proteins may constitute a novel host-directed therapeutic approach for treating malaria.

  12. Chitosan-doxycycline hydrogel: An MMP inhibitor/sclerosing embolizing agent as a new approach to endoleak prevention and treatment after endovascular aneurysm repair.

    Science.gov (United States)

    Zehtabi, Fatemeh; Ispas-Szabo, Pompilia; Djerir, Djahida; Sivakumaran, Lojan; Annabi, Borhane; Soulez, Gilles; Mateescu, Mircea Alexandru; Lerouge, Sophie

    2017-12-01

    The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment. In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)-a sclerosant and MMP inhibitor-was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks. An injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX

  13. Small-Scale Bullying Prevention Discussion Video for Classrooms: A Preliminary Evaluation

    Science.gov (United States)

    Migliaccio, Todd; Raskauskas, Juliana

    2013-01-01

    Bullying has been shown to be negatively related to both academic performance and attendance among students. The present study examined a small-scale bullying intervention using a video-discussion model. Eighty-one students in grades 4 through 6 completed pre- and posttests examining gains in knowledge of bullying and responses to it. Results…

  14. Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models.

    Science.gov (United States)

    Wen, Li; Voronina, Svetlana; Javed, Muhammad A; Awais, Muhammad; Szatmary, Peter; Latawiec, Diane; Chvanov, Michael; Collier, David; Huang, Wei; Barrett, John; Begg, Malcolm; Stauderman, Ken; Roos, Jack; Grigoryev, Sergey; Ramos, Stephanie; Rogers, Evan; Whitten, Jeff; Velicelebi, Gonul; Dunn, Michael; Tepikin, Alexei V; Criddle, David N; Sutton, Robert

    2015-08-01

    Sustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release-activated calcium modulator ORAI1 is the most abundant Ca(2+) entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice. Mouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK-7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects. GSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca(2+) currents after Ca(2+) release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis. Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed for the treatment of patients with pancreatitis

  15. An appraisal of female sex work in Nigeria--implications for designing and scaling up HIV prevention programmes.

    Directory of Open Access Journals (Sweden)

    Akudo Ikpeazu

    Full Text Available BACKGROUND: The HIV epidemic in Nigeria is complex with diverse factors driving the epidemic. Accordingly, Nigeria's National Agency for the Control of AIDS is coordinating a large-scale initiative to conduct HIV epidemic appraisals across all states. These appraisals will help to better characterize the drivers of the epidemic and ensure that the HIV prevention programmes match the local epidemic context, with resources allocated to interventions that have the greatest impact locally. Currently, the mapping and size estimation of Female Sex Workers (FSWs--a major component of the appraisal has been completed in seven states. These states are using the data generated to plan, prioritize and scale-up sub-national HIV prevention programmes. METHODOLOGY: It involved a two-level process of identifying and validating locations where FSWs solicit and/or meet clients ("hotspots". In the first level, secondary key informants were interviewed to collect information about the geographic location and description of the hotspots. For the second level, FSWs were interviewed at each hotspot and information on population size estimates, typologies and operational dynamics of the FSWs were collected. RESULTS: Across the seven states, a total of 17,266 secondary key informants and 5,732 FSWs were interviewed. 10,233 hotspots were identified with an estimated 126,489 FSWs ranging from 5,920 in Anambra to 46,691 in Lagos. The most common hotspots were bars/nightclubs (30%, hotels/lodges (29.6%, streets (16.6%, and brothels (14.6%. Furthermore, the population density of FSWs (per thousand adult men across the states ranged from 2 in Anambra to 17 in the Federal Capital Territory. CONCLUSION: FSW populations in Nigeria are large and diverse, with substantial differences between and within states. Improved understanding of the location, population size, density, organizational typologies and clients of sex work has informed and is central to Nigeria's planning

  16. Scaling up integrated prevention campaigns for global health: costs and cost-effectiveness in 70 countries.

    Science.gov (United States)

    Marseille, Elliot; Jiwani, Aliya; Raut, Abhishek; Verguet, Stéphane; Walson, Judd; Kahn, James G

    2014-06-26

    This study estimated the health impact, cost and cost-effectiveness of an integrated prevention campaign (IPC) focused on diarrhoea, malaria and HIV in 70 countries ranked by per capita disability-adjusted life-year (DALY) burden for the three diseases. We constructed a deterministic cost-effectiveness model portraying an IPC combining counselling and testing, cotrimoxazole prophylaxis, referral to treatment and condom distribution for HIV prevention; bed nets for malaria prevention; and provision of household water filters for diarrhoea prevention. We developed a mix of empirical and modelled cost and health impact estimates applied to all 70 countries. One-way, multiway and scenario sensitivity analyses were conducted to document the strength of our findings. We used a healthcare payer's perspective, discounted costs and DALYs at 3% per year and denominated cost in 2012 US dollars. The primary outcome was cost-effectiveness expressed as net cost per DALY averted. Other outcomes included cost of the IPC; net IPC costs adjusted for averted and additional medical costs and DALYs averted. Implementation of the IPC in the 10 most cost-effective countries at 15% population coverage would cost US$583 million over 3 years (adjusted costs of US$398 million), averting 8.0 million DALYs. Extending IPC programmes to all 70 of the identified high-burden countries at 15% coverage would cost an adjusted US$51.3 billion and avert 78.7 million DALYs. Incremental cost-effectiveness ranged from US$49 per DALY averted for the 10 countries with the most favourable cost-effectiveness to US$119, US$181, US$335, US$1692 and US$8340 per DALY averted as each successive group of 10 countries is added ordered by decreasing cost-effectiveness. IPC appears cost-effective in many settings, and has the potential to substantially reduce the burden of disease in resource-poor countries. This study increases confidence that IPC can be an important new approach for enhancing global health

  17. Prevention of Smoking in Middle School Students: Psychometric Assessment of the Temptations to Try Smoking Scale

    Science.gov (United States)

    McGee, Heather A.; Babbin, Steven F.; Redding, Colleen; Pavia, Andrea; Oatley, Karin; Meier, Kathryn; Harrington, Magdalena; Velicer, Wayne F.

    2011-01-01

    Establishment of psychometrically sound measures is critical to the development of effective interventions. The current study examined the psychometric properties, including factorial invariance, of a six item Temptations to Try Smoking Scale on a sample of middle school students. The sample of 6th grade students (N = 3527) was from 20 Rhode Island middle schools and was 52% male and 84% white. The Temptations to Try Smoking Scale consisted of two correlated subscales: Positive Social and Curiosity/Stress. Structural equation modeling was implemented to evaluate the factorial invariance across four different subgroups defined by gender (male/female), race (white/black), ethnicity (Hispanic/Non-Hispanic), and school size (200 6th graders). A model is factorially invariant when the measurement model is the same in each of the subgroups. Three levels of invariance were examined in sequential order: 1) Configural Invariance (unconstrained nonzero factor loadings); 2) Pattern Identity Invariance (equal factor loadings); and 3) Strong Factorial Invariance (equal factor loadings and measurement errors). Strong Factorial Invariance provided a good fit to the model across gender (CFI = .96), race (CFI = .96), ethnicity (CFI = .94), and school size (CFI = .97). Coefficient Alphas for the two subscales, Positive Social and Curiosity/Stress, were .87 and .86, respectively. These findings provide empirical support for the construct validity of the Temptations to Try Smoking Scale in middle school students. PMID:22265238

  18. The association of albuminuria and high-sensitivity C-reactive protein with the efficacy of HMG-coenzyme A reductase inhibitors for cardiovascular event prevention.

    Science.gov (United States)

    Özyilmaz, Akin; Boersma, Cornelis; Visser, Sipke T; Postma, Maarten J; de Jong-van den Berg, Lolkje Tw; Lambers-Heerspink, Hiddo J; de Jong, Paul E; Gansevoort, Ron T

    2016-05-01

    It is not clear which hypercholesterolemic patients benefit most from β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitors with respect to the prevention of cardiovascular events. Early signs of atherosclerotic vascular damage may identify high-risk patients. We studied whether subjects with hypercholesterolemia will benefit more from starting statin treatment in the case of high albuminuria and/or high-sensitivity C-reactive protein (hsCRP). Included were subjects who had hypercholesterolemia at baseline, a negative cardiovascular disease history and who were not treated with statins. In total, 2011 subjects were analysed, of whom 695 started with a statin during a follow-up of 7.0 ± 1.7 years. Adjusted hazard ratios (HRs) for cardiovascular events were calculated in subjects who started versus those who did not start a statin stratified for albuminuria less than or ≥ 15 mg/day and/or hsCRP less than or ≥ 3 mg/L. The start of a statin was associated with a beneficial effect on cardiovascular risk in subjects with high albuminuria (HR 0.38 (0.23-0.60)), while the effect of starting a statin was non-significant in subjects with low albuminuria (HR 0.74 (0.44-1.24), P for interaction albuminuria and hsCRP subgroups, the start of statin treatment was associated with a lower risk of cardiovascular events dependent on albuminuria and not on the hsCRP level. The start of statin treatment is associated with a significantly lower absolute as well as relative risk of cardiovascular events in subjects with hypercholesterolemia and elevated albuminuria, whereas these drugs had less effect in subjects with normal albuminuria. © The European Society of Cardiology 2015.

  19. Application of Pulse Spark Discharges for Scale Prevention and Continuous Filtration Methods in Coal-Fired Power Plant

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Young; Fridman, Alexander

    2012-06-30

    The overall objective of the present work was to develop a new scale-prevention technology by continuously precipitating and removing dissolved mineral ions (such as calcium and magnesium) in cooling water while the COC could be doubled from the present standard value of 3.5. The hypothesis of the present study was that if we could successfully precipitate and remove the excess calcium ions in cooling water, we could prevent condenser-tube fouling and at the same time double the COC. The approach in the study was to utilize pulse spark discharges directly in water to precipitate dissolved mineral ions in recirculating cooling water into relatively large suspended particles, which could be removed by a self-cleaning filter. The present study began with a basic scientific research to better understand the mechanism of pulse spark discharges in water and conducted a series of validation experiments using hard water in a laboratory cooling tower. Task 1 of the present work was to demonstrate if the spark discharge could precipitate the mineral ions in water. Task 2 was to demonstrate if the selfcleaning filter could continuously remove these precipitated calcium particles such that the blowdown could be eliminated or significantly reduced. Task 3 was to demonstrate if the scale could be prevented or minimized at condenser tubes with a COC of 8 or (almost) zero blowdown. In Task 1, we successfully completed the validation study that confirmed the precipitation of dissolved calcium ions in cooling water with the supporting data of calcium hardness over time as measured by a calcium ion probe. In Task 2, we confirmed through experimental tests that the self-cleaning filter could continuously remove precipitated calcium particles in a simulated laboratory cooling tower such that the blowdown could be eliminated or significantly reduced. In addition, chemical water analysis data were obtained which were used to confirm the COC calculation. In Task 3, we conducted a series

  20. Development of a community commitment scale with cross-sectional survey validation for preventing social isolation in older Japanese people.

    Science.gov (United States)

    Kono, Ayumi; Tadaka, Etsuko; Kanaya, Yukiko; Dai, Yuka; Itoi, Waka; Imamatsu, Yuki

    2012-10-24

    Elderly social isolation could be prevented by facilitating communication or mutual helping at the neighborhood level. The helping of elderly neighbors by local volunteers may relate to their community commitment (CC), but ways to measure CC have not been identified. The aim of the present study was to develop a Community Commitment Scale (CCS) to measure psychological sense of belonging and socializing in the community among local volunteers, for research in prevention of elderly social isolation. We also tested the CCS in a general population of the elderly. A pilot test of 266 Japanese urban residents was conducted to examine face validity for 24 identified items, of which 12 items were selected for the CCS, based on a 4-point Likert-type scale. The CCS was developed via self-report questionnaires to 859 local volunteers in two suburban cities and to 3484 randomly sampled general residents aged 55 years or older living in one of the cities. To assess concurrent validity, data were collected using the Brief Sense of Community Scale (Peterson; 2008) and two types of single questions on self-efficacy for helping elderly neighbors. Item analysis and factor analysis identified 8 items, which were classified between two datasets under the domains of "belonging" and "socializing" in the local volunteers and the general residents. Cronbach's alpha (which conveyed the internal consistency of the CCS) was 0.75 in local volunteers and 0.78 in general residents. The correlation coefficients between the scores of the CCS and BSCS were 0.54 for local volunteers and 0.62 for general residents. ANOVA comparing the CCS between the confidence levels of the two types of single question of self-efficacy on helping elderly neighbors showed a strong relationship in the volunteers and residents. These results demonstrate acceptable internal consistency and concurrent validity for the CCS, with the two dimensions "belonging" and "socializing", among the local volunteers and general

  1. Development of a Community Commitment Scale with Cross-sectional Survey Validation for Preventing Social Isolation in Older Japanese People

    Directory of Open Access Journals (Sweden)

    Kono Ayumi

    2012-10-01

    Full Text Available Abstract Background Elderly social isolation could be prevented by facilitating communication or mutual helping at the neighborhood level. The helping of elderly neighbors by local volunteers may relate to their community commitment (CC, but ways to measure CC have not been identified. The aim of the present study was to develop a Community Commitment Scale (CCS to measure psychological sense of belonging and socializing in the community among local volunteers, for research in prevention of elderly social isolation. We also tested the CCS in a general population of the elderly. Methods A pilot test of 266 Japanese urban residents was conducted to examine face validity for 24 identified items, of which 12 items were selected for the CCS, based on a 4-point Likert-type scale. The CCS was developed via self-report questionnaires to 859 local volunteers in two suburban cities and to 3484 randomly sampled general residents aged 55 years or older living in one of the cities. To assess concurrent validity, data were collected using the Brief Sense of Community Scale (Peterson; 2008 and two types of single questions on self-efficacy for helping elderly neighbors. Results Item analysis and factor analysis identified 8 items, which were classified between two datasets under the domains of “belonging” and “socializing” in the local volunteers and the general residents. Cronbach’s alpha (which conveyed the internal consistency of the CCS was 0.75 in local volunteers and 0.78 in general residents. The correlation coefficients between the scores of the CCS and BSCS were 0.54 for local volunteers and 0.62 for general residents. ANOVA comparing the CCS between the confidence levels of the two types of single question of self-efficacy on helping elderly neighbors showed a strong relationship in the volunteers and residents. Conclusions These results demonstrate acceptable internal consistency and concurrent validity for the CCS, with the two dimensions

  2. Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus.

    Science.gov (United States)

    Hemmingsen, Bianca; Sonne, David P; Metzendorf, Maria-Inti; Richter, Bernd

    2017-05-10

    The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the

  3. Oral versus intravenous proton pump inhibitors in preventing re-bleeding for patients with peptic ulcer bleeding after successful endoscopic therapy.

    Science.gov (United States)

    Yen, Hsu-Heng; Yang, Chia-Wei; Su, Wei-Wen; Soon, Maw-Soan; Wu, Shun-Sheng; Lin, Hwai-Jeng

    2012-06-08

    High dose intravenous proton pump inhibitor after endoscopic therapy for peptic ulcer bleeding has been recommended as adjuvant therapy. Whether oral proton pump inhibitor can replace intravenous proton pump inhibitor in this setting is unknown. This study aims to compare the clinical efficacy of oral and intravenous proton pump inhibitor after endoscopic therapy. Patients with high-risk bleeding peptic ulcers after successful endoscopic therapy were randomly assigned as oral lansoprazole or intravenous esomeprazole group. Primary outcome of the study was re-bleeding rate within 14 days. Secondary outcome included hospital stay, volume of blood transfusion, surgical intervention and mortality within 1 month. From April 2010 to Feb 2011, 100 patients were enrolled in this study. The re-bleeding rates were 4% (2/50) in the intravenous group and 4% (2/50) in the oral group. There was no difference between the two groups with regards to the hospital stay, volume of blood transfusion, surgery or mortality rate. The mean duration of hospital stay was 1.8 days in the oral lansoprazole group and 3.9 days in the intravenous esomeprazole group (p > 0.01). Patients receiving oral proton pump inhibitor have a shorter hospital stay. There is no evidence of a difference in clinical outcomes between oral and intravenous PPI treatment. However, the study was not powered to prove equivalence or non-inferiority. Future studies are still needed. NCT01123031.

  4. Vascular endothelial growth factor inhibitor-induced hypertension: from pathophysiology to prevention and treatment based on long-acting nitric oxide donors.

    Science.gov (United States)

    Kruzliak, Peter; Novák, Jan; Novák, Miroslav

    2014-01-01

    Hypertension is the most common adverse effect of the inhibitors of vascular endothelial growth factor (VEGF) pathway-based therapy (VEGF pathway inhibitors therapy, VPI therapy) in cancer patients. VPI includes monoclonal antibodies against VEGF, tyrosine kinase inhibitors, VEGF Traps, and so-called aptamers that may become clinically relevant in the future. All of these substances inhibit the VEGF pathway, which in turn causes a decrease in nitric oxide (NO) and an increase in blood pressure, with the consequent development of hypertension and its final events (e.g., myocardial infarction or stroke). To our knowledge, there is no current study on how to provide an optimal therapy for patients on VPI therapy with hypertension. This review summarizes the roles of VEGF and NO in vessel biology, provides an overview of VPI agents, and suggests a potential treatment procedure for patients with VPI-induced hypertension.

  5. Cost-effectiveness of ACE inhibitor therapy to prevent dialysis in nondiabetic nephropathy : Influence of the ACE insertion/deletion polymorphism

    NARCIS (Netherlands)

    Vegter, Stefan; Perna, A.; Hiddema, W.; Ruggenenti, P.; Remuzzi, G.; Navis, Ger Jan; Postma, Maarten

    Introduction End-stage renal disease is associated with high health-care costs and low quality of life compared with chronic kidney disease. The renoprotective effectiveness of angiotensin-converting enzyme inhibitors (ACEi) is largely determined by the ACE insertion/deletion (I/D) polymorphism. We

  6. Network Meta-Analysis Comparing Relatively Selective COX-2 Inhibitors Versus Coxibs for the Prevention of NSAID-Induced Gastrointestinal Injury.

    Science.gov (United States)

    Yang, Man; Wang, Hong-Tao; Zhao, Miao; Meng, Wen-Bo; Ou, Jin-Qing; He, Jun-Hui; Zou, Bing; Lei, Ping-Guang

    2015-10-01

    Currently 2 difference classes of cyclooxygenase (COX)-2 inhibitors, coxibs and relatively selective COX-2 inhibitors, are available for patients requiring nonsteroidal anti-inflammatory drug (NSAID) therapy; their gastroprotective effect is hardly directly compared. The aim of this study was to compare the gastroprotective effect of relatively selective COX-2 inhibitors with coxibs. MEDLINE, EMBASE, and the Cochrane Library (from their inception to March 2015) were searched for potential eligible studies. We included randomized controlled trials comparing coxibs (celecoxib, etoricoxib, parecoxib, and lumiracoxib), relatively selective COX-2 inhibitors (nabumetone, meloxicam, and etodolac), and nonselective NSAIDs with a study duration ≥ 4 weeks. Comparative effectiveness and safety data were pooled by Bayesian network meta-analysis. The primary outcomes were ulcer complications and symptomatic ulcer. Summary effect-size was calculated as risk ratio (RR), together with the 95% confidence interval (CI). This study included 36 trials with a total of 112,351 participants. Network meta-analyses indicated no significant difference between relatively selective COX-2 inhibitors and coxibs regarding ulcer complications (RR, 1.38; 95% CI, 0.47-3.27), symptomatic ulcer (RR, 1.02; 95% CI, 0.09-3.92), and endoscopic ulcer (RR, 1.18; 95% CI, 0.37-2.96). Network meta-analyses adjusting potential influential factors (age, sex, previous ulcer disease, and follow-up time), and sensitivity analyses did not reveal any major change to the main results. Network meta-analyses suggested that relatively selective COX-2 inhibitors and coxibs were associated with comparable incidences of total adverse events (AEs) (RR, 1.09; 95% CI, 0.93-1.31), gastrointestinal AEs (RR, 1.04; 95% CI, 0.87-1.25), total withdrawals (RR, 1.00; 95% CI, 0.74-1.33), and gastrointestinal AE-related withdrawals (RR, 1.02; 95% CI, 0.57-1.74). Relatively selective COX-2 inhibitors appear to be associated with

  7. Oral versus intravenous proton pump inhibitors in preventing re-bleeding for patients with peptic ulcer bleeding after successful endoscopic therapy

    Directory of Open Access Journals (Sweden)

    Yen Hsu-Heng

    2012-06-01

    Full Text Available Abstract Background High dose intravenous proton pump inhibitor after endoscopic therapy for peptic ulcer bleeding has been recommended as adjuvant therapy. Whether oral proton pump inhibitor can replace intravenous proton pump inhibitor in this setting is unknown. This study aims to compare the clinical efficacy of oral and intravenous proton pump inhibitor after endoscopic therapy. Methods Patients with high-risk bleeding peptic ulcers after successful endoscopic therapy were randomly assigned as oral lansoprazole or intravenous esomeprazole group. Primary outcome of the study was re-bleeding rate within 14 days. Secondary outcome included hospital stay, volume of blood transfusion, surgical intervention and mortality within 1 month. Results From April 2010 to Feb 2011, 100 patients were enrolled in this study. The re-bleeding rates were 4% (2/50 in the intravenous group and 4% (2/50 in the oral group. There was no difference between the two groups with regards to the hospital stay, volume of blood transfusion, surgery or mortality rate. The mean duration of hospital stay was 1.8 days in the oral lansoprazole group and 3.9 days in the intravenous esomeprazole group (p > 0.01. Conclusion Patients receiving oral proton pump inhibitor have a shorter hospital stay. There is no evidence of a difference in clinical outcomes between oral and intravenous PPI treatment. However, the study was not powered to prove equivalence or non-inferiority. Future studies are still needed. Trial registration NCT01123031

  8. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors

    OpenAIRE

    Rostom, Alaa

    2009-01-01

    Alaa Rostom1, Katherine Muir2, Catherine Dube3, Angel Lanas4, Emilie Jolicoeur3, Peter Tugwell31University of Calgary, Calgary, Alberta, Canada; 2University of Toronto, Toronto, Ontario, Canada; 3University of Ottawa, Ottawa, Ontario, Canada; 4University Hospital Lozano Blesa, Instituto Aragones de Ciencias de la Salud, Zaragoza, SpainBackground: Traditional NSAIDs (tNSAIDs) and COX-2 inhibitors (COX-2s) are important agents for the treatment of a variety or arthritic conditions. The purpose ...

  9. LOW OZONE-DEPLETING HALOCARBONS AS TOTAL-FLOOD AGENTS: VOLUME 2. LABORATORY-SCALE FIRE SUPPRESSION AND EXPLOSION PREVENTION TESTING

    Science.gov (United States)

    The report gives results from (1) flame suppression testing of potential Halon-1301 (CF3Br) replacement chemicals in a laboratory cup burner using n-heptane fuel and (2) explosion prevention (inertion) testing in a small-scale explosion sphere using propane and methane as fuels. ...

  10. Pretreatment with Pancaspase Inhibitor (Z-VAD-FMK Delays but Does Not Prevent Intraperitoneal Heat-Killed Group B Streptococcus-Induced Preterm Delivery in a Pregnant Mouse Model

    Directory of Open Access Journals (Sweden)

    Ozlem Equils

    2009-01-01

    Full Text Available Caspases and apoptosis are thought to play a role in infection-associated preterm-delivery. We have shown that in vitro treatment with pancaspase inhibitor Z-VAD-FMK protects trophoblasts from microbial antigen-induced apoptosis. Objective. To examine whether in vivo administration of Z-VAD-FMK would prevent infection-induced preterm-delivery. Methods. We injected 14.5 day-pregnant-mice with heat-killed group B streptococcus (HK-GBS. Apoptosis within placentas and membranes was assessed by TUNEL staining. Calpain expression and caspase-3 activation were assessed by immunohistochemistry. Preterm-delivery was defined as expulsion of a fetus within 48 hours after injection. Results. Intrauterine (i.u. or intraperitoneal (i.p. HK-GBS injection led to preterm-delivery and induced apoptosis in placentas and membranes at 14 hours. The expression of calpain, a caspase-independent inducer of apoptosis, was increased in placenta. Treatment with the specific caspase inhibitor Z-VAD-FMK (i.p. prior to HK-GBS (i.p. delayed but did not prevent preterm-delivery. Conclusion. Caspase-dependent apoptosis appears to play a role in the timing but not the occurrence of GBS-induced preterm delivery in the mouse.

  11. METHODS OF TREATING OR PREVENTING DEMYELINATION USING THROMBIN INHIBITORS AND METHODS OF DETECTING DEMYELINATION USING NEUROFASCIN 155 | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    Researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (“NICHD”), seek CRADA partner or collaboration for development of agents to treat multiple sclerosis or other conditions associated with myelin remodeling by administering an agent that inhibits cleavage of Neurofascin 155 or Caspr1. The agent could be a thrombin inhibitor, an agent that inhibits thrombin expression, an anti-thrombin antibody that specifically inhibits thrombin mediated cleavage of Neurofascin 155, a mutated version or fragment of Neurofascin 155 or Caspr1, or antibodies to Neurofascin 155 or Caspr1.

  12. Application of poly(aspartic acid-citric acid copolymer compound inhibitor as an effective and environmental agent against calcium phosphate in cooling water systems

    Directory of Open Access Journals (Sweden)

    Yu-ling Zhang

    2016-12-01

    Full Text Available Poly(aspartic acid-citric acid copolymer (PAC is a new product of poly(carboxylic acid scale inhibitor. The study aims to develop a “green” water treatment agent for calcium phosphate scale. The article compares the efficiency of three polymeric antiscalants, poly(aspartic acid-citric acid copolymer (PAC, polymaleic acid (HPMA and a compound inhibitor (PAC-HPMA, for calcium phosphate scale prevention under varying experimental conditions. Inhibitor concentration, calcium concentration, system pH, temperature and experimental time were varied to determine their influences on inhibitor performance by the static scale inhibition method. The copolymer (PAC was characterized by FTIR, 1H NMR and 13C NMR. The compound inhibitor was applied in the actual circulating cooling water system. An atomic force microscope (AFM, X-ray powder diffraction (XRD and a scale formation process analysis were used to explore the scale inhibition mechanism. The results showed that scale inhibition rates of PAC, HPMA and PAC-HPMA against Ca3(PO42 were, respectively, about 23%, 41.5% and 63% when the dosage was 8 mg/L in the experiment. The compound inhibitor showed the better inhibition performance than the above two kinds of monomers. Under the actual working conditions, the inhibition rate of compound inhibitor was close to 100% and completely met the actual application requirements of scale inhibitor in circulating cooling water systems. The main inhibition mechanism was the decomposition-chelation dispersion effect. The compound inhibitor can be used as an efficient “green” scale inhibitor for calcium phosphate.

  13. Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates.

    Science.gov (United States)

    Hobbs, Charlotte V; Dixit, Saurabh; Penzak, Scott R; Sahu, Tejram; Orr-Gonzalez, Sachy; Lambert, Lynn; Zeleski, Katie; Chen, Jingyang; Neal, Jillian; Borkowsky, William; Wu, Yimin; Duffy, Patrick E

    2014-01-01

    Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.

  14. Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates.

    Directory of Open Access Journals (Sweden)

    Charlotte V Hobbs

    Full Text Available Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.

  15. Symptomatic benign prostatic hyperplasia: the role of 5-alpha-reductase inhibitors in the prevention of acute urinary retention and surgical therapy

    Directory of Open Access Journals (Sweden)

    Norma Marigliano

    2012-01-01

    Full Text Available Benign prostatic hyperplasia (BPH is a disease that affects over 50% of males aged 50 years or older. In men aged >80 years, the incidence is 90%. BPH occurs in 9-25% of males aged 40 to 79 years. Fifty percent of patients with BPH are symptomatic. The symptoms include reduced urinary flow, nocturia, defective bladder emptying, urinary hesitancy, and dysuria. Disease progression can be associated with acute urinary retention (AUR. Prostatic obstruction includes mechanical and dynamic components, the latter mediated by alpha-muscarinic receptors. Treatment with alpha-1-blockers (alfuzosin, doxazosin, tamsulosin, and terazosin leads to rapid amelioration of symptoms and urinary flow, usually within one or two weeks. The 5-alpha reductase inhibitors (5-ARIs are “disease-modifying drugs.” They control the growth of the prostate by blocking the conversion of testosterone into dihydrotestosterone (DHT. Finasteride is a 5–ARI that is selective for type 2 receptors. Dutasteride is a powerful inhibitor of both 5- alpha reductase isoforms (type 1 and 2 and produces more complete suppression of DHT synthesis than finasteride. Dutasteride also has a much longer half-life than finasteride (five weeks versus five to six hours. The authors review the results of clinical trials involving finasteride and dutasteride, with and without alpha-1-blockers, highlighting the important role of dutasteride in improving acute urinary retention and eliminating the need for surgical therapy.

  16. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB).

    Science.gov (United States)

    Jatoi, Aminah; Rowland, Kendrith; Sloan, Jeff A; Gross, Howard M; Fishkin, Paul A; Kahanic, Stephen P; Novotny, Paul J; Schaefer, Paul L; Johnson, David B; Tschetter, Loren K; Loprinzi, Charles L

    2008-08-15

    Epidermal growth factor receptor (EGFR) inhibitors are effective cancer therapies, but they are reported to cause a rash in >50% of patients. In the current study, the authors examined the use of tetracycline for rash prevention. This placebo-controlled, double-blinded trial enrolled patients who were starting cancer treatment with an EGFR inhibitor. Patients could not have had a rash at the time of enrollment. All patients were randomly assigned to receive either tetracycline at a dose of 500 mg orally twice a day for 28 days versus a placebo. Patients were monitored for rash (through monthly physician assessment and weekly patient-reported questionnaires), quality of life (using the SKINDEX-16, a skin-specific quality of life index), and adverse events. Monitoring occurred during the 4-week intervention and then for an additional 4 weeks. The primary objective of the current study was to compare the incidence of rash between the study arms, and the enrollment of 30 patients per arm provided a 90% probability of detecting a 40% difference in incidence with a P value of .05 (2-sided). A total of 61 evaluable patients were enrolled. The 2 treatment arms were well balanced with regard to baseline characteristics, dropout rates, and rates of discontinuation of the EGFR inhibitor. The incidence of rash was found to be comparable across treatment arms. Physicians reported that 16 patients treated with tetracycline (70%) and 22 patients treated with placebo (76%) developed a rash (P = .61). Tetracycline appears to have lessened the rash severity, although the high dropout rates invite caution when interpreting these findings. By Week 4, physician-reported grade 2 rash (using the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]) occurred in 17% of tetracycline-treated patients (n = 4 patients) and in 55% of placebo-exposed patients (n = 16 patients) (P = .04). Patients treated with tetracycline reported better scores, as per the

  17. Tetracycline to Prevent Epidermal Growth Factor Receptor Inhibitor-Induced Skin Rashes: Results of a Placebo-Controlled Trial from the North Central Cancer Treatment Group (N03CB)1

    Science.gov (United States)

    Jatoi, Aminah; Rowland, Kendrith; Sloan, Jeff A.; Gross, Howard M.; Fishkin, Paul A.; Kahanic, Stephen P.; Novotny, Paul J.; Schaefer, Paul L.; Johnson, David B.; Tschetter, Loren K.; Loprinzi, Charles L.

    2014-01-01

    PURPOSE Epidermal growth factor receptor inhibitors are effective cancer therapies, but they cause a rash in greater than 50% of patients. This study tested tetracycline for rash prevention. METHODS This placebo-controlled, double-blinded trial enrolled patients who were starting cancer treatment with an epidermal growth factor receptor inhibitor. Patients could not have had a rash at enrollment. All were randomly assigned to either tetracycline 500 milligrams orally twice a day for 28 days versus a placebo. Patients were monitored for rash (monthly physician assessment and weekly patient-reported questionnaires), quality of life (SKINDEX-16), and adverse events. Monitoring occurred during the 4-week intervention and then for an additional 4 weeks. The primary objective was to compare the incidence of rash between study arms, and 30 patients per arm provided a 90% probability of detecting a 40% difference in incidence with a p-value of 0.05 (2-sided). RESULTS Sixty-one evaluable patients were enrolled, and arms were well balanced on baseline characteristics, rates of drop out, and rates of discontinuation of the epidermal growth factor receptor inhibitor. Rash incidence was comparable across arms. Physicians reported that 16 tetracycline-treated patients (70%) and 22 placebo-exposed patients (76%) developed a rash (p=0.61). Tetracycline appears to have lessened rash severity, although high drop out rates invite caution in interpreting findings. By week 4, physician-reported grade 2 rash occurred in 17% of tetracycline-treated patients (n=4) and in 55% of placebo-exposed patients (n=16); (p=0.04). Tetracycline-treated patients reported better scores, as per the SKINDEX-16, on certain quality of life parameters, such as skin burning or stinging, skin irritation, and being bothered by a persistence/recurrence of a skin condition. Adverse events were comparable across arms. CONCLUSION Tetracycline did not prevent epidermal growth factor receptor inhibitor

  18. [ALK inhibitor].

    Science.gov (United States)

    Mano, Hiroyuki

    2011-01-01

    While lung cancer is the leading cause of cancer deaths worldwide, the molecular mechanism underlying its carcinogenesis is mainly unknown. We have discovered a small, fusion-type tyrosine kinase EML4-ALK that is generated through a tiny inversion within the short arm of human chromosome 2. Transgenic mice expressing EML4-ALK in lung developed hundreds of lung cancer nodules soon after birth, but such nodules were readily eradicated upon treatment with an ALK inhibitor. Clinical trials for EML4-ALK-positive lung cancer with an ALK inhibitor is ongoing, with its interim results being highly promising.

  19. Effects of a secondary prevention combination therapy with an aspirin, an ACE inhibitor and a statin on 1-year mortality of patients with acute myocardial infarction treated with a beta-blocker. Support for a polypill approach.

    Science.gov (United States)

    Zeymer, Uwe; Jünger, Claus; Zahn, Ralf; Bauer, Timm; Bestehorn, Kurt; Senges, Jochen; Gitt, Anselm

    2011-08-01

    Large randomized clinical trials have shown the efficacy of aspirin, ACE (angiotensin converting enzyme) inhibitors and statins as secondary prevention measures in patients after an acute coronary syndrome with and without ST elevations. Therefore we aimed to determine the effect of a combination therapy with these three drugs on 1-year mortality after acute myocardial infarction (AMI). We prospectively followed 9998 survivors of acute myocardial infarction treated with a beta-blocker for 1 year. Patients were divided into three groups according to their therapy with aspirin, ACE inhibitors and statins: 3 drugs, 2 drugs or 0-1 drug. The majority of patients (n = 6260, 62.6%) were treated with 3 drugs, 2986 (29.9%) with 2 drugs and 752 (7.5%) with 0-1 drug. In the univariate analysis 1-year mortality was 4.9%, 9.7% and 13.6%, respectively. After adjusting for confounding factors in the propensity score analysis the odds ratios for 1-year mortality were significantly increased with 0-1 drug (odds ratio 1.67, 95% CI 1.24-2.27) and with 2 drugs (odds ratio 1.54, 95% CI 1.26-1.87) in comparison with the group treated with all 3 drugs. However, in the ACOS registry the treatment was left to the discretion of the physician. This could lead to a selection bias, which cannot be fully eliminated by using multiple regression analysis. A combination therapy with aspirin, an ACE inhibitor and a statin reduces 1-year mortality in patients after AMI. Therefore a polypill approach with these three agents should be considered to increase drug compliance and reduce mortality after acute myocardial infarction.

  20. [Progress on matrix metalloproteinase inhibitors].

    Science.gov (United States)

    Lingling, Jia; Qianbing, Wan

    2017-04-01

    Continuing advances in dentin bonding technology and adhesives revolutionized bonding of resin-based composite restorations. However, hybrid layers created by contemporary dentin adhesives present imperfect durability, and degradation of collagen matrix by endogenous enzymes is a significant factor causing destruction of hybrid layers. Bond durability can be improved by using enzyme inhibitors to prevent collagen degradation and to preserve integrity of collagen matrix. This review summarizes progress on matrix metalloproteinase inhibitors (including chlorhexidine, ethylenediaminetetraacetic acid, quaternary ammonium salt, tetracycline and its derivatives, hydroxamic acid inhibitors, bisphosphonate derivative, and cross-linking agents) and suggests prospects for these compounds.

  1. Mapping wildland-urban interfaces at large scales integrating housing density and vegetation aggregation for fire prevention in the South of France

    OpenAIRE

    Lampin-Maillet, C.; Jappiot, M.; Long, M; Bouillon, C.; Morge, D.; Ferrier, J.P.

    2009-01-01

    Every year, more than 50,000 wildland fires affect about 500,000 ha of vegetation in southern European countries, particularly in wildland-urban interfaces (WUI). This paper presents a method to characterize and map WUIs at large scales and over large areas for wildland fire prevention in the South of France. Based on the combination of four types of building configuration and three classes of vegetation structure, 12 interface types were classified. Through spatial analysis, fire ignition de...

  2. Proteins in Soy Might Have a Higher Role in Cancer Prevention than Previously Expected: Soybean Protein Fractions Are More Effective MMP-9 Inhibitors Than Non-Protein Fractions, Even in Cooked Seeds.

    Science.gov (United States)

    Lima, Ana; Oliveira, Jennifer; Saúde, Filipe; Mota, Joana; Ferreira, Ricardo Boavida

    2017-02-27

    The search for anticancer MMP-9 inhibitors (MMPIs) in food products has become a major goal for research. MMPIs in soy have been related only to saponins and isoflavones, but recently, low specific protein fractions in soybeans were shown to reduce MMP-9 activity as well. The present work aimed at comparing the MMPI potential of protein fractions (P) and non-protein fractions (NP) isolated from soybean seeds, before and after soaking and cooking, mimicking dietary exposures. Reverse and substrate zymography, as well as a fluoregenic DQ gelatin assay were used to evaluate MMP-9 activities. Colon cancer cell migration and proliferation was also tested in HT29 cells. Regarding MMP-9 inhibition, proteins in soy presented IC50 values 100 times lower than non-protein extracts, and remained active after cooking, suggesting that proteins may be more effective MMP-9 inhibitors than non-protein compounds. Using the determined IC50 concentrations, NP fractions were able to induce higher inhibitions of HT29 cell migration and proliferation, but not through MMP-9 inhibition, whilst protein fractions were shown to specifically inhibit MMP-9 activity. Overall, our results show that protein fractions in soybeans might have a higher role in soy-related cancer prevention as MMPIs than previously expected. Being nontoxic and active at lower concentrations, the discovery of these heat-resistant specific MMPI proteins in soy can be of significant importance for cancer preventive diets, particularly considering the increasing use of soy proteins in food products and the controversy around isoflavones amongst consumers.

  3. Proteins in Soy Might Have a Higher Role in Cancer Prevention than Previously Expected: Soybean Protein Fractions Are More Effective MMP-9 Inhibitors Than Non-Protein Fractions, Even in Cooked Seeds

    Directory of Open Access Journals (Sweden)

    Ana Lima

    2017-02-01

    Full Text Available The search for anticancer MMP-9 inhibitors (MMPIs in food products has become a major goal for research. MMPIs in soy have been related only to saponins and isoflavones, but recently, low specific protein fractions in soybeans were shown to reduce MMP-9 activity as well. The present work aimed at comparing the MMPI potential of protein fractions (P and non-protein fractions (NP isolated from soybean seeds, before and after soaking and cooking, mimicking dietary exposures. Reverse and substrate zymography, as well as a fluoregenic DQ gelatin assay were used to evaluate MMP-9 activities. Colon cancer cell migration and proliferation was also tested in HT29 cells. Regarding MMP-9 inhibition, proteins in soy presented IC50 values 100 times lower than non-protein extracts, and remained active after cooking, suggesting that proteins may be more effective MMP-9 inhibitors than non-protein compounds. Using the determined IC50 concentrations, NP fractions were able to induce higher inhibitions of HT29 cell migration and proliferation, but not through MMP-9 inhibition, whilst protein fractions were shown to specifically inhibit MMP-9 activity. Overall, our results show that protein fractions in soybeans might have a higher role in soy-related cancer prevention as MMPIs than previously expected. Being nontoxic and active at lower concentrations, the discovery of these heat-resistant specific MMPI proteins in soy can be of significant importance for cancer preventive diets, particularly considering the increasing use of soy proteins in food products and the controversy around isoflavones amongst consumers.

  4. Angiogenesis Inhibitors

    Science.gov (United States)

    ... blood vessels “feed” growing tumors with oxygen and nutrients , allowing the cancer cells to invade nearby tissue , to move throughout ... any angiogenesis inhibitors currently being used to treat cancer in humans? Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to ...

  5. A qualitative assessment of participation in a rapid scale-up, diagonally-integrated MDG-related disease prevention campaign in Rural Kenya.

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    Timothy De Ver Dye

    Full Text Available BACKGROUND: Many countries face severe scale-up barriers toward achievement of MDGs. We ascertained motivational and experiential dimensions of participation in a novel, rapid, "diagonal" Integrated Prevention Campaign (IPC in rural Kenya that provided prevention goods and services to 47,000 people within one week, aimed at rapidly moving the region toward MDG achievement. Specifically, the IPC provided interventions and commodities targeting disease burden reduction in HIV/AIDS, malaria, and water-borne illness. METHODS: Qualitative in-depth interviews (IDI were conducted with 34 people (18 living with HIV/AIDS and 16 not HIV-infected randomly selected from IPC attendees consenting to participate. Interviews were examined for themes and patterns to elucidate participant experience and motivation with IPC. FINDINGS: Participants report being primarily motivated to attend IPC to learn of their HIV status (through voluntary counseling and testing, and with receipt of prevention commodities (bednets, water filters, and condoms providing further incentive. Participants reported that they were satisfied with the IPC experience and offered suggestions to improve future campaigns. INTERPRETATION: Learning their HIV status motivated participants along with the incentive of a wider set of commodities that were rapidly deployed through IPC in this challenging region. The critical role of wanting to know their HIV status combined with commodity incentives may offer a new model for rapid scaled-up of prevention strategies that are wider in scope in rural Africa.

