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Sample records for high consequence multidrug

  1. An examination of the consequences in high consequence operations

    Energy Technology Data Exchange (ETDEWEB)

    Spray, S.D.; Cooper, J.A.

    1996-06-01

    Traditional definitions of risk partition concern into the probability of occurrence and the consequence of the event. Most safety analyses focus on probabilistic assessment of an occurrence and the amount of some measurable result of the event, but the real meaning of the ``consequence`` partition is usually afforded less attention. In particular, acceptable social consequence (consequence accepted by the public) frequently differs significantly from the metrics commonly proposed by risk analysts. This paper addresses some of the important system development issues associated with consequences, focusing on ``high consequence operations safety.``

  2. [Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance].

    Science.gov (United States)

    Martínez-Múgica, Cristina

    2015-12-01

    Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.

  3. Consequence Prioritization Process for Potential High Consequence Events (HCE)

    Energy Technology Data Exchange (ETDEWEB)

    Freeman, Sarah G. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2016-10-31

    This document describes the process for Consequence Prioritization, the first phase of the Consequence-Driven Cyber-Informed Engineering (CCE) framework. The primary goal of Consequence Prioritization is to identify potential disruptive events that would significantly inhibit an organization’s ability to provide the critical services and functions deemed fundamental to their business mission. These disruptive events, defined as High Consequence Events (HCE), include both events that have occurred or could be realized through an attack of critical infrastructure owner assets. While other efforts have been initiated to identify and mitigate disruptive events at the national security level, such as Presidential Policy Directive 41 (PPD-41), this process is intended to be used by individual organizations to evaluate events that fall below the threshold for a national security. Described another way, Consequence Prioritization considers threats greater than those addressable by standard cyber-hygiene and includes the consideration of events that go beyond a traditional continuity of operations (COOP) perspective. Finally, Consequence Prioritization is most successful when organizations adopt a multi-disciplinary approach, engaging both cyber security and engineering expertise, as in-depth engineering perspectives are required to recognize and characterize and mitigate HCEs. Figure 1 provides a high-level overview of the prioritization process.

  4. Avoid the Consequences of High Blood Pressure

    Science.gov (United States)

    ... Thromboembolism Aortic Aneurysm More Avoid the Consequences of High Blood Pressure Infographic Updated:Oct 31,2016 View a downloadable version of this infographic High Blood Pressure • Home • Get the Facts About HBP • Know Your ...

  5. Software development methodology for high consequence systems

    Energy Technology Data Exchange (ETDEWEB)

    Baca, L.S.; Bouchard, J.F.; Collins, E.W.; Eisenhour, M.; Neidigk, D.D.; Shortencarier, M.J.; Trellue, P.A.

    1997-10-01

    This document describes a Software Development Methodology for High Consequence Systems. A High Consequence System is a system whose failure could lead to serious injury, loss of life, destruction of valuable resources, unauthorized use, damaged reputation or loss of credibility or compromise of protected information. This methodology can be scaled for use in projects of any size and complexity and does not prescribe any specific software engineering technology. Tasks are described that ensure software is developed in a controlled environment. The effort needed to complete the tasks will vary according to the size, complexity, and risks of the project. The emphasis of this methodology is on obtaining the desired attributes for each individual High Consequence System.

  6. Low-Incidence, High-Consequence Pathogens

    Centers for Disease Control (CDC) Podcasts

    2014-02-21

    Dr. Stephan Monroe, a deputy director at CDC, discusses the impact of low-incidence, high-consequence pathogens globally.  Created: 2/21/2014 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 2/26/2014.

  7. Biofilm-Forming Capability of Highly Virulent, Multidrug-Resistant Candida auris

    Science.gov (United States)

    Sherry, Leighann; Ramage, Gordon; Kean, Ryan; Borman, Andrew; Johnson, Elizabeth M.; Richardson, Malcolm D.

    2017-01-01

    The emerging multidrug-resistant yeast pathogen Candida auris has attracted considerable attention as a source of healthcare–associated infections. We report that this highly virulent yeast has the capacity to form antifungal resistant biofilms sensitive to the disinfectant chlorhexidine in vitro. PMID:28098553

  8. Assuring quality in high-consequence engineering

    Energy Technology Data Exchange (ETDEWEB)

    Hoover, Marcey L.; Kolb, Rachel R.

    2014-03-01

    In high-consequence engineering organizations, such as Sandia, quality assurance may be heavily dependent on staff competency. Competency-dependent quality assurance models are at risk when the environment changes, as it has with increasing attrition rates, budget and schedule cuts, and competing program priorities. Risks in Sandia's competency-dependent culture can be mitigated through changes to hiring, training, and customer engagement approaches to manage people, partners, and products. Sandia's technical quality engineering organization has been able to mitigate corporate-level risks by driving changes that benefit all departments, and in doing so has assured Sandia's commitment to excellence in high-consequence engineering and national service.

  9. High prevalence of multidrug resistance in bacterial uropathogens from Kathmandu, Nepal

    Directory of Open Access Journals (Sweden)

    Baral Pankaj

    2012-01-01

    Full Text Available Abstract Background Urinary Tract Infection (UTI is one of the most common infectious diseases and people of all age-groups and geographical locations are affected. The impact of disease is even worst in low-resource developing countries due to unaware of the UTIs caused by multidrug-resistant (MDR pathogens and the possibility of transfer of MDR traits between them. The present study aimed to determine the prevalence of MDR bacterial isolates from UTI patients, the antibiotic resistance pattern and the conjugational transfer of multidrug resistance phenotypes in Escherichia coli (E. coli. Results Two hundred and nineteen bacterial isolates were recovered from 710 urine samples at Kathmandu Model hospital during the study period. All samples and isolates were investigated by standard laboratory procedures. Among the significant bacterial growth (30.8%, 219 isolates, 41.1% isolates were MDR. The most prevailing organism, E. coli (81.3%, 178 isolates was 38.2% MDR, whereas second most common organism, Citrobacter spp. (5%, 11 isolates was found 72.7% MDR. Extended-spectrum β-lactamase (ESBL production was detected in 55.2% of a subset of MDR E. coli isolates. Among the 29 MDR E. coli isolates, plasmids of size ranging 2-51 kb were obtained with different 15 profiles. The most common plasmid of size 32 kb was detected in all of the plasmid-harbored E. coli strains. The majority of E. coli isolates investigated for the multidrug resistance transfer were able to transfer plasmid-mediated MDR phenotypes along with ESBL pattern with a frequency ranging from 0.3 × 10-7 to 1.5 × 10-7 to an E. coli HB101 recipient strain by conjugation. Most of the donor and recipient strain showed high levels of minimum inhibitory concentration (MIC values for commonly-used antibiotics. Conclusions The high prevalence of multidrug resistance in bacterial uropathogens was observed. Particularly, resistance patterns were alarmingly higher for amoxycillin, co

  10. High prevalence of multi-drug resistant Streptococcus pneumoniae among healthy children in Thailand.

    Science.gov (United States)

    Thummeepak, Rapee; Leerach, Nontapat; Kunthalert, Duangkamol; Tangchaisuriya, Udomsak; Thanwisai, Aunchalee; Sitthisak, Sutthirat

    2015-01-01

    Antibiotic resistance in Streptococcus pneumoniae is an emerging health problem worldwide. The incidence of antimicrobial-resistant S. pneumoniae is increasing, and nasal colonization of S. pneumoniae in children increases the risk of pneumococcal infection. In this study, the prevalence of S. pneumoniae nasal colonization was studied in Thai children from three different districts. S. pneumoniae nasal colonization was found in 38 of 237 subjects (16.0%). The carriage rate indicated higher rates in two rural districts (18.2% and 29.8%) than in the urban district (2.8%). The antibiotic susceptibility pattern was determined using the disk diffusion method. Prevalence of multi-drug resistance S. pneumoniae (MDR-SP) was 31.6%. Resistance to commonly prescribed antibiotics was found for ampicillin (5.3%), azithromycin (26.3%), cefepime (2.6%), chloramphenicol (18.4%), clindamycin (18.4%), erythromycin (21.1%), oxacillin (44.7%), trimethoprim/sulfamethoxazole (78.9%) and tetracycline (15.8%). All isolates were sensitive to ceftriaxone. The pulsed-field gel electrophoresis pattern was used to compare genetic diversity of the S. pneumoniae isolates. PFGE demonstrated the variation in genotypes of S. pneumoniae from different areas. High prevalence of multi-drug resistance S. pneumoniae nasal colonization in healthy Thai children was indicated. Effective strategies for appropriate use of antibiotics are therefore needed in the community.

  11. Identification of multi-drug resistant Pseudomonas aeruginosa clinical isolates that are highly disruptive to the intestinal epithelial barrier

    Directory of Open Access Journals (Sweden)

    Shevchenko Olga

    2006-06-01

    Full Text Available Abstract Background Multi-drug resistant Pseudomonas aeruginosa nosocomial infections are increasingly recognized worldwide. In this study, we focused on the virulence of multi-drug resistant clinical strains P. aeruginosa against the intestinal epithelial barrier, since P. aeruginosa can cause lethal sepsis from within the intestinal tract of critically ill and immuno-compromised patients via mechanisms involving disruption of epithelial barrier function. Methods We screened consecutively isolated multi-drug resistant P. aeruginosa clinical strains for their ability to disrupt the integrity of human cultured intestinal epithelial cells (Caco-2 and correlated these finding to related virulence phenotypes such as adhesiveness, motility, biofilm formation, and cytotoxicity. Results Results demonstrated that the majority of the multi-drug resistant P. aeruginosa clinical strains were attenuated in their ability to disrupt the barrier function of cultured intestinal epithelial cells. Three distinct genotypes were found that displayed an extreme epithelial barrier-disrupting phenotype. These strains were characterized and found to harbor the exoU gene and to display high swimming motility and adhesiveness. Conclusion These data suggest that detailed phenotypic analysis of the behavior of multi-drug resistant P. aeruginosa against the intestinal epithelium has the potential to identify strains most likely to place patients at risk for lethal gut-derived sepsis. Surveillance of colonizing strains of P. aeruginosa in critically ill patients beyond antibiotic sensitivity is warranted.

  12. Tailoring Cytotoxicity of Antimicrobial Peptidomimetics with High Activity against Multidrug-Resistant Escherichia coli

    DEFF Research Database (Denmark)

    Jahnsen, Rasmus D; Sandberg-Schaal, Anne; Vissing, Karina Juul

    2014-01-01

    Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide-peptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimeti...

  13. [The role of CCLINs in the event of an epidemic of multi-drug and highly resistant bacteria].

    Science.gov (United States)

    Landriu, Danièle

    2015-01-01

    The management of epidemics of multi-drug and highly resistant bacteria must be based on a structured organisation. Within each region it requires the expertise of centres for the interregional coordination of nosocomial infection control (CCLINs) and their regional branches of nosocomial infection control (Arlin) which support hospitals in reporting these types of epidemics. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  14. Neoadjuvant multidrug chemotherapy including High-Dose Methotrexate modifies VEGF expression in Osteosarcoma: an immunohistochemical analysis

    Directory of Open Access Journals (Sweden)

    Rosa Michele A

    2010-02-01

    Full Text Available Abstract Background Angiogenesis plays a role in the progression of osteosarcoma, as well as in other mesenchymal tumors and carcinomas, and it is most commonly assessed by vascular endothelial growth factor (VEGF expression or tumor CD31-positive microvessel density (MVD. Tumor VEGF expression is predictive of poor prognosis, and chemotherapy can affect the selection of angiogenic pattern. The aim of the study was to investigate the clinical and prognostic significance of VEGF and CD31 in osteosarcoma, both at diagnosis and after neoadjuvant chemotherapy, in order to identify a potential role of chemotherapy in angiogenic phenotype. Methods A retrospective analysis was performed on 16 patients with high grade osteosarcoma. In each case archival pre-treatment biopsy tissue and post-chemotherapy tumor specimens were immunohistochemically stained against CD31 and VEGF, as markers of angiogenic proliferation both in newly diagnosed primary osteosarcoma and after multidrug chemotherapy including high-dose methotrexate (HDMTX. The correlation between clinicopathological parameters and the degree of tumor VEGF and CD31 expression was statistically assessed using the χ2 test verified with Yates' test for comparison of two groups. Significance was set at p Results Expression of VEGF was positive in 11 cases/16 of cases at diagnosis. Moreover, 8 cases/16 untreated osteosarcomas were CD31-negative, but the other 8 showed an high expression of CD31. VEGF expression in viable tumor cells after neoadjuvant chemotherapy was observed in all cases; in particular, there was an increased VEGF expression (post-chemotherapy VEGF - biopsy VEGF in 11 cases/16. CD31 expression increased in 11 cases/16 and decreased in 3 cases after chemotherapy. The data relating to the change in staining following chemotherapy appear statistically significant for VEGF expression (p p > 0,05. Conclusions Even if the study included few patients, these results confirm that VEGF and CD

  15. Prevalence and consequences of substance use among high school ...

    African Journals Online (AJOL)

    African Journal of Drug and Alcohol Studies ... Further, cannabis was used in selected high schools, and its abuse prevalence was greater in urban private schools, ... enhanced sexual activity, with increased risks for negative consequences.

  16. A high-resolution genomic analysis of multidrug-resistant hospital outbreaks of Klebsiella pneumoniae.

    Science.gov (United States)

    Chung The, Hao; Karkey, Abhilasha; Pham Thanh, Duy; Boinett, Christine J; Cain, Amy K; Ellington, Matthew; Baker, Kate S; Dongol, Sabina; Thompson, Corinne; Harris, Simon R; Jombart, Thibaut; Le Thi Phuong, Tu; Tran Do Hoang, Nhu; Ha Thanh, Tuyen; Shretha, Shrijana; Joshi, Suchita; Basnyat, Buddha; Thwaites, Guy; Thomson, Nicholas R; Rabaa, Maia A; Baker, Stephen

    2015-03-01

    Multidrug-resistant (MDR) Klebsiella pneumoniae has become a leading cause of nosocomial infections worldwide. Despite its prominence, little is known about the genetic diversity of K. pneumoniae in resource-poor hospital settings. Through whole-genome sequencing (WGS), we reconstructed an outbreak of MDR K. pneumoniae occurring on high-dependency wards in a hospital in Kathmandu during 2012 with a case-fatality rate of 75%. The WGS analysis permitted the identification of two MDR K. pneumoniae lineages causing distinct outbreaks within the complex endemic K. pneumoniae. Using phylogenetic reconstruction and lineage-specific PCR, our data predicted a scenario in which K. pneumoniae, circulating for 6 months before the outbreak, underwent a series of ward-specific clonal expansions after the acquisition of genes facilitating virulence and MDR. We suggest that the early detection of a specific NDM-1 containing lineage in 2011 would have alerted the high-dependency ward staff to intervene. We argue that some form of real-time genetic characterisation, alongside clade-specific PCR during an outbreak, should be factored into future healthcare infection control practices in both high- and low-income settings.

  17. Lethal neonatal meningoencephalitis caused by multi-drug resistant, highly virulent Escherichia coli.

    Science.gov (United States)

    Iqbal, Junaid; Dufendach, Kevin R; Wellons, John C; Kuba, Maria G; Nickols, Hilary H; Gómez-Duarte, Oscar G; Wynn, James L

    2016-01-01

    Neonatal meningitis is a rare but devastating condition. Multi-drug resistant (MDR) bacteria represent a substantial global health risk. This study reports on an aggressive case of lethal neonatal meningitis due to a MDR Escherichia coli (serotype O75:H5:K1). Serotyping, MDR pattern and phylogenetic typing revealed that this strain is an emergent and highly virulent neonatal meningitis E. coli isolate. The isolate was resistant to both ampicillin and gentamicin; antibiotics currently used for empiric neonatal sepsis treatment. The strain was also positive for multiple virulence genes including K1 capsule, fimbrial adhesion fimH, siderophore receptors iroN, fyuA and iutA, secreted autotransporter toxin sat, membrane associated proteases ompA and ompT, type II polysaccharide synthesis genes (kpsMTII) and pathogenicity-associated island (PAI)-associated malX gene. The presence of highly-virulent MDR organisms isolated in neonates underscores the need to implement rapid drug resistance diagnostic methods and should prompt consideration of alternate empiric therapy in neonates with Gram negative meningitis.

  18. Cockroaches as a Source of High Bacterial Pathogens with Multidrug Resistant Strains in Gondar Town, Ethiopia.

    Science.gov (United States)

    Moges, Feleke; Eshetie, Setegn; Endris, Mengistu; Huruy, Kahsay; Muluye, Dagnachew; Feleke, Tigist; G/Silassie, Fisha; Ayalew, Getenet; Nagappan, Raja

    2016-01-01

    Background. Cockroaches are source of bacterial infections and this study was aimed to assess bacterial isolates and their antimicrobial profiles from cockroaches in Gondar town, Ethiopia. Methods. A total of 60 cockroaches were collected from March 1 to May 30, 2014, in Gondar town. Bacterial species were isolated from external and internal parts of cockroaches. Disk diffusion method was used to determine antibiotic susceptibility patterns. Data were entered and analyzed by using SPSS version 20; P values cockroaches, respectively. Klebsiella pneumoniae 32 (17.7%), Escherichia coli 29 (16%), and Citrobacter spp. 27 (15%) were the predominant isolates. High resistance rate was observed to cotrimoxazole, 60 (33.1%), and least resistance rate was noted to ciprofloxacin, 2 (1.1%). Additionally, 116 (64.1%) of the isolates were MDR strains; Salmonella spp. were the leading MDR isolates (100%) followed by Enterobacter (90.5%) and Shigella spp. (76.9%). Conclusion. Cockroaches are the potential source of bacteria pathogens with multidrug resistant strains and hence effective preventive and control measures are required to minimize cockroach related infections.

  19. Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009

    NARCIS (Netherlands)

    van Altena, R.; de Vries, G.; Haar, C. H.; de Lange, W. C. M.; Magis-Escurra, C.; van den Hof, S.; van Soolingen, D.; Boeree, M. J.; van der Werf, T. S.

    2015-01-01

    SETTING: Resistance to the two key anti-tuberculosis drugs isoniazid and rifampicin is a characteristic of multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a scourge requiring toxic, prolonged treatment and is associated with poor outcomes. The Netherlands is a country with a long-standing, inte

  20. Exposure of Salmonella enterica serovar Typhimurium to high level biocide challenge can select multidrug resistant mutants in a single step.

    Directory of Open Access Journals (Sweden)

    Rebekah N Whitehead

    Full Text Available BACKGROUND: Biocides are crucial to the prevention of infection by bacteria, particularly with the global emergence of multiply antibiotic resistant strains of many species. Concern has been raised regarding the potential for biocide exposure to select for antibiotic resistance due to common mechanisms of resistance, notably efflux. METHODOLOGY/PRINCIPAL FINDINGS: Salmonella enterica serovar Typhimurium was challenged with 4 biocides of differing modes of action at both low and recommended-use concentration. Flow cytometry was used to investigate the physiological state of the cells after biocide challenge. After 5 hours exposure to biocide, live cells were sorted by FACS and recovered. Cells recovered after an exposure to low concentrations of biocide had antibiotic resistance profiles similar to wild-type cells. Live cells were recovered after exposure to two of the biocides at in-use concentration for 5 hours. These cells were multi-drug resistant and accumulation assays demonstrated an efflux phenotype of these mutants. Gene expression analysis showed that the AcrEF multidrug efflux pump was de-repressed in mutants isolated from high-levels of biocide. CONCLUSIONS/SIGNIFICANCE: These data show that a single exposure to the working concentration of certain biocides can select for mutant Salmonella with efflux mediated multidrug resistance and that flow cytometry is a sensitive tool for identifying biocide tolerant mutants. The propensity for biocides to select for MDR mutants varies and this should be a consideration when designing new biocidal formulations.

  1. NSC23925, identified in a high-throughput cell-based screen, reverses multidrug resistance.

    Directory of Open Access Journals (Sweden)

    Zhenfeng Duan

    Full Text Available BACKGROUND: Multidrug resistance (MDR is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted to overcome MDR. To date, none of these attempts have yielded a tolerable and effective therapy to reverse MDR; thus, identification of new agents would be useful both clinically and scientifically. METHODOLOGY/PRINCIPAL FINDINGS: To identify small molecule compounds that can reverse chemoresistance, we developed a 96-well plate high-throughput cell-based screening assay in a paclitaxel resistant ovarian cancer cell line. Coincubating cells with a sublethal concentration of paclitaxel in combination with each of 2,000 small molecule compounds from the National Cancer Institute Diversity Set Library, we identified a previously uncharacterized molecule, NSC23925, that inhibits Pgp1 and reverses MDR1 (Pgp1 but does not inhibit MRP or BCRP-mediated MDR. The cytotoxic activity of NSC23925 was further evaluated using a panel of cancer cell lines expressing Pgp1, MRP, and BCRP. We found that at a concentration of >10 microM NSC23925 moderately inhibits the proliferation of both sensitive and resistant cell lines with almost equal activity, but its inhibitory effect was not altered by co-incubation with the Pgp1 inhibitor, verapamil, suggesting that NSC23925 itself is not a substrate of Pgp1. Additionally, NSC23925 increases the intracellular accumulation of Pgp1 substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin. Interestingly, we further observed that, although NSC23925 directly inhibits the function of Pgp1 in a dose-dependent manner without altering the total expression level of Pgp1, NSC23925 actually stimulates ATPase activity of Pgp, a phenomenon seen in other Pgp inhibitors. CONCLUSIONS/SIGNIFICANCE: The ability of NSC23925 to restore sensitivity to the cytotoxic effects of chemotherapy or to prevent resistance could significantly benefit cancer patients.

  2. Proceedings of the High Consequence Operations Safety Symposium

    Energy Technology Data Exchange (ETDEWEB)

    1994-12-01

    Many organizations face high consequence safety situations where unwanted stimuli due to accidents, catastrophes, or inadvertent human actions can cause disasters. In order to improve interaction among such organizations and to build on each others` experience, preventive approaches, and assessment techniques, the High Consequence Operations Safety Symposium was held July 12--14, 1994 at Sandia National Laboratories, Albuquerque, New Mexico. The symposium was conceived by Dick Schwoebel, Director of the SNL Surety Assessment Center. Stan Spray, Manager of the SNL System Studies Department, planned strategy and made many of the decisions necessary to bring the concept to fruition on a short time scale. Angela Campos and about 60 people worked on the nearly limitless implementation and administrative details. The initial symposium (future symposia are planned) was structured around 21 plenary presentations in five methodology-oriented sessions, along with a welcome address, a keynote address, and a banquet address. Poster papers addressing the individual session themes were available before and after the plenary sessions and during breaks.

  3. Effects of highly purified anthraquinoid compounds from Aloe vera on sensitive and multidrug resistant leukemia cells.

    Science.gov (United States)

    Grimaudo, S; Tolomeo, M; Gancitano, R; Dalessandro, N; Aiello, E

    1997-01-01

    Folk medicine has attributed antitumor properties to preparations from Aloe vera. We have studied the effects of five purified compounds from the plant on human K562 leukemia and on its multidrug resistant (MDR) variant, K562/R. The glycosides aloin A and B, aloesin and aloeresin were devoid of antitumor activity up to 200 mu M concentrations. Only the aglycone aloe emodin produced reproducible antitumor effects, which, interestingly, were more pronounced in the MDR, P-glycoprotein overexpressing, cell line. Its IC50 was in fact 29 mu M in K562 and 10.5 mu M in K562/R. Aloe emodine caused mainly cytostasis and accumulation of the cells in the S and G(2)-M phases of the cell cycle during the first 48 h of treatment. Thereafter, massive cell death ensued. Research on the antitumor activity of compounds extracted from Aloe vera probably deserves continuation.

  4. Jet fire consequence modeling for high-pressure gas pipelines

    Science.gov (United States)

    Coccorullo, Ivano; Russo, Paola

    2016-12-01

    A simple and reliable approach for sizing the hazard area potentially affected by a jet fire as consequence of the failure of high-pressure pipeline is proposed. A release rate model, taking pipeline operation properties and source release properties into account, is coupled with SLAB dispersion model and point source radiation model to calculate the hazard distance. The hazard distance is set beyond the distance at which a low chance of fatality can occur to people exposed and a wooden structure is not expected to burn due to radiation heat of jet fire. The comparison between three gases with different physico-chemical properties (i.e. natural gas, hydrogen, ethylene) is shown. The influence of pipeline operating parameters, such as: pressure, pipeline diameter and length, hole size, on the hazard area for the three gases is evaluated. Finally, a simple correlation is proposed for calculating the hazard distance as function of these parameters.

  5. High risk and rapid appearance of multidrug resistance during tuberculosis treatment in Moldova.

    Science.gov (United States)

    Jenkins, Helen E; Crudu, Valeriu; Soltan, Viorel; Ciobanu, Ana; Domente, Liliana; Cohen, Ted

    2014-04-01

    Multidrug-resistant tuberculosis (MDR-TB) is a serious problem in the former Soviet Union and may appear during TB treatment. We aimed to estimate the prevalence of, timing of and factors associated with MDR-TB diagnosis during TB treatment in Moldova, which was part of the former Soviet Union. We analysed data on 3 754 confirmed non-MDR-TB cases (between January 1, 2007 and December 31, 2010) in the Moldovan TB surveillance database, where patients provided sputum specimens for drug-susceptibility testing, multiple times, during treatment. We estimated the percentage of individuals with confirmed baseline non-MDR-TB that were diagnosed with MDR-TB during treatment, documented the time at which MDR-TB was diagnosed, and used a failure-time model to identify factors associated with MDR-TB diagnosis. Between 7.2% and 9.2% of initially non-MDR-TB cases were diagnosed with MDR-TB during treatment. Half of these MDR-TB diagnoses occurred with 3 months of the initial diagnosis. An increased MDR-TB risk during treatment was associated with baseline resistance to first-line TB drugs (linear increase in risk per additional drug), previous incarceration and HIV co-infection. MDR can appear rapidly during TB treatment. Policy considerations should emphasise management during early treatment by increasing ambulatory TB treatment to prevent nosocomial transmission, and ensuring universal rapid diagnostics access to prevent acquisition and transmission of drug resistance.

  6. Integration of human reliability analysis into the high consequence process

    Energy Technology Data Exchange (ETDEWEB)

    Houghton, F.K.; Morzinski, J.

    1998-12-01

    When performing a hazards analysis (HA) for a high consequence process, human error often plays a significant role in the hazards analysis. In order to integrate human error into the hazards analysis, a human reliability analysis (HRA) is performed. Human reliability is the probability that a person will correctly perform a system-required activity in a required time period and will perform no extraneous activity that will affect the correct performance. Even though human error is a very complex subject that can only approximately be addressed in risk assessment, an attempt must be made to estimate the effect of human errors. The HRA provides data that can be incorporated in the hazard analysis event. This paper will discuss the integration of HRA into a HA for the disassembly of a high explosive component. The process was designed to use a retaining fixture to hold the high explosive in place during a rotation of the component. This tool was designed as a redundant safety feature to help prevent a drop of the explosive. This paper will use the retaining fixture to demonstrate the following HRA methodology`s phases. The first phase is to perform a task analysis. The second phase is the identification of the potential human, both cognitive and psychomotor, functions performed by the worker. During the last phase the human errors are quantified. In reality, the HRA process is an iterative process in which the stages overlap and information gathered in one stage may be used to refine a previous stage. The rationale for the decision to use or not use the retaining fixture and the role the HRA played in the decision will be discussed.

  7. Proactive Disciplinary Consequences in Three Illinois High Schools

    Science.gov (United States)

    Golomb, Sara R.

    2010-01-01

    Disciplinary codes of conduct guide administrators when determining the consequences for student misconduct. The codes of conduct commonly found in schools rely on exclusionary measures that have been associated with negative student outcomes and controversy but little is being done to provide positive model for these written policies. Schools…

  8. High rates of multidrug resistance among uropathogenic Escherichia coli in children and analyses of ESBL producers from Nepal

    Directory of Open Access Journals (Sweden)

    Narayan Prasad Parajuli

    2017-01-01

    Full Text Available Abstract Background Emergence of Extended-spectrum beta-lactamase producing Escherichia coli causing urinary tract infections (UTI among pediatric patients is an increasing problem worldwide. However, very little is known about pediatric urinary tract infections and antimicrobial resistance trend from Nepal. This study was conducted to assess the current antibiotic resistance rate and ESBL production among uropathogenic Escherichia coli in pediatric patients of a tertiary care teaching hospital of Nepal. Methods A total of 5,484 urinary tract specimens from children suspected with UTI attending a teaching hospital of Nepal over a period of one year were processed for the isolation of bacterial pathogens and their antimicrobial susceptibility testing. Escherichia coli (n = 739, the predominant isolate in pediatric UTI, was further selected for the detection of ESBL-production by phenotypic combination disk diffusion test. Results Incidence of urinary tract infection among pediatric patients was found to be 19.68% and E coli (68.4% was leading pathogen involved. Out of 739 E coli isolates, 64.9% were multidrug resistant (MDR and 5% were extensively drug resistant (XDR. Extended spectrum beta lactamase (ESBL was detected in 288 (38.9% of the E coli isolates. Conclusion Alarming rate of drug resistance among pediatric uropathogens and high rate of ESBL-producing E. coli was observed. It is extremely necessary to routinely investigate the drug resistance among all isolates and formulate strict antibiotics prescription policy in our country.

  9. Role of multidrug resistance in photodynamic therapy

    Science.gov (United States)

    Diddens, Heyke C.

    1992-06-01

    Multidrug resistance in cancer chemotherapy is a well established phenomenon. One of the most common phenotypical changes in acquired or intrinsic multidrug resistance in human tumor cells is the overexpression of the mdrl gene product P-glycoprotein, which acts as an active efflux pump. Increased levels of P-glycoprotein are associated with resistance to a variety of anticancer drugs commonly used in tumor chemotherapy like anthracyclins, vinca- alcaloids, epipodophyllotoxins or actinomycin D. We investigated the efficacy or photodynamic therapy in the treatment of tumor cells expressing the multidrug resistance phenotype. Our data show that multidrug resistant cells are highly cross resistant to the phototoxic stain rhodamine 123 but exhibit only low degrees of cross resistance (2 - 3 -folds) to the photosensitizers Photosan-3, Clorin-2, methylene blue and meso-tetra (4- sulfonatophenyl) porphine (TPPS4). Resistance is associated with a decrease in intracellular accumulation of the photosensitizer. Verapamil, a membrane active compound known to enhance drug sensitivity in multidrug resistant cells by inhibition of P-glycoprotein, also increases phototoxicity in multidrug resistant cells. Our results imply that tumors expressing the multidrug resistance phenotype might fail to respond to photochemotherapy with rhodamine 123. On the other hand, multidrug resistance may not play an important role in photodynamic therapy with Photosan-3, Chlorin-2, methylene blue or TPPS4.

  10. In vitro activity of a polyhexanide-betaine solution against high-risk clones of multidrug-resistant nosocomial pathogens.

    Science.gov (United States)

    López-Rojas, Rafael; Fernández-Cuenca, Felipe; Serrano-Rocha, Lara; Pascual, Álvaro

    2017-01-01

    To determine the in vitro activity of a polyhexanide-betaine solution against collection strains and multidrug-resistant (MDR) nosocomial isolates, including high-risk clones. We studied of 8 ATCC and 21 MDR clinical strains of Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, including the multiresistant high-risk clones. The MICs and MBCs of a 0.1% polyhexanide-0.1% betaine solution were determined by microdilution. For each species, strains with the highest MICs were selected for further experiments. The dilution-neutralization test (PrEN 12054) was performed by incubating bacterial inocula of 10(6)CFU/mL for 1min with undiluted 0.1% polyhexanide-betaine solution. The CFUs were counted after neutralization. Growth curves and time-kill curves at concentrations of 0.25, 1, 4, and 8×MIC, were performed. MICs of recovered strains were determined when regrowth was observed in time-kill studies after 24h of incubation. Strains with reduced susceptibility were selected by serial passage on plates with increasing concentrations of polyhexanide-betaine, and MICs were determined. Polyhexanide-betaine MIC range was 0.5-8mg/L. MBCs equalled or were 1 dilution higher than MICs. The dilution-neutralization method showed total inoculum clearance of all strains. In time-kill curves, no regrowth was observed at 4×MIC, except for S. aureus (8×MIC). Increased MICs were not observed in time-kill curves, or after serial passages after exposure to polyhexanide-betaine. Polyhexanide-betaine presented bactericidal activity against all MDR clinical isolates tested, including high-risk clones, at significantly lower concentrations and time of activity than those commercially used. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  11. Multidrug resistance associated proteins in multidrug resistance

    OpenAIRE

    Sodani, Kamlesh; Patel, Atish; Kathawala, Rishil J.; Chen, Zhe-Sheng

    2012-01-01

    Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters. These ABC transporters together form the largest branch of proteins within the human body. The MRP family comprises of 13 members, of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell. They are mainly lipophilic anionic transporters and are reported to transport fr...

  12. Consequences of high-frequency operation on EUV source efficiency

    Science.gov (United States)

    Sizyuk, Tatyana

    2017-08-01

    A potential problem of future extreme ultraviolet (EUV) sources, required for high volume manufacture regimes, can be related to the contamination of the chamber environment by products of preceding laser pulse/droplet interactions. Implementation of high, 100 kHz and higher, repetition rate of EUV sources using Sn droplets ignited with laser pulses can cause high accumulation of tin in the chamber in the form of vapor, fine mist, or fragmented clusters. In this work, the effects of the residual tin accumulation in the EUV chamber in dependence on laser parameters and mitigation system efficiency were studied. The effect of various pressures of tin vapor on the CO2 and Nd:YAG laser beam propagation and on the size, the intensity, and the resulting efficiency of the EUV sources was analyzed. The HEIGHTS 3D package was used for this analysis to study the effect of residual background pressure and spatial distribution on EUV photon emission and collection. It was found that background pressure in the range of 1-5 Pa does not significantly influence the EUV source produced by CO2 lasers. A larger volume with this pressure condition, however, can reduce the efficiency of the source. However, an optimized volume of mix with proper density could increase the efficiency of the sources produced by CO2 lasers.

  13. High plasma uric acid concentration: causes and consequences

    Directory of Open Access Journals (Sweden)

    de Oliveira Erick

    2012-04-01

    Full Text Available Abstract High plasma uric acid (UA is a precipitating factor for gout and renal calculi as well as a strong risk factor for Metabolic Syndrome and cardiovascular disease. The main causes for higher plasma UA are either lower excretion, higher synthesis or both. Higher waist circumference and the BMI are associated with higher insulin resistance and leptin production, and both reduce uric acid excretion. The synthesis of fatty acids (tryglicerides in the liver is associated with the de novo synthesis of purine, accelerating UA production. The role played by diet on hyperuricemia has not yet been fully clarified, but high intake of fructose-rich industrialized food and high alcohol intake (particularly beer seem to influence uricemia. It is not known whether UA would be a causal factor or an antioxidant protective response. Most authors do not consider the UA as a risk factor, but presenting antioxidant function. UA contributes to > 50% of the antioxidant capacity of the blood. There is still no consensus if UA is a protective or a risk factor, however, it seems that acute elevation is a protective factor, whereas chronic elevation a risk for disease.

  14. High Tc as a consequence of structure deformation

    Energy Technology Data Exchange (ETDEWEB)

    Djajic, R.P. (Faculty of Technical Sciences, Univ. of Novi Sad (Yugoslavia)); Tosic, B.S.; Setrajcic, J.P. (Inst. of Physics, Univ. of Novi Sad (Yugoslavia)); Mirjanic, D.L. (Faculty of Tech., Univ. of Banja Luka (Yugoslavia))

    1991-12-01

    Based on the experimental fact that doped perovskite structures behave as a system of energetically independent thin layers we developed a theoretical model for a single layer behaviour. It was shown that electron and phonon spectra are functions of azimuthal angle which in turn gives the specific relations for Tc which on the other hand differs significantly from the corresponding value in the BCS theory. The crucial fact, which allows the solution of this equation with high Tc, is the electron-electron interaction constant which in a thin doped layer is for an order or two orders of magnitude greater than the same interaction constant in the ideal infinite structure. (orig.).

  15. A probabilistic consequence assessment for a very high temperature reactor

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joeun; Kim, Jintae; Jae, Moosung [Hanyang Univ., Seoul (Korea, Republic of). Dept. of Nuclear Engineering

    2017-02-15

    Currently, fossil fuel is globally running out. If current trends continue, crude oil will be depleted in 20 years and natural gas in 40 years. In addition, the use of fossil resource has increased emissions of green gas such as carbon dioxide. Therefore, there has been a strong demand in recent years for producing large amounts of hydrogen as an alternative energy [1]. To generate hydrogen energy, very high temperature more than 900 C is required but this level is not easy to reach. Because a Very High Temperature Reactor (VHTR), one of next generation reactor, is able to make the temperature, it is regarded as a solution of the problem. Also, VHTR has an excellent safety in comparison with existing and other next generation reactors. Especially, a passive system, Reactor Cavity Cooling System (RCCS), is adopted to get rid of radiant heat in case of accidents. To achieve variety requirements of new designed-reactors, however, it needs to develop new methodologies and definitions different with existing method. At the same time, an application of probability safety assessment (PSA) has been proposed to ensure the safety of next generation NPPs. For this, risk-informed designs of structures have to be developed and verified. Particularly, the passive system requires to be evaluated for its reliability. The objective of this study is to improve safety of VIITR by conducting risk profile.

  16. Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids

    Directory of Open Access Journals (Sweden)

    Susu He

    2016-12-01

    Full Text Available The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance.