  6. Prevention of Diet-Induced Metabolic Dysregulation, Inflammation, and Atherosclerosis in Ldlr(-/-) Mice by Treatment With the ATP-Citrate Lyase Inhibitor Bempedoic Acid.

    Science.gov (United States)

    Samsoondar, Joshua P; Burke, Amy C; Sutherland, Brian G; Telford, Dawn E; Sawyez, Cynthia G; Edwards, Jane Y; Pinkosky, Stephen L; Newton, Roger S; Huff, Murray W

    2017-04-01

    Bempedoic acid (ETC-1002, 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel low-density lipoprotein cholesterol-lowering compound. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and through activation of AMP-activated protein kinase. In this study, we tested the hypothesis that bempedoic acid would prevent diet-induced metabolic dysregulation, inflammation, and atherosclerosis. APPROACH AND RESULTS: Ldlr(-/-) mice were fed a high-fat, high-cholesterol diet (42% kcal fat, 0.2% cholesterol) supplemented with bempedoic acid at 0, 3, 10 and 30 mg/kg body weight/day. Treatment for 12 weeks dose-dependently attenuated diet-induced hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity. Compared to high-fat, high-cholesterol alone, the addition of bempedoic acid decreased plasma triglyceride (up to 64%) and cholesterol (up to 50%) concentrations, and improved glucose tolerance. Adiposity was significantly reduced with treatment. In liver, bempedoic acid prevented cholesterol and triglyceride accumulation, which was associated with increased fatty acid oxidation and reduced fatty acid synthesis. Hepatic gene expression analysis revealed that treatment significantly increased expression of genes involved in fatty acid oxidation while suppressing inflammatory gene expression. In full-length aorta, bempedoic acid markedly suppressed cholesteryl ester accumulation, attenuated the expression of proinflammatory M1 genes and attenuated the iNos/Arg1 ratio. Treatment robustly attenuated atherosclerotic lesion development in the aortic sinus by 44%, with beneficial changes in morphology, characteristic of earlier-stage lesions. Bempedoic acid effectively prevents plasma and tissue lipid elevations and attenuates the onset of inflammation, leading to the prevention of atherosclerotic lesion development in a mouse model of metabolic

  7. Preventive effect of dipeptidyl peptidase-4 inhibitor on atherosclerosis is mainly attributable to incretin's actions in nondiabetic and diabetic apolipoprotein E-null mice.

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    Michishige Terasaki

    Full Text Available AIM: Several recent reports have revealed that dipeptidyl peptidase (DPP-4 inhibitors have suppressive effects on atherosclerosis in apolipoprotein E-null (Apoe (-/- mice. It remains to be seen, however, whether this effect stems from increased levels of the two active incretins, glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP. METHODS: Nontreated Apoe (-/- mice, streptozotocin-induced diabetic Apoe (-/- mice, and db/db diabetic mice were administered the DPP-4 inhibitor vildagliptin in drinking water and co-infused with either saline, the GLP-1 receptor blocker, exendin(9-39, the GIP receptor blocker, (Pro(3GIP, or both via osmotic minipumps for 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages were determined. RESULTS: Vildagliptin increased plasma GLP-1 and GIP levels without affecting food intake, body weight, blood pressure, or plasma lipid profile in any of the animals tested, though it reduced HbA1c in the diabetic mice. Diabetic Apoe (-/- mice exhibited further-progressed atherosclerotic lesions and foam cell formation compared with nondiabetic counterparts. Nondiabetic and diabetic Apoe (-/- mice showed a comparable response to vildagliptin, namely, remarkable suppression of atherosclerotic lesions with macrophage accumulation and foam cell formation in peritoneal macrophages. Exendin(9-39 or (Pro(3GIP partially attenuated the vildagliptin-induced suppression of atherosclerosis. The two blockers in combination abolished the anti-atherosclerotic effect of vildagliptin in nondiabetic mice but only partly attenuated it in diabetic mice. Vildagliptin suppressed macrophage foam cell formation in nondiabetic and diabetic mice, and this suppressive effect was abolished by infusions with exendin(9-39+(Pro(3GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation. CONCLUSIONS: Vildagliptin

  8. Rutaecarpine and evodiamine selected as β1-AR inhibitor candidates using β1-AR/CMC-offline-UPLC/MS prevent cardiac ischemia-reperfusion injury via energy modulation.

    Science.gov (United States)

    Xue, Hui; Cheng, Yongjie; Wang, Xin; Yue, Yuan; Zhang, Weifang; Li, Xiaoni

    2015-11-10

    In the present study, an offline analytical method combining β1-adrenergic receptor/cell membrane chromatography (β1-AR/CMC) with ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) was used for direct recognition, separation, and identification of β1-AR inhibitors from Evodia rutaecarpa (Juss) Benth, by which rutaecarpine and evodiamine were screened and identified as potential β1-AR antagonists and the β1-AR inhibition activity of them was confirmed by downregulation of cAMP and PKA in vitro test. In addition, the results of in vivo pharmacological trials revealed that rutaecarpine (1.1mg/ml) and evodiamine (1.1mg/ml) attenuated myocardial infarct size injured by myocardial ischemia/reperfusion, improved metabolism disorders between fatty acid and glucose, increased the content of ATP, Ca(2+)-ATPase activity and reduced the content of peroxisome proliferator-activated receptor α (PPARα) protein level. Thus, the β1-AR/CMC-offline-UPLC/MS method developed in this study could be used as an effective alternative for screening β1-AR binding bioactive components in traditional Chinese medicines and the bioactive components could be used to remedy cardiac diseases via energy modulation. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Pretreatment with a γ-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Toshiki Okubo

    2016-10-01

    Full Text Available Neural stem/progenitor cells (NS/PCs derived from human induced pluripotent stem cells (hiPSCs are considered to be a promising cell source for cell-based interventions that target CNS disorders. We previously reported that transplanting certain hiPSC-NS/PCs in the spinal cord results in tumor-like overgrowth of hiPSC-NS/PCs and subsequent deterioration of motor function. Remnant immature cells should be removed or induced into more mature cell types to avoid adverse effects of hiPSC-NS/PC transplantation. Because Notch signaling plays a role in maintaining NS/PCs, we evaluated the effects of γ-secretase inhibitor (GSI and found that pretreating hiPSC-NS/PCs with GSI promoted neuronal differentiation and maturation in vitro, and GSI pretreatment also reduced the overgrowth of transplanted hiPSC-NS/PCs and inhibited the deterioration of motor function in vivo. These results indicate that pretreatment with hiPSC-NS/PCs decreases the proliferative capacity of transplanted hiPSC-NS/PCs, triggers neuronal commitment, and improves the safety of hiPSC-based approaches in regenerative medicine.

  10. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor (DSM421) with improved drug-like properties for treatment and prevention of malaria

    Science.gov (United States)

    Phillips, Margaret A.; White, Karen L.; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; Mazouni, Farah El; Marsh, Kennan; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N; Marfurt, Jutta; Shackleford, David M.; Chiu, Francis C.K.; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N.; Waterson, David; Palmer, Michael J.; Rathod, Pradipsinh K.; Charman, Susan A.

    2016-01-01

    The emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclinical development candidate. PMID:27641613

  11. Components of an effective large scale program for the prevention of inherited hemoglobin disorders; the paradigm of Greece

    Directory of Open Access Journals (Sweden)

    D. Loukopoulos

    2012-12-01

    Full Text Available Large scale prevention programs for Thalassemia major or Sickle cell disease have already been set up in several places with high frequency of the deleterious genes. The Greek health authorities realized the magnitude of the problem and allowed the creation of a National Thalassemia Center in 1972. The incidence of thalassemia in Greece varies from 1-2 per cent up to 15%, the mean being around 8 per cent. With an annual number of births around 100,000, if no prevention measures are taken, the expected yearly number of newborns with thalassemia major in Greece should be of the order of 100-120. To these one should add a few decades of sickle cell patients, homozygotes or compound HbS/β-thalassemia heterozygotes. The total number of patients with thalassemia major now surviving is estimated at 4,000 plus another 600-800 patients with sickle cell disease. The National Thalassemia Center Center defined a network of peripheral Thalassemia Units in the major regional hospitals of the country, let them provide free carrier identification to couples requesting the test. When both partners were identified as carriers, they were given preliminary information locally and were referred to the Central Laboratory in Athens for further genetic counselling and, if so decided, prenatal diagnosis. Prenatal diagnosis was provided initially by fetoscopy and fetal blood biosynthesis; this approach was soon replaced by chorionic villi sampling and molecular techniques. The number of prenatal diagnoses carried out yearly over the last decade appears to cover the needs; the number of positive diagnoses is very close to the expected 25%, which also excludes overdiagnosis. The overall evaluation of the the program is reflected in the number of infants who were admitted to the pediatric clinics of the country in need of transfusion over the years the program was functioning. In fact, over the past years this number has steadily decreased to approximately 10 missed

  12. Prevention of peridural fibrosis using a cyclooxygenase-2 inhibitor (nonsteroidal anti-inflammatory drug) soaked in absorbable gelatin sponge: an experimental comparative animal model.

    Science.gov (United States)

    Sae-Jung, Surachai; Jirarattanaphochai, Kitti

    2013-07-15

    Experimental study. To evaluate the efficacy and safety of peridural parecoxib-soaked absorbable gelatin sponge, and cellulose membrane on peridural fibrosis prevention in an animal model. Postoperative peridural fibrosis is one of the causes of failed back surgery syndrome. Nonsteroidal anti-inflammatory drugs inhibit the inflammatory response, while an absorbable gelatin sponge or cellulose membrane interposes between the dura and the paraspinal muscle to staunch the surgical bleeding. These mechanisms may prevent peridural fibrosis. Forty L5-L6 laminectomized adult Sprague-Dawley rats were randomly allocated into 4 groups. The high parecoxib group received 6 mg of parecoxib soaked into an absorbable gelatin sponge placed over the dura. The low parecoxib group was given 2 mg of parecoxib soaked into an absorbable gelatin sponge. The dura in the cellulose group was covered with a cellulose membrane, while the control group received normal saline drip before surgical wound closure. All rats were killed at 6 weeks for histopathological assessment. The fibroblast density, inflammatory cell density, fibrous adherence, and adverse events were quantified. The obtained results were analyzed statistically. The respective mean fibroblast density in the high parecoxib, low parecoxib, cellulose, and control groups was 217.77 ± 51.76, 317.51 ± 126.92, 321.80 ± 90.94, and 328.48 ± 73.41 cells/mm², while the respective mean inflammatory cell density was 539.65 ± 236.52, 910.17 ± 242.59, 1011.84 ± 239.30, and 1261.78 ± 319.68 cells/mm². The mean fibroblast and inflammatory cell densities of the high parecoxib group were significantly lower than the control. The high parecoxib group also showed statistically less fibrous adherence than low parecoxib, cellulose, and control groups. The high-dose parecoxib-soaked absorbable gelatin sponge can prevent peridural fibrosis without complications. The low-dose parecoxib and cellulose membrane provided no significant benefit vis

  13. Effect of the temperature and the CO2 concentration on the behaviour of the citric acid as a scale inhibitor of CaCO3

    Science.gov (United States)

    Blanco, K.; Aponte, H.; Vera, E.

    2017-12-01

    For all Industrial sector is important to extend the useful life of the materials that they use in their process, the scales of CaCO3 are common in situation where fluids are handled with high concentration of ions and besides this temperatures and CO2 concentration dissolved, that scale generates large annual losses because there is a reduction in the process efficiency or corrosion damage under deposit, among other. In order to find new alternatives to this problem, the citric acid was evaluated as scale of calcium carbonate inhibition in critical condition of temperature and concentration of CO2 dissolved. Once the results are obtained it was carried out the statistical evaluation in order to generate an equation that allow to see that behaviour, giving as result, a good efficiency of inhibition to the conditions evaluated the scales of products obtained were characterized through scanning electron microscopy.

  14. The Efficacy of the Quorum Sensing Inhibitor FS8 and Tigecycline in Preventing Prosthesis Biofilm in an Animal Model of Staphylococcal Infection

    Directory of Open Access Journals (Sweden)

    Andrea Giacometti

    2013-08-01

    Full Text Available We investigated the efficacy of tigecycline and FS8, alone or combined, in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2 x 107 colony-forming units of Staphylococcus aureus, strain Smith diffuse. The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis, and three contaminated groups that received: (i intraperitoneal tigecycline, (ii FS8-soaked graft, and (iii tigecycline plus FS8-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro binding-study was performed to quantify the how much FS8 was coated to the surface of the prosthesis. Tigecycline, combined with FS8, against the adherent bacteria showed MICs (2.00 mg/L and MBCs (4.00 mg/L four-fold lower with respect to tigecycline alone in in vitro studies. The rat groups treated with tigecycline showed the lowest bacterial numbers (4.4 x 104 ± 1.2 x 104 CFU/mL. The FS8-treated group showed a good activity and significant differences compared to control group with bacterial numbers of 6.8 x 104 ± 2.0 x 104 CFU/mL. A stronger inhibition of bacterial growth was observed in rats treated with a combined FS8 and tigecycline therapy than in those that were singly treated with bacterial numbers of 101 CFU/mL graft. In conclusion, the ability to affect biofilm formation as well, its property to be an antibiotic enhancer suggests FS8 as alternative or additional agent to use in conjunction with conventional antimicrobial for prevention of staphylococcal biofilm related infection.

  15. Development and validation of the Italian version of the Mobile Application Rating Scale and its generalisability to apps targeting primary prevention.

    Science.gov (United States)

    Domnich, Alexander; Arata, Lucia; Amicizia, Daniela; Signori, Alessio; Patrick, Bernard; Stoyanov, Stoyan; Hides, Leanne; Gasparini, Roberto; Panatto, Donatella

    2016-07-07

    A growing body of literature affirms the usefulness of mobile technologies, including mobile applications (apps), in the primary prevention field. The quality of health apps, which today number in the thousands, is a crucial parameter, as it may affect health-related decision-making and outcomes among app end-users. The mobile application rating scale (MARS) has recently been developed to evaluate the quality of such apps, and has shown good psychometric properties. Since there is no standardised tool for assessing the apps available in Italian app stores, the present study developed and validated an Italian version of MARS in apps targeting primary prevention. The original 23-item version of the MARS assesses mobile app quality in four objective quality dimensions (engagement, functionality, aesthetics, information) and one subjective dimension. Validation of this tool involved several steps; the universalist approach to achieving equivalence was adopted. Following two backward translations, a reconciled Italian version of MARS was produced and compared with the original scale. On the basis of sample size estimation, 48 apps from three major app stores were downloaded; the first 5 were used for piloting, while the remaining 43 were used in the main study in order to assess the psychometric properties of the scale. The apps were assessed by two raters, each working independently. The psychometric properties of the final version of the scale was assessed including the inter-rater reliability, internal consistency, convergent, divergent and concurrent validities. The intralingual equivalence of the Italian version of the MARS was confirmed by the authors of the original scale. A total of 43 apps targeting primary prevention were tested. The MARS displayed acceptable psychometric properties. The MARS total score showed an excellent level of both inter-rater agreement (intra-class correlation coefficient of .96) and internal consistency (Cronbach's α of .90 and .91

  16. The angiotensin converting enzyme inhibitor, captopril, prevents the hyperactivity and impulsivity of neurokinin-1 receptor gene 'knockout' mice: sex differences and implications for the treatment of attention deficit hyperactivity disorder.

    Science.gov (United States)

    Porter, Ashley J; Pillidge, Katharine; Grabowska, Ewelina M; Stanford, S Clare

    2015-04-01

    Mice lacking functional neurokinin-1 receptors (NK1R-/-) display behavioural abnormalities resembling attention deficit hyperactivity disorder (ADHD): locomotor hyperactivity, impulsivity and inattentiveness. The preferred ligand for NK1R, substance P, is metabolised by angiotensin converting enzyme (ACE), which forms part of the brain renin angiotensin system (BRAS). In view of evidence that the BRAS modulates locomotor activity and cognitive performance, we tested the effects of drugs that target the BRAS on these behaviours in NK1R-/- and wildtype mice. We first tested the effects of the ACE inhibitor, captopril, on locomotor activity. Because there are well-established sex differences in both ADHD and ACE activity, we compared the effects of captopril in both male and female mice. Locomotor hyperactivity was evident in male NK1R-/- mice, only, and this was abolished by treatment with captopril. By contrast, male wildtypes and females of both genotypes were unaffected by ACE inhibition. We then investigated the effects of angiotensin AT1 (losartan) and AT2 (PD 123319) receptor antagonists on the locomotor activity of male NK1R-/- and wildtype mice. Both antagonists increased the locomotor activity of NK1R-/- mice, but neither affected the wildtypes. Finally, we tested the effects of captopril on the performance of male NK1R-/- and wildtype mice in the 5-choice serial reaction-time task (5-CSRTT) and found that ACE inhibition prevented the impulsivity of NK1R-/- mice. These results indicate that certain behaviours, disrupted in ADHD, are influenced by an interaction between the BRAS and NK1R, and suggest that ACE inhibitors could provide a novel treatment for this disorder. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  17. ACE inhibitors

    Science.gov (United States)

    ... 23. Ridker PM, Libby P, Buring JE. Risk markers and the primary prevention of cardiovascular disease. In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ed. ...

  18. The relationship between social, policy and physical venue features and social cohesion on condom use for pregnancy prevention among sex workers: a safer indoor work environment scale.

    Science.gov (United States)

    Duff, Putu; Shoveller, Jean; Dobrer, Sabina; Ogilvie, Gina; Montaner, Julio; Chettiar, Jill; Shannon, Kate

    2015-07-01

    This study aims to report on a newly developed Safer Indoor Work Environmental Scale that characterises the social, policy and physical features of indoor venues and social cohesion; and using this scale, longitudinally evaluate the association between these features on sex workers' (SWs') condom use for pregnancy prevention. Drawing on a prospective open cohort of female SWs working in indoor venues, a newly developed Safer Indoor Work Environment Scale was used to build six multivariable models with generalised estimating equations (GEE), to determine the independent effects of social, policy and physical venue-based features and social cohesion on condom use. Of 588 indoor SWs, 63.6% used condoms for pregnancy prevention in the last month. In multivariable GEE analysis, the following venue-based features were significantly correlated with barrier contraceptive use for pregnancy prevention: managerial practices and venue safety policies (adjusted OR (AOR)=1.09; 95% CI 1.01 to 1.17), access to sexual and reproductive health services/supplies (AOR=1.10; 95% CI 1.00 to 1.20), access to drug harm reduction (AOR=1.13; 95% CI 1.01 to 1.28) and social cohesion among workers (AOR=1.05; 95% CI 1.03 to 1.07). Access to security features was marginally associated with condom use (AOR=1.13; 95% CI 0.99 to 1.29). The findings of the current study highlight how work environment and social cohesion among SWs are related to improved condom use. Given global calls for the decriminalisation of sex work, and potential legislative reforms in Canada, this study points to the critical need for new institutional arrangements (eg, legal and regulatory frameworks; labour standards) to support safer sex workplaces. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α, prevents retinal ganglion cell loss in a rat model of glaucoma.

    Directory of Open Access Journals (Sweden)

    Miin Roh

    Full Text Available Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor-α (TNF-α as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF-α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death.Episcleral vein cauterization (EVC caused intraocular pressure (IOP to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH. Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs.Ocular hypertension (OHT triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF-α antagonists or suppressors of inflammation.

  20. Etanercept, a Widely Used Inhibitor of Tumor Necrosis Factor-α (TNF- α), Prevents Retinal Ganglion Cell Loss in a Rat Model of Glaucoma

    Science.gov (United States)

    Roh, Miin; Zhang, Yan; Murakami, Yusuke; Thanos, Aristomenis; Lee, Sung Chul; Vavvas, Demetrios G.; Benowitz, Larry I.; Miller, Joan W.

    2012-01-01

    Background Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC) axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor- α (TNF-α) as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF- α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death. Methodology/Principal Findings Episcleral vein cauterization (EVC) caused intraocular pressure (IOP) to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH). Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs. Conclusions/Significance Ocular hypertension (OHT) triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF- α antagonists or suppressors of inflammation. PMID:22802951

  1. Rapid implementation of an integrated large-scale HIV counseling and testing, malaria, and diarrhea prevention campaign in rural Kenya.

    Directory of Open Access Journals (Sweden)

    Eric Lugada

    Full Text Available BACKGROUND: Integrated disease prevention in low resource settings can increase coverage, equity and efficiency in controlling high burden infectious diseases. A public-private partnership with the Ministry of Health, CDC, Vestergaard Frandsen and CHF International implemented a one-week integrated multi-disease prevention campaign. METHOD: Residents of Lurambi, Western Kenya were eligible for participation. The aim was to offer services to at least 80% of those aged 15-49. 31 temporary sites in strategically dispersed locations offered: HIV counseling and testing, 60 male condoms, an insecticide-treated bednet, a household water filter for women or an individual filter for men, and for those testing positive, a 3-month supply of cotrimoxazole and referral for follow-up care and treatment. FINDINGS: Over 7 days, 47,311 people attended the campaign with a 96% uptake of the multi-disease preventive package. Of these, 99.7% were tested for HIV (87% in the target 15-49 age group; 80% had previously never tested. 4% of those tested were positive, 61% were women (5% of women and 3% of men, 6% had median CD4 counts of 541 cell/µL (IQR; 356, 754. 386 certified counselors attended to an average 17 participants per day, consistent with recommended national figures for mass campaigns. Among women, HIV infection varied by age, and was more likely with an ended marriage (e.g. widowed vs. never married, OR.3.91; 95% CI. 2.87-5.34, and lack of occupation. In men, quantitatively stronger relationships were found (e.g. widowed vs. never married, OR.7.0; 95% CI. 3.5-13.9. Always using condoms with a non-steady partner was more common among HIV-infected women participants who knew their status compared to those who did not (OR.5.4 95% CI. 2.3-12.8. CONCLUSION: Through integrated campaigns it is feasible to efficiently cover large proportions of eligible adults in rural underserved communities with multiple disease preventive services simultaneously achieving

  2. AS-2, a novel inhibitor of p53-dependent apoptosis, prevents apoptotic mitochondrial dysfunction in a transcription-independent manner and protects mice from a lethal dose of ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Morita, Akinori, E-mail: morita@tokushima-u.ac.jp [Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Ariyasu, Shinya [Center for Technologies against Cancer, Tokyo University of Science, Chiba 278-8510 (Japan); Wang, Bing [Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Asanuma, Tetsuo; Onoda, Takayoshi [Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Sawa, Akiko [Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510 (Japan); Tanaka, Kaoru [Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Takahashi, Ippei [Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553 (Japan); Togami, Shotaro [Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510 (Japan); Nenoi, Mitsuru [Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Inaba, Toshiya [Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553 (Japan); Aoki, Shin [Center for Technologies against Cancer, Tokyo University of Science, Chiba 278-8510 (Japan); Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510 (Japan)

    2014-08-08

    Highlights: • A bidentate HQ derivative, AS-2, suppresses p53-dependent apoptosis by DNA damage. • AS-2 does not significantly affect nuclear p53 response. • UV-excited blue emission of AS-2 clearly showed its extranuclear localization. • AS-2 prevents mitochondrial dysfunction despite the increase of mitochondrial p53. • AS-2 protects mice from a radiation dose that causes lethal hematopoietic syndrome. - Abstract: In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated mice because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53-inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53-dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription-dependent events than pifithrin-μ (PFTμ), an inhibitor of transcription-independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription-dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2. AS-2 also

  3. Evaluation of polymer efficiency on the inhibition of calcium carbonate scale in synthetic brines; Avaliacao da acao de polimeros sobre a inibicao de incrustacoes de carbonato de calcio em salmouras sinteticas

    Energy Technology Data Exchange (ETDEWEB)

    Freitas, Juliana M.; Rodrigues, Jessica S.; Loureiro, Tatiana S.; Lucas, Elizabete F.; Spinelli, Luciana S. [Universidade Federal do Rio de Janeiro, Instituto de Macromoleculas, Laboratorio de Macromoleculas e Coloides na Industria de Petroleo, RJ (Brazil)], e-mail: julianamatos@ima.ufrj.br

    2011-07-01

    The inorganic scale results in serious problems for oil production. This scale results from the incompatibility between the chemical compositions of formation water and injection, and the changes of thermodynamic system. These deposits consist mainly of calcium carbonate and barium sulfate. In order to prevent the formation of these deposits, the petroleum industry has made use of chemicals that act as scale inhibitors. The aim of this study was to test the ability of two types of polymeric inhibitors prevent the formation of calcium carbonate from brines of different compositions with high concentrations of calcium. The inhibitors were tested at varying concentrations and at fixed conditions of temperature, pH, pressure and time. The estimated effectiveness of each inhibitor was measured by complexometric titration. The inhibitor carboxylic acid-based (poly (maleic acid)) was more efficient at relatively low concentrations, which is important both economically and environmentally. (author)

  4. Systems pharmacology dissection of multi-scale mechanisms of action for herbal medicines in stroke treatment and prevention.

    Directory of Open Access Journals (Sweden)

    Jingxiao Zhang

    Full Text Available Annually, tens of millions of first-ever strokes occur in the world; however, currently there is lack of effective and widely applicable pharmacological treatments for stroke patients. Herbal medicines, characterized as multi-constituent, multi-target and multi-effect, have been acknowledged with conspicuous effects in treating stroke, and attract extensive interest of researchers although the mechanism of action is yet unclear. In this work, we introduce an innovative systems-pharmacology method that combines pharmacokinetic prescreening, target fishing and network analysis to decipher the mechanisms of action of 10 herbal medicines like Salvia miltiorrhizae, Ginkgo biloba and Ephedrae herba which are efficient in stroke treatment and prevention. Our systematic analysis results display that, in these anti-stroke herbal medicines, 168 out of 1285 constituents with the favorable pharmacokinetic profiles might be implicated in stroke therapy, and the systematic use of these compounds probably acts through multiple mechanisms to synergistically benefit patients with stroke, which can roughly be classified as preventing ischemic inflammatory response, scavenging free radicals and inhibiting neuronal apoptosis against ischemic cerebral damage, as well as exhibiting lipid-lowering, anti-diabetic, anti-thrombotic and antiplatelet effects to decrease recurrent strokes. Relying on systems biology-based analysis, we speculate that herbal medicines, being characterized as the classical combination therapies, might be not only engaged in multiple mechanisms of action to synergistically improve the stroke outcomes, but also might be participated in reducing the risk factors for recurrent strokes.

  5. Transitioning a Large Scale HIV/AIDS Prevention Program to Local Stakeholders: Findings from the Avahan Transition Evaluation.

    Directory of Open Access Journals (Sweden)

    Sara Bennett

    Full Text Available Between 2009-2013 the Bill and Melinda Gates Foundation transitioned its HIV/AIDS prevention initiative in India from being a stand-alone program outside of government, to being fully government funded and implemented. We present an independent prospective evaluation of the transition.The evaluation drew upon (1 a structured survey of transition readiness in a sample of 80 targeted HIV prevention programs prior to transition; (2 a structured survey assessing institutionalization of program features in a sample of 70 targeted intervention (TI programs, one year post-transition; and (3 case studies of 15 TI programs.Transition was conducted in 3 rounds. While the 2009 transition round was problematic, subsequent rounds were implemented more smoothly. In the 2011 and 2012 transition rounds, Avahan programs were well prepared for transition with the large majority of TI program staff trained for transition, high alignment with government clinical, financial and managerial norms, and strong government commitment to the program. One year post transition there were significant program changes, but these were largely perceived positively. Notable negative changes were: limited flexibility in program management, delays in funding, commodity stock outs, and community member perceptions of a narrowing in program focus. Service coverage outcomes were sustained at least six months post-transition.The study suggests that significant investments in transition preparation contributed to a smooth transition and sustained service coverage. Notwithstanding, there were substantive program changes post-transition. Five key lessons for transition design and implementation are identified.

  6. Invasive species information networks: Collaboration at multiple scales for prevention, early detection, and rapid response to invasive alien species

    Science.gov (United States)

    Simpson, Annie; Jarnevich, Catherine S.; Madsen, John; Westbrooks, Randy G.; Fournier, Christine; Mehrhoff, Les; Browne, Michael; Graham, Jim; Sellers, Elizabeth A.

    2009-01-01

    Accurate analysis of present distributions and effective modeling of future distributions of invasive alien species (IAS) are both highly dependent on the availability and accessibility of occurrence data and natural history information about the species. Invasive alien species monitoring and detection networks (such as the Invasive Plant Atlas of New England and the Invasive Plant Atlas of the MidSouth) generate occurrence data at local and regional levels within the United States, which are shared through the US National Institute of Invasive Species Science. The Inter-American Biodiversity Information Network's Invasives Information Network (I3N), facilitates cooperation on sharing invasive species occurrence data throughout the Western Hemisphere. The I3N and other national and regional networks expose their data globally via the Global Invasive Species Information Network (GISIN). International and interdisciplinary cooperation on data sharing strengthens cooperation on strategies and responses to invasions. However, limitations to effective collaboration among invasive species networks leading to successful early detection and rapid response to invasive species include: lack of interoperability; data accessibility; funding; and technical expertise. This paper proposes various solutions to these obstacles at different geographic levels and briefly describes success stories from the invasive species information networks mentioned above. Using biological informatics to facilitate global information sharing is especially critical in invasive species science, as research has shown that one of the best indicators of the invasiveness of a species is whether it has been invasive elsewhere. Data must also be shared across disciplines because natural history information (e.g. diet, predators, habitat requirements, etc.) about a species in its native range is vital for effective prevention, detection, and rapid response to an invasion. Finally, it has been our

  7. Clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors.

    Science.gov (United States)

    Rockwood, Kenneth; Howlett, Susan E; Hoffman, Deborah; Schindler, Rachel; Mitnitski, Arnold

    2017-10-01

    The clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement. Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog "no change" (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5-19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14-0.64). ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. ISRCTN26167328. Copyright © 2017. Published by Elsevier Inc.

  8. UISESS scale for staging and classifying clinical-epidemiological risk in type 2 diabetes mellitus and for establishing multidisciplinary preventive actions.

    Science.gov (United States)

    García de Alba, Javier E; Salcedo Rocha, Ana L; Colunga Rodríguez, Cecilia; González Barrera, Juan Antonio; Herrera Solís, Evangelina; Milke Najar, María Eugenia

    2005-07-01

    The goal of this study is the creation and use of a five-stage scale for the description of the health status of a type 2 diabetes mellitus patient population, as individuals and as a set. The scale, named UISESS, ranges from the pre-pathological to the sequelae stage, and can help orient multidisciplinary prevention actions. SETTING AND SAMPLING: A sample of nondiabetics (n = 404), together with a census of all type 2 diabetic patients (n = 2,702) over 30 years of age, were obtained from a family medicine clinic of the Mexican Federal Social Security System (IMSS) in Guadalajara, Mexico. A descriptive study in which the Natural History of the Disease and an epidemiological focus on risk were used to create the UISESS scale. Case histories of a total of 3,106 persons from a family practice clinic were used. The data was classified in five stages and three risk control levels were used for analysis. In the type 2 diabetic group, the average age was 57.6 years; 58% were women. In the nondiabetic group, the average age was 55.38 years; 63% were women. The UISESS scale was applied. A large majority (86%) of the studied type 2 diabetic patients were classified within unfavorable stages for controlling their illness, and 65% of the 3,106 people were at high or very high risk of increasing deterioration of their health status. The UISESS scale appears to be a useful tool to detect the distribution, evolution and control of type 2 diabetes in a population attended at the outpatient clinic of a family medicine unit, according to the Natural History of the Disease.

  9. Follow YOUR Heart: development of an evidence-based campaign empowering older women with HIV to participate in a large-scale cardiovascular disease prevention trial.

    Science.gov (United States)

    Zanni, Markella V; Fitch, Kathleen; Rivard, Corinne; Sanchez, Laura; Douglas, Pamela S; Grinspoon, Steven; Smeaton, Laura; Currier, Judith S; Looby, Sara E

    2017-03-01

    Women's under-representation in HIV and cardiovascular disease (CVD) research suggests a need for novel strategies to ensure robust representation of women in HIV-associated CVD research. To elicit perspectives on CVD research participation among a community-sample of women with or at risk for HIV, and to apply acquired insights toward the development of an evidence-based campaign empowering older women with HIV to participate in a large-scale CVD prevention trial. In a community-based setting, we surveyed 40 women with or at risk for HIV about factors which might facilitate or impede engagement in CVD research. We applied insights derived from these surveys into the development of the Follow YOUR Heart campaign, educating women about HIV-associated CVD and empowering them to learn more about a multi-site HIV-associated CVD prevention trial: REPRIEVE. Endorsed best methods for learning about a CVD research study included peer-to-peer communication (54%), provider communication (46%) and video-based communication (39%). Top endorsed non-monetary reasons for participating in research related to gaining information (63%) and helping others (47%). Top endorsed reasons for not participating related to lack of knowledge about studies (29%) and lack of request to participate (29%). Based on survey results, the REPRIEVE Follow YOUR Heart campaign was developed. Interwoven campaign components (print materials, video, web presence) offer provider-based information/knowledge, peer-to-peer communication, and empowerment to learn more. Campaign components reflect women's self-identified motivations for research participation - education and altruism. Investigation of factors influencing women's participation in HIV-associated CVD research may be usefully applied to develop evidence-based strategies for enhancing women's enrollment in disease-specific large-scale trials. If proven efficacious, such strategies may enhance conduct of large-scale research studies across disciplines.

  10. Integrating participatory community mobilization processes to improve dengue prevention: an eco-bio-social scaling up of local success in Machala, Ecuador.

    Science.gov (United States)

    Mitchell-Foster, Kendra; Ayala, Efraín Beltrán; Breilh, Jaime; Spiegel, Jerry; Wilches, Ana Arichabala; Leon, Tania Ordóñez; Delgado, Jefferson Adrian

    2015-02-01

    This project investigates the effectiveness and feasibility of scaling-up an eco-bio-social approach for implementing an integrated community-based approach for dengue prevention in comparison with existing insecticide-based and emerging biolarvicide-based programs in an endemic setting in Machala, Ecuador. An integrated intervention strategy (IIS) for dengue prevention (an elementary school-based dengue education program, and clean patio and safe container program) was implemented in 10 intervention clusters from November 2012 to November 2013 using a randomized controlled cluster trial design (20 clusters: 10 intervention, 10 control; 100 households per cluster with 1986 total households). Current existing dengue prevention programs served as the control treatment in comparison clusters. Pupa per person index (PPI) is used as the main outcome measure. Particular attention was paid to social mobilization and empowerment with IIS. Overall, IIS was successful in reducing PPI levels in intervention communities versus control clusters, with intervention clusters in the six paired clusters that followed the study design experiencing a greater reduction of PPI compared to controls (2.2 OR, 95% CI: 1.2 to 4.7). Analysis of individual cases demonstrates that consideration for contexualizing programs and strategies to local neighborhoods can be very effective in reducing PPI for dengue transmission risk reduction. In the rapidly evolving political climate for dengue control in Ecuador, integration of successful social mobilization and empowerment strategies with existing and emerging biolarvicide-based government dengue prevention and control programs is promising in reducing PPI and dengue transmission risk in southern coastal communities like Machala. However, more profound analysis of social determination of health is called for to assess sustainability prospects. © The author 2015. The World Health Organization has granted Oxford University Press permission for the

  11. Strengthening government management capacity to scale up HIV prevention programs through the use of Technical Support Units: lessons from Karnataka state, India

    Science.gov (United States)

    Sgaier, Sema K; Anthony, John; Bhattacharjee, Parinita; Baer, James; Malve, Vidyacharan; Bhalla, Aparajita; Hugar, Vijaykumar S

    2014-01-01

    ABSTRACT Scaling up HIV prevention programming among key populations (female sex workers and men who have sex with men) has been a central strategy of the Government of India. However, state governments have lacked the technical and managerial capacity to oversee and scale up interventions or to absorb donor-funded programs. In response, the national government contracted Technical Support Units (TSUs), teams with expertise from the private and nongovernmental sectors, to collaborate with and assist state governments. In 2008, a TSU was established in Karnataka, one of 6 Indian states with the highest HIV prevalence in the country and where monitoring showed that its prevention programs were reaching only 5% of key populations. The TSU provided support to the state in 5 key areas: assisting in strategic planning, rolling out a comprehensive monitoring and evaluation system, providing supportive supervision to intervention units, facilitating training, and assisting with information, education, and communication activities. This collaborative management model helped to increase capacity of the state, enabling it to take over funding and oversight of HIV prevention programs previously funded through donors. With the combined efforts of the TSU and the state government, the number of intervention units statewide increased from 40 to 126 between 2009 and 2013. Monthly contacts with female sex workers increased from 5% in 2008 to 88% in 2012, and with men who have sex with men, from 36% in 2009 to 81% in 2012. There were also increases in the proportion of both populations who visited HIV testing and counseling centers (from 3% to 47% among female sex workers and from 6% to 33% among men who have sex with men) and sexually transmitted infection clinics (from 4% to 75% among female sex workers and from 7% to 67% among men who have sex with men). Changes in sexual behaviors among key populations were also documented. For example, between 2008 and 2010, the proportion of

  12. Strip Coating Metrology on Large Scale Telescope Optics: Scalable Cost Saving Preventative Maintenance with First Contact Polymer

    Science.gov (United States)

    Hamilton, J.

    2012-09-01

    Protection and cleaning of precision optical surfaces on large scale astronomical instruments has entered a new era. First surface mirrors have been restored to "like-new" condition avoiding the expense and downtime of recoating. Nearly 10 years of testing and evaluation at a variety of sites including optics at Vandenberg Air Force Base, the Canada France Hawaii Telescope (CFHT) and the W.M Keck Telescope on Mauna Kea, have yielded impressive results: restored reflectivity, no residue, insitu cleaning and better coating performance when used as a precleaner when coating. Metrology and research in our labs has resulted in these novel, commercially available polymeric stripcoatings that are applied as a liquid and subsequently peeled off the substrate as a solid film. These designer polymer solutions safely clean and protect a wide variety of nanostructured surfaces and leave the surface almost atomically clean. Contaminant removal was monitored by a variety of techniques including Reflectivity, Nomarski, Atomic Force and Scanning Electron Microscopy as well as XPS. In addition, data demonstrates that the material safely removes particulate contamination and finger oils from nanostructures such as the 300nm wide lines on diffraction gratings and similar submicron features on Si wafers. High power laser damage testing found no residue on the optical surfaces following dried film removal and YAG laser damage thresholds after cleaning on coated BK7 of 15J/cm2 at 20ns and 20Hz were unchanged. Additionally to these adhesion tunable polymer systems, nanotube and graphene doped, ESD free polymer strip coatings for surface protection, nanoreplication, cleaning and dust mitigation have also been developed. Our coatings have been successfully used on diverse surfaces like high power laser optics, the Hope Diamond in Washington DC, CCD s for the 520 megapixel Dark Energy Survey Camera being built at Fermilab and lithographically fabbed detector surfaces for the Cryogenic Dark

  13. The role of quality improvement in achieving effective large-scale prevention of mother-to-child transmission of HIV in South Africa.

    Science.gov (United States)

    Barker, Pierre; Barron, Peter; Bhardwaj, Sanjana; Pillay, Yogan

    2015-07-01

    After a late start and poor initial performance, the South African Prevention of Mother-To-Child Transmission (PMTCT) programme achieved rapid progress in achieving effective national-scale implementation of a complex intervention across a large number of different geographic and socioeconomic contexts. This study shows how quality-improvement methods played a significant part in PMTCT improvements. The South African rollout of the PMTCT programme underwent significant evolution, from a largely ineffective, context-insensitive, top-down cascaded training approach to a sophisticated bottom-up health systems' intervention that used modern adaptive designs. Several demonstration projects used quality-improvement methods to improve the performance of the PMTCT programme. These results prompted a national redesign of key elements of the PMTCT programme which were rapidly scaled up across the country using a unified, simplified data-driven approach. The scale up of the quality-improvement approach contributed to a dramatic fall in the nationally reported transmission rate for mother to child transmission of HIV. By 2012, measured infection rate of HIV-exposed infants at around 6 weeks after birth was 2.6%, close to the reported transmission rates under clinical trial conditions. Quality-improvement methods can be used to improve reliability of complex treatment programmes delivered at primary-care level. Rapid scale up and effective population coverage can be accomplished through a sequence of demonstration, testing and rapid spread of locally tested implementation strategies supported by real-time feedback of a simplified indicator dataset and multilevel leadership support.

  14. Hepatitis C virus treatment for prevention among people who inject drugs: Modeling treatment scale-up in the age of direct-acting antivirals.

    Science.gov (United States)

    Martin, Natasha K; Vickerman, Peter; Grebely, Jason; Hellard, Margaret; Hutchinson, Sharon J; Lima, Viviane D; Foster, Graham R; Dillon, John F; Goldberg, David J; Dore, Gregory J; Hickman, Matthew

    2013-11-01

    Substantial reductions in hepatitis C virus (HCV) prevalence among people who inject drugs (PWID) cannot be achieved by harm reduction interventions such as needle exchange and opiate substitution therapy (OST) alone. Current HCV treatment is arduous and uptake is low, but new highly effective and tolerable interferon-free direct-acting antiviral (DAA) treatments could facilitate increased uptake. We projected the potential impact of DAA treatments on PWID HCV prevalence in three settings. A dynamic HCV transmission model was parameterized to three chronic HCV prevalence settings: Edinburgh, UK (25%); Melbourne, Australia (50%); and Vancouver, Canada (65%). Using realistic scenarios of future DAAs (90% sustained viral response, 12 weeks duration, available 2015), we projected the treatment rates required to reduce chronic HCV prevalence by half or three-quarters within 15 years. Current HCV treatment rates may have a minimal impact on prevalence in Melbourne and Vancouver (scale-up to 15, 40, or 76 per 1,000 PWID annually in Edinburgh, Melbourne, or Vancouver, respectively (2-, 13-, and 15-fold increases, respectively). Scale-up to 22, 54, or 98 per 1,000 PWID annually could reduce prevalence by three-quarters within 15 years. Less impact occurs with delayed scale-up, higher baseline prevalence, or shorter average injecting duration. Results are insensitive to risk heterogeneity or restricting treatment to PWID on OST. At existing HCV drug costs, halving chronic prevalence would require annual treatment budgets of US $3.2 million in Edinburgh and approximately $50 million in Melbourne and Vancouver. Interferon-free DAAs could enable increased HCV treatment uptake among PWID, which could have a major preventative impact. However, treatment costs may limit scale-up, and should be addressed. © 2013 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.

  15. The Parenting to Reduce Adolescent Depression and Anxiety Scale: Assessing parental concordance with parenting guidelines for the prevention of adolescent depression and anxiety disorders

    Directory of Open Access Journals (Sweden)

    Mairead C. Cardamone-Breen

    2017-09-01

    Full Text Available Background Despite substantial evidence demonstrating numerous parental risk and protective factors for the development of adolescent depression and anxiety disorders, there is currently no single measure that assesses these parenting factors. To address this gap, we developed the Parenting to Reduce Adolescent Depression and Anxiety Scale (PRADAS as a criterion-referenced measure of parental concordance with a set of evidence-based parenting guidelines for the prevention of adolescent depression and anxiety disorders. In this paper, we used a sample of Australian parents of adolescents to: (1 validate the PRADAS as a criterion-referenced measure; (2 examine parental concordance with the guidelines in the sample; and (3 examine correlates of parental concordance with the guidelines. Methods Seven hundred eleven parents completed the PRADAS, as well as two established parenting measures, and parent-report measures of adolescent depression and anxiety symptoms. Six hundred sixty adolescent participants (aged 12–15 also completed the symptom measures. Concordance with the guidelines was assessed via nine subscale scores and a total score. Reliability of the scores was assessed with an estimate of the agreement coefficient, as well as 1-month test-retest reliability. Convergent validity was examined via correlations between the scale and two established parenting measures. Results One proposed subscale was removed from the final version of the scale, resulting in a total of eight subscales. Reliability was high for the total score, and acceptable to high for seven of the eight subscales. One-month test-retest reliability was acceptable to high for the total score. Convergent validity was supported by moderate to high correlations with two established measures of parenting. Overall, rates of parental concordance with the guidelines were low in our sample. Higher scores were associated with being female and higher levels of parental education

  16. The Parenting to Reduce Adolescent Depression and Anxiety Scale: Assessing parental concordance with parenting guidelines for the prevention of adolescent depression and anxiety disorders.

    Science.gov (United States)

    Cardamone-Breen, Mairead C; Jorm, Anthony F; Lawrence, Katherine A; Mackinnon, Andrew J; Yap, Marie B H

    2017-01-01

    Despite substantial evidence demonstrating numerous parental risk and protective factors for the development of adolescent depression and anxiety disorders, there is currently no single measure that assesses these parenting factors. To address this gap, we developed the Parenting to Reduce Adolescent Depression and Anxiety Scale (PRADAS) as a criterion-referenced measure of parental concordance with a set of evidence-based parenting guidelines for the prevention of adolescent depression and anxiety disorders. In this paper, we used a sample of Australian parents of adolescents to: (1) validate the PRADAS as a criterion-referenced measure; (2) examine parental concordance with the guidelines in the sample; and (3) examine correlates of parental concordance with the guidelines. Seven hundred eleven parents completed the PRADAS, as well as two established parenting measures, and parent-report measures of adolescent depression and anxiety symptoms. Six hundred sixty adolescent participants (aged 12-15) also completed the symptom measures. Concordance with the guidelines was assessed via nine subscale scores and a total score. Reliability of the scores was assessed with an estimate of the agreement coefficient, as well as 1-month test-retest reliability. Convergent validity was examined via correlations between the scale and two established parenting measures. One proposed subscale was removed from the final version of the scale, resulting in a total of eight subscales. Reliability was high for the total score, and acceptable to high for seven of the eight subscales. One-month test-retest reliability was acceptable to high for the total score. Convergent validity was supported by moderate to high correlations with two established measures of parenting. Overall, rates of parental concordance with the guidelines were low in our sample. Higher scores were associated with being female and higher levels of parental education. Greater parental concordance with the guidelines

  17. Mapping wildland-urban interfaces at large scales integrating housing density and vegetation aggregation for fire prevention in the South of France.

    Science.gov (United States)

    Lampin-Maillet, Corinne; Jappiot, Marielle; Long, Marlène; Bouillon, Christophe; Morge, Denis; Ferrier, Jean-Paul

    2010-01-01

    Every year, more than 50,000 wildland fires affect about 500,000ha of vegetation in southern European countries, particularly in wildland-urban interfaces (WUI). This paper presents a method to characterize and map WUIs at large scales and over large areas for wildland fire prevention in the South of France. Based on the combination of four types of building configuration and three classes of vegetation structure, 12 interface types were classified. Through spatial analysis, fire ignition density and burned area ratio were linked with the different types of WUI. Among WUI types, isolated WUIs with the lowest housing density represent the highest level of fire risk. 2009 Elsevier Ltd. All rights reserved.

  18. Introducing a model of cardiovascular prevention in Nairobi's slums by integrating a public health and private-sector approach: the SCALE-UP study

    Directory of Open Access Journals (Sweden)

    Steven van de Vijver

    2013-10-01

    Full Text Available Introduction: Cardiovascular disease (CVD is a leading cause of death in sub-Saharan Africa (SSA, with annual deaths expected to increase to 2 million by 2030. Currently, most national health systems in SSA are not adequately prepared for this epidemic. This is especially so in slum settlements where access to formal healthcare and resources is limited. Objective: To develop and introduce a model of cardiovascular prevention in the slums of Nairobi by integrating public health and private sector approaches. Study design: Two non-profit organizations that conduct public health research, Amsterdam Institute for Global Health and Development (AIGHD and African Population and Health Research Center (APHRC, collaborated with private-sector Boston Consulting Group (BCG to develop a service delivery package for CVD prevention in slum settings. A theoretic model was designed based on the integration of public and private sector approaches with the focus on costs and feasibility. Results: The final model includes components that aim to improve community awareness, a home-based screening service, patient and provider incentives to seek and deliver treatment specifically for hypertension, and adherence support. The expected outcomes projected by this model could prove potentially cost effective and affordable (1 USD/person/year. The model is currently being implemented in a Nairobi slum and is closely followed by key stakeholders in Kenya including the Ministry of Health, the World Health Organization (WHO, and leading non-governmental organizations (NGOs. Conclusion: Through the collaboration of public health and private sectors, a theoretically cost-effective model was developed for the prevention of CVD and is currently being implemented in the slums of Nairobi. If results are in line with the theoretical projections and first impressions on the ground, scale-up of the service delivery package could be planned in other poor urban areas in Kenya by

  19. THE RELATIONSHIP BETWEEN SOCIAL, POLICY AND PHYSICAL VENUE FEATURES AND SOCIAL COHESION ON CONDOM USE FOR PREGNANCY PREVENTION AMONG SEX WORKERS: A SAFER INDOOR WORK ENVIRONMENT SCALE

    Science.gov (United States)

    Duff, Putu; Shoveller, Jean; Dobrer, Sabina; Ogilvie, Gina; Montaner, Julio; Chettiar, Jill; Shannon, Kate

    2015-01-01

    Background This study aims to: report on a newly developed ‘Safer Indoor Work Environmental Scale’ that characterizes the social, policy and physical features of indoor venues and social cohesion; and using this scale, longitudinally evaluate the association between these features on sex workers’ (SWs’) condom use for pregnancy prevention. Methods Drawing on a prospective open cohort of female SWs working in indoor venues, a newly-developed ‘Safer Indoor Work Environment Scale’ was used to build six multivariable models with generalized estimating equations (GEE), to determine the independent effects of social, policy and venue-based features and social cohesion on condom use. Results Of 588 indoor SWs, 63.6% used condoms for pregnancy prevention in the last month. In multivariable GEE analysis, the following venue-based features were significantly correlated with barrier contraceptive use for pregnancy prevention: managerial practices and venue safety policies (Adjusted Odds Ratio (AOR)=1.09; 95% Confidence Interval (95%CI) 1.01–1.17) access to sexual and reproductive health services/supplies (AOR=1.10; 95%CI 1.00–1.20) access to drug harm reduction (AOR=1.13; 95%CI 1.01–1.28), and social cohesion among workers (AOR=1.05; 95%CI 1.03–1.07). Access to security features was marginally associated with condom use (AOR=1.13; 95%CI 0.99–1.29). Conclusion The findings of the current study highlight how work environment and social cohesion among SWs are related to improved condom use. Given global calls for the decriminalization of sex work, and potential legislative reforms in Canada, this study points to the critical need for new institutional arrangements (e.g., legal and regulatory frameworks; labour standards) to support safer sex workplaces. PMID:25678713

  20. Introducing a model of cardiovascular prevention in Nairobi's slums by integrating a public health and private-sector approach: the SCALE-UP study.

    Science.gov (United States)

    van de Vijver, Steven; Oti, Samuel; Tervaert, Thijs Cohen; Hankins, Catherine; Kyobutungi, Catherine; Gomez, Gabriela B; Brewster, Lizzy; Agyemang, Charles; Lange, Joep

    2013-10-21

    Cardiovascular disease (CVD) is a leading cause of death in sub-Saharan Africa (SSA), with annual deaths expected to increase to 2 million by 2030. Currently, most national health systems in SSA are not adequately prepared for this epidemic. This is especially so in slum settlements where access to formal healthcare and resources is limited. To develop and introduce a model of cardiovascular prevention in the slums of Nairobi by integrating public health and private sector approaches. Two non-profit organizations that conduct public health research, Amsterdam Institute for Global Health and Development (AIGHD) and African Population and Health Research Center (APHRC), collaborated with private-sector Boston Consulting Group (BCG) to develop a service delivery package for CVD prevention in slum settings. A theoretic model was designed based on the integration of public and private sector approaches with the focus on costs and feasibility. The final model includes components that aim to improve community awareness, a home-based screening service, patient and provider incentives to seek and deliver treatment specifically for hypertension, and adherence support. The expected outcomes projected by this model could prove potentially cost effective and affordable (1 USD/person/year). The model is currently being implemented in a Nairobi slum and is closely followed by key stakeholders in Kenya including the Ministry of Health, the World Health Organization (WHO), and leading non-governmental organizations (NGOs). Through the collaboration of public health and private sectors, a theoretically cost-effective model was developed for the prevention of CVD and is currently being implemented in the slums of Nairobi. If results are in line with the theoretical projections and first impressions on the ground, scale-up of the service delivery package could be planned in other poor urban areas in Kenya by relevant policymakers and NGOs.

  1. Formulary management of ACE inhibitors.

    Science.gov (United States)

    Gerbrandt, K R; Yedinak, K C

    1996-12-01

    An increasing number of ACE inhibitors have become available in recent years. Because these agents are all similar, careful scrutiny is required in order to determine specific advantages of particular agents when making formulary decisions. Differences between agents with regard to structure and tissue specificity have been identified, but the clinical relevance of these differences is not clear. ACE inhibitors vary greatly with regard to bioconversion, distribution and elimination. Disease states such as congestive heart failure (CHF) and hepatic or renal insufficiency may affect the disposition of specific ACE inhibitors. These agents may differ substantially in duration of action, and ACE inhibitors that are given once daily may optimise patient compliance and decrease costs. ACE inhibitors have been extensively studied in patients with hypertension, CHF or nephropathy, and following myocardial infarction (MI). Differences in efficacy between agents are often a result of variations in study design, or because nonequipotent dosages were compared. It is likely that the benefits of ACE inhibitors are class effects, and it is probably reasonable to use an agent even if large scale clinical trials have not been performed with that particular drug. Few differences have been found between ACE inhibitors with regard to adverse effects or drug interactions, and these factors are of minor importance when making formulary decisions. Cost and availability may vary among agents, and will depend on geographical location and institution-specific purchasing contracts. ACE inhibitors have shown positive effects on quality of life when compared with agents of other classes. Quality-of-life studies that have directly compared ACE inhibitors have produced conflicting results. In the setting of hypertension, cost-effectiveness evaluations typically find that the newer, longer-acting ACE inhibitors provide the greatest financial benefit. Differences in cost effectiveness in the post

  2. Are Virtual Rehabilitation Technologies Feasible Models to Scale an Evidence-Based Fall Prevention Program? A Pilot Study Using the Kinect Camera

    Science.gov (United States)

    Basnett, Jeanna; Chokshi, Anang; Barrett, Mark; Komatireddy, Ravi

    2015-01-01

    Background Falls in older adults are a significant public health issue. Interventions have been developed and proven effective to reduce falls in older adults, but these programs typically last several months and can be resource intensive. Virtual rehabilitation technologies may offer a solution to bring these programs to scale. Off-the-shelf and custom exergames have demonstrated to be a feasible adjunct to rehabilitation with older adults. However, it is not known if older adults will be able or willing to use a virtual rehabilitation technology to participate in an evidence-based fall prevention program. To have the greatest impact, virtual rehabilitation technologies need to be acceptable to older adults from different backgrounds and level of fall risk. If these technologies prove to be a feasible option, they offer a new distribution channel to disseminate fall prevention programs. Objective Stand Tall (ST) is a virtual translation of the Otago Exercise Program (OEP), an evidence-based fall prevention program. Stand Tall was developed using the Virtual Exercise Rehabilitation Assistant (VERA) software, which uses a Kinect camera and a laptop to deliver physical therapy exercise programs. Our purpose in this pilot study was to explore if ST could be a feasible platform to deliver the OEP to older adults from a variety of fall risk levels, education backgrounds, and self-described level of computer expertise. Methods Adults age 60 and over were recruited to participate in a one-time usability study. The study included orientation to the program, navigation to exercises, and completion of a series of strength and balance exercises. Quantitative analysis described participants and the user experience. Results A diverse group of individuals participated in the study. Twenty-one potential participants (14 women, 7 men) met the inclusion criteria. The mean age was 69.2 (± 5.8) years, 38% had a high school education, 24% had a graduate degree, and 66% classified as

  3. A scoping study to identify opportunities to advance the ethical implementation and scale-up of HIV treatment as prevention: priorities for empirical research.

    Science.gov (United States)

    Knight, Rod; Small, Will; Pakula, Basia; Thomson, Kimberly; Shoveller, Jean

    2014-07-03

    Despite the evidence showing the promise of HIV treatment as prevention (TasP) in reducing HIV incidence, a variety of ethical questions surrounding the implementation and "scaling up" of TasP have been articulated by a variety of stakeholders including scientists, community activists and government officials. Given the high profile and potential promise of TasP in combatting the global HIV epidemic, an explicit and transparent research priority-setting process is critical to inform ongoing ethical discussions pertaining to TasP. We drew on the Arksey and O'Malley framework for conducting scoping review studies as well as systematic approaches to identifying empirical and theoretical gaps within ethical discussions pertaining to population-level intervention implementation and scale up. We searched the health science database PubMed to identify relevant peer-reviewed articles on ethical and implementation issues pertaining to TasP. We included English language articles that were published after 2009 (i.e., after the emergence of causal evidence within this field) by using search terms related to TasP. Given the tendency for much of the criticism and support of TasP to occur outside the peer-reviewed literature, we also included grey literature in order to provide a more exhaustive representation of how the ethical discussions pertaining to TasP have and are currently taking place. To identify the grey literature, we systematically searched a set of search engines, databases, and related webpages for keywords pertaining to TasP. Three dominant themes emerged in our analysis with respect to the ethical questions pertaining to TasP implementation and scale-up: (a) balancing individual- and population-level interests; (b) power relations within clinical practice and competing resource demands within health care systems; (c) effectiveness considerations and socio-structural contexts of HIV treatment experiences within broader implementation contexts. Ongoing research

  4. The effect of chemical anti-inhibitors on fibrinolytic enzymes and inhibitors

    DEFF Research Database (Denmark)

    Sidelmann, Johannes Jakobsen; Jespersen, J; Kluft, C

    1997-01-01

    proteases. We studied the influence of chemical anti-inhibitors (chloramine T, flufenamate, sodium lauryl sulfate, and methylamine) on fibrinolytic serine proteases and fibrinolytic enzyme inhibitors using the physiological substrate fibrin as plasmin substrate. Low concentrations of chloramine T (0.01 mmol....../l) prevent the inhibition of plasminogen activators. Higher concentrations (1 mmol/l) reduce the inhibition of plasmin, but simultaneously quench the plasminogen activator activity. Flufenamate eliminates most fibrinolytic enzyme inhibitors, but increases the activity of plasmin (apparent recovery 140......Fibrinolytic enzyme inhibitors hamper the determination of the specific fibrinolytic serine protease activity. Reportedly, chemical anti-inhibitors eliminate the influence of fibrinolytic inhibitors, but it remains unclear to what extent they change the specific activity of fibrinolytic serine...

  5. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.

    Science.gov (United States)

    Alexander, John H; Becker, Richard C; Bhatt, Deepak L; Cools, Frank; Crea, Filippo; Dellborg, Mikael; Fox, Keith A A; Goodman, Shaun G; Harrington, Robert A; Huber, Kurt; Husted, Steen; Lewis, Basil S; Lopez-Sendon, Jose; Mohan, Puneet; Montalescot, Gilles; Ruda, Mikhail; Ruzyllo, Witold; Verheugt, Freek; Wallentin, Lars

    2009-06-09

    After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding. Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone. We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome

  6. Condom use and prevalence of syphilis and HIV among female sex workers in Andhra Pradesh, India – following a large-scale HIV prevention intervention

    Directory of Open Access Journals (Sweden)

    Rachakulla Hari Kumar

    2011-12-01

    Full Text Available Abstract Background Avahan, the India AIDS initiative began HIV prevention interventions in 2003 in Andhra Pradesh (AP among high-risk groups including female sex workers (FSWs, to help contain the HIV epidemic. This manuscript describes an assessment of this intervention using the published Avahan evaluation framework and assesses the coverage, outcomes and changes in STI and HIV prevalence among FSWs. Methodology Multiple data sources were utilized including Avahan routine program monitoring data, two rounds of cross-sectional survey data (in 2006 and 2009 and STI clinical quality monitoring assessments. Bi-variate and multivariate analyses, Wald Chi-square tests and multivariate logistic regressions were used to measure changes in behavioural and biological outcomes over time and their association. Results Avahan scaled up in conjunction with the Government program to operate in all districts in AP by March 2009. By March 2009, 80% of the FSWs were being contacted monthly and 21% were coming to STI services monthly. Survey data confirmed an increase in peer educator contacts with the mean number increasing from 2.9 in 2006 to 5.3 in 2009. By 2008 free and Avahan-supported socially marketed condoms were adequate to cover the estimated number of commercial sex acts, at 45 condoms/FSW/month. Consistent condom use was reported to increase with regular (63.6% to 83.4%; AOR=2.98; p Conclusions The absence of control groups is a limitation of this study and does not allow attribution of changes in outcomes and declines in HIV and STI to the Avahan program. However, the large scale implementation, high coverage, intermediate outcomes and association of these outcomes to the Avahan program provide plausible evidence that the declines were likely associated with Avahan. Declining HIV prevalence among the general population in Andhra Pradesh points towards a combined impact of Avahan and government interventions.

  7. Solderability preservation through the use of organic inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sorensen, N.R.; Hosking, F.M.

    1994-12-01

    Organic inhibitors can be used to prevent corrosion of metals and have application in the electronics industry as solderability preservatives. We have developed a model to describe the action of two inhibitors (benzotriazole and imidazole) during the environmental aging and soldering process. The inhibitors bond with the metal surface and form a barrier that prevents or retards oxidation. At soldering temperatures, the metal-organic complex breaks down leaving an oxide-free metal surface that allows excellent wetting by molten solder. The presence of the inhibitor retards the wetting rate relative to clean copper, but provides a vast improvement relative to oxidized copper.

  8. Estimated impact on birth weight of scaling up intermittent preventive treatment of malaria in pregnancy given sulphadoxine-pyrimethamine resistance in Africa: A mathematical model.

    Science.gov (United States)

    Walker, Patrick G T; Floyd, Jessica; Ter Kuile, Feiko; Cairns, Matt

    2017-02-01

    estimates of resistance. Forty-four percent of these pregnancies (23% of all pregnancies) were not receiving any IPTp-SP despite making ≥3 ANC visits, representing 160,000 (94,000-236,000 95% crI) preventable low birthweight (LBW) deliveries. Only 4% (1.4 million) of pregnancies occurred in settings with >10% prevalence of the sextuple haplotype associated with compromised SP effectiveness. Forty-two percent of all pregnancies occurred in settings where the quintuple dhfr/dhps haplotype had become established but where in vivo efficacy data suggest SP maintains the majority of its effectiveness in clearing infections. Not accounting for protection from the use of ITNs during pregnancy, expanding IPTp-SP to all women with ≥3 ANC visits in Africa could prevent an additional 215,000 (128,000-318,000 95% crI) LBW deliveries. In 26 countries with sufficient recent data to estimate ITN impact (population-based ITN usage data that can be stratified by gravidity), we estimate that, due primarily to low ITN use by primigravidae, only 16.5% of the potential LBW births prevented by scaling up IPTp-SP would in fact have already have been prevented through ITN use. Our analysis also highlights the difficulties associated with estimating the relationship between the effectiveness of interventions against parasitological endpoints such as placental infection at delivery and health outcomes including birthweight, which is also determined by a wide range of unrelated factors. We also did not capture other aspects of malaria burden such as clinical malaria, maternal and neonatal anaemia, and miscarriage, all of which increase the overall importance of effective preventative strategies but have their own relationship with transmission intensity, parity, and SP resistance. Despite recent declines in malaria transmission in Africa, the burden of MiP in the absence of adequate prevention remains substantial. Even accounting for SP resistance, extending IPTp-SP to all women attending ANC, as

  9. Alpha glucosidase inhibitors

    National Research Council Canada - National Science Library

    Kalra, Sanjay

    2014-01-01

    Alpha glucosidase inhibitors (AGIs) are a unique class of anti-diabetic drugs. Derived from bacteria, these oral drugs are enzyme inhibitors which do not have a pancreato -centred mechanism of action...

  10. Proton pump inhibitors

    Science.gov (United States)

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by glands in ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  11. Scale up use of family planning services to prevent maternal transmission of HIV among discordant couples: a cross-sectional study within a resource-limited setting

    Directory of Open Access Journals (Sweden)

    Kuete M

    2016-10-01

    abortions, 65% had tried to avoid the current pregnancy, and 12% of women were ART naïve. Several predictors such as education, abortion rate, unplanned pregnancies, and partners’ decision were associated with the nonuse of effective contraceptive methods. Moreover, barriers including sex inequity, lack of partner support, ART shortages, and lack of HIV viral load monitoring were prevalent among the participants (P=0.001. However FPS use, ART compliance, and safe options to PMTCT significantly increased after the educational counseling interventions (P=0.001.Conclusion: Scaling up the FPS by incorporating routine PMTCT services into reproductive health care should contribute to preventing both horizontal and vertical transmission of HIV. Keywords: contraception, HIV infected women, transmission, interventions, education

  12. The potential of involving traditional practitioners in the scaling up of male circumcision in the context of HIV prevention in Tanzania.

    Science.gov (United States)

    Kilima, Stella P; Shayo, Elizabeth H; Msovela, Judith; Senkoro, Kesheni P; Mayala, Benjamin K; Mboera, Leonard E G; Massaga, Julius J

    2012-01-01

    Male circumcision (MC) has been practiced worldwide for religious, cultural, social and medical reasons. Recent studies in Africa have indicated MC to be highly protective against HIV transmission. However, incorporating MC in HIV/AIDS prevention programme will increase its demand in Tanzania where traditional male circumcision is common and the health care system is weak. The objective of this study was to determine the challenges and opportunities of involving traditional practitioners in scaling up safe MC in the context of HIV prevention in Tanzania. The study was conducted in Monduli, Bahi and Mkuranga districts of Tanzania. Both quantitative and qualitative methods were employed. Household survey involved community members from the selected villages. In-depth interviews involved traditional practitioners and key informants at national, district and facility levels. A total of 601 householders were interviewed. Most (71.4%) household respondents preferred traditional MC as it was part of their culture and tradition. A similar response was obtained from other respondents. It was mostly preferred because it was used as an initiation school, turning of boys to warriors and sense of social cohesion. Only 228 (37.9%) of the respondents were aware of the adverse events associated with MC. The most frequently mentioned adverse effects were severe bleeding (65.0%), delayed wound healing (17.5%) and wound sepsis (8.4%). The risk of acquiring HIV through male circumcision practice was poorly known among community members except medical respondents. Single unsterilized local surgical equipment was used to circumcise several initiates. It was observed that interference with traditional values associated with circumcision to be the main hindrance of linkage between traditional and conventional practitioners. On the other hand it was reported that there was no policy or guidelines on Traditional MC (TMC). Most of respondents supported the efforts to establish and promote

  13. Scale-Up of Voluntary Medical Male Circumcision Services for HIV Prevention - 12 Countries in Southern and Eastern Africa, 2013-2016.

    Science.gov (United States)

    Hines, Jonas Z; Ntsuape, Onkemetse Conrad; Malaba, Kananga; Zegeye, Tiruneh; Serrem, Kennedy; Odoyo-June, Elijah; Nyirenda, Rose Kolola; Msungama, Wezi; Nkanaunena, Kondwani; Come, Jotamo; Canda, Marcos; Nhaguiombe, Herminio; Shihepo, Ella K; Zemburuka, Brigitte L T; Mutandi, Gram; Yoboka, Emmanuel; Mbayiha, André H; Maringa, Hilda; Bere, Alfred; Lawrence, J Joseph; Lija, Gissenge J I; Simbeye, Daimon; Kazaura, Kokuhumbya; Mwiru, Ramadhani S; Talisuna, Stella Alamo; Lubwama, Joseph; Kabuye, Geoffrey; Zulu, James Exnobert; Chituwo, Omega; Mumba, Maybin; Xaba, Sinokuthemba; Mandisarisa, John; Baack, Brittney N; Hinkle, Lawrence; Grund, Jonathan M; Davis, Stephanie M; Toledo, Carlos

    2017-12-01

    Countries in Southern and Eastern Africa have the highest prevalence of human immunodeficiency virus (HIV) infection in the world; in 2015, 52% (approximately 19 million) of all persons living with HIV infection resided in these two regions.* Voluntary medical male circumcision (VMMC) reduces the risk for heterosexually acquired HIV infection among males by approximately 60% (1). As such, it is an essential component of the Joint United Nations Programme on HIV/AIDS (UNAIDS) strategy for ending acquired immunodeficiency syndrome (AIDS) by 2030 (2). Substantial progress toward achieving VMMC targets has been made in the 10 years since the World Health Organization (WHO) and UNAIDS recommended scale-up of VMMC for HIV prevention in 14 Southern and Eastern African countries with generalized HIV epidemics and low male circumcision prevalence (3).† This has been enabled in part by nearly $2 billion in cumulative funding through the President's Emergency Plan for AIDS Relief (PEPFAR), administered through multiple U.S. governmental agencies, including CDC, which has supported nearly half of all PEPFAR-supported VMMCs to date. Approximately 14.5 million VMMCs were performed globally during 2008-2016, which represented 70% of the original target of 20.8 million VMMCs in males aged 15-49 years through 2016 (4). Despite falling short of the target, these VMMCs are projected to avert 500,000 HIV infections by the end of 2030 (4). However, UNAIDS has estimated an additional 27 million VMMCs need to be performed by 2021 to meet the Fast Track targets (2). This report updates a previous report covering the period 2010-2012, when VMMC implementing partners supported by CDC performed approximately 1 million VMMCs in nine countries (5). During 2013-2016, these implementing partners performed nearly 5 million VMMCs in 12 countries. Meeting the global target will require redoubling current efforts and introducing novel strategies that increase demand among subgroups of males who

  14. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Aaboe, K; Knop, F K; Vilsbøll, T

    2010-01-01

    To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients with...

  15. Recent Natural Corrosion Inhibitors for Mild Steel: An Overview

    Directory of Open Access Journals (Sweden)

    Marko Chigondo

    2016-01-01

    Full Text Available Traditionally, reduction of corrosion has been managed by various methods including cathodic protection, process control, reduction of the metal impurity content, and application of surface treatment techniques, as well as incorporation of suitable alloys. However, the use of corrosion inhibitors has proven to be the easiest and cheapest method for corrosion protection and prevention in acidic media. These inhibitors slow down the corrosion rate and thus prevent monetary losses due to metallic corrosion on industrial vessels, equipment, or surfaces. Inorganic and organic inhibitors are toxic and costly and thus recent focus has been turned to develop environmentally benign methods for corrosion retardation. Many researchers have recently focused on corrosion prevention methods using green inhibitors for mild steel in acidic solutions to mimic industrial processes. This paper provides an overview of types of corrosion, corrosion process, and mainly recent work done on the application of natural plant extracts as corrosion inhibitors for mild steel.

  16. Developing ER Stress Inhibitors for Treating ALS

    Science.gov (United States)

    2015-11-01

    in response to thapsigargin, an inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase ( SERCA ) channels which initiates ER stress by preventing...O’Regan, J. P., Deng, H. X., and et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral

  17. Supporting Option B+ scale up and strengthening the prevention of mother-to-child transmission cascade in central Malawi: results from a serial cross-sectional study.

    Science.gov (United States)

    Herce, Michael E; Mtande, Tiwonge; Chimbwandira, Frank; Mofolo, Innocent; Chingondole, Christine K; Rosenberg, Nora E; Lancaster, Kathy E; Kamanga, Esmie; Chinkonde, Jacqueline; Kumwenda, Wiza; Tegha, Gerald; Hosseinipour, Mina C; Hoffman, Irving F; Martinson, Francis E; Stein, Eva; van der Horst, Charles M

    2015-08-12

    We established Safeguard the Family (STF) to support Ministry of Health (MoH) scale-up of universal antiretroviral therapy (ART) for HIV-infected pregnant and breastfeeding women (Option B+) and to strengthen the prevention of mother-to-child transmission (PMTCT) cascade from HIV testing and counseling (HTC) through maternal ART provision and post-delivery early infant HIV diagnosis (EID). To these ends, we implemented the following interventions in 5 districts: 1) health worker training and mentorship; 2) couples' HTC and male partner involvement; 3) women's psychosocial support groups; and 4) health and laboratory system strengthening for EID. We conducted a serial cross-sectional study using facility-level quarterly (Q) program data and individual-level infant HIV-1 DNA PCR data to evaluate STF performance on PMTCT indicators for project years (Y) 1 (April-December 2011) through 3 (January-December 2013), and compared these results to national averages. Facility-level uptake of HTC, ART, infant nevirapine prophylaxis, and infant DNA PCR testing increased significantly from quarterly baselines of 66 % (n/N = 32,433/48,804), 23 % (n/N = 442/1,958), 1 % (n/N = 10/1,958), and 52 % (n/N = 1,385/2,644) to 87 % (n/N = 39,458/45,324), 96 % (n/N = 2,046/2,121), 100 % (n/N = 2,121/2,121), and 62 % (n/N = 1,462/2,340), respectively, by project end (all p ART, and infant nevirapine prophylaxis uptake outperformed national averages over years 2-3. While transitioning EID laboratory services to MoH, STF provided first-time HIV-1 DNA PCR testing for 2,226 of 11,261 HIV-exposed infants (20 %) tested in the MoH EID program in STF districts from program inception (Y2) through Y3. Of these, 78 (3.5 %) tested HIV-positive. Among infants with complete documentation (n = 608), median age at first testing decreased from 112 days (interquartile range, IQR: 57-198) in Y2 to 76 days (IQR: 46-152) in Y3 (p ART, infant prophylaxis, and EID services uptake, and a low proportion of infants

  18. The proteosome inhibitor MG132 attenuates Retinoic Acid Receptor trans-activation and enhances trans-repression of Nuclear Factor κB. Potential relevance to chemo-preventive interventions with retinoids

    Directory of Open Access Journals (Sweden)

    Rosier Randy N

    2004-03-01

    Full Text Available Abstract Background Nuclear factor kappa B (NFκB is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression. Interestingly, NFκB blockade results in the reciprocal induction of retinoic acid receptors (RARs. Given the established property of RARs as negative regulators of malignant progression, we postulated that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression. Using Line 1 tumor cells as a model for signal regulation of metastatic gene expression, we investigated the reciprocal interactions between NFκB and RARs in response to the pan-RAR agonist, all-trans retinoic acid (at-RA and the pan-RAR antagonist, AGN193109. Results At-RA [0.1–1 μM] dose-dependently activated RAR and coordinately trans-repressed NFκB, while AGN193109 [1–10 μM] dose-dependently antagonized the effects of at-RA. At-RA and AGN193109 reciprocally regulate pro-metastatic matrix metalloprotease 9 (MMP 9 and its endogenous inhibitor, the tissue inhibitor of metalloprotease 1 (TIMP 1, in a manner consistent with the putative roles of NFκB and RAR in malignant progression. Activation of RAR concurs with its ubiquitination and proteosomal degradation. Accordingly, the proteosome inhibitor, MG132 [5 μM], blocked RAR degradation, quelled RAR trans-activation and enhanced RAR trans-repression of NFκB. Conclusion We conclude that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.

  19. Natural compounds as corrosion inhibitors for highly cycled systems

    Energy Technology Data Exchange (ETDEWEB)

    Quraishi, M.A.; Farooqi, I.H.; Saini, P.A. [Corrosion Research Lab., Aligarh (India)

    1999-11-01

    Strict environmental legislations have led to the development of green inhibitors in recent years. In continuation of the authors` research work on development of green inhibitors, they have investigated the aqueous extracts of three plants namely: Azadirachta indica, Punica Granatum and Momordica charantia as corrosion inhibitors for mild steel in 3% NaCl using weight loss and electrochemical methods. All the investigated compounds exhibited excellent corrosion inhibition properties comparable to that of HEDP. Azadirachta showed better scale inhibition effect than HEDP.

  20. DPP-4 inhibitors

    DEFF Research Database (Denmark)

    Deacon, Carolyn F.

    2016-01-01

    Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects.......Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects....

  1. The Cysteine Protease–Cysteine Protease Inhibitor System Explored in Soybean Nodule Development

    Directory of Open Access Journals (Sweden)

    Marian Dorcas Quain

    2013-08-01

    Full Text Available Almost all protease families have been associated with plant development, particularly senescence, which is the final developmental stage of every organ before cell death. Proteolysis remobilizes and recycles nitrogen from senescent organs that is required, for example, seed development. Senescence-associated expression of proteases has recently been characterized using large-scale gene expression analysis seeking to identify and characterize senescence-related genes. Increasing activities of proteolytic enzymes, particularly cysteine proteases, are observed during the senescence of legume nodules, in which a symbiotic relationship between the host plant and bacteria (Rhizobia facilitate the fixation of atmospheric nitrogen. It is generally considered that cysteine proteases are compartmentalized to prevent uncontrolled proteolysis in nitrogen-fixing nodules. In addition, the activities of cysteine proteases are regulated by endogenous cysteine protease inhibitors called cystatins. These small proteins form reversible complexes with cysteine proteases, leading to inactivation. However, very little is currently known about how the cysteine protease-cysteine protease inhibitor (cystatin system is regulated during nodule development. Moreover, our current understanding of the expression and functions of proteases and protease inhibitors in nodules is fragmented. To address this issue, we have summarized the current knowledge and techniques used for studying proteases and their inhibitors including the application of “omics” tools, with a particular focus on changes in the cysteine protease-cystatin system during nodule development.

  2. Inhibitor for the Corrosion of Mild Steel in H SO

    African Journals Online (AJOL)

    NJD

    Terminalia chebula, acid corrosion inhibitor, electrochemical polarization, electrochemical impedance spectroscopy, mild steel. 1. Introduction. Large amounts of sulphuric acid are used in the chemical in- dustry for the removal of undesired scale and rust. The addition of corrosion inhibitors effectively protects the metal ...

  3. The effect of prevention methods on reducing sexual risk for HIV and their potential impact on a large-scale: a literature review

    Directory of Open Access Journals (Sweden)

    Alexandre Grangeiro

    2015-09-01

    Full Text Available ABSTRACTA spectrum of diverse prevention methods that offer high protection against HIV has posed the following challenge: how can national AIDS policies with high coverage for prevention and treatment make the best use of new methods so as to reverse the current high, and even rising, incidence rates among specific social groups? We conducted a narrative review of the literature to examine the prevention methods and the structural interventions that can have a higher impact on incidence rates in the context of socially and geographically concentrated epidemics. Evidence on the protective effect of the methods against sexual exposure to HIV, as well as their limits and potential, is discussed. The availability and effectiveness of prevention methods have been hindered by structural and psychosocial barriers such as obstacles to adherence, inconsistent use over time, or only when individuals perceive themselves at higher risk. The most affected individuals and social groups have presented limited or absence of use of methods as this is moderated by values, prevention needs, and life circumstances. As a result, a substantial impact on the epidemic cannot be achieved by one method alone. Programs based on the complementarity of methods, the psychosocial aspects affecting their use and the mitigation of structural barriers may have the highest impact on incidence rates, especially if participation and community mobilization are part of their planning and implementation.

  4. Preventing stroke

    Science.gov (United States)

    Stroke - prevention; CVA - prevention; Cerebral vascular accident - prevention; TIA - prevention; Transient ischemic attack - prevention ... something that increases your chance of having a stroke. You can't change some risk factors for ...

  5. Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Hemmingsen, Bianca; Sonne, David P; Metzendorf, Maria-Inti

    2017-01-01

    haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews......, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 12 weeks or more...... comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION...

  6. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose- and non-glucose-induced insulin secretion in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Aaboe, Kasper; Knop, Filip Krag; Vilsbøll, Tina

    2010-01-01

    glucagon-like peptide 2 (GLP-2) and GLP-1. RESULTS: All patients [sitagliptin n = 12, age: 59.5 (39-64) years, HbA1c: 8.0 (7.3-10.0)%, BMI: 33.2 (29.3-39.4); placebo n = 12, age: 60 (31-72) years, HbA1c: 7.7 (7.1-9.8)%, BMI: 30.7 (25.7-40.5)] [median (range)] completed the trial. Sitagliptin treatment......AIM: To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients...... between 1 and 12 weeks of treatment....

  7. A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice.

    Science.gov (United States)

    Park, Doori; Park, Chan-Won; Choi, YoungJin; Lin, Jingjing; Seo, Dong-Hyun; Kim, Han-Sung; Lee, Soo Young; Kang, In-Cheol

    2016-08-01

    Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin αvβ3-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silico structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin αvβ3, an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin αvβ3 linked to Pyk2, c-Src, PLCγ2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Validity and reliability of the Early Childhood Caries Perceptions Scale (ECCPS) to assess health beliefs related to early childhood caries prevention among primary caregivers of children under 5 years of age.

    Science.gov (United States)

    Pisarnturakit, Pagaporn P; Shaw, Bret R; Tanasukarn, Chanuantong; Vatanasomboon, Paranee

    2012-09-01

    Primary caregivers' child oral health care beliefs and practices are major factors in the prevention of Early Childhood Caries (ECC). This study assessed the validity and reliability of a newly-developed scale--the Early Childhood Caries Perceptions Scale (ECCPS)--used to measure beliefs regarding ECC preventive practices among primary caregivers of young children. The ECCPS was developed based on the Health Belief Model. The construct validity and reliability of the ECCPS were examined among 254 low-socioeconomic status primary caregivers with children under five years old, recruifed from 4 Bangkok Metropolitan Administration Health Centers and a kindergarten school. Exploratory factor analysis (EFA) revealed a four-factor structure. The four factors were labeled as Perceived Susceptibility, Perceived Severity, Perceived Benefits and Perceived Barriers. Internal consistency measured by the Cronbach's coefficient alpha for those four factors were 0.897, 0.971, 0.975 and 0.789, respectively. The ECCPS demonstrated satisfactory levels of reliability and validity for assessing the health beliefs related to ECC prevention among low-socioeconomic primary caregivers.

  9. The determinants of technical efficiency of a large scale HIV prevention project: application of the DEA double bootstrap using panel data from the Indian Avahan.

    Science.gov (United States)

    Lépine, Aurélia; Vassall, Anna; Chandrashekar, Sudhashree

    2015-01-01

    In 2004, the largest HIV prevention project (Avahan) conducted globally was implemented in India. Avahan was implemented by NGOs supported by state lead partners in order to provide HIV prevention services to high-risk population groups. In 2007, most of the NGOs reached full coverage. Using a panel data set of the NGOs that implemented Avahan, we investigate the level of technical efficiency as well as the drivers of technical inefficiency by using the double bootstrap procedure developed by Simar & Wilson (2007). Unlike the two-stage traditional method, this method allows valid inference in the presence of measurement error and serial correlation. We find that over the 4 years, Avahan NGOs could have reduced the level of inputs by 43% given the level of outputs reached. We find that efficiency of the project has increased over time. Results indicate that main drivers of inefficiency come from the characteristics of the state lead partner, the NGOs and the catchment area. These organisational factors are important to explicitly consider and assess when designing and implementing HIV prevention programmes and in setting benchmarks in order to optimise the use and allocation of resources. C14, I1.