  17. Experimental consequences of quantum critical points at high temperatures

    Science.gov (United States)

    Freitas, D. C.; Rodière, P.; Núñez, M.; Garbarino, G.; Sulpice, A.; Marcus, J.; Gay, F.; Continentino, M. A.; Núñez-Regueiro, M.

    2015-11-01

    We study the C r1 -xR ex phase diagram finding that its phase transition temperature towards an antiferromagnetic order TN follows a quantum [(xc-x ) /xc ] ψ law, with ψ =1 /2 , from the quantum critical point (QCP) at xc=0.25 up to TN≈600 K . We compare this system to others in order to understand why this elemental material is affected by the QCP up to such unusually high temperatures. We determine a general criterion for the crossover, as a function of an external parameter such as concentration, from the region controlled solely by thermal fluctuations to that where quantum effects become observable. The properties of materials with low coherence lengths will thus be altered far away from the QCP.

  18. High prevalence of multidrug resistance and random distribution of mobile genetic elements among uropathogenic Escherichia coli (UPEC) of the four major phylogenetic groups.

    Science.gov (United States)

    Rijavec, Matija; Starcic Erjavec, Marjanca; Ambrozic Avgustin, Jerneja; Reissbrodt, Rolf; Fruth, Angelika; Krizan-Hergouth, Veronika; Zgur-Bertok, Darja

    2006-08-01

    One hundred and ten UTI Escherichia coli strains, from Ljubljana, Slovenia, were analyzed for antibiotic resistances, mobile DNA elements, serotype, and phylogenetic origin. A high prevalence of drug resistance and multidrug resistance was found. Twenty-six percent of the isolates harbored a class 1 integron, while a majority of the strains (56%) harbored rep sequences characteristic of F-like plasmids. int as well as rep sequences were found to be distributed in a random manner among strains of the four major phylogenetic groups indicating that all groups have a similar tendency to acquire and maintain mobile genetic elements frequently associated with resistance determinants.

  19. Financial system loss as an example of high consequence, high frequency events

    Energy Technology Data Exchange (ETDEWEB)

    McGovern, D.E.

    1996-07-01

    Much work has been devoted to high consequence events with low frequency of occurrence. Characteristic of these events are bridge failure (such as that of the Tacoma Narrows), building failure (such as the collapse of a walkway at a Kansas City hotel), or compromise of a major chemical containment system (such as at Bhopal, India). Such events, although rare, have an extreme personal, societal, and financial impact. An interesting variation is demonstrated by financial losses due to fraud and abuse in the money management system. The impact can be huge, entailing very high aggregate costs, but these are a result of the contribution of many small attacks and not the result of a single (or few) massive events. Public awareness is raised through publicized events such as the junk bond fraud perpetrated by Milikin or gross mismanagement in the failure of the Barings Bank through unsupervised trading activities by Leeson in Singapore. These event,s although seemingly large (financial losses may be on the order of several billion dollars), are but small contributors to the estimated $114 billion loss to all types of financial fraud in 1993. This paper explores the magnitude of financial system losses and identifies new areas for analysis of high consequence events including the potential effect of malevolent intent.

  20. THE IMPORTANCE OF AFFECT TO BUILD CONSUMER TRUST IN HIGH-CONSEQUENCES EXCHANGES

    Directory of Open Access Journals (Sweden)

    Mellina da Silva Terres

    2012-12-01

    Full Text Available The present article investigates the importance of affect displayed by service provider to build consumer trust in high consequence exchanges. High-consequence exchanges are difficult situations in which the choices present a dilemma that can cause stress and severe emotional reactions (KAHN; LUCE, 2003. In this specific case, trust based on affect seems to become important; mainly because consumers may not have ability to evaluate the cognitive aspects of the situation, and moreover, a medical services failure can be highly problematic or even fatal (LEISEN; HYMAN, 2004. On the other hand, in low-consequence choices, we are predicting that cognition will be more important than affect in building trust. In this kind of situation, patients are more self-confident, less sensitive, and don’t perceive a high probability of loss (KUNREUTHER et al., 2002, and therefore focuses more on the rational outcomes.

  1. Ambulatory Treatment of Multidrug-Resistant Staphylococcus-Infected Orthopedic Implants with High-Dose Oral Co-trimoxazole (Trimethoprim-Sulfamethoxazole)

    Science.gov (United States)

    Stein, Andreas; Bataille, Jean Francois; Drancourt, Michel; Curvale, Georges; Argenson, Jean Noel; Groulier, Pierre; Raoult, Didier

    1998-01-01

    We examined the effectiveness and safety of high-dose oral co-trimoxazole (trimethoprim-sulfamethoxazole) for the treatment of orthopedic implants infected with multidrug-resistant Staphylococcus species. The prospective study was conducted between 1989 and 1997 in a university medical center with ambulatory-care services. Patients eligible for the study consisted of those from whom multidrug-resistant Staphylococcus spp. organisms susceptible only to glycopeptides and co-trimoxazole were isolated from their orthopedic implants and for whom there was no contraindication to the treatment. All patients were treated orally with high-dose co-trimoxazole (trimethoprim, 20 mg/kg of body weight/day; sulfamethoxazole, 100 mg/kg/day). Patients with prosthetic hip infections were treated for 6 months, with removal of any unstable prosthesis after 5 months of treatment; patients with prosthetic knee infections were treated for 9 months, with removal of any unstable prosthesis after 6 months of treatment; and patients with infected osteosynthetic devices were treated for 6 months, with removal of the device after 3 months of treatment, if necessary. Monthly clinical evaluations were conducted until the completion of the treatment, and follow-up examinations were conducted regularly for up to 6 years. The overall treatment success rate was 66.7% (26 of 39 patients), with success rates of 62.5% for patients with prosthetic knee infections, 50% for those with prosthetic hip infections, and 78.9% for those with other device infections. Seventeen of the 28 (60.7%) patients who did not have any orthopedic material removed were cured. Eight patients stopped the treatment because of side effects, and one patient was not compliant. In three patients treatment failed because of the appearance of a resistant bacterium. Long-term oral ambulatory treatment with co-trimoxazole appears to be an effective alternative to the conventional medicosurgical treatment of chronic multidrug

  2. Increased expression of the yeast multidrug resistance ABC transporter Pdr18 leads to increased ethanol tolerance and ethanol production in high gravity alcoholic fermentation

    Directory of Open Access Journals (Sweden)

    Teixeira Miguel C

    2012-07-01

    Full Text Available Abstract Background The understanding of the molecular basis of yeast tolerance to ethanol may guide the design of rational strategies to increase process performance in industrial alcoholic fermentations. A set of 21 genes encoding multidrug transporters from the ATP-Binding Cassette (ABC Superfamily and Major Facilitator Superfamily (MFS in S. cerevisiae were scrutinized for a role in ethanol stress resistance. Results A yeast multidrug resistance ABC transporter encoded by the PDR18 gene, proposed to play a role in the incorporation of ergosterol in the yeast plasma membrane, was found to confer resistance to growth inhibitory concentrations of ethanol. PDR18 expression was seen to contribute to decreased 3 H-ethanol intracellular concentrations and decreased plasma membrane permeabilization of yeast cells challenged with inhibitory ethanol concentrations. Given the increased tolerance to ethanol of cells expressing PDR18, the final concentration of ethanol produced during high gravity alcoholic fermentation by yeast cells devoid of PDR18 was lower than the final ethanol concentration produced by the corresponding parental strain. Moreover, an engineered yeast strain in which the PDR18 promoter was replaced in the genome by the stronger PDR5 promoter, leading to increased PDR18 mRNA levels during alcoholic fermentation, was able to attain a 6 % higher ethanol concentration and a 17 % higher ethanol production yield than the parental strain. The improved fermentative performance of yeast cells over-expressing PDR18 was found to correlate with their increased ethanol tolerance and ability to restrain plasma membrane permeabilization induced throughout high gravity fermentation. Conclusions PDR18 gene over-expression increases yeast ethanol tolerance and fermentation performance leading to the production of highly inhibitory concentrations of ethanol. PDR18 overexpression in industrial yeast strains appears to be a promising approach to

  3. Awareness of Consequence of High School Students on Loss of Bio-Diversity

    Science.gov (United States)

    Kasot, Nazim; Özbas, Serap

    2015-01-01

    The aim of this study is to assess the egoistic, altruistic and biospheric awareness of the consequence of high school students regarding the loss of bio-diversity, then comparing the results on the basis of some independent variables (gender, class and family income). The research data were collected from 884 ninth and tenth grade high school…

  4. 49 CFR 195.452 - Pipeline integrity management in high consequence areas.

    Science.gov (United States)

    2010-10-01

    ... as to fall within the definition in § 195.450 of a high population area or other populated area, the... protection history; (iv) Product transported; (v) Operating stress level; (vi) Existing or projected... failure would affect the high consequence area, such as location of the water intake. (h) What...

  5. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.

    Science.gov (United States)

    Roesch, Alexander; Vultur, Adina; Bogeski, Ivan; Wang, Huan; Zimmermann, Katharina M; Speicher, David; Körbel, Christina; Laschke, Matthias W; Gimotty, Phyllis A; Philipp, Stephan E; Krause, Elmar; Pätzold, Sylvie; Villanueva, Jessie; Krepler, Clemens; Fukunaga-Kalabis, Mizuho; Hoth, Markus; Bastian, Boris C; Vogt, Thomas; Herlyn, Meenhard

    2013-06-10

    Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. A review of research and methods for producing high-consequence software

    Energy Technology Data Exchange (ETDEWEB)

    Collins, E.; Dalton, L.; Peercy, D.; Pollock, G.; Sicking, C.

    1994-12-31

    The development of software for use in high-consequence systems mandates rigorous (formal) processes, methods, and techniques to improve the safety characteristics of those systems. This paper provides a brief overview of current research and practices in high-consequence software, including applied design methods. Some of the practices that are discussed include: fault tree analysis, failure mode effects analysis, petri nets, both hardware and software interlocks, n-version programming, Independent Vulnerability Analyses, and watchdogs. Techniques that offer improvement in the dependability of software in high-consequence systems applications are identified and discussed. Limitations of these techniques are also explored. Research in formal methods, the cleanroom process, and reliability models are reviewed. In addition, current work by several leading researchers as well as approaches being used by leading practitioners are examined.

  7. Plastic Instabilities and Their Consequences in Steels and Other High Strength Alloys

    Science.gov (United States)

    1991-09-01

    rate yes Superalloys * Alloy 600 quasi-static no Rend 41 quasi-static no Steels * HY80 quasi-static no ultra-soft5 no low temperatures no AISI 4340...AD-A240 976 ([f) A Final Technical Report Contract No. N00014-88-K-0111 S PLASTIC INSTABILITIES AND THEIR CONSEQUENCES IN STEELS AND OTHER HIGH...PLASTIC INSTABILITIES AND THEIR CONSEQUENCES IN STEELS AND OTHER HIGH STRENGTH ALLOYS Submitted to: Office of Naval Research 800 North Quincy Street

  8. N-alkanol-N-cyclohexanol amine aryl esters: Multidrug resistance (MDR) reversing agents with high potency and efficacy.

    Science.gov (United States)

    Teodori, Elisabetta; Dei, Silvia; Coronnello, Marcella; Floriddia, Elisa; Bartolucci, Gianluca; Manetti, Dina; Romanelli, Maria Novella; Santo Domingo Porqueras, Diego; Salerno, Milena

    2017-02-15

    In a continuing search for potent P-gp-dependent multidrug-resistant (MDR) reversers we synthesized and studied a new series of N-alkanol-N-cyclohexanol amine aryl esters characterized by the presence of two linkers with different flexibility: a polymethylene chain of variable length and a cyclohexylic scaffold, that gave origin to two geometrical isomers (cis and trans). The reversal activity of the new compounds was evaluated on the K562/DOX cell line by three tests: pirarubicin uptake modulation, doxorubicin cytotoxicity enhancement (reversal fold, RF) and inhibition of P-gp-mediated rhodamine-123 (Rhd 123) efflux tests. The chemical stability of their ester function was evaluated in the experimental conditions utilized (phosphate buffer solution (PBS), bovine serum and in the presence of K562/DOX cells) and in human plasma. The new series of molecules showed very interesting MDR reversing properties; in particular compound 5b (ELF26B), characterized by trans stereochemistry and a 5-methylene chain, presented the best pharmacological profile and is stable in each tested medium. Compound 5b could be an interesting lead for the development of new potent and efficacious P-gp-dependent MDR modulators.

  9. Household Consequences of High Fertility in Pakistan. World Bank Discussion Paper Series No. 111.

    Science.gov (United States)

    Cochrane, Susan Hill; And Others

    The theory and evidence of the consequences of high fertility in Pakistan are reviewed in this paper. Several data sets are analyzed to examine the effects of the number of children on school participation and labor participation in urban Pakistan. Other data are utilized to examine the effects of children on savings in urban and rural areas.…

  10. 49 CFR 192.905 - How does an operator identify a high consequence area?

    Science.gov (United States)

    2010-10-01

    ... SAFETY TRANSPORTATION OF NATURAL AND OTHER GAS BY PIPELINE: MINIMUM FEDERAL SAFETY STANDARDS Gas... 49 Transportation 3 2010-10-01 2010-10-01 false How does an operator identify a high consequence area? 192.905 Section 192.905 Transportation Other Regulations Relating to Transportation (Continued...

  11. Outcomes of comprehensive care for children empirically treated for multidrug-resistant tuberculosis in a setting of high HIV prevalence.

    Directory of Open Access Journals (Sweden)

    Hind Satti

    Full Text Available BACKGROUND: Few studies have examined outcomes for children treated for multidrug-resistant tuberculosis (MDR-TB, including those receiving concomitant treatment for MDR-TB and HIV co-infection. In Lesotho, where the adult HIV seroprevalence is estimated to be 24%, we sought to measure outcomes and adverse events in a cohort of children treated for MDR-TB using a community-based treatment delivery model. METHODS: We reviewed retrospectively the clinical charts of children ≤15 years of age treated for culture-confirmed or suspected MDR-TB between July 2007 and January 2011. RESULTS: Nineteen children, ages two to 15, received treatment. At baseline, 74% of patients were co-infected with HIV, 63% were malnourished, 84% had severe radiographic findings, and 21% had extrapulmonary disease. Five (26% children had culture-confirmed MDR-TB, ten (53% did not have culture results available, and four (21% subsequently had results indicating drug-susceptible TB. All children with HIV co-infection who were not already on antiretroviral therapy (ART were initiated on ART a median of two weeks after the start of the MDR-TB regimen. Among the 17 patients with final outcomes, 15 (88% patients were cured or completed treatment, two (12% patients died, and none defaulted or were lost to follow-up. The majority of patients (95% experienced adverse events; only two required permanent discontinuation of the offending agent, and only one required suspension of MDR-TB treatment for more than one week. CONCLUSIONS: Pediatric MDR-TB and MDR-TB/HIV co-infection can be successfully treated using a combination of social support, close monitoring by community health workers and clinicians, and inpatient care when needed. In this cohort, adverse events were well tolerated and treatment outcomes were comparable to those reported in children with drug-susceptible TB and no HIV infection.

  12. High prevalence and molecular characteristics of multidrug-resistant Salmonella in pigs, pork and humans in Thailand and Laos provinces.

    Science.gov (United States)

    Sinwat, Nuananong; Angkittitrakul, Sunpetch; Coulson, Kari F; Pilapil, Flor Marie Immanuelle R; Meunsene, Dethaloun; Chuanchuen, Rungtip

    2016-10-01

    This study aimed to examine occurrence and antimicrobial resistance characteristics of Salmonella from pigs, pork and humans in Thailand and Laos provinces. The samples were collected from pigs, carcasses and workers in slaughterhouses, retail pork and butchers in fresh markets and patients in hospitals in Thailand (n=729) and Laos (n=458). A total of 295 of 729 samples (34.6 %) collected in Thailand and 253 of 458 (47.4 %) samples collected in Laos were positive for Salmonella. A total of 548 Salmonella isolates from Thailand (n=295) and Laos (n=253) were further analysed. Serovar Typhimurium was the most common serotype in Thai (34 %) and Laos (20.6 %) samples. Approximately 2.4 % of Thai isolates produced extended-spectrum β-lactamase (ESBL). All the ESBL producers possessed blaCTX-M-14, some of which were horizontally transferred. Class 1 integrons were common in Thai (31.9 %) and Laos (39.1 %) isolates, but none were associated with SGI1. The resistance cassette dfrA12-aadA2 was the most common, while the least common was aadA2-linG (n=1). The dfrA12-aadA2 gene cassette in five isolates and aadA2-linG were located on conjugative plasmid. Three pork isolates were fluoroquinolone resistant and carried an amino acid substitute, Ser-83-Tyr, in GyrA. The qnrS gene was found in 7.1 and 5.5 % of the Thai and Laos isolates, respectively, while qnrB was carried in another Laos isolate (1.9 %). All ESBL producers carried qnrS. In conclusion, multidrug-resistant Salmonella was common in pigs, pork and human samples in this region. The bacteria carried mobile genetic elements and resistance genes on conjugative plasmids that could be readily transferred to other bacterial species.

  13. Multidrug resistance associated proteins in multidrug resistance

    Institute of Scientific and Technical Information of China (English)

    Kamlesh Sodani; Atish Patel; Rishil J. Kathawala; Zhe-Sheng Chen

    2012-01-01

    Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters.These ABC transporters together form the largest branch of proteins within the human body.The MRP family comprises of 13 members,of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell.They are mainly lipophilic anionic transporters and are reported to transport free or conjugates of glutathione (GSH),glucuronate,or sulphate.In addition,MRP1 to MRP3 can transport neutral organic drugs in free form in the presence of free GSH.Collectively,MRPs can transport drugs that differ structurally and mechanistically,including natural anticancer drugs,nucleoside analogs,antimetabolites,and tyrosine kinase inhibitors.Many of these MRPs transport physiologically important anions such as leukotriene C4,bilirubin glucuronide,and cyclic nucleotides.This review focuses mainly on the physiological functions,cellular resistance characteristics,and probable in vivo role of MRP1 to MRP9.

  14. Does Alcohol Use Mediate the Association between Consequences Experienced in High School and Consequences Experienced during the First Semester of College?

    Science.gov (United States)

    Romosz, Ann Marie; Quigley, Brian M.

    2013-01-01

    Approximately 80% of college students drink alcohol; almost half of these students reporting that they drink to get drunk and over 22% engage in heavy episodic drinking. Heavy alcohol consumption during the transition from high school to college is associated with negative personal and academic consequences. Sixty-seven freshmen volunteered to…

  15. High Prevalence of Multidrug-Resistant Community-Acquired Methicillin-Resistant Staphylococcus aureus at the Largest Veterinary Teaching Hospital in Costa Rica.

    Science.gov (United States)

    Rojas, Irene; Barquero-Calvo, Elías; van Balen, Joany C; Rojas, Norman; Muñoz-Vargas, Lohendy; Hoet, Armando E

    2017-09-01

    Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen associated with severe infections in companion animals present in the community, and it is diagnosed in animals admitted to veterinary hospitals. However, reports that describe the circulation of MRSA in animal populations and veterinary settings in Latin America are scarce. Therefore, the objective of this study was to determine the prevalence and investigate the molecular epidemiology of MRSA in the environment of the largest veterinary teaching hospital in Costa Rica. Preselected contact surfaces were sampled twice within a 6-week period. Antimicrobial resistance, SCCmec type, Panton-Valentine leukocidin screening, USA type, and clonality were assessed in all recovered isolates. Overall, MRSA was isolated from 26.5% (27/102) of the surfaces sampled, with doors, desks, and examination tables most frequently contaminated. Molecular analysis demonstrated a variety of surfaces from different sections of the hospital contaminated by three highly related clones/pulsotypes. All, but one of the isolates were characterized as multidrug-resistant SCCmec type IV-USA700, a strain sporadically described in other countries and often classified as community acquired. The detection and frequency of this unique strain in this veterinary setting suggest Costa Rica has a distinctive MRSA ecology when compared with other countries/regions. The high level of environmental contamination highlights the necessity to establish and enforce standard cleaning and disinfection protocols to minimize further spread of this pathogen and reduce the risk of nosocomial and/or occupational transmission of MRSA.

  16. High prevalence of multidrug-resistant Escherichia coli and Enterococcus spp. in river water, upstream and downstream of a wastewater treatment plant.

    Science.gov (United States)

    Bessa, Lucinda J; Barbosa-Vasconcelos, Ana; Mendes, Angelo; Vaz-Pires, Paulo; Martins da Costa, Paulo

    2014-09-01

    In this study, microbial quality and antimicrobial resistance of faecal bacteria from a Portuguese river were assessed. River water samples collected upstream and downstream of a wastewater treatment plant, throughout a 3-month period, were used for the enumeration of Escherichia coli and Enterococcus spp. The highest numbers found for E. coli and enterococci were 1.1 × 10⁴ and 1.2 × 10⁴ colony forming units (CFU)/100 ml, respectively. In total, 144 isolates of E. coli and 144 of enterococci were recovered and tested for antimicrobial susceptibility; 104 E. coli and 78 Enterococcus spp. showed resistance to one or more antimicrobial drugs. Overall, 70 and 32 different resistance patterns were found for E. coli and enterococci, respectively. One E. coli showed resistance to imipenem and 29 isolates were extended spectrum β-lactamase-producers. Multidrug-resistant E. coli belonged mostly to groups A, B1 and group D. Enterococcus spp. were mostly resistant to rifampicin, tetracycline, azithromycin and erythromycin; six isolates showed resistance to vancomycin, presenting the VanA phenotype. The high levels of E. coli and enterococci and the remarkable variety of antimicrobial resistance profiles, reinforces the theory that these river waters can be a pool of antimicrobial resistance determinants, which can be easily spread among different bacteria and reach other environments and hosts.

  17. High load of multi-drug resistant nosocomial neonatal pathogens carried by cockroaches in a neonatal intensive care unit at Tikur Anbessa specialized hospital, Addis Ababa, Ethiopia

    Directory of Open Access Journals (Sweden)

    Tilahun Birkneh

    2012-03-01

    Full Text Available Abstract Background Cockroaches have been described as potential vectors for various pathogens for decades; although studies from neonatal intensive care units are scarce. This study assessed the vector potential of cockroaches (identified as Blatella germanica in a neonatal intensive care unit setup in Tikur Anbessa Hospital, Addis Ababa, Ethiopia. Methods A total of 400 Blatella germanica roaches were aseptically collected for five consecutive months. Standard laboratory procedures were used to process the samples. Results From the external and gut homogenates, Klebsiella oxytoca, Klebsiella pneumoniae, Citrobacter spp. Enterobacter cloacae, Citrobacter diversus, Pseudomonas aeruginosa, Providencia rettgeri, Klebsiella ozaenae, Enterobacter aeruginosa, Salmonella C1, Non Group A streptococcus, Staphylococcus aureus, Escherichia coli, Acinetobacter spp. and Shigella flexneri were isolated. Multi-drug resistance was seen in all organisms. Resistance to up to all the 12 antimicrobials tested was observed in different pathogens. Conclusion Cockroaches could play a vector role for nosocomial infections in a neonatal intensive care unit and environmental control measures of these vectors is required to reduce the risk of infection. A high level of drug resistance pattern of the isolated pathogens was demonstrated.

  18. Azithromycin Synergizes with Cationic Antimicrobial Peptides to Exert Bactericidal and Therapeutic Activity Against Highly Multidrug-Resistant Gram-Negative Bacterial Pathogens

    Directory of Open Access Journals (Sweden)

    Leo Lin

    2015-07-01

    Full Text Available Antibiotic resistance poses an increasingly grave threat to the public health. Of pressing concern, rapid spread of carbapenem-resistance among multidrug-resistant (MDR Gram-negative rods (GNR is associated with few treatment options and high mortality rates. Current antibiotic susceptibility testing guiding patient management is performed in a standardized manner, identifying minimum inhibitory concentrations (MIC in bacteriologic media, but ignoring host immune factors. Lacking activity in standard MIC testing, azithromycin (AZM, the most commonly prescribed antibiotic in the U.S., is never recommended for MDR GNR infection. Here we report a potent bactericidal action of AZM against MDR carbapenem-resistant isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. This pharmaceutical activity is associated with enhanced AZM cell penetration in eukaryotic tissue culture media and striking multi-log-fold synergies with host cathelicidin antimicrobial peptide LL-37 or the last line antibiotic colistin. Finally, AZM monotherapy exerts clear therapeutic effects in murine models of MDR GNR infection. Our results suggest that AZM, currently ignored as a treatment option, could benefit patients with MDR GNR infections, especially in combination with colistin.

  19. A treatment plant receiving waste water from multiple bulk drug manufacturers is a reservoir for highly multi-drug resistant integron-bearing bacteria.

    Directory of Open Access Journals (Sweden)

    Nachiket P Marathe

    Full Text Available The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range. In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86% of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE, Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1 was resistant to 36 antibiotics, while P. rettgeri (OSR3 was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80% strains each, and 88/93 (95% strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides

  20. Multidrug-Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    2008-10-28

    In this podcast, Dr. Oeltmann discusses multidrug-resistant tuberculosis. An outbreak occurred in Thailand, which led to 45 cases in the U.S. This serious illness can take up to 2 years to treat. MDR TB is a real threat and a serious condition.  Created: 10/28/2008 by Emerging Infectious Diseases.   Date Released: 10/28/2008.

  1. Predominant Mycobacterium tuberculosis Families and High Rates of Recent Transmission among New Cases Are Not Associated with Primary Multidrug Resistance in Lima, Peru.

    Science.gov (United States)

    Barletta, Francesca; Otero, Larissa; de Jong, Bouke C; Iwamoto, Tomotada; Arikawa, Kentaro; Van der Stuyft, Patrick; Niemann, Stefan; Merker, Matthias; Uwizeye, Cécile; Seas, Carlos; Rigouts, Leen

    2015-06-01

    Sputum samples from new tuberculosis (TB) cases were collected over 2 years as part of a prospective study in the northeastern part of Lima, Peru. To measure the contribution of recent transmission to the high rates of multidrug resistance (MDR) in this area, Mycobacterium tuberculosis complex (MTBc) isolates were tested for drug susceptibility to first-line drugs and were genotyped by spoligotyping and 15-locus mycobacterial interspersed repetitive-unit (MIRU-15)-variable-number tandem repeat (VNTR) analysis. MDR was found in 6.8% of 844 isolates, of which 593 (70.3%) were identified as belonging to a known MTBc lineage, whereas 198 isolates (23.5%) could not be assigned to these lineages and 12 (1.4%) represented mixed infections. Lineage 4 accounted for 54.9% (n = 463) of the isolates, most of which belonged to the Haarlem family (n = 279). MIRU-15 analysis grouped 551/791 isolates (69.7%) in 102 clusters, with sizes ranging from 2 to 46 strains. The overall high clustering rate suggests a high level of recent transmission in this population, especially among younger patients (odds ratio [OR], 1.6; P = 0.01). Haarlem strains were more prone to cluster, compared to the other families taken together (OR, 2.0; P rates did not differ between MDR and non-MDR strains (OR, 1.8; P = 0.1). Furthermore, only 16/51 MDR strains clustered with other MDR strains, suggesting that patients with primary MDR infections acquired the infections mostly from index cases outside the study population, such as retreated cases.

  2. Comparison of multi-drug resistant environmental methicillin-resistant Staphylococcus aureus [MRSA] isolated from recreational beaches and high touch surfaces in built environments

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    Marilyn C Roberts

    2013-04-01

    Full Text Available Over the last decade community-acquired methicillin-resistant Staphylococcus aureus [MRSA] has emerged as a major cause of disease in the general population with no health care exposure or known classical risk factors for MRSA infections. The potential community reservoirs have not been well defined though certain strains such as ST398 and USA300 have been well studied in some settings. MRSA has been isolated from recreational beaches, high-touch surfaces in homes, universities and other community environmental surfaces. However, in most cases the strains were not characterized to determine if they are related to community-acquired or hospital-acquired clinical strains. We compared 55 environmental MRSA from 805 samples including sand, fresh and marine water samples from local marine and fresh water recreational beaches (n=296, high touch surfaces on the University of Washington campus (n=294, surfaces in UW undergraduate housing (n=85, and the local community (n=130. Eleven USA300, representing 20% of the isolates, were found on the UW campus surfaces, student housing surfaces and on the community surfaces but not in the recreational beach samples from the Northwest USA. Similarly, the predominant animal ST133 was found in the recreational beach samples but not in the high touch surface samples. All USA300 isolates were multi-drug resistant carrying 2-6 different antibiotic resistance genes coding for kanamycin, macrolides and/or macrolides-lincosamides-streptogramin B and tetracycline, with the majority [72%] carrying 4-6 different antibiotic resistance genes. A surprising 98% of the 55 MRSA isolates were resistant to other classes of antibiotics and most likely represent reservoirs for these genes in the environment.

  3. Global situational awareness and early warning of high-consequence climate change.

    Energy Technology Data Exchange (ETDEWEB)

    Backus, George A.; Carr, Martin J.; Boslough, Mark Bruce Elrick

    2009-08-01

    Global monitoring systems that have high spatial and temporal resolution, with long observational baselines, are needed to provide situational awareness of the Earth's climate system. Continuous monitoring is required for early warning of high-consequence climate change and to help anticipate and minimize the threat. Global climate has changed abruptly in the past and will almost certainly do so again, even in the absence of anthropogenic interference. It is possible that the Earth's climate could change dramatically and suddenly within a few years. An unexpected loss of climate stability would be equivalent to the failure of an engineered system on a grand scale, and would affect billions of people by causing agricultural, economic, and environmental collapses that would cascade throughout the world. The probability of such an abrupt change happening in the near future may be small, but it is nonzero. Because the consequences would be catastrophic, we argue that the problem should be treated with science-informed engineering conservatism, which focuses on various ways a system can fail and emphasizes inspection and early detection. Such an approach will require high-fidelity continuous global monitoring, informed by scientific modeling.

  4. Multidrug-resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    McNerney Ruth

    2008-01-01

    Full Text Available Abstract Background With almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data. Discussion Whereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose

  5. Burden and consequences of child maltreatment in high-income countries.

    Science.gov (United States)

    Gilbert, Ruth; Widom, Cathy Spatz; Browne, Kevin; Fergusson, David; Webb, Elspeth; Janson, Staffan

    2009-01-03

    Child maltreatment remains a major public-health and social-welfare problem in high-income countries. Every year, about 4-16% of children are physically abused and one in ten is neglected or psychologically abused. During childhood, between 5% and 10% of girls and up to 5% of boys are exposed to penetrative sexual abuse, and up to three times this number are exposed to any type of sexual abuse. However, official rates for substantiated child maltreatment indicate less than a tenth of this burden. Exposure to multiple types and repeated episodes of maltreatment is associated with increased risks of severe maltreatment and psychological consequences. Child maltreatment substantially contributes to child mortality and morbidity and has longlasting effects on mental health, drug and alcohol misuse (especially in girls), risky sexual behaviour, obesity, and criminal behaviour, which persist into adulthood. Neglect is at least as damaging as physical or sexual abuse in the long term but has received the least scientific and public attention. The high burden and serious and long-term consequences of child maltreatment warrant increased investment in preventive and therapeutic strategies from early childhood.

  6. Multidrug resistance: Physiological principles and nanomedical solutions.

    Science.gov (United States)

    Kunjachan, Sijumon; Rychlik, Błażej; Storm, Gert; Kiessling, Fabian; Lammers, Twan

    2013-11-01

    Multidrug resistance (MDR) is a pathophysiological phenomenon employed by cancer cells which limits the prolonged and effective use of chemotherapeutic agents. MDR is primarily based on the over-expression of drug efflux pumps in the cellular membrane. Prominent examples of such efflux pumps, which belong to the ATP-binding cassette (ABC) superfamily of proteins, are Pgp (P-glycoprotein) and MRP (multidrug resistance-associated protein), nowadays officially known as ABCB1 and ABCC1. Over the years, several strategies have been evaluated to overcome MDR, based not only on the use of low-molecular-weight MDR modulators, but also on the implementation of 1-100(0) nm-sized drug delivery systems. In the present manuscript, after introducing the most important physiological principles of MDR, we summarize prototypic nanomedical strategies to overcome multidrug resistance, including the use of carrier materials with intrinsic anti-MDR properties, the use of nanomedicines to modify the mode of cellular uptake, and the co-formulation of chemotherapeutic drugs together with low- and high-molecular-weight MDR inhibitors within a single drug delivery system. While certain challenges still need to be overcome before such constructs and concepts can be widely applied in the clinic, the insights obtained and the progress made strongly suggest that nanomedicine formulations hold significant potential for improving the treatment of multidrug-resistant malignancies.

  7. Rapid detection of multidrug-resistant Mycobacterium tuberculosis by use of real-time PCR and high-resolution melt analysis.

    Science.gov (United States)

    Ramirez, Melissa V; Cowart, Kelley C; Campbell, Patricia J; Morlock, Glenn P; Sikes, David; Winchell, Jonas M; Posey, James E

    2010-11-01

    The current study describes the development of a unique real-time PCR assay for the detection of mutations conferring drug resistance in Mycobacterium tuberculosis. The rifampicin resistance determinant region (RRDR) of rpoB and specific regions of katG and the inhA promoter were targeted for the detection of rifampin (RIF) and isoniazid (INH) resistance, respectively. Additionally, this assay was multiplexed to discriminate Mycobacterium tuberculosis complex (MTC) strains from nontuberculous Mycobacteria (NTM) strains by targeting the IS6110 insertion element. High-resolution melting (HRM) analysis following real-time PCR was used to identify M. tuberculosis strains containing mutations at the targeted loci, and locked nucleic acid (LNA) probes were used to enhance the detection of strains containing specific single-nucleotide polymorphism (SNP) transversion mutations. This method was used to screen 252 M. tuberculosis clinical isolates, including 154 RIF-resistant strains and 174 INH-resistant strains based on the agar proportion method of drug susceptibility testing (DST). Of the 154 RIF-resistant strains, 148 were also resistant to INH and therefore classified as multidrug resistant (MDR). The assay demonstrated sensitivity and specificity of 91% and 98%, respectively, for the detection of RIF resistance and 87% and 100% for the detection of INH resistance. Overall, this assay showed a sensitivity of 85% and a specificity of 98% for the detection of MDR strains. This method provides a rapid, robust, and inexpensive way to detect the dominant mutations known to confer MDR in M. tuberculosis strains and offers several advantages over current molecular and culture-based techniques.

  8. Identification of natural compound inhibitors for multidrug efflux pumps of Escherichia coli and Pseudomonas aeruginosa using in silico high-throughput virtual screening and in vitro validation.

    Science.gov (United States)

    Aparna, Vasudevan; Dineshkumar, Kesavan; Mohanalakshmi, Narasumani; Velmurugan, Devadasan; Hopper, Waheeta

    2014-01-01

    Pseudomonas aeruginosa and Escherichia coli are resistant to wide range of antibiotics rendering the treatment of infections very difficult. A main mechanism attributed to the resistance is the function of efflux pumps. MexAB-OprM and AcrAB-TolC are the tripartite efflux pump assemblies, responsible for multidrug resistance in P. aeruginosa and E. coli respectively. Substrates that are more susceptible for efflux are predicted to have a common pharmacophore feature map. In this study, a new criterion of excluding compounds with efflux substrate-like features was used, thereby refining the selection process and enriching the inhibitor identification process. An in-house database of phytochemicals was created and screened using high-throughput virtual screening against AcrB and MexB proteins and filtered by matching with the common pharmacophore models (AADHR, ADHNR, AAHNR, AADHN, AADNR, AAADN, AAADR, AAANR, AAAHN, AAADD and AAADH) generated using known efflux substrates. Phytochemical hits that matched with any one or more of the efflux substrate models were excluded from the study. Hits that do not have features similar to the efflux substrate models were docked using XP docking against the AcrB and MexB proteins. The best hits of the XP docking were validated by checkerboard synergy assay and ethidium bromide accumulation assay for their efflux inhibition potency. Lanatoside C and diadzein were filtered based on the synergistic potential and validated for their efflux inhibition potency using ethidium bromide accumulation study. These compounds exhibited the ability to increase the accumulation of ethidium bromide inside the bacterial cell as evidenced by these increase in fluorescence in the presence of the compounds. With this good correlation between in silico screening and positive efflux inhibitory activity in vitro, the two compounds, lanatoside C and diadzein could be promising efflux pump inhibitors and effective to use in combination therapy against drug

  9. High rates of multidrug-resistant and rifampicin-resistant tuberculosis among re-treatment cases: where do they come from?

    Science.gov (United States)

    Ragonnet, Romain; Trauer, James M; Denholm, Justin T; Marais, Ben J; McBryde, Emma S

    2017-01-06

    Globally 3.9% of new and 21% of re-treatment tuberculosis (TB) cases are multidrug-resistant or rifampicin-resistant (MDR/RR), which is often interpreted as evidence that drug resistance results mainly from poor treatment adherence. This study aims to assess the respective contributions of the different causal pathways leading to MDR/RR-TB at re-treatment. We use a simple mathematical model to simulate progression between the different stages of disease and treatment for patients diagnosed with TB. The model is parameterised using region and country-specific TB disease burden data reported by the World Health Organization (WHO). The contributions of four separate causal pathways to MDR/RR-TB among re-treatment cases are estimated: I) initial drug-susceptible TB with resistance amplification during treatment; II) initial MDR/RR-TB inappropriately treated as drug-susceptible TB; III) MDR/RR-TB relapse despite appropriate treatment; and IV) re-infection with MDR/RR-TB. At the global level, Pathways I, II, III and IV contribute 38% (28-49, 95% Simulation Interval), 44% (36-52, 95% SI), 6% (5-7, 95% SI) and 12% (7-19, 95% SI) respectively to the burden of MDR/RR-TB among re-treatment cases. Pathway II is dominant in the Western Pacific (74%; 67-80 95% SI), Eastern Mediterranean (68%; 60-74 95% SI) and European (53%; 48-59 95% SI) regions, while Pathway I makes the greatest contribution in the American (53%; 40-66 95% SI), African (43%; 28-61 95% SI) and South-East Asian (50%; 40-59 95% SI) regions. Globally, failure to diagnose MDR/RR-TB at first presentation is the leading cause of the high proportion of MDR/RR-TB among re-treatment cases. These findings highlight the need for contextualised solutions to limit the impact and spread of MDR/RR-TB.