  10. Wastewater Treatment Anaerobic Digester Foaming Prevention and Control Methods - Literature Review and Survey - Full-Scale Studies (WERF Report INFR1SG10)

    Science.gov (United States)

    This project addresses the issue of anaerobic digester (AD) foaming in different water resource recovery facilities (WRRFs). This two-volume report is a compilation of an AD foaming literature review, a plant survey, and findings from full-scale studies. The literature review hel...

  11. Proteasome inhibitor patents (2010 - present).

    Science.gov (United States)

    Metcalf, Rainer; Scott, Latanya M; Daniel, Kenyon G; Dou, Q Ping

    2014-04-01

    Over the past 3 years, numerous patents and patent applications have been submitted and published involving compounds designed to inhibit the proteasome. Proteasome inhibition has been of great interest in cancer research since disruption of proteolysis leads to a significant buildup of cytotoxic proteins and activation of apoptotic pathways, particularly in rapidly proliferating cells. The current standards in proteasome inhibition are the only FDA-approved inhibitors, bortezomib and carfilzomib. Although these drugs are quite effective in treating multiple myeloma and other blood tumors, there are shortcomings, including toxicities and resistance. Most of the current patents attempt to improve on existing compounds, by increasing bioavailability and selectivity, while attempting to reduce toxicity. A general categorization of similar compounds was employed to evaluate and compare drug design strategies. This review focuses on novel compounds and subsequent analogs developed for proteasome inhibition, used in preventing and treating human cancers. A comprehensive description and categorization of patents related to each type of compound and its derivatives, as well as their uses and efficacies as anticancer agents is included. A review of combination therapy patents has also been included. Although there are many diverse chemical scaffolds being published, there are few patented proteasome inhibitors whose method of inhibition is genuinely novel. Most patents utilize a destructive chemical warhead to attack the catalytic threonine residue of the proteasome active sites. Few patents try to depart from this, emphasizing the need for developing new mechanisms of action and specific targeting.

  12. Obsessive Compulsive Personality Disorder as a Predictor of Exposure and Ritual Prevention Outcome for Obsessive Compulsive Disorder

    OpenAIRE

    Pinto, Anthony; Liebowitz, Michael R; Foa, Edna B.; Simpson, H. Blair

    2011-01-01

    Despite elevated rates of obsessive compulsive personality disorder (OCPD) in patients with obsessive compulsive disorder (OCD), no study has specifically examined comorbid OCPD as a predictor of exposure and ritual prevention (EX/RP) outcome. Participants were adult outpatients (n = 49) with primary OCD and a Yale-Brown Obsessive Compulsive Scale (YBOCS) total score ≥ 16 despite a therapeutic serotonin reuptake inhibitor dose for at least 12 weeks prior to entry. Participants received 17 ses...

  13. Study on the Effect of Jet Velocity on Mixing Performance and Sludge Prevention in Large-Scale Crude-Oil Tanks by the CFD Technique

    OpenAIRE

    Ali Akbar Lotfi Neyestanak; Mohammad Reza Tarybakhsh; Saeed Daneshmand

    2017-01-01

    In this paper, computational fluid dynamic modelling was developed to study the effect of the floating jet velocity or submerged rotary jet in sludge prevention in a large crude-oil storage tank. The Euler-Euler method was used in a two-dimensional CFD model to describe oil and sludge flow behaviour at the bottom of the storage tank. By modifying some parameters, the k-e model was used to describe the turbulence of the mixing flow. The results show the effect of jet velocity, angle, and time ...

  14. Effect of cholinesterase inhibitors on attention.

    Science.gov (United States)

    Pepeu, Giancarlo; Giovannini, Maria Grazia; Bracco, Laura

    2013-03-25

    Advantages and limits of the use of cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) are well established. Their effects result from an increase in extracellular acetylcholine (ACh) whose hydrolysis is prevented by cholinesterase inhibition. In this way, the cholinergic deficit which characterizes AD may be corrected. This overview discusses which components of the cognitive process are improved by ChEI administration. In animal experiments, the increase in ACh release, detected in brain areas during behavioral tasks designed to tax attentional processes, demonstrates that an activation of cholinergic neurons underlies arousal and attention. Since arousal and attention depend on activation of the forebrain cholinergic system, it is to be expected that the loss of cholinergic neurons occurring in AD may lead to impairment of the attentional processes. Indeed, a consensus exists that attention is the first non-memory domain to be affected in AD, before deficits in language and visuo-spatial functions. The difficulties with daily living, which occur even in mild AD, may be related to attentional deficits. ChEIs, by restoring the cholinergic activity, should improve attention. If the cognitive changes resulting from ChEI treatment in AD patients are assessed with appropriate tests or selected items of the scales, a predominant effect on attention and executive functions emerges. In a group of 121 subjects with mild to moderate AD, (MMSE score 21.88 ± 3.63) followed in the Alzheimer Unit in Florence, after a year of treatment with standard doses of ChEIs, it was observed a stabilization of the disease, characterized by no changes of the tests evaluating attention and executive functions but a worsening of those involving memory mechanisms. These findings suggest that ChEI treatment preserves attention more than memory. Finally, the electrophysiological and neurochemical mechanisms through which the activation of the cholinergic forebrain neurons enhance

  15. A Culturally Sensitive Approach to Large-Scale Prevention Studies: A Case Study of a Randomized Controlled Trial With Low-Income Latino Communities.

    Science.gov (United States)

    Rangel, David E; Valdez, Carmen R

    2017-12-01

    In response to U.S. federal mandates to increase the presence of underrepresented populations in prevention research, investigators have increasingly focused on using culturally sensitive research practices. However, scholars have rarely discussed these practices in terms of a larger culturally sensitive framework. Further, while the literature has explored how culturally sensitive approaches can be employed in a variety of methods, there has been little examination of how to incorporate such approaches into experimental designs. In this paper, we explain how we incorporated a culturally sensitive framework in a cluster randomized field trial with over 3000 predominantly low-income Latino families, utilizing an intervention designed to improve social relations and enhance family functioning. We offer conceptual and practical examples to guide other researchers who want to adopt a similar approach in their research designs. In addition, we discuss the benefits of forging local partnerships throughout the research process to ensure respect for racial and ethnic minorities participating in social and behavioral experimental studies. We conclude with practical considerations for utilizing a culturally sensitive framework to advance prevention programs, policies, and practices among underrepresented groups in order to achieve the ultimate goal of addressing the traditional underrepresentation of racial and ethnic minorities in research.

  16. [Acquired coagulant factor inhibitors].

    Science.gov (United States)

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  17. Proteasome inhibitors prevent bi-directional HER2/estrogen-receptor cross-talk leading to cell death in endocrine and lapatinib-resistant HER2+/ER+ breast cancer cells.

    Science.gov (United States)

    Thaler, Sonja; Schmidt, Marcus; Roβwag, Sven; Thiede, Gitta; Schad, Arno; Sleeman, Jonathan P

    2017-09-22

    Amplification and/or overexpression of the human epidermal growth factor 2 (HER2) oncogene occurs in about 13-15% of invasive breast cancer and triggers breast cancer cell proliferation, survival and metastatic progression. Around half of all breast cancers with HER2 overexpression co-express hormone receptors (HR) such as those for estrogen and progesterone. Aberrant signaling through HER2 and other members of the HER-family mediates endocrine-resistance in estrogen receptor alpha (ERα) positive breast cancer. On the other hand, ERα co-expression has been shown to attenuate the efficiency of anti-HER2 therapies. These findings indicate that HER2 and ERα synergize to escape from both anti-ERα and anti-HER2-targeted therapies. Rationally designed clinical trials that combine endocrine therapy with anti-HER2 agents to interfere with HER2/ERα cross-talk have been conducted. However, the outcome of these trials suggests that novel therapeutic approaches are needed to further improve inhibition of HER2 and other HER-family members in conjunction with a more efficient ERα blockade. Here, we demonstrate that carfilzomib and bortezomib stabilize the HER2-specific protein tyrosine phosphatase BDP1 leading to decreased HER2 autophosphorylation, reduced HER2 activity and subsequently attenuated activation of the PI3K/Akt-pathway, together with blockade of ERα expression. We further observed that proteasome inhibitors (PIs) reverse autophosphorylation and thereby inhibit the activity of constitutively active mutant HER2. We also demonstrate that PIs cause cell death in lapatinib and endocrine-resistant HER2+/ER+ breast cancer cells. These findings suggest that PIs might have the potential to improve the management of HER2+/ER+ breast cancer patients by efficiently disrupting the bi-directional HER2/ERα cross-talk.

  18. ROS inhibitor N-acetyl-l-cysteine antagonizes the activity of proteasome inhibitors

    Science.gov (United States)

    Halasi, Marianna; Wang, Ming; Chavan, Tanmay S.; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L.

    2015-01-01

    NAC (N-acetyl-l-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H2O2. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis. PMID:23772801

  19. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  20. Vascular calcification: Inducers and inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Donghyun, E-mail: dhlee@cau.ac.kr [Department of Biomedical Engineering, Division of Integrative Engineering, Chung-Ang University, 221 Heukseok-Dong, Dongjak-Gu, Seoul 156-756 (Korea, Republic of)

    2011-09-15

    Highlights: {center_dot} Types of vascular calcification processes. {center_dot} Inducers of vascular calcification. {center_dot} Inhibitors of vascular calcifications. {center_dot} Clinical utility for vascular calcification therapy. {center_dot} Implications for the development of new tissue engineering strategies. - Abstract: Unlike the traditional beliefs, there are mounting evidences suggesting that ectopic mineral depositions, including vascular calcification are mostly active processes, many times resembling that of the bone mineralization. Numbers of agents are involved in the differentiation of certain subpopulation of smooth muscle cells (SMCs) into the osteoblast-like entity, and the activation and initiation of extracellular matrix ossification process. On the other hand, there are factors as well, that prevent such differentiation and ectopic calcium phosphate formation. In normal physiological environments, activities of such procalcific and anticalcific regulatory factors are in harmony, prohibiting abnormal calcification from occurring. However, in certain pathophysiological conditions, such as atherosclerosis, chronic kidney disease (CKD), and diabetes, such balances are altered, resulting in abnormal ectopic mineral deposition. Understanding the factors that regulate the formation and inhibition of ectopic mineral formation would be beneficial in the development of tissue engineering strategies for prevention and/or treatment of such soft-tissue calcification. Current review focuses on the factors that seem to be clinically relevant and/or could be useful in developing future tissue regeneration strategies. Clinical utilities and implications of such factors are also discussed.

  1. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications.

    Science.gov (United States)

    Nagai, Ryoji; Murray, David B; Metz, Thomas O; Baynes, John W

    2012-03-01

    This article outlines evidence that advanced glycation end product (AGE) inhibitors and breakers act primarily as chelators, inhibiting metal-catalyzed oxidation reactions that catalyze AGE formation. We then present evidence that chelation is the most likely mechanism by which ACE inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors inhibit AGE formation in diabetes. Finally, we note several recent studies demonstrating therapeutic benefits of chelators for diabetic cardiovascular and renal disease. We conclude that chronic, low-dose chelation therapy deserves serious consideration as a clinical tool for prevention and treatment of diabetes complications.

  2. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  3. Protease inhibitors and beyond.

    Science.gov (United States)

    1997-03-01

    A new generation of protease inhibitors is entering studies. Abbott Lab's ABT-378 and Pharmacia/Upjohn's PNU-140690 are beginning clinical studies and both are designed to overcome resistance problems. Several companies are developing new compounds to inhibit reverse transcriptase, such as Bristol-Myers Squibb's lobucavir and Hoechst/Bayer's HBY097. Calanolide A, which will soon begin trials, has a different resistance pattern than other non-nucleoside reverse transcriptase inhibitors, which may be an important advantage. Several groups are developing compounds to inhibit the HIV zinc finger, such as Parke-Davis' compound, CI-1012; and a Dutch company who is developing Azodicarbonamide, a drug currently in phase I/II trials for people with advanced disease in Europe. HIV drugs to date have not been successful in blocking viral fusion. However, three new fusion inhibitors are showing promise within the laboratory: Pentafuside (currently in phase I trials), Fuji ImmunoPharmaceuticals' FP-21399 (currently in phase I trials), and ISIS Pharmaceuticals' ISIS 5320. A new class of drugs known as integrase inhibitors has been of interest to pharmaceutical companies for the past several years; only one drug, Aronex Pharmaceuticals' Zintevir, has reached phase I/II trials.

  4. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  5. HIV protease inhibitor resistance

    NARCIS (Netherlands)

    Wensing, Annemarie M.J.; Fun, Axel; Nijhuis, Monique

    2017-01-01

    HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of

  6. Phosphodiesterase 4 inhibitors.

    Science.gov (United States)

    Zebda, Rema; Paller, Amy S

    2018-03-01

    Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety. Copyright © 2017. Published by Elsevier Inc.

  7. Proton-pump inhibitors

    African Journals Online (AJOL)

    Proton-pump inhibitors (PPIs) work by binding irreversibly to the. H+/K+-ATPase pump of the parietal cell, leading to inhibition of acid production in approximately 70% of active pumps.1The result is a dramatic increase in gastric pH mitigating the deleterious effects of acid in gastro-oesophageal reflux disease (GORD) and.

  8. Study on the Effect of Jet Velocity on Mixing Performance and Sludge Prevention in Large-Scale Crude-Oil Tanks by the CFD Technique

    Directory of Open Access Journals (Sweden)

    Ali Akbar Lotfi Neyestanak

    2017-06-01

    Full Text Available In this paper, computational fluid dynamic modelling was developed to study the effect of the floating jet velocity or submerged rotary jet in sludge prevention in a large crude-oil storage tank. The Euler-Euler method was used in a two-dimensional CFD model to describe oil and sludge flow behaviour at the bottom of the storage tank. By modifying some parameters, the k-e model was used to describe the turbulence of the mixing flow. The results show the effect of jet velocity, angle, and time on the mixing process. By increasing the velocity from 5 m s−1, the mixing pattern significantly changes and improves the mixing of the sludge with crude oil. To evaluate the results, chosen was the sludge profile related to the bottom of the sample tank, and modelling results showed an 80 cm reduction in thickness of the sludge, which corresponds well to the profile of the bottom of the tank. In addition, the y+ axis indicated that the amounts at all points were less than 300, which is acceptable in two-phase modelling.

  9. Dengue Prevention

    Science.gov (United States)

    ... Address What's this? Submit What's this? Submit Button Prevention Recommend on Facebook Tweet Share Compartir This photograph ... medications to treat a dengue infection. This makes prevention the most important step, and prevention means avoiding ...

  10. Calcineurin inhibitors in heart transplantation.

    Science.gov (United States)

    Keogh, Anne

    2004-05-01

    The use of calcineurin inhibitors (CNIs; cyclosporine and tacrolimus) has dramatically increased medium-term life expectancy after heart transplantation but has had only limited impact on long-term outcomes for heart transplant recipients. The original oil-based formulation of cyclosporine has been superceded by a microemulsion formulation (Neoral), which has more predictable pharmacokinetics and allows more precise dose-tailoring. Cyclosporine microemulsion and tacrolimus (Prograf) have a similar efficacy in the prevention of acute rejection of heart transplants, but their use is accompanied by nephrotoxicity and by cardiovascular side effects. The efficacy of immunosuppression can be improved by adjunctive therapy, such as azathioprine, mycophenolate mofetil (MMF; Cellcept), corticosteroids, and induction therapy. One of the most important predictors of patient mortality at >5 years after heart transplantation is cardiac allograft vasculopathy (CAV)/late graft failure, which accounts for 31% of deaths. Neither cyclosporine nor tacrolimus have been shown to prevent the development of CAV. In terms of efficacy, MMF provides a modest advantage over azathioprine in preventing CAV, and the combination of cyclosporine plus MMF results in significantly lower mortality than cyclosporine plus azathioprine. Overall, CNIs have multiple cardiovascular side effects, such as hypertension, hyperlipidemia and new-onset diabetes after transplantation, although cyclosporine and tacrolimus have somewhat different cardiovascular side-effect profiles. The challenge in choosing the best immunosuppressive regimen is to balance efficacy and safety to optimize graft and patient survival over the course of many decades. Because cyclosporine and tacrolimus have similar efficacy against acute rejection the choice of CNI for heart transplant recipients should be based on the relative risk of cardiovascular and renal side effects.

  11. Crystallization and preliminary X-ray crystallographic studies on a Kunitz-type potato serine protease inhibitor.

    NARCIS (Netherlands)

    Thomassen, E.A.J.; Pouvreau, L.A.M.; Gruppen, H.; Abrahams, J.P.

    2004-01-01

    Interest in protease inhibitors has been renewed because of their potent activity in preventing carcinogenesis in a wide variety of in vivo and in vitro model systems. Potato tubers contain a wide range of such protease inhibitors. In cv. Elkana potato tubers, protease inhibitors represent about 50%

  12. Scale formation at various locations in a geothermal operation due to injection of imported waters

    Energy Technology Data Exchange (ETDEWEB)

    Vetter, O.J.; Kandarpa, V.

    1982-06-22

    The injection of waters that are not native to a geothermal formation generates various physical and chemical problems. The major chemical problem resulting from such injections is the formation of sulfate scales (particularly CaSO4, BaSO4 and SrSO4) at various locations starting from the injection well through the production well to the surface facilities of any geothermal operation. One of the ways to prevent this type of scale formation is by reducing the sulfate concentration of the injection waters. The effect of sulfate deionization on scale formation at various locations of the geothermal operations is studied. Some experimental results on the CaSO4 scale formation in porous media upon heating an injection water with and without addition of scale inhibitors are also given.

  13. The cost and impact of scaling up pre-exposure prophylaxis for HIV prevention: a systematic review of cost-effectiveness modelling studies.

    Directory of Open Access Journals (Sweden)

    Gabriela B Gomez

    Full Text Available Cost-effectiveness studies inform resource allocation, strategy, and policy development. However, due to their complexity, dependence on assumptions made, and inherent uncertainty, synthesising, and generalising the results can be difficult. We assess cost-effectiveness models evaluating expected health gains and costs of HIV pre-exposure prophylaxis (PrEP interventions.We conducted a systematic review comparing epidemiological and economic assumptions of cost-effectiveness studies using various modelling approaches. The following databases were searched (until January 2013: PubMed/Medline, ISI Web of Knowledge, Centre for Reviews and Dissemination databases, EconLIT, and region-specific databases. We included modelling studies reporting both cost and expected impact of a PrEP roll-out. We explored five issues: prioritisation strategies, adherence, behaviour change, toxicity, and resistance. Of 961 studies retrieved, 13 were included. Studies modelled populations (heterosexual couples, men who have sex with men, people who inject drugs in generalised and concentrated epidemics from Southern Africa (including South Africa, Ukraine, USA, and Peru. PrEP was found to have the potential to be a cost-effective addition to HIV prevention programmes in specific settings. The extent of the impact of PrEP depended upon assumptions made concerning cost, epidemic context, programme coverage, prioritisation strategies, and individual-level adherence. Delivery of PrEP to key populations at highest risk of HIV exposure appears the most cost-effective strategy. Limitations of this review include the partial geographical coverage, our inability to perform a meta-analysis, and the paucity of information available exploring trade-offs between early treatment and PrEP.Our review identifies the main considerations to address in assessing cost-effectiveness analyses of a PrEP intervention--cost, epidemic context, individual adherence level, PrEP programme coverage

  14. Impact evaluation of a community-based intervention for prevention of cardiovascular diseases in the slums of Nairobi: the SCALE-UP study.

    Science.gov (United States)

    van de Vijver, Steven; Oti, Samuel Oji; Gomez, Gabriela B; Agyemang, Charles; Egondi, Thaddaeus; Moll van Charante, Eric; Brewster, Lizzy M; Hankins, Catherine; Tanovic, Zlata; Ezeh, Alex; Kyobutungi, Catherine; Stronks, Karien

    2016-01-01

    A combination of increasing urbanization, behaviour change, and lack of health services in slums put the urban poor specifically at risk of cardiovascular disease (CVD). This study aimed to evaluate the impact of a community-based CVD prevention intervention on blood pressure (BP) and other CVD risk factors in a slum setting in Nairobi, Kenya. Prospective intervention study includes awareness campaigns, household visits for screening, and referral and treatment of people with hypertension. The primary outcome was overall change in mean systolic blood pressure (SBP), while secondary outcomes were changes in awareness of hypertension and other CVD risk factors. We evaluated the intervention's impact through consecutive cross-sectional surveys at baseline and after 18 months, comparing outcomes of intervention and control group, through a difference-in-difference method. We screened 1,531 and 1,233 participants in the intervention and control sites. We observed a significant reduction in mean SBP when comparing before and after measurements in both intervention and control groups, -2.75 mmHg (95% CI -4.33 to -1.18, p=0.001) and -1.67 mmHg (95% CI -3.17 to -0.17, p=0.029), respectively. Among people with hypertension at baseline, SBP was reduced by -14.82 mmHg (95% CI -18.04 to -11.61, p<0.001) in the intervention and -14.05 (95% CI -17.71 to -10.38, p<0.001) at the control site. However, comparing these two groups, we found no difference in changes in mean SBP or hypertension prevalence. We found significant declines in SBP over time in both intervention and control groups. However, we found no additional effect of a community-based intervention involving awareness campaigns, screening, referral, and treatment. Possible explanations include the beneficial effect of baseline measurements in the control group on behaviour and related BP levels, and the limited success of treatment and suboptimal adherence in the intervention group.

  15. Identification of Neutrophil Exocytosis Inhibitors (Nexinhibs), Small Molecule Inhibitors of Neutrophil Exocytosis and Inflammation

    Science.gov (United States)

    Johnson, Jennifer L.; Ramadass, Mahalakshmi; He, Jing; Brown, Steven J.; Zhang, Jinzhong; Abgaryan, Lusine; Biris, Nikolaos; Gavathiotis, Evripidis; Rosen, Hugh; Catz, Sergio D.

    2016-01-01

    Neutrophils constitute the first line of cellular defense in response to bacterial and fungal infections and rely on granular proteins to kill microorganisms, but uncontrolled secretion of neutrophil cargos is injurious to the host and should be closely regulated. Thus, increased plasma levels of neutrophil secretory proteins, including myeloperoxidase and elastase, are associated with tissue damage and are hallmarks of systemic inflammation. Here, we describe a novel high-throughput screening approach to identify small molecule inhibitors of the interaction between the small GTPase Rab27a and its effector JFC1, two central regulators of neutrophil exocytosis. Using this assay, we have identified small molecule inhibitors of Rab27a-JFC1 binding that were also active in cell-based neutrophil-specific exocytosis assays, demonstrating the druggability of Rab GTPases and their effectors. These compounds, named Nexinhibs (neutrophil exocytosis inhibitors), inhibit exocytosis of azurophilic granules in human neutrophils without affecting other important innate immune responses, including phagocytosis and neutrophil extracellular trap production. Furthermore, the compounds are reversible and potent inhibitors of the extracellular production of superoxide anion by preventing the up-regulation of the granule membrane-associated subunit of the NADPH oxidase at the plasma membrane. Nexinhibs also inhibit the up-regulation of activation signature molecules, including the adhesion molecules CD11b and CD66b. Importantly, by using a mouse model of endotoxin-induced systemic inflammation, we show that these inhibitors have significant activity in vivo manifested by decreased plasma levels of neutrophil secretory proteins and significantly decreased tissue infiltration by inflammatory neutrophils. Altogether, our data present the first neutrophil exocytosis-specific inhibitor with in vivo anti-inflammatory activity, supporting its potential use as an inhibitor of systemic

  16. Implementing at-scale, community-based distribution of misoprostol tablets to mothers in the third stage of labor for the prevention of postpartum haemorrhage in Sokoto State, Nigeria: Early results and lessons learned.

    Directory of Open Access Journals (Sweden)

    Nosakhare Orobaton

    Full Text Available Postpartum haemorrhage (PPH is a leading cause of maternal death in Sokoto State, Nigeria, where 95% of women give birth outside of a health facility. Although pilot schemes have demonstrated the value of community-based distribution of misoprostol for the prevention of PPH, none have provided practical insight on taking such programs to scale.A community-based system for the distribution of misoprostol tablets (in 600ug and chlorhexidine digluconate gel 7.1% to mother-newborn dyads was introduced by state government officials and community leaders throughout Sokoto State in April 2013, with the potential to reach an estimated 190,467 annual births. A simple outcome form that collected distribution and consumption data was used to assess the percentage of mothers that received misoprostol at labor through December 2014. Mothers' conditions were tracked through 6 weeks postpartum. Verbal autopsies were conducted on associated maternal deaths.Misoprostol distribution was successfully introduced and reached mothers in labor in all 244 wards in Sokoto State. Community data collection systems were successfully operational in all 244 wards with reliable capacity to record maternal deaths. 70,982 women or 22% of expected births received misoprostol from April 2013 to December 2014. Between April and December 2013, 33 women (< 1% reported that heavy bleeding persisted after misoprostol use and were promptly referred. There were a total of 11 deaths in the 2013 cohort which were confirmed as maternal deaths by verbal autopsies. Between January and December of 2014, a total 434 women (1.25% that ingested misoprostol reported associated side effects.It is feasible and safe to utilize government guidelines on results-based primary health care to successfully introduce community distribution of life saving misoprostol at scale to reduce PPH and improve maternal outcomes. Lessons from Sokoto State's at-scale program implementation, to assure every mother

  17. Use of the oral platelet inhibitors dipyridamole and acetylsalicylic acid is associated with increased risk of fracture

    DEFF Research Database (Denmark)

    Vestergaard, Peter; Steinberg, Thomas H; Schwarz, P

    2012-01-01

    BACKGROUND: Platelet inhibitors are widely used in the treatment and prevention of coronary artery disease. In addition to acetylsalicylic acid, two major groups of platelet inhibitors are used; phosphodiesterase inhibitors including dipyridamole, and thienopyridines (ticlopidine and clopidogrel)...... is not associated with increased fracture risk. CONCLUSIONS: Use of some oral platelet inhibitors is associated with increased risk of fractures, and more studies are warranted to determine the potential effect of platelet inhibitors on bone metabolism in vivo.......BACKGROUND: Platelet inhibitors are widely used in the treatment and prevention of coronary artery disease. In addition to acetylsalicylic acid, two major groups of platelet inhibitors are used; phosphodiesterase inhibitors including dipyridamole, and thienopyridines (ticlopidine and clopidogrel......). Clopidogrel is the most widely used, and in combination with acetylsalicylic acid it is the standard of care for acute coronary syndromes and percutaneous coronary interventions. However, the modes of action involve pathways that are involved in the metabolic activity in bone cells and pharmacologic...

  18. Improving outcomes in heart transplantation: the potential of proliferation signal inhibitors.

    Science.gov (United States)

    Eisen, H; Kobashigawa, J; Starling, R C; Valantine, H; Mancini, D

    2005-05-01

    Graft failure and mortality among heart transplant recipients remains higher than in populations receiving renal transplants. A major cause of graft loss is cardiac allograft vasculopathy (CAV), a condition characterized by diffuse thickening of coronary blood vessels. CAV often progresses silently, with major cardiac events (eg, ventricular arrhythmia) being the first presentation. Better diagnosis and monitoring of CAV is now possible with intravascular ultrasonography, a sensitive technique for measuring intimal thickness. To date, immunosuppressants have shown little efficacy for preventing CAV. However, a new class of agents, proliferation signal inhibitors (sirolimus and everolimus), have shown considerable efficacy in this regard and for preventing rejection. In an open-label trial, sirolimus therapy was associated with less intimal and medial proliferation than azathioprine. More robust evidence is available from a larger-scale, double-blind trial involving everolimus. At 12-month follow-up the incidence of CAV was significantly lower in patients receiving everolimus (35.7% and 30.4% for everolimus 1.5 and 3.0 mg/d vs 52.8% for azathioprine; P nephrotoxicity, but evidence suggests that everolimus administered with reduced-exposure cyclosporine in the maintenance phase preserves renal function without loss of immunosuppressive efficacy. Reduced CNI dosing in de novo patients is also a potential future benefit. Proliferation signal inhibitors have considerable potential for improving outcomes in heart transplantation.

  19. The water footprint of human-made reservoirs for hydropower, irrigation, water supply, flood prevention, fishing and recreation on a global scale

    Science.gov (United States)

    Hogeboom, Rick; Knook, Luuk; Hoekstra, Arjen

    2017-04-01

    Increasing the availability of freshwater to meet growing and competing demands is on many policy agendas. The Sustainable Development Goals (SDGs) prescribe sustainable management of water for human consumption. For centuries humans have resorted to building dams to store water in periods of excess for use in times of shortage. Although dams and their reservoirs have made important contributions to human development, it is increasingly acknowledged that reservoirs can be substantial water consumers as well. We estimated the water footprint of human-made reservoirs on a global scale and attributed it to the various reservoir purposes (hydropower generation, residential and industrial water supply, irrigation water supply, flood protection, fishing and recreation) based on their economic value. We found that economic benefits from derived products and services from 2235 reservoirs globally, amount to 311 billion US dollar annually, with residential and industrial water supply and hydropower generation as major contributors. The water footprint associated with these benefits is the sum of the water footprint of dam construction (water evaporation. The total water footprint of reservoirs globally adds up to ˜104 km3yr-1. Attribution per purpose shows that, with a global average water footprint of 21,5 m3GJ,-1 hydropower on average is a water intensive form of energy. We contextualized the water footprint of reservoirs and their purposes with regard to the water scarcity level of the river basin in which they occur. We found the lion's share (55%) of the water footprint is located in non-water scarce basins and only 1% in year-round scarce basins. The purpose for which the reservoir is primarily used changes with increasing water scarcity, from mainly hydropower generation in non-scarce basins, to the (more essential) purposes residential and industrial water supply, irrigation and flood control in scarcer areas. The quantitative explication of how the burden of water

  20. Pharmacological Prevention of Posttraumatic Stress Disorder: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Ravi Philip Rajkumar

    2014-01-01

    Full Text Available Introduction. Various interventions, both psychological and pharmacological, have been studied for their efficacy in preventing posttraumatic stress disorder (PTSD following trauma exposure. However, the preventive effect of pharmacotherapy has not been systematically assessed. Methodology. A systematic review of all clinical trials of drug therapy to prevent PTSD, available through the PubMed and EMBASE databases, was conducted. This included an assessment of each study’s quality. Results. A total of 13 studies were reviewed. The drugs examined in these papers included propranolol, hydrocortisone, serotonin reuptake inhibitors, gabapentin, omega-3 fatty acids, and benzodiazepines. There was marked heterogeneity across studies in terms of quality, study populations, and methodology. Analysis of the outcomes revealed preliminary evidence for the efficacy of hydrocortisone, particularly in critical care settings. There was no consistent evidence to support the use of other drugs to prevent PTSD. Discussion. There may be a limited role for hydrocortisone in preventing the development of PTSD in specific settings. Results with other drugs are inconsistent. Further large-scale studies should assess the efficacy of these approaches in other contexts, such as natural disasters, and the time frame within which they should be used.

  1. Advances in non-peptidomimetic HIV protease inhibitors.

    Science.gov (United States)

    Pang, X; Liu, Z; Zhai, G

    2014-06-01

    HIV protease plays a crucial role in the viral life cycle. It can cleave a series of heptamers in the viral Gag and GagPol precursor proteins to generate mature infectious virus particles. Successful inhibition of the protease will prevent this maturation step and hence block the spreading of HIV. However, the rapid emergence of drug resistance makes it urgent to develop new HIV protease inhibitors to combat the global disease. Besides, poor oral bioavailability, unacceptable side effects, high treatment cost and pill burden also trouble the application of HIV protease inhibitors. In such situations, non-peptidomimetic HIV protease inhibitors have drawn an increasing interest as a potential therapeutic option due to their small molecular weight, favorable bioavailability, high stability in vivo, low resistance and cost of production. In this review, we present the recent advances in non-peptidomimetic HIV protease inhibitors. Their design strategies, biological activities, resistance profiles, as well as clinical application will also be discussed.

  2. And then there were acyl coenzyme A:cholesterol acyl transferase inhibitors

    NARCIS (Netherlands)

    Meuwese, Marijn C.; Franssen, Remco; Stroes, Erik S. G.; Kastelein, John J. P.

    2006-01-01

    PURPOSE OF REVIEW: The reputation of acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitors has changed profoundly from promising new drugs for cardiovascular prevention to drugs without clinical benefits or possibly even with adverse effects. RECENT FINDINGS: ACAT inhibitors decrease the

  3. Corroded scale analysis from water distribution pipes

    Directory of Open Access Journals (Sweden)

    Rajaković-Ognjanović Vladana N.

    2011-01-01

    Full Text Available The subject of this study was the steel pipes that are part of Belgrade's drinking water supply network. In order to investigate the mutual effects of corrosion and water quality, the corrosion scales on the pipes were analyzed. The idea was to improve control of corrosion processes and prevent impact of corrosion on water quality degradation. The instrumental methods for corrosion scales characterization used were: scanning electron microscopy (SEM, for the investigation of corrosion scales of the analyzed samples surfaces, X-ray diffraction (XRD, for the analysis of the presence of solid forms inside scales, scanning electron microscopy (SEM, for the microstructural analysis of the corroded scales, and BET adsorption isotherm for the surface area determination. Depending on the composition of water next to the pipe surface, corrosion of iron results in the formation of different compounds and solid phases. The composition and structure of the iron scales in the drinking water distribution pipes depends on the type of the metal and the composition of the aqueous phase. Their formation is probably governed by several factors that include water quality parameters such as pH, alkalinity, buffer intensity, natural organic matter (NOM concentration, and dissolved oxygen (DO concentration. Factors such as water flow patterns, seasonal fluctuations in temperature, and microbiological activity as well as water treatment practices such as application of corrosion inhibitors can also influence corrosion scale formation and growth. Therefore, the corrosion scales found in iron and steel pipes are expected to have unique features for each site. Compounds that are found in iron corrosion scales often include goethite, lepidocrocite, magnetite, hematite, ferrous oxide, siderite, ferrous hydroxide, ferric hydroxide, ferrihydrite, calcium carbonate and green rusts. Iron scales have characteristic features that include: corroded floor, porous core that contains

  4. Individualized dosing of calcineurin inhibitors in renal transplantation

    NARCIS (Netherlands)

    Press, Rogier Raphael

    2011-01-01

    Calcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these

  5. [Cytoplasmic kinase inhibitors].

    Science.gov (United States)

    Mano, Hiroyuki

    2010-10-01

    Protein kinases play essential roles in the regulation of cell proliferation. Point mutations or/and fusions of protein kinases are frequently identified in human cancers, and targeting such activated kinases provides us with a chance to eradicate tumor cells. This was first proved by imatinib mesylate that inhibits ABL tyrosine kinase and, thereby, efficiently kills malignant cells in chronic myeloid leukemia. In addition, other clinical trials are ongoing for kinase inhibitors against EML4--ALK in lung cancer, JAK2 in myeloproliferative disorders and BRAF in malignant melanoma. Early reports indeed reveal that such targeting compounds are promising drugs for human cancers with activated kinases.

  6. Poison Prevention

    Science.gov (United States)

    ... the Word Shop AAP Find a Pediatrician Safety & Prevention Immunizations All Around At Home At Play On ... Listen Español Text Size Email Print Share Poison Prevention Page Content Article Body Post the Poison Help ...

  7. Angiotensin-I-converting enzyme (ACE) inhibitors from marine resources: prospects in the pharmaceutical industry

    National Research Council Canada - National Science Library

    Wijesekara, Isuru; Kim, Se-Kwon

    2010-01-01

    .... Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides...

  8. Preventing Addiction.

    Science.gov (United States)

    Moore, Susan Fordney

    The purpose of this paper is to provide the beginning counselor with an overview of prevention concepts. Prevention is a relatively new emphasis in community efforts to stem the rising costs of substance abuse and other high-risk behaviors. The paper discusses agent, host, and environmental prevention models and how they relate to causal theories…

  9. Development of a high-throughput cell-based reporter assay for screening of JAK3 inhibitors.

    Science.gov (United States)

    Yin, Chang-Hong; Bach, Erika A; Baeg, Gyeong-Hun

    2011-04-01

    JAK3 is an ideal target for the treatment of immune-related diseases and the prevention of organ allograft rejection. Several JAK3 inhibitors have been identified by biochemical enzymatic assays, but the majority display significant off-target effects on JAK2. Therefore, there is a need to develop new experimental approaches to identify compounds that specifically inhibit JAK3. Here, we show that in 32D/IL-2Rβ cells, STAT5 becomes phosphorylated by an IL-3/JAK2- or IL-2/JAK3-dependent pathway. Importantly, the selective JAK3 inhibitor CP-690,550 blocked the phosphorylation and the nuclear translocation of STAT5 following treatment of cells with IL-2 but not with IL-3. In an attempt to use the cells for large-scale chemical screens to identify JAK3 inhibitors, we established a cell line, 32D/IL-2Rβ/6xSTAT5, stably expressing a STAT5 reporter gene. Treatment of this cell line with IL-2 or IL-3 dramatically increased the reporter activity in a high-throughput format. As expected, CP-690,550 selectively inhibited the activity of the 6xSTAT5 reporter following treatment with IL-2. By contrast, the pan-JAK inhibitor curcumin inhibited the activity of this reporter following treatment with either IL-2 or IL-3. Thus, this study indicates that the STAT5 reporter cell line can be used as an efficacious cellular model for chemical screens to identify selective JAK3 inhibitors.

  10. Calcite scale prediction at the near-well region: A radiotracer approach

    Directory of Open Access Journals (Sweden)

    Bjørnstad T.

    2013-05-01

    Full Text Available Effective prediction of calcite scaling requires a reliable thermodynamic model for the prediction of the scaling tendency, a kinetic model for the prediction of scaling rate and a transport model to simulate flow in a porous medium. The accurate prediction of the scale deposition can warn the engineers to “treat” the formation around the wellbore in time. In addition, the prediction of the distribution of the scale deposition can direct the engineers to ensure the placement of the inhibitors into the formation zones where the deposition is expected, thus maximizing the probability of successful prevention of formation damage and minimizing at the same time the amount of the required inhibitors. In this contribution, we present a geochemical computational model that combines existing thermodynamic and kinetic models for CaCO3 precipitation, with treatments of flow and diffusion in electrolyte systems, in an one-dimensional porous medium. The geochemical model has the ability to predict the distribution of scale deposition along and around the production wells, as well as the distribution of formation damage (pore blocking, permeability reduction around the wells.

  11. Selection of Protease Inhibitors to Prevent or Attenuate Inflammatory Processes

    Science.gov (United States)

    2007-08-01

    described in vertebrates, but have also been found in invertabrates and plants . They are distinguished from other endopeptidases by their dependence...evolutionary relationships of the primary sequence. Today, a lot of bacterial, archaeal, protozoal, fungal, plant , animal and viral genome sequences...Legionella, Listeria , Clostridium, Helicobacter, Pseudomonas and Vibrio [Barrett et al.. 1998]. In contrast with the specific inhibition of gluzincin

  12. Methyl Jasmonate Induces Papain Inhibitor(s) in Tomato Leaves.

    Science.gov (United States)

    Bolter, C. J.

    1993-12-01

    Leaves of 18- to 24-d-old tomato (Lycopersicon esculentum) plants exposed to gaseous methyl jasmonate (MJ) for 24 h at 30[deg]C in continuous light contained high levels of soluble protein that inhibited papain. Chromatographic analysis demonstrated that the active protein had a molecular mass of 80 to 90 kD. Induction of papain inhibitor was directly related to the concentration of air-borne MJ up to a maximum of 0.1 [mu]L MJ per treatment and depended on the duration of exposure up to 18 h. Inhibitor activity in plants treated for less than 18 h increased with time after treatment. Levels remained constant for up to 4 d after treatment, after which time activity decreased. The youngest leaf, leaf 5, consistently lost activity at a faster rate than older, lower leaves. Inhibitor concentration in all leaves was reduced to minimum levels by 11 d after MJ treatment, but did not return to control levels. Treatment with MJ in the dark did induce inhibitor activity, but at a significantly lower rate. Polyclonal antibodies raised to purified potato tuber skin cysteine proteinase inhibitors (CPI) cross-reacted with the tomato inhibitor, suggesting that the tomato papain inhibitor and the potato CPI are closely related. No papain inhibitor activity was observed in extracts from wounded tomato leaves, nor was there any immunoreactivity with antibodies raised to potato tuber skin CPI.

  13. Corrosion protection with eco-friendly inhibitors

    Science.gov (United States)

    Shahid, Muhammad

    2011-12-01

    Corrosion occurs as a result of the interaction of a metal with its environment. The extent of corrosion depends on the type of metal, the existing conditions in the environment and the type of aggressive ions present in the medium. For example, CO3-2 and NO-3 produce an insoluble deposit on the surface of iron, resulting in the isolation of metal and consequent decrease of corrosion. On the other hand, halide ions are adsorbed selectively on the metal surface and prevent formation of the oxide phase on the metal surface, resulting in continuous corrosion. Iron, aluminum and their alloys are widely used, both domestically and industrially. Linear alkylbenzene and linear alkylbenzene sulfonate are commonly used as detergents. They have also been found together in waste water. It is claimed that these chemicals act as inhibitors for stainless steel and aluminum. Release of toxic gases as a result of corrosion in pipelines may lead in certain cases to air pollution and possible health hazards. Therefore, there are two ways to look at the relationship between corrosion and pollution: (i) corrosion of metals and alloys due to environmental pollution and (ii) environmental pollution as a result of corrosion protection. This paper encompasses the two scenarios and possible remedies for various cases, using 'green' inhibitors obtained either from plant extracts or from pharmaceutical compounds. In the present study, the effect of piperacillin sodium as a corrosion inhibitor for mild steel was investigated using a weight-loss method as well as a three-electrode dc electrochemical technique. It was found that the corrosion rate decreased as the concentration of the inhibitor increased up to 9×10-4 M 93% efficiency was exhibited at this concentration.

  14. Stroke Prevention: Managing Modifiable Risk Factors

    Directory of Open Access Journals (Sweden)

    Silvia Di Legge

    2012-01-01

    Full Text Available Prevention plays a crucial role in counteracting morbidity and mortality related to ischemic stroke. It has been estimated that 50% of stroke are preventable through control of modifiable risk factors and lifestyle changes. Antihypertensive treatment is recommended for both prevention of recurrent stroke and other vascular events. The use of antiplatelets and statins has been shown to reduce the risk of recurrent stroke and other vascular events. Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin II receptor blockers (ARBs are indicated in stroke prevention because they also promote vascular health. Effective secondary-prevention strategies for selected patients include carotid revascularization for high-grade carotid stenosis and vitamin K antagonist treatment for atrial fibrillation. The results of recent clinical trials investigating new anticoagulants (factor Xa inhibitors and direct thrombin inhibitors clearly indicate alternative strategies in stroke prevention for patients with atrial fibrillation. This paper describes the current landscape and developments in stroke prevention with special reference to medical treatment in secondary prevention of ischemic stroke.

  15. Preventing Interpersonal Violence in Europe

    Directory of Open Access Journals (Sweden)

    Dinesh Sethi

    2014-06-01

    CONCLUSION: Community surveys can play an important role to better understand the scale and risk factors of different types of interpersonal violence. Readers are called upon to support a coordinated public health response to prevent this societal and health threat.

  16. ACE inhibitors and calcium antagonists in the treatment of congestive heart failure

    DEFF Research Database (Denmark)

    Hansen, J F

    1995-01-01

    The increased mortality after myocardial infarction is related to the risk of reinfarction, sudden death, and the development and progression of heart failure; in congestive heart failure it is due to the progression of heart failure and sudden death. ACE inhibitors have been proven to prevent...... cardiovascular events, especially the progression of heart failure, in postinfarct patients with reduced ejection fraction and heart failure in the SAVE and AIRE trials. In patients with congestive heart failure, ACE inhibitor treatment has prevented cardiovascular death and reduced morbidity due to progressive...... by prevention of reinfarction and sudden death. Combination treatment with both verapamil, which has pronounced antiischemic properties and prevents sudden death and reinfarction, and an ACE inhibitor, which prevents the progression of heart failure, is a possibility for future cardiovascular therapy...

  17. Prevention: Exercise

    Medline Plus

    Full Text Available ... Therapy Postural Training Traction Watchful Waiting and Education Injection Treatments for Spinal Pain Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices ...

  18. Prevention: Exercise

    Medline Plus

    Full Text Available ... Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 Tips for a Healthy Back Smoking Weight Patient Safety Exercise Strengthening Strengthen ...

  19. Validación de una escala de autoeficacia para la prevención del SIDA en adolescentes Validation of a self-efficacy scale for AIDS prevention among adolescents

    Directory of Open Access Journals (Sweden)

    Fuensanta López-Rosales

    2001-10-01

    pez and Padilla (1999. Instruments: It is employed the Self-efficacy to Prevent the AIDS Scale of 27 items of López and Padilla (1999, together with closed questions Likert type, dicotomics and two opened questions on relevant aspects of the sexual conduct to validate the scale, under a format self-applied test of pencil and paper. Material and Methods. It is a correlacional study with a not experimental design of transverse type. It was accomplished with a simple random sample of 962 adolescents wich were taken of 60 public health centers of Monterrey. None went to consult by motives related to the AIDS. Results. The scale was adjusted to a normal distribution (Zk-s(Normal=1.369; p=0.047. It presents a mean of 95.14 and a standard deviation of 25.80. Its reliability, by the alpha of Cronbach, was 0.89. SEA - 27 shows a structure of four independent factors that explain 58.47% of the total variance. Conclusions: Thus, it is concluded that SEA - 27 is a reliable and valid scale. The English version of this paper is available at: http://www.insp.mx/salud/index.html

  20. Proteinase inhibitors in Brazilian leguminosae

    Directory of Open Access Journals (Sweden)

    C. A. M. Sampaio

    1991-01-01

    Full Text Available Serine proteinase inhitors, in the seeds of several Leguminosae from the Pantanal region (West Brazil, were studied using bovine trypsin, a digestive enzyme, Factor XIIa and human plasma Kallikrein, two blood clotting factors. The inhibitors were purified from Enterolobium contortisiliquum (Mr=23,000, Torresea cearensis (Mr = 13,000, Bauhinia pentandra (Mr = 20,000 and Bauhinia bauhinioides (Mr = 20,000. E. contortisiliquum inhibitor inactivates all three enzymes, whereas the T. cearensis inhibitor inactivates trypsin and Factor XSSa, but does nor affect plasma kallikrein; both Bauhinia inhibitors, on the other hand, inactivate trypsin and plasma kallikrein but only the Bpentandra inhibitor affects Factor XIIa. Ki values were calculated between 10 [raised to the power of] -7 and 10 [raised to the power of] -8 M.

  1. Ginger extract as green corrosion inhibitor of mild steel in hydrochloric acid solution

    Science.gov (United States)

    Fidrusli, A.; Suryanto; Mahmood, M.

    2018-01-01

    Ginger extract as corrosion inhibitor from natural resources was studied to prevent corrosion of mild steel in acid media. Ginger rhizome was extracted to produce green corrosion inhibitor (G-1) while ginger powder bought at supermarket was also extract to form green corrosion inhibitor (G-2). Effectiveness of inhibitor in preventing corrosion process of mild steel was studied in 1.0 M of hydrochloric acid. The experiment of weight loss method and polarization technique were conducted to measure corrosion rate and inhibition efficiency of mild steel in solution containing 1.0 M of hydrochloric acid with various concentration of inhibitor at room temperature. The results showed that, the rate of corrosion dropped from 8.09 mmpy in solution containing no inhibitor to 0.72 mmpy in solution containing 150g/l inhibitor while inhibition efficiency up to 91% was obtained. The polarization curve in polarization experiments shows that the inhibition efficiency is 86% with high concentration of inhibitor. The adsorption of ginger extract on the surface of mild steel was observed by using optical microscope and the characterization analysis was done by using pH measurement method. When high concentration of green inhibitor in the acid solution is used, the pH at the surface of steel is increasing.

  2. Arginase Inhibitor in the Pharmacological Correction of Endothelial Dysfunction

    Science.gov (United States)

    Pokrovskiy, Mihail V.; Korokin, Mihail V.; Tsepeleva, Svetlana A.; Pokrovskaya, Tatyana G.; Gureev, Vladimir V.; Konovalova, Elena A.; Gudyrev, Oleg S.; Kochkarov, Vladimir I.; Korokina, Liliya V.; Dudina, Eleonora N.; Babko, Anna V.; Terehova, Elena G.

    2011-01-01

    This paper is about a way of correction of endothelial dysfunction with the inhibitor of arginase: L-norvaline. There is an imbalance between vasoconstriction and vasodilatation factors of endothelium on the basis of endothelial dysfunction. Among vasodilatation agents, nitrogen oxide plays the basic role. Amino acid L-arginine serves as a source of molecules of nitrogen oxide in an organism. Because of the high activity of arginase enzyme which catalyzes the hydrolysis of L-arginine into ornithine and urea, the bioavailability of nitrogen oxide decreases. The inhibitors of arginase suppress the activity of the given enzyme, raising and production of nitrogen oxide, preventing the development of endothelial dysfunction. PMID:21747978

  3. New synthetic thrombin inhibitors: molecular design and experimental verification.

    Directory of Open Access Journals (Sweden)

    Elena I Sinauridze

    Full Text Available BACKGROUND: The development of new anticoagulants is an important goal for the improvement of thromboses treatments. OBJECTIVES: The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. METHODS: Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. RESULTS: New compounds that are both effective direct thrombin inhibitors (the best K(I was 1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C. CONCLUSIONS: The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications.

  4. Preventative Maintenance.

    Science.gov (United States)

    Migliorino, James

    Boards of education must be convinced that spending money up front for preventive maintenance will, in the long run, save districts' tax dollars. A good program of preventive maintenance can minimize disruption of service; reduce repair costs, energy consumption, and overtime; improve labor productivity and system equipment reliability; handle…

  5. Fiber Optic Sensor for Real-Time Sensing of Silica Scale Formation in Geothermal Water.

    Science.gov (United States)

    Okazaki, Takuya; Orii, Tatsuya; Ueda, Akira; Ozawa, Akiko; Kuramitz, Hideki

    2017-06-13

    We present a novel fiber optic sensor for real-time sensing of silica scale formation in geothermal water. The sensor is fabricated by removing the cladding of a multimode fiber to expose the core to detect the scale-formation-induced refractive index change. A simple experimental setup was constructed to measure the transmittance response using white light as a source and a spectroscopy detector. A field test was performed on geothermal water containing 980 mg/L dissolved silica at 93 °C in Sumikawa Geothermal Power Plant, Japan. The transmittance response of the fiber sensor decreased due to the formation of silica scale on the fiber core from geothermal water. An application of this sensor in the evaluation of scale inhibitors was demonstrated. In geothermal water containing a pH modifier, the change of transmittance response decreased with pH decrease. The effectiveness of a polyelectrolyte inhibitor in prevention of silica scale formation was easily detectable using the fiber sensor in geothermal water.

  6. A dose-response relationship between exposure to a large-scale HIV preventive intervention and consistent condom use with different sexual partners of female sex workers in southern India

    Directory of Open Access Journals (Sweden)

    Deering Kathleen N

    2011-12-01

    Full Text Available Abstract Background The Avahan Initiative, a large-scale HIV preventive intervention targeted to high-risk populations including female sex workers (FSWs, was initiated in 2003 in six high-prevalence states in India, including Karnataka. This study assessed if intervention exposure was associated with condom use with FSWs’ sexual partners, including a dose-response relationship. Methods Data were from a cross-sectional study (2006-07 of 775 FSWs in three districts in Karnataka. Survey methods accounted for the complex cluster sampling design. Bivariate and multivariable logistic regression was used to separately model the relationships between each of five intervention exposure variables and five outcomes for consistent condom use (CCU= always versus frequently/sometimes/never with different sex partners, including with: all clients; occasional clients; most recent repeat client; most recent non-paying partner; and the husband or cohabiting partner. Linear tests for trends were conducted for three continuous intervention exposure variables. Results FSWs reported highest CCU with all clients (81.7%; CCU was lowest with FSWs’ husband or cohabiting partner (9.6%. In multivariable analysis, the odds of CCU with all clients and with occasional clients were 6.3-fold [95% confidence intervals, CIs: 2.8-14.5] and 2.3-fold [95% CIs: 1.4-4.1] higher among FSWs contacted by intervention staff and 4.9-fold [95% CIs: 2.6-9.3] and 2.3-fold [95% CIs: 1.3-4.1] higher among those who ever observed a condom demonstration by staff, respectively, compared to those who had not. A significant dose-response relationship existed between each of these CCU outcomes and increased duration since first contacted by staff (P=0.001; P=0.006 and numbers of condom demonstrations witnessed (P=0.004; P=0.026; a dose-response relationship was also observed between condom use with all clients and number of times contacted by staff (P=0.047. Intervention exposure was not

  7. THE CAPABILITIES OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN CLINICAL PRACTICE: FOCUS ON VASOPROTECTION

    Directory of Open Access Journals (Sweden)

    D. B. Nebieridze

    2007-01-01

    Full Text Available Data of large-scale research that shows comprehensive abilities of an angiotensin converting enzyme (ACE inhibitors in clinical practice were represented. The traditional usage of ACE inhibitors in patients with arterial hypertension and chronic heart failure has extended recently. The study results demonstrate the efficacy of ACE inhibitors in slowing down of disease progression related to atherosclerosis and prove the possibility of a new clinical approach. Evidences support new strategic abilities of a number of ACE inhibitors (ramipril, perindopril, which are associated with vasoprotection.

  8. Reliability, validity and factorial structure of the Arabic version of the international suicide prevention trial (InterSePT) scale for suicidal thinking in schizophrenia patients in Doha, Qatar.

    Science.gov (United States)

    Hammoudeh, Samer; Ghuloum, Suhaila; Mahfoud, Ziyad; Opler, Mark; Khan, Anzalee; Yehya, Arij; Abdulhakam, Abdulmoneim; Al-Mujalli, Azza; Hani, Yahya; Elsherbiny, Reem; Al-Amin, Hassen

    2016-12-07

    Patients with schizophrenia are known to have higher rates of mortality and morbidity when compared to the general population. Suicidality is a major contributor to increased mortality. The International Suicide Prevention Trial (InterSePT) Scale for Suicidal Thinking (ISST) is a validated tool to assess current suicidal ideation in patients with schizophrenia. The aims of the study were to culturally adapt the Arabic translation of ISST and to examine the psychometric characteristics of the Arabic version of the ISST among patients with schizophrenia in Qatar. ISST was translated and adapted into formal Arabic using the back translation method. Patients diagnosed with schizophrenia were randomly recruited from the department of Psychiatry, Rumailah Hospital, Doha, Qatar. Healthy controls were randomly recruited from two primary health care centers in Doha, Qatar. The Arabic version of Module B for suicidality in Mini International Neuropsychiatric Interview was used as the gold standard to which the Arabic ISST was compared. The study sample (n = 199) was composed of 100 patients diagnosed with schizophrenia (age 35.30 ± 10.04 years; M/F is 2/1) and 99 controls (age 33.98 ± 8.33 years; M/F is 2/3). The mean score on the ISST was 3.03 ± 4.75 vs. 0.47 ± 1.44 for the schizophrenia and control groups, respectively. Inter-rater reliability coefficient was 0.95, p > 0.001. The overall Cronbach's alpha was 0.92. Principal Component Analysis produced 3 factors explaining a total of 73.8% of variance. This is the first study in the Arab countries to validate the Arabic version of the ISST. The psychometric properties indicate that the Arabic ISST is a valid tool to assess the severity of suicidal ideation in Arabic patients with schizophrenia.

  9. 6beta,19-Bridged androstenedione analogs as aromatase inhibitors.

    Science.gov (United States)

    Komatsu, Sachiko; Yaguchi, Ayaka; Yamashita, Kouwa; Nagaoka, Masao; Numazawa, Mitsuteru

    2009-11-01

    Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New 6beta,19-bridged steroid analogs of androstenedione, 6beta,19-epithio- and 6beta,19-methano compounds 11 and 17, were synthesized starting from 19-hydroxyandrostenedione (6) and 19-formylandrost-5-ene-3beta,17beta-yl diacetate (12), respectively, as aromatase inhibitors. All of the compounds including known steroids 6beta,19-epoxyandrostenedione (4) and 6beta,19-cycloandrostenedione (5) tested were weak to poor competitive inhibitors of aromatase and, among them, 6beta,19-epoxy steroid 4 provided only moderate inhibition (K(i): 2.2 microM). These results show that the 6beta,19-bridged groups of the inhibitors interfere with binding in active site of aromatase.

  10. Angiogenesis Inhibitors in NSCLC

    Directory of Open Access Journals (Sweden)

    Anna Manzo

    2017-09-01

    Full Text Available Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC. Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL that demonstrated an improvement of about two months in progression-free survival (PFS in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR 0.857, p = 0.0235. In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (p = 0.0019, and improved OS (12.6 versus 10.3 months in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge.

  11. Prevention: Exercise

    Medline Plus

    Full Text Available ... Physical Therapy Postural Training Traction Watchful Waiting and Education Injection Treatments for Spinal Pain Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 Tips for a Healthy Back ...

  12. Prevention: Exercise

    Medline Plus

    Full Text Available ... Exercise Strength Training for the Elderly Other Back Pack Safety Pregnancy and Back Pain Preventing Osteoporosis Back ... in very slightly. Hold a ball directly in front of you. Keep your abdominal muscles tight and ...

  13. Prevention: Exercise

    Medline Plus

    Full Text Available ... A SPECIALIST Prevention Strengthening Exercise Committee Exercise Committee Core Strengthening Many popular forms of exercise focus on ... acute pain, you should stop doing it. Transverse Core Strengthening This strengthens the muscles that cross from ...

  14. Preventive analgesia

    DEFF Research Database (Denmark)

    Dahl, Jørgen B; Kehlet, Henrik

    2011-01-01

    This paper will discuss the concepts of pre-emptive and preventive analgesia in acute and persistent postsurgical pain, based on the most recent experimental and clinical literature, with a special focus on injury-induced central sensitization and the development from acute to chronic pain. Recent...... findings: The nature of central sensitization during acute and chronic postsurgical pain share common features, and there may be interactions between acute and persistent postoperative pain. The term ‘pre-emptive analgesia’ should be abandoned and replaced by the term ‘preventive analgesia’. Recent studies...... of preventive analgesia for persistent postoperative pain are promising. However, clinicians must be aware of the demands for improved design of their clinical studies in order to get more conclusive answers regarding the different avenues for intervention. Summary: The concept of preventive analgesia is still...

  15. Prevention: Exercise

    Medline Plus

    Full Text Available ... 10 Tips for a Healthy Back Smoking Weight Patient Safety Exercise Strengthening Strengthen Your Core! Stretching/Flexibility ... Pain Preventing Osteoporosis Back Pain Basics Book RESOURCES Patient Information Feature Articles Patient Q&A Success Stories ...

  16. Prevention: Exercise

    Medline Plus

    Full Text Available ... Tips for a Healthy Back Smoking Weight Patient Safety Exercise Strengthening Strengthen Your Core! Stretching/Flexibility Aerobic ... Strength Training for the Elderly Other Back Pack Safety Pregnancy and Back Pain Preventing Osteoporosis Back Pain ...

  17. Prevention: Exercise

    Medline Plus

    Full Text Available ... Changes Hydrotherapy Manual Therapy Physical Therapy Postural Training Traction Watchful Waiting and Education Injection Treatments for Spinal Pain Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 ...

  18. Prevention: Exercise

    Medline Plus

    Full Text Available ... and Education Injection Treatments for Spinal Pain Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle ... Z Spine Specialists Videos 9 for Spine Epidural Steroid Injections Exercise: The Backbone of Spine Treatment Spondylolisthesis ...

  19. Prevention: Exercise

    Medline Plus

    Full Text Available ... Low Back Pain Chronic Low Back Pain SI Joint Pain Other Scoliosis Back Pain and Emotional Distress ... Spinal Pain Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 Tips for a ...

  20. Prevention: Exercise

    Medline Plus

    Full Text Available ... Strengthen Your Core! Stretching/Flexibility Aerobic Exercise Cervical Exercise Strength Training for the Elderly Other Back Pack Safety Pregnancy and Back Pain Preventing Osteoporosis Back Pain Basics ...

  1. Salmonella Prevention

    Science.gov (United States)

    ... indirect contact between reptiles (turtles, iguanas, other lizards, snakes) and infants or immunocompromised persons. Don't work ... help prevent salmonellosis caused by contaminated foods. Better education of food industry workers in basic food safety ...

  2. Thrombin inhibitors from different animals.

    Science.gov (United States)

    Tanaka-Azevedo, A M; Morais-Zani, K; Torquato, R J S; Tanaka, A S

    2010-01-01

    Venous and arterial thromboembolic diseases are still the most frequent causes of death and disability in high-income countries. Clinical anticoagulants are inhibitors of enzymes involved in the coagulation pathway, such as thrombin and factor X(a). Thrombin is a key enzyme of blood coagulation system, activating the platelets, converting the fibrinogen to the fibrin net, and amplifying its self-generation by the activation of factors V, VIII, and XI. Thrombin has long been a target for the development of oral anticoagulants. Furthermore, selective inhibitors of thrombin represent a new class of antithrombotic agents. For these reasons, a number of specific thrombin inhibitors are under evaluation for possible use as antithrombotic drugs. This paper summarizes old and new interests of specific thrombin inhibitors described in different animals.

  3. Thrombin Inhibitors from Different Animals

    Directory of Open Access Journals (Sweden)

    A. M. Tanaka-Azevedo

    2010-01-01

    Full Text Available Venous and arterial thromboembolic diseases are still the most frequent causes of death and disability in high-income countries. Clinical anticoagulants are inhibitors of enzymes involved in the coagulation pathway, such as thrombin and factor Xa. Thrombin is a key enzyme of blood coagulation system, activating the platelets, converting the fibrinogen to the fibrin net, and amplifying its self-generation by the activation of factors V, VIII, and XI. Thrombin has long been a target for the development of oral anticoagulants. Furthermore, selective inhibitors of thrombin represent a new class of antithrombotic agents. For these reasons, a number of specific thrombin inhibitors are under evaluation for possible use as antithrombotic drugs. This paper summarizes old and new interests of specific thrombin inhibitors described in different animals.

  4. Selective Serotonin Reuptake Inhibitors (SSRIs)

    Science.gov (United States)

    ... Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects. http://www.uptodate.com/home. Accessed June 2, 2016. Mental health medications. National Institute of Mental Health. http://www. ...

  5. HIV Prevention

    Centers for Disease Control (CDC) Podcasts

    2012-02-01

    Dr. Kevin Fenton, Director of CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, talks about steps people can take to protect their health from HIV.  Created: 2/1/2012 by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP).   Date Released: 2/1/2012.

  6. JAK protein kinase inhibitors.

    Science.gov (United States)

    Thompson, James E

    2005-06-01

    In humans, the Janus protein tyrosine kinase family (JAKs) contains four members: JAK1, JAK2, JAK3 and TYK2. JAKs phosphorylate signal transducers and activators of transcription (STATs) simultaneously with other phosphorylations required for activation, and there are several cellular mechanisms in place to inhibit JAK/STAT signaling. That one might be able to modulate selected JAK/STAT-mediated cellular signals by inhibiting JAK kinase activity to effect a positive therapeutic outcome is a tantalizing prospect, as yet incompletely realized. While current data suggest no therapeutic use for JAK1 and TYK2 inhibition, JAK2 inhibition seems a promising but not definitively tested mechanism for treatment of leukemia. More promising, however, are data indicating a possible therapeutic use of JAK3 inhibition. The restriction of the JAK3-deficient phenotype to the hematopoietic system and the resulting profound immune suppression suggest that JAK3 could be a target for immunosuppressive therapies used to prevent organ transplant rejection.

  7. Lonafarnib is a potential inhibitor for neovascularization.

    Directory of Open Access Journals (Sweden)

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  8. Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria

    Directory of Open Access Journals (Sweden)

    Martin Haluzík

    2013-01-01

    Full Text Available Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4 inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1 dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

  9. Allosteric Small-Molecule Inhibitors of the AKT Kinase

    Science.gov (United States)

    Dalafave, D. S.

    This research addresses computational design of small druglike molecules for possible anticancer applications. AKT and SGK are kinases that control important cellular functions. They are highly homologous, having similar activators and targets. Cancers with increased SGK activity may develop resistance to AKT-specific inhibitors. Our goal was to design new molecules that would bind both AKT and SGK, thus preventing the development of drug resistance. Most kinase inhibitors target the kinase ATP-binding site. However, the high similarity in this site among kinases makes it difficult to target specifically. Furthermore, mutations in this site can cause resistance to ATP-competitive kinase inhibitors. We used existing AKT inhibitors as initial templates to design molecules that could potentially bind the allosteric sites of both AKT and SGK. Molecules with no implicit toxicities and optimal drug-like properties were used for docking studies. Binding energies of the stable complexes that the designed molecules formed with AKT and SGK were calculated. Possible applications of the designed putative inhibitors against cancers with overexpressed AKT/SGK is discussed.

  10. Novel Synthesis of Vegetable Oil Derived Corrosion Inhibitors

    OpenAIRE

    Paul Rostron; Sonia Kasshanna

    2015-01-01

    Two different naturally occurring vegetable oils, Cress seed oil, and Linseed oil were chemically modified via novel one pot synthesis to produce fatty acid derived amides. These were characterized by their ability to prevent corrosion of carbon steel in vigorously stirred, aerated seawater, one of the most corrosive naturally occurring environments. Corrosion inhibitor efficiencies of up to 99.6% or a corrosion rate reduction factor of 250 in this medium is reported. The one pot synthetic st...

  11. The role of factor Xa inhibitors in venous thromboembolism treatment

    Science.gov (United States)

    Cabral, Katherine P; Ansell, Jack E

    2015-01-01

    Three factor Xa inhibitors have been studied in the treatment of venous thromboembolism, both for acute therapy and as extended therapy to prevent recurrent events. Rivaroxaban, apixaban, and edoxaban have all proven to be effective in Phase III clinical trials for this indication when compared to current standard of therapy with similar or less bleeding. Nevertheless, the agents all offer different pharmacological profiles, which have an impact on patient selection and potential advantages in clinical practice. PMID:25673997

  12. Protease inhibitors targeting coronavirus and filovirus entry.

    Science.gov (United States)

    Zhou, Yanchen; Vedantham, Punitha; Lu, Kai; Agudelo, Juliet; Carrion, Ricardo; Nunneley, Jerritt W; Barnard, Dale; Pöhlmann, Stefan; McKerrow, James H; Renslo, Adam R; Simmons, Graham

    2015-04-01

    In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and

  13. Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.

    Science.gov (United States)

    Heikkilä, Timo; Ramsey, Christopher; Davies, Matthew; Galtier, Christophe; Stead, Andrew M W; Johnson, A Peter; Fishwick, Colin W G; Boa, Andrew N; McConkey, Glenn A

    2007-01-25

    Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.

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

    Science.gov (United States)

    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.

  15. Prevent Pneumonia

    Centers for Disease Control (CDC) Podcasts

    2015-08-06

    CDC’s Matthew Westercamp explains what pneumonia is, its symptoms, and how to prevent it.  Created: 8/6/2015 by National Center for Immunization and Respiratory Diseases (NCIRD), Division of Bacterial Diseases (DBD), Respiratory Diseases Branch (RDB).   Date Released: 8/6/2015.

  16. Bullying Prevention

    Science.gov (United States)

    Kemp, Patrice

    2016-01-01

    The focus of the milestone project is to focus on bridging the gap of bullying and classroom instruction methods. There has to be a defined expectations and level of accountability that has to be defined when supporting and implementing a plan linked to bullying prevention. All individuals involved in the student's learning have to be aware of…

  17. HIV Prevention

    Science.gov (United States)

    ... Abroad Treatment Basic Statistics Get Tested Find an HIV testing site near you. Enter ZIP code or city Follow HIV/AIDS CDC HIV CDC HIV/AIDS See RSS | ... Collapse All Is abstinence the only 100% effective HIV prevention option? Yes. Abstinence means not having oral, ...

  18. Concepts of scale and scaling

    Science.gov (United States)

    Jianguo Wu; Harbin Li

    2006-01-01

    The relationship between pattern and process is of great interest in all natural and social sciences, and scale is an integral part of this relationship. It is now well documented that biophysical and socioeconomic patterns and processes operate on a wide range of spatial and temporal scales. In particular, the scale multiplicity and scale dependence of pattern,...

  19. Positron emitter labeled enzyme inhibitors

    Science.gov (United States)

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

    1987-05-22

    This invention involved a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide in activators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

  20. Screening for vaccinia virus egress inhibitors: separation of IMV, IEV, and EEV.

    Science.gov (United States)

    Byrd, Chelsea M; Hruby, Dennis E

    2012-01-01

    Concerns about the possible use of variola virus as a biological weapon as well as the need for therapeutics for the treatment or prevention of naturally acquired poxvirus infections or vaccination complications have led to the search for small molecule inhibitors of poxvirus replication. One unique and attractive target for antiviral development is viral egress. Part of understanding the mechanism of action of viral egress inhibitors involves determining which virion form is being made. This can be accomplished through buoyant density centrifugation.

  1. PROTEIN INHIBITORS SYNTHESISED BY MICROORGANISMS

    Directory of Open Access Journals (Sweden)

    O. V. Matseliukh

    2013-12-01

    Full Text Available In a review the literature data on protein inhibitors of peptidases synthesised by different types of microorganisms are systematized. It is shown that at the present time on the basis of amino acid sequence homology protein inhibitors are grouped into 77 families, 29 of which include inhibitors of microorganisms. The mechanism of inhibition of peptidases by proteins may be related to their catalytic mechanism of action or include unrelated blocking of the active site or its surroundings. The structural elements of the protein inhibitors are responsible for binding to the peptidases, mostly include the N- or C-terminal sequences, the unprotected polypeptide loops (chains, which are acting independently or in combination with other elements. The basic properties, structural features and, where it is established, the functions of the protein inhibitors of peptidases are considered. Since some of these proteins effectively inhibit such peptidases as subtilisin, chymotrypsin, pancreatic elastase, their practical use in the treatment of diseases such as emphysema, arthritis, pancreatitis, thrombosis, hypertension, muscular dystrophy, cancer. It is suggested that the role of a bacterial homologue of Escherichia coli alphaacroglobulin, which is a periplasmic protein, is to protect the periplasmic space from the action of bacteria own proteases. Based on the specific properties of alpha-2-macroglobulin to bind endopeptidases active molecules, they are used in biotechnology to isolate endopeptidases from crude biological preparations and titration of its active centers. Some free–living bacteria are able to synthesize protein inhibitors to protect from the effects of its own enzymes, while the presence of these proteins in pathogens may play a certain role both in the infectious process and in the protection of the host proteases.

  2. Evolution of resistance to quorum sensing inhibitors

    Science.gov (United States)

    Kalia, Vipin C.; Wood, Thomas K.; Kumar, Prasun

    2013-01-01

    The major cause of mortality and morbidity in human beings is bacterial infection. Bacteria have developed resistance to most of the antibiotics primarily due to large scale and “indiscriminate” usage. The need is to develop novel mechanisms to treat bacterial infections. The expression of pathogenicity during bacterial infections is mediated by a cell density dependent phenomenon known as quorum sensing (QS). A wide array of QS systems (QSS) is operative in expressing the virulent behavior of bacterial pathogens. Each QSS may be mediated largely by a few major signals along with others produced in minuscule quantities. Efforts to target signal molecules and their receptors have proved effective in alleviating the virulent behavior of such pathogenic bacteria. These QS inhibitors (QSIs) have been reported to be effective in influencing the pathogenicity without affecting bacterial growth. However, evidence is accumulating that bacteria may develop resistance to QSIs. The big question is whether QSIs will meet the same fate as antibiotics? PMID:24194099

  3. Alternative Agents in Type 1 Diabetes in Addition to Insulin Therapy: Metformin, Alpha-Glucosidase Inhibitors, Pioglitazone, GLP-1 Agonists, DPP-IV Inhibitors, and SGLT-2 Inhibitors.

    Science.gov (United States)

    DeGeeter, Michelle; Williamson, Bobbie

    2016-04-01

    Insulin is the mainstay of current treatment for patients with type 1 diabetes mellitus (T1DM). Due to increasing insulin resistance, insulin doses are often continually increased, which may result in weight gain for patients. Medications currently approved for the treatment of type 2 diabetes offer varying mechanisms of action that can help to reduce insulin resistance and prevent or deter weight gain. A MEDLINE search was conducted to review literature evaluating the use of metformin, alpha-glucosidase inhibitors, pioglitazone, glucagon-like peptide 1 agonists, dipeptidyl peptidase, and sodium-dependent glucose transporter 2 inhibitors, in patients with T1DM. Varying results were found with some benefits including reductions in hemoglobin A1c, decreased insulin doses, and favorable effects on weight. Of significance, a common fear of utilizing multiple therapies for diabetes treatment is the risk of hypoglycemia, and this review displayed limited evidence of hypoglycemia with multiple agents. © The Author(s) 2014.

  4. Combination therapy with beta-adrenergic receptor antagonists and phosphodiesterase inhibitors for chronic heart failure.

    Science.gov (United States)

    Van Tassell, Benjamin W; Radwanski, Przemyslaw; Movsesian, Matthew; Munger, Mark A

    2008-12-01

    Abstract Rational use of phosphodiesterase inhibitors represents an ongoing controversy in contemporary pharmacotherapy for heart failure. In randomized clinical trials, phosphodiesterase inhibitors increased cardiac output at the expense of worsening the rates of sudden cardiac death and cardiovascular mortality. Preliminary findings from ongoing clinical and preclinical investigations of phosphodiesterase activity suggest that combined use of phosphodiesterase inhibitors with beta-adrenergic antagonists may prevent these adverse outcomes. Compartmentation of cyclic adenosine 3',5'-monophosphate signaling may prove critical in determining myocardial response to combination therapy.

  5. The Inhibitor of wax 1 locus (Iw1) prevents formation of β- and OH-β-diketones in wheat cuticular waxes and maps to a sub-cM interval on chromosome arm 2BS

    DEFF Research Database (Denmark)

    Adamski, Nikolai; Bush, Maxwell; Simmonds, James

    2013-01-01

    Glaucousness is described as the scattering effect of visible light from wax deposited on the cuticle of plant aerial organs. In wheat, two dominant genes lead to non-glaucous phenotypes: Inhibitor of wax 1 (Iw1) and Iw2. The molecular mechanisms and the exact extent (beyond visual assessment) by...

  6. Angiotensin-I-Converting Enzyme (ACE Inhibitors from Marine Resources: Prospects in the Pharmaceutical Industry

    Directory of Open Access Journals (Sweden)

    Isuru Wijesekara

    2010-03-01

    Full Text Available Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension.

  7. Role of Factor Xa Inhibitors in Cancer-Associated Thrombosis: Any New Data?

    Directory of Open Access Journals (Sweden)

    Ali Zalpour

    2011-01-01

    Full Text Available The association between cancer and venous thromboembolism (VTE has been well documented in the literature. Prevention and treatment of VTE in cancer patients is imperative. Typically, the mainstay regimen for VTE prevention and treatment has been anticoagulation therapy, unless contraindicated. This therapy consists of unfractionated heparin (UFH, low-molecular-weight heparin (LMWH, factor Xa inhibitor, or vitamin K antagonist (VKA. Current guidelines recommend LMWH over VKA for the treatment of VTE in cancer patients. Factor-specific anticoagulants have been proven safe and effective, and recently factor Xa inhibitors have emerged as a treatment alternative to heparins and VKA. Currently, three factor Xa inhibitors have been identified: fondaparinux (the only one approved so far by the US Food and Drug Administration, idraparinux (in clinical trials, and idrabiotaparinux (in clinical trials. This paper will examine the role of these agents, focusing on fondaparinux, for the prevention and treatment of VTE in cancer patients.

  8. Proton pump inhibitors and gastroenteritis

    NARCIS (Netherlands)

    R.J. Hassing (Robert); A. Verbon (Annelies); H. de Visser (Herman); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

    2016-01-01

    textabstractAn association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam

  9. DETERMINATION OF CORROSION INHIBITOR CRITERIA FOR TYPE III/IIIA TANKS DURING SALT DISSOLUTION OPERATIONS SUMMARY DOCUMENT

    Energy Technology Data Exchange (ETDEWEB)

    Mickalonis, J.; Wiersma, B.; Garcia-Diaz, B.

    2009-10-01

    Dissolution of salt from Type III/IIIA waste tanks at the Savannah River Site may create solutions with inhibitor concentrations below those currently required (0.6M OH{sup -} and 1.1M OH{sup -} + NO{sub 2}{sup -}) per the Corrosion Control Program for high nitrate salt solutions (5.5 to 8.5M NO{sub 3}{sup -}). An experimental program was conducted to evaluate the corrosion susceptibility of grade A537 carbon steel for waste simulants containing 4.5-8.5M NaNO{sub 3} with maximum inhibitor concentrations of 0.6M NaOH and 0.2M NaNO{sub 2}. These maximum inhibitor concentrations used in this program are at a reduced level from those currently required. Current requirements were initially established for the Types I, II and IV tanks made of A285 carbon steel. The experimental program involved corrosion testing to evaluate the pitting and stress corrosion stress corrosion cracking (SCC) susceptibility of the Type III/IIIA waste tank materials. The program was conducted in two phases; the results of the first phase were reported previously (WSRC-STI-2006-00029). In this second phase, the corrosion specimens were modified to represent the 'as-fabricated' condition of the tank wall, and included specimens with mill scale, ground welds and stress-relief heat treatments. The complete description of the corrosion testing and the results are reported herein. The collective corrosion test results for A537 carbon steel in high nitrate waste simulants (4.5 - 8.5M) with the maximum inhibitor concentrations of 0.6M NaOH and 0.2M NaNO{sub 2} were as follows: (1) In long-term non-polarized U-bend testing, heat treatment, similar to the waste tank stress relief regime, reduced the incidence of cracking over the 18-month test period. Vapor space SCC was found to initiate on non-heat treated U-bend coupons. (2) In polarized U-bend testing, cracking occurred on U-bend coupons that had welds prepared similar to those in the waste tanks, i.e. ground and heat treated. (3) In

  10. Antiretroviral protease inhibitors accelerate glutathione export from viable cultured rat neurons.

    Science.gov (United States)

    Brandmann, Maria; Hohnholt, Michaela C; Petters, Charlotte; Dringen, Ralf

    2014-05-01

    Antiretroviral protease inhibitors are crucial components of the antiretroviral combination therapy that is successfully used for the treatment of patients with HIV infection. To test whether such protease inhibitors affect the glutathione (GSH) metabolism of neurons, cultured cerebellar granule neurons were exposed to indinavir, nelfinavir, lopinavir or ritonavir. In low micromolar concentrations these antiretroviral protease inhibitors did not acutely compromise the cell viability, but caused a time- and concentration-dependent increase in the accumulation of extracellular GSH which was accompanied by a matching loss in cellular GSH. The stimulating effect by indinavir, lopinavir and ritonavir on GSH export was immediately terminated upon removal of the protease inhibitors, while the nelfinavir-induced stimulated GSH export persisted after washing the cells. The stimulation of neuronal GSH export by protease inhibitors was completely prevented by MK571, an inhibitor of the multidrug resistance protein 1, suggesting that this transporter mediates the accelerated GSH export during exposure of neurons to protease inhibitors. These data suggest that alterations in brain GSH metabolism should be considered as potential side-effects of a treatment with antiretroviral protease inhibitors.

  11. Selective serotonin reuptake inhibitors for depression in pregnancy.

    Science.gov (United States)

    Susser, Leah C; Sansone, Stephanie A; Hermann, Alison D

    2016-12-01

    Perinatal depression is associated with a high risk of morbidity and mortality and may have long-term consequences on child development. The US Preventive Services Task Force has recently recognized the importance of identifying and treating women with depression in the perinatal period. However, screening and accessing appropriate treatment come with logistical challenges. In many areas, there may not be sufficient access to psychiatric care, and, until these resources develop, the burden may inadvertently fall on obstetricians. As a result, understanding the risks of perinatal depression in comparison with the risks of treatment is important. Many studies of selective serotonin reuptake inhibitors in pregnancy fail to control for underlying depressive illness, which can lead to misinterpretation of selective serotonin reuptake inhibitor risk by clinicians. This review discusses the risks and benefits of selective serotonin reuptake inhibitor treatment in pregnancy within the context of perinatal depression. Whereas selective serotonin reuptake inhibitors may be associated with certain risks, the absolute risks are low and may be outweighed by the risks of untreated depression for many women and their offspring. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Gene therapy for immune tolerance induction in hemophilia with inhibitors.

    Science.gov (United States)

    Arruda, V R; Samelson-Jones, B J

    2016-06-01

    The development of inhibitors, i.e. neutralizing alloantibodies against factor (F) VIII or FIX, is the most significant complication of protein replacement therapy for patients with hemophilia, and is associated with both increased mortality and substantial physical, psychosocial and financial morbidity. Current management, including bypassing agents to treat and prevent bleeding, and immune tolerance induction for inhibitor eradication, is suboptimal for many patients. Fortunately, there are several emerging gene therapy approaches aimed at addressing these unmet clinical needs of patients with hemophilia and inhibitors. Herein, we review the mounting evidence from preclinical hemophilia models that the continuous uninterrupted expression of FVIII or FIX delivered as gene therapy can bias the immune system towards tolerance induction, and even promote the eradication of pre-existing inhibitors. We also discuss several gene transfer approaches that directly target immune cells in order to promote immune tolerance. These preclinical findings also shed light on the immunologic mechanisms that underlie tolerance induction. © 2016 International Society on Thrombosis and Haemostasis.

  13. [Anxiety prevention among schoolchildren].

    Science.gov (United States)

    Essau, C A; Conradt, J; Ederer, E M

    2004-09-01

    The FRIENDS programme is a prevention and early intervention programme, which teaches children strategies to cope with anxiety and challenging situations. This paper examines the social validity of the German version of the FRIENDS programme using data from a large-scale study on the prevention of anxiety disorders in schoolchildren, which is funded by the Dr. Karl-Wilder Stiftung. In this paper, data of 208 schoolchildren (aged 9 to 12 years) are used. Results show that the children and their parents were highly satisfied with the FRIENDS programme. Childrens attendance and completion of their homework assignments were very high. Both the children and their parents rated relaxation exercises and thinking helpful thoughts as being more useful for the children than other skills. Treatment acceptability correlated significantly with the childrens clinical outcome. The implications of our findings for future research are discussed.

  14. Nicotinamide phosphoribosyltransferase inhibitors, design, preparation and SAR

    DEFF Research Database (Denmark)

    Christensen, Mette Knak; Erichsen, Kamille Dumong; Olesen, Uffe Hogh

    2013-01-01

    Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. Using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described and compounds optimize...

  15. Anti-corrosion performance of composite inhibitor for N80 steel in NaIO4 solution

    Science.gov (United States)

    Zhao, Liqiang; Zhu, Yanhua; Zhang, Jian; Liu, Pingli; Liu, Yigang; Meng, Xianghai; Liu, Changlong

    2017-10-01

    A kind of composite inhibitor was chosen and compounded by zinc nitrate, sodium silicate, sodium tri-polyphosphate by orthogonal design method. The anti-corrosion performance of this composite inhibitor for N80 steel in sodium periodate solution was investigated through electrochemical measurements and soaking experiments, followed by corrosion morphology observations and corrosion products analysis. The results indicated that the composite inhibitor is a cathodic inhibitor and suitable for application in sodium periodate solution, the inhibition efficiency of optimal inhibitor can reach to 95.3%. The composite inhibitor inhibited the corrosion process by preventing the contact of corrosive medium and steel surface through formation of a protective film on the surface of N80 steel.