  10. Positive and negative perceived consequences of first intercourse among middle and high school students in Puebla, Mexico.

    Science.gov (United States)

    Vasilenko, Sara A; Espinosa-Hernández, Graciela; Halgunseth, Linda C

    2016-01-01

    Relatively little is known about young people's interpretations of sexual behaviour in Latin America. In this study, we examine the most commonly perceived consequences of first sexual intercourse among Mexican middle and high school students, how perceived consequences differ by gender, and factors that may predict experiencing more positive or negative consequences. Sexually active Mexican students aged 12-19 years (n = 268) reported whether they had experienced each of 19 consequences following first intercourse. Both positive consequences, such as physical satisfaction and closeness to partner, and negative consequences, such as worry about STDs and pregnancy, were common. Sex with a non-relationship partner was associated with fewer positive and more negative consequences, with the effect for positive consequences being stronger for young women. Pressure to have sex was associated with fewer positive consequences of first intercourse, and pressure to remain a virgin was associated with more positive and negative consequences. These findings suggest that young people often report mixed feelings about their first sexual intercourse and that relationship context and sexual socialisation influence their perceptions of the event.

  11. Climatic consequences of very high carbon dioxide levels in the earth's early atmosphere

    Science.gov (United States)

    Kasting, James F.; Ackerman, Thomas P.

    1986-01-01

    The possible consequences of very high carbon dioxide concentrations in the earth's early atmosphere have been investigated with a radiative-convective climate model. The early atmosphere would apparently have been stable against the onset of a runaway greenhouse (that is, the complete evaporation of the oceans) for carbon dioxide pressures up to at least 100 bars. A 10- to 20-bar carbon dioxide atmosphere, such as may have existed during the first several hundred million years of the earth's history, would have had a surface temperature of approximately 85 to 110 C. The early stratosphere should have been dry, thereby precluding the possibility of an oxygenic prebiotic atmosphere caused by photodissociation of water vapor followed by escape of hydrogen to space. Earth's present atmosphere also appears to be stable against a carbon dioxide-induced runaway greenhouse.

  12. International biosecurity symposium : securing high consequence pathogens and toxins : symposium summary.

    Energy Technology Data Exchange (ETDEWEB)

    2004-06-01

    The National Nuclear Security Administration (NNSA) Office of Nonproliferation Policy sponsored an international biosecurity symposium at Sandia National Laboratories (SNL). The event, entitled 'Securing High Consequence Pathogens and Toxins', took place from February 1 to February 6, 2004 and was hosted by Dr. Reynolds M. Salerno, Principal Member of the Technical Staff and Program Manager of the Biosecurity program at Sandia. Over 60 bioscience and policy experts from 14 countries gathered to discuss biosecurity, a strategy aimed at preventing the theft and sabotage of dangerous pathogens and toxins from bioscience facilities. Presentations delivered during the symposium were interspersed with targeted discussions that elucidated, among other things, the need for subsequent regional workshops on biosecurity, and a desire for additional work toward developing international biosecurity guidelines.

  13. Risk management & organizational uncertainty implications for the assessment of high consequence organizations

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, C.T.

    1995-02-23

    Post hoc analyses have demonstrated clearly that macro-system, organizational processes have played important roles in such major catastrophes as Three Mile Island, Bhopal, Exxon Valdez, Chernobyl, and Piper Alpha. How can managers of such high-consequence organizations as nuclear power plants and nuclear explosives handling facilities be sure that similar macro-system processes are not operating in their plants? To date, macro-system effects have not been integrated into risk assessments. Part of the reason for not using macro-system analyses to assess risk may be the impression that standard organizational measurement tools do not provide hard data that can be managed effectively. In this paper, I argue that organizational dimensions, like those in ISO 9000, can be quantified and integrated into standard risk assessments.

  14. Climatic consequences of very high carbon dioxide levels in the earth's early atmosphere

    Science.gov (United States)

    Kasting, James F.; Ackerman, Thomas P.

    1986-01-01

    The possible consequences of very high carbon dioxide concentrations in the earth's early atmosphere have been investigated with a radiative-convective climate model. The early atmosphere would apparently have been stable against the onset of a runaway greenhouse (that is, the complete evaporation of the oceans) for carbon dioxide pressures up to at least 100 bars. A 10- to 20-bar carbon dioxide atmosphere, such as may have existed during the first several hundred million years of the earth's history, would have had a surface temperature of approximately 85 to 110 C. The early stratosphere should have been dry, thereby precluding the possibility of an oxygenic prebiotic atmosphere caused by photodissociation of water vapor followed by escape of hydrogen to space. Earth's present atmosphere also appears to be stable against a carbon dioxide-induced runaway greenhouse.

  15. High prevalence of multidrug-tolerant bacteria and associated antimicrobial resistance genes isolated from ornamental fish and their carriage water.

    Directory of Open Access Journals (Sweden)

    David W Verner-Jeffreys

    Full Text Available BACKGROUND: Antimicrobials are used to directly control bacterial infections in pet (ornamental fish and are routinely added to the water these fish are shipped in to suppress the growth of potential pathogens during transport. METHODOLOGY/PRINCIPAL FINDINGS: To assess the potential effects of this sustained selection pressure, 127 Aeromonas spp. isolated from warm and cold water ornamental fish species were screened for tolerance to 34 antimicrobials. Representative isolates were also examined for the presence of 54 resistance genes by a combination of miniaturized microarray and conventional PCR. Forty-seven of 94 Aeromonas spp. isolates recovered from tropical ornamental fish and their carriage water were tolerant to > or =15 antibiotics, representing seven or more different classes of antimicrobial. The quinolone and fluoroquinolone resistance gene, qnrS2, was detected at high frequency (37% tested recent isolates were positive by PCR. Class 1 integrons, IncA/C broad host range plasmids and a range of other antibiotic resistance genes, including floR, bla(TEM-1, tet(A, tet(D, tet(E, qacE2, sul1, and a number of different dihydrofolate reductase and aminoglycoside transferase coding genes were also detected in carriage water samples and bacterial isolates. CONCLUSIONS: These data suggest that ornamental fish and their carriage water act as a reservoir for both multi-resistant bacteria and resistance genes.

  16. Structural basis of RND-type multidrug exporters.

    Science.gov (United States)

    Yamaguchi, Akihito; Nakashima, Ryosuke; Sakurai, Keisuke

    2015-01-01

    Bacterial multidrug exporters are intrinsic membrane transporters that act as cellular self-defense mechanism. The most notable characteristics of multidrug exporters is that they export a wide range of drugs and toxic compounds. The overexpression of these exporters causes multidrug resistance. Multidrug-resistant pathogens have become a serious problem in modern chemotherapy. Over the past decade, investigations into the structure of bacterial multidrug exporters have revealed the multidrug recognition and export mechanisms. In this review, we primarily discuss RND-type multidrug exporters particularly AcrAB-TolC, major drug exporter in Gram-negative bacteria. RND-type drug exporters are tripartite complexes comprising a cell membrane transporter, an outer membrane channel and an adaptor protein. Cell membrane transporters and outer membrane channels are homo-trimers; however, there is no consensus on the number of adaptor proteins in these tripartite complexes. The three monomers of a cell membrane transporter have varying conformations (access, binding, and extrusion) during transport. Drugs are exported following an ordered conformational change in these three monomers, through a functional rotation mechanism coupled with the proton relay cycle in ion pairs, which is driven by proton translocation. Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules. The voluminous multidrug-binding pocket may have numerous binding sites even for a single substrate, suggesting that substrates may move between binding sites during transport, an idea named as multisite-drug-oscillation hypothesis. This hypothesis is consistent with the apparently broad substrate specificity of cell membrane exporters and their highly efficient

  17. Determination of plasma concentrations of levofloxacin by high performance liquid chromatography for use at a multidrug-resistant tuberculosis hospital in Tanzania

    Science.gov (United States)

    Mpagama, Stellah; Kisonga, Riziki; Lekule, Isaack; Liu, Jie; Heysell, Scott

    2017-01-01

    Therapeutic drug monitoring may improve multidrug-resistant tuberculosis (MDR-TB) treatment outcomes. Levofloxacin demonstrates significant individual pharmacokinetic variability. Thus, we sought to develop and validate a high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection for levofloxacin in patients on MDR-TB treatment. The HPLC-UV method is based on a solid phase extraction (SPE) and a direct injection into the HPLC system. The limit of quantification was 0.25 μg/mL, and the assay was linear over the concentration range of 0.25—15 μg/mL (y = 0.5668x—0.0603, R2 = 0.9992) for the determination of levofloxacin in plasma. The HPLC-UV methodology achieved excellent accuracy and reproducibility along a clinically meaningful range. The intra-assay RSD% of low, medium, and high quality control samples (QC) were 1.93, 2.44, and 1.90, respectively, while the inter-assay RSD% were 3.74, 5.65, and 3.30, respectively. The mean recovery was 96.84%. This method was then utilized to measure levofloxacin concentrations from patients’ plasma samples from a retrospective cohort of consecutive enrolled subjects treated for MDR-TB at the national TB hospital in Tanzania during 5/3/2013–8/31/2015. Plasma was collected at 2 hours after levofloxacin administration, the time of estimated peak concentration (eCmax) treatment. Forty-one MDR-TB patients had plasma available and 39 had traceable programmatic outcomes. Only 13 (32%) patients had any plasma concentration that reached the lower range of the expected literature derived Cmax with the median eCmax being 5.86 (3.33–9.08 μg/ml). Using Classification and Regression Tree analysis, an eCmax ≥7.55 μg/mL was identified as the threshold which best predicted cure. Analyzing this CART derived threshold on treatment outcome, the time to sputum culture conversion was 38.3 ± 22.7 days vs. 47.8 ± 26.5 days (p = 0.27) and a greater proportion were cured, in 10 out of 15 (66.7%) vs. 6 out of 18

  18. High levels of multidrug resistant tuberculosis in new and treatment-failure patients from the Revised National Tuberculosis Control Programme in an urban metropolis (Mumbai in Western India

    Directory of Open Access Journals (Sweden)

    Nicol Mark

    2009-06-01

    Full Text Available Abstract Background India, China and Russia account for more than 62% of multidrug resistant tuberculosis (MDRTB globally. Within India, locations like urban metropolitan Mumbai with its burgeoning population and high incidence of TB are suspected to be a focus for MDRTB. However apart from sporadic surveys at watched sites in the country, there has been no systematic attempt by the Revised National Tuberculosis Control Programme (RNTCP of India to determine the extent of MDRTB in Mumbai that could feed into national estimates. Drug susceptibility testing (DST is not routinely performed as a part of programme policy and public health laboratory infrastructure, is limited and poorly equipped to cope with large scale testing. Methods From April 2004 to January 2007 we determined the extent of drug resistance in 724 {493 newly diagnosed, previously untreated and 231 first line treatment failures (sputum-smear positive at the fifth month after commencement of therapy} cases of pulmonary tuberculosis drawn from the RNTCP in four suboptimally performing municipal wards of Mumbai. The observations were obtained using a modified radiorespirometric Buddemeyer assay and validated by the Swedish Institute for Infectious Disease Control, Stockholm, a supranational reference laboratory. Data was analyzed utilizing SPSS 10.0 and Epi Info 2002. Results This study undertaken for the first time in RNTCP outpatients in Mumbai reveals a high proportion of MDRTB strains in both previously untreated (24% and treatment-failure cases (41%. Amongst new cases, resistance to 3 or 4 drug combinations (amplified drug resistance including isoniazid (H and rifampicin (R, was greater (20% than resistance to H and R alone (4% at any point in time during the study. The trend for monoresistance was similar in both groups remaining highest to H and lowest to R. External quality control revealed good agreement for H and R resistance (k = 0.77 and 0.76 respectively. Conclusion

  19. Direct detection of multidrug-resistant Mycobacterium tuberculosis in clinical specimens in low- and high-incidence countries by line probe assay

    DEFF Research Database (Denmark)

    Johansen, Isik Somuncu; Lundgren, Bettina; Sosnovskaja, Anaida;

    2003-01-01

    The INNO-LiPA Rif.TB assay is designed for the detection of rpoB gene mutations causing rifampin resistance in isolates. We applied the method directly to 60 Lithuanian and Danish clinical specimens to detect rifampin resistance rapidly. Results were obtained in 78.3% of clinical specimens, and a...... were concordant with those obtained by BACTEC 460. The assay could have major impact on the management of multidrug-resistant tuberculosis....

  20. Multidrug-resistant tuberculosis: rapid detection of resistance to rifampin and high or low levels of isoniazid in clinical specimens and isolates

    DEFF Research Database (Denmark)

    Vijdea, R.; Stegger, M.; Sosnovskaja, A.

    2008-01-01

    The aim of the present study was to evaluate a new improved multiplex polymerase chain reaction (PCR) hybridisation assay to detect multidrug-resistant tuberculosis. The assay, developed to detect rifampin (rpoB) and isoniazid (katG) gene mutations causing Mycobacterium tuberculosis resistance, w...... tool to combat and prevent new cases of multi- and extensively drug-resistant tuberculosis Udgivelsesdato: 2008/11...

  1. Statistical Surrogate Models for Estimating Probability of High-Consequence Climate Change

    Science.gov (United States)

    Field, R.; Constantine, P.; Boslough, M.

    2011-12-01

    We have posed the climate change problem in a framework similar to that used in safety engineering, by acknowledging that probabilistic risk assessments focused on low-probability, high-consequence climate events are perhaps more appropriate than studies focused simply on best estimates. To properly explore the tails of the distribution requires extensive sampling, which is not possible with existing coupled atmospheric models due to the high computational cost of each simulation. We have developed specialized statistical surrogate models (SSMs) that can be used to make predictions about the tails of the associated probability distributions. A SSM is different than a deterministic surrogate model in that it represents each climate variable of interest as a space/time random field, that is, a random variable for every fixed location in the atmosphere at all times. The SSM can be calibrated to available spatial and temporal data from existing climate databases, or to a collection of outputs from general circulation models. Because of its reduced size and complexity, the realization of a large number of independent model outputs from a SSM becomes computationally straightforward, so that quantifying the risk associated with low-probability, high-consequence climate events becomes feasible. A Bayesian framework was also developed to provide quantitative measures of confidence, via Bayesian credible intervals, to assess these risks. To illustrate the use of the SSM, we considered two collections of NCAR CCSM 3.0 output data. The first collection corresponds to average December surface temperature for years 1990-1999 based on a collection of 8 different model runs obtained from the Program for Climate Model Diagnosis and Intercomparison (PCMDI). We calibrated the surrogate model to the available model data and make various point predictions. We also analyzed average precipitation rate in June, July, and August over a 54-year period assuming a cyclic Y2K ocean model. We

  2. Consequences of high-$x$ proton size fluctuations in small collision systems at RHIC

    CERN Document Server

    McGlinchey, D; Perepelitsa, D V

    2016-01-01

    Recent measurements of jet production rates at large transverse momentum ($p_T$) in the collisions of small projectiles with large nuclei at RHIC and the LHC indicate that they have an unexpected relationship with estimates of the collision centrality. One compelling interpretation of the data is that it captures an $x_p$-dependent decrease in the average interaction strength of the nucleon in the projectile undergoing a hard scattering. A weakly interacting or "shrinking" nucleon in the projectile strikes fewer nucleons in the nucleus, resulting in a particular pattern of centrality-dependent modifications to high-$p_T$ processes. We describe a simple one-parameter geometric implementation of this picture within a modified Monte Carlo Glauber model tuned to $d$$+$Au jet data, and explore two of its major consequences. First, the model predicts a particular projectile-species dependence to the centrality dependence at high-$x_p$, opposite to that expected from an energy loss effect. Second, we find that some ...

  3. Short-term herbivory has long-term consequences in warmed and ambient high Arctic tundra

    Science.gov (United States)

    Little, Chelsea J.; Cutting, Helen; Alatalo, Juha; Cooper, Elisabeth

    2017-02-01

    Climate change is occurring across the world, with effects varying by ecosystem and region but already occurring quickly in high-latitude and high-altitude regions. Biotic interactions are important in determining ecosystem response to such changes, but few studies have been long-term in nature, especially in the High Arctic. Mesic tundra plots on Svalbard, Norway, were subjected to grazing at two different intensities by captive Barnacle geese from 2003–2005, in a factorial design with warming by Open Top Chambers. Warming manipulations were continued through 2014, when we measured vegetation structure and composition as well as growth and reproduction of three dominant species in the mesic meadow. Significantly more dead vascular plant material was found in warmed compared to ambient plots, regardless of grazing history, but in contrast to many short-term experiments no difference in the amount of living material was found. This has strong implications for nutrient and carbon cycling and could feed back into community productivity. Dominant species showed increased flowering in warmed plots, especially in those plots where grazing had been applied. However, this added sexual reproduction did not translate to substantial shifts in vegetative cover. Forbs and rushes increased slightly in warmed plots regardless of grazing, while the dominant shrub, Salix polaris, generally declined with effects dependent on grazing, and the evergreen shrub Dryas octopetala declined with previous intensive grazing. There were no treatment effects on community diversity or evenness. Thus despite no changes in total live abundance, a typical short-term response to environmental conditions, we found pronounced changes in dead biomass indicating that tundra ecosystem processes respond to medium- to long-term changes in conditions caused by 12 seasons of summer warming. We suggest that while high arctic tundra plant communities are fairly resistant to current levels of climate warming

  4. Multidrug- and Extensively Drug-Resistant Uropathogenic Escherichia coli Clinical Strains: Phylogenetic Groups Widely Associated with Integrons Maintain High Genetic Diversity

    Science.gov (United States)

    Ochoa, Sara A.; Cruz-Córdova, Ariadnna; Luna-Pineda, Victor M.; Reyes-Grajeda, Juan P.; Cázares-Domínguez, Vicenta; Escalona, Gerardo; Sepúlveda-González, Ma. Eugenia; López-Montiel, Fernanda; Arellano-Galindo, José; López-Martínez, Briceida; Parra-Ortega, Israel; Giono-Cerezo, Silvia; Hernández-Castro, Rigoberto; de la Rosa-Zamboni, Daniela; Xicohtencatl-Cortes, Juan

    2016-01-01

    In recent years, an increase of uropathogenic Escherichia coli (UPEC) strains with Multidrug-resistant (MDR) and Extensively Drug-resistant (XDR) profiles that complicate therapy for urinary tract infections (UTIs) has been observed and has directly impacted costs and extended hospital stays. The aim of this study was to determine MDR- and XDR-UPEC clinical strains, their virulence genes, their phylogenetic groups and to ascertain their relationship with integrons and genetic diversity. From a collection of 500 UPEC strains, 103 were selected with MDR and XDR characteristics. MDR-UPEC strains were mainly associated with phylogenetic groups D (54.87%) and B2 (39.02%) with a high percentage (≥70%) of several fimbrial genes (ecpA, fimH, csgA, and papGII), an iron uptake gene (chuA), and a toxin gene (hlyA). In addition, a moderate frequency (40–70%) of other genes (iutD, tosA, and bcsA) was observed. XDR-UPEC strains were predominantly associated with phylogenetic groups B2 (47.61%) and D (42.85%), which grouped with ≥80 virulence genes, including ecpA, fimH, csgA, papGII, iutD, and chuA. A moderate frequency (40–70%) of the tosA and hlyA genes was observed. The class 1 and 2 integrons that were identified in the MDR- and XDR-UPEC strains were associated with phylogenetic groups D, B2, and A, while the XDR-UPEC strains that were associated with phylogenetic groups B2, D, and A showed an extended-spectrum beta-lactamase (ESBL) phenotype. The modifying enzymes (aadA1, aadB, aacC, ant1, dfrA1, dfrA17, and aadA4) that were identified in the variable region of class 1 and 2 integrons from the MDR strains showed resistance to gentamycin (56.25 and 66.66%, respectively) and trimethoprim-sulfamethoxazole (84.61 and 66.66%, respectively). The MDR- and XDR-UPEC strains were distributed into seven clusters and were closely related to phylogenic groups B2 and D. The diversity analysis by PFGE showed 42.68% of clones of MDR-UPEC and no clonal association in the XDR

  5. High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence.

    Science.gov (United States)

    Lucas, Samuel J E; Cotter, James D; Brassard, Patrice; Bailey, Damian M

    2015-06-01

    Exercise is a uniquely effective and pluripotent medicine against several noncommunicable diseases of westernised lifestyles, including protection against neurodegenerative disorders. High-intensity interval exercise training (HIT) is emerging as an effective alternative to current health-related exercise guidelines. Compared with traditional moderate-intensity continuous exercise training, HIT confers equivalent if not indeed superior metabolic, cardiac, and systemic vascular adaptation. Consequently, HIT is being promoted as a more time-efficient and practical approach to optimize health thereby reducing the burden of disease associated with physical inactivity. However, no studies to date have examined the impact of HIT on the cerebrovasculature and corresponding implications for cognitive function. This review critiques the implications of HIT for cerebrovascular function, with a focus on the mechanisms and translational impact for patient health and well-being. It also introduces similarly novel interventions currently under investigation as alternative means of accelerating exercise-induced cerebrovascular adaptation. We highlight a need for studies of the mechanisms and thereby also the optimal dose-response strategies to guide exercise prescription, and for studies to explore alternative approaches to optimize exercise outcomes in brain-related health and disease prevention. From a clinical perspective, interventions that selectively target the aging brain have the potential to prevent stroke and associated neurovascular diseases.

  6. Cry me a river: identifying the behavioral consequences of extremely high-stakes interpersonal deception.

    Science.gov (United States)

    Ten Brinke, Leanne; Porter, Stephen

    2012-12-01

    Deception evolved as a fundamental aspect of human social interaction. Numerous studies have examined behavioral cues to deception, but most have involved inconsequential lies and unmotivated liars in a laboratory context. We conducted the most comprehensive study to date of the behavioral consequences of extremely high-stakes, real-life deception--relative to comparable real-life sincere displays--via 3 communication channels: speech, body language, and emotional facial expressions. Televised footage of a large international sample of individuals (N = 78) emotionally pleading to the public for the return of a missing relative was meticulously coded frame-by-frame (30 frames/s for a total of 74,731 frames). About half of the pleaders eventually were convicted of killing the missing person on the basis of overwhelming evidence. Failed attempts to simulate sadness and leakage of happiness revealed deceptive pleaders' covert emotions. Liars used fewer words but more tentative words than truth-tellers, likely relating to increased cognitive load and psychological distancing. Further, each of these cues explained unique variance in predicting pleader sincerity.

  7. Surety of human elements of high consequence systems: An organic model

    Energy Technology Data Exchange (ETDEWEB)

    FORSYTHE,JAMES C.; WENNER,CAREN A.

    2000-04-25

    Despite extensive safety analysis and application of safety measures, there is a frequent lament, ``Why do we continue to have accidents?'' Two breakdowns are prevalent in risk management and prevention. First, accidents result from human actions that engineers, analysts and management never envisioned and second, controls, intended to preclude/mitigate accident sequences, prove inadequate. This paper addresses the first breakdown, the inability to anticipate scenarios involving human action/inaction. The failure of controls has been addressed in a previous publication (Forsythe and Grose, 1998). Specifically, this paper presents an approach referred to as surety. The objective of this approach is to provide high levels of assurance in situations where potential system failure paths cannot be fully characterized. With regard to human elements of complex systems, traditional approaches to human reliability are not sufficient to attain surety. Consequently, an Organic Model has been developed to account for the organic properties exhibited by engineered systems that result from human involvement in those systems.

  8. Primary multidrug resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    Sarkar Supriya

    2007-01-01

    Full Text Available A 37-year old man presented at our institution with back pain, low-grade fever and weight-loss. X-ray of chest (postero-anterior view showed multiple opacities with erosion of right 2nd and left 6th ribs. CT-scan of thorax and CT-guided FNAC con-firmed the diagnosis of tuberculosis of ribs. Even after 5-months of treatment with four first line drugs, the patient developed a cold abscess at the back. Mycobacterial culture and drug sensitivity of material aspirated by Radiometric method from the cold abscess showed growth of Mycobacterium tuberculosis, and those bacilli were resistant to both isoniazide and rifampicin. The patient did not have anti-tubercu-lar medication in the past, and that established the diagnosis of primary multidrug resistant tuberculosis of ribs. Patient was treated successfully with 2nd line drugs at the cost of moderate degree of hearing loss. After one and half years of treatment X-ray of chest (PA view showed complete healing of rib erosions with new bone formation.

  9. Multidrug-Resistant TB

    Science.gov (United States)

    Cox, Helen; Coomans, Fons

    2016-01-01

    Abstract The right to enjoy the benefits of scientific progress (REBSP) is a little-known but potentially valuable right that can contribute to rights-based approaches to addressing multidrug-resistant TB (MDR-TB). We argue that better understanding of the REBSP may help to advance legal and civil society action for health rights. While the REBSP does not provide an individual entitlement to have a new drug developed for MDR-TB, it sets up entitlements to expect a state to establish a legislative and policy framework aimed at developing scientific capacity to address the most important health issues and at disseminating the outcomes of scientific research. By making scientific findings available and accessible, people can be enabled to claim the use of science for social benefits. Inasmuch as the market fails to address neglected diseases such as MDR-TB, the REBSP provides a potential counterbalance to frame a positive obligation on states to both marshal their own resources and to coordinate the actions of multiple other actors towards this goal, including non-state actors. While the latter do not hold the same level of accountability as states, the REBSP can still enable the recognition of obligations at a level of “soft law” responsibilities.

  10. Multidrug-resistant Gram-negative bacteria: a product of globalization.

    Science.gov (United States)

    Hawkey, P M

    2015-04-01

    Global trade and mobility of people has increased rapidly over the last 20 years. This has had profound consequences for the evolution and the movement of antibiotic resistance genes. There is increasing exposure of populations all around the world to resistant bacteria arising in the emerging economies. Arguably the most important development of the last two decades in the field of antibiotic resistance is the emergence and spread of extended-spectrum β-lactamases (ESBLs) of the CTX-M group. A consequence of the very high rates of ESBL production among Enterobacteriaceae in Asian countries is that there is a substantial use of carbapenem antibiotics, resulting in the emergence of plasmid-mediated resistance to carbapenems. This article reviews the emergence and spread of multidrug-resistant Gram-negative bacteria, focuses on three particular carbapenemases--imipenem carbapenemases, Klebsiella pneumoniae carbapenemase, and New Delhi metallo-β-lactamase--and highlights the importance of control of antibiotic use.

  11. Multidrug Resistance: An Emerging Crisis

    Directory of Open Access Journals (Sweden)

    Jyoti Tanwar

    2014-01-01

    Full Text Available The resistance among various microbial species (infectious agents to different antimicrobial drugs has emerged as a cause of public health threat all over the world at a terrifying rate. Due to the pacing advent of new resistance mechanisms and decrease in efficiency of treating common infectious diseases, it results in failure of microbial response to standard treatment, leading to prolonged illness, higher expenditures for health care, and an immense risk of death. Almost all the capable infecting agents (e.g., bacteria, fungi, virus, and parasite have employed high levels of multidrug resistance (MDR with enhanced morbidity and mortality; thus, they are referred to as “super bugs.” Although the development of MDR is a natural phenomenon, the inappropriate use of antimicrobial drugs, inadequate sanitary conditions, inappropriate food-handling, and poor infection prevention and control practices contribute to emergence of and encourage the further spread of MDR. Considering the significance of MDR, this paper, emphasizes the problems associated with MDR and the need to understand its significance and mechanisms to combat microbial infections.

  12. Multidrug resistance: an emerging crisis.

    Science.gov (United States)

    Tanwar, Jyoti; Das, Shrayanee; Fatima, Zeeshan; Hameed, Saif

    2014-01-01

    The resistance among various microbial species (infectious agents) to different antimicrobial drugs has emerged as a cause of public health threat all over the world at a terrifying rate. Due to the pacing advent of new resistance mechanisms and decrease in efficiency of treating common infectious diseases, it results in failure of microbial response to standard treatment, leading to prolonged illness, higher expenditures for health care, and an immense risk of death. Almost all the capable infecting agents (e.g., bacteria, fungi, virus, and parasite) have employed high levels of multidrug resistance (MDR) with enhanced morbidity and mortality; thus, they are referred to as "super bugs." Although the development of MDR is a natural phenomenon, the inappropriate use of antimicrobial drugs, inadequate sanitary conditions, inappropriate food-handling, and poor infection prevention and control practices contribute to emergence of and encourage the further spread of MDR. Considering the significance of MDR, this paper, emphasizes the problems associated with MDR and the need to understand its significance and mechanisms to combat microbial infections.

  13. Multidrug toxicity involving sumatriptan.

    Science.gov (United States)

    Knittel, Jessica L; Vorce, Shawn P; Levine, Barry; Hughes, Rhome L; Bosy, Thomas Z

    2015-01-01

    A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident.

  14. The choreography of multidrug export.

    Science.gov (United States)

    Doshi, Rupak; Gutmann, Daniel A P; Khoo, Yvonne S K; Fagg, Lisa A; van Veen, Hendrik W

    2011-06-01

    Multidrug transporters have a crucial role in causing the drug resistance that can arise in infectious micro-organisms and tumours. These integral membrane proteins mediate the export of a broad range of unrelated compounds from cells, including antibiotics and anticancer agents, thus reducing the concentration of these compounds to subtoxic levels in target cells. In spite of intensive research, it is not clear exactly how multidrug transporters work. The present review focuses on recent advancements in the biochemistry and structural biology of bacterial and human multidrug ABC (ATP-binding cassette) transporters. These advancements point to a common mechanism in which polyspecific drug-binding surfaces in the membrane domains are alternately exposed to the inside and outside surface of the membrane in response to the ATP-driven dimerization of nucleotide-binding domains and their dissociation following ATP hydrolysis.

  15. Multidrug-exporting secondary transporters.

    Science.gov (United States)

    Murakami, Satoshi; Yamaguchi, Akihito

    2003-08-01

    The major cause of intrinsic drug resistance in Gram-negative bacteria is a resistance nodulation division type multidrug exporter, which couples with an outer membrane channel and a membrane fusion protein and exports drugs out of the cell, bypassing the periplasm; this process is driven by proton motive force. A recent crystal structure determination of a major resistance nodulation division type multidrug exporter, AcrB in Escherichia coli, greatly advances our understanding of the multidrug export mechanism. The most striking feature of the AcrB trimer is the presence of three vestibules open to the periplasm at the boundary between the periplasmic headpiece and the transmembrane region. Substrates can gain access to the central cavity from the periplasmic surface of the cytoplasmic membrane and are then actively transported through the extramembrane pore into the outer membrane channel TolC, via the funnel at the top of the AcrB headpiece.

  16. Draft Genome of the Multidrug-Resistant Acinetobacter baumannii Strain A155 Clinical Isolate.

    Science.gov (United States)

    Arivett, Brock A; Fiester, Steven E; Ream, David C; Centrón, Daniela; Ramírez, Maria S; Tolmasky, Marcelo E; Actis, Luis A

    2015-03-26

    Acinetobacter baumannii is a bacterial pathogen with serious implications on human health, due to increasing reports of multidrug-resistant strains isolated from patients. Total DNA from the multidrug-resistant A. baumannii strain A155 clinical isolate was sequenced to greater than 65× coverage, providing high-quality contig assemblies.

  17. CAUSES AND CONSEQUENCES OF THE SCHOOL IN HIGH SCHOOL DROPOUT: CASE UNIVERSIDAD AUTÓNOMA DE SINALOA

    OpenAIRE

    Rosalva Ruiz-Ramírez; José Luis García-Cué; María Antonia Pérez-Olvera

    2014-01-01

    The present investigation has the objective to establish the personal, economic and social causes and consequences that create school desertion of high school in Universidad Autónoma de Sinaloa (UAS). The investigation took place in the high school located in the municipality of El Fuerte, Sinaloa, in the academic unit (UA) of San Blas and its extensions The Constancia and The Higueras of the Natoches in 2013. A mixed approach was used to analyze qualitative and quantitative information; the...

  18. Biochemistry of Bacterial Multidrug Efflux Pumps

    Directory of Open Access Journals (Sweden)

    Sanath Kumar

    2012-04-01

    Full Text Available Bacterial pathogens that are multi-drug resistant compromise the effectiveness of treatment when they are the causative agents of infectious disease. These multi-drug resistance mechanisms allow bacteria to survive in the presence of clinically useful antimicrobial agents, thus reducing the efficacy of chemotherapy towards infectious disease. Importantly, active multi-drug efflux is a major mechanism for bacterial pathogen drug resistance. Therefore, because of their overwhelming presence in bacterial pathogens, these active multi-drug efflux mechanisms remain a major area of intense study, so that ultimately measures may be discovered to inhibit these active multi-drug efflux pumps.

  19. What's new in multidrug-resistant pathogens in the ICU?

    Science.gov (United States)

    Zilahi, Gabor; Artigas, Antonio; Martin-Loeches, Ignacio

    2016-12-01

    Over the last several decades, antibacterial drug use has become widespread with their misuse being an ever-increasing phenomenon. Consequently, antibacterial drugs have become less effective or even ineffective, resulting in a global health security emergency. The prevalence of multidrug-resistant organisms (MDROs) varies widely among regions and countries. The primary aim of antibiotic stewardship programs is to supervise the three most influential factors contributing to the development and transmission of MDROs, namely: (1) appropriate antibiotic prescribing; (2) early detection and prevention of cross-colonization of MDROs; and (3) elimination of reservoirs. In the future, it is expected that a number of countries will experience a rise in MDROs. These infections will be associated with a high consumption of healthcare resources manifested by a prolonged hospital stay and high mortality. As a counteractive strategy, minimization of broad-spectrum antibiotic use and prompt antibiotic administration will aid in reduction of antibiotic resistance. Innovative management approaches include development and implementation of rapid diagnostic tests that will help in both shortening the duration of therapy and allowing early targeted therapy. The institution of more accessible therapeutic drug monitoring will help to optimize drug administration and support a patient-specific approach. Areas where further research is required are investigation into the heterogeneity of critically ill patients and the need for new antibacterial drug development.

  20. Probability, consequences, and mitigation for lightning strikes of Hanford high level waste tanks

    Energy Technology Data Exchange (ETDEWEB)

    Zach, J.J.

    1996-06-05

    The purpose of this report is to summarize selected lightning issues concerning the Hanford Waste Tanks. These issues include the probability of a lightning discharge striking the area immediately adjacent to a tank including a riser, the consequences of significant energy deposition from a lightning strike in a tank, and mitigating actions that have been or are being taken. The major conclusion of this report is that the probability of a lightning strike deposition sufficient energy in a tank to cause an effect on employees or the public is unlikely;but there are insufficient, quantitative data on the tanks and waste to prove that. Protection, such as grounding of risers and air terminals on existing light poles, is recommended.

  1. Probability, consequences, and mitigation for lightning strikes to Hanford site high-level waste tanks

    Energy Technology Data Exchange (ETDEWEB)

    Zach, J.J.

    1996-08-01

    The purpose of this report is to summarize selected lightning issues concerning the Hanford Waste Tanks. These issues include the probability of lightning discharge striking the area immediately adjacent to a tank including a riser, the consequences of significant energy deposition from a lightning strike in a tank, and mitigating actions that have been or are being taken. The major conclusion of this report is that the probability of a lightning strike depositing sufficient energy in a tank to cause an effect on employees or the public is unlikely;but there are insufficient, quantitative data on the tanks and waste to prove that. Protection, such as grounding of risers and air terminals on existing light poles, is recommended.

  2. Transformations, transport, and potential unintended consequences of high sulfur inputs to Napa Valley vineyards.

    Science.gov (United States)

    Hinckley, Eve-Lyn S; Matson, Pamela A

    2011-08-23

    Unintended anthropogenic deposition of sulfur (S) to forest ecosystems has a range of negative consequences, identified through decades of research. There has been far less study of purposeful S use in agricultural systems around the world, including the application of elemental sulfur (S(0)) as a quick-reacting fungicide to prevent damage to crops. Here we report results from a three-year study of the transformations and flows of applied S(0) in soils, vegetation, and hydrologic export pathways of Napa Valley, CA vineyards, documenting that all applied S is lost from the vineyard ecosystem on an annual basis. We found that S(0) oxidizes rapidly to sulfate ( ) on the soil surface where it then accumulates over the course of the growing season. Leaf and grape tissues accounted for only 7-13% of applied S whereas dormant season cover crops accounted for 4-10% of applications. Soil S inventories were largely and ester-bonded sulfates; they decreased from 1,623 ± 354 kg ha(-1) during the dry growing season to 981 ± 526 kg ha(-1) (0-0.5 m) during the dormant wet season. Nearly all S applied to the vineyard soils is transported offsite in dissolved oxidized forms during dormant season rainstorms. Thus, the residence time of reactive S is brief in these systems, and largely driven by hydrology. Our results provide new insight into how S use in vineyards constitutes a substantial perturbation of the S cycle in Northern California winegrowing regions and points to the unintended consequences that agricultural S use may have at larger scales.

  3. CAUSES AND CONSEQUENCES OF THE SCHOOL IN HIGH SCHOOL DROPOUT: CASE UNIVERSIDAD AUTÓNOMA DE SINALOA

    Directory of Open Access Journals (Sweden)

    Rosalva Ruiz-Ramírez

    2014-07-01

    Full Text Available The present investigation has the objective to establish the personal, economic and social causes and consequences that create school desertion of high school in Universidad Autónoma de Sinaloa (UAS. The investigation took place in the high school located in the municipality of El Fuerte, Sinaloa, in the academic unit (UA of San Blas and its extensions The Constancia and The Higueras of the Natoches in 2013. A mixed approach was used to analyze qualitative and quantitative information; the studied population was 18 women and 17 men deserters of the school cycle 2011-2012, ten teachers, four directors and twenty non-deserting students. In the results one can see that the principal factor for school desertion was the personnel to be married and not approving classes. The main consequence was economic, highlighting that the poverty cycle is hard to break.

  4. A New Method to Generate the Complete Set of Unique Signals for Application in High Consequence System

    Institute of Scientific and Technical Information of China (English)

    TAN Shun-yi; CHEN Wen-yuan; ZHANG Wei-ping; FENG Min-hua; LI Sheng-yong

    2007-01-01

    This paper proposed a new method to generate the complete sets of unique signals. It contains sequences comparing, improved exhaustive searches and ranking method. Characters of this new method are complete set;higher effective ;independent of certain mathematical constraints. And also some 24 bi-valued events sets generated by this method were discussed and these set are now used in our high consequence system.

  5. Expression of the human multidrug transporter in insect cells by a recombinant baculovirus

    Energy Technology Data Exchange (ETDEWEB)

    Germann, U.A.; Willingham, M.C.; Pastan, I.; Gottesman, M.M. (National Institutes of Health, Bethesda, MD (USA))

    1990-03-06

    The plasma membrane associated human multidrug resistance (MDR1) gene product, known as the 170-kDa P-glycoprotein or the multidrug transporter, acts as an ATP-dependent efflux pump for various cytotoxic agents. The authors expressed recombinant human multidrug transporter in a baculovirus expression system to obtain large quantities and further investigate its structure and mechanism of action. MDR1 cDNA was inserted into the genome of the Autographa californica nuclear polyhedrosis virus under the control of the polyhedrin promoter. Spodoptera frugiperda insect cells synthesized high levels of recombinant multidrug transporter 2-3 days after infection. The transporter was localized by immunocytochemical methods on the external surface of the plasma membranes, in the Golgi apparatus, and within the nuclear envelope. The human multidrug transporter expressed in insect cells is not susceptible to endoglycosidase F treatment and has a lower apparent molecular weight of 140,000, corresponding to the nonglycosylated precursor of its authentic counterpart expressed in multidrug-resistant cells. Labeling experiments showed that the recombinant multidrug transporter is phosphorylated and can be photoaffinity labeled by ({sup 3}H)azidopine, presumably at the same two sites as the native protein. Various drugs and reversing agents compete with the ({sup 3}H)azidopine binding reaction when added in excess, indicating that the recombinant human multidrug transporter expressed in insect cells is functionally similar to its authentic counterpart.

  6. 2-Pyrrolinodoxorubicin and its peptide-vectorized form bypass multidrug resistance.

    Science.gov (United States)

    Castex, Cédric; Merida, Peggy; Blanc, Emmanuelle; Clair, Philippe; Rees, Anthony R; Temsamani, Jamal

    2004-07-01

    A well-known mechanism leading to the emergence of multidrug-resistant tumor cells is the overexpression of P-glycoprotein, which is capable of lowering intracellular drug concentrations. In the present study, we tested the capability of 2-pyrrolinodoxorubicin (p-DOX), a highly potent derivative of DOX, to bypass multidrug resistance. The accumulation, intracellular distribution and cytotoxicity of p-DOX were tested in two cell lines (K562 and A2780) and their DOX-resistant counterparts (K562/ADR and A2780/ADR). Cellular accumulation and cytotoxicity were dramatically lowered for DOX in resistant cell lines, in comparison with non-resistant cells. In contrast, cellular accumulation, intracellular distribution and cytotoxicity of p-DOX were independent of the nature of the cell lines. The p-DOX showed potent dose-dependent inhibition of cell growth against resistant cells as compared with DOX. After treatment of resistant cells with verapamil, the intracellular levels of DOX were markedly increased and consequent cytotoxicity improved. In contrast, treatment of resistant cells with verapamil did not cause any further enhancement of cell uptake or an increase in the cytotoxic effect of the derivative p-DOX, indicating that the compound bypasses the P-glycoprotein. Finally, we show that vectorization of p-DOX by a peptide vector (SynB3) which has been shown to enhance the brain uptake of DOX and to decrease its heart accumulation does not affect this property. These results indicate that p-DOX and its vectorized form are potent and effective in overcoming multidrug resistance.

  7. The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation

    Directory of Open Access Journals (Sweden)

    Yann ePelloux

    2014-12-01

    Full Text Available The subthalamic nucleus (STN belongs to the basal ganglia and is the current target for the surgical treatment of neurological and psychiatric disorders such as Parkinson’s Disease (PD and obsessive compulsive disorders, but also a proposed site for the treatment of addiction. It is therefore very important to understand its functions in order to anticipate and prevent possible side-effects in the patients. Although the involvement of the STN is well documented in motor, cognitive and motivational processes, less is known regarding emotional processes. Here we have investigated the direct consequences of STN inactivation by excitotoxic lesions on emotional processing and reinforcement in the rat. We have used various behavioral procedures to assess affect for neutral, positive and negative reinforcers in STN lesioned rats. STN lesions reduced affective responses for positive (sweet solutions and negative (electric foot shock, Lithium Chloride-induced sickness reinforcers while they had no effect on responses for a more neutral reinforcer (novelty induced place preference. Furthermore, when given the choice between saccharine, a sweet but non caloric solution, and glucose, a more bland but caloric solution, in contrast to sham animals that preferred saccharine, STN lesioned animals preferred glucose over saccharine. Taken altogether these results reveal that STN plays a critical role in emotional processing. These results, in line with some clinical observations in PD patients subjected to STN surgery, suggest possible emotional side-effects of treatments targeting the STN. They also suggest that the increased motivation for sucrose previously reported cannot be due to increased pleasure, but could be responsible for the decreased motivation for cocaine reported after STN inactivation.

  8. Effects of mefloquine use on Plasmodium vivax multidrug resistance.

    Science.gov (United States)

    Khim, Nimol; Andrianaranjaka, Voahangy; Popovici, Jean; Kim, Saorin; Ratsimbasoa, Arsene; Benedet, Christophe; Barnadas, Celine; Durand, Remy; Thellier, Marc; Legrand, Eric; Musset, Lise; Menegon, Michela; Severini, Carlo; Nour, Bakri Y M; Tichit, Magali; Bouchier, Christiane; Mercereau-Puijalon, Odile; Ménard, Didier

    2014-10-01

    Numerous studies have indicated a strong association between amplification of the multidrug resistance-1 gene and in vivo and in vitro mefloquine resistance of Plasmodium falciparum. Although falciparum infection usually is not treated with mefloquine, incorrect diagnosis, high frequency of undetected mixed infections, or relapses of P. vivax infection triggered by P. falciparum infections expose non-P. falciparum parasites to mefloquine. To assess the consequences of such unintentional treatments on P. vivax, we studied variations in number of Pvmdr-1 (PlasmoDB accession no. PVX_080100, NCBI reference sequence NC_009915.1) copies worldwide in 607 samples collected in areas with different histories of mefloquine use from residents and from travelers returning to France. Number of Pvmdr-1 copies correlated with drug use history. Treatment against P. falciparum exerts substantial collateral pressure against sympatric P. vivax, jeopardizing future use of mefloquine against P. vivax. A drug policy is needed that takes into consideration all co-endemic species of malaria parasites.

  9. Loss of genetic diversity as a consequence of selection in response to high pCO 2

    OpenAIRE

    Lloyd, Melanie M.; Makukhov, April D.; Pespeni, Melissa H.

    2016-01-01

    Abstract Standing genetic variation may allow for rapid evolutionary response to the geologically unprecedented changes in global conditions. However, there is little known about the consequences of such rapid evolutionary change. Here, we measure genetic responses to experimental low and high pCO 2 levels in purple sea urchin larvae, Strongylocentrotus purpuratus. We found greater loss of nucleotide diversity in high pCO 2 levels (18.61%; 900 μatm) compared to low pCO 2 levels (10.12%; 400 μ...

  10. EMBRYONIC VASCULAR DISRUPTION ADVERSE OUTCOMES: LINKING HIGH THROUGHPUT SIGNALING SIGNATURES WITH FUNCTIONAL CONSEQUENCES

    Science.gov (United States)

    Embryonic vascular disruption is an important adverse outcome pathway (AOP) given the knowledge that chemical disruption of early cardiovascular system development leads to broad prenatal defects. High throughput screening (HTS) assays provide potential building blocks for AOP d...

  11. Multidrug-resistant Mycoplasma genitalium infections in Europe.

    Science.gov (United States)

    Braam, J F; van Dommelen, L; Henquet, C J M; van de Bovenkamp, J H B; Kusters, J G

    2017-03-30

    In Japan and Australia, multidrug-resistant Mycoplasma genitalium infections are reported with increasing frequency. Although macrolide-resistant M. genitalium strains are common in Europe and North America, fluoroquinolone-resistant strains are still exceptional. However, an increase of multidrug-resistant M. genitalium in Europe and America is to be expected. The aim of this paper is to increase awareness on the rising number of multidrug-resistant M. genitalium strains. Here, one of the first cases of infection with a genetically proven multidrug-resistant M. genitalium strain in Europe is described. The patient was a native Dutch 47-year-old male patient with urethritis. Mycoplasma genitalium was detected, but treatment failed with azithromycin, doxycycline and moxifloxacin. A urogenital sample was used to determine the sequence of the 23S rRNA, gyrA, gyrB and parC genes. The sample contained an A2059G single nucleotide polymorphism (SNP) in the 23S rRNA gene and an SNP in the parC gene, resulting in an amino acid change of Ser83 → Ile, explaining both azithromycin and moxifloxacin treatment failure. The SNPs associated with resistance were probably generated de novo, as a link with high-prevalence areas was not established. It is, thus, predictable that there is going to be an increase of multidrug-resistant M. genitalium strains in Europe. As treatment options for multidrug-resistant M. genitalium are limited, the treatment of M. genitalium infections needs to be carefully considered in order to limit the rapid increase of resistance to macrolides and fluoroquinolones.

  12. Antimicrobial activity of peptidomimetics against multidrug-resistant Escherichia coli

    DEFF Research Database (Denmark)

    Jahnsen, Rasmus D; Frimodt-Møller, Niels; Franzyk, Henrik

    2012-01-01

    -lactamase-producing Escherichia coli was assessed by testing an array comprising different types of cationic peptidomimetics obtained by a general monomer-based solid-phase synthesis protocol. Most of the peptidomimetics possessed high to moderate activity toward multidrug-resistant E. coli as opposed to the corresponding...

  13. Carriage and transmission dynamics of multidrug-resistant Enterobacteriaceae

    NARCIS (Netherlands)

    Haverkate, M.R.

    2015-01-01

    Antimicrobial-resistant bacteria cause big problems in health care. Infections with these bacteria are hard to treat and lead to high morbidity, mortality, and costs. In this PhD thesis, carriage and transmission dynamics of multidrug-resistant Enterobacteriaceae have been investigated in various se

  14. High Rate of Multidrug-Resistant Gram-Negative Bacilli Carriage and Infection in Hospitalized Returning Travelers: A Cross-Sectional Cohort Study.

    Science.gov (United States)

    Epelboin, Loïc; Robert, Jérôme; Tsyrina-Kouyoumdjian, Ellina; Laouira, Sonia; Meyssonnier, Vanina; Caumes, Eric

    2015-01-01

    Carriage of and infection with multidrug-resistant Gram-negative bacilli (MDR-GNB) are a potential cause of concern in travelers with no history of hospitalization abroad. All consecutive returning travelers hospitalized in our department between February 2012 and January 2013 were prospectively screened for MDR-GNB gastrointestinal tract carriage or infection. We compared the prevalence of MDR-GNB in travelers to a non-travelers nonexposed group. Then among the travelers, MDR-GNB carriers were compared to noncarriers to determine risk factors of acquisition of MDR-GNB. Overall, 359 patients (191 travelers, 168 non-travelers) were included, and 25 (6.4%), including 23 travelers, harbored MDR-GNB. Five travelers had an MDR-GNB infection while 18 were asymptomatic enteric carriers. MDR-GNB carriage or infection was significantly more frequent in travelers (11.0% vs 1.2% for non-travelers, odds ratio (OR) = 11.3, p < 0.001) and in patients born outside France (OR = 1.67; p = 0.03). Among travelers, in multivariate analysis, factors independently associated with MDR-GNB carriage or infection were traveling to Asia (OR = 3.1; p = 0.01) and visiting friends and relatives (VFR) or migrants (OR=3.6; p = 0.01). The 10-fold higher prevalence rate of MDR-GNB in travelers raises the issues of systematic screening of all travelers, and of the choice of first line antibiotic therapy when treating urinary tract infections in travelers, especially those VFR, migrants, and those returning from Asia. © 2015 International Society of Travel Medicine.

  15. Permissive and Non-permissive Hypercapnia: Mechanisms of Action and Consequences of High Carbon Dioxide Levels

    Science.gov (United States)

    Briva, Arturo; Lecuona, Emilia; Sznajder, Jacob I.

    2013-01-01

    Acute lung injury is a disease with high mortality, which affects a large numbers of patients whose treatment continues to be debated. It has recently been postulated that hypercapnia can attenuate the inflammatory response during lung injury, which would assign it a specific role within lung protection strategies during mechanical ventilation. In this paper, we review current evidence on the role that high levels of CO2 in the blood play in lung injury. We conclude that, although there are reports that show benefits, the most recent evidence suggests that hypercapnia can be harmful and can contribute to worsening lung damage. PMID:20303638

  16. Experimental Consequences of Mottness in High-Temperature Copper-Oxide Superconductors

    Science.gov (United States)

    Chakraborty, Shiladitya

    2009-01-01

    It has been more than two decades since the copper-oxide high temperature superconductors were discovered. However, building a satisfactory theoretical framework to study these compounds still remains one of the major challenges in condensed matter physics. In addition to the mechanism of superconductivity, understanding the properties of the…

  17. Portal hypertension in children: High-risk varices, primary prophylaxis and consequences of bleeding.

    Science.gov (United States)

    Duché, Mathieu; Ducot, Béatrice; Ackermann, Oanez; Guérin, Florent; Jacquemin, Emmanuel; Bernard, Olivier

    2017-02-01

    Primary prophylaxis of bleeding is debated for children with portal hypertension because of the limited number of studies on its safety and efficacy, the lack of a known endoscopic pattern carrying a high-risk of bleeding for all causes, and the assumption that the mortality of a first bleed is low. We report our experience with these issues. From 1989 to 2014, we managed 1300 children with portal hypertension. Endoscopic features were recorded; high-risk varices were defined as: grade 3 esophageal varices, grade 2 varices with red wale markings, or gastric varices. Two hundred forty-six children bled spontaneously and 182 underwent primary prophylaxis. The results of primary prophylaxis were reviewed as well as bleed-free survival, overall survival and life-threatening complications of bleeding. High-risk varices were found in 96% of children who bled spontaneously and in 11% of children who did not bleed without primary prophylaxis (phypertension. Life-threatening complications of bleeding were recorded in 19% of children with cirrhosis and high-risk varices who bled spontaneously. Ten-year probabilities of bleed-free survival after primary prophylaxis in children with high-risk varices were 96% and 72% for non-cirrhotic causes and cirrhosis respectively. Ten-year probabilities of overall survival after primary prophylaxis were 100% and 93% in children with non-cirrhotic causes and cirrhosis respectively. In children with portal hypertension, bleeding is linked to the high-risk endoscopic pattern reported here. Primary prophylaxis of bleeding based on this pattern is fairly effective and safe. In children with liver disease, the risk of bleeding from varices in the esophagus is linked to their large size, the presence of congestion on their surface and their expansion into the stomach but not to the child's age nor to the cause of portal hypertension. Prevention of the first bleed in children with high-risk varices can be achieved by surgery or endoscopic

  18. High Risk Behaviors in Marine Mammals: Linking Behavioral Responses to Anthropogenic Disturbance to Biological Consequences

    Science.gov (United States)

    2015-09-30

    attributes of each species that are associated with susceptibility to acoustically mediated disturbance and tissue damage. Furthermore, by identifying high... mediated trauma, 1) tissue/whole animal/physiological exercise assessments to determine the impact of behavioral and environmental challenges to the...susceptibility to acoustically mediated disturbance and tissue damage. This will subsequently allow us to achieve our overall goal of enabling Navy personnel

  19. Chemical interferences when using high gradient magnetic separation for phosphate removal: consequences for lake restoration.

    Science.gov (United States)

    de Vicente, I; Merino-Martos, A; Guerrero, F; Amores, V; de Vicente, J

    2011-09-15

    A promising method for lake restoration is the treatment of lake inlets through the specific adsorption of phosphate (P) on strongly magnetizable particles (Fe) and their subsequent removal using in-flow high gradient magnetic separation (HGMS) techniques. In this work, we report an extensive investigation on the chemical interferences affecting P removal efficiencies in natural waters from 20 Mediterranean ponds and reservoirs. A set of three treatments were considered based on different Fe particles/P concentration ratios. High P removal efficiencies (>80%) were found in freshwater lakes (conductivities<600 μ S cm(-1)). However, a significant reduction in P removal was observed for extremely high mineralized waters. Correlation analysis showed that major cations (Mg(2+), Na(+) and K(+)) and anions (SO(4)(2-) and Cl(-)) played an essential role in P removal efficiency. Comparison between different treatments have shown that when increasing P and Fe concentrations at the same rate or when increasing Fe concentrations for a fixed P concentration, there exist systematic reductions in the slope of the regression lines relating P removal efficiency and the concentration of different chemical variables. These results evidence a general reduction in the chemical competition between P and other ions for adsorption sites on Fe particles. Additional analyses also revealed a reduction in water color, dissolved organic carbon (DOC) and reactive silicate (Si) concentrations with the addition of Fe microparticles.

  20. The consequences of high cigarette excise taxes for low-income smokers.

    Directory of Open Access Journals (Sweden)

    Matthew C Farrelly

    Full Text Available BACKGROUND: To illustrate the burden of high cigarette excise taxes on low-income smokers. METHODOLOGY/PRINCIPAL FINDINGS: Using data from the New York and national Adult Tobacco Surveys from 2010-2011, we estimated how smoking prevalence, daily cigarette consumption, and share of annual income spent on cigarettes vary by annual income (less than $30,000; $30,000-$59,999; and more than $60,000. The 2010-2011 sample includes 7,536 adults and 1,294 smokers from New York and 3,777 adults and 748 smokers nationally. Overall, smoking prevalence is lower in New York (16.1% than nationally (22.2% and is strongly associated with income in New York and nationally (P<.001. Smoking prevalence ranges from 12.2% to 33.7% nationally and from 10.1% to 24.3% from the highest to lowest income group. In 2010-2011, the lowest income group spent 23.6% of annual household income on cigarettes in New York (up from 11.6% in 2003-2004 and 14.2% nationally. Daily cigarette consumption is not related to income. CONCLUSIONS/SIGNIFICANCE: Although high cigarette taxes are an effective method for reducing cigarette smoking, they can impose a significant financial burden on low-income smokers.

  1. Effects of strength training on muscle fiber types and size; consequences for athletes training for high-intensity sport

    DEFF Research Database (Denmark)

    Andersen, J L; Aagaard, P

    2010-01-01

    of the muscle and finally how will this affect the performance of the athlete. In addition, the review will deal with muscle hypertrophy and how it develops with strength training. Overall, it is not the purpose of this review to give a comprehensive up-date of the area, but to pin-point a few issues from which...... way into almost all sports in which high intense work is conducted. In this review we will focus on a few selected aspects and consequences of strength training; namely what effects do strength training have of muscle fiber type composition, and how may these effects change the contractile properties...

  2. Key drivers and economic consequences of high-end climate scenarios: uncertainties and risks

    DEFF Research Database (Denmark)

    Halsnæs, Kirsten; Kaspersen, Per Skougaard; Drews, Martin

    2015-01-01

    of extreme events and damage costs is developed and applied to a case study of urban flooding for the medium sized Danish city of Odense. Moving from our current climate to higher atmospheric greenhouse gas (GHG) concentrations including a 2°, 4°, and a high-end 6°C scenario implies that the frequency...... of extreme events increase beyond scaling, and in combination with economic assumptions we find a very wide range of risk estimates for urban precipitation events. A sensitivity analysis addresses 32 combinations of climate scenarios, damage cost curve approaches, and economic assumptions, including risk...... in determining the risks of extreme climate events and, thereby, of the level of cost-effective adaptation seen from the society’s point of view....

  3. Consequences of bursty star formation on galaxy observables at high redshifts

    CERN Document Server

    Domínguez, Alberto; Brooks, Alyson M; Christensen, Charlotte R; Bruzual, Gustavo; Stark, Daniel P; Alavi, Anahita

    2014-01-01

    The star formation histories (SFHs) of dwarf galaxies are thought to be bursty, with large -- order of magnitude -- changes in the star formation rate on timescales similar to O-star lifetimes. As a result, the standard interpretations of many galaxy observables (which assume a slowly varying SFH) are often incorrect. Here we use the SFHs from hydro-dynamical simulations to investigate the effects of bursty SFHs on sample selection and interpretation of observables and make predictions to confirm such SFHs in future surveys. First, because dwarf galaxies' star formation rates change rapidly, the mass-to-light ratio is also changing rapidly in both the ionizing continuum and, to a lesser extent, the non-ionizing UV continuum. Therefore, flux limited surveys are highly biased toward selecting galaxies in the burst phase and very deep observations are required to detect all dwarf galaxies at a given stellar mass. Second, we show that a $\\log_{10}[\

  4. High CO₂ and marine animal behaviour: potential mechanisms and ecological consequences.

    Science.gov (United States)

    Briffa, Mark; de la Haye, Kate; Munday, Philip L

    2012-08-01

    Exposure to pollution and environmental change can alter the behaviour of aquatic animals and here we review recent evidence that exposure to elevated CO₂ and reduced sea water pH alters the behaviour of tropical reef fish and hermit crabs. Three main routes through which behaviour might be altered are discussed; elevated metabolic load, 'info-disruption' and avoidance behaviour away from polluted locations. There is clear experimental evidence that exposure to high CO₂ disrupts the ability to find settlement sites and shelters, the ability to detect predators and the ability to detect prey and food. In marine vertebrates and marine crustaceans behavioural change appears to occur via info-disruption. In hermit crabs and other crustaceans impairment of performance capacities might also play a role. We discuss the implications for such behavioural changes in terms of potential impacts at the levels of population health and ecosystem services, and consider future directions for research.

  5. Uremic anorexia: a consequence of persistently high brain serotonin levels? The tryptophan/serotonin disorder hypothesis.

    Science.gov (United States)

    Aguilera, A; Selgas, R; Codoceo, R; Bajo, A

    2000-01-01

    Anorexia is a frequent part of uremic syndrome, contributing to malnutrition in dialysis patients. Many factors have been suggested as responsible for uremic anorexia. In this paper we formulate a new hypothesis to explain the appetite disorders in dialysis patients: "the tryptophan/serotonin disorder hypothesis." We review current knowledge of normal hunger-satiety cycle control and the disorders described in uremic patients. There are four phases in food intake regulation: (1) the gastric phase, during which food induces satiety through gastric distention and satiety peptide release; (2) the post absorptive phase, during which circulating compounds, including glucose and amino acids, cause satiety by hepatic receptors via the vagus nerve; (3) the hepatic phase, during which adenosine triphosphate (ATP) concentration is the main stimulus inducing hunger or satiety, with cytokines inhibiting ATP production; and (4) the central phase, during which appetite is regulated through peripheral (circulating plasma substances and neurotransmitters) and brain stimuli. Brain serotonin is the final target for peripheral mechanisms controlling appetite. High brain serotonin levels and a lower serotonin/dopamine ratio cause anorexia. Plasma and brain amino acid concentrations are recognized factors involved in neurotransmitter synthesis and appetite control. Tryptophan is the substrate of serotonin synthesis. High plasma levels of anorectics such as tryptophan (plasma and brain), cholecystokinin, tumor necrosis factor alpha, interleukin-1, and leptin, and deficiencies of nitric oxide and neuropeptide Y have been described in uremia; all increase intracerebral serotonin. We suggest that brain serotonin hyperproduction due to a uremic-dependent excess of tryptophan may be the final common pathway involved in the genesis of uremic anorexia. Various methods of ameliorating anorexia by decreasing the central effects of serotonin are proposed.

  6. Bacterial multidrug resistance mediated by a homologue of the human multidrug transporter P-glycoprotein

    NARCIS (Netherlands)

    Konings, WN; Poelarends, GJ

    2002-01-01

    Most ATP-binding cassette (ABC) multidrug transporters known to date are of eukaryotic origin, such as the P-glycoproteins (Pgps) and multidrug resistance-associated proteins (MRPs). Only one well-characterized ABC multidrug transporter, LmrA, is of bacterial origin. On the basis of its structural a

  7. On the value of aiming high: the causes and consequences of ambition.

    Science.gov (United States)

    Judge, Timothy A; Kammeyer-Mueller, John D

    2012-07-01

    Ambition is a commonly mentioned but poorly understood concept in social science research. We sought to contribute to understanding of the concept by developing and testing a model in which ambition is a middle-level trait (Cantor, 1990)-predicted by more distal characteristics but, due to its teleological nature, more proximally situated to predict career success. A 7-decade longitudinal sample of 717 high-ability individuals from the Terman life-cycle study (Terman, Sears, Cronbach, & Sears, 1989) was used in the current study. Results indicated that ambition was predicted by individual differences-conscientiousness, extraversion, neuroticism, and general mental ability-and a socioeconomic background variable: parents' occupational prestige. Ambition, in turn, was positively related to educational attainment, occupation prestige, and income. Ambition had significant total effects with all of the endogenous variables except mortality. Overall, the results support the thesis that ambition is a middle-level trait-related to but distinct from more distal individual difference variables-that has meaningful effects on career success.

  8. SIM and PALM: high-resolution microscopy methods and their consequences for cell biology

    Science.gov (United States)

    Krampert, Gerhard; Kleppe, Ingo; Kalkbrenner, Thomas; Weisshart, Klaus; Wolleschensky, Ralf; Kempe, Michael

    2010-04-01

    The diffraction limit in traditional fluorescence microscopy (approximately 200 and 600 nanometers in lateral and axial directions, respectively) has restricted the applications in bio-medical research. However, over the last 10 years various techniques have emerged to overcome this limit. Each of these techniques has its own characteristics that influence its application in biology. This paper will show how two of the techniques, Structured Illumination Microscopy (SIM) and PhotoActivated Localization Microscopy (PALM), complement each other in imaging of biological samples beyond the resolution of classical widefield fluorescence microscopy. As a reference the properties of two well known standard imaging techniques in this field, confocal Laser Scanning Microscopy (LSM) and Total Internal Reflection (TIRF) microscopy, are compared to the properties of the two high resolution techniques. Combined SIM/PALM imaging allows the extremely accurate localization of individual molecules within the context of various fluorescent structures already resolved in 3D with a resolution of up to 100nm using SIM. Such a combined system provides the biologist with an unprecedented view of the sub-cellular organization of life.

  9. Consequences of brief exposure to high concentrations of carbon monoxide in conscious rats.

    Science.gov (United States)

    Gu, Zengfa; Januszkiewicz, Adolph J; Mayorga, Maria A; Coleman, Gary D; Morrissette, Craig R

    2005-12-01

    Exposure to high-concentration carbon monoxide (CO) is of concern in military operations. Experimentally, the physiologic manifestations of a brief exposure to elevated levels of CO have not been fully described. This study investigated the development of acute CO poisoning in conscious male Sprague-Dawley rats (220-380 g). Animals were randomly grouped (n = 6) and exposed to either air or 1 of 6 CO concentrations (1000, 3000, 6000, 10,000, 12,000, or 24,000 ppm) in a continuous air/CO dynamic exposure chamber for 5 min. Respiration was recorded prior to and during exposures. Mixed blood carboxyhemoglobin (COHb) and pH were measured before and immediately after exposure. Before exposure the mean baselines of respiratory minute volumes (RMVs) were 312.6 +/- 43.9, 275.2 +/- 40.8, and 302.3 +/- 39.1 ml/min for the 10,000, 12,000 and 24,000 ppm groups, respectively. In the last minute of exposure RMVs were 118.9 +/- 23.7, 62.1 +/- 10.4, and 22.0 +/- 15.1% (p 82%. Blood pH was unaltered and no death occurred in rats exposed to CO at concentrations 10,000 ppm for brief periods as short as 5 min may change RMV, resulting in acute respiratory failure, acidemia, and even death.

  10. Behavioral and cellular consequences of high-electrode count Utah Arrays chronically implanted in rat sciatic nerve

    Science.gov (United States)

    Wark, H. A. C.; Mathews, K. S.; Normann, R. A.; Fernandez, E.

    2014-08-01

    Objective. Before peripheral nerve electrodes can be used for the restoration of sensory and motor functions in patients with neurological disorders, the behavioral and histological consequences of these devices must be investigated. These indices of biocompatibility can be defined in terms of desired functional outcomes; for example, a device may be considered for use as a therapeutic intervention if the implanted subject retains functional neurons post-implantation even in the presence of a foreign body response. The consequences of an indwelling device may remain localized to cellular responses at the device-tissue interface, such as fibrotic encapsulation of the device, or they may affect the animal more globally, such as impacting behavioral or sensorimotor functions. The objective of this study was to investigate the overall consequences of implantation of high-electrode count intrafascicular peripheral nerve arrays, High Density Utah Slanted Electrode Arrays (HD-USEAs; 25 electrodes mm-2). Approach. HD-USEAs were implanted in rat sciatic nerves for one and two month periods. We monitored wheel running, noxious sensory paw withdrawal reflexes, footprints, nerve morphology and macrophage presence at the tissue-device interface. In addition, we used a novel approach to contain the arrays in actively behaving animals that consisted of an organic nerve wrap. A total of 500 electrodes were implanted across all ten animals. Main results. The results demonstrated that chronic implantation (⩽8 weeks) of HD-USEAs into peripheral nerves can evoke behavioral deficits that recover over time. Morphology of the nerve distal to the implantation site showed variable signs of nerve fiber degeneration and regeneration. Cytology adjacent to the device-tissue interface also showed a variable response, with some electrodes having many macrophages surrounding the electrodes, while other electrodes had few or no macrophages present. This variability was also seen along the length

  11. ABC multidrug transporters in schistosomes and other parasitic flatworms.

    Science.gov (United States)

    Greenberg, Robert M

    2013-12-01

    Schistosomiasis, a neglected tropical disease affecting hundreds of millions, is caused by parasitic flatworms of the genus Schistosoma. Treatment and control of schistosomiasis relies almost exclusively on a single drug, praziquantel (PZQ), a dangerous situation for a disease of this magnitude. Though PZQ is highly effective overall, it has drawbacks, and reports of worms showing PZQ resistance, either induced in the laboratory or isolated from the field, are disconcerting. Multidrug transporters underlie multidrug resistance (MDR), a phenomenon in which resistance to a single drug is accompanied by unexpected cross-resistance to several structurally unrelated compounds. Some of the best studied multidrug transporters are members of the ancient and very large ATP-binding cassette (ABC) superfamily of efflux transporters. ABC multidrug transporters such as P-glycoprotein (Pgp; ABCB1) are also associated with drug resistance in parasites, including helminths such as schistosomes. In addition to their association with drug resistance, however, ABC transporters also function in a wide variety of physiological processes in metazoans. In this review, we examine recent studies that help define the role of schistosome ABC transporters in regulating drug susceptibility, and in normal schistosome physiology, including reproduction and excretory activity. We postulate that schistosome ABC transporters could be useful targets for compounds that enhance the effectiveness of current therapeutics as well as for agents that act as antischistosomals on their own.

  12. Effects of strength training on muscle fiber types and size; consequences for athletes training for high-intensity sport

    DEFF Research Database (Denmark)

    Andersen, J L; Aagaard, P

    2010-01-01

    Training toward improving performance in sports involving high intense exercise can and is done in many different ways based on a mixture of tradition in the specific sport, coaches' experience and scientific recommendations. Strength training is a form of training that now-a-days have found its...... way into almost all sports in which high intense work is conducted. In this review we will focus on a few selected aspects and consequences of strength training; namely what effects do strength training have of muscle fiber type composition, and how may these effects change the contractile properties...... of the muscle and finally how will this affect the performance of the athlete. In addition, the review will deal with muscle hypertrophy and how it develops with strength training. Overall, it is not the purpose of this review to give a comprehensive up-date of the area, but to pin-point a few issues from which...

  13. Differential expression of sphingolipids in P-glycoprotein or multidrug resistance-related protein 1 expressing human neuroblastoma cell lines

    NARCIS (Netherlands)

    Dijkhuis, AJ; Douwes, J; Kamps, W; Sietsma, H; Kok, JW

    2003-01-01

    The sphingolipid composition and multidrug resistance status of three human neuroblastoma cell lines were established. SK-N-FI cells displayed high expression and functional (efflux) activity of P-glycoprotein, while multidrug resistance-related protein 1 was relatively abundant and most active in S

  14. Are all drug addicts impulsive? Effects of antisociality and extent of multidrug use on cognitive and motor impulsivity.

    Science.gov (United States)

    Vassileva, Jasmin; Gonzalez, Raul; Bechara, Antoine; Martin, Eileen M

    2007-12-01

    The purpose of this investigation was to examine the influence of antisociality and extent of multidrug use on cognitive and motor impulsivity among substance-dependent individuals (SDIs) that used primarily cocaine and/or heroin. One hundred currently abstinent male SDIs participated in the study. Extent of multidrug use and degree of antisociality, assessed with the Socialization Scale of the California Psychological Inventory (So-CPI), were used to classify participants into one of four groups: high antisocial/low multidrug use, high antisocial/high multidrug use, low antisocial/low multidrug use, and low antisocial/high multidrug use. All subjects completed the Iowa Gambling Task to assess cognitive impulsivity and the Stroop Task to measure motor impulsivity. Contrary to expectations, antisociality was associated with more advantageous performance on the Iowa Gambling Task, independent of extent of multidrug use. In contrast, greater multidrug use was associated with general psychomotor slowing on the Stroop Task. Results suggest that a subclinical form of antisociality may have a paradoxically facilitating effect on decision-making and cognitive impulsivity among SDIs.

  15. Differential expression of sphingolipids in P-glycoprotein or multidrug resistance-related protein 1 expressing human neuroblastoma cell lines

    NARCIS (Netherlands)

    Dijkhuis, AJ; Douwes, J; Kamps, W; Sietsma, H; Kok, JW

    2003-01-01

    The sphingolipid composition and multidrug resistance status of three human neuroblastoma cell lines were established. SK-N-FI cells displayed high expression and functional (efflux) activity of P-glycoprotein, while multidrug resistance-related protein 1 was relatively abundant and most active in

  16. Actual directions in study of ecological consequences of a highly toxic 1,1-dimethylhydrazine-based rocket fuel spills

    Directory of Open Access Journals (Sweden)

    Bulat Kenessov

    2012-05-01

    Full Text Available The paper represents a review of the actual directions in study of ecological consequences of highly toxic 1,1-dimethylhydrazine-based rocket fuel spills. Recent results on study of processes of transformation of 1,1-dimethylhydrazine, identification of its main metabolites and development of analytical methods for their determination are generalized. Modern analytical methods of determination of 1,1-dimethylhydrazine and its transformation products in environmental samples are characterized. It is shown that in recent years, through the use of most modern methods of physical chemical analysis and sample preparation, works in this direction made significant progress and contributed to the development of studies in adjacent areas. A character of distribution of transformation products in soils of fall places of first stages of rocket-carriers is described and the available methods for their remediation are characterized.

  17. Radioiodinated agents for imaging multidrug resistant tumors.

    Science.gov (United States)

    Kortylewicz, Zbigniew P; Augustine, Ann M; Nearman, Jessica; McGarry, Jonathon; Baranowska-Kortylewicz, Janina

    2009-03-01

    Diagnostic agents enabling characterization of multidrug resistance (MDR) in tumors can aid in the selection of chemotherapy regimens. We report here synthesis and evaluation of radiopharmaceuticals based on the second-generation MDR-reversing drug MS-209. 5-[3-{4-(2-Phenyl-2-(4'-[(125)I]iodo-phenyl)acetyl)piperazin-1-yl}-2-hydroxypropoxy]quino-line (17) was prepared from the 4'-tributylstannyl precursor (16) in >95% radiochemical yield. (16) was synthesized in a six-step process with the overall yield of 25%. In vitro studies were conducted in MES-SA (drug-sensitive) and MES-SA/Dx5 (MDR) human uterine sarcoma cell lines. In vivo studies were performed in athymic mice bearing MES-SA and MES-SA/Dx5 xenografts. The uptake of (17) is higher in MES-SA than MES-SA/Dx5 cells. The uptake and efflux of (17) depend on temperature and concentration, and indicate active transport mechanism(s). Incubation of drug sensitive MES-SA cells with verapamil or (15), a nonradioactive analog of (17), alters the cellular retention of radioactivity only marginally. However, MES-SA/Dx5 cells retain approximately 12% more of (17) when incubated with 10 muM verapamil. The addition of (15) or high concentrations of (17) also increase the uptake of (17) in MES-SA/Dx5 up to 200%, depending on the concentration and temperature. The dependence of (17) uptake on the MDR status is also evident in the ex vivo binding studies. In vivo tests in mice xenografted simultaneously with both tumor cell lines indicate distinct pharmacokinetics for each tumor. The absorption half-life in MES-SA/Dx5 xenograft is approximately 10x shorter and the mean residence time approximately 50% shorter compared to MES-SA xenograft in the same mouse. Radioiodinated derivatives of MS-209 appear to be good indicators of multidrug resistance.