  16. First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus.

    Science.gov (United States)

    Kaku, Kohei

    2015-01-01

    Dipeptidyl peptidase-4 (DPP-4) inhibitors are weight neutral and well tolerated, and provide better glycaemic control for a longer period compared to conventional therapies. Despite the fact that various drugs are available, glycaemic control remains suboptimal in approximately half of patients with type 2 diabetes mellitus; one of the major reasons for low medication adherence. A novel DPP-4 inhibitor, trelagliptin, was approved in Japan in March 2015, and is the first once-weekly oral antidiabetic agent in the world. In this review, current issues concerning medication adherence for the treatment of diabetes are discussed followed by a summary of the characteristics and future expectations of trelagliptin, by reviewing the recent phase I, II, and III clinical studies of trelagliptin. Trelagliptin has demonstrated superiority to placebo and non-inferiority to alogliptin, indicating its efficacy and tolerance in Japanese patients. Trelagliptin is expected to improve adherence and prevent complications. Due to the convenient dosing regimen, it is expected to be widely used in the clinical setting. A large-scale long-term study will help further confirm its long-term efficacy and safety, patients' satisfaction, and medication adherence.

  17. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

    Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

    2015-01-01

    current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small...

  18. Identification of small molecule inhibitors of Pseudomonas aeruginosa exoenzyme S using a yeast phenotypic screen.

    OpenAIRE

    Anthony Arnoldo; Jasna Curak; Saranya Kittanakom; Igor Chevelev; Vincent T Lee; Mehdi Sahebol-Amri; Becky Koscik; Lana Ljuma; Peter J Roy; Antonio Bedalov; Guri Giaever; Corey Nislow; A Rod Merrill; Stephen Lory; Igor Stagljar

    2008-01-01

    Pseudomonas aeruginosa is an opportunistic human pathogen that is a key factor in the mortality of cystic fibrosis patients, and infection represents an increased threat for human health worldwide. Because resistance of Pseudomonas aeruginosa to antibiotics is increasing, new inhibitors of pharmacologically validated targets of this bacterium are needed. Here we demonstrate that a cell-based yeast phenotypic assay, combined with a large-scale inhibitor screen, identified small molecule inhibi...

  19. Arginase Inhibitor in the Pharmacological Correction of Endothelial Dysfunction

    Directory of Open Access Journals (Sweden)

    Mihail V. Pokrovskiy

    2011-01-01

    Full Text Available This paper is about a way of correction of endothelial dysfunction with the inhibitor of arginase: L-norvaline. There is an imbalance between vasoconstriction and vasodilatation factors of endothelium on the basis of endothelial dysfunction. Among vasodilatation agents, nitrogen oxide plays the basic role. Amino acid L-arginine serves as a source of molecules of nitrogen oxide in an organism. Because of the high activity of arginase enzyme which catalyzes the hydrolysis of L-arginine into ornithine and urea, the bioavailability of nitrogen oxide decreases. The inhibitors of arginase suppress the activity of the given enzyme, raising and production of nitrogen oxide, preventing the development of endothelial dysfunction.

  20. Proteasome inhibitors with photocontrolled activity.

    Science.gov (United States)

    Hansen, Mickel J; Velema, Willem A; de Bruin, Gerjan; Overkleeft, Herman S; Szymanski, Wiktor; Feringa, Ben L

    2014-09-22

    Proteasome inhibitors are widely used in cancer treatment as chemotherapeutic agents. However, their employment often results in severe side effects, due to their non-specific cytotoxicity towards healthy tissue. This problem might be overcome by using a photopharmacological approach, that is, by attaining external, dynamic, spatiotemporal photocontrol over the activity of a cytotoxic agent, achieved by the introduction of a photoswitchable moiety into its molecular structure. Here we describe the design, synthesis, and activity of photoswitchable proteasome inhibitors. Substantial differences in proteasome inhibitory activity in cell extracts were observed before and after irradiation with light. The presented results show potential for the development of chemotherapeutic agents that can be switched on and off with light, constituting a new strategy for spatiotemporally modulating proteasomal activity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Small-molecule arginase inhibitors.

    Science.gov (United States)

    Ivanenkov, Yan A; Chufarova, Nina V

    2014-01-01

    Arginase is an enzyme that metabolizes L-arginine to L-ornithine and urea. In addition to its fundamental role in the hepatic ornithine cycle, it also influences the immune systems in humans and mice. Arginase participates in many inflammatory disorders by decreasing the synthesis of nitric oxide and inducing fibrosis and tissue regeneration. L-arginine deficiency, which is modulated by myeloid cell arginase, suppresses T-cell immune response. This mechanism plays a fundamental role in inflammation-associated immunosuppression. Pathogens can synthesize their own arginase to elude immune reaction. Small-molecule arginase inhibitors are currently described as promising therapeutics for the treatment of several diseases, including allergic asthma, inflammatory bowel disease, ulcerative colitis, cardiovascular diseases (atherosclerosis and hypertension), diseases associated with pathogens (e.g., Helicobacter pylori, Trypanosoma cruzi, Leishmania, Mycobacterium tuberculosis and Salmonella), cancer and induced or spontaneous immune disorders. This article summarizes recent patents in the area of arginase inhibitors and discusses their properties.

  2. Proteasome inhibitors in cancer therapy

    Directory of Open Access Journals (Sweden)

    Wioletta Romaniuk

    2015-12-01

    Full Text Available Proteasomes are multisubunit enzyme complexes. They contain three enzymatic active sites which are termed chymotrypsin-like, trypsin-like, and caspase-like. The elementary function of the proteasomes is degradation of damaged proteins. Proteasome inhibition leads to accumulation of damaged protein, which leads to caspase activation and cell death. This relationship is used in cancer therapy. Bortezomib is the first proteasome inhibitor approved by the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma. Carfilzomib belongs to the second generation of drugs, which was approved by the US FDA in 2012. Currently in the study phase there are four new inhibitors: ixazomib (MLN9780/MLN2238, delanzomib (CEP-18770, oprozomib (ONX0912/PR-047 and marizomib (NPI-0052.

  3. Natural Inhibitors of Maillard Browning

    Science.gov (United States)

    2013-12-01

    incorporated into pre-selected candidate ration components for evaluation via storage, sensory and chemical analysis. The concentration of inhibitor was...inhibiting Maillard browning, also known as non-enzymatic browning, a complex reaction which can lead to darkening of color, off- odors , off-flavors...nutritional intake, and decrease waste due to non-consumption of sensory degraded ration components. 1.1 Maillard Browning Maillard browning, also

  4. Proton Pump Inhibitors and Gastritis

    OpenAIRE

    Suzuki, Masayuki; Suzuki, Hidekazu; Hibi, Toshifumi

    2008-01-01

    Proton pump inhibitors (PPIs) are novel compounds that strongly inhibit the H+/K+-ATPase in the gastric parietal cells to cause profound suppression of acid secretion. Acid-generating ATPase, also known as vacuolar-type ATPase, is located in the lysozomes of leukocytes and osteoclasts and its activity is also reportedly influenced by treatment with PPIs. This concept is supported by the results of studies using autoradiography in which 3H-Lansoprazole uptake sites were clearly detected in the...

  5. Computational analysis of epidermal growth factor receptor mutations predicts differential drug sensitivity profiles towards kinase inhibitors.

    Science.gov (United States)

    Akula, Sravani; Kamasani, Swapna; Sivan, SreeKanth; Manga, Vijjulatha; Vudem, Dashavantha Reddy; Kancha, Rama Krishna

    2018-01-21

    A significant proportion of lung cancer patients carry mutations in the epidermal growth factor receptor (EGFR) kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain were shown to cause enhanced efficacy of inhibitor treatment in NSCLC patients. Several less frequent ("Uncommon") mutations in the EGFR kinase domain with potential implications in treatment response were also reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity/resistance. A large scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed and drug sensitivity profiles for each mutant towards seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity (RIBA) towards each drug as compared to that of the ATP was calculated for each mutant. The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity towards first and next generation kinase inhibitors. The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations towards multiple inhibitors which may help clinicians in deciding mutant-specific treatment strategies. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  6. Structural characterization of Spinacia oleracea trypsin inhibitor III (SOTI-III).

    Science.gov (United States)

    Glotzbach, Bernhard; Schmelz, Stefan; Reinwarth, Michael; Christmann, Andreas; Heinz, Dirk W; Kolmar, Harald

    2013-01-01

    In recent decades, several canonical serine protease inhibitor families have been classified and characterized. In contrast to most trypsin inhibitors, those from garden four o'clock (Mirabilis jalapa) and spinach (Spinacia oleracea) do not share sequence similarity and have been proposed to form the new Mirabilis serine protease inhibitor family. These 30-40-amino-acid inhibitors possess a defined disulfide-bridge topology and belong to the cystine-knot miniproteins (knottins). To date, no atomic structure of this inhibitor family has been solved. Here, the first structure of S. oleracea trypsin inhibitor III (SOTI-III), in complex with bovine pancreatic trypsin, is reported. The inhibitor was synthesized by solid-phase peptide synthesis on a multi-milligram scale and was assayed to test its inhibitory activity and binding properties. The structure confirmed the proposed cystine-bridge topology. The structural features of SOTI-III suggest that it belongs to a new canonical serine protease inhibitor family with promising properties for use in protein-engineering and medical applications.

  7. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome

    DEFF Research Database (Denmark)

    Steg, Ph Gabriel; Mehta, Shamir R; Jukema, J Wouter

    2011-01-01

    To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS).......To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS)....

  8. Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro

    NARCIS (Netherlands)

    Walker, J.B.; Hughes, B.; James, I.; Haddock, P.; Kluft, C.; Bajzar, L.

    2003-01-01

    Two competitive inhibitors of TAFIa (activated thrombin-activable fibrinolysis inhibitor), 2-guanidinoethyl-mercaptosuccinic acid and potato tuber carboxypeptidase inhibitor, variably affect fibrinolysis of clotted human plasma. Depending on their concentration, the inhibitors shortened, prolonged,

  9. Maslowian Scale.

    Science.gov (United States)

    Falk, C.; And Others

    The development of the Maslowian Scale, a method of revealing a picture of one's needs and concerns based on Abraham Maslow's levels of self-actualization, is described. This paper also explains how the scale is supported by the theories of L. Kohlberg, C. Rogers, and T. Rusk. After a literature search, a list of statements was generated…

  10. HIV protease inhibitors in pregnancy : pharmacology and clinical use.

    Science.gov (United States)

    Andany, Nisha; Loutfy, Mona R

    2013-03-01

    The impact of antiretroviral therapy (ART) on the natural history of HIV-1 infection has resulted in dramatic reductions in disease-associated morbidity and mortality. Additionally, the epidemiology of HIV-1 infection worldwide is changing, as women now represent a substantial proportion of infected adults. As more highly effective and tolerable antiretroviral regimens become available, and as the prevention of mother-to-child transmission becomes an attainable goal in the management of HIV-infected individuals, more and more HIV-positive women are choosing to become pregnant and have children. Consequently, it is important to consider the efficacy and safety of antiretroviral agents in pregnancy. Protease inhibitors are a common class of medication used in the treatment of HIV-1 infection and are increasingly being used in pregnancy. However, several studies have raised concerns regarding pharmacokinetic alterations in pregnancy, particularly in the third trimester, which results in suboptimal drug concentrations and a theoretically higher risk of virologic failure and perinatal transmission. Drug level reductions have been observed with each individual protease inhibitor and dose adjustments in pregnancy are suggested for certain agents. Furthermore, studies have also raised concerns regarding the safety of protease inhibitors in pregnancy, particularly as they may increase the risk of pre-term birth and metabolic disturbances. Overall, protease inhibitors are safe and effective for the treatment of HIV-infected pregnant women. Specifically, ritonavir-boosted lopinavir- and atazanavir-based regimens are preferred in pregnancy, while ritonavir-boosted darunavir- and saquinavir-based therapies are reasonable alternatives. This paper reviews the use of protease inhibitors in pregnancy, focusing on pharmacokinetic and safety considerations, and outlines the recommendations for use of this class of medication in the HIV-1-infected pregnant woman.

  11. Helicity scalings

    Energy Technology Data Exchange (ETDEWEB)

    Plunian, F [ISTerre, CNRS, Universite Joseph Fourier, Grenoble (France); Lessinnes, T; Carati, D [Physique Statistique et Plasmas, Universite Libre de Bruxelles (Belgium); Stepanov, R, E-mail: Franck.Plunian@ujf-grenoble.fr [Institute of Continuous Media Mechanics of the Russian Academy of Science, Perm (Russian Federation)

    2011-12-22

    Using a helical shell model of turbulence, Chen et al. (2003) showed that both helicity and energy dissipate at the Kolmogorov scale, independently from any helicity input. This is in contradiction with a previous paper by Ditlevsen and Giuliani (2001) in which, using a GOY shell model of turbulence, they found that helicity dissipates at a scale larger than the Kolmogorov scale, and does depend on the helicity input. In a recent paper by Lessinnes et al. (2011), we showed that this discrepancy is due to the fact that in the GOY shell model only one helical mode (+ or -) is present at each scale instead of both modes in the helical shell model. Then, using the GOY model, the near cancellation of the helicity flux between the + and - modes cannot occur at small scales, as it should be in true turbulence. We review the main results with a focus on the numerical procedure needed to obtain accurate statistics.

  12. Emerging therapies for atopic dermatitis: JAK inhibitors.

    Science.gov (United States)

    Cotter, David G; Schairer, David; Eichenfield, Lawrence

    2018-03-01

    The Janus kinase-signal transducer and activator of transcription pathway is a conserved master regulator of immunity and myeloproliferation. Advanced understanding of this pathway has led to development of targeted inhibitors of Janus kinases (Jakinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Given such success, use of JAK inhibitors for mitigation of atopic dermatitis is under active investigation. Herein, we review the evolving data on the safety and efficacy of JAK inhibitors in treatment of atopic dermatitis. Although it is still early in the study of JAK inhibitors for atopic dermatitis, evidence identifies JAK inhibitors as effective alternatives to conventional therapies. Nonetheless, multiple large safety and efficacy trials are needed before widespread use of JAK inhibitors can be advocated for atopic dermatitis. Copyright © 2017. Published by Elsevier Inc.

  13. Primary measures for reduction of PCDD/F in co-combustion of lignite coal and waste: effect of various inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Marchela E. Pandelova; Dieter Lenoir; Antonius Kettrup; Karl-Werner Schramm [Institute of Ecological Chemistry, Neuherberg (Germany). GSF National Research Center for Environment and Health

    2005-05-01

    A series of experiments was performed focusing on the prevention of polychlorinated dibenzo-p-dioxin and furan (PCDD/F) formation by the use of various inhibitors added to the fuel before co-combustion. A mixture of lignite coal, solid waste, and poly(vinyl chloride) (PVC) was thermally treated in a laboratory-scale furnace at 400{degree} C. Twenty additives were investigated at a level of 10 wt % of the total fuel during the experiments. These were divided into four groups: metal oxides,N-containing compounds, S-containing compounds, and N- and S-containing compounds. The resulting values showed a significant reduction of PCDD/F levels when N- and S-containing compounds were used as additives to the fuel. Principle component analysis (PCA) was used to illustrate the effect of the 20 different inhibitors on the congener patterns emitted. The most effective inhibitors for PCDD/F formation in flue gases were determined to be (NH{sub 4}){sub 2}SO{sub 4} and (NH{sub 4}){sub 2}S{sub 2}O{sub 3}. Both compounds can suppress the formation ofPCDD/Fs by more than 98-99%. (NH{sub 4}){sub 2}SO{sub 4} resulted in over 90% reduction of PCDD/F even when composing only 3% of the fuel combusted. Less than 5% (NH{sub 4}){sub 2}S{sub 2}O{sub 3} resulted in far weaker inhibition. Higher percentages of the inhibitors produced a lower percentage of lower chlorinated PCDDs. The opposite effect was found for PCDFs. 33 refs., 6 figs., 2 tabs.

  14. PCSK9 inhibitors in the current management of atherosclerosis.

    Science.gov (United States)

    Whayne, Thomas F

    The history of proprotein convertase subtilisin/kexin type 9 (PCSK9) in medical science is fascinating and the evolution of knowledge of its function has resulted in new medications of major importance for the cardiovascular (CV) patient. PCSK9 functions as a negative control or feedback for the cell surface receptors for low-density lipoprotein including its component of cholesterol (LDL-C). The initial and key findings were that different abnormalities of PCSK9 can result in an increase or a decrease of LDL-C because of more or less suppression of cell surface receptors. These observations gave hints and awoke interest that it might be possible to prepare monoclonal antibodies to PCSK9 and decrease its activity, after which there should be more active LDL-C cell receptors. The rest is a fascinating story that currently has resulted in two PCSK9 inhibitors, alirocumab and evolocumab, which, on average, decrease LDL-C approximately 50%. Nevertheless, if there are no contraindications, statins remain the standard of prevention for the high-risk CV patient and this includes both secondary and primary prevention. The new inhibitors are for the patient that does not attain the desired target for LDL-C reduction while taking a maximum statin dose or who does not tolerate any statin dose whatsoever. Atherosclerosis can be considered a metabolic disease and the clinician needs to realize this and think more and more of CV prevention. These inhibitors can contribute to both the stabilization and regression of atherosclerotic plaques and thereby avoid or delay major adverse cardiac events. (United States). Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

  15. Suppression of Coronavirus Replication by Cyclophilin Inhibitors

    Directory of Open Access Journals (Sweden)

    Takashi Sasaki

    2013-05-01

    Full Text Available Coronaviruses infect a variety of mammalian and avian species and cause serious diseases in humans, cats, mice, and birds in the form of severe acute respiratory syndrome (SARS, feline infectious peritonitis (FIP, mouse hepatitis, and avian infectious bronchitis, respectively. No effective vaccine or treatment has been developed for SARS-coronavirus or FIP virus, both of which cause lethal diseases. It has been reported that a cyclophilin inhibitor, cyclosporin A (CsA, could inhibit the replication of coronaviruses. CsA is a well-known immunosuppressive drug that binds to cellular cyclophilins to inhibit calcineurin, a calcium-calmodulin-activated serine/threonine-specific phosphatase. The inhibition of calcineurin blocks the translocation of nuclear factor of activated T cells from the cytosol into the nucleus, thus preventing the transcription of genes encoding cytokines such as interleukin-2. Cyclophilins are peptidyl-prolyl isomerases with physiological functions that have been described for many years to include chaperone and foldase activities. Also, many viruses require cyclophilins for replication; these include human immunodeficiency virus, vesicular stomatitis virus, and hepatitis C virus. However, the molecular mechanisms leading to the suppression of viral replication differ for different viruses. This review describes the suppressive effects of CsA on coronavirus replication.

  16. Framing scales and scaling frames

    NARCIS (Netherlands)

    Lieshout, van M.; Dewulf, A.; Aarts, M.N.C.; Termeer, C.J.A.M.

    2009-01-01

    Policy problems are not just out there. Actors highlight different aspects of a situation as problematic and situate the problem on different scales. In this study we will analyse the way actors apply scales in their talk (or texts) to frame the complex decision-making process of the establishment

  17. A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema.

    Science.gov (United States)

    Guarnieri, Frank; Spencer, Jean L; Lucey, Edgar C; Nugent, Matthew A; Stone, Phillip J

    2010-06-08

    Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastase-induced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy.

  18. Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires.

    Science.gov (United States)

    Conant, Genevieve; Ahadian, Samad; Zhao, Yimu; Radisic, Milica

    2017-09-18

    Kinase inhibitors are often used as cancer targeting agents for their ability to prevent the activation of cell growth and proliferation signals. Cardiotoxic effects have been identified for some marketed kinase inhibitors that were not detected during clinical trials. We hypothesize that more predictive cardiac functional assessments of kinase inhibitors on human myocardium can be established by combining a high-throughput two-dimensional (2D) screening assay and a high-content three-dimensional (3D) engineered cardiac tissue (BiowireTM) based assay, and using human induced pluripotent stem cell-derived CMs (hiPSC-CMs). A subset (80) of compounds from the GlaxoSmithKline published kinase inhibitor set were tested on hiPSC-CM monolayers and significant effects on cell viability, calcium transients, and contraction frequency were observed. Artificial neural network modelling was then used to analyze the experimental results in an efficient and unbiased manner to select for kinase inhibitors with minimal effects on cell viability and function. Inhibitors of specific interest based on the modeling were evaluated in the 3D Biowire tissues. The three-dimensional Biowire platform eliminated oversensitivity in detecting both Ca2+ transient amplitude enhancements as well as the acute detrimental effects on cell viability due to the kinase inhibitor application as compared to the monolayer testing.

  19. Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium.

    Science.gov (United States)

    van Hinsbergh, V W; Bertina, R M; van Wijngaarden, A; van Tilburg, N H; Emeis, J J; Haverkate, F

    1985-02-01

    Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator-inhibitor. High concentrations of thrombin-but not of factor Xa or IXa--had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.

  20. A DPP-4 inhibitor suppresses fibrosis and inflammation on experimental autoimmune myocarditis in mice.

    Directory of Open Access Journals (Sweden)

    Hiroyuki Hirakawa

    Full Text Available Myocarditis is a critical inflammatory disorder which causes life-threatening conditions. No specific or effective treatment has been established. DPP-4 inhibitors have salutary effects not only on type 2 diabetes but also on certain cardiovascular diseases. However, the role of a DPP-4 inhibitor on myocarditis has not been investigated. To clarify the effects of a DPP-4 inhibitor on myocarditis, we used an experimental autoimmune myocarditis (EAM model in Balb/c mice. EAM mice were assigned to the following groups: EAM mice group treated with a DPP-4 inhibitor (linagliptin (n = 19 and those untreated (n = 22. Pathological analysis revealed that the myocardial fibrosis area ratio in the treated group was significantly lower than in the untreated group. RT-PCR analysis demonstrated that the levels of mRNA expression of IL-2, TNF-α, IL-1β and IL-6 were significantly lower in the treated group than in the untreated group. Lymphocyte proliferation assay showed that treatment with the DPP-4 inhibitor had no effect on antigen-induced spleen cell proliferation. Administration of the DPP-4 inhibitor remarkably suppressed cardiac fibrosis and reduced inflammatory cytokine gene expression in EAM mice. Thus, the agents present in DPP-4 inhibitors may be useful to treat and/or prevent clinical myocarditis.

  1. Respiratory syncytial virus disease: prevention and treatment.

    Science.gov (United States)

    Chu, Helen Y; Englund, Janet A

    2013-01-01

    Respiratory syncytial virus (RSV) is one of the most clinically important viruses infecting young children, the elderly, and the immunocompromised. Over the past decade, the most significant advance in the prevention of RSV disease has been the development of high-titered antibody products. Infection control is the only other strategy to prevent RSV disease. A humanized monoclonal antibody directed against the fusion (F) protein palivizumab, (Synagis®, MedImmune, Inc., Gaithersburg, MD), is given routinely on a monthly basis to premature infants and young children less than 24 months of age with underlying medical problems including prematurity, chronic lung disease, or cardiac disease to prevent RSV disease and hospitalization. Other products utilizing polyclonal or monoclonal antibodies or antibody fragments against the F protein have been developed and some already tested in patient populations. The only licensed antiviral treatment available today is ribavirin, a guanosine analogue generally administered as a small particle aerosol to immunocompromised patients with lower respiratory tract disease due to RSV. This drug has also been utilized in oral and intravenous forms, again mainly in immunocompromised patients. Promising new antiviral agents under development by multiple pharmaceutical and biotechnology companies include small molecule fusion inhibitors, attachment inhibitors, inhibitors of RNA synthesis, and small interfering RNA particles (siRNA).

  2. Secreted Wnt Signaling Inhibitors in Disuse-Induced Bone Loss

    Science.gov (United States)

    2014-07-01

    other peripheral nerve injuries that  induce  paralysis.  Disuse  osteoporosis  is a com‐ mon sequelae of spinal cord injury (SCI) an peripheral nerve damage...AND SUBTITLE Secreted Wnt inhibitors in disuse- induced bone loss 5a. CONTRACT NUMBER 5b. GRANT NUMBER 6. AUTHOR(S) Alexander G. Robling, PhD...preventing paralysis- induced bone loss. In the first series, adult female mice were subjected to unilateral Botox- induced muscle paralysis of the

  3. Development of inhibitors of heterotrimeric Gαi subunits

    OpenAIRE

    Appleton, Kathryn M.; Bigham, Kevin J.; Lindsey, Christopher C.; Hazard, Starr; Lirjoni, Jonel; Parnham, Stuart; Hennig, Mirko; Peterson, Yuri K.

    2014-01-01

    Heterotrimeric G-proteins are the immediate downstream effectors of G-protein coupled receptors (GPCRs). Endogenous protein guanine nucleotide dissociation inhibitors (GDIs) like AGS3/4 and RGS12/14 function through GPR/Goloco GDI domains. Extensive characterization of GPR domain peptides indicate they function as selective GDIs for Gαi by competing for the GPCR and Gβγ and preventing GDP release. We modified a GPR consensus peptide by testing FGF and TAT leader sequences to make the peptide ...

  4. Lipopeptides as dimerization inhibitors of HIV-1 protease

    OpenAIRE

    Schramm, H. J.; de Rosny, E.; Reboud-Ravaux, M.; Büttner, J.; Dick, A.; Schramm, W.

    1999-01-01

    In AIDS therapy, attempts have been made to inhibit the virus-encoded enzymes, e.g, HIV-1 protease, using active site-directed inhibitors. This approach is questionable, however, due to virus mutations and the high toxicity of the drugs, An alternative method to inhibit the dimeric HIV protease is the targeting of the interface region of the protease subunits in order to prevent subunit dimerization and enzyme activity, This approach should be less prone to inactivation by mutation, A list of...

  5. Polio and Prevention

    Science.gov (United States)

    ... Photo Collections Videos Polio Today → Polio + Prevention Polio + Prevention Polio and prevention Polio is a crippling and ... a child for life. Learn more about polio + prevention The Virus The Vaccines The Communities Related resources ...

  6. Language impairment in Alzheimer's disease and benefits of acetylcholinesterase inhibitors.

    Science.gov (United States)

    Ferris, Steven H; Farlow, Martin

    2013-01-01

    Alzheimer's disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer's disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer's disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer's disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important.

  7. First Study of Poly(3-Methylene-2-Pyrrolidone) as a Kinetic Hydrate Inhibitor

    DEFF Research Database (Denmark)

    Abrahamsen, Eirin; Heyns, Ingrid Marié; von Solms, Nicolas

    2017-01-01

    Formation of gas hydrates is a problem in the petroleum industry where the gas hydrates can cause blockage of the flowlines. Kinetic hydrate inhibitors (KHIs) are water-soluble polymers, sometimes used in combination synergistically or with non-polymeric synergists, that are used to prevent gas...

  8. Should Helicobacter pylori be eradicated before starting long-term proton pump inhibitors?

    NARCIS (Netherlands)

    Rauws, E. A.

    1997-01-01

    Symptomatic gastro-oesophageal reflux disease is a common disorder characterized by pathological exposure of the distal oesophagus to acid. The management requires the control of symptoms, prevention of relapse and complications. Proton pump inhibitors are without doubt the most effective agents in

  9. Localization of Tissue Inhibitor of Metalloproteinases 1 (TIMP-1) in Human Colorectal Adenoma and Adenocarcinoma

    DEFF Research Database (Denmark)

    Holten-Andersen, Mads N.; Hansen, Ulla; Brünner, Nils

    2005-01-01

    Tissue inhibitor of matrix metalloproteases 1 (TIMP-1) inhibits the proteolytic activity of matrix metalloproteases and hereby prevents cancer invasion. However, TIMP-1 also possesses other functions such as inhibition of apoptosis, induction of malignant transformation and stimulation of cell-gr...

  10. The influence of proton pump inhibitors and other commonly used medication on the gut microbiota

    NARCIS (Netherlands)

    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

    2017-01-01

    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

  11. Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model

    NARCIS (Netherlands)

    Schalkwijk, S.J.; Greupink, R.; Colbers, A.P.; Wouterse, A.C.; Verweij, V.G.M.; Drongelen, J. van; Teulen, M.J.A.; Oetelaar, D. van den; Burger, D.M.; Russel, F.G.

    2016-01-01

    OBJECTIVES: Data on fetal exposure to antiretroviral agents during pregnancy are important to estimate their potential for prevention of mother-to-child transmission (PMTCT) and possible toxicity. For the recently developed HIV integrase inhibitor dolutegravir, clinical data on fetal disposition are

  12. Evaluation of Prevention Programs for Children.

    Science.gov (United States)

    Valente, Ernest, Jr.; Dodge, Kenneth A.

    This article focuses on the formal evaluation of large-scale preventive interventions promoting positive mental health in children and adolescents, using examples of conduct problems. The state of the art in program evaluation is discussed based on quantitative evaluations of mental illness prevention programs. The article reviews current thinking…

  13. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions.

    Science.gov (United States)

    Scheen, André J

    2010-09-01

    Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally

  14. Effect of pre-stroke use of ACE inhibitors on ischemic stroke severity

    Directory of Open Access Journals (Sweden)

    Caplan Louis

    2005-06-01

    Full Text Available Abstract Background Recent trials suggest that angiotensin-converting enzyme inhibitors (ACEI are effective in prevention of ischemic stroke, as measured by reduced stroke incidence. We aimed to compare stroke severity between stroke patients who were taking ACEI before their stroke onset and those who were not, to examine the effects of pretreatment with ACEI on ischemic stroke severity. Methods We retrospectively studied 126 consecutive patients presenting within 24 hours of ischemic stroke onset, as confirmed by diffusion-weighted magnetic resonance imaging (DWI. We calculated the NIHSS score at presentation, as the primary measure of clinical stroke severity, and categorized stroke severity as mild (NIHSS [less than or equal to] 7, moderate (NIHSS 8–13 or severe (NIHSS [greater than or equal to] 14. We analyzed demographic data, risk-factor profile, blood pressure (BP and medications on admissions, and determined stroke mechanism according to TOAST criteria. We also measured the volumes of admission diffusion- and perfusion-weighted (DWI /PWI magnetic resonance imaging lesions, as a secondary measure of ischemic tissue volume. We compared these variables among patients on ACEI and those who were not. Results Thirty- three patients (26% were on ACE-inhibitors. The overall median baseline NIHSS score was 5.5 (range 2–21 among ACEI-treated patients vs. 9 (range 1–36 in non-ACEI patients (p = 0.036. Patients on ACEI prior to their stroke had more mild and less severe strokes, and smaller DWI and PWI lesion volumes compared to non-ACEI treated patients. However, none of these differences were significant. Predictably, a higher percentage of patients on ACEI had a history of heart failure (p = 0.03. Age, time-to-imaging or neurological evaluation, risk-factor profile, concomitant therapy with lipid lowering, other antihypertensives or antithrombotic agents, or admission BP were comparable between the two groups. Conclusion Our results

  15. Trypsin inhibitor from tamarindus indica L. seeds reduces weight gain and food consumption and increases plasmatic cholecystokinin levels

    Directory of Open Access Journals (Sweden)

    Joycellane Alline do Nascimento Campos Ribeiro

    2015-02-01

    Full Text Available OBJECTIVES: Seeds are excellent sources of proteinase inhibitors, some of which may have satietogenic and slimming actions. We evaluated the effect of a trypsin inhibitor from Tamarindus indica L. seeds on weight gain, food consumption and cholecystokinin levels in Wistar rats. METHODS: A trypsin inhibitor from Tamarindus was isolated using ammonium sulfate (30-60% following precipitation with acetone and was further isolated with Trypsin-Sepharose affinity chromatography. Analyses were conducted to assess the in vivo digestibility, food intake, body weight evolution and cholecystokinin levels in Wistar rats. Histological analyses of organs and biochemical analyses of sera were performed. RESULTS: The trypsin inhibitor from Tamarindus reduced food consumption, thereby reducing weight gain. The in vivo true digestibility was not significantly different between the control and Tamarindus trypsin inhibitor-treated groups. The trypsin inhibitor from Tamarindus did not cause alterations in biochemical parameters or liver, stomach, intestine or pancreas histology. Rats treated with the trypsin inhibitor showed significantly elevated cholecystokinin levels compared with animals receiving casein or water. CONCLUSION: The results indicate that the isolated trypsin inhibitor from Tamarindus reduces weight gain by reducing food consumption, an effect that may be mediated by increased cholecystokinin. Thus, the potential use of this trypsin inhibitor in obesity prevention and/or treatment should be evaluated.

  16. Dual antiplatelet therapy for secondary prevention of coronary artery disease

    Science.gov (United States)

    Degrauwe, Sophie; Pilgrim, Thomas; Aminian, Adel; Noble, Stephane; Meier, Pascal; Iglesias, Juan F

    2017-01-01

    Dual antiplatelet therapy (DAPT) combining aspirin and a P2Y12 receptor inhibitor has been consistently shown to reduce recurrent major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) compared with aspirin monotherapy, but at the expense of an increased risk of major bleeding. Nevertheless, the optimal duration of DAPT for secondary prevention of CAD remains uncertain, owing to the conflicting results of several large randomised trials. Among patients with stable CAD undergoing PCI with drug-eluting stents (DES), shorter durations of DAPT (3–6 months) were shown non-inferior to 12 or 24 months duration with respect to MACE, but reduced the rates of major bleeding. Contrariwise, prolonged DAPT durations (18–48 months) reduced the incidence of myocardial infarction and stent thrombosis, but at a cost of an increased risk of major bleeding and all-cause mortality. Until more evidence becomes available, the choice of optimal DAPT regimen and duration for patients with CAD requires a tailored approach based on the patient clinical presentation, baseline risk profile and management strategy. Future studies are however needed to identify patients who may derive benefit from shortened or extended DAPT courses for secondary prevention of CAD based on their individual ischaemic and bleeding risk. Based on limited evidence, 12 months duration of DAPT is currently recommended in patients with ACS irrespective of their management strategy, but large ongoing randomised trials are currently assessing the efficacy and safety of a short-term DAPT strategy (3–6 months) for patients with ACS undergoing PCI with newer generation DES. Finally, several ongoing, large-scale, randomised trials are challenging the current concept of DAPT by investigating P2Y12 receptor inhibitors as single antiplatelet therapy and may potentially shift the paradigm of

  17. Dual antiplatelet therapy for secondary prevention of coronary artery disease.

    Science.gov (United States)

    Degrauwe, Sophie; Pilgrim, Thomas; Aminian, Adel; Noble, Stephane; Meier, Pascal; Iglesias, Juan F

    2017-01-01

    Dual antiplatelet therapy (DAPT) combining aspirin and a P2Y 12 receptor inhibitor has been consistently shown to reduce recurrent major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) compared with aspirin monotherapy, but at the expense of an increased risk of major bleeding. Nevertheless, the optimal duration of DAPT for secondary prevention of CAD remains uncertain, owing to the conflicting results of several large randomised trials. Among patients with stable CAD undergoing PCI with drug-eluting stents (DES), shorter durations of DAPT (3-6 months) were shown non-inferior to 12 or 24 months duration with respect to MACE, but reduced the rates of major bleeding. Contrariwise, prolonged DAPT durations (18-48 months) reduced the incidence of myocardial infarction and stent thrombosis, but at a cost of an increased risk of major bleeding and all-cause mortality. Until more evidence becomes available, the choice of optimal DAPT regimen and duration for patients with CAD requires a tailored approach based on the patient clinical presentation, baseline risk profile and management strategy. Future studies are however needed to identify patients who may derive benefit from shortened or extended DAPT courses for secondary prevention of CAD based on their individual ischaemic and bleeding risk. Based on limited evidence, 12 months duration of DAPT is currently recommended in patients with ACS irrespective of their management strategy, but large ongoing randomised trials are currently assessing the efficacy and safety of a short-term DAPT strategy (3-6 months) for patients with ACS undergoing PCI with newer generation DES. Finally, several ongoing, large-scale, randomised trials are challenging the current concept of DAPT by investigating P2Y 12 receptor inhibitors as single antiplatelet therapy and may potentially shift the paradigm of

  18. Targeting telomerase with radiolabeled inhibitors.

    Science.gov (United States)

    Waghorn, Philip A; Jackson, Mark R; Gouverneur, Veronique; Vallis, Katherine A

    2017-01-05

    The expression of telomerase in approximately 85% of cancers and its absence in the majority of normal cells makes it an attractive target for cancer therapy. However the lag period between initiation of telomerase inhibition and growth arrest makes direct inhibition alone an insufficient method of treatment. However, telomerase inhibition has been shown to enhance cancer cell radiosensitivity. To investigate the strategy of simultaneously inhibiting telomerase while delivering targeted radionuclide therapy to cancer cells, 123 I-radiolabeled inhibitors of telomerase were synthesized and their effects on cancer cell survival studied. An 123 I-labeled analogue of the telomerase inhibitor MST-312 inhibited telomerase with an IC 50 of 1.58 μM (MST-312 IC 50 : 0.23 μM). Clonogenic assays showed a dose dependant effect of 123 I-MST-312 on cell survival in a telomerase positive cell line, MDA-MB-435. Copyright © 2016 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

  19. Vanadium Compounds as PTP Inhibitors

    Directory of Open Access Journals (Sweden)

    Elsa Irving

    2017-12-01

    Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

  20. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  1. Laura: Soybean variety lacking Kunitz trypsin inhibitor

    Directory of Open Access Journals (Sweden)

    Srebrić Mirjana

    2010-01-01

    Full Text Available Grain of conventional soybean varieties requires heat processing to break down trypsin inhibitor's activity before using as food or animal feed. At the same time, protein denaturation and other qualitative changes occur in soybean grain, especially if the temperature of heating is not controlled. Two types of trypsin inhibitor were found in soybean grain the Kunitz trypsin inhibitor and the Bowman-Birk inhibitor. Mature grain of soybean Laura is lacking Kunitz trypsin inhibitor. Grain yield of variety Laura is equal to high yielding varieties from the maturity group I, where it belongs. Lacking of Kunitz-trypsin inhibitor makes soybean grain suitable for direct feeding in adult non ruminant animals without previous thermal processing. Grain of variety Laura can be processed for a shorter period of time than conventional soybeans. This way we save energy, and preserve valuable nutritional composition of soybean grain, which is of interest in industrial processing.

  2. Research progress on criteria for discontinuation of EGFR inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Zhuang HQ

    2012-10-01

    Full Text Available Hong-qing Zhuang, Zhi-yong Yuan, Jun Wang, Ping Wang, Lu-jun Zhao, Bai-lin ZhangDepartment of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Tianjin, People's Republic of ChinaAbstract: The clinical success of the epidermal growth factor receptor (EGFR tyrosine kinase inhibitors (TKI as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is “until progression”, based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer.Keywords: epidermal growth factor receptor, drug discontinuation, acquired drug-resistance

  3. PCSK9 Inhibitors: Treating the Right Patients in Daily Practice.

    Science.gov (United States)

    King, Peta; Nicholls, Stephen J

    2017-08-01

    Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as a novel approach to low-density lipoprotein cholesterol (LDL-C) lowering. The potential role of PCSK9 inhibitors in clinical practice will be reviewed. Clinical trials have demonstrated that PCSK9 inhibitors produce robust LDL-C lowering when administered either as monotherapy or in combination with statins. This provides the opportunity to achieve effective lipid lowering in familial hypercholesterolemia, patients with either established atherosclerotic cardiovascular disease or high risk primary prevention and an important opportunity to treat patients with statin intolerance. The findings from plaque imaging and patients with established atherosclerotic cardiovascular disease suggest that PCSK9 inhibition has favorable outcomes beyond improving lipid profiles, which has the opportunity to expand their use. PCSK9 inhibitors represent a new approach to achieving effective cardiovascular risk reduction in a broader number of patients. How these agents will be taken up in clinical practice remains to be determined.

  4. Small-Molecule Inhibitors of the Type III Secretion System

    Directory of Open Access Journals (Sweden)

    Lingling Gu

    2015-09-01

    Full Text Available Drug-resistant pathogens have presented increasing challenges to the discovery and development of new antibacterial agents. The type III secretion system (T3SS, existing in bacterial chromosomes or plasmids, is one of the most complicated protein secretion systems. T3SSs of animal and plant pathogens possess many highly conserved main structural components comprised of about 20 proteins. Many Gram-negative bacteria carry T3SS as a major virulence determinant, and using the T3SS, the bacteria secrete and inject effector proteins into target host cells, triggering disease symptoms. Therefore, T3SS has emerged as an attractive target for antimicrobial therapeutics. In recent years, many T3SS-targeting small-molecule inhibitors have been discovered; these inhibitors prevent the bacteria from injecting effector proteins and from causing pathophysiology in host cells. Targeting the virulence of Gram-negative pathogens, rather than their survival, is an innovative and promising approach that may greatly reduce selection pressures on pathogens to develop drug-resistant mutations. This article summarizes recent progress in the search for promising small-molecule T3SS inhibitors that target the secretion and translocation of bacterial effector proteins.

  5. Hedgehog Signaling Inhibitors as Anti-Cancer Agents in Osteosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Ram Kumar, Ram Mohan, E-mail: rkumar@research.balgrist.ch; Fuchs, Bruno [Laboratory for Orthopaedic Research, Balgrist University Hospital, Sarcoma Center-UZH University of Zurich, Zurich 8008 (Switzerland)

    2015-05-13

    Osteosarcoma is a rare type of cancer associated with a poor clinical outcome. Even though the pathologic characteristics of OS are well established, much remains to be understood, particularly at the molecular signaling level. The molecular mechanisms of osteosarcoma progression and metastases have not yet been fully elucidated and several evolutionary signaling pathways have been found to be linked with osteosarcoma pathogenesis, especially the hedgehog signaling (Hh) pathway. The present review will outline the importance and targeting the hedgehog signaling (Hh) pathway in osteosarcoma tumor biology. Available data also suggest that aberrant Hh signaling has pro-migratory effects and leads to the development of osteoblastic osteosarcoma. Activation of Hh signaling has been observed in osteosarcoma cell lines and also in primary human osteosarcoma specimens. Emerging data suggests that interference with Hh signal transduction by inhibitors may reduce osteosarcoma cell proliferation and tumor growth thereby preventing osteosarcomagenesis. From this perspective, we outline the current state of Hh pathway inhibitors in osteosarcoma. In summary, targeting Hh signaling by inhibitors promise to increase the efficacy of osteosarcoma treatment and improve patient outcome.