  18. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants.

    Science.gov (United States)

    Ziech, Rosangela Estel; Lampugnani, Camila; Perin, Ana Paula; Sereno, Mallu Jagnow; Sfaciotte, Ricardo Antônio Pilegi; Viana, Cibeli; Soares, Vanessa Mendonça; Pinto, José Paes de Almeida Nogueira; Bersot, Luciano dos Santos

    2016-01-01

    The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL) producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%), tetracycline (91%), and the beta-lactams: ampicillin and cefachlor (45%), followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp.

  19. [Significance of efflux pumps in multidrug resistance of Gram-negative bacteria].

    Science.gov (United States)

    Wiercińska, Olga; Chojecka, Agnieszka; Kanclerski, Krzysztof; Rőhm-Rodowald, Ewa; Jakimiak, Bożenna

    2015-01-01

    The phenomenon of multidrug. resistance of bacteria is a serious problem of modern medicine. This resistance largely is a consequence of abuse and improper use of antibacterial substances, especially antibiotics and chemotherapeutics in hospital settings. Multidrug resistance is caused by a number of interacting mechanisms of resistance. Recent studies have indicated that efflux pumps and systems of efflux pumps are an important determinant of this phenomenon. Contribute to this particular RND efflux systems of Gram-negative bacteria, which possess a wide range of substrates such as antibiotics, dyes, detergents, toxins and active substances of disinfectants and antiseptics. These transporters are usually encoded on bacterial chromosomes. Genes encoding efflux pumps' proteins may also be carried on plasmids and other mobile genetic elements. Such pumps are usually specific to a small group of substrates, but as an additional mechanism of resistance may contribute to the multidrug resistance.

  20. Economic consequences of mastitis and withdrawal of milk with high somatic cell count in Swedish dairy herds.

    Science.gov (United States)

    Nielsen, C; Ostergaard, S; Emanuelson, U; Andersson, H; Berglund, B; Strandberg, E

    2010-10-01

    The main aim was to assess the impact of mastitis on technical and economic results of a dairy herd under current Swedish farming conditions. The second aim was to investigate the effects obtained by withdrawing milk with high somatic cell count (SCC). A dynamic and stochastic simulation model, SimHerd, was used to study the effects of mastitis in a herd with 150 cows. Results given the initial incidence of mastitis (32 and 33 clinical and subclinical cases per 100 cow-years, respectively) were studied, together with the consequences of reducing or increasing the incidence of mastitis by 50%, modelling no clinical mastitis (CM) while keeping the incidence of subclinical mastitis (SCM) constant and vice versa. Six different strategies to withdraw milk with high SCC were compared. The decision to withdraw milk was based on herd-level information in three scenarios: withdrawal was initiated when the predicted bulk tank SCC exceeded 220 000, 200 000 or 180 000 cells/ml, and on cow-level information in three scenarios: withdrawal was initiated when the predicted SCC in an individual cow's milk exceeded 1 000 000, 750 000 or 500 000 cells/ml. The accuracy with which SCC was measured and predicted was assumed to affect the profitability of withdrawing milk with high SCC and this was investigated by applying high, low or no uncertainty to true SCC. The yearly avoidable cost of mastitis was estimated at €8235, assuming that the initial incidence of mastitis could be reduced by 50%. This cost corresponded to 5% of the herd net return given the initial incidence of mastitis. Expressed per cow-year, the avoidable cost of mastitis was €55. The costs per case of CM and SCM were estimated at €278 and €60, respectively. Withdrawing milk with high SCC was never profitable because this generated a substantial amount of milk withdrawal that was not offset by a sufficient increase in the average price per delivered kg milk. It had the most negative impact on net return when

  1. Molecular analysis of plasmid encoded multi-drug resistance (MDR) in Salmonella enterica animal isolates by PFGE, replicon typing, and DNA microarray screening followed by high-throughput DNA sequencing

    Science.gov (United States)

    Background: The development of Multi-Drug Resistant (MDR) Salmonella is of global concern. MDR Salmonella genes can be transmitted in a number of ways including transfer of plasmids. To understand how MDR plasmids develop and are transmitted, their genetics must be thoroughly described. To achieve t...

  2. The complete genome sequence of Escherichia coli EC958: a high quality reference sequence for the globally disseminated multidrug resistant E. coli O25b:H4-ST131 clone.

    Directory of Open Access Journals (Sweden)

    Brian M Forde

    Full Text Available Escherichia coli ST131 is now recognised as a leading contributor to urinary tract and bloodstream infections in both community and clinical settings. Here we present the complete, annotated genome of E. coli EC958, which was isolated from the urine of a patient presenting with a urinary tract infection in the Northwest region of England and represents the most well characterised ST131 strain. Sequencing was carried out using the Pacific Biosciences platform, which provided sufficient depth and read-length to produce a complete genome without the need for other technologies. The discovery of spurious contigs within the assembly that correspond to site-specific inversions in the tail fibre regions of prophages demonstrates the potential for this technology to reveal dynamic evolutionary mechanisms. E. coli EC958 belongs to the major subgroup of ST131 strains that produce the CTX-M-15 extended spectrum β-lactamase, are fluoroquinolone resistant and encode the fimH30 type 1 fimbrial adhesin. This subgroup includes the Indian strain NA114 and the North American strain JJ1886. A comparison of the genomes of EC958, JJ1886 and NA114 revealed that differences in the arrangement of genomic islands, prophages and other repetitive elements in the NA114 genome are not biologically relevant and are due to misassembly. The availability of a high quality uropathogenic E. coli ST131 genome provides a reference for understanding this multidrug resistant pathogen and will facilitate novel functional, comparative and clinical studies of the E. coli ST131 clonal lineage.

  3. Establishment of a Multidrug Resistance Cell Line A549/cDDP of Human Lung Adenocarcinoma and Expression Analysis of Multidrug Resistance-Associated Genes

    Directory of Open Access Journals (Sweden)

    Yongcheng PAN

    2009-03-01

    Full Text Available Background and objective It has been proven that chemotherapy failure caused by multidrug resistance in lung tumor cells is the main cause for the patient's survival rate. The aim of this study is to establish a multidrug resistance cell line of human lung adenocarcinoma and study the mechanism of multidrug resistance. Methods Human lung adenocarcinoma cell line A549 was induced to multidrug resistance cell line A549/cDDP by intermittentadministration of high dose of cisplatin (cDDP. The multidrug resistance was detected by using MTT assay. The levels of expression of MDR-1 gene-coded P-glycoportein (P-gp, multidrug resistance-associated protein (MRP, and GSH/GST were examined by flow cytometric assay. The levels of expression of MDR and MRP gene were also detected by RTPCR in both A549/cDDP and A549 cell lines. Results A549/cDDP was resistant to many anti-tumor agents. The IC50 of A549/cDDP was 16.87 times higher than that of A549. The expressions of P-gp and MRP in A549/cDDP were increased significantly to (70.5±4.9% and (29.4±2.9%, respectively, vs (42.4±5.6% and (21.4±3.5% in A549. There was no difference of the GSH/GST expression between A549/cDDPand A549 cells. Conclusion A549/cDDP is a model with multidrug resistance and the levels of MDR and MRP mRNA expressions are remarkably higher in A549/cDDP than those in A549.

  4. MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation

    Science.gov (United States)

    Kuster, Diederik W. D.

    2014-01-01

    Hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease and the leading cause of sudden cardiac death in young people. HCM is caused by mutations in genes encoding contractile proteins. Cardiac myosin binding protein-C (cMyBP-C) is a thick filament contractile protein that regulates sarcomere organization and cardiac contractility. About 200 different mutations in the cMyBP-C gene (MYBPC3) have thus far been reported as causing HCM. Among them, a 25 base pair deletion in the branch point of intron 32 of MYBPC3 is widespread, particularly in South Asia, where it affects ≈4% of South Asian descendants worldwide. This polymorphic mutation results in skipping of exon 33 and a reading frame shift, which, in turn, replaces the last 65 amino acids of the C-terminal C10 domain of cMyBP-C (cMyBP-CC10mut) with a novel sequence of 58 residues. Carriers of the 25 base pair deletion mutation are at increased risk of developing cardiomyopathy and heart failure. Because of the high prevalence of this mutation in certain populations, genetic screening of at-risk groups might be beneficial. Scientifically, the functional consequences of C-terminal mutations and the precise mechanisms leading to HCM should be defined using induced pluripotent stem cells and engineered heart tissue in vitro, or mouse models in vivo. Most importantly, therapeutic strategies that include pharmacology, gene repair and gene therapy should be developed to prevent the adverse clinical effects of cMyBP-CC10mut. This review article aims to examine the effects of cMyBP-CC10mut on cardiac function, emphasizing the need for the development of genetic testing and expanded therapeutic strategies. PMID:24327208

  5. Custom database development and biomarker discovery methods for MALDI-TOF mass spectrometry-based identification of high-consequence bacterial pathogens.

    Science.gov (United States)

    Tracz, Dobryan M; Tyler, Andrea D; Cunningham, Ian; Antonation, Kym S; Corbett, Cindi R

    2017-03-01

    A high-quality custom database of MALDI-TOF mass spectral profiles was developed with the goal of improving clinical diagnostic identification of high-consequence bacterial pathogens. A biomarker discovery method is presented for identifying and evaluating MALDI-TOF MS spectra to potentially differentiate biothreat bacteria from less-pathogenic near-neighbour species.

  6. Choice & Consequence

    DEFF Research Database (Denmark)

    Khan, Azam

    between cause and effect in complex systems complicates decision making. To address this issue, we examine the central role that data-driven decision making could play in critical domains such as sustainability or medical treatment. We developed systems for exploratory data analysis and data visualization...... of data analysis and instructional interface design, to both simulation systems and decision support interfaces. We hope that projects such as these will help people to understand the link between their choices and the consequences of their decisions....

  7. Choice & Consequence

    DEFF Research Database (Denmark)

    Khan, Azam

    between cause and effect in complex systems complicates decision making. To address this issue, we examine the central role that data-driven decision making could play in critical domains such as sustainability or medical treatment. We developed systems for exploratory data analysis and data visualization...... of data analysis and instructional interface design, to both simulation systems and decision support interfaces. We hope that projects such as these will help people to understand the link between their choices and the consequences of their decisions....

  8. Multidrug resistant bacteria isolated from septic arthritis in horses

    Directory of Open Access Journals (Sweden)

    Rodrigo G. Motta

    Full Text Available ABSTRACT: Septic arthritis is a debilitating joint infectious disease of equines that requires early diagnosis and immediate therapeutic intervention to prevent degenerative effects on the articular cartilage, as well as loss of athletic ability and work performance of the animals. Few studies have investigated the etiological complexity of this disease, as well as multidrug resistance of isolates. In this study, 60 horses with arthritis had synovial fluid samples aseptically collected, and tested by microbiological culture and in vitro susceptibility test (disk diffusion using nine antimicrobials belonging to six different pharmacological groups. Bacteria were isolated in 45 (75.0% samples, as follows: Streptococcus equi subsp. equi (11=18.3%, Escherichia coli (9=15.0%, Staphylococcus aureus (6=10.0%, Streptococcus equi subsp. zooepidemicus (5=8.3%, Staphylococcus intermedius (2=3.3%, Proteus vulgaris (2=3.3%, Trueperella pyogenes (2=3.3%, Pseudomonas aeruginosa (2=3.3%, Klebsiella pneumoniae (1=1.7%, Rhodococcus equi (1=1.7%, Staphylococcus epidermidis (1=1.7%, Klebsiella oxytoca (1=1.7%, Nocardia asteroides (1=1.7%, and Enterobacter cloacae (1=1.7%. Ceftiofur was the most effective drug (>70% efficacy against the pathogens in the disk diffusion test. In contrast, high resistance rate (>70% resistance was observed to penicillin (42.2%, enrofloxacin (33.3%, and amikacin (31.2%. Eleven (24.4% isolates were resistant to three or more different pharmacological groups and were considered multidrug resistant strains. The present study emphasizes the etiological complexity of equine septic arthritis, and highlights the need to institute treatment based on the in vitro susceptibility pattern, due to the multidrug resistance of isolates. According to the available literature, this is the first report in Brazil on the investigation of the etiology. of the septic arthritis in a great number of horses associated with multidrug resistance of the isolates.

  9. Compliance with a three-day course of artesunate-mefloquine combination and baseline anti-malarial treatment in an area of Thailand with highly multidrug resistant falciparum malaria

    Directory of Open Access Journals (Sweden)

    Na-Bangchang Kesara

    2010-02-01

    and primaquine levels were observed in 24 and 16% of the patients. Conclusion The current first-line treatment and a three-day combination regimen of artesunate-mefloquine provides excellent patient compliance with good efficacy and tolerability in the treatment of highly multidrug resistance falciparum malaria. Previous treatment with mefloquine and primaquine were common in this area.

  10. Deciphering the molecular basis of multidrug recognition: crystal structures of the Staphylococcus aureus multidrug binding transcription regulator QacR.

    Science.gov (United States)

    Schumacher, Maria A; Brennan, Richard G

    2003-03-01

    Multidrug transporters and their transcriptional regulators are key components of bacterial multidrug resistance (MDR). How these multidrug binding proteins can recognize such chemically disparate compounds represents a fascinating question from a structural standpoint and an important question in future drug development efforts. The Staphylococcus aureus multidrug binding regulator, QacR, is soluble and recognizes an especially wide range of structurally dissimilar compounds, properties making it an ideal model system for deciphering the molecular basis of multidrug recognition. Recent structures of QacR have afforded the first view of any MDR protein bound to multiple drugs, revealing key structural features of multidrug recognition, including a multisite binding pocket.

  11. High prevalence of multidrug-resistance in Acinetobacter baumannii and dissemination of carbapenemase-encoding genes blaOXA-23-like, blaOXA-24-like and blaNDM-1 in Algiers hospitals

    Institute of Scientific and Technical Information of China (English)

    Khadidja Khorsi; Yamina Messai; Moufida Hamidi; Houria Ammari; Rabah Bakour

    2015-01-01

    Objective:To assess and characterize antibiotic resistance in Acinetobacter baumannii strains recovered from 5 health-care facilities in Algiers. Methods:Antibiotic susceptibility testing was performed by agar diffusion and agar dilution methods, resistance genes were identified by PCR and sequencing, and molecular typing of isolates was carried out by enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR). Results:Among 125 tested isolates, 117 (93.6%) were multidrug-resistant, of which 94 (75.2%) were imipenem resistant. The blaADC and blaOXA-51-like genes were detected in all isolates, in association with ISAba1 sequence in 84%and 8%(imipenem resistant) of isolates, respectively. The blaOXA-23-like and blaOXA-24-like carbapenemase genes were detected in 67.02%and 20.21%of imipenem-resistant isolates, respectively. The blaOXA-23-like gene is linked to ISAba1 or ISAba4 elements. The metallo-β-lactamase NDM-1 gene was found in 10 (10.6%) imipenem-resistant strains from three hospitals, it is linked to ISAba125 element in nine strains. Extended spectrumβ-lactamases production was not detected. Imipenem and cefotaxime resistance phenotypes could not be transferred to Escherichia coli by conjugation. Outer membrane protein CarO gene was not detected in four imipenem-resistant isolates. The aac(6’)-Ib, sul1, sul2, tetA and tetB genes were present in 5.31%, 36.17%, 77.65%, 1.06%and 65.92%of strains, respectively. Class 1 integrons were detected in 23.4%strains. ERIC-PCR typing showed a genetic diversity among blaOXA-23-like and blaOXA-24-like positive strains, while clonality was observed among blaNDM-1 positives. Conclusions:This study highlighted the high prevalence of imipenem resistance in Acinetobacter baumannii in Algiers hospitals mediated mainly by blaOXA-23-like, blaOXA-24-like, and blaNDM-1 genes.

  12. Multidrug resistance and high virulence genotype in uropathogenic Escherichia coli due to diffusion of ST131 clonal group producing CTX-M-15: an emerging problem in a Tunisian hospital.

    Science.gov (United States)

    Ferjani, Sana; Saidani, Mabrouka; Ennigrou, Samir; Hsairi, Mohamed; Slim, Amine Faouzi; Ben Boubaker, Ilhem Boutiba

    2014-05-01

    A collection of 201 Escherichia coli strains isolated from urine of patients in a Tunisian hospital between January 2006 and July 2008 was studied. Microbial identification was done by conventional methods, and antibiotic susceptibility with disk diffusion method was performed according to the Clinical Laboratory and Standards Institute guidelines. Detection of extended-spectrum beta-lactamase (ESBL) was performed by double-disk synergy test (DDST) and identification was done by PCR and sequencing. ESBL-producing isolates were subjected to molecular typing by random amplified polymorphic DNA (RAPD) and ST131 detection by PCR. Four phylogenetic groups (A, B1, B2 and D), 18 virulence genes and CTX-M group were individualized using PCR. Statistical analysis was done by Pearson χ2 test and Mann-Whitney U test. The strains were recovered primarily from urology (28%), maternity (19%) and medicine (16%) wards. Antibiotic resistance rates were ampicilin (72.1%), nalidixic acid (41.8%), ciprofloxacin (38.8%), gentamicin (23.9%) and cefotaxime (17.4%). Thirty-one of cefotaxime-resistant isolates (n = 35) had a positive DDST and harboured bla CTX-M-15 gene. Twenty of them (64.5%) belonged to the ST131 clone and showed the same RAPD DNA profile. Ciprofloxacin- and cotrimoxazole-susceptible isolates were significantly associated with phylogenetic group B2, whereas isolates that were resistant to these molecules were associated with B1 and D phylogenetic groups, respectively. Virulence genes were significantly more frequent among ciprofloxacin- and cotrimoxazole-susceptible strains than those resistant to these antibiotics. However, CXT-M-15-producing isolates were associated with many virulence genes. Isolates concomitantly susceptible to the three antimicrobials agents (ciprofloxacin, cefotaxime and cotrimoxazole) were significantly associated with group B2 and high virulence score, whereas isolates with resistance patterns especially those including resistance to

  13. Direct Application of the INNO-LiPA Rif.TB Line-Probe Assay for Rapid Identification of Mycobacterium tuberculosis Complex Strains and Detection of Rifampin Resistance in 360 Smear-Positive Respiratory Specimens from an Area of High Incidence of Multidrug-Resistant Tuberculosis

    Science.gov (United States)

    Viveiros, Miguel; Leandro, Clara; Rodrigues, Liliana; Almeida, Josefina; Bettencourt, Rosário; Couto, Isabel; Carrilho, Lurdes; Diogo, José; Fonseca, Ana; Lito, Luís; Lopes, João; Pacheco, Teresa; Pessanha, Mariana; Quirim, Judite; Sancho, Luísa; Salfinger, Max; Amaral, Leonard

    2005-01-01

    The INNO-LiPA Rif.TB assay for the identification of Mycobacterium tuberculosis complex strains and the detection of rifampin (RIF) resistance has been evaluated with 360 smear-positive respiratory specimens from an area of high incidence of multidrug-resistant tuberculosis (MDR-TB). The sensitivity when compared to conventional identification/culture methods was 82.2%, and the specificity was 66.7%; the sensitivity and specificity were 100.0% and 96.9%, respectively, for the detection of RIF resistance. This assay has the potential to provide rapid information that is essential for the effective management of MDR-TB. PMID:16145166

  14. The consequences of "Culture's consequences"

    DEFF Research Database (Denmark)

    Knudsen, Fabienne; Loloma Froholdt, Lisa

    2009-01-01

    , but it may also have unintentional outcomes. It may lead to a deterministic view of other cultures, thereby reinforcing prejudices and underestimating other forms of differences; it risks blinding the participants of the specific context of a given communicative situation. The article opens with a critical...... review of the theory of Geert Hofstede, the most renowned representative of this theoretical approach. The practical consequences of using such a concept of culture is then analysed by means of a critical review of an article applying Hofstede to cross-cultural crews in seafaring. Finally, alternative...... views on culture are presented. The aim of the article is, rather than to promote any specific theory, to reflect about diverse perspectives of cultural sense-making in cross-cultural encounters. Udgivelsesdato: Oktober...

  15. Multidrug resistant Acinetobacter baumannii in veterinary medicine--emergence of an underestimated pathogen?

    Science.gov (United States)

    Müller, Stefanie; Janssen, Traute; Wieler, Lothar H

    2014-01-01

    The proportion of multidrug resistant bacteria causing infections in animals has continuously been increasing. While the relevance of ESBL (extended spectrum beta-lactamase)-producing Enterobacteriaceae spp. and MRSA (methicillin resistant Staphylococcus aureus) is unquestionable, knowledge about multidrug resistant Acinetobacter baumannii in veterinary medicine is scarce. This is a worrisome situation, as A. baumannii are isolated from veterinary clinical specimens with rising frequency. The remarkable ability of A. baumannii to develop multidrug resistance and the high risk of transmission are known in human medicine for years. Despite this, data regarding A. baumannii isolates of animal origin are missing. Due to the changing role of companion animals with closer contact between animal and owner, veterinary intensive care medicine is steadily developing. It can be assumed that the number of "high risk" patients with an enhanced risk for hospital acquired infections will be rising simultaneously. Thus, development and spread of multidrug resistant pathogens is envisioned to rise. It is possible, that A. baumannii will evolve into a veterinary nosocomial pathogen similar to ESBL-producing Enterobacteriaceae and MRSA. The lack of attention paid to A. baumannii in veterinary medicine is even more worrying, as first reports indicate a transmission between humans and animals. Essential questions regarding the role of livestock, especially as a potential source of multidrug resistant isolates, remain unanswered. This review summarizes the current knowledge on A. baumannii in veterinary medicine for the first time. It underlines the utmost significance of further investigations of A. baumannii animal isolates, particularly concerning epidemiology and resistance mechanisms.

  16. Bacteriophages: biosensing tools for multi-drug resistant pathogens.

    Science.gov (United States)

    Tawil, N; Sacher, E; Mandeville, R; Meunier, M

    2014-03-21

    Pathogen detection is of utmost importance in many sectors, such as in the food industry, environmental quality control, clinical diagnostics, bio-defence and counter-terrorism. Failure to appropriately, and specifically, detect pathogenic bacteria can lead to serious consequences, and may ultimately be lethal. Public safety, new legislation, recent outbreaks in food contamination, and the ever-increasing prevalence of multidrug-resistant infections have fostered a worldwide research effort targeting novel biosensing strategies. This review concerns phage-based analytical and biosensing methods targeted towards theranostic applications. We discuss and review phage-based assays, notably phage amplification, reporter phage, phage lysis, and bioluminescence assays for the detection of bacterial species, as well as phage-based biosensors, including optical (comprising SPR sensors and fiber optic assays), electrochemical (comprising amperometric, potentiometric, and impedimetric sensors), acoustic wave and magnetoelastic sensors.

  17. Photodynamic therapy of cancer — Challenges of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Zheng Huang

    2015-01-01

    Full Text Available Photodynamic therapy (PDT of cancer is a two-step drug-device combination modality, which involves the topical or systemic administration of a photosensitizer followed by light illumination of cancer site. In the presence of oxygen molecules, the light illumination of photosensitizer (PS can lead to the generation of cytotoxic reactive oxygen species (ROS and consequently destroy cancer. Similar to many other anticancer therapies, PDT is also subject to intrinsic cancer resistance mediated by multidrug resistance (MDR mechanisms. This paper will review the recent progress in understanding the interaction between MDR transporters and PS uptake. The strategies that can be used in a clinical setting to overcome or bypass MDR will also be discussed.

  18. The ABC family of multidrug transporters in microorganisms

    NARCIS (Netherlands)

    van Veen, H.W; Konings, W.N

    1998-01-01

    Multidrug transporters are membrane proteins that are able to expel a broad range of toxic molecules from the cell. In humans, the overexpression of the multidrug resistance P-glycoprotein (Pgp) and the multidrug resistance-associated protein MRP1 (MRP) is a principal cause of resistance of cancers

  19. Virulence and genomic feature of multidrug resistant Campylobacter jejuni isolated from broiler chicken

    Directory of Open Access Journals (Sweden)

    Haihong Hao

    2016-10-01

    Full Text Available The aim of this study was to reveal the molecular mechanism involved in multidrug resistance and virulence of Campylobacter jejuni isolated from broiler chickens. The virulence of six multidrug resistant C. jejuni was determined by in vitro and in vivo methods. The de novo whole genome sequencing technology and molecular biology methods were used to analyze the genomic features associated with the multidrug resistance and virulence of a selected isolate (C. jejuni 1655. The comparative genomic analyses revealed a large number of single nucleotide polymorphisms, deletions, rearrangements, and inversions in C. jejuni 1655 compared to reference C. jejuni genomes. The co-emergence of Thr-86-Ile mutation in gyrA gene, A2075G mutation in 23S rRNA gene, tetO, aphA and aadE genes and pTet plasmid in C. jejuni 1655 contributed its multidrug resistance to fluoroquinolones, macrolides, tetracycline and aminoglycosides. The combination of multiple virulence genes may work together to confer the relative higher virulence in C. jejuni 1655. The co-existence of mobile gene elements (e.g. pTet and CRISPR-Cas system in C. jejuni 1655 may play an important role in the gene transfer and immune defense. The present study provides basic information of phenotypic and genomic features of C. jejuni 1655, a strain recently isolated from a chicken displaying multidrug resistance and relatively high level of virulence.

  20. Virulence and Genomic Feature of Multidrug Resistant Campylobacter jejuni Isolated from Broiler Chicken

    Science.gov (United States)

    Hao, Haihong; Ren, Ni; Han, Jing; Foley, Steven L.; Iqbal, Zahid; Cheng, Guyue; Kuang, Xiuhua; Liu, Jie; Liu, Zhenli; Dai, Menghong; Wang, Yulian; Yuan, Zonghui

    2016-01-01

    The aim of this study was to reveal the molecular mechanism involved in multidrug resistance and virulence of Campylobacter jejuni isolated from broiler chickens. The virulence of six multidrug resistant C. jejuni was determined by in vitro and in vivo methods. The de novo whole genome sequencing technology and molecular biology methods were used to analyze the genomic features associated with the multidrug resistance and virulence of a selected isolate (C. jejuni 1655). The comparative genomic analyses revealed a large number of single nucleotide polymorphisms, deletions, rearrangements, and inversions in C. jejuni 1655 compared to reference C. jejuni genomes. The co-emergence of Thr-86-Ile mutation in gyrA gene, A2075G mutation in 23S rRNA gene, tetO, aphA and aadE genes and pTet plasmid in C. jejuni 1655 contributed its multidrug resistance to fluoroquinolones, macrolides, tetracycline, and aminoglycosides. The combination of multiple virulence genes may work together to confer the relative higher virulence in C. jejuni 1655. The co-existence of mobile gene elements (e.g., pTet) and CRISPR-Cas system in C. jejuni 1655 may play an important role in the gene transfer and immune defense. The present study provides basic information of phenotypic and genomic features of C. jejuni 1655, a strain recently isolated from a chicken displaying multidrug resistance and relatively high level of virulence. PMID:27790202

  1. The role of ATP-binding cassette transporter A2 in childhood acute lymphoblastic leukemia multidrug resistance

    OpenAIRE

    Aberuyi, N; Rahgozar, S; Moafi, A

    2014-01-01

    Acute lymphoblastic leukemia (ALL) is one of the most prevalent hematologic malignancies in children. Although the cure rate of ALL has improved over the past decades, the most important reason for ALL treatment failure is multidrug resistance (MDR) phenomenon. The current study aims to explain the mechanisms involved in multidrug resistance of childhood ALL, and introduces ATP-binding cassette transporterA2 (ABCA2) as an ABC transporter gene which may have a high impact on MDR. Benefiting fr...

  2. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    1997-01-01

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  3. Molecular properties of bacterial multidrug transporters

    NARCIS (Netherlands)

    Putman, M; van Veen, HW; Konings, WN

    2000-01-01

    One of the mechanisms that bacteria utilize to evade the toxic effects of antibiotics is the active extrusion of structurally unrelated drugs from the cell. Both intrinsic and acquired multidrug transporters play an important role in antibiotic resistance of several pathogens, including Neisseria go

  4. Multidrug resistance: Physiological principles and nanomedical solutions

    NARCIS (Netherlands)

    Kunjachan, S.; Rychlik, B.; Storm, G.; Kiessling, F.; Lammers, T.G.G.M.

    2013-01-01

    Multidrug resistance (MDR) is a pathophysiological phenomenon employed by cancer cells which limits the prolonged and effective use of chemotherapeutic agents. MDR is primarily based on the over-expression of drug efflux pumps in the cellular membrane. Prominent examples of such efflux pumps, which

  5. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  6. Multidrug transporters in lactic acid bacteria

    NARCIS (Netherlands)

    Mazurkiewicz, P; Sakamoto, K; Poelarends, GJ; Konings, WN

    2005-01-01

    Gram-positive lactic acid bacteria possess several Multi-Drug Resistance systems (MDRs) that excrete out of the cell a wide variety of mainly cationic lipophilic cytotoxic compounds as well as many clinically relevant antibiotics. These MDRs are either proton/drug antiporters belonging to the major

  7. Multidrug transporters in lactic acid bacteria

    NARCIS (Netherlands)

    Mazurkiewicz, P; Sakamoto, K; Poelarends, GJ; Konings, WN

    2005-01-01

    Gram-positive lactic acid bacteria possess several Multi-Drug Resistance systems (MDRs) that excrete out of the cell a wide variety of mainly cationic lipophilic cytotoxic compounds as well as many clinically relevant antibiotics. These MDRs are either proton/drug antiporters belonging to the major

  8. The ABCs of multidrug resistance in malaria.

    NARCIS (Netherlands)

    Koenderink, J.B.; Kavishe, R.A.; Rijpma, S.R.; Russel, F.G.M.

    2010-01-01

    Expanding drug resistance could become a major problem in malaria treatment, as only a limited number of effective antimalarials are available. Drug resistance has been associated with single nucleotide polymorphisms and an increased copy number of multidrug resistance protein 1 (MDR1), an ATP-bindi

  9. [Exploration of the Factors Influencing Multi-Drug Cancer Chemotherapy in the Elderly - A Retrospective Study].

    Science.gov (United States)

    Ogata, Kentaro; Tamura, Kazuo; Kiyomi, Fumiaki; Takamatsu, Yasushi; Kamimura, Hidetoshi

    2016-12-01

    Multi-drug administration is problematic in elderly patients, and the situation is further complicated in those with cancer, owing to a high possibility of side effects and augmentation due to interactions between concomitant or previous drugs the patients are receiving and the anti-cancer drugs administered. Analysis of the factors that influence the likelihood of cancer chemotherapy multi-drug administration in the elderly showed that age alone was a fundamental risk factor for multi-drug administration, comorbidities, and drug interactions. In addition, the risks of drug interaction with chemotherapy were approximately 5.8 fold for drugs administered to treat hypertension, and approximately 10.3 fold for cardiovascular agents. Because of increased cancer morbidity, it is important to reduce the risks associated with the treatment.

  10. Psychosocial consequences of leprosy and the related deformity in Bangladesh

    Directory of Open Access Journals (Sweden)

    Qazi Azad-uz-zaman

    2017-01-01

    Full Text Available Objective: To explore the psychosocial condition and consequences of the people affected by leprosy and the related deformity in some selected areas of Bangladesh. Methods: A cross-sectional study was conducted from July to December 2015 among 92 leprosy-affected people. A pretested semi-structure questionnaire was used for collecting data by face to face interview from both the low prevalent areas of Khulna and the high prevalent area of Rangpur Division in Bangladesh. Results: Nearly two-fifth of respondents were observed having deformity. Among them, around four-fifth was from Khulna region, about half were above 50 years of age and more than half had monthly family income lower than 5 000 BDT. The development of deformity is found having highly significant association with region (P < 0.001, residence (P < 0.004, and family income (P < 0.004. Differences in consequences between ‘with deformity’ and ‘without deformity’ were found very high. About 65% of the respondents with deformity ‘think less’ of himself, and nearly 60% felt ashamed or embarrassed, 53% had to change job, and 47% was used to think having less respect in the society where the percentage was much lower in all cases to ‘without deformity’ group. Conclusions: Early diagnosis and start multidrug therapy at the earliest stages have chanced to reduce the leprosy-resulted deformity, disfigurement and disability. For those who already have had some nerve damages, health education is highly important to prevent further injury and hence psychosocial consequences.

  11. Targeted multidrug delivery system to overcome chemoresistance in breast cancer

    Directory of Open Access Journals (Sweden)

    Tang Y

    2017-01-01

    Full Text Available Yuan Tang,1 Fariborz Soroush,1 Zhaohui Tong,2 Mohammad F Kiani,1 Bin Wang1,3 1Department of Mechanical Engineering, Temple University, Philadelphia, PA, 2Department of Agricultural and Biological Engineering, University of Florida, Gainesville, FL, 3Department of Biomedical Engineering, Widener University, Chester, PA, USA Abstract: Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX into immunoliposomes where the human epidermal growth factor receptor 2 (HER2 antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR, and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly

  12. A multidrug ABC transporter with a taste for salt.

    Directory of Open Access Journals (Sweden)

    Saroj Velamakanni

    Full Text Available BACKGROUND: LmrA is a multidrug ATP-binding cassette (ABC transporter from Lactococcus lactis with no known physiological substrate, which can transport a wide range of chemotherapeutic agents and toxins from the cell. The protein can functionally replace the human homologue ABCB1 (also termed multidrug resistance P-glycoprotein MDR1 in lung fibroblast cells. Even though LmrA mediates ATP-dependent transport, it can use the proton-motive force to transport substrates, such as ethidium bromide, across the membrane by a reversible, H(+-dependent, secondary-active transport reaction. The mechanism and physiological context of this reaction are not known. METHODOLOGY/PRINCIPAL FINDINGS: We examined ion transport by LmrA in electrophysiological experiments and in transport studies using radioactive ions and fluorescent ion-selective probes. Here we show that LmrA itself can transport NaCl by a similar secondary-active mechanism as observed for ethidium bromide, by mediating apparent H(+-Na(+-Cl(- symport. Remarkably, LmrA activity significantly enhances survival of high-salt adapted lactococcal cells during ionic downshift. CONCLUSIONS/SIGNIFICANCE: The observations on H(+-Na(+-Cl(- co-transport substantiate earlier suggestions of H(+-coupled transport by LmrA, and indicate a novel link between the activity of LmrA and salt stress. Our findings demonstrate the relevance of investigations into the bioenergetics of substrate translocation by ABC transporters for our understanding of fundamental mechanisms in this superfamily. This study represents the first use of electrophysiological techniques to analyze substrate transport by a purified multidrug transporter.

  13. Bacillus subtilis from Soybean Food Shows Antimicrobial Activity for Multidrug-Resistant Acinetobacter baumannii by Affecting the adeS Gene.

    Science.gov (United States)

    Wang, Tieshan; Su, Jianrong

    2016-12-28

    Exploring novel antibiotics is necessary for multidrug-resistant pathogenic bacteria. Because the probiotics in soybean food have antimicrobial activities, we investigated their effects on multidrug-resistant Acinetobacter baumannii. Nineteen multidrug-resistant A. baumannii strains were clinifcally isolated as an experimental group and 11 multidrug-sensitive strains as controls. The growth rates of all bacteria were determined by using the analysis for xCELLigence Real-Time Cell. The combination of antibiotics showed synergistic effects on the strains in the control group but no effect on the strains in the experimental group. Efflux pump gene adeS was absent in all the strains from the control group, whereas it exists in all the strains from the experimental group. Furthermore, all the strains lost multidrug resistance when an adeS inhibitor was used. One strain of probiotics isolated from soybean food showed high antimicrobial activity for multidrug-resistant A. baumannii. The isolated strain belongs to Bacillus subtilis according to 16S RNA analysis. Furthermore, E. coli showed multidrug resistance when it was transformed with the adeS gene from A. baumannii whereas the resistant bacteria could be inhibited completely by isolated Bacillus subtilis. Thus, probiotics from soybean food provide potential antibiotics against multidrug-resistant pathogenic bacteria.

  14. Low-Probability High-Consequence (LPHC) Failure Events in Geologic Carbon Sequestration Pipelines and Wells: Framework for LPHC Risk Assessment Incorporating Spatial Variability of Risk

    Energy Technology Data Exchange (ETDEWEB)

    Oldenburg, Curtis M. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Budnitz, Robert J. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2016-08-31

    If Carbon dioxide Capture and Storage (CCS) is to be effective in mitigating climate change, it will need to be carried out on a very large scale. This will involve many thousands of miles of dedicated high-pressure pipelines in order to transport many millions of tonnes of CO2 annually, with the CO2 delivered to many thousands of wells that will inject the CO2 underground. The new CCS infrastructure could rival in size the current U.S. upstream natural gas pipeline and well infrastructure. This new infrastructure entails hazards for life, health, animals, the environment, and natural resources. Pipelines are known to rupture due to corrosion, from external forces such as impacts by vehicles or digging equipment, by defects in construction, or from the failure of valves and seals. Similarly, wells are vulnerable to catastrophic failure due to corrosion, cement degradation, or operational mistakes. While most accidents involving pipelines and wells will be minor, there is the inevitable possibility of accidents with very high consequences, especially to public health. The most important consequence of concern is CO2 release to the environment in concentrations sufficient to cause death by asphyxiation to nearby populations. Such accidents are thought to be very unlikely, but of course they cannot be excluded, even if major engineering effort is devoted (as it will be) to keeping their probability low and their consequences minimized. This project has developed a methodology for analyzing the risks of these rare but high-consequence accidents, using a step-by-step probabilistic methodology. A key difference between risks for pipelines and wells is that the former are spatially distributed along the pipe whereas the latter are confined to the vicinity of the well. Otherwise, the methodology we develop for risk assessment of pipeline and well failures is similar and provides an analysis both of the annual probabilities of

  15. The secondary resistome of multidrug-resistant Klebsiella pneumoniae

    Science.gov (United States)

    Jana, Bimal; Cain, Amy K.; Doerrler, William T.; Boinett, Christine J.; Fookes, Maria C.; Parkhill, Julian; Guardabassi, Luca

    2017-01-01

    Klebsiella pneumoniae causes severe lung and bloodstream infections that are difficult to treat due to multidrug resistance. We hypothesized that antimicrobial resistance can be reversed by targeting chromosomal non-essential genes that are not responsible for acquired resistance but essential for resistant bacteria under therapeutic concentrations of antimicrobials. Conditional essentiality of individual genes to antimicrobial resistance was evaluated in an epidemic multidrug-resistant clone of K. pneumoniae (ST258). We constructed a high-density transposon mutant library of >430,000 unique Tn5 insertions and measured mutant depletion upon exposure to three clinically relevant antimicrobials (colistin, imipenem or ciprofloxacin) by Transposon Directed Insertion-site Sequencing (TraDIS). Using this high-throughput approach, we defined three sets of chromosomal non-essential genes essential for growth during exposure to colistin (n = 35), imipenem (n = 1) or ciprofloxacin (n = 1) in addition to known resistance determinants, collectively termed the “secondary resistome”. As proof of principle, we demonstrated that inactivation of a non-essential gene not previously found linked to colistin resistance (dedA) restored colistin susceptibility by reducing the minimum inhibitory concentration from 8 to 0.5 μg/ml, 4-fold below the susceptibility breakpoint (S ≤ 2 μg/ml). This finding suggests that the secondary resistome is a potential target for developing antimicrobial “helper” drugs that restore the efficacy of existing antimicrobials. PMID:28198411

  16. Molecular characterisation of multidrug-resistant Salmonella enterica serovar Typhimurium isolates from Gomel region, Belarus

    DEFF Research Database (Denmark)

    Tapalski, D.; Hendriksen, Rene S.; Hasman, Henrik;

    2007-01-01

    an infection outside hospitals in the Gomel region of Belarus. Thirty-one isolates were highly similar according to PFGE and MLVA typing, were multidrug-resistant, including resistance to ceftiofur, and harboured the bla(CTX-M-5) gene. These results indicate that a common source may have been responsible...

  17. Multidrug-resistant gram-negative bacilli colonization risk factors among trauma patients.

    Science.gov (United States)

    Gilbert, Laura J; Li, Ping; Murray, Clinton K; Yun, Heather C; Aggarwal, Deepak; Weintrob, Amy C; Tribble, David R

    2016-04-01

    Prior studies have demonstrated high rates of colonization and infection with multidrug-resistant gram-negative bacilli (MDR-GNB) in injured military personnel. Our analysis shows that injuries inflicted during peak combat periods, massive blood transfusion requirement, and posttrauma cefazolin prophylaxis (additive effect with fluoroquinolones) were risk factors for MDR-GNB colonization. Published by Elsevier Inc.

  18. Multidrug resistant Acinetobacter baumannii reaches a new frontier: prosthetic hip joint infection.

    Science.gov (United States)

    Hischebeth, G T R; Wimmer, M D; Molitor, E; Seifert, H; Gravius, S; Bekeredjian-Ding, I

    2015-02-01

    Acinetobacter baumannii is an emerging nosocomial pathogen primarily in countries with a high prevalence of multidrug resistance. Here we report the detection of a bla OXA23 carbapenemase-producing A. baumannii strain in a German patient with prosthetic hip joint infection following several hip joint surgeries but no history of foreign travel.

  19. Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

    NARCIS (Netherlands)

    Alsaad, Noor; Wilffert, Bob; van Altena, Richard; de Lange, Wiel C. M.; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

    2014-01-01

    Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of alre

  20. Drugs, ionophoric peptides, and steroids as substrates of the yeast multidrug transporter Pdr5p

    NARCIS (Netherlands)

    Kolaczkowski, M; vanderRest, M; CybularzKolaczkowska, A; Soumillion, JP; Konings, WN; Goffeau, A

    1996-01-01

    Pdr5p is the yeast Saccharomyces cerevisiae ATP-binding cassette transporter conferring resistance to several unrelated drugs. Its high overproduction in Pdr1p transcription factor mutants allows us to study the molecular mechanism of multidrug transport and substrate specificity. We have developed

  1. Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

    NARCIS (Netherlands)

    Alsaad, Noor; Wilffert, Bob; van Altena, Richard; de Lange, Wiel C. M.; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

    2014-01-01

    Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of

  2. Consequences of exchanging carbohydrates for proteins in the cholesterol metabolism of mice fed a high-fat diet.

    Directory of Open Access Journals (Sweden)

    Frédéric Raymond

    Full Text Available Consumption of low-carbohydrate, high-protein, high-fat diets lead to rapid weight loss but the cardioprotective effects of these diets have been questioned. We examined the impact of high-protein and high-fat diets on cholesterol metabolism by comparing the plasma cholesterol and the expression of cholesterol biosynthesis genes in the liver of mice fed a high-fat (HF diet that has a high (H or a low (L protein-to-carbohydrate (P/C ratio. H-P/C-HF feeding, compared with L-P/C-HF feeding, decreased plasma total cholesterol and increased HDL cholesterol concentrations at 4-wk. Interestingly, the expression of genes involved in hepatic steroid biosynthesis responded to an increased dietary P/C ratio by first down-regulation (2-d followed by later up-regulation at 4-wk, and the temporal gene expression patterns were connected to the putative activity of SREBF1 and 2. In contrast, Cyp7a1, the gene responsible for the conversion of cholesterol to bile acids, was consistently up-regulated in the H-P/C-HF liver regardless of feeding duration. Over expression of Cyp7a1 after 2-d and 4-wk H-P/C-HF feeding was connected to two unique sets of transcription regulators. At both time points, up-regulation of the Cyp7a1 gene could be explained by enhanced activations and reduced suppressions of multiple transcription regulators. In conclusion, we demonstrated that the hypocholesterolemic effect of H-P/C-HF feeding coincided with orchestrated changes of gene expressions in lipid metabolic pathways in the liver of mice. Based on these results, we hypothesize that the cholesterol lowering effect of high-protein feeding is associated with enhanced bile acid production but clinical validation is warranted. (246 words.

  3. Fragmentation of urban forms and the environmental consequences: results from a high-spatial resolution model system

    Science.gov (United States)

    Tang, U. W.; Wang, Z. S.

    2008-10-01

    Each city has its unique urban form. The importance of urban form on sustainable development has been recognized in recent years. Traditionally, air quality modelling in a city is in a mesoscale with grid resolution of kilometers, regardless of its urban form. This paper introduces a GIS-based air quality and noise model system developed to study the built environment of highly compact urban forms. Compared with traditional mesoscale air quality model system, the present model system has a higher spatial resolution down to individual buildings along both sides of the street. Applying the developed model system in the Macao Peninsula with highly compact urban forms, the average spatial resolution of input and output data is as high as 174 receptor points per km2. Based on this input/output dataset with a high spatial resolution, this study shows that even the highly compact urban forms can be fragmented into a very small geographic scale of less than 3 km2. This is due to the significant temporal variation of urban development. The variation of urban form in each fragment in turn affects air dispersion, traffic condition, and thus air quality and noise in a measurable scale.

  4. Economic consequences of mastitis and withdrawal of milk with high somatic cell count in Swedish dairy herds

    DEFF Research Database (Denmark)

    Nielsen, C; Østergaard, Søren; Emanuelson, U

    2010-01-01

    no clinical mastitis (CM) while keeping the incidence of subclinical mastitis (SCM) constant and vice versa. Six different strategies to withdraw milk with high SCC were compared. The decision to withdraw milk was based on herd-level information in three scenarios: withdrawal was initiated when the predicted......% of the herd net return given the initial incidence of mastitis. Expressed per cow-year, the avoidable cost of mastitis was €55. The costs per case of CM and SCM were estimated at €278 and €60, respectively. Withdrawing milk with high SCC was never profitable because this generated a substantial amount of milk...... resulted in less negative effect on net return. It was concluded that the current milk-pricing system makes it more profitable for farmers to sell a larger amount of milk with higher SCC than to withdraw milk with high SCC to obtain payment premiums, at least in herds with mastitis incidences within...

  5. Primary disseminated extrapulmonary multidrug resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    S K Das

    2012-01-01

    Full Text Available Disseminated tuberculosis is a common mode of presentation of tuberculosis in patients both with and without HIV/AIDS in India. However, primary multidrug resistance in disseminated tuberculosis involving only the extrapulmonary sites in an immunocompetent adult is rare. Here, we report a case of a 19-year-old man who had disseminated tuberculosis involving left pleura, pericardium, peritoneum and intraabdominal lymph nodes. He was initially taking WHO category I antituberculous drugs, but was not responding in spite of 5 months of chemotherapy. Culture of the pleural biopsy specimen grew Mycobacterium tuberculosis which was resistant to isoniazid and rifampicin. He was put on therapy for multidrug resistant tuberculosis,following 24 months of chemotherapyhe had an uneventful recovery.

  6. Chromosomal Instability Confers Intrinsic Multidrug Resistance

    DEFF Research Database (Denmark)

    Lee, Alvin J. X.; Endesfelder, David; Rowan, Andrew J.

    2011-01-01

    their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN+ displayed multidrug resistance relative to their CIN- parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse progression......-free or disease-free survival relative to patients with CIN- disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity. Cancer Res; 71(5); 1858-70. (c......Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models...

  7. [Travellers and multi-drug resistance bacteria].

    Science.gov (United States)

    Takeshita, Nozomi

    2012-02-01

    The number of international travellers has increased. There is enormous diversity in medical backgrounds, purposes of travel, and travelling styles among travellers. Travellers are hospitalized abroad because of exotic and common diseases via medical tourism. This is one way of transporting and importing human bacteria between countries, including multi-drug resistant organisms. In developing countries, the antimicrobial resistance in Shigella sp. and Salmonella sp. have been a problem, because of this trend, the first choice of antibiotics has changed in some countries. Community acquired infections as well as hospital acquired infections with MRSA, multi-drug resistance (MDR) Pseudomonas aeruginosa, and ESBL have been a problem. This review will discuss the risk of MDR bacterial infectious diseases for travellers.

  8. Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells

    Energy Technology Data Exchange (ETDEWEB)

    Fuchs, Dominik [Research Group Molecular Neuro-Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg (Germany); Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany); Daniel, Volker; Sadeghi, Mahmoud; Opelz, Gerhard [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany); Naujokat, Cord, E-mail: cord.naujokat@med.uni-heidelberg.de [Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg (Germany)

    2010-04-16

    Leukemia stem cells are known to exhibit multidrug resistance by expression of ATP-binding cassette (ABC) transporters which constitute transmembrane proteins capable of exporting a wide variety of chemotherapeutic drugs from the cytosol. We show here that human promyeloblastic leukemia KG-1a cells exposed to the histone deacetylase inhibitor phenylbutyrate resemble many characteristics of leukemia stem cells, including expression of functional ABC transporters such as P-glycoprotein, BCRP and MRP8. Consequently, KG-1a cells display resistance to the induction of apoptosis by various chemotherapeutic drugs. Resistance to apoptosis induction by chemotherapeutic drugs can be reversed by cyclosporine A, which effectively inhibits the activity of P-glycoprotein and BCRP, thus demonstrating ABC transporter-mediated drug resistance in KG-1a cells. However, KG-1a are highly sensitive to apoptosis induction by salinomycin, a polyether ionophore antibiotic that has recently been shown to kill human breast cancer stem cell-like cells and to induce apoptosis in human cancer cells displaying multiple mechanisms of drug and apoptosis resistance. Whereas KG-1a cells can be adapted to proliferate in the presence of apoptosis-inducing concentrations of bortezomib and doxorubicin, salinomycin does not permit long-term adaptation of the cells to apoptosis-inducing concentrations. Thus, salinomycin should be regarded as a novel and effective agent for the elimination of leukemia stem cells and other tumor cells exhibiting ABC transporter-mediated multidrug resistance.

  9. High-Achieving Black Students, Biculturalism, and Out-of-School STEM Learning Experiences: Exploring Some Unintended Consequences

    Science.gov (United States)

    McGee, Ebony O.

    2013-01-01

    In this article, the author discusses the complex challenges of high-achieving Black students who are successful in becoming immersed in predominately White STEM (science, technology, engineering, and mathematics) spaces and how such immersion can exacerbate their experiences of racial stereotyping and other forms of racial bias. The author…

  10. Purification of a Multidrug Resistance Transporter for Crystallization Studies

    Directory of Open Access Journals (Sweden)

    Kamela O. Alegre

    2015-03-01

    Full Text Available Crystallization of integral membrane proteins is a challenging field and much effort has been invested in optimizing the overexpression and purification steps needed to obtain milligram amounts of pure, stable, monodisperse protein sample for crystallography studies. Our current work involves the structural and functional characterization of the Escherichia coli multidrug resistance transporter MdtM, a member of the major facilitator superfamily (MFS. Here we present a protocol for isolation of MdtM to increase yields of recombinant protein to the milligram quantities necessary for pursuit of structural studies using X-ray crystallography. Purification of MdtM was enhanced by introduction of an elongated His-tag, followed by identification and subsequent removal of chaperonin contamination. For crystallization trials of MdtM, detergent screening using size exclusion chromatography determined that decylmaltoside (DM was the shortest-chain detergent that maintained the protein in a stable, monodispersed state. Crystallization trials of MdtM performed using the hanging-drop diffusion method with commercially available crystallization screens yielded 3D protein crystals under several different conditions. We contend that the purification protocol described here may be employed for production of high-quality protein of other multidrug efflux members of the MFS, a ubiquitous, physiologically and clinically important class of membrane transporters.

  11. Lipid bilayer composition influences small multidrug transporters

    Directory of Open Access Journals (Sweden)

    Curnow Paul

    2008-11-01

    Full Text Available Abstract Background Membrane proteins are influenced by their surrounding lipids. We investigate the effect of bilayer composition on the membrane transport activity of two members of the small multidrug resistance family; the Escherichia coli transporter, EmrE and the Mycobacterium tuberculosis, TBsmr. In particular we address the influence of phosphatidylethanolamine and anionic lipids on the activity of these multidrug transporters. Phosphatidylethanolamine lipids are native to the membranes of both transporters and also alter the lateral pressure profile of a lipid bilayer. Lipid bilayer lateral pressures affect membrane protein insertion, folding and activity and have been shown to influence reconstitution, topology and activity of membrane transport proteins. Results Both EmrE and TBsmr are found to exhibit a similar dependence on lipid composition, with phosphatidylethanolamine increasing methyl viologen transport. Anionic lipids also increase transport for both EmrE and TBsmr, with the proteins showing a preference for their most prevalent native anionic lipid headgroup; phosphatidylglycerol for EmrE and phosphatidylinositol for TBsmr. Conclusion These findings show that the physical state of the membrane modifies drug transport and that substrate translocation is dependent on in vitro lipid composition. Multidrug transport activity seems to respond to alterations in the lateral forces exerted upon the transport proteins by the bilayer.

  12. Dissection of mechanistic principles of a secondary multidrug efflux protein.

    Science.gov (United States)

    Fluman, Nir; Ryan, Christopher M; Whitelegge, Julian P; Bibi, Eitan

    2012-09-14

    Multidrug transporters are ubiquitous efflux pumps that provide cells with defense against various toxic compounds. In bacteria, which typically harbor numerous multidrug transporter genes, the majority function as secondary multidrug/proton antiporters. Proton-coupled secondary transport is a fundamental process that is not fully understood, largely owing to the obscure nature of proton-transporter interactions. Here we analyzed the substrate/proton coupling mechanism in MdfA, a model multidrug/proton antiporter. By measuring the effect of protons on substrate binding and by directly measuring proton binding and release, we show that substrates and protons compete for binding to MdfA. Our studies strongly suggest that competition is an integral feature of secondary multidrug transport. We identified the proton-binding acidic residue and show that, surprisingly, the substrate binds at a different site. Together, the results suggest an interesting mode of indirect competition as a mechanism of multidrug/proton antiport.

  13. When do ego threats lead to self-regulation failure? Negative consequences of defensive high self-esteem.

    Science.gov (United States)

    Lambird, Kathleen Hoffman; Mann, Traci

    2006-09-01

    High self-esteem (HSE) is increasingly recognized as heterogeneous. By measuring subtypes of HSE, the present research reevaluates the finding that HSE individuals show poor self-regulation following ego threat (Baumeister, Heatherton, & Tice, 1993). In Experiment 1, participants with HSE showed poor self-regulation after ego threat only if they also were defensive (high in self-presentation bias). In Experiment 2, two measures--self-presentation bias and implicit self-esteem--were used to subtype HSE individuals as defensive. Both operationalizations of defensive HSE predicted poor self-regulation after ego threat. The results indicate that (a) only defensive HSE individuals are prone to self-regulation failure following ego threat and (b) measures of self-presentation bias and implicit self-esteem can both be used to detect defensiveness.

  14. Consequences of a Maternal High-Fat Diet and Late Gestation Diabetes on the Developing Rat Lung

    OpenAIRE

    Michelle L Baack; Forred, Benjamin J.; Larsen, Tricia D.; Jensen, Danielle N.; Wachal, Angela L.; Khan, Muhammad Ali; Vitiello, Peter F.

    2016-01-01

    Rationale Infants born to diabetic or obese mothers are at risk of respiratory distress and persistent pulmonary hypertension of the newborn (PPHN), conceivably through fuel-mediated pathogenic mechanisms. Prior research and preventative measures focus on controlling maternal hyperglycemia, but growing evidence suggests a role for additional circulating fuels including lipids. Little is known about the individual or additive effects of a maternal high-fat diet on fetal lung development. Objec...

  15. Water, proton, and oxygen transport in high IEC, short side chain PFSA ionomer membranes: consequences of a frustrated network.

    Science.gov (United States)

    Luo, Xiaoyan; Holdcroft, Steven; Mani, Ana; Zhang, Yongming; Shi, Zhiqing

    2011-10-28

    The effect of ion exchange capacity (IEC) on the water sorption properties of high IEC, short side chain (SSC) PFSA ionomer membranes, and the relationships between water content, proton conductivity, proton mobility, water permeation, oxygen diffusion, and oxygen permeation are investigated. SSC PFSA ionomer membranes possessing 1.3, 1.4, and 1.5 mmol g(-1) IEC are compared to a series of long side chain (LSC) PFSA ionomer membranes ranging in IEC from 0.9 to 1.13 mmol g(-1). At 25 °C, fully-hydrated SSC ionomer membranes are characterized as possessing higher water contents (56-75 vol%), moderate λ values (15-18), high analytical acid concentrations (2-2.8 M), and moderate conductivity (88-115 mS/cm); but lower than anticipated effective proton mobility. Complementary measurements of water permeability, oxygen diffusion, and oxygen permeability also yield lower than expected values given their much higher water contents. Potential benefits afforded by reducing the side chain length of PFSA ionomer membranes, such as increased crystallinity, higher IEC, and high hydrated acid concentration are offset by a less-developed, frustrated hydrophilic percolation network, which provides a motivation for future improvements of transport properties for this class of material. This journal is © the Owner Societies 2011

  16. A new dynamic model for highly efficient mass transfer in aerated bioreactors and consequences for kLa identification.

    Science.gov (United States)

    Müller, Stefan; Murray, Douglas B; Machne, Rainer

    2012-12-01

    Gas-liquid mass transfer is often rate-limiting in laboratory and industrial cultures of aerobic or autotrophic organisms. The volumetric mass transfer coefficient k(L) a is a crucial characteristic for comparing, optimizing, and upscaling mass transfer efficiency of bioreactors. Reliable dynamic models and resulting methods for parameter identification are needed for quantitative modeling of microbial growth dynamics. We describe a laboratory-scale stirred tank reactor (STR) with a highly efficient aeration system (k(L) a ≈ 570 h(-1)). The reactor can sustain yeast culture with high cell density and high oxygen uptake rate, leading to a significant drop in gas concentration from inflow to outflow (by 21%). Standard models fail to predict the observed mass transfer dynamics and to identify k(L) a correctly. In order to capture the concentration gradient in the gas phase, we refine a standard ordinary differential equation (ODE) model and obtain a system of partial integro-differential equations (PIDE), for which we derive an approximate analytical solution. Specific reactor configurations, in particular a relatively short bubble residence time, allow a quasi steady-state approximation of the PIDE system by a simpler ODE model which still accounts for the concentration gradient. Moreover, we perform an appropriate scaling of all variables and parameters. In particular, we introduce the dimensionless overall efficiency κ, which is more informative than k(L) a since it combines the effects of gas inflow, exchange, and solution. Current standard models of mass transfer in laboratory-scale aerated STRs neglect the gradient in the gas concentration, which arises from highly efficient bubbling systems and high cellular exchange rates. The resulting error in the identification of κ (and hence k(L) a) increases dramatically with increasing mass transfer efficiency. Notably, the error differs between cell-free and culture-based methods of parameter identification

  17. ABC transporters and multidrug resistance in Aspergillus nidulans

    OpenAIRE

    ANDRADE, A. C.

    2000-01-01

    The term multidrug resistance (MDR) stands for simultaneous cellular resistance to chemically unrelated toxicants and is often associated with overproduction of multidrug-efflux proteins of the A TP- b inding- c assette (ABC) superfamily. The ABC transporters comprise a large and multifunctional family of proteins. Besides multidrug transporters, the superfamily includes proteins involved in transmembrane transport of various substances such as ions, amino acids, peptides, sugars, vitamins, s...

  18. The behavioral and health consequences of sleep deprivation among U.S. high school students: relative deprivation matters.

    Science.gov (United States)

    Meldrum, Ryan Charles; Restivo, Emily

    2014-06-01

    To evaluate whether the strength of the association between sleep deprivation and negative behavioral and health outcomes varies according to the relative amount of sleep deprivation experienced by adolescents. 2011 Youth Risk Behavior Survey data of high school students (N=15,364) were analyzed. Associations were examined on weighted data using logistic regression. Twelve outcomes were examined, ranging from weapon carrying to obesity. The primary independent variable was a self-reported measure of average number of hours slept on school nights. Participants who reported deprivations in sleep were at an increased risk of a number of negative outcomes. However, this varied considerably across different degrees of sleep deprivation. For each of the outcomes considered, those who slept less than 5h were more likely to report negative outcomes (adjusted odds ratios ranging from 1.38 to 2.72; prelative to sleeping 8 or more hours. However, less extreme forms of sleep deprivation were, in many instances, unrelated to the outcomes considered. Among U.S. high school students, deficits in sleep are significantly and substantively associated with a variety of negative outcomes, and this association is particularly pronounced for students achieving fewer than 5h of sleep at night. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. High-quality forage can replace concentrate when cows enter the deposition phase without negative consequences for milk production

    DEFF Research Database (Denmark)

    Hymøller, Lone; Alstrup, Lene; Larsen, Mette Krogh

    2014-01-01

    -RP), and low CFR (30:70) and low CP (14% of DM; LCFR-LP), where RP met the Danish recommendations. Cows were fed concentrate in an automatic milking unit. After calving, cows were fed HCFR-RP until entering deposition, defined as 11 kg (Jersey) or 15 kg (Holstein) of weight gain from the lowest weight after...... cows were assigned to 4 mixed rations in a 2 × 2 factorial design with 2 concentrate to forage ratios (CFR) and 2 CP levels: high CFR (40:60) and recommended CP [16% of dry matter (DM); HCFR-RP], high CFR (40:60) and low CP (14% of DM; HCFR-LP), low CFR (30:70) and recommended CP (16% of DM; LCFR...... calving. Subsequently, cows either remained on HCFR-RP or changed to one of the other mixed rations. Comparing strategies during wk 9 to 30 of lactation showed higher dry matter intake (DMI) of mixed ration on HCFR compared with LCFR and on RP compared with LP. The DMI of the concentrate was higher...

  20. Prevalence of multidrug resistant pathogens in children with urinary tract infection: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Srinivasan S, Madhusudhan NS

    2014-11-01

    Full Text Available Urinary tract infection (UTI is one of the commonest medical problems in children. It can distress the child and may cause kidney damage. Prompt diagnosis and effective treatment can prevent complications in the child. But treatment of UTI in children has now become a challenge due to the emergence of multidrug resistant bacteria. Aims & Objectives: To know the bacteriological profile and susceptibility pattern of urinary tract infections in children and to know the prevalence of multidrug resistant uropathogens. Materials & Methods: A retrospective analysis was done on all paediatric urine samples for a period of one year. A total of 1581 samples were included in the study. Antimicrobial susceptibility testing was done on samples showing significant growth by Kirby-Bauer disc diffusion method. Statistical analysis: Prevalence and pattern were analyzed using proportions and percentages. Results: E.coli was the most predominant organism (56% causing UTI in children followed by Klebsiella sp (17%. Fifty three percent of gram negative organisms isolated from children were found to be multidrug resistant. Majority of E. coli isolates were found to be highly resistant to Ampicillin (91% and Cotrimoxazole (82% and highly sensitive to Imipenem (99% and Amikacin (93%. Conclusion: Paediatric UTI was common in children less than 5 years of age. Gram negative bacteria (E. coli and Klebsiella sp were more common than gram positive bacteria. Our study revealed that multidrug resistance was higher in E.coli.

  1. Resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients.

    Science.gov (United States)

    Ahmad, Nafees; Javaid, Arshad; Sulaiman, Syed Azhar Syed; Ming, Long Chiau; Ahmad, Izaz; Khan, Amer Hayat

    2016-01-01

    Fluoroquinolones are the backbone of multidrug resistant tuberculosis treatment regimens. Despite the high burden of multidrug resistant tuberculosis in the country, little is known about drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance among multidrug resistant tuberculosis patients from Pakistan. To evaluate drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients. This was a cross-sectional study conducted at a programmatic management unit of drug resistant tuberculosis, Lady Reading Hospital Peshawar, Pakistan. Two hundred and forty-three newly diagnosed multidrug resistant tuberculosis patients consecutively enrolled for treatment at study site from January 1, 2012 to July 28, 2013 were included in the study. A standardized data collection form was used to collect patients' socio-demographic, microbiological, and clinical data. SPSS 16 was used for data analysis. High degree of drug resistance (median 5 drugs, range 2-8) was observed. High proportion of patients was resistant to all five first-line anti-tuberculosis drugs (62.6%), and more than half were resistant to second line drugs (55.1%). The majority of the patients were ofloxacin resistant (52.7%). Upon multivariate analysis previous tuberculosis treatment at private (OR=1.953, p=0.034) and public private mix (OR=2.824, p=0.046) sectors were predictors of ofloxacin resistance. The high degree of drug resistance observed, particularly to fluoroquinolones, is alarming. We recommend the adoption of more restrictive policies to control non-prescription sale of fluoroquinolones, its rational use by physicians, and training doctors in both private and public-private mix sectors to prevent further increase in fluoroquinolones resistant Mycobacterium tuberculosis strains. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

  2. Resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients

    Directory of Open Access Journals (Sweden)

    Nafees Ahmad

    Full Text Available Abstract Background Fluoroquinolones are the backbone of multidrug resistant tuberculosis treatment regimens. Despite the high burden of multidrug resistant tuberculosis in the country, little is known about drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance among multidrug resistant tuberculosis patients from Pakistan. Objective To evaluate drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients. Methods This was a cross-sectional study conducted at a programmatic management unit of drug resistant tuberculosis, Lady Reading Hospital Peshawar, Pakistan. Two hundred and forty-three newly diagnosed multidrug resistant tuberculosis patients consecutively enrolled for treatment at study site from January 1, 2012 to July 28, 2013 were included in the study. A standardized data collection form was used to collect patients’ socio-demographic, microbiological, and clinical data. SPSS 16 was used for data analysis. Results High degree of drug resistance (median 5 drugs, range 2–8 was observed. High proportion of patients was resistant to all five first-line anti-tuberculosis drugs (62.6%, and more than half were resistant to second line drugs (55.1%. The majority of the patients were ofloxacin resistant (52.7%. Upon multivariate analysis previous tuberculosis treatment at private (OR = 1.953, p = 0.034 and public private mix (OR = 2.824, p = 0.046 sectors were predictors of ofloxacin resistance. Conclusion The high degree of drug resistance observed, particularly to fluoroquinolones, is alarming. We recommend the adoption of more restrictive policies to control non-prescription sale of fluoroquinolones, its rational use by physicians, and training doctors in both private and public–private mix sectors to prevent further increase in fluoroquinolones resistant Mycobacterium tuberculosis strains.

  3. On the counterintuitive consequences of high-performance work practices in cross-border post-merger human integration

    DEFF Research Database (Denmark)

    Vasilaki, A.; Smith, Pernille; Giangreco, A.

    2012-01-01

    , such as communication, employee involvement, and team building, may not always produce the expected effects on human integration; rather, it can have the opposite effects if top management does not closely monitor the immediate results of deploying such practices. Implications for managers dealing with post......Human integration in cross-border mergers poses challenges to the successful implementation of post-merger processes. Executives often rely on human resource practices to achieve human integration in newly formed organisations. Using an ethnographic study of a merger of four banks in four countries......, this article investigates the impact of systemic and integrated human resource practices [i.e., high-performance work practices (HPWPs)] on human integration and how their implementation affects employees' behaviours and attitudes towards post-merger human integration. We find that the implementation of HPWPs...

  4. Sensitivity of (d,p) reactions to high n-p momenta and the consequences for nuclear spectroscopy studies

    CERN Document Server

    Bailey, G W; Tostevin, J A

    2016-01-01

    Theoretical models of low-energy (d,p) single-neutron transfer reactions are a crucial link between experimentation, nuclear structure and nuclear astrophysical studies. Whereas reaction models that use local optical potentials are insensitive to short-range physics in the deuteron, we show that including the inherent nonlocality of the nucleon-target interactions and realistic deuteron wave functions generates significant sensitivity to high n-p relative momenta and to the underlying nucleon-nucleon interaction. We quantify this effect upon the deuteron channel distorting potentials within the framework of the adiabatic deuteron breakup model. The implications for calculated (d,p) cross sections and spectroscopic information deduced from experiments are discussed.

  5. Selection of high temperatures for hibernation by the pocket mouse, Perognathus longimembris: ecological advantages and energetic consequences

    Energy Technology Data Exchange (ETDEWEB)

    French, A.R.

    Daily metabolism was calculated from food consumption in pocket mice, Perognathus longimembris, at 8/sup 0/C, 18/sup 0/C, and 31/sup 0/C. At temperatures below thermal neutrality for this species, daily metabolism was related to the amount of time the mice spent in torpor. Ambient temperature has no net effect on the minimum energy expenditure during a typical 5-mo hibernation season. Once an animal has accumulated a food store of approximately 130 g of millet seeds, it has the minimum energy necessary to hibernate at any environmental temperature. Such temperature compensation results from the complex effects of temperature on (1) the ratio of time of euthermy to time of torpor, (2) the energetic cost per hour of torpor, (3) the energetic cost per hour of euthermy, and (4) the energetic cost of arousal from torpor. The amount of time spent in torpor was inversely dependent on the food supply, indicating that euthermia is preferred even during the hibernation season. Mice also maximize the time of euthermia by selecting high environmental temperatures at all times of the year. Torpor probably occurs naturally only during the winter when the highest temperatures available to the mice are below thermal neutrality. The maximization of the time of euthermia reduces the chances of freezing during hibernation and enhances the animal's ability to excape from predators.

  6. Age effect on fatigue-induced limb acceleration as a consequence of high-level sustained submaximal contraction.

    Science.gov (United States)

    Huang, Chien-Ting; Huang, Chien-Chun; Young, Ming-Shing; Hwang, Ing-Shiou

    2007-08-01

    In reference to electromyographic measurement, the study was conducted to reassess differences in the behavior of fatigue-related neuromuscular function between young and elderly humans with limb acceleration (LA). Fourteen young and fourteen elderly subjects performed sustained index abduction at 75% of their maximal voluntary contractions (MVC) until task failure. Measures of neuromuscular function, including temporal/spectral features of muscle activity of the first dorsal interosseous (FDI) and LA of the index and hand, were monitored. The results showed a manifest fatigue-induced increase in LA of the index in the elderly group, but not in the young group. In contrast, only the young group developed a significant increase in amplitude of the electromyography (EMG) until task failure. Spectral analyses of LA in the index reflected marked age-dependent reorganization following muscle fatigue, with a greater reduction of relative spectral amplitude of LA in the range of 20-40 Hz, but a lesser reduction in coherence between EMG and LA in the elderly group. In line with fatigue-associated restructuring of LA, the mechanical coupling of the metacarpophalangeal joint was more severely undermined in the elderly group than in the young group. The present study manifested an age-related difference in the relative contributions of neural versus mechanical factors to muscle fatigue. Subsequent to a high-level sustained submaximal isometric contraction, a predominant mechanical failure of the musculotendon complex in the elderly was featured with LA, whereas EMG measurement characterized prevailing impairment of neuromuscular propagation in the young.

  7. High multiple paternity and low last-male sperm precedence in a hermaphroditic planarian flatworm: consequences for reciprocity patterns.

    Science.gov (United States)

    Pongratz, N; Michiels, N K

    2003-06-01

    It is difficult to predict a priori how mating success translates into fertilization success in simultaneous hermaphrodites with internal fertilization. Whereas insemination decisions will be determined by male interests, fertilization will depend on female interests, possibly leading to discrepancies between insemination and fertilization patterns. The planarian flatworm Schmidtea polychroa, a simultaneous hermaphrodite in which mating partners trade sperm was studied. Sperm can be stored for months yet individuals mate frequently. Using microsatellites, maternity and paternity data were obtained from 748 offspring produced in six groups of 10 individuals during four weeks. Adults produced young from four mates on average. Reciprocal fertilization between two mates was found in only 41 out of 110 registered mate combinations, which is clearly less than what is predicted from insemination patterns. Multiple paternity was high: > 80% of all cocoons had two to five fathers for only three to five offspring per cocoon. Because animals were collected from a natural population, 28% of all hatchlings were sired by unknown sperm donors in the field, despite a 10-day period of acclimatization and within-group mating. This percentage decreased only moderately throughout the experiment, showing that sperm can be stored and used for at least a month, despite frequent mating and sperm digestion. The immediate paternity a sperm donor could expect to obtain was only about 25%. Male reproductive success increased linearly with the number of female partners, providing support for Bateman's principle in hermaphrodites. Our results suggest that hermaphrodites do not trade fertilizations when trading sperm during insemination, lending support to the view that such conditional sperm exchange is driven by exchange of resources.

  8. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants

    Science.gov (United States)

    Ziech, Rosangela Estel; Lampugnani, Camila; Perin, Ana Paula; Sereno, Mallu Jagnow; Sfaciotte, Ricardo Antônio Pilegi; Viana, Cibeli; Soares, Vanessa Mendonça; de Almeida Nogueira Pinto, José Paes; dos Santos Bersot, Luciano

    2016-01-01

    The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL) producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%), tetracycline (91%), and the beta-lactams: ampicillin and cefachlor (45%), followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp. PMID:26887244

  9. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants

    Directory of Open Access Journals (Sweden)

    Rosangela Estel Ziech

    2016-03-01

    Full Text Available Abstract The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%, tetracycline (91%, and the beta-lactams: ampicillin and cefachlor (45%, followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp.

  10. Isolation and characterization of antimicrobial compounds in plant extracts against multidrug-resistant Acinetobacter baumannii.

    Directory of Open Access Journals (Sweden)

    Yoko Miyasaki

    Full Text Available The number of fully active antibiotic options that treat nosocomial infections due to multidrug-resistant Acinetobacter baumannii (A. baumannii is extremely limited. Magnolia officinalis, Mahonia bealei, Rabdosia rubescens, Rosa rugosa, Rubus chingii, Scutellaria baicalensis, and Terminalia chebula plant extracts were previously shown to have growth inhibitory activity against a multidrug-resistant clinical strain of A. baumannii. In this study, the compounds responsible for their antimicrobial activity were identified by fractionating each plant extract using high performance liquid chromatography, and determining the antimicrobial activity of each fraction against A. baumannii. The chemical structures of the fractions inhibiting >40% of the bacterial growth were elucidated by liquid chromatography/mass spectrometry analysis and nuclear magnetic resonance spectroscopy. The six most active compounds were identified as: ellagic acid in Rosa rugosa; norwogonin in Scutellaria baicalensis; and chebulagic acid, chebulinic acid, corilagin, and terchebulin in Terminalia chebula. The most potent compound was identified as norwogonin with a minimum inhibitory concentration of 128 µg/mL, and minimum bactericidal concentration of 256 µg/mL against clinically relevant strains of A. baumannii. Combination studies of norwogonin with ten anti-Gram negative bacterial agents demonstrated that norwogonin did not enhance the antimicrobial activity of the synthetic antibiotics chosen for this study. In conclusion, of all identified antimicrobial compounds, norwogonin was the most potent against multidrug-resistant A. baumannii strains. Further studies are warranted to ascertain the prophylactic and therapeutic potential of norwogonin for infections due to multidrug-resistant A. baumannii.