  6. Checkpoint inhibitors and gastrointestinal immune-related adverse events.

    Science.gov (United States)

    Pernot, Simon; Ramtohul, Toulsie; Taieb, Julien

    2016-07-01

    Recent development of checkpoint inhibitors is a challenge for oncologists. Indeed, it leads to specific immune adverse events, close to autoimmune disorders, which require a specific management. Colitis is one of the most frequent immune adverse events, in particular with anticytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) therapy. Severe colitis is frequent with immune checkpoint inhibitors and leads in a few cases to bowel perforation and death. This review focuses on specific pathogenic pathway and recent findings on risk factors and managements of colitis. Anti-CTLA-4 antibodies are the most involved immune checkpoint inhibitors in colitis, and the combinations with anti-programmed death ligand 1 dramatically increase the rate of colitis. The early use of budesonide, and in some cases corticosteroids and/or infliximab should be recommended, as colitis is responsive to infliximab in almost all cases. Immune-related colitis shares some characteristics with inflammatory bowel disease but with little specificity. In particular, it has been recently showed that gut microbiota could interact with anti-CTLA-4 treatment to modulate efficacy but also to induce colitis. This opens the way for preventive or curative treatments capable of inducing modulation of the microbiota or fecal transplantation.

  7. Carrageenan is a potent inhibitor of papillomavirus infection.

    Directory of Open Access Journals (Sweden)

    Christopher B Buck

    2006-07-01

    Full Text Available Certain sexually transmitted human papillomavirus (HPV types are causally associated with the development of cervical cancer. Our recent development of high-titer HPV pseudoviruses has made it possible to perform high-throughput in vitro screens to identify HPV infection inhibitors. Comparison of a variety of compounds revealed that carrageenan, a type of sulfated polysaccharide extracted from red algae, is an extremely potent infection inhibitor for a broad range of sexually transmitted HPVs. Although carrageenan can inhibit herpes simplex viruses and some strains of HIV in vitro, genital HPVs are about a thousand-fold more susceptible, with 50% inhibitory doses in the low ng/ml range. Carrageenan acts primarily by preventing the binding of HPV virions to cells. This finding is consistent with the fact that carrageenan resembles heparan sulfate, an HPV cell-attachment factor. However, carrageenan is three orders of magnitude more potent than heparin, a form of cell-free heparan sulfate that has been regarded as a highly effective model HPV inhibitor. Carrageenan can also block HPV infection through a second, postattachment heparan sulfate-independent effect. Carrageenan is in widespread commercial use as a thickener in a variety of cosmetic and food products, ranging from sexual lubricants to infant feeding formulas. Some of these products block HPV infectivity in vitro, even when diluted a million-fold. Clinical trials are needed to determine whether carrageenan-based products are effective as topical microbicides against genital HPVs.

  8. Scaling down

    Directory of Open Access Journals (Sweden)

    Ronald L Breiger

    2015-11-01

    Full Text Available While “scaling up” is a lively topic in network science and Big Data analysis today, my purpose in this essay is to articulate an alternative problem, that of “scaling down,” which I believe will also require increased attention in coming years. “Scaling down” is the problem of how macro-level features of Big Data affect, shape, and evoke lower-level features and processes. I identify four aspects of this problem: the extent to which findings from studies of Facebook and other Big-Data platforms apply to human behavior at the scale of church suppers and department politics where we spend much of our lives; the extent to which the mathematics of scaling might be consistent with behavioral principles, moving beyond a “universal” theory of networks to the study of variation within and between networks; and how a large social field, including its history and culture, shapes the typical representations, interactions, and strategies at local levels in a text or social network.

  9. An inhibitor of phospholipase D in saliva

    Science.gov (United States)

    Dawson, Rex M. C.; Hemington, Norma

    1974-01-01

    1. Bovine, dog and human saliva contain substances which inhibit the soluble phospholipase D present in grass leaf or celery stalk. 2. The inhibitor in bovine saliva is of high molecular weight and exhibits considerable stability to heat, acids and alkalis. 3. The inhibitor has been purified free from salivary mucoprotein. 4. It is suggested that the inhibitor could protect the upper alimentary tract of a herbage-eating animal from the necrotic action of phospholipase D. PMID:4376946

  10. Playing the Catch-Up Game: Accelerating the Scale-Up of Prevention of Mother-To-Child Transmission of HIV (PMTCT) Services to Eliminate New Pediatric HIV Infection in Nigeria

    Science.gov (United States)

    Oladele, Edward Adekola; Khamofu, Hadiza; Asala, Seun; Saleh, Mariya; Ralph-Opara, Uche; Nwosisi, Charles; Anyaike, Chukwuma; Gana, Catherine; Adedokun, Oluwasanmi; Dirks, Rebecca; Adebayo, Olufunsho; Oduwole, Modupe; Mandala, Justin; Torpey, Kwasi

    2017-01-01

    Introduction As the world is making progress towards elimination of mother-to-child transmission of HIV, poor coverage of PMTCT services in Nigeria remains a major challenge. In order to address this, scale-up was planned with activities organized into 3 phases. This paper describes the process undertaken in eight high burden Nigerian states to rapidly close PMTCT coverage gaps at facility and population levels between February 2013 and March 2014. Methods Activities were grouped into three phases–pre-assessment phase (engagement of a wide range of stakeholders), assessment (rapid health facility assessment, a cross sectional survey using mixed methods conducted in the various states between Feb and May 2013 and impact modelling), and post-assessment (drawing up costed state operational plans to achieve eMTCT by 2015, data-driven smart scale-up). Results Over a period of 10 months starting June 2013, 2044 facilities were supported to begin provision of PMTCT services. This increased facility coverage from 8% to 50%. A 246% increase was also recorded in the number of pregnant women and their families who have access to HIV testing and counselling in the context of PMTCT. Similarly, access to antiretrovirals for PMTCT has witnessed a 152% increase in these eight states between October 2013 and October 2014. Conclusion A data-driven and participatory approach can be used to rapidly scale-up PMTCT services at community and facility levels in this region. These results present us with hope for real progress in Nigeria. We are confident that the efforts described here will contribute significantly to eliminating new pediatric HIV infection in Nigeria. PMID:28046045

  11. Playing the Catch-Up Game: Accelerating the Scale-Up of Prevention of Mother-To-Child Transmission of HIV (PMTCT) Services to Eliminate New Pediatric HIV Infection in Nigeria.

    Science.gov (United States)

    Oladele, Edward Adekola; Khamofu, Hadiza; Asala, Seun; Saleh, Mariya; Ralph-Opara, Uche; Nwosisi, Charles; Anyaike, Chukwuma; Gana, Catherine; Adedokun, Oluwasanmi; Dirks, Rebecca; Adebayo, Olufunsho; Oduwole, Modupe; Mandala, Justin; Torpey, Kwasi

    2017-01-01

    As the world is making progress towards elimination of mother-to-child transmission of HIV, poor coverage of PMTCT services in Nigeria remains a major challenge. In order to address this, scale-up was planned with activities organized into 3 phases. This paper describes the process undertaken in eight high burden Nigerian states to rapidly close PMTCT coverage gaps at facility and population levels between February 2013 and March 2014. Activities were grouped into three phases-pre-assessment phase (engagement of a wide range of stakeholders), assessment (rapid health facility assessment, a cross sectional survey using mixed methods conducted in the various states between Feb and May 2013 and impact modelling), and post-assessment (drawing up costed state operational plans to achieve eMTCT by 2015, data-driven smart scale-up). Over a period of 10 months starting June 2013, 2044 facilities were supported to begin provision of PMTCT services. This increased facility coverage from 8% to 50%. A 246% increase was also recorded in the number of pregnant women and their families who have access to HIV testing and counselling in the context of PMTCT. Similarly, access to antiretrovirals for PMTCT has witnessed a 152% increase in these eight states between October 2013 and October 2014. A data-driven and participatory approach can be used to rapidly scale-up PMTCT services at community and facility levels in this region. These results present us with hope for real progress in Nigeria. We are confident that the efforts described here will contribute significantly to eliminating new pediatric HIV infection in Nigeria.

  12. Playing the Catch-Up Game: Accelerating the Scale-Up of Prevention of Mother-To-Child Transmission of HIV (PMTCT Services to Eliminate New Pediatric HIV Infection in Nigeria.

    Directory of Open Access Journals (Sweden)

    Edward Adekola Oladele

    Full Text Available As the world is making progress towards elimination of mother-to-child transmission of HIV, poor coverage of PMTCT services in Nigeria remains a major challenge. In order to address this, scale-up was planned with activities organized into 3 phases. This paper describes the process undertaken in eight high burden Nigerian states to rapidly close PMTCT coverage gaps at facility and population levels between February 2013 and March 2014.Activities were grouped into three phases-pre-assessment phase (engagement of a wide range of stakeholders, assessment (rapid health facility assessment, a cross sectional survey using mixed methods conducted in the various states between Feb and May 2013 and impact modelling, and post-assessment (drawing up costed state operational plans to achieve eMTCT by 2015, data-driven smart scale-up.Over a period of 10 months starting June 2013, 2044 facilities were supported to begin provision of PMTCT services. This increased facility coverage from 8% to 50%. A 246% increase was also recorded in the number of pregnant women and their families who have access to HIV testing and counselling in the context of PMTCT. Similarly, access to antiretrovirals for PMTCT has witnessed a 152% increase in these eight states between October 2013 and October 2014.A data-driven and participatory approach can be used to rapidly scale-up PMTCT services at community and facility levels in this region. These results present us with hope for real progress in Nigeria. We are confident that the efforts described here will contribute significantly to eliminating new pediatric HIV infection in Nigeria.

  13. Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells.

    Directory of Open Access Journals (Sweden)

    Michele Cea

    Full Text Available Aberrant histone deacetylase (HDAC activity is frequent in human leukemias. However, while classical, NAD(+-independent HDACs are an established therapeutic target, the relevance of NAD(+-dependent HDACs (sirtuins in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527 and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction was monitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD(+ levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD(+-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited.

  14. β Adrenergic blockers lower renin in patients treated with ACE inhibitors and diuretics

    Science.gov (United States)

    Holmer, S; Hense, H; Danser, A; Mayer, B; Riegger, G; Schunkert, H

    1998-01-01

    Objective—To examine the effect of concomitant intake of β blockers with angiotensin converting enzyme (ACE) inhibitors, diuretics, or both on plasma renin concentrations in a population based sample (MONICA survey, Augsburg, Germany).
Subject and methods—728 individuals were studied, of whom 171 were treated using monotherapy (ACE inhibitor (n = 21), diuretic (n = 10), or β blocker (n = 72)), or combination treatment (ACE inhibitor + diuretic (n = 32), ACE inhibitor + β blocker (n = 7), diuretic + β blocker (n = 22), ACE inhibitor + diuretic + β blocker (n = 7)). The remaining 557 individuals were untreated. Indications for treatment were hypertension (75%), coronary artery disease with (12%) or without (3%) hypertension, or unknown (10%).
Results—Mean (SEM) renin concentrations in individuals treated with an ACE inhibitor (41 (8) mU/l), a diuretic (41 (10) mU/l), or the combination of an ACE inhibitor and a diuretic (54 (10) mU/l) were raised compared with untreated individuals (17 (1) mU/l; p diuretic (22 (4) mU/l), or with both an ACE inhibitor and a diuretic (21 (7) mU/L), were significantly lower compared with renin concentrations in groups not receiving β blocker treatment (p diuretics, or both can be largely prevented by concomitant β blocker treatment.

 Keywords: adrenergic β receptor blocker;  angiotensin converting enzyme inhibitor;  renin;  hypertension PMID:9764058

  15. Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis

    Directory of Open Access Journals (Sweden)

    Roesel M

    2011-09-01

    Full Text Available Martin Roesel1, Christoph Tappeiner2, Arnd Heiligenhaus1,3, Carsten Heinz1,31Department of Ophthalmology, St Franziskus-Hospital, Muenster, Germany; 2Department of Ophthalmology, Inselspital, University of Bern, Switzerland; 3University Duisburg-Essen, GermanyAbstract: Voclosporin, a novel immunomodulatory drug inhibiting the calcineurin enzyme, was developed to prevent organ graft rejection and to treat autoimmune diseases. The chemical structure of voclosporin is similar to that of cyclosporine A, with a difference in one amino acid, leading to superior calcineurin inhibition and less variability in plasma concentration. Compared with placebo, voclosporin may significantly reduce inflammation and prevent recurrences of inflammation in patients with noninfectious uveitis. Future studies have to show if these advantages are accompanied by greater clinical efficacy and fewer side effects compared with the classic calcineurin inhibitors.Keywords: uveitis, immunosuppression, voclosporin

  16. Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases

    Directory of Open Access Journals (Sweden)

    Krisna C. Duong-Ly

    2016-02-01

    Full Text Available Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases, including ALK, LRRK2, RET, and EGFR, as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development.

  17. The discovery and development of modified penicillin- and cephalosporin-derived beta-lactamase inhibitors.

    Science.gov (United States)

    Buynak, John D

    2004-07-01

    While beta-lactam antibiotics remain among the most commonly prescribed pharmaceutical products, their effectiveness is currently threatened by the development of bacterial resistance. One key resistance mechanism is the ability to destroy the antibiotic through utilization of one or more types of beta-lactamase. An effective countermeasure is to employ a combination product, consisting of both a beta-lactam antibiotic and a beta-lactamase inhibitor. Unfortunately, currently available inhibitors narrowly target only class A beta-lactamases. This review will detail our research, directed toward the development of a useful broad-spectrum beta-lactamase inhibitor. In the process, we have discovered new inhibitors capable of simultaneously inactivating class A, C, and D beta-lactamase, produced conjugate siderophore/beta-lactamase inhibitors, and explored the SAR's of tunable, cephalosporin-derived beta-lactamase inactivators. Useful synthetic methodology will be described, which simplifies the large scale production of many known inhibitors and which allows the rapid preparation of libraries of prospective inhibitors.

  18. USING A DOE AND EIS TO EVALUATE THE SYNERGISTIC EFFECTS OF LOW TOXICITY INHIBITORS FOR MILD STEEL

    Directory of Open Access Journals (Sweden)

    G. V. Bueno

    2015-03-01

    Full Text Available Abstract Inhibitors are widely used to prevent corrosion in cooling-water systems, and their protective performance can be enhanced by combination. The aim of this paper is to identify possible synergistic effects between four low toxicity substances used as corrosion inhibitors for mild steel in industrial cooling-water systems. Electrochemical measurements were obtained following a design of experiments (DOE where the independent variables were the inhibitors concentrations and the response variable the charge transfer resistance estimated from impedance diagrams. Potentiodynamic polarization curves show that all of them act as anodic corrosion inhibitors. Among the tested formulations, only the interaction between sodium molybdate and sodium tungstate showed statistically significant effects, indicating that they can perform better when used together. The results of this work show the importance of using a statistical tool when designing inhibitor mixtures.

  19. Histone deacetylase inhibitors in cancer therapy.

    Science.gov (United States)

    Lane, Andrew A; Chabner, Bruce A

    2009-11-10

    Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors. In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy. HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials. HDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

  20. Scaling Rules!

    Science.gov (United States)

    Malkinson, Dan; Wittenberg, Lea

    2015-04-01

    Scaling is a fundamental issue in any spatially or temporally hierarchical system. Defining domains and identifying the boundaries of the hierarchical levels may be a challenging task. Hierarchical systems may be broadly classified to two categories: compartmental and continuous ones. Examples of compartmental systems include: governments, companies, computerized networks, biological taxonomy and others. In such systems the compartments, and hence the various levels and their constituents are easily delineated. In contrast, in continuous systems, such as geomorphological, ecological or climatological ones, detecting the boundaries of the various levels may be difficult. We propose that in continuous hierarchical systems a transition from one functional scale to another is associated with increased system variance. Crossing from a domain of one scale to the domain of another is associated with a transition or substitution of the dominant drivers operating in the system. Accordingly we suggest that crossing this boundary is characterized by increased variance, or a "variance leap", which stabilizes, until crossing to the next domain or hierarchy level. To assess this we compiled sediment yield data from studies conducted at various spatial scales and from different environments. The studies were partitioned to ones conducted in undisturbed environments, and those conducted in disturbed environments, specifically by wildfires. The studies were conducted in plots as small as 1 m2, and watersheds larger than 555000 ha. Regressing sediment yield against plot size, and incrementally calculating the variance in the systems, enabled us to detect domains where variance values were exceedingly high. We propose that at these domains scale-crossing occurs, and the systems transition from one hierarchical level to another. Moreover, the degree of the "variance leaps" characterizes the degree of connectivity among the scales.

  1. [Development of new antiatherosclerotic agents--ACAT inhibitors and CETP inhibitors].

    Science.gov (United States)

    Miyazaki, A; Horiuchi, S

    1999-12-01

    Development of new antiatherosclerotic agents were reviewed focusing on ACAT inhibitors and CETP inhibitors. ACAT inhibitors enhance intracellular degradation of VLDL in hepatocytes. Cholesterol absorption in small intestine is inhibited by ACAT inhibitors. Thus, ACAT inhibitors reduce plasma cholesterol levels. In atherosclerotic lesions, ACAT inhibitors suppress foam cell formation (cholesteryl ester accumulation) in macrophages. Since ACAT inhibitors have multiple anti-atherogenic effects, they are considered future drugs controlling hypercholesterolemia and atherosclerosis. CETP inhibitors are expected to increase HDL and decrease LDL. Although the patients with CETP deficiency show high level of HDL, recent studies showed that they are not necessarily resistant to atherosclerosis. The strategy to inhibit CETP for suppressing atherosclerosis has not been established.

  2. Development of immune checkpoint inhibitors.

    Science.gov (United States)

    Kitano, Shigehisa

    2017-01-01

    Immune checkpoint inhibitors are the most striking innovation in the clinical development of immunotherapy. Monoclonal antibodies (mAbs) restore and augment the antitumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen-presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of mAb in various cancers. The A first-in-class approved immune checkpoint inhibitor is ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen 4. In 2011, the US Food and Drug Administration approved the use of ipilimumab for the treatment of advanced metastatic melanoma. Then, nivolumab, which is a humanized mAb that blocks programmed death-1 (PD-1), was approved for use in the treatment of advanced melanoma in 2014 and of advanced non-small-cell lung carcinoma (NSCLC) in 2015 in Japan. Pembrolizumab, which is another anti-PD-1 antibody, was approved for use in the treatment of advanced melanoma and advanced NSCLC as the first-line therapy in 2016 in Japan. Thereafter, nivolumab was also approved for use in the treatment of advanced renal cell cancer in August 2016, of Hodgkin's lymphoma in December 2016, and of head and neck cancer in March 2017 in Japan. Moreover, phase III trials of anti-PD-1 mAb and anti-PD-ligand 1 mAb for use in the treatment of cancers, such as gastric, ovarian, bladder, and esophageal cancers, are ongoing. Several clinical trials have investigated new agents, alone and in combination, for use in the treatment of various cancers. Current advances in tumor immunology have unveiled the importance of immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, especially in a tumor microenvironment (TME). Some data from basic research in mouse models and the immunomonitoring of cancer patients

  3. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism.

    Science.gov (United States)

    Robertson, Lindsay; Kesteven, Patrick; McCaslin, James E

    2015-12-04

    using an odds ratio (OR) with a 95% confidence interval (CI). We included five randomised controlled trials with a total of 7897 participants. Two studies tested oral DTIs (dabigatran) and three studies tested oral factor Xa inhibitors (one rivaroxaban, one edoxaban and one apixaban).Analysis showed no difference in the effectiveness of oral DTIs and standard anticoagulation in preventing recurrent pulmonary embolism (OR 1.02, 95% CI 0.50 to 2.04; two studies; 1602 participants; high quality evidence), recurrent venous thromboembolism (OR 0.93, 95% CI 0.52 to 1.66; two studies; 1602 participants; high quality evidence), deep vein thrombosis (DVT) (OR 0.79, 95% CI 0.29 to 2.13; two studies; 1602 participants; high quality evidence) and major bleeding (OR 0.50, 95% CI 0.15 to 1.68; two studies; 1527 participants; high quality evidence).For oral factor Xa inhibitors, when we combined the three included studies together in meta-analyses, there was significant heterogeneity for recurrent pulmonary embolism (OR 1.08, 95% CI 0.46 to 2.56; two studies; 4509 participants; I(2) = 58%; moderate quality evidence). The oral factor Xa inhibitors were no more or less effective in the prevention of recurrent venous thromboembolism (OR 0.85, 95% CI 0.63 to 1.15; three studies; 6295 participants; high quality evidence), DVT (OR 0.72, 95% CI 0.39 to 1.32; two studies; 4509 participants; high quality evidence), all-cause mortality (OR 1.16, 95% CI 0.79 to 1.70; one study; 4817 participants; moderate quality evidence) or major bleeding (OR 0.97, 95% CI 0.59 to 1.62; two studies; 4507 participants; high quality evidence). None of the studies measured quality of life. Moderate to high quality evidence suggests that there are no differences between DOACs and standard anticoagulation for the long-term treatment of pulmonary embolism, for the outcomes recurrent pulmonary embolism, recurrent venous thromboembolism, DVT, all-cause mortality and major bleeding.

  4. Preventing Informal Urban Development

    DEFF Research Database (Denmark)

    Enemark, Stig; McLaren, Robin

    2008-01-01

    . This is directly linked to citizen participation in the process of land use control. Decentralisation should aim to combine responsibility for decision making with accountability for financial, social, and environmental consequences. Decentralisation requires access to appropriate quality of land information......The issue of informal development was discussed in details at the joint FIG Com 3 and UNECE/WPLA workshop in Sounio, Greece, March 2007. Emphasis was given to the scale of the problem in Southern and Eastern Europe and to means of legalising such informal urban development. This paper, instead......, addresses the main issue of how to prevent informal urban development, especially through the use of adequate and sustainable means of land use control and good governance. Three key means are addressed: Decentralisation: There is a need to separate central policy/regulation making and local decision making...

  5. Calcineurin inhibitor minimisation versus continuation of calcineurin inhibitor treatment for liver transplant recipients

    DEFF Research Database (Denmark)

    Penninga, Luit; Wettergren, Andre; Chan, An-Wen

    2012-01-01

    The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver...... transplant recipients are treated with the calcineurin inhibitor cyclosporine or tacrolimus. Unfortunately, calcineurin inhibitors cause adverse events, such as nephrotoxicity, and because of this, minimisation (reduction and withdrawal) regimens of calcineurin inhibitor have been developed and studied...

  6. Efficacy of Mixtures of Magnesium, Citrate and Phytate as Calcium Oxalate Crystallization Inhibitors in Urine.

    Science.gov (United States)

    Grases, Felix; Rodriguez, Adrian; Costa-Bauza, Antonia

    2015-09-01

    The main aim of the current study was to evaluate the effectiveness of mixtures of magnesium, citrate and phytate as calcium oxalate crystallization inhibitors. A turbidimetric assay in synthetic urine was performed to obtain induction times for calcium oxalate crystallization in the absence and presence of different mixtures of inhibitors. The morphology of calcium oxalate crystals in the absence or presence of inhibitors and mixtures of the inhibitors was evaluated in 2 crystallization experiments at low and high calcium oxalate supersaturation. The crystals formed were examined using scanning electron microscopy. Examination of crystallization induction times revealed clear inhibitory effects of magnesium, citrate and phytate on calcium oxalate crystallization, supporting usefulness in the treatment and prevention of calcium oxalate nephrolithiasis. Significant synergistic effects between magnesium and phytate were observed. Scanning electron microscopy images revealed that phytate is a powerful crystal growth inhibitor of calcium oxalate, totally preventing the formation of trihydrate and monohydrate. In addition to crystallization inhibition capacity, citrate and magnesium avoided calcium oxalate crystallization by decreasing its supersaturation. The synergistic effect between magnesium and phytate on calcium oxalate crystallization suggests that a combination of these 2 compounds may be highly useful as antilithiasis therapy. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  7. Integrin Inhibitors in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Maylein C. Juan-Rivera

    2018-02-01

    Full Text Available Prostate cancer (PCa is the most frequently diagnosed cancer and the third highest cause of cancer-related deaths in men in the U.S. The development of chemotherapeutic agents that can bind PCa tumor cells with high specificity is critical in order to increase treatment effectiveness. Integrin receptors and their corresponding ligands have different expression patterns in PCa cells. They have been identified as promising targets to inhibit pathways involved in PCa progression. Currently, several compounds have proven to target specific integrins and their subunits in PCa cells. In this article, we review the role of integrins inhibitors in PCa and their potential as therapeutic targets for PCa treatments. We have discussed the following: natural compounds, monoclonal antibodies, statins, campothecins analog, aptamers, d-aminoacid, and snake venom. Recent studies have shown that their mechanisms of action result in decrease cell migration, cell invasion, cell proliferation, and metastasis of PCa cells.

  8. Protein C inhibitor (plasminogen activator inhibitor-3) and the risk of venous thrombosis

    NARCIS (Netherlands)

    Meijers, JCM; Marquart, JA; Bertina, RM; Rosendaal, FR; Bouma, Bonno N.

    Protein C inhibitor (PCI), also known as plasminogen activator inhibitor-3, is a serine proteinase inhibitor that can inhibit enzymes in blood coagulation, fibrinolysis and fertility. The role of PCI in regulating the blood coagulation mechanism is not known, as it can inhibit both procoagulant

  9. The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines

    DEFF Research Database (Denmark)

    Kirkegaard, Tove; Yde, Christina Westmose; Kveiborg, Marie

    2014-01-01

    cells. This was prevented by treatment of resistant cells with the metalloproteinase inhibitor TAPI-2. Only the broad-spectrum metalloproteinase inhibitor BB-94, and not the more selective inhibitors GM6001 or TAPI-2, which inhibited shedding of the HER ligands produced by the fulvestrant...... of ligands. Only the broad-spectrum metalloproteinase inhibitor BB-94 could abrogate HER3 and Erk activation in the resistant cells, which stresses the complexity of the resistance mechanisms and the requirement of targeting signaling from HER receptors by multiple strategies....

  10. Poison prevention: engineering in primary prevention.

    Science.gov (United States)

    Marcus, Steven Matthew

    2012-03-01

    Over the past 50 years we have seen improvements in outcomes of poisonings in the United States. I intend to discuss the approaches to prevention. I review various primary, secondary, and tertiary prevention strategies in relationship to poison prevention. We have made strong efforts in some ways, but our efforts in primary prevention have often been less than maximal. We propose requiring lockable medicine cabinets and lockable storage cabinets for dangerous substances.

  11. Two additive mechanisms impair the differentiation of 'substrate-selective' p38 inhibitors from classical p38 inhibitors in vitro

    Directory of Open Access Journals (Sweden)

    Seidl Kelly M

    2010-03-01

    Full Text Available Abstract Background The success of anti-TNF biologics for the treatment of rheumatoid arthritis has highlighted the importance of understanding the intracellular pathways that regulate TNF production in the quest for an orally-available small molecule inhibitor. p38 is known to strongly regulate TNF production via MK2. The failure of several p38 inhibitors in the clinic suggests the importance of other downstream pathways in normal cell function. Recent work has described a 'substrate-selective' p38 inhibitor that is able to preferentially block the activity of p38 against one substrate (MK2 versus another (ATF2. Using a combined experimental and computational approach, we have examined this mechanism in greater detail for two p38 substrates, MK2 and ATF2. Results We found that in a dual (MK2 and ATF2 substrate assay, MK2-p38 interaction reduced the activity of p38 against ATF2. We further constructed a detailed kinetic mechanistic model of p38 phosphorylation in the presence of multiple substrates and successfully predicted the performance of classical and so-called 'substrate-selective' p38 inhibitors in the dual substrate assay. Importantly, it was found that excess MK2 results in a stoichiometric effect in which the formation of p38-MK2-inhibitor complex prevents the phosphorylation of ATF2, despite the preference of the compound for the p38-MK2 complex over the p38-ATF2 complex. MK2 and p38 protein expression levels were quantified in U937, Thp-1 and PBMCs and found that [MK2] > [p38]. Conclusion Our integrated mechanistic modeling and experimental validation provides an example of how systems biology approaches can be applied to drug discovery and provide a basis for decision-making with limited chemical matter. We find that, given our current understanding, it is unlikely that 'substrate-selective' inhibitors of p38 will work as originally intended when placed in the context of more complex cellular environments, largely due to a

  12. A method for preventing salt sedimentation and corrosion

    Energy Technology Data Exchange (ETDEWEB)

    Chalyy, G.A.; Bekstov, V.A.; Bogdan, V.N.; Korneyev, S.N.; Pernak, Yu.; Shagaydenko, V.I.

    1982-01-01

    A method is proposed for preventing salt sedimentation and corrosion through processing water with a surfacant (PAV) inhibitor. The method is distinguished by the fact that in order to increase the length of the effect of the inhibitor for preventing salt sedimentation and reducing the speed of the corrosion process in lift pipes of wells of gas condensate deposits, a mixture of a monotheanolamine salt ot alkylsulfate with a long C10 to C20 alkyl radical and a chloride of n-alyklthiomethylpyridine with a long C 6 to C12 alkyl radical is used as the inhibitor. The method is further distinguished by the fact that the processing is conducted at a weight relationship of components of the mixture in percent of: monoethanolamine salt of alkylsulfate, 95 to 97 and chloride of n-alkylthiomethylpyridine, 3 to 5.

  13. The interaction between Helminthosporium carbonum and maize: Induced resistance and the role of an inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Cantone, F.A.

    1989-01-01

    Helminthosporium carbonum race 1 produces large, necrotic lesions on susceptible leaves of maize, whereas race 2 causes small, chlorotic flecks. Resistance to race 1 on susceptible leaves was induced when race 2 was inoculated for at least 10 h prior to a challenge inoculation with the pathogen and was manifest as a decrease in the number of appressoria and reduced penetration by race 1 conidia. Induced resistance was prevented or reversed when HC-toxin was added to challenge race 1 inoculum. The basis for protection appears to be a volatile, inhibitory compound produced by the host. This inhibitor was always associated with treatments that resulted in resistance, whereas no inhibitory activity was detected in diffusates from susceptible reactions. The appearance of inhibitor in diffusates coincided with the appearance of protection on the leaf. In addition to race 2 of H. carbonum, other fungi (H. victoriae, H. turcicum, and Alternaria) also induced production of the inhibitor as well as resistance to race 1. The inhibitor prevented the germination of conidia of all fungi tested. The growth of two phytopathogenic bacteria was also completely inhibited. Incorporation of {sup 3}H-leucine and {sup 14}C-uridine into protein and RNA, respectively, by conidia of H. carbonum was prevented within 15 min of exposure to inhibitor. In addition, respiration of conidia in inhibitor was reduced within 90 min to just 25% of the rate of conidia germinated in water. However, inhibitory activity of the diffusates was readily reversed when conidia were rinsed with water or when organic or amino acids were added to inhibited conidia. The addition of sodium acetate to race 2 and race 1 inocula resulted in lesion enlargement and also nullified inhibitory activity in vitro.

  14. Intellectual property issues of immune checkpoint inhibitors.

    Science.gov (United States)

    Storz, Ulrich

    2016-01-01

    Immune checkpoint inhibitors are drugs that interfere with tumor escape responses. Some members of this class are already approved, and expected to be blockbusters in the future. Many companies have developed patent activities in this field. This article focuses on the patent landscape, and discusses key players and cases related to immune checkpoint inhibitors.

  15. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...

  16. [Interaction between clopidogrel and proton pump inhibitors

    NARCIS (Netherlands)

    Harmsze, A.M.; Boer, A. de; Boot, H.; Deneer, V.H.; Heringa, M.; Mol, P.G.; Schalekamp, T.; Verduijn, M.M.; Verheugt, F.W.A.; Comte, M. le

    2011-01-01

    The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in

  17. ACE Inhibitor-Induced Angioedema of the Intestine: Case Report, Incidence, Pathophysiology, Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Gavin Oudit

    2001-01-01

    Full Text Available A case report of fosinopril-induced angioedema of the intestine with a chronic course accompanied by multiple acute exacerbations is described. Angiotensin-converting enzyme (ACE inhibitor-induced angioedema of the intestine (AIAI occurs in a minority of patients taking an ACE inhibitor. The clinical presentation encompasses acute abdominal symptoms, pronounced bowel edema and ascites with occasional facial and/or oropharyngeal swelling. AIAI is diagnosed based on the temporal relationship between the symptomatic presentation and drug use, absence of alternative diagnoses including other causes of angioedema, and the prompt resolution of symptoms upon discontinuation of the ACE inhibitor. Prompt radiological investigation (abdominal computerized tomography and/or ultrasound is critical in making an early diagnosis and in preventing unnecessary surgical intervention. There is a female predominance of AIAI, which may reflect the interaction of estradiol with the various pathways involved in the pathophysiology of AIAI. Management of AIAI consists mainly of conservative measures and discontinuation of the ACE inhibitor. Angiotensin II receptor antagonists should not be considered as appropriate alternatives. Awareness and knowledge of AIAI are important because of the increasing use of ACE inhibitors, current delays in making the diagnosis, obvious management strategies once the diagnosis is made and the dysutility of alternative diagnoses, which may lead to considerable morbidity. AIAI must be considered in patients taking ACE inhibitors who develop gastrointestinal complaints irrespective of the duration of the therapy.

  18. Study on tea leaves extract as green corrosion inhibitor of mild steel in hydrochloric acid solution

    Science.gov (United States)

    Hamdan, A. B.; Suryanto; Haider, F. I.

    2018-01-01

    Corrosion inhibitor from extraction of plant has been considered as the most preferable and most chosen technique to prevent corrosion of metal in acidic medium because of the environmental friendly factor. In this study, black tea leaves extraction was tested as corrosion inhibitor for mild steel in 0.1M of hydrochloric acid (HCl) with the absence and presence of corrosion inhibitor. The efficiency and effectiveness of black tea as corrosion inhibitor was tested by using corrosion weight loss measurement experiment was carried out with varies parameters which with different concentration of black tea extract solution. The extraction of black tea solution was done by using aqueous solvent method. The FT-IR result shows that black tea extract containing compounds such as catechin, caffeine and tannins that act as anti-corrosive reagents and responsible to enhance the effectiveness of black tea extract as corrosion inhibitor by forming the hydrophobic thin film through absorption process. As a result of weight loss measurement, it shows that loss in weight of mild steel reduces as the concentration of inhibitor increases. The surface analysis was done on the mild steel samples by using SEM.

  19. Plasminogen activator inhibitor 1 and Antipain preserve acrosome integrity of bovine spermatozoa during cryopreservation

    Directory of Open Access Journals (Sweden)

    M.A. Castelo Branco

    Full Text Available ABSTRACT Seminal plasma contains serine proteases and serine protease inhibitor, which are involved in mammalian fertilization, and the inhibitors can be applied to prevent cold-induced sperm capacitation. The effects of different concentrations of two serine protease inhibitors were analyzed, Plasminogen activator inhibitor 1 - PAI-1 (70ƞg, 140ƞg and 210 ƞg and Antipain (10µg, 50µg and 100µg as supplementation to bovine semen cryopreservation extender. The effects of the inhibitors on the sperm parameters (sperm kinetics - CASA, acrosome integrity, plasma membrane integrity, mitochondrial membrane potential, sperm defects and acrosome reaction rate were evaluated in the post-thaw semen. Cryopreservation of sperm with Antipain decreased post-thaw kinetic parameters of MP, VSL, LIN, SRT and the percentage of hyper-activated sperm while PAI-1 (210 ƞg decreased VSL and LIN. Antipain and PAI-1 had no effect on the integrity parameters of the plasma membrane, mitochondrial membrane potential and sperm defects. Sperm cryopreserved in the presence of Antipain and PAI-1 (70 and 140 ƞg preserved acrosome integrity, as they were able to complete the in vitro acrosome reaction. In conclusion, the serine protease inhibitors, Antipain and PAI-1 (70 and 140ƞg are able to preserve the acrosome integrity of cryopreserved bovine sperm.

  20. Prodrugs of herpes simplex thymidine kinase inhibitors.

    Science.gov (United States)

    Yanachkova, Milka; Xu, Wei-Chu; Dvoskin, Sofya; Dix, Edward J; Yanachkov, Ivan B; Focher, Federico; Savi, Lida; Sanchez, M Dulfary; Foster, Timothy P; Wright, George E

    2015-04-01

    Because guanine-based herpes simplex virus thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent herpes simplex virus-1 reactivation from latency in a mouse model. Organic synthesis was used to prepare compounds, High Performance Liquid Chromatography (HPLC) to analyze hydrolytic conversion, Mass Spectrometry (MS) to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug. Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovir™ (6-deoxy-mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N(2)-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir™ in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication. Ad libitum oral delivery of sacrovir™ was effective in suppressing herpes simplex virus-1 reactivation in ocularly infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia positive for infectious virus, number of corneas that had detectable infectious virus, and herpes simplex virus-1 genome copy numbers in trigeminal ganglia following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing herpes simplex virus-1 reactivation in vivo. © The Author(s) 2015.

  1. Food Fortification to Prevent and Control Iron Deficiency | Chen ...

    African Journals Online (AJOL)

    It is essential to prevent the fortification iron from reacting with the absorption inhibitors. To ensure adequate absorption therefore, various factors must be considered before initiating a fortification programme. These include cost effectiveness of fortification in increasing absorbable iron, palatability of the fortified food and the ...

  2. Identification of Neutrophil Exocytosis Inhibitors (Nexinhibs), Small Molecule Inhibitors of Neutrophil Exocytosis and Inflammation: DRUGGABILITY OF THE SMALL GTPase Rab27a.

    Science.gov (United States)

    Johnson, Jennifer L; Ramadass, Mahalakshmi; He, Jing; Brown, Steven J; Zhang, Jinzhong; Abgaryan, Lusine; Biris, Nikolaos; Gavathiotis, Evripidis; Rosen, Hugh; Catz, Sergio D

    2016-12-09

    Neutrophils constitute the first line of cellular defense in response to bacterial and fungal infections and rely on granular proteins to kill microorganisms, but uncontrolled secretion of neutrophil cargos is injurious to the host and should be closely regulated. Thus, increased plasma levels of neutrophil secretory proteins, including myeloperoxidase and elastase, are associated with tissue damage and are hallmarks of systemic inflammation. Here, we describe a novel high-throughput screening approach to identify small molecule inhibitors of the interaction between the small GTPase Rab27a and its effector JFC1, two central regulators of neutrophil exocytosis. Using this assay, we have identified small molecule inhibitors of Rab27a-JFC1 binding that were also active in cell-based neutrophil-specific exocytosis assays, demonstrating the druggability of Rab GTPases and their effectors. These compounds, named Nexinhibs (neutrophil exocytosis inhibitors), inhibit exocytosis of azurophilic granules in human neutrophils without affecting other important innate immune responses, including phagocytosis and neutrophil extracellular trap production. Furthermore, the compounds are reversible and potent inhibitors of the extracellular production of superoxide anion by preventing the up-regulation of the granule membrane-associated subunit of the NADPH oxidase at the plasma membrane. Nexinhibs also inhibit the up-regulation of activation signature molecules, including the adhesion molecules CD11b and CD66b. Importantly, by using a mouse model of endotoxin-induced systemic inflammation, we show that these inhibitors have significant activity in vivo manifested by decreased plasma levels of neutrophil secretory proteins and significantly decreased tissue infiltration by inflammatory neutrophils. Altogether, our data present the first neutrophil exocytosis-specific inhibitor with in vivo anti-inflammatory activity, supporting its potential use as an inhibitor of systemic

  3. Nuclear scales

    Energy Technology Data Exchange (ETDEWEB)

    Friar, J.L.

    1998-12-01

    Nuclear scales are discussed from the nuclear physics viewpoint. The conventional nuclear potential is characterized as a black box that interpolates nucleon-nucleon (NN) data, while being constrained by the best possible theoretical input. The latter consists of the longer-range parts of the NN force (e.g., OPEP, TPEP, the {pi}-{gamma} force), which can be calculated using chiral perturbation theory and gauged using modern phase-shift analyses. The shorter-range parts of the force are effectively parameterized by moments of the interaction that are independent of the details of the force model, in analogy to chiral perturbation theory. Results of GFMC calculations in light nuclei are interpreted in terms of fundamental scales, which are in good agreement with expectations from chiral effective field theories. Problems with spin-orbit-type observables are noted.

  4. Potential physiological role of plant glycosidase inhibitors

    DEFF Research Database (Denmark)

    Bellincampi, D.; Carmadella, L.; Delcour, J.A.

    2004-01-01

    Carbohydrate-active enzymes including glycosidases, transglycosidases, glycosyltransferases, polysaccharide lyases and carbohydrate esterases are responsible for the enzymatic processing of carbohydrates in plants. A number of carbohydrate-active enzymes are produced by microbial pathogens...... and insects responsible of severe crop losses. Plants have evolved proteinaceous inhibitors to modulate the activity of several of these enzymes. The continuing discovery of new inhibitors indicates that this research area is still unexplored and may lead to new exciting developments. To date, the role...... of the inhibitors is not completely understood. Here we review recent results obtained on the best characterised inhibitors, pointing to their possible biological role in vivo. Results recently obtained with plant transformation technology indicate that this class of inhibitors has potential biotechnological...