  11. Multi-drug resistant E.coli urosepsis in physicians following transrectal ultrasound guided prostate biopsies--three cases including one death.

    Science.gov (United States)

    Carlson, William H; Bell, David G; Lawen, Joseph G; Rendon, Ricardo A

    2010-04-01

    Three male physicians underwent transrectal ultrasound guided prostate biopsies for elevated prostate-specific antigen levels or irregular digital rectal exam findings. All three of these patients developed urosepsis secondary to multi-drug resistant organisms despite antibiotic prophylaxis. There are increasing reports of infectious complications following prostate biopsy caused by multi-drug resistant organisms. These cases highlight the potentially lethal risks to healthcare workers who are more likely to harbor multi-drug resistant organisms than the general population. Further research into preoperative assessment and appropriate antibiotic prophylaxis in all potentially high risk patients is warranted.

  12. Multidrug-Resistant Tuberculosis Complicated by Nosocomial Infection with Multidrug-Resistant Enterobacteriaceae

    NARCIS (Netherlands)

    Gröschel, Matthias I; Omansen, Till F; de Lange, Wiel; van der Werf, Tjip S; Lokate, M.; Bathoorn, Erik; Akkerman, Onno W; Stienstra, Ymkje

    2016-01-01

    Treatment of mycobacterial diseases such as tuberculosis (TB) entails long and intense antimicrobial therapy. TB patients are at risk of coinfection with other multidrug-resistant bacteria, such as those from Enterobacteriaceae family, because of antimicrobial selection pressure and nosocomial trans

  13. Phenomenological consequences of supersymmetry

    Energy Technology Data Exchange (ETDEWEB)

    Hinchliffe, I.; Littenberg, L.

    1982-01-01

    This report deals with the phenomenological consequences of supersymmetric theories, and with the implications of such theories for future high energy machines. It is concerned only with high energy predictions of supersymmetry; low energy consequences (for example in the K/sub o/anti K/sub o/ system) are discussed in the context of future experiments by another group, and will be mentioned briefly only in the context of constraining existing models. However a brief section is included on the implication for proton decay, although detailed experimental questions are not discussed. The report is organized as follows. Section I consists of a brief review of supersymmetry and the salient features of existing supersymmetric models; this section can be ignored by those familiar with such models since it contains nothing new. Section 2 deals with the consequences for nucleon decay of SUSY. The remaining sections then discuss the physics possibilities of various machines; e anti e in Section 3, ep in Section 4, pp (or anti pp) colliders in Section 5 and fixed target hadron machines in Section 6.

  14. Structure-function analysis of multidrug transporters in Lactococcus lactis

    NARCIS (Netherlands)

    van Veen, HW; Putman, M; Margolles, A; Sakamoto, K; Konings, WN

    1999-01-01

    The active extrusion of cytotoxic compounds from the cell by multidrug transporters is one of the major causes of failure of chemotherapeutic treatment of tumor cells and of infections by pathogenic microorganisms. A multidrug transporter in Lactococcus lactis, LmrA, is a member of the ATP-binding c

  15. ABC transporters and multidrug resistance in Aspergillus nidulans

    NARCIS (Netherlands)

    Andrade, A.C.

    2000-01-01

    The term multidrug resistance (MDR) stands for simultaneous cellular resistance to chemically unrelated toxicants and is often associated with overproduction of multidrug-efflux proteins of the A TP- b inding- c assette (ABC) superfamily. The ABC tr

  16. Inactivation of Multidrug Resistance Proteins Disrupts Both Cellular Extrusion and Intracellular Degradation of cAMP

    OpenAIRE

    Xie, Moses; Rich, Thomas C.; Scheitrum, Colleen; Conti, Marco; Richter, Wito

    2011-01-01

    In addition to xenobiotics and several other endogenous metabolites, multidrug-resistance proteins (MRPs) extrude the second-messenger cAMP from various cells. Pharmacological and/or genetic inactivation of MRPs has been shown to augment intracellular cAMP signaling, an effect assumed to be a direct consequence of the blockade of cAMP extrusion. Here we provide evidence that the augmented intracellular cAMP levels are not due exclusively to the prevention of cAMP efflux because MRP inactivati...

  17. Multidrug resistant Acinetobacter baumannii: a descriptive study in a city hospital

    Directory of Open Access Journals (Sweden)

    Pratap Siddharth

    2010-07-01

    Full Text Available Abstract Background Multidrug resistant Acinetobacter baumannii, (MRAB is an important cause of hospital acquired infection. The purpose of this study is to determine the risk factors for MRAB in a city hospital patient population. Methods This study is a retrospective review of a city hospital epidemiology data base and includes 247 isolates of Acinetobacter baumannii (AB from 164 patients. Multidrug resistant Acinetobacter baumannii was defined as resistance to more than three classes of antibiotics. Using the non-MRAB isolates as the control group, the risk factors for the acquisition of MRAB were determined. Results Of the 247 AB isolates 72% (177 were multidrug resistant. Fifty-eight percent (143/247 of isolates were highly resistant (resistant to imipenem, amikacin, and ampicillin-sulbactam. Of the 37 patients who died with Acinetobacter colonization/infection, 32 (86% patients had the organism recovered from the respiratory tract. The factors which were found to be significantly associated (p ≤ 0.05 with multidrug resistance include the recovery of AB from multiple sites, mechanical ventilation, previous antibiotic exposure, and the presence of neurologic impairment. Multidrug resistant Acinetobacter was associated with significant mortality when compared with sensitive strains (p ≤ 0.01. When surgical patients (N = 75 were considered separately, mechanical ventilation and multiple isolates remained the factors significantly associated with the development of multidrug resistant Acinetobacter. Among surgical patients 46/75 (61% grew a multidrug resistant strain of AB and 37/75 (40% were resistant to all commonly used antibiotics including aminoglycosides, cephalosporins, carbepenems, extended spectrum penicillins, and quinolones. Thirty-five percent of the surgical patients had AB cultured from multiple sites and 57% of the Acinetobacter isolates were associated with a co-infecting organism, usually a Staphylococcus or Pseudomonas. As

  18. Adipose Tissue-Specific Deletion of 12/15-Lipoxygenase Protects Mice from the Consequences of a High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Banumathi K. Cole

    2012-01-01

    Full Text Available Type 2 diabetes is associated with obesity, insulin resistance, and inflammation in adipose tissue. 12/15-Lipoxygenase (12/15-LO generates proinflammatory lipid mediators, which induce inflammation in adipose tissue. Therefore we investigated the role of 12/15-LO activity in mouse white adipose tissue in promoting obesity-induced local and systemic inflammatory consequences. We generated a mouse model for fat-specific deletion of 12/15-LO, aP2-Cre; 12/15-LOloxP/loxP, which we call ad-12/15-LO mice, and placed wild-type controls and ad-12/15-LO mice on a high-fat diet for 16 weeks and examined obesity-induced inflammation and insulin resistance. High-fat diet-fed ad-12/15-LO exhibited improved fasting glucose levels and glucose metabolism, and epididymal adipose tissue from these mice exhibited reduced inflammation and macrophage infiltration compared to wild-type mice. Furthermore, fat-specific deletion of 12/15-LO led to decreased peripheral pancreatic islet inflammation with enlarged pancreatic islets when mice were fed the high-fat diet compared to wild-type mice. These results suggest an interesting crosstalk between 12/15-LO expression in adipose tissue and inflammation in pancreatic islets. Therefore, deletion of 12/15-LO in adipose tissue can offer local and systemic protection from obesity-induced consequences, and blocking 12/15-LO activity in adipose tissue may be a novel therapeutic target in the treatment of type 2 diabetes.

  19. Characterization of multidrug-resistant diabetic foot ulcer enterococci.

    Science.gov (United States)

    Semedo-Lemsaddek, Teresa; Mottola, Carla; Alves-Barroco, Cynthia; Cavaco-Silva, Patrícia; Tavares, Luís; Oliveira, Manuela

    2016-02-01

    Diabetes mellitus is a highly prevalent chronic progressive disease with complications that include diabetic-foot ulcers. Enterococci isolated from diabetic-foot infections were identified, evaluated by macro-restriction analysis, and screened for virulence traits and antimicrobial resistance. All isolates were considered multidrug-resistant, cytolysin and gelatinase producers, and the majority also demonstrated the ability to produce biofilms. These results indicate the importance of enterococci in diabetic-foot infection development and persistence, especially regarding their biofilm-forming ability and resistance to clinically relevant antibiotics. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  20. [Multidrug-Resistant Tuberculosis by Strains of Beijing Family, in Patients from Lisbon, Portugal: Preliminary Report].

    Science.gov (United States)

    Maltez, Fernando; Martins, Teresa; Póvoas, Diana; Cabo, João; Peres, Helena; Antunes, Francisco; Perdigão, João; Portugal, Isabel

    2017-03-31

    Beijing family strains of Mycobacterium tuberculosis are associated with multidrug-resistance. Although strains of the Lisboa family are the most common among multidrug-resistant and extensively drug-resistant patients in the region, several studies have reported the presence of the Beijing family. However, the features of patients from whom they were isolated, are not yet known. Retrospective study involving 104 multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, from the same number of patients, isolated and genotyped between 1993 and 2015 in Lisbon. We assessed the prevalence of strains of both families and the epidemiologic and clinical features of those infected with Beijing family strains. Seventy-four strains (71.2%) belonged to the Lisboa family, 25 (24.0%) showed a unique genotypic pattern and five (4.8%) belonged to the Beijing family, the latter identified after 2009. Those infected with Beijing family strains were angolan (n = 1), ukrainian (n = 2) and portuguese (n = 2), mainly young-aged and, four of five immunocompetent and with no past history of tuberculosis. All had multidrug-resistant tuberculosis. We did not find any distinctive clinical or radiological features, neither a predominant resistance pattern. Cure rate was high (four patients). Although the number of infected patients with Beijing strains was small, it suggests an important proportion of primary tuberculosis, a potential for transmission in the community but also a better clinical outcome when compared to other reported strains, such as W-Beijing and Lisboa. Although Lisboa family strains account for most of the multidrug and extensively drug-resistant tuberculosis cases in Lisbon area, Beijing strains are transmitted in the city and might change the local characteristics of the epidemics.

  1. Dual-responsive mPEG-PLGA-PGlu hybrid-core nanoparticles with a high drug loading to reverse the multidrug resistance of breast cancer: an in vitro and in vivo evaluation.

    Science.gov (United States)

    Xu, Helin; Yang, Dan; Cai, Cuifang; Gou, Jingxin; Zhang, Yu; Wang, Lihui; Zhong, Haijun; Tang, Xing

    2015-04-01

    In this study, monomethoxy (polyethylene glycol)-b-P (d,l-lactic-co-glycolic acid)-b-P (l-glutamic acid) (mPEG-PLGA-PGlu) nanoparticles with the ability to rapidly respond to the endolysosomal pH and hydrolase were prepared and the pH-sensitivity was tuned by adjusting the length of the PGlu segment. The mPEG5k-PLGA20k-PGlu (60) nanoparticles were specifically responsive to an endosomal pH of 5.0-6.0 due to the configuration transition of the PGlu segment and rapidly initiated chemical degradation after incubation with proteinase k for 10 min. Doxorubicin hydrochloride (DOX), used as a model drug, was easily encapsulated into nanoparticles and the DOX-loaded nanoparticles (DOX-NPs) exhibited a pH-dependent and enzyme-sensitive release profile in vitro. The dual sensitivity enabled the rapid escape of DOX-loaded nanoparticles from the endolysosomal system to target cellular nuclei, which resulted in increased cell toxicity against MCF/ADR resistant breast cancer cells and a higher cellular uptake than free DOX. In Vivo Imaging studies indicated that the nanoparticles could continuously accumulate in the tumor tissues through EPR effects and Ex vivo Imaging biodistribution studies indicated that DOX-NPs increased drug penetration into tumors compared with normal tissues. The in vivo antitumor activity demonstrated that DOX-loaded NPs had less body loss and a significant regression of tumor growth, indicating the increased anti-tumor efficacy and lower systemic toxicity. Therefore, this dual sensitive nanoparticle system may be a potential nanocarrier to overcome the multidrug resistance exhibited by breast cancer.

  2. Prolonged weightlessness affects promyelocytic multidrug resistance.

    Science.gov (United States)

    Piepmeier, E H; Kalns, J E; McIntyre, K M; Lewis, M L

    1997-12-15

    An immortalized promyelocytic cell line was studied to detect how doxorubicin uptake is affected by microgravity. The purpose of this experiment was to identify the effect that microgravity may have on multidrug resistance in leukocytes. HL60 cells and HL60 cells resistant to anthracycline (HL60/AR) were grown in RPMI and 10% FBS. Upon reaching orbit in the Space Shuttle Endeavour, the cells were robotically mixed with doxorubicin. Three days after mixing, cells were fixed with paraformaldehyde/glutaraldehyde. Ground control experiments were conducted concurrently using a robot identical to the one used on the Shuttle. Fixed cells were analyzed within 2 weeks of launch. Confocal micrographs identified changes in cell structure (transmittance), drug distribution (fluorescence), and microtubule polymerization (fluorescence). Flight cells showed a lack of cytoskeletal polymerization resulting in an overall amorphic globular shape. Doxorubicin distribution in ground cells included a large numbers of vesicles relative to flight cells. There was a greater amount of doxorubicin present in flight cells (85% +/- 9.7) than in ground control cells (43% +/- 26) as determined by image analysis. Differences in microtubule formation between flight cells and ground cells could be partially responsible for the differences in drug distribution. Cytoskeletal interactions are critical to the function of P-glycoprotein as a drug efflux pump responsible for multidrug resistance.

  3. Multidrug-resistant breast cancer: current perspectives

    Directory of Open Access Journals (Sweden)

    Martin HL

    2014-01-01

    Full Text Available Heather L Martin,1 Laura Smith,2 Darren C Tomlinson11BioScreening Technology Group, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK; 2Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UKAbstract: Breast cancer is the most common cancer in women worldwide, and resistance to the current therapeutics, often concurrently, is an increasing clinical challenge. By understanding the molecular mechanisms behind multidrug-resistant breast cancer, new treatments may be developed. Here we review the recent advances in this understanding, emphasizing the common mechanisms underlying resistance to both targeted therapies, notably tamoxifen and trastuzumab, and traditional chemotherapies. We focus primarily on three molecular mechanisms, the phosphatidylinositide 3-kinase/Akt pathway, the role of microRNAs in gene silencing, and epigenetic alterations affecting gene expression, and discuss how these mechanisms can interact in multidrug resistance. The development of therapeutics targeting these mechanisms is also addressed.Keywords: PI3K/Akt, epigenetics, miRNA, ER, HER2, triple negative

  4. Failure to Respond to Food Resource Decline Has Catastrophic Consequences for Koalas in a High-Density Population in Southern Australia.

    Directory of Open Access Journals (Sweden)

    Desley A Whisson

    Full Text Available Understanding the ability of koalas to respond to changes in their environment is critical for conservation of the species and their habitat. We monitored the behavioural response of koalas to declining food resources in manna gum (Eucalyptus viminalis woodland at Cape Otway, Victoria, Australia, from September 2011 to November 2013. Over this period, koala population density increased from 10.1 to 18.4 koalas.ha-1. As a result of the high browsing pressure of this population, manna gum canopy condition declined with 71.4% manna gum being completely or highly defoliated in September 2013. Despite declining food resources, radio collared koalas (N = 30 exhibited high fidelity to small ranges (0.4-1.2 ha. When trees became severely defoliated in September 2013, koalas moved relatively short distances from their former ranges (mean predicted change in range centroid = 144 m and remained in areas of 0.9 to 1.0 ha. This was despite the high connectivity of most manna gum woodland, and close proximity of the study site (< 3 km to the contiguous mixed forest of the Great Otway National Park. Limited movement had catastrophic consequences for koalas with 71% (15/21 of radio collared koalas dying from starvation or being euthanased due to their poor condition between September and November 2013.

  5. Intracellular targeted co-delivery of shMDR1 and gefitinib with chitosan nanoparticles for overcoming multidrug resistance

    Science.gov (United States)

    Yu, Xiwei; Yang, Guang; Shi, Yijie; Su, Chang; Liu, Ming; Feng, Bo; Zhao, Liang

    2015-01-01

    Nowadays, multidrug resistance and side effects of drugs limit the effectiveness of chemotherapies in clinics. P-glycoprotein (P-gp) (MDR1), as a member of the ATP-binding cassette family, acts on transporting drugs into cell plasma across the membrane of cancer cells and leads to the occurrence of multidrug resistance, thus resulting in the failure of chemotherapy in cancer. The main aims of this research were to design a nanodelivery system for accomplishing the effective co-delivery of gene and antitumor drug and overcoming multidrug resistance effect. In this study, shMDR1 and gefitinib-encapsulating chitosan nanoparticles with sustained release, small particle size, and high encapsulation efficiency were prepared. The serum stability, protection from nuclease, and transfection efficiency of gene in vitro were investigated. The effects of co-delivery of shMDR1 and gefitinib in nanoparticles on reversing multidrug resistance were also evaluated by investigating the cytotoxicity, cellular uptake mechanism, and cell apoptosis on established gefitinib-resistant cells. The results demonstrated that chitosan nanoparticles entrapping gefitinib and shMDR1 had the potential to overcome the multidrug resistance and improve cancer treatment efficacy, especially toward resistant cells. PMID:26648717

  6. Erratic pollination, high selfing levels and their correlates and consequences in an altitudinally widespread above-tree-line species in the high Andes of Chile

    Science.gov (United States)

    Arroyo, Mary T. K.; Muñoz, María S.; Henríquez, Carolina; Till-Bottraud, Irène; Pérez, Fernánda

    2006-09-01

    Unfavorable temperatures and weather conditions for biotic pollination in above-tree-line alpine habitats predict self-compatibility, high levels of autogamy and small flower size ("autogamy reproductive assurance hypothesis"), or alternatively, compensatory measures such as greater flower longevity and larger display size so as to capture scarce visits and maintain outcrossing ("increased pollination probability hypothesis"). We assess these possibilities in a fine-tuned study of Chaetanthera euphrasioides (Asteraceae) populations located above-tree-line in the Andes of central Chile, where prior, independently obtained information on community flower visitation rates is available. Visitation by flies and Andrenid bees was highly erratic in all populations and among years, and the rates well below the community averages. We found evidence for high levels of self-compatibility, equally high autogamous potential, low genetic diversity and high and similar F IS in all populations studied, associated with no clear trends in floral morphology. Strong decoupling of C. euphrasioides reproductive biology with community-level pollinator availability in the alpine fails to support either of the above-mentioned hypotheses and suggests early acquisition of autogamy with present-day pollinator conditions being adequate to maintain low visitation rates at all elevations. Our study provides the only instance where alternative hypotheses on alpine breeding systems have been tested with prior access to independently quantified community-level flower visitation rates.

  7. Nanodrug Delivery in Reversing Multidrug Resistance in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sonali eKapse-Mistry

    2014-07-01

    Full Text Available Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance(MDR which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp, multidrug resistance-associated proteins(MRP1, MRP2 and breast cancer resistance protein(BCRP. Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1 gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-B. Theragnostics combining a cytotoxic agent, targeting moiety, chemosensitizing agent and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome

  8. Consequences of Delay in Postsecondary Education: Degree Attainment for 1972, 1980, and 1982 High School Graduates. E.D. TABS. National Longitudinal Study 1972. High School and Beyond.

    Science.gov (United States)

    Eagle, Eva; Schmitt, Carl

    This Department of Education (ED) Tabulation provides data in six tables on the effect of delay in entering postsecondary education (PE) on degree attainment for 1972, 1980, and 1982 high school graduates. The data compare the patterns of delay in PE among these three cohorts by pattern of enrollment, type of institution, and selected student…

  9. Patterns and Consequences of Delay in Postsecondary Education: 1972, 1980, and 1982 High School Graduates. Survey Report. National Longitudinal Study 1972. High School and Beyond.

    Science.gov (United States)

    Eagle, Eva; Schmitt, Carl

    Patterns of delay in entering 4-year, 2-year, and less-than-2-year postsecondary institutions (PIs) for 1972, 1980, and 1982 high school graduates are described. Two types of delay were studied: (1) delay in beginning at a particular type of institution, and (2) stopping out for a period before returning (i.e., leaving school for over 2 months or…

  10. Highly Resistant Salmonella enterica Serovar Typhi with a Novel gyrA Mutation Raises Questions about the Long-Term Efficacy of Older Fluoroquinolones for Treating Typhoid Fever

    Science.gov (United States)

    Koirala, Kanika Deshpande; Thanh, Duy Pham; Thapa, Sudeep Dhoj; Arjyal, Amit; Karkey, Abhilasha; Dongol, Sabina; Shrestha, Upendra Man; Farrar, Jeremy J.; Baker, Stephen

    2012-01-01

    As a consequence of multidrug resistance, clinicians are highly dependent on fluoroquinolones for treating the serious systemic infection typhoid fever. While reduced susceptibility to fluoroquinolones, which lessens clinical efficacy, is becoming ubiquitous, comprehensive resistance is exceptional. Here we report ofloxacin treatment failure in typhoidal patient infected with a novel, highly fluoroquinolone-resistant isolate of Salmonella enterica serovar Typhi. The isolation of this organism has serious implications for the long-term efficacy of ciprofloxacin and ofloxacin for typhoid treatment. PMID:22371897

  11. Consequences for selected high-elevation butterflies and moths from the spread of Pinus mugo into the alpine zone in the High Sudetes Mountains

    OpenAIRE

    Bílá, Karolína; Šipoš, Jan; Kindlmann, Pavel; Kuras, Tomáš

    2016-01-01

    Due to changes in the global climate, isolated alpine sites have become one of the most vulnerable habitats worldwide. The indigenous fauna in these habitats is threatened by an invasive species, dwarf pine (Pinus mugo), which is highly competitive and could be important in determining the composition of the invertebrate community. In this study, the association of species richness and abundance of butterflies with the extent of Pinus mugo cover at individual alpine sites was determined. Butt...

  12. Novel Bis-Indole Agents Active Against Multidrug-Resistant Acinetobacter baumannii

    Science.gov (United States)

    Jacobs, Michael R.; Bajaksouzian, Saralee; Good, Caryn E.; Butler, Michelle M.; Williams, John D.; Peet, Norton P.; Bowlin, Terry L.; Endimiani, Andrea; Bonomo, Robert A

    2013-01-01

    The in vitro activity of five novel Microbiotix bis-indole agents (MBXs) against 30 multidrug-resistant (MDR) A. baumannii (including 18 resistant to carbapenems) was evaluated. Overall, MIC90s ranged from 1-8 μg/ml, whereas those for imipenem were > 64 μg/ml. MBX 1196 was the most potent (MIC90 1 μg/ml). MBXs are compounds that are highly effective against MDR A. baumannii. PMID:21146724

  13. Consequences for selected high-elevation butterflies and moths from the spread of Pinus mugo into the alpine zone in the High Sudetes Mountains.

    Science.gov (United States)

    Bílá, Karolína; Šipoš, Jan; Kindlmann, Pavel; Kuras, Tomáš

    2016-01-01

    Due to changes in the global climate, isolated alpine sites have become one of the most vulnerable habitats worldwide. The indigenous fauna in these habitats is threatened by an invasive species, dwarf pine (Pinus mugo), which is highly competitive and could be important in determining the composition of the invertebrate community. In this study, the association of species richness and abundance of butterflies with the extent of Pinus mugo cover at individual alpine sites was determined. Butterflies at alpine sites in the High Sudetes Mountains (Mts.) were sampled using Moericke yellow water traps. The results of a Canonical Correspondence Analysis (CCA) indicated that at a local scale the area of alpine habitats is the main limiting factor for native species of alpine butterflies. Butterfly assemblages are associated with distance to the tree-line with the optimum situated in the lower forest zone. In addition the CCA revealed that biotic factors (i.e. Pinus mugo and alpine tundra vegetation) accounted for a significant amount of the variability in species data. Regionally, the CCA identified that the species composition of butterflies and moths is associated with presence and origin of Pinus mugo. Our study provides evidence that the structure of the Lepidopteran fauna that formed during the postglacial period and also the present composition of species assemblages is associated with the presence of Pinus mugo. With global warming, Pinus mugo has the potential to spread further into alpine areas and negatively affect the local species communities.

  14. Consequences for selected high-elevation butterflies and moths from the spread of Pinus mugo into the alpine zone in the High Sudetes Mountains

    Directory of Open Access Journals (Sweden)

    Karolína Bílá

    2016-06-01

    Full Text Available Due to changes in the global climate, isolated alpine sites have become one of the most vulnerable habitats worldwide. The indigenous fauna in these habitats is threatened by an invasive species, dwarf pine (Pinus mugo, which is highly competitive and could be important in determining the composition of the invertebrate community. In this study, the association of species richness and abundance of butterflies with the extent of Pinus mugo cover at individual alpine sites was determined. Butterflies at alpine sites in the High Sudetes Mountains (Mts. were sampled using Moericke yellow water traps. The results of a Canonical Correspondence Analysis (CCA indicated that at a local scale the area of alpine habitats is the main limiting factor for native species of alpine butterflies. Butterfly assemblages are associated with distance to the tree-line with the optimum situated in the lower forest zone. In addition the CCA revealed that biotic factors (i.e. Pinus mugo and alpine tundra vegetation accounted for a significant amount of the variability in species data. Regionally, the CCA identified that the species composition of butterflies and moths is associated with presence and origin of Pinus mugo. Our study provides evidence that the structure of the Lepidopteran fauna that formed during the postglacial period and also the present composition of species assemblages is associated with the presence of Pinus mugo. With global warming, Pinus mugo has the potential to spread further into alpine areas and negatively affect the local species communities.

  15. Study of multidrug resistance and radioresistance

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yoon Koo; Yoo, Young Do

    1999-04-01

    We investigated the mechanism of 5-FU, adriamycin, radiation resistance in Korean gastric cancer cells. First we investigated the relation between Rb and multidrug resistance. Rb stable transfectants exhibited 5- to 10- fold more resistance to adriamycin than the control cells. These Rb transfectants showed increased MDR1 expression. We also investigated up-regulation in radiation-resistant tumor tissues. HSP27, MRP-8, GST, and NKEF-B were up-regulated in radiation resistant tumor. Expression of NKEF-B was also increased by radiation exposure in Head and Neck cells. These results demonstrated that NKEF-B is a stress response protein and it may have an important role in radiation resistance.

  16. Yeast ABC proteins involved in multidrug resistance.

    Science.gov (United States)

    Piecuch, Agata; Obłąk, Ewa

    2014-03-01

    Pleiotropic drug resistance is a complex phenomenon that involves many proteins that together create a network. One of the common mechanisms of multidrug resistance in eukaryotic cells is the active efflux of a broad range of xenobiotics through ATP-binding cassette (ABC) transporters. Saccharomyces cerevisiae is often used as a model to study such activity because of the functional and structural similarities of its ABC transporters to mammalian ones. Numerous ABC transporters are found in humans and some are associated with the resistance of tumors to chemotherapeutics. Efflux pump modulators that change the activity of ABC proteins are the most promising candidate drugs to overcome such resistance. These modulators can be chemically synthesized or isolated from natural sources (e.g., plant alkaloids) and might also be used in the treatment of fungal infections. There are several generations of synthetic modulators that differ in specificity, toxicity and effectiveness, and are often used for other clinical effects.

  17. Implications of Public Reporting of Risk-Adjusted Mortality Following Percutaneous Coronary Intervention: Misperceptions and Potential Consequences for High-Risk Patients Including Nonsurgical Patients.

    Science.gov (United States)

    Gupta, Anuj; Yeh, Robert W; Tamis-Holland, Jacqueline E; Patel, Shalin H; Guyton, Robert A; Klein, Lloyd W; Rab, Tanveer; Kirtane, Ajay J

    2016-10-24

    Assessment of clinical outcomes such as 30-day mortality following coronary revascularization procedures has historically been used to spur quality improvement programs. Public reporting of risk-adjusted outcomes is already mandated in several states, and proposals to further expand public reporting have been put forward as a means of increasing transparency and potentially incentivizing high quality care. However, for public reporting of outcomes to be considered a useful surrogate of procedural quality of care, several prerequisites must be met. First, the reporting measure must be truly representative of the quality of the procedure itself, rather than be dominated by other underlying factors, such as the overall level of illness of a patient. Second, to foster comparisons among physicians and institutions, the metric requires accurate ascertainment of and adjustment for differences in patient risk profiles. This is particularly relevant for high-risk clinical patient scenarios. Finally, the potential deleterious consequences of public reporting of a quality metric should be considered prior to expanding the use of public reporting more broadly. In this viewpoint, the authors review in particular the characterization of high-risk patients currently treated by percutaneous coronary interventional procedures, assessing the adequacy of clinical risk models used in this population. They then expand upon the limitations of 30-day mortality as a quality metric for percutaneous coronary intervention, addressing the strengths and limitations of this metric, as well as offering suggestions to enhance its future use in public reporting. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  18. Antibiotic Synergy Interaction against Multidrug-Resistant Pseudomonas aeruginosa Isolated from an Abattoir Effluent Environment

    Directory of Open Access Journals (Sweden)

    Etinosa O. Igbinosa

    2012-01-01

    Full Text Available Pseudomonas aeruginosa is an opportunistic pathogen in environmental waters with a high prevalence of multidrug resistance. In this study the synergistic efficacy of synergy antibiotic combinations in multidrug-resistant P. aeruginosa strains isolated from an abattoir effluent was investigated. Water samples were processed using membrane filtration; Pseudomonas was isolated with Pseudomonas Isolation Agar and confirmed using polymerase chain reaction with specie-specific primer. Susceptibility studies and in vitro synergy interaction testing were carried out, employing agar dilution and Etest procedure, respectively. Resistance was noted for clinically relevant antipseudomonal agents tested. Finding from antibiotic synergy interaction studies revealed that cefepime, imipenem, and meropenem combined with amikacin resulted in statistically significant (P<0.0001 in vitro antibiotics synergy interaction, indicating the possible use of this regimen in treatment of pseudomonal infections.

  19. Severe infection with multidrug-resistant Salmonella choleraesuis in a young patient with primary sclerosing cholangitis

    Science.gov (United States)

    Ferstl, Philip G; Reinheimer, Claudia; Jozsa, Katalin; Zeuzem, Stefan; Kempf, Volkhard AJ; Waidmann, Oliver; Grammatikos, Georgios

    2017-01-01

    Massive global spread of multidrug-resistant (MDR) Salmonella spp. expressing extended-spectrum beta-lactamase (ESBL) and additional resistance to fluoroquinolones has often been attributed to high international mobility as well as excessive use of oral antibiotics in livestock farming. However, MDR Salmonella spp. have not been mentioned as a widespread pathogen in clinical settings so far. We demonstrate the case of a 25-year-old male with primary sclerosing cholangitis who tested positive for MDR Salmonella enterica serotype Choleraesuis expressing ESBL and fluoroquinolone resistance. The pathogen was supposedly acquired during a trip to Thailand, causing severe fever, cholangitis and pancreatitis. To our knowledge, this is the first report of Salmonella enterica serotype Choleraesuis in Europe expressing such a multidrug resistance pattern. ESBL resistance of Salmonella enterica spp. should be considered in patients with obstructive biliary tract pathology and travel history in endemic countries. PMID:28373776

  20. Doctors Seeing More HIV Patients with Multidrug Resistance

    Science.gov (United States)

    ... html Doctors Seeing More HIV Patients With Multidrug Resistance People resistant to older medication also have problems ... to modern drugs had HIV mutations linked with resistance to older drugs called thymidine analogues. Among patients ...

  1. Isolation and characterization of multidrug-resistant side population ...

    African Journals Online (AJOL)

    Isolation and characterization of multidrug-resistant side population cells in prostate carcinoma. ... PROMOTING ACCESS TO AFRICAN RESEARCH ... Keywords: Side population cells, ABC transporters, Cancer stem cells, Chemotherapy, ...

  2. Epidemiologic analysis: Prophylaxis and multidrug-resistance in surgery

    Directory of Open Access Journals (Sweden)

    H. Solís-Téllez

    2017-04-01

    Conclusions: The prophylactic guidelines are not strictly adhered to in our environment. There was a significant association between the development of nosocomial infections from multidrug-resistant germs and admission to the intensive care unit.

  3. Fluo-cAMP is transported by multidrug resistance-associated protein isoform 4 in rat choroid plexus.

    NARCIS (Netherlands)

    Reichel, V.; Klas, J.; Fricker, G.; Masereeuw, R.

    2010-01-01

    The choroid plexuses (CP) are responsible for transport of micronutrients into brain and clearance of toxic compounds, in addition to its barrier function and production of CSF. Multidrug resistance-associated protein (Mrp) 4 is one transport protein highly expressed in CP tissue and is characterize

  4. Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis

    NARCIS (Netherlands)

    Dijkstra, J.A.; van Altena, R.; Akkerman, O. W.; de Lange, W. C. M.; Proost, J. H.; van der Werf, T. S.; Kosterink, J. G. W.; Alffenaar, J. W. C.

    2015-01-01

    Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population phar

  5. Fluo-cAMP is transported by multidrug resistance-associated protein isoform 4 in rat choroid plexus.

    NARCIS (Netherlands)

    Reichel, V.; Klas, J.; Fricker, G.; Masereeuw, R.

    2010-01-01

    The choroid plexuses (CP) are responsible for transport of micronutrients into brain and clearance of toxic compounds, in addition to its barrier function and production of CSF. Multidrug resistance-associated protein (Mrp) 4 is one transport protein highly expressed in CP tissue and is

  6. Transcriptomic analysis of multidrug-resistant Salmonella enterica serovar Typhimurium isolates that exhibit a tetracycline-induced invasion phenotype

    Science.gov (United States)

    Salmonella is a highly prevalent bacterial food-borne disease in the U.S. and is estimated to cause over 1 million cases, 19,000 hospitalizations, and 350 deaths every year. Multidrug-resistant (MDR) Salmonella has emerged as an important food safety concern as it is associated with increased morbi...

  7. Effects of treatment interruption patterns on treatment success among patients with multidrug-resistant tuberculosis in Armenia and Abkhazia.

    NARCIS (Netherlands)

    Bastard, M.; Sanchez-Padilla, E.; Hewison, C.; Hayrapetyan, A.; Khurkhumal, S.; Varaine, F.; Bonnet, M.

    2015-01-01

    BACKGROUND: The success of the current treatment regimen for multidrug-resistant (MDR) tuberculosis is poor partly owing to a high default rate. Many studies have explored predictors of poor outcomes, but very few have assessed the effects of treatment interruptions on treatment outcomes for MDR

  8. Managing and understanding risk perception of surface leaks from CCS sites: risk assessment for emerging technologies and low-probability, high-consequence events

    Science.gov (United States)

    Augustin, C. M.