  5. Risk Factors and Prevention

    Science.gov (United States)

    ... Factors & Prevention Back to Patient Resources Risk Factors & Prevention Even people who look healthy and free of ... as possible. Share: The Normal Heart Risk Factors & Prevention Heart Diseases & Disorders Substances & Heart Rhythm Disorders Symptoms & ...

  6. Prevent Back Pain

    Science.gov (United States)

    ... Prevent Back Pain Print This Topic En español Prevent Back Pain Browse Sections The Basics Overview Am ... at Risk? 3 of 5 sections Take Action: Prevent Injuries Focus on good posture. Good posture can ...

  7. Prevent Bite Wounds

    Science.gov (United States)

    ... Issues Listen Español Text Size Email Print Share Prevent Bite Wounds Page Content Article Body Each year, ... bite Swollen glands that occur above the bite Prevention of Bites and Infections To prevent bites and ...

  8. Stomach (Gastric) Cancer Prevention

    Science.gov (United States)

    ... Stomach Cancer Prevention Stomach Cancer Screening Research Stomach (Gastric) Cancer Prevention (PDQ®)–Patient Version What is prevention? Go ... has stayed about the same since 2005. Stomach (gastric) cancer is a disease in which malignant (cancer) cells ...

  9. Cardiotoxicity in anthracycline therapy: Prevention strategies.

    Science.gov (United States)

    Cruz, Margarida; Duarte-Rodrigues, Joana; Campelo, Manuel

    2016-06-01

    The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to detect, prevent or mitigate anthracycline-induced cardiomyopathy, it is essential that all patients undergo a rigorous initial cardiovascular assessment, followed by close monitoring. Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise, healthy lifestyles, control of risk factors and treatment of comorbidities; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, statins, dexrazoxane and liposomal formulations. However, there are currently no guidelines for managing prevention in these patients. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline-induced cardiotoxicity. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  10. Inhibiting properties and adsorption of an amine based fatty acid corrosion inhibitor on carbon steel in aqueous carbon dioxide solutions

    Energy Technology Data Exchange (ETDEWEB)

    Buchweishaija, Joseph

    1997-12-31

    Carbon dioxide corrosion is a major corrosion problem in oil and gas production systems and many organic inhibitors have been tested and used to protect the substrate from corrosion. This thesis studies the mechanism of interaction of the inhibitor molecule with the metallic substrate and how this affects the dissolution rate of the metal. The performance of a commercial amine based fatty acid corrosion inhibitor has been investigated using rotating cylinder electrodes and carbon steel electrodes in CO{sub 2} saturated formation water in the temperature range between 35 to 80{sup o}C. The corrosion process was monitored by electrochemical impedance measurements, and at the end of each experiment full polarization curves were recorded. When the inhibitor was applied on noncorroded electrodes, high inhibitor performance, over 99.7%, was observed independent of temperature. On precorroded electrodes inhibitor performance was found to depend on temperature and time of precorrosion. Above 60{sup o}C, the inhibitor performance decreased with increasing time of precorrosion, presumably because of the formation of a corrosion film of either iron carbonate or a combination of iron carbonate and iron carbide which prevent the inhibitor from reaching the surface. The inhibitor protection efficiency was assumed to be associated with the degree of inhibitor coverage at the material surface, and adsorption isotherms have been calculated in the concentration range between 0.1 ppm and 100 ppm. A Langmuir isotherm was found to give the best fit. The inhibitor performance on a 2 days precorroded rotating electrode was investigated at different solution pH ranging between 4.5 and 6.5 at 35{sup o}C. 130 refs., 80 figs., 22 tabs.

  11. General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

    Directory of Open Access Journals (Sweden)

    Hui Wang

    Full Text Available Islet amyloid polypeptide (IAPP or amylin forms amyloid deposits in the islets of Langerhans; a process that is believed to contribute to the progression of type 2 diabetes and to the failure of islet transplants. An emerging theme in amyloid research is the hypothesis that the toxic species produced during amyloid formation by different polypeptides share common features and exert their effects by common mechanisms. If correct, this suggests that inhibitors of amyloid formation by one polypeptide might be effective against other amyloidogenic sequences. IAPP and Aβ, the peptide responsible for amyloid formation in Alzheimer's disease, are particularly interesting in this regard as they are both natively unfolded in their monomeric states and share some common characteristics. Comparatively little effort has been expended on the design of IAPP amyloid inhibitors, thus it is natural to inquire if Aβ inhibitors are effective against IAPP, especially since no IAPP inhibitors have been clinically approved. A range of compounds inhibit Aβ amyloid formation, including various stereoisomers of inositol. Myo-, scyllo-, and epi-inositol have been shown to induce conformational changes in Aβ and prevent Aβ amyloid fibril formation by stabilizing non-fibrillar β-sheet structures. We investigate the ability of inositol stereoisomers to inhibit amyloid formation by IAPP. The compounds do not induce a conformational change in IAPP and are ineffective inhibitors of IAPP amyloid formation, although some do lead to modest apparent changes in IAPP amyloid fibril morphology. Thus not all classes of Aβ inhibitors are effective against IAPP. This work provides a basis of comparison to work on polyphenol based inhibitors of IAPP amyloid formation and helps provide clues as to the features which render them effective. The study also helps provide information for further efforts in rational inhibitor design.

  12. Polymeric Materials For Scale Inhibition In Cooling Water Systems

    Directory of Open Access Journals (Sweden)

    Najwa S.Majeed

    2013-04-01

    Full Text Available Calcium carbonate deposition is generally predominant in cooling water-circulating system. For the control of calcium carbonate scale formation two types of polymeric scale inhibitors were used Polyamino polyether methylene phosphonate  (PAPEMPand polyacrylaminde(PAA.Model of cooling tower system have been built up in laboratory scale. Experiments were carried out using different inhibitor concentrations(0.5,1,1.5,2,3ppm ,at water temperature of  40oC and flow rate of 150 l/hr. It was found that Polyamino polyether methylene phosphonate    more effective than polyacryle amide'  as scale inhibitor in all used concentrations and the best inhibition efficiency (95% was at (2.5ppm of Polyamino polyether methylene phosphonate  and (85% with poly acryle amide at concentrations of (3 ppm. The performance of the polymeric scale inhibitors was compared with a method used to control heavy calcium carbonate scale forming by the deposition of sufficiently thin protective calcium carbonate scale using sulfuric acid and depending on Ryznar stability index controlling method. 

  13. AZT as a telomerase inhibitor

    Directory of Open Access Journals (Sweden)

    Daniel E Gomez

    2012-09-01

    Full Text Available Telomerase is a highly specialized reverse transcriptase and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic reverse transcriptase prompted studies of inhibiting telomerase with the HIV reverse transcriptase inhibitor azidothymidine (AZT. Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

  14. ALK inhibitors, a pharmaceutical perspective

    Directory of Open Access Journals (Sweden)

    Arturo eGalvani

    2012-02-01

    Full Text Available In 2007, the ALK tyrosine kinase, already known to be translocated and activated in Anaplastic Large Cell Lymphoma, and a few other rare cancers, was described as a potential therapeutic target for a subset of non small-cell lung cancer (NSCLC patients. Clinical proof of concept, culminating in the recent approval by the FDA of the Pfizer drug Xalkori (crizotinib, formerly known as PF-02341066 followed in record time. The drug was approved together with a companion diagnostic, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc. for detection of eligible patients. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in this rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib has already been observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy, and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may also occur through ALK-independent mechanisms, which still need to be elucidated in detail.

  15. Novel Toxoplasma gondii inhibitor chemotypes.

    Science.gov (United States)

    Sanford, A G; Schulze, T T; Potluri, L P; Hemsley, R M; Larson, J J; Judge, A K; Zach, S J; Wang, X; Charman, S A; Vennerstrom, J L; Davis, P H

    2018-04-01

    We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC 50 values ranging from 0.3 to 2μM, comparable to that of 0.25 to 1.5μM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD 7.4 and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Development of green vapour corrosion inhibitor

    Science.gov (United States)

    Asmara, Y. P.; Suraj, V.; Siregar, J. P.; Kurniawan, T.; Bachtiar, D.; Mohamed, N. M. Z. N.

    2017-10-01

    Corrosion control using inhibitor is an effective method to protect carbon steel from corrosion. Due to environmental toxicity of chemical inorganic corrosion inhibitors (synthetic), green inhibitors are potentially to develop. In atmospheric conditions, green vapour corrosion inhibitors are the best solutions to replace the uses of inorganic corrosion inhibitors. This research used chemical acid extraction from the key lime (citrus aurantiifolia) leaves and seeds. They are used as the main ingredients to produce this effective green corrosion inhibitor. The experiments investigated effects of corrosion inhibition on corrosion rate of low carbon steel in 3% NaCl solution using both fog salt chamber and electrochemical cell. Using salt fog chamber to represent atmospheric conditions, and corrosion rates are evaluated visually and calculated using weight loss methods. Corrosion rate on electrochemical cell were calculated using linear polarization resistance (LPR) methods. All of the experiments were set in natural conditions at pH 7. Using weight loss for three days exposure time, the efficiency of the inhibitor reached 82.39%.

  17. Histone Deacetylase Inhibitors as Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  18. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Science.gov (United States)

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  19. Computational analysis of ABL kinase mutations allows predicting drug sensitivity against selective kinase inhibitors.

    Science.gov (United States)

    Kamasani, Swapna; Akula, Sravani; Sivan, Sree Kanth; Manga, Vijjulatha; Duyster, Justus; Vudem, Dashavantha Reddy; Kancha, Rama Krishna

    2017-05-01

    The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive chronic myeloid leukemia. However, a significant proportion of imatinib-treated patients relapse due to occurrence of mutations in the ABL kinase domain. Although inhibitor sensitivity for a set of mutations was reported, the role of less frequent ABL kinase mutations in drug sensitivity/resistance is not known. Moreover, recent reports indicate distinct resistance profiles for second-generation ABL inhibitors. We thus employed a computational approach to predict drug sensitivity of 234 point mutations that were reported in chronic myeloid leukemia patients. Initial validation analysis of our approach using a panel of previously studied frequent mutations indicated that the computational data generated in this study correlated well with the published experimental/clinical data. In addition, we present drug sensitivity profiles for remaining point mutations by computational docking analysis using imatinib as well as next generation ABL inhibitors nilotinib, dasatinib, bosutinib, axitinib, and ponatinib. Our results indicate distinct drug sensitivity profiles for ABL mutants toward kinase inhibitors. In addition, drug sensitivity profiles of a set of compound mutations in ABL kinase were also presented in this study. Thus, our large scale computational study provides comprehensive sensitivity/resistance profiles of ABL mutations toward specific kinase inhibitors.

  20. Safe corrosion inhibitor for treating cooling water on heat power engineering plants

    Science.gov (United States)

    Nikolaeva, L. A.; Khasanova, D. I.; Mukhutdinova, E. R.; Safin, D. Kh.; Sharifullin, I. G.

    2017-08-01

    Heat power engineering (HPE) consumes significant volumes of water. There are, therefore, problems associated with corrosion, biological fouling, salt deposits, and sludge formation on functional surfaces of heat power equipment. One of the effective ways to solve these problems is the use of inhibitory protection. The development of new Russian import-substituting environmentally friendly inhibitors is very relevant. This work describes experimental results on the OPC-800 inhibitor (TU 2415-092-00206 457-2013), which was produced at Karpov Chemical Plant and designed to remove mineral deposits, scale, and biological fouling from the surfaces of water-rotation node systems on HPE objects. This reagent is successfully used as an effective corrosion inhibitor in the water recycling systems of Tatarstan petrochemical enterprises. To save fresh make-up water, the circulating system is operated in a no-blow mode, which is characterized by high evaporation and salt content coefficients. It was experimentally found that corrosion rate upon treatment of recycled water with the OPC-800 inhibitor is 0.08-0.10 mm/year. HPE mainly uses inhibitors based on oxyethylidene diphosphonic (OEDPA) and nitrilotrimethylphosphonic (NTMPA) acids. The comparative characteristic of inhibition efficiency for OPC-800 and OEDF-Zn-U2 is given. The results obtained indicate that OPC-800 can be used as an inhibitor for treatment of cooling water in HPE plants. In this case, it is necessary to take into account the features of water rotation of a thermal power plant.

  1. Influence of biofilm formation on corrosion and scaling in geothermal plants

    Science.gov (United States)

    Kleyböcker, Anne; Lerm, Stephanie; Monika, Kasina; Tobias, Lienen; Florian, Eichinger; Andrea, Seibt; Markus, Wolfgramm; Hilke, Würdemann

    2017-04-01

    Process failures may occur due to corrosion and scaling processes in open loop geothermal systems. Especially after heat extraction, sulfate reducing bacteria (SRB) contribute to corrosion processes due to a more favorable temperature for their growth. In biofilms containing FeS scales, corrosion processes are enhanced. Furthermore, scales can lead to reduced pipe profiles, to a diminished heat transfer and a decrease in the wellbore injectivity. Inhibitors are frequently applied to minimize scaling in technical systems. A prerequisite for the application of inhibitors in geothermal plants located in the Molasse basin is their degradability under reservoir conditions, e. g. in a reduced environment. In order to determine the effects of scale-inhibitors on the subsurface and microbial processes, laboratory experiments were performed focusing on the microbial inhibitor degradation. First results indicate that the inhibitor degradation under anaerobic conditions is possible. Besides the inhibitor application also other techniques are investigated to economically reduce corrosion and scaling in geothermal plants. In a mobile bypass system, the influence of biofilm formation on corrosion and scaling was investigated. The bypass system was tested at a geothermal heat store in the North German Basin. The plant is operated with highly saline fluid (salinity 130 g/L) and known to be affected by SRB. The SRB contributed to corrosion damages especially at the pump in the well on the cold side. Heat shocks were successfully used in the bypass system to reduce biofilm formation as well as corrosion and scaling processes.

  2. An Updated Review of Tyrosinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Te-Sheng Chang

    2009-05-01

    Full Text Available Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

  3. Contemporary protease inhibitors and cardiovascular risk

    DEFF Research Database (Denmark)

    Lundgren, Jens; Mocroft, Amanda; Ryom, Lene

    2018-01-01

    PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted...... with ritonavir (/r)], darunavir/r has been shown to be associated with increased CVD risk. The effect is cumulative with longer exposure increasing risk and an effect size comparable to what has been observed for previously developed protease inhibitors. Biological mechanisms may be overlapping and include...... on individualization of care based on underlying risk of CVD....

  4. SGLT 2 Inhibitors: A New Therapeutic Target And Its Role In Current Clinical Practice

    Directory of Open Access Journals (Sweden)

    PV Shiji

    2015-10-01

    Full Text Available Diabetes, one of the major life style diseases, is associated with high morbidity and mortality owing to its microvascular and macrovascular complications. The chance of development of various complications can be effectively prevented by tight glycemic control. We have various groups of drugs like Biguanides, Sulfonyl ureas, Glitazones, Alpha-glucosidase inhibitors, Incretin based therapy, Insulin and Insulin analogues in the armamentarium to treat diabetes. But still, the number of patients attaining glycemic targets are relatively low and various adverse effect limit the use of some of these drugs, especially in special groups. Hence there is ongoing research to develop newer and newer drugs which provide sustained blood glucose reduction with minimal adverse effects. SGLT-2 inhibitors are a new group of drugs recently approved by FDA to treat Diabetes. In this review we discuss about mechanism of action, various adverse effects and the clinical role of various SGLT-2 Inhibitors.

  5. Soybean-derived Bowman-Birk inhibitor (BBI) blocks HIV entry into macrophages.

    Science.gov (United States)

    Ma, Tong-Cui; Le Guo; Zhou, Run-Hong; Wang, Xu; Liu, Jin-Biao; Li, Jie-Liang; Zhou, Yu; Hou, Wei; Ho, Wen-Zhe

    2018-01-01

    Bowman-Birk inhibitor (BBI) is a soybean-derived protease inhibitor that has anti-inflammation and anti-HIV effect. Here, we further investigated the anti-HIV action of BBI in macrophages, focusing on its effect on viral entry. We found that BBI could significantly block HIV entry into macrophages. Investigation of the mechanism(s) of the BBI action on HIV inhibition showed that BBI down-regulated the expression of CD4 receptor (as much as 80%) and induced the production of the CC chemokines (up to 60 folds at protein level) in macrophages. This inhibitory effect of BBI on HIV entry could be blocked by the neutralization antibodies to CC chemokines. These findings indicate that BBI may have therapeutic potential as a viral entry inhibitor for the prevention and treatment of HIV infection. Copyright © 2017. Published by Elsevier Inc.

  6. Inhibitors of MyD88-dependent proinflammatory cytokine production identified utilizing a novel RNA interference screening approach.

    Directory of Open Access Journals (Sweden)

    John S Cho

    2009-09-01

    Full Text Available The events required to initiate host defenses against invading pathogens involve complex signaling cascades comprised of numerous adaptor molecules, kinases, and transcriptional elements, ultimately leading to the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha. How these signaling cascades are regulated, and the proteins and regulatory elements participating are still poorly understood.We report here the development a completely random short-hairpin RNA (shRNA library coupled with a novel forward genetic screening strategy to identify inhibitors of Toll-like receptor (TLR dependent proinflammatory responses. We developed a murine macrophage reporter cell line stably transfected with a construct expressing diphtheria toxin-A (DT-A under the control of the TNF-alpha-promoter. Stimulation of the reporter cell line with the TLR ligand lipopolysaccharide (LPS resulted in DT-A induced cell death, which could be prevented by the addition of an shRNA targeting the TLR adaptor molecule MyD88. Utilizing this cell line, we screened a completely random lentiviral short hairpin RNA (shRNA library for sequences that inhibited TLR-mediated TNF-alpha production. Recovery of shRNA sequences from surviving cells led to the identification of unique shRNA sequences that significantly inhibited TLR4-dependent TNF-alpha gene expression. Furthermore, these shRNA sequences specifically blocked TLR2 but not TLR3-dependent TNF-alpha production.Thus, we describe the generation of novel tools to facilitate large-scale forward genetic screens in mammalian cells and the identification of potent shRNA inhibitors of TLR2 and TLR4- dependent proinflammatory responses.

  7. Comparative protection against rat intestinal reperfusion injury by a new inhibitor of sPLA2, COX-1 and COX-2 selective inhibitors, and an LTC4 receptor antagonist

    Science.gov (United States)

    Arumugam, Thiruma V; Arnold, Naomi; Proctor, Lavinia M; Newman, Michelle; Reid, Robert C; Hansford, Karl A; Fairlie, David P; Shiels, Ian A; Taylor, Stephen M

    2003-01-01

    A new group IIa sPLA2 inhibitor was compared with selective inhibitors of COX-1, COX-2 and an LTC4 antagonist for effects on local and remote tissue injuries following ischaemia and reperfusion (I/R) of the small intestine in rats. In an acute model of ischaemia (30 min) and reperfusion (150 min) injury in the absence of inhibitors, there was significant intestinal haemorrhage, oedema and mucosal damage, neutropenia, elevated serum levels of aspartate aminotransferase (AST) and hypotension. Preischaemic treatment with the inhibitor of sPLA2 (Group IIa), at 5 mg kg−1 i.v. or 10 mg kg−1 p.o. significantly inhibited I/R-induced neutropenia, the elevation of serum levels of AST, intestinal oedema and hypotension. Pretreatment with the COX-2 inhibitor celebrex (10 mg kg−1 i.v.) and the LTC4 antagonist zafirlukast (1 mg kg−1 i.v.) also showed marked improvement with I/R-induced AST, oedema and neutropenia. Hypotension was only reduced by the LTC4 antagonist. The COX-1 inhibitor flunixin (1 mg kg−1 i.v.) did not effect improvement in the markers of tissue injury. Histological examination of rat I/R injury showed that all of the drugs offered some protection to the mucosal layer damage compared to no drug treatment. Given i.v., the sPLA2 inhibitor was more effective than either the COX-1 or COX-2 inhibitors in preventing rat I/R injury. These results indicate that a potent new inhibitor of sPLA2 (group IIa) protects the rat small intestine from I/R injury after oral or intravenous administration. COX-2 and LTC4 inhibitors also showed some beneficial effects against intestinal I/R injury. Our study suggests that sPLA2 (Group IIa) may have a pathogenic role in intestinal I/R in rats. PMID:12967936

  8. Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties.

    Science.gov (United States)

    Ferri, Nicola; Corsini, Alberto; Bellosta, Stefano

    2013-10-01

    The P2Y(12) receptor is a key player in platelet activation and represents an effective pharmacological target for the inhibition of platelet aggregation and prevention of atherothrombotic events. Indeed, the clinical use of the P2Y(12) receptor inhibitor clopidogrel is an effective strategy for inhibiting platelet activity in patients with acute coronary syndrome, and for preventing thrombotic events in those undergoing percutaneous coronary intervention with stenting. However, clopidogrel has several drawbacks, which include delayed onset of action, large inter-individual variability in platelet response, genetic polymorphism of the metabolizing enzyme, drug-drug interactions (DDIs), and the two-step activation process catalyzed by a series of cytochrome P450 (CYP) isoenzymes. For these reasons, new P2Y(12) receptor inhibitors have been developed in an attempt to improve on the pharmacological and clinical profile of clopidogrel. Three new P2Y(12) receptor inhibitors--prasugrel, cangrelor, and ticagrelor--have arrived, and more are coming into clinical use. Each of these antagonists has individual properties and, according to their mechanism of inhibition, can be divided into irreversible (prasugrel) and reversible inhibitors (ticagrelor, cangrelor). These agents also have different metabolic pathways: prasugrel is a prodrug that requires metabolic activation through a cytochrome-dependent pathway, while ticagrelor and cangrelor do not require metabolic conversion. However, ticagrelor is a CYP3A4 substrate/inhibitor and thus it can be involved in DDIs. Indeed, ticagrelor significantly increases the plasma levels of CYP3A4 substrates such as statins. Moreover, concomitant use with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, clarithromycin, ritonavir, telithromycin, etc.) is contraindicated, while the co-administration of ticagrelor with potent CYP3A inducers (carbamazepine, rifampicin, phenytoin, phenobarbital) is discouraged. Prasugrel and

  9. DETERMINATION OF CORROSION INHIBITOR CRITERIA FOR TYPE III IIIA TANKS DURING SALT DISSOLUTION OPERATIONS

    Energy Technology Data Exchange (ETDEWEB)

    Wiersma, B

    2008-01-04

    Preparation of high level waste for vitrification involves in part the dissolution of salt cake from the carbon steel storage tanks. The salt crystals composing this cake are high in nitrate concentration with the interstitial liquid being high in hydroxide and nitrite concentration. During the salt dissolution process, a stage is reached in which the inhibitors, hydroxide and nitrite, are insufficient to prevent nitrate stress corrosion cracking (SCC) and fall outside the requirements of the corrosion control program. Additional inhibitors, which are necessary to meet the requirements, may be counterproductive to the efficiency of the process and waste minimization. Corrosion testing was initiated to better characterize the necessary inhibitor concentration for high nitrate waste during salt dissolution processing. A four-phase test program is being conducted: (1) electrochemical characterization, (2) accelerated or polarized U-bend testing, (3) long-term (non-polarized) U-bend testing and (4) vapor space U-bend tests. Electrochemical testing, which included cyclic potentiodynamic polarization (CPP), linear polarization resistance (LPR) and open-circuit potential (OCP) measurements, was performed to identify stress corrosion cracking susceptibility, to characterize pitting resistance and to determine the general corrosion rate. Polarized U-bend tests were utilized to assess the effect of minimum inhibitor concentrations and heat treatment on SCC and to determine test parameters for future long-term U-bend testing. Results from CPP, LPR and OCP tests demonstrated that carbon steel formed a protective oxide film and the potential became electropositive during exposure to the waste at all inhibitor concentrations. The tenacity of this film improved as the inhibitor concentration level was increased and the temperature was decreased. This passive film increased the resistance to localized corrosion significantly. Therefore if any of these inhibitor levels are selected

  10. Study of the chemical inhibition of the scaling of large Agadir water

    Directory of Open Access Journals (Sweden)

    Driouiche A.

    2013-07-01

    Full Text Available The distribution mains of drinking water of Large Agadir are the seat of chemical scaling. This phenomenon is due primarily to the precipitation of calcium carbonate. The effectiveness of two chemical inhibitors containing phosphorus was quantified on underground water samples of the area of Agadir. The effective concentrations of these two inhibitors were given.

  11. Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Kai [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of Life Science and Technology, Jinan University, Guangzhou (China); Chen, Maoyun [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of pharmacy, Jinan University, Guangzhou (China); Xiang, Yangfei; Ma, Kaiqi [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); Jin, Fujun [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); College of pharmacy, Jinan University, Guangzhou (China); Wang, Xiao [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006 (China); Wang, Xiaoyan; Wang, Shaoxiang [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China); Wang, Yifei, E-mail: twang-yf@163.com [Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou (China)

    2014-04-18

    Highlights: • We analyze the anti-HSV potential of chloride channel inhibitors. • Tamoxifen and NPPB show anti-HSV-1 and anti-ACV-resistant HSV-1 activities. • HSV-1 infection induces intracellular chloride concentration increasing. • Tamoxifen and NPPB inhibit HSV-1 early infection. • Tamoxifen and NPPB prevent the fusion process of HSV-1. - Abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.

  12. Predicting the Performance of Organic Corrosion Inhibitors

    Directory of Open Access Journals (Sweden)

    David A. Winkler

    2017-12-01

    Full Text Available The withdrawal of effective but toxic corrosion inhibitors has provided an impetus for the discovery of new, benign organic compounds to fill that role. Concurrently, developments in the high-throughput synthesis of organic compounds, the establishment of large libraries of available chemicals, accelerated corrosion inhibition testing technologies, and the increased capability of machine learning methods have made discovery of new corrosion inhibitors much faster and cheaper than it used to be. We summarize these technical developments in the corrosion inhibition field and describe how data-driven machine learning methods can generate models linking molecular properties to corrosion inhibition that can be used to predict the performance of materials not yet synthesized or tested. We briefly summarize the literature on quantitative structure–property relationships models of small organic molecule corrosion inhibitors. The success of these models provides a paradigm for rapid discovery of novel, effective corrosion inhibitors for a range of metals and alloys in diverse environments.

  13. Kinase inhibitors for advanced medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Martin Schlumberger

    2012-01-01

    Full Text Available The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

  14. Electrochemical Behaviour of Environmentally Friendly Inhibitor of ...

    African Journals Online (AJOL)

    Electrochemical Behaviour of Environmentally Friendly Inhibitor of Aloe Secundiflora Extract in Corrosion Control of Carbon Steel in Soft Water Media. ... corrosion control in neutral and aerated soft water solutions have been investigated using electrochemical impedance spectroscopy and Tafel polarization techniques.

  15. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

    Directory of Open Access Journals (Sweden)

    Miroslav Pohanka

    2014-06-01

    Full Text Available Acetylcholinesterase (AChE inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE. Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.

  16. Small-Molecule Inhibitors of Urea Transporters

    Science.gov (United States)

    Verkman, Alan S.; Esteva-Font, Cristina; Cil, Onur; Anderson, Marc O.; Li, Fei; Li, Min; Lei, Tianluo; Ren, Huiwen; Yang, Baoxue

    2015-01-01

    Urea transporter (UT) proteins, which include isoforms of UT-A in kidney tubule epithelia and UT-B in vasa recta endothelia and erythrocytes, facilitate urinary concentrating function. Inhibitors of urea transporter function have potential clinical applications as sodium-sparing diuretics, or ‘urearetics,’ in edema from different etiologies, such as congestive heart failure and cirrhosis, as well as in syndrome of inappropriate antidiuretic hormone (SIADH). High-throughput screening of drug-like small molecules has identified UT-A and UT-B inhibitors with nanomolar potency. Inhibitors have been identified with different UT-A versus UT-B selectivity profiles and putative binding sites on UT proteins. Studies in rodent models support the utility of UT inhibitors in reducing urinary concentration, though testing in clinically relevant animal models of edema has not yet been done. PMID:25298345

  17. A Broad-Spectrum Inhibitor of CRISPR-Cas9.

    Science.gov (United States)

    Harrington, Lucas B; Doxzen, Kevin W; Ma, Enbo; Liu, Jun-Jie; Knott, Gavin J; Edraki, Alireza; Garcia, Bianca; Amrani, Nadia; Chen, Janice S; Cofsky, Joshua C; Kranzusch, Philip J; Sontheimer, Erik J; Davidson, Alan R; Maxwell, Karen L; Doudna, Jennifer A

    2017-09-07

    CRISPR-Cas9 proteins function within bacterial immune systems to target and destroy invasive DNA and have been harnessed as a robust technology for genome editing. Small bacteriophage-encoded anti-CRISPR proteins (Acrs) can inactivate Cas9, providing an efficient off switch for Cas9-based applications. Here, we show that two Acrs, AcrIIC1 and AcrIIC3, inhibit Cas9 by distinct strategies. AcrIIC1 is a broad-spectrum Cas9 inhibitor that prevents DNA cutting by multiple divergent Cas9 orthologs through direct binding to the conserved HNH catalytic domain of Cas9. A crystal structure of an AcrIIC1-Cas9 HNH domain complex shows how AcrIIC1 traps Cas9 in a DNA-bound but catalytically inactive state. By contrast, AcrIIC3 blocks activity of a single Cas9 ortholog and induces Cas9 dimerization while preventing binding to the target DNA. These two orthogonal mechanisms allow for separate control of Cas9 target binding and cleavage and suggest applications to allow DNA binding while preventing DNA cutting by Cas9. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Monoamine Oxidase B Inhibitors in Parkinson's Disease.

    Science.gov (United States)

    Dezsi, Livia; Vecsei, Laszlo

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Update on TNF Inhibitors in Dermatology.

    Science.gov (United States)

    Sobell, Jeffrey M

    2016-06-01

    Emerging data describe new potential indications for tumor necrosis factor (TNF) inhibitors in dermatology, including pediatric psoriasis and hidradenitis suppurativa. New biosimilar TNF agents are in late stages of development and may be available in the United States in the near future. Biosimilar agents are similar but not identical to available TNF inhibitors, and approval requires extensive analytic, toxicity, pharmacokinetic, pharmacodynamic, and clinical testing. Semin Cutan Med Surg 35(supp6):S104-S106. 2016 published by Frontline Medical Communications.

  20. Current treatment of dyslipidaemia: PCSK9 inhibitors and statin intolerance.

    Science.gov (United States)

    Koskinas, Konstantinos; Wilhelm, Matthias; Windecker, Stephan

    2016-01-01

    Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients.

  1. Identifying HER2 inhibitors from natural products database.

    Directory of Open Access Journals (Sweden)

    Shun-Chieh Yang

    Full Text Available The relationship between abnormal HER2 expression and cancer is important in cancer therapeutics. Formation and spread of cancer cells may be restricted by inhibiting HER2. We conducted ligand-based and structure-based studies to assess the potency of natural compounds as potential HER2 inhibitors. Multiple linear regression (MLR and support vector machine (SVM models were constructed to predict biological activities of natural compounds, and molecular dynamics (MD was used to assess their stability with HER2 under a dynamic environment. Predicted bioactivities of the natural compounds ranged from 6.014-9.077 using MLR (r(2 = 0.7954 and 5.122-6.950 using SVM (r(2 = 0.8620. Both models were in agreement and suggest bioactivity based on candidate structure. Conformation changes caused by MD favored the formation of stabilizing H-bonds. All candidates had higher stability than Lapinatib, which may be due to the number and spatial distribution of additional H-bonds and hydrophobic interactions. Amino acids Lys724 and Lys736 are critical for binding in HER2, and Thr798, Cys805, and Asp808 are also important for increased stability. Candidates may block the entrance to the ATP binding site located within the inner regions and prevent downstream activation of HER2. Our multidirectional approach indicates that the natural compounds have good ligand efficacy in addition to stable binding affinities to HER2, and should be potent candidates of HER2 inhibitors. With regard to drug design, designing HER2 inhibitors with carboxyl or carbonyl groups available for H-bond formation with Lys724 and Lys736, and benzene groups for hydrophobic contact with Cys805 may improve protein-ligand stability.

  2. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis.

    Science.gov (United States)

    Pisithkul, Tippapha; Jacobson, Tyler B; O'Brien, Thomas J; Stevenson, David M; Amador-Noguez, Daniel

    2015-09-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using (13)C-labeled sugars and [(15)N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. Copyright © 2015, Pisithkul et al.

  3. Emerging Corrosion Inhibitors for Interfacial Coating

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    Mona Taghavikish

    2017-12-01

    Full Text Available Corrosion is a deterioration of a metal due to reaction with environment. The use of corrosion inhibitors is one of the most effective ways of protecting metal surfaces against corrosion. Their effectiveness is related to the chemical composition, their molecular structures and affinities for adsorption on the metal surface. This review focuses on the potential of ionic liquid, polyionic liquid (PIL and graphene as promising corrosion inhibitors in emerging coatings due to their remarkable properties and various embedment or fabrication strategies. The review begins with a precise description of the synthesis, characterization and structure-property-performance relationship of such inhibitors for anti-corrosion coatings. It establishes a platform for the formation of new generation of PIL based coatings and shows that PIL corrosion inhibitors with various heteroatoms in different form can be employed for corrosion protection with higher barrier properties and protection of metal surface. However, such study is still in its infancy and there is significant scope to further develop new structures of PIL based corrosion inhibitors and coatings and study their behaviour in protection of metals. Besides, it is identified that the combination of ionic liquid, PIL and graphene could possibly contribute to the development of the ultimate corrosion inhibitor based coating.

  4. Aromatase inhibitors in the treatment of endometriosis

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    Radosław Słopień

    2016-03-01

    Full Text Available Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia, pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs. A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body’s oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis.

  5. Diapause prevention effect of Bombyx mori by dimethyl sulfoxide.

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    Yamamoto, Takayuki; Mase, Keisuke; Sawada, Hiroshi

    2013-01-01

    HCl treatment has been, for about 80 years, the primary method for the prevention of entry into embryonic diapauses of Bombyx mori. This is because no method is as effective as the HCl treatment. In this study, we discovered that dimethyl sulfoxide (DMSO) prevented entry into the diapause of the silkworm, Bombyx mori. The effect of diapause prevention was 78% as a result of treatment with 100% DMSO concentration, and the effect was comparable to that of the HCl treatment. In contrast, in the case of non-diapause eggs, hatchability was decreased by DMSO in a concentration-dependent manner. The effect of DMSO was restricted within 24 hours after oviposition of diapause eggs, and the critical period was slightly shorter than the effective period of the HCl treatment. DMSO analogs, such as dimethyl formamide (DMF) and dimethyl sulfide (DMS), did little preventive effect against the diapause. Furthermore, we also investigated the permeation effects of chemical compounds by DMSO. When treated with an inhibitor of protein kinase CK2 (CK2) dissolved in DMSO, the prevention rate of the diapause was less than 40%. This means that the inhibition effect by the CK2 inhibitor was the inhibition of embryonic development after diapause prevention by DMSO. These data suggest that DMSO has the effects of preventing from entering into the diapause and permeation of chemicals into diapause eggs.

  6. Diapause prevention effect of Bombyx mori by dimethyl sulfoxide.

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    Takayuki Yamamoto

    Full Text Available HCl treatment has been, for about 80 years, the primary method for the prevention of entry into embryonic diapauses of Bombyx mori. This is because no method is as effective as the HCl treatment. In this study, we discovered that dimethyl sulfoxide (DMSO prevented entry into the diapause of the silkworm, Bombyx mori. The effect of diapause prevention was 78% as a result of treatment with 100% DMSO concentration, and the effect was comparable to that of the HCl treatment. In contrast, in the case of non-diapause eggs, hatchability was decreased by DMSO in a concentration-dependent manner. The effect of DMSO was restricted within 24 hours after oviposition of diapause eggs, and the critical period was slightly shorter than the effective period of the HCl treatment. DMSO analogs, such as dimethyl formamide (DMF and dimethyl sulfide (DMS, did little preventive effect against the diapause. Furthermore, we also investigated the permeation effects of chemical compounds by DMSO. When treated with an inhibitor of protein kinase CK2 (CK2 dissolved in DMSO, the prevention rate of the diapause was less than 40%. This means that the inhibition effect by the CK2 inhibitor was the inhibition of embryonic development after diapause prevention by DMSO. These data suggest that DMSO has the effects of preventing from entering into the diapause and permeation of chemicals into diapause eggs.

  7. GALK inhibitors for classic galactosemia.

    Science.gov (United States)

    Lai, Kent; Boxer, Matthew B; Marabotti, Anna

    2014-06-01

    Classic galactosemia is an inherited metabolic disease for which, at present, no therapy is available apart from galactose-restricted diet. However, the efficacy of the diet is questionable, since it is not able to prevent the insurgence of chronic complications later in life. In addition, it is possible that dietary restriction itself could induce negative side effects. Therefore, there is a need for an alternative therapeutic approach that can avert the manifestation of chronic complications in the patients. In this review, the authors describe the development of a novel class of pharmaceutical agents that target the production of a toxic metabolite, galactose-1-phosphate, considered as the main culprit for the cause of the complications, in the patients.

  8. Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Garzan, Atefeh; Willby, Melisa J.; Green, Keith D.; Gajadeera, Chathurada S.; Hou, Caixia; Tsodikov, Oleg V.; Posey, James E.; Garneau-Tsodikova, Sylvie

    2016-12-08

    A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28–37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB.

  9. Respiratory Syncytial Virus Entry Inhibitors Targeting the F Protein

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    Shibo Jiang

    2013-01-01

    Full Text Available Human respiratory syncytial virus (RSV is the main viral cause of respiratory tract infection in infants as well as some elderly and high-risk adults with chronic pulmonary disease and the severely immunocompromised. So far, no specific anti-RSV therapeutics or effective anti-RSV vaccines have been reported. Only one humanized monoclonal antibody, Palivizumab, has been approved for use in high-risk infants to prevent RSV infection. Ribavirin is the only drug licensed for therapy of RSV infection, but its clinical use is limited by its nonspecific anti-RSV activity, toxic effect, and relatively high cost. Therefore, development of novel effective anti-RSV therapeutics is urgently needed. The RSV envelope glycoprotein F plays an important role in RSV fusion with, and entry into, the host cell and, consequently, serves as an attractive target for developing RSV entry inhibitors. This article reviews advances made in studies of the structure and function of the F protein and the development of RSV entry inhibitors targeting it.

  10. Discovery of selective inhibitors of the Clostridium difficile dehydroquinate dehydratase.

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    Kiira Ratia

    Full Text Available A vibrant and healthy gut flora is essential for preventing the proliferation of Clostridium difficile, a pathogenic bacterium that causes severe gastrointestinal symptoms. In fact, most C. difficile infections (CDIs occur after broad-spectrum antibiotic treatment, which, by eradicating the commensal gut bacteria, allows its spores to proliferate. Hence, a C. difficile specific antibiotic that spares the gut flora would be highly beneficial in treating CDI. Towards this goal, we set out to discover small molecule inhibitors of the C. difficile enzyme dehydroquinate dehydratase (DHQD. DHQD is the 3(rd of seven enzymes that compose the shikimate pathway, a metabolic pathway absent in humans, and is present in bacteria as two phylogenetically and mechanistically distinct types. Using a high-throughput screen we identified three compounds that inhibited the type I C. difficile DHQD but not the type II DHQD from Bacteroides thetaiotaomicron, a highly represented commensal gut bacterial species. Kinetic analysis revealed that the compounds inhibit the C. difficile enzyme with Ki values ranging from 10 to 20 µM. Unexpectedly, kinetic and biophysical studies demonstrate that inhibitors also exhibit selectivity between type I DHQDs, inhibiting the C. difficile but not the highly homologous Salmonella enterica DHQD. Therefore, the three identified compounds seem to be promising lead compounds for the development of C. difficile specific antibiotics.

  11. Xanthine oxidoreductase and its inhibitors: relevance for gout.

    Science.gov (United States)

    Day, Richard O; Kamel, Bishoy; Kannangara, Diluk R W; Williams, Kenneth M; Graham, Garry G

    2016-12-01

    Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism and converts hypoxanthine to xanthine, and xanthine into uric acid. When concentrations of uric acid exceed its biochemical saturation point, crystals of uric acid, in the form of monosodium urate, emerge and can predispose an individual to gout, the commonest form of inflammatory arthritis in men aged over 40 years. XOR inhibitors are primarily used in the treatment of gout, reducing the formation of uric acid and thereby, preventing the formation of monosodium urate crystals. Allopurinol is established as first-line therapy for gout; a newer alternative, febuxostat, is used in patients unable to tolerate allopurinol. This review provides an overview of gout, a detailed analysis of the structure and function of XOR, discussion on the pharmacokinetics and pharmacodynamics of XOR inhibitors-allopurinol and febuxostat, and the relevance of XOR in common comorbidities of gout. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  12. Peripheral artery disease: potential role of ACE-inhibitor therapy

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    Giuseppe Coppola

    2008-12-01

    Full Text Available Giuseppe Coppola, Giuseppe Romano, Egle Corrado, Rosa Maria Grisanti, Salvatore NovoDepartment of Internal Medicine, Cardiovascular and Nephro-Urological Diseases, Chair of Cardiovascular Disease, University of Palermo, Palermo, ItalyAbstract: Subjects with peripheral arterial disease (PAD of the lower limbs are at high risk for cardiovascular and cerebrovascular events and the prevalence of coronary artery disease in such patients is elevated. Recent studies have shown that regular use of cardiovascular medications, such as therapeutic and preventive agents for PAD patients, seems to be promising in reducing long-term mortality and morbidity. The angiotensin-converting-enzyme (ACE system plays an important role in the pathogenesis and progression of atherosclerosis, and ACE-inhibitors (ACE-I seem to have vasculoprotective and antiproliferative effects as well as a direct antiatherogenic effect. ACE-I also promote the degradation of bradykinin and the release of nitric oxide, a potent vasodilator; further, thay have shown impor