    2015-12-01

    Carbon capture and storage (CCS) has been suggested by the Intergovernmental Panel on Climate Change as a partial solution to the greenhouse gas emissions problem. As CCS has become mainstream, researchers have raised multiple risk assessment issues typical of emerging technologies. In our research, we examine issues occuring when stored carbon dioxide (CO2) migrates to the near-surface or surface. We believe that both the public misperception and the physical reality of potential environmental, health, and commercial impacts of leak events from such subsurface sites have prevented widespread adoption of CCS. This paper is presented in three parts; the first is an evaluation of the systemic risk of a CCS site CO2 leak and models indicating potential likelihood of a leakage event. As the likelihood of a CCS site leak is stochastic and nonlinear, we present several Bayesian simulations for leak events based on research done with other low-probability, high-consequence gaseous pollutant releases. Though we found a large, acute leak to be exceptionally rare, we demonstrate potential for a localized, chronic leak at a CCS site. To that end, we present the second piece of this paper. Using a combination of spatio-temporal models and reaction-path models, we demonstrate the interplay between leak migrations, material interactions, and atmospheric dispersion for leaks of various duration and volume. These leak-event scenarios have implications for human, environmental, and economic health; they also have a significant impact on implementation support. Public acceptance of CCS is essential for a national low-carbon future, and this is what we address in the final part of this paper. We demonstrate that CCS remains unknown to the general public in the United States. Despite its unknown state, we provide survey findings -analyzed in Slovic and Weber's 2002 framework - that show a high unknown, high dread risk perception of leaks from a CCS site. Secondary findings are a

  9. Multidrug therapy for leprosy: a game changer on the path to elimination.

    Science.gov (United States)

    Smith, Cairns S; Aerts, Ann; Saunderson, Paul; Kawuma, Joseph; Kita, Etsuko; Virmond, Marcos

    2017-09-01

    Leprosy is present in more than 100 countries, where it remains a major cause of peripheral neuropathy and disability. Attempts to eliminate the disease have faced various obstacles, including characteristics of the causative bacillus Mycobacterium leprae: the long incubation period, limited knowledge about its mode of transmission, and its poor growth on culture media. Fortunately, the leprosy bacillus is sensitive to several antibiotics. The first antibiotic to be widely used for leprosy treatment was dapsone in the 1950s, which had to be taken over several years and was associated with increasing bacterial resistance. Therefore, in 1981, WHO recommended that all registered patients with leprosy should receive combination therapy with three antibiotics: rifampicin, clofazimine, and dapsone. Global implementation of this highly effective multidrug therapy took about 15 years. In 1985, 5·3 million patients were receiving multidrug therapy; by 1991, this figure had decreased to 3·1 million (a decrease of 42%) and, by 2000, to 597 232 (a decrease of almost 90%). This reduction in the number of patients registered for treatment was due to shortening of the treatment regimen and achievement of 100% coverage with multidrug therapy. This achievement, which owed much to WHO and the donors of the multidrug therapy components, prompted WHO in 1991 to set a global target of less than one case per 10 000 population by 2000 to eliminate the disease as a public health problem. All but 15 countries achieved this target. Since 2000, about 250 000 new cases of leprosy have been detected every year. We believe an all-out campaign by a global leprosy coalition is needed to bring that figure down to zero. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Influence of multidrug resistance on {sup 18}F-FCH cellular uptake in a glioblastoma model

    Energy Technology Data Exchange (ETDEWEB)

    Vanpouille, Claire; Jeune, Nathalie le; Clotagatide, Anthony; Dubois, Francis [Universite de Lyon, Universite Jean Monnet-Cancer Research Group IFRESIS 143, Saint-Etienne (France); Kryza, David; Janier, Marc [Hospice Civils de Lyon, Quai Des Celestins, CREATIS, UMR CNRS, Lyon (France); Perek, Nathalie [Universite de Lyon, Universite Jean Monnet-Cancer Research Group IFRESIS 143, Saint-Etienne (France); Laboratoire de Biophysique, Faculte de Medecine, Saint-Etienne (France)

    2009-08-15

    Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like {sup 18}F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and {sup 18}F-FCH tracer uptake. We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model. As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89{+-}0.14; U87MG-CIS: 1.27{+-}0.18; U87MG-DOX: 1.33{+-}0.13) in line with accelerated choline metabolism and aggressive phenotype. FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance. (orig.)

  11. Household Risk Factors for Colonization with Multidrug-Resistant Staphylococcus aureus Isolates

    Science.gov (United States)

    Davis, Meghan F.; Peterson, Amy E.; Julian, Kathleen G.; Greene, Wallace H.; Price, Lance B.; Nelson, Kenrad; Whitener, Cynthia J.; Silbergeld, Ellen K.

    2013-01-01

    Antimicrobial resistance, particularly in pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), limits treatment options and increases healthcare costs. To understand patient risk factors, including household and animal contact, potentially associated with colonization with multidrug-resistant MRSA isolates, we performed a prospective study of case patients colonized with MRSA on admission to a rural tertiary care hospital. Patients were interviewed and antimicrobial resistance patterns were tested among isolates from admitted patients colonized with MRSA in 2009–10. Prevalence of resistance was compared by case-patient risk factors and length-of-stay outcome among 88 MRSA case patients. Results were compared to NHANES 2003–04. Overall prevalence of multidrug resistance (non-susceptibility to ≥four antimicrobial classes) in MRSA nasal isolates was high (73%) and was associated with a 1.5-day increase in subsequent length of stay (p = 0.008). History of hospitalization within the past six months, but not antimicrobial use in the same time period, was associated with resistance patterns. Within a subset of working-age case patients without recent history of hospitalization, animal contact was potentially associated with multidrug resistance. History of hospitalization, older age, and small household size were associated with multidrug resistance in NHANES data. In conclusion, recent hospitalization of case patients was predictive of antimicrobial resistance in MRSA isolates, but novel risk factors associated with the household may be emerging in CA-MRSA case patients. Understanding drivers of antimicrobial resistance in MRSA isolates is important to hospital infection control efforts, relevant to patient outcomes and to indicators of the economic burden of antimicrobial resistance. PMID:23359808

  12. Biofilm formation in clinical isolates of nosocomial Acinetobacter baumannii and its relationship with multidrug resistance

    Institute of Scientific and Technical Information of China (English)

    Ebrahim Babapour; Azam Haddadi; Reza Mirnejad; Seyed-Abdolhamid Angaji; Nour Amirmozafari

    2016-01-01

    Objective: To check biofilm formation by Acinetobacter baumannii(A. baumannii)clinical isolates and show their susceptibility to different antibiotics and investigate a possible link between establishment of biofilm and multidrug resistance.Methods: This study was performed on clinical samples collected from patients with nosocomial infections in three hospitals of Tehran. Samples were initially screened by culture and biochemical tests for the presence of different species of Acinetobacter. Identifications were further confirmed by PCR assays. Their susceptibilities to 11 antibiotics of different classes were determined by disc diffusion method according to Clinical and Laboratory Standards Institute guidelines. The ability to produce biofilm was investigated using methods: culture on Congo red agar, microtiter plate, and test tube method.Results: From the overall clinical samples, 156 specimens were confirmed to contain A. baumannii. The bacteria were highly resistant to most antibiotics except polymyxin B.Of these isolates, 10.26% were able to produce biofilms as shown on Congo red agar.However, the percentage of bacteria with positive biofilm in test tube, standard microtiter plate, and modified microtiter plate assays were 48.72%, 66.66%, and 73.72%, respectively. At least 92% of the biofilm forming isolates were multidrug resistant.Conclusions: Since most of the multidrug resistant strains produce biofilm, it seems necessary to provide continuous monitoring and determination of antibiotic susceptibility of clinical A. baumannii. This would help to select the most appropriate antibiotic for treatment.

  13. Biofilm formation in clinical isolates of nosocomial Acinetobacter baumannii and its relationship with multidrug resistance

    Institute of Scientific and Technical Information of China (English)

    Ebrahim Babapour; Azam Haddadi; Reza Mirnejad; Seyed-Abdolhamid Angaji; Nour Amirmozafari

    2016-01-01

    Objective: To check biofilm formation by Acinetobacter baumannii (A. baumannii) clinical isolates and show their susceptibility to different antibiotics and investigate a possible link between establishment of biofilm and multidrug resistance. Methods: This study was performed on clinical samples collected from patients with nosocomial infections in three hospitals of Tehran. Samples were initially screened by culture and biochemical tests for the presence of different species of Acinetobacter. Iden-tifications were further confirmed by PCR assays. Their susceptibilities to 11 antibiotics of different classes were determined by disc diffusion method according to Clinical and Laboratory Standards Institute guidelines. The ability to produce biofilm was investigated using methods:culture on Congo red agar, microtiter plate, and test tube method. Results: From the overall clinical samples, 156 specimens were confirmed to contain A. baumannii. The bacteria were highly resistant to most antibiotics except polymyxin B. Of these isolates, 10.26% were able to produce biofilms as shown on Congo red agar. However, the percentage of bacteria with positive biofilm in test tube, standard microtiter plate, and modified microtiter plate assays were 48.72%, 66.66%, and 73.72%, respec-tively. At least 92%of the biofilm forming isolates were multidrug resistant. Conclusions: Since most of the multidrug resistant strains produce biofilm, it seems necessary to provide continuous monitoring and determination of antibiotic susceptibility of clinical A. baumannii. This would help to select the most appropriate antibiotic for treatment.

  14. Treatment of complicated intra-abdominal infections in the era of multi-drug resistant Bacteria

    Directory of Open Access Journals (Sweden)

    Herzog T

    2010-11-01

    Full Text Available Abstract The management of severe intra-abdominal infections remains a major challenge facing surgeons and intensive care physicians, because of its association with high morbidity and mortality. Surgical management and intensive care medicine have constantly improved, but in the recent years a rapidly continuing emergence of resistant pathogens led to treatment failure secondary to infections with multi-drug resistant bacteria. In secondary peritonitis the rate of resistant germs at the initial operation is already 30%. The lack of effective antibiotics against these pathogens resulted in the development of new broad-spectrum compounds and antibiotics directed against resistant germs. But so far no "super-drug" with efficacy against all resistant bacteria exists. Even more, soon after their approval, reports on resistance against these novel drugs have been reported, or the drugs were withdrawn from the market due to severe side effects. Since pharmaceutical companies reduced their investigations on antibiotic research, only few new antimicrobial derivates are available. In abdominal surgery you may be in fear that in the future more and more patients with tertiary peritonitis secondary to multi-drug resistant species are seen with an increase of mortality after secondary peritonitis. This article reviews the current treatment modalities for complicated intra-abdominal infections with special reference to the antibiotic treatment of complicated intra-abdominal infections with multi-drug resistant species.

  15. Reducing the price of treatment for multidrug-resistant tuberculosis through the Global Drug Facility.

    Science.gov (United States)

    Lunte, Kaspars; Cordier-Lassalle, Thierry; Keravec, Joel

    2015-04-01

    Many countries have limited experience of securing the best prices for drugs and have little negotiating power. This is particularly true for the complex, lengthy and expensive regimens used to treat multidrug-resistant tuberculosis. The Stop TB Partnership's Global Drug Facility is dedicated to improving worldwide access to antituberculosis medicines and diagnostic techniques that meet international quality standards. The Global Drug Facility is able to secure price reductions through competitive tendering among prequalified drug manufacturers and by consolidating orders to achieve large purchase volumes. Consolidating the market in this way increases the incentives for suppliers of quality-assured medicines. In 2013 the Global Drug Facility reduced the price of the second-line drugs it supplies for multidrug-resistant tuberculosis: the overall cost of the longest and most expensive treatment regimen for a patient decreased by 26% - from 7890 United States dollars (US$) in 2011 to US$ 5822 in 2013. The price of treatment for multidrug-resistant tuberculosis supplied by the Global Drug Facility was reduced by consolidating orders to achieve large purchase volumes, by international, competitive bidding and by the existence of donor-funded medicine stockpiles. The rise in the number of suppliers of internationally quality-assured drugs was also important. The savings achieved from lower drug costs could be used to increase the number of patients on high-quality treatment.

  16. Communicating Low-Probability High-Consequence Risk, Uncertainty and Expert Confidence: Induced Seismicity of Deep Geothermal Energy and Shale Gas.

    Science.gov (United States)

    Knoblauch, Theresa A K; Stauffacher, Michael; Trutnevyte, Evelina

    2017-08-10

    Subsurface energy activities entail the risk of induced seismicity including low-probability high-consequence (LPHC) events. For designing respective risk communication, the scientific literature lacks empirical evidence of how the public reacts to different written risk communication formats about such LPHC events and to related uncertainty or expert confidence. This study presents findings from an online experiment (N = 590) that empirically tested the public's responses to risk communication about induced seismicity and to different technology frames, namely deep geothermal energy (DGE) and shale gas (between-subject design). Three incrementally different formats of written risk communication were tested: (i) qualitative, (ii) qualitative and quantitative, and (iii) qualitative and quantitative with risk comparison. Respondents found the latter two the easiest to understand, the most exact, and liked them the most. Adding uncertainty and expert confidence statements made the risk communication less clear, less easy to understand and increased concern. Above all, the technology for which risks are communicated and its acceptance mattered strongly: respondents in the shale gas condition found the identical risk communication less trustworthy and more concerning than in the DGE conditions. They also liked the risk communication overall less. For practitioners in DGE or shale gas projects, the study shows that the public would appreciate efforts in describing LPHC risks with numbers and optionally risk comparisons. However, there seems to be a trade-off between aiming for transparency by disclosing uncertainty and limited expert confidence, and thereby decreasing clarity and increasing concern in the view of the public. © 2017 Society for Risk Analysis.

  17. Unusual Complication of Multidrug Resistant Tuberculosis

    Directory of Open Access Journals (Sweden)

    Prerna Sharma

    2017-01-01

    Full Text Available Introduction. Capreomycin is a second-line drug often used for multidrug-resistant tuberculosis which can result in nephrotoxic effects similar to other aminoglycosides. We describe a case of capreomycin induced Bartter-like syndrome with hypocalcemic tetany. Case Report. 23-year-old female patient presented with carpopedal spasms and tingling sensations in hands. Patient was being treated with capreomycin for two months for tuberculosis. On further investigation, hypocalcemia, hyponatremia, hypomagnesemia, hypokalemia, and hypochloremic metabolic alkalosis were noted. Vitamin D and serum PTH levels were within normal limits. Hypercalciuria was confirmed by urine calcium/creatinine ratio. Calcium, potassium, and magnesium supplementation was given and capreomycin was discontinued. Electrolytes normalized in two days after cessation of capreomycin with no further abnormalities on repeat investigations. Discussion. Aminoglycosides can result in renal tubular dysfunction leading to Fanconi syndrome, Bartter syndrome, and distal tubular acidosis. Impaired mitochondrial function in the tubular cells has been hypothesized as the possible cause of these tubulopathies. Acquired Bartter-like syndrome phenotypically resembles autosomal dominant type 5 Bartter syndrome. Treatment consists of correction of electrolyte abnormalities, indomethacin, and potassium-sparing diuretics. Prompt diagnosis and treatment of severe dyselectrolytemia are warranted in patients on aminoglycoside therapy.

  18. Tripartite assembly of RND multidrug efflux pumps

    Science.gov (United States)

    Daury, Laetitia; Orange, François; Taveau, Jean-Christophe; Verchère, Alice; Monlezun, Laura; Gounou, Céline; Marreddy, Ravi K. R.; Picard, Martin; Broutin, Isabelle; Pos, Klaas M.; Lambert, Olivier

    2016-02-01

    Tripartite multidrug efflux systems of Gram-negative bacteria are composed of an inner membrane transporter, an outer membrane channel and a periplasmic adaptor protein. They are assumed to form ducts inside the periplasm facilitating drug exit across the outer membrane. Here we present the reconstitution of native Pseudomonas aeruginosa MexAB-OprM and Escherichia coli AcrAB-TolC tripartite Resistance Nodulation and cell Division (RND) efflux systems in a lipid nanodisc system. Single-particle analysis by electron microscopy reveals the inner and outer membrane protein components linked together via the periplasmic adaptor protein. This intrinsic ability of the native components to self-assemble also leads to the formation of a stable interspecies AcrA-MexB-TolC complex suggesting a common mechanism of tripartite assembly. Projection structures of all three complexes emphasize the role of the periplasmic adaptor protein as part of the exit duct with no physical interaction between the inner and outer membrane components.

  19. Mechanisms of multidrug resistance in cancer.

    Science.gov (United States)

    Gillet, Jean-Pierre; Gottesman, Michael M

    2010-01-01

    The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by numerous mechanisms including decreased drug uptake, increased drug efflux, activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis, etc. In the first part of this chapter, we briefly summarize the current knowledge on individual cellular mechanisms responsible for MDR, with a special emphasis on ATP-binding cassette transporters, perhaps the main theme of this textbook. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been crowned with success. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict the development of resistance and lead to treatments designed to circumvent it. Our thoughts about translational research needed to achieve significant progress in the understanding of this complex phenomenon are therefore discussed in a third section. The pleotropic response of cancer cells to chemotherapy is summarized in a concluding diagram.

  20. High temperature oxidation of metals: vacancy injection and consequences on the mechanical properties; Consequences de l'oxydation haute temperature sur l'injection de defauts et le comportement mecanique des materiaux metalliques

    Energy Technology Data Exchange (ETDEWEB)

    Perusin, S

    2004-11-15

    The aim of this work is to account for the effects of the high temperature oxidation of metals on their microstructure and their mechanical properties. 'Model' materials like pure nickel, pure iron and the Ni-20Cr alloy are studied. Nickel foils have been oxidised at 1000 C on one side only in laboratory air, the other side being protected from oxidation by a reducing atmosphere. After the oxidation treatment, the unoxidized face was carefully examined by using an Atomic Force Microscope (AFM). Grain boundaries grooves were characterised and their depth were compared to the ones obtained on the same sample heat treated in the reducing atmosphere during the same time. They are found to be much deeper in the case of the single side oxidised samples. It is shown that this additional grooving is directly linked to the growth of the oxide scale on the opposite side and that it can be explained by the diffusion of the vacancies produced at the oxide scale - metal interface, across the entire sample through grain boundaries. Moreover, the comparison between single side oxidised samples and samples oxidised on both sides points out that voids in grain boundaries are only observed in this latter case proving the vacancies condensation in the metal when the two faces are oxidised. The role of the carbon content and the sample's geometry on this phenomenon is examined in detail. The diffusion of vacancies is coupled with the transport of oxygen so that a mechanism of oxygen transport by vacancies is suggested. The tensile tests realised at room temperature on nickel foils (bamboo microstructure) show that the oxide scale can constitute a barrier to the emergence of dislocations at the metal surface. Finally, the Ni-20Cr alloy is tested in tensile and creep tests between 25 and 825 C in oxidising or reducing atmospheres. (author)

  1. Vertical Equity Consequences of Very High Cigarette Tax Increases: If the Poor Are the Ones Smoking, How Could Cigarette Tax Increases Be Progressive?

    Science.gov (United States)

    Colman, Gregory J.; Remler, Dahlia K.

    2008-01-01

    Cigarette smoking is concentrated among low-income groups. Consequently, cigarette taxes are considered regressive. However, if poorer individuals are much more price sensitive than richer individuals, then tax increases would reduce smoking much more among the poor and their cigarette tax expenditures as a share of income would rise by much less…

  2. Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps.

    Science.gov (United States)

    Yılmaz, Çiğdem; Özcengiz, Gülay

    2017-06-01

    The discovery of penicillin followed by streptomycin, tetracycline, cephalosporins and other natural, semi-synthetic and synthetic antimicrobials completely revolutionized medicine by reducing human morbidity and mortality from most of the common infections. However, shortly after they were introduced to clinical practice, the development of resistance was emerged. The decreasing interest from antibiotic industry in spite of rapid global emergence of antibiotic resistance is a tough dilemma from the pointview of public health. The efficiency of antimicrobial treatment is determined by both pharmacokinetics and pharmacodynamics. In spite of their selective toxicity, antibiotics still cause severe, life-threatening adverse reactions in host body mostly due to defective drug metabolism or excessive dosing regimen. The present article aims at updating current knowledge on pharmacokinetics/pharmacodynamics concepts and models, toxicity of antibiotics as well as antibiotic resistance mechanisms, resistome analyses and search for novel antibiotic resistance determinants with special emphasis given to the-state-of-the-art regarding multidrug efflux pumps and their additional physiological functions in stress adaptation and virulence of bacteria. All these issues are highly linked to each other and not only important for most efficient and prolonged use of current antibiotics, but also for discovery and development of new antibiotics and novel inhibitors of antibiotic resistance determinants of pathogens. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Multidrug resistant citrobacter: an unusual cause of liver abscess.

    Science.gov (United States)

    Kumar, Prabhat; Ghosh, Soumik; Rath, Deepak; Gadpayle, A K

    2013-04-22

    Liver abscesses are infectious, space occupying lesions in the liver, the two most common abscesses being pyogenic and amoebic. A pyogenic liver abscess (PLA) is a rare condition with a reported incidence of 20 per 100 000 hospital admissions in the western population. The right lobe of the liver is the most common site in both types of liver abscess. Clinical presentation is elusive with complaints of fever, right upper quadrant pain in the abdomen and hepatomegaly with or without jaundice. The aetiology of PLA has changed in the past few decades and may be of biliary, portal, arterial or traumatic origin, but many cases are still cryptogenic. The most common organisms causing PLA are Gram-negative aerobes, especially Escherichia coli and Klebsiella pneumoniae. Studies have shown a high degree of antimicrobial susceptibility of isolated organism resulting in an overall lower mortality in PLA. Here, we present a case of PLA caused by multidrug-resistant Citrobacter freundii, which is an unusual organism to be isolated.

  4. [Multidrug-resistant tuberculosis: challenges of a global emergence].

    Science.gov (United States)

    Comolet, T

    2015-10-01

    Drug-resistant tuberculosis, in particular Multi-Drug Resistant (MDR-TB) is an increasing global concern and a major burden for some developing countries, especially the BRICS. It is assumed that every year roughly 350 000 new MDR-TB cases occur in the world, on average in 20.5% of TB patients that have been previously treated but also in 3.5% of persons that have never been on TB treatment before. The global distribution of cases is very heterogeneous and is now better understood thanks to a growing number of specific surveys and routine surveillance systems: incidence is much higher in southern Africa and in all countries formerly part of the USSR. Countries with weak health systems and previously inefficient TB control programs are highly vulnerable to MDR epidemics because program failures do help creating, maintaining and spreading resistances. Global response is slowly rolled out and diagnosis capacities are on the rise (mostly with genotypic methods) but adequate and successful treatment and care is still limited to a minority of global cases. From a public health perspective the MDR-TB growing epidemics will not be controlled merely by the introduction of few new antibiotics because it is also linked to patient's compliance and adequate case management supported by efficient TB program. In depth quality improvement will only be achieved after previous errors are thoroughly analyzed and boldly corrected.

  5. Prevalence and risk factors for carriage of multi-drug resistant Staphylococci in healthy cats and dogs.

    Science.gov (United States)

    Gandolfi-Decristophoris, Paola; Regula, Gertraud; Petrini, Orlando; Zinsstag, Jakob; Schelling, Esther

    2013-01-01

    We investigated the distribution of commensal staphylococcal species and determined the prevalence of multi-drug resistance in healthy cats and dogs. Risk factors associated with the carriage of multi-drug resistant strains were explored. Isolates from 256 dogs and 277 cats were identified at the species level using matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The diversity of coagulase-negative Staphylococci (CNS) was high, with 22 species in dogs and 24 in cats. Multi-drug resistance was frequent (17%) and not always associated with the presence of the mecA gene. A stay in a veterinary clinic in the last year was associated with an increased risk of colonisation by multi-drug resistant Staphylococci (OR = 2.4, 95% CI: 1.1~5.2, p value LRT = 0.04). When identifying efficient control strategies against antibiotic resistance, the presence of mechanisms other than methicillin resistance and the possible role of CNS in the spread of resistance determinants should be considered.

  6. Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants

    Science.gov (United States)

    Blanco, Paula; Hernando-Amado, Sara; Reales-Calderon, Jose Antonio; Corona, Fernando; Lira, Felipe; Alcalde-Rico, Manuel; Bernardini, Alejandra; Sanchez, Maria Blanca; Martinez, Jose Luis

    2016-01-01

    Bacterial multidrug efflux pumps are antibiotic resistance determinants present in all microorganisms. With few exceptions, they are chromosomally encoded and present a conserved organization both at the genetic and at the protein levels. In addition, most, if not all, strains of a given bacterial species present the same chromosomally-encoded efflux pumps. Altogether this indicates that multidrug efflux pumps are ancient elements encoded in bacterial genomes long before the recent use of antibiotics for human and animal therapy. In this regard, it is worth mentioning that efflux pumps can extrude a wide range of substrates that include, besides antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals or bacterial metabolites, among others. In the current review, we present information on the different functions that multidrug efflux pumps may have for the bacterial behaviour in different habitats as well as on their regulation by specific signals. Since, in addition to their function in non-clinical ecosystems, multidrug efflux pumps contribute to intrinsic, acquired, and phenotypic resistance of bacterial pathogens, the review also presents information on the search for inhibitors of multidrug efflux pumps, which are currently under development, in the aim of increasing the susceptibility of bacterial pathogens to antibiotics. PMID:27681908

  7. Resistant plasmid profile analysis of multidrug resistant Escherichia coli isolated from urinary tract infections in Abeokuta, Nigeria.

    Science.gov (United States)

    Akingbade, O; Balogun, S; Ojo, D; Akinduti, P; Okerentugba, P O; Nwanze, J C; Okonko, I O

    2014-12-01

    Multi-drug resistant Escherichia coli has become a major threat and cause of many urinary tract infections (UTIs) in Abeokuta, Nigeria. This study was carried out to determine the resistant plasmids of multidrug resistant Escherichia coli isolated from (Urinary tract infections)UTIs in Abeokuta. A total of 120 Escherichia coli isolates were obtained from urine samples collected from patients attending inpatient and outpatient clinics presenting UTI; with their biodata. Antibiotics susceptibility was performed and multi-drug resistant isolates were selected for plasmid profiling. Plasmids were extracted by the alkaline lysis method, electrophoresed on 0.8% agarose gel and profiled using a gel-photo documentation system gel. Escherichia coli isolates obtained shows high resistance to cloxacillin (92.5%), amoxicillin (90.8%), ampicillin (90.8%), erythromycin (75.8%), cotrimoxazole (70.0%), streptomycin (70.0%) and tetracycline (68.3%) while 85.8% and 84.2% were susceptible to gentamycin and ceftazidime respectively. Sixteen Escherichia coli strains were observed to be resistant to more than two classes of antibiotics. The resistant plasmid DNA was detectable in 6(37.5%) of the 16 multidrug resistant Escherichia coli having single sized plasmids of the same weight 854bp and were all resistant to erythromycin, cefuroxime, cloxacillin, amoxicillin, ampicillin and cotrimoxazole. This study has highlighted the emergence of multidrug resistant R-plasmids among Escherichia coli causing urinary tract infections in Abeokuta, Nigeria. There is a high level of resistance to many antimicrobials that are frequently used in Abeokuta, Nigeria.

  8. The MSSA consequence tables

    Energy Technology Data Exchange (ETDEWEB)

    Sacks, I.J.

    1988-01-01

    The Master Safeguards and Security Agreement (MSSA) is the mechanism through which the U.S. Department of Energy is implementing a policy of graded safeguards. Under this concept, the level of protection provided to a target is proportional to the ''cost'' of the loss of the target. Cost is measured by use of the conditional risk equation in which the protection system ineffectiveness is multiplied by the consequence to society of a successful adversary attempt. The consequences which are used in the MSSA process were developed in the summer of the 1986 by a consensus of DOE personnel and contractors. There are separate consequence tables for theft of SNM, radiological sabotage. The consequence values in the tables were deliberately not cross-normalized. The consequence values in each table correspond to a societal or DOE cost, for example, the consequence values for SNM theft compared to a normalized estimate of the expected number of fatalities from a successful use of the stolen material times an estimate of the likelihood of successfully using the material. Consequence values for radiological sabotage correspond very roughly to a similar expected fatality level. Values for industrial sabotage are an estimate of the impact on DOE weapons production or impact on the nuclear weapons stockpile. Problems have arisen in the use of these tables and are discussed in the paper.

  9. Establishment of a human hepatoma multidrug resistant cell line in vitro

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To establish a multidrug-resistant hepatoma cell line(SK-Hep-1),and to investigate its biological characteristics.METHODS:A highly invasive SK-Hep-1 cell line of human hepatocellular carcinoma,also known as malignant hepatoma was incubated with a high concentration of cisplatin(CDDP) to establish a CDDP-resistant cell subline(SK-Hep-1/CDDP).The 50% inhibitory dose(IC50) values and the resistance indexes [(IC50 SK-Hep-1/CDDP)/(IC50 SK-Hep-1)] for other chemotherapeutic agents and the growth curve of cell...

  10. Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Torsten Dittrich

    2012-10-01

    Full Text Available The inhibition of ABC (ATP binding cassette transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrug-resistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.

  11. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria?

    Directory of Open Access Journals (Sweden)

    Exner, Martin

    2017-04-01

    Full Text Available In the past years infections caused by multidrug-resistant Gram-negative bacteria have dramatically increased in all parts of the world. This consensus paper is based on presentations, subsequent discussions and an appraisal of current literature by a panel of international experts invited by the Rudolf Schülke Stiftung, Hamburg. It deals with the epidemiology and the inherent properties of Gram-negative bacteria, elucidating the patterns of the spread of antibiotic resistance, highlighting reservoirs as well as transmission pathways and risk factors for infection, mortality, treatment and prevention options as well as the consequences of their prevalence in livestock. Following a global, One Health approach and based on the evaluation of the existing knowledge about these pathogens, this paper gives recommendations for prevention and infection control measures as well as proposals for various target groups to tackle the threats posed by Gram-negative bacteria and prevent the spread and emergence of new antibiotic resistances.

  12. Multidrug resistance in tumour cells: characterisation of the multidrug resistant cell line K562-Lucena 1

    Directory of Open Access Journals (Sweden)

    VIVIAN M. RUMJANEK

    2001-03-01

    Full Text Available Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multidrug resistant cell line, originally selected for resistance to the Vinca alkaloid vincristine and derived from the human erythroleukaemia cell K562. This cell line, named Lucena 1, overexpresses P-glycoprotein and have its resistance reversed by the chemosensitisers verapamil, trifluoperazine and cyclosporins A, D and G. Furthermore, we demonstrated that methylene blue was capable of partially reversing the resistance in this cell line. On the contrary, the use of 5-fluorouracil increased the resistance of Lucena 1. In addition to chemotherapics, Lucena 1 cells were resistant to ultraviolet A radiation and hydrogen peroxide and failed to mobilise intracellular calcium when thapsigargin was used. Changes in the cytoskeleton of this cell line were also observed.A resistência a múltiplos fármacos é o principal obstáculo no tratamento de pacientes com câncer. O mecanismo responsável pela resistência múltipla mais bem caracterizado envolve a expressão do produto do gene MDR-1, a glicoproteína P. Entretanto, o processo de resistência tem fatores múltiplos. Estudos de mecanismos de resistência m��ltipla a fármacos têm dependido da análise de linhagens celulares tumorais que foram selecionadas e apresentam reatividade cruzada a uma ampla faixa de agentes anti-tumorais. Este trabalho caracteriza uma linhagem celular com múltipla resistência a fármacos, selecionada originalmente pela resistência ao alcalóide de Vinca vincristina e derivado

  13. Multidrug transport by ATP binding cassette transporters : a proposed two-cylinder engine mechanism

    NARCIS (Netherlands)

    van Veen, HW; Higgins, CF; Konings, WN

    2001-01-01

    The elevated expression of ATP binding cassette (ABC) multidrug transporters in multidrug-resistant cells interferes with the drug-based control of cancers and infectious pathogenic microorganisms. Multidrug transporters interact directly with the drug substrates. This review summarizes current insi

  14. Consequences of Accounting Standards

    Institute of Scientific and Technical Information of China (English)

    Cai Mingyue

    2009-01-01

    The first part of this article consists in attempting to highlight the importance of concerning about the economic consequences and introducing the foundation of economic consequence theory, proposing that the accounting standard is not only a kind of technical standard, it also has the economic consequences, so it becomes the object which all quarters special interest group gambles to get latent profit. After general characterization of the economic consequences in the second part, the article gives a description of the influences the change of accounting standards bring to the government, the ordinary investors and creditors, the auditors, and the enterprise, establishing a framework that how those groups react as the economic consequences in the third part. The fourth section compare technical theory and accounting standards theory, links the basic norms of accounting such as conservatism, relevance and reliability to the methods of escaping the harm of economic consequences, then proposes some specific methods in the formuhtion of accounting standard. Finally, the article utilizes the methods to settle the problems appearing in Chinese market.

  15. Structures of BmrR-Drug Complexes Reveal a Rigid Multidrug Binding Pocket And Transcription Activation Through Tyrosine Expulsion

    Energy Technology Data Exchange (ETDEWEB)

    Newberry, K.J.; Huffman, J.L.; Miller, M.C.; Vazquez-Laslop, N.; Neyfakh, A.A.; Brennan, R.G.

    2009-05-22

    BmrR is a member of the MerR family and a multidrug binding transcription factor that up-regulates the expression of the bmr multidrug efflux transporter gene in response to myriad lipophilic cationic compounds. The structural mechanism by which BmrR binds these chemically and structurally different drugs and subsequently activates transcription is poorly understood. Here, we describe the crystal structures of BmrR bound to rhodamine 6G (R6G) or berberine (Ber) and cognate DNA. These structures reveal each drug stacks against multiple aromatic residues with their positive charges most proximal to the carboxylate group of Glu-253 and that, unlike other multidrug binding pockets, that of BmrR is rigid. Substitution of Glu-253 with either alanine (E253A) or glutamine (E253Q) results in unpredictable binding affinities for R6G, Ber, and tetraphenylphosphonium. Moreover, these drug binding studies reveal that the negative charge of Glu-253 is not important for high affinity binding to Ber and tetraphenylphosphonium but plays a more significant, but unpredictable, role in R6G binding. In vitro transcription data show that E253A and E253Q are constitutively active, and structures of the drug-free E253A-DNA and E253Q-DNA complexes support a transcription activation mechanism requiring the expulsion of Tyr-152 from the multidrug binding pocket. In sum, these data delineate the mechanism by which BmrR binds lipophilic, monovalent cationic compounds and suggest the importance of the redundant negative electrostatic nature of this rigid drug binding pocket that can be used to discriminate against molecules that are not substrates of the Bmr multidrug efflux pump.

  16. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    1997-01-01

    We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...... P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced...

  17. Multidrug-Resistant Gram-Negative Bacilli: Infection Control Implications.

    Science.gov (United States)

    Adler, Amos; Friedman, N Deborah; Marchaim, Dror

    2016-12-01

    Antimicrobial resistance is a common iatrogenic complication of both modern life and medical care. Certain multidrug resistant and extensively drug resistant Gram-negative organisms pose the biggest challenges to health care today, predominantly owing to a lack of therapeutic options. Containing the spread of these organisms is challenging, and in reality, the application of multiple control measures during an evolving outbreak makes it difficult to measure the relative impact of each measure. This article reviews the usefulness of various infection control measures in containing the spread of multidrug-resistant Gram-negative bacilli. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. RISK FACTORS FOR INEFFECTIVE CHEMOTHERAPY IN PATIENTS WITH MULTIDRUG-RESISTANT TUBERCULOSIS

    Directory of Open Access Journals (Sweden)

    O. V. Filinyuk

    2014-01-01

    Full Text Available The social, clinical, radiological, and bacteriological causes of DOTS-PLUS failure were analyzed. According to the findings, diagnosis at the early stage of fibrocavernous tuberculosis, respiratory failure, or hemoptysis in the presence of chronic bronchitis, gastrointestinal and urinary tract diseases, as well as in prison increased the risk of poor therapy outcome. Massive bacterial excretion, high rate of secondary resistance development in Mycobacterium tuberculosis, and its drug resistance to five agents or more are maximally associated with treatment failure in patients with multidrug-resistant tuberculosis.

  19. Multidrug-resistant Streptococcus pneumoniae isolates from healthy Ghanaian preschool children

    DEFF Research Database (Denmark)

    Dayie, Nicholas Tete Kwaku Dzifa; Arhin, Reuben E.; Newman, Mercy J.

    2015-01-01

    Streptococcus pneumoniae is the cause of high mortality among children worldwide. Antimicrobial treatment and vaccination are used to control pneumococcal infections. In Ghana, data on antimicrobial resistance and the prevalence of multidrug-resistant pneumococcal clones are scarce; hence, the aim...... of this study was to determine the antibiogram of S. pneumoniae recovered from Ghanaian children younger than six years of age and to what extent resistances were due to the spread of certain sero- and multilocus sequence typing (MLST) types. The susceptibility of 115 pneumococcal isolates, recovered...

  20. Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells

    DEFF Research Database (Denmark)

    Ozvegy, C; Litman, Thomas; Szakács, G

    2001-01-01

    ABCG2 (also called MXR (3), BCRP (4), or ABCP (5) is a recently-identified ABC half-transporter, which causes multidrug resistance in cancer. Here we report that the expression of the ABCG2 protein in Sf9 insect cells resulted in a high-capacity, vanadate-sensitive ATPase activity in isolated...... transporter, probably working as a homodimer. We suggest that the Sf9 cell membrane ATPase system is an efficient tool for examining the interactions of ABCG2 with pharmacological agents....

  1. Multi-drug resistant tuberculosis in Chuuk State Federated States of Micronesia, 2008-2009.

    Science.gov (United States)

    Fred, D; Desai, M; Song, R; Bamrah, S; Pavlin, B I; Heetderks, A; Ekiek, M J

    2010-04-01

    Multi-drug resistant tuberculosis (MDR TB) is a growing public health concern, particularly for the Pacific, where rates of tuberculosis infection are extremely high. In May 2008, a cluster of patients with MDR TB were identified in Chuuk State, Federated States of Micronesia. A multi-agency investigation led to the eventual discovery of 21 cases, and over 100 latent TB infections. Incomplete implementation of Directly Observed Therapy (DOT) and contact investigation were major contributors to the outbreak. The problem of MDR TB in Chuuk was controlled only after a concerted effort on the part of multiple agencies coupled with the highest level of political commitment.

  2. Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation.

    Science.gov (United States)

    Sharma, C; Kumar, N; Pandey, R; Meis, J F; Chowdhary, A

    2016-09-01

    Candida auris is an emerging multidrug resistant yeast that causes nosocomial fungaemia and deep-seated infections. Notably, the emergence of this yeast is alarming as it exhibits resistance to azoles, amphotericin B and caspofungin, which may lead to clinical failure in patients. The multigene phylogeny and amplified fragment length polymorphism typing methods report the C. auris population as clonal. Here, using whole genome sequencing analysis, we decipher for the first time that C. auris strains from four Indian hospitals were highly related, suggesting clonal transmission. Further, all C. auris isolates originated from cases of fungaemia and were resistant to fluconazole (MIC >64 mg/L).

  3. Enterococcus faecalis as multidrug resistance strains in clinical isolates in Imam Reza Hospital in Kermanshah, Iran.

    Science.gov (United States)

    Mohammadi, F; Ghafourian, S; Mohebi, R; Taherikalani, M; Pakzad, I; Valadbeigi, H; Hatami, V; Sadeghifard, N

    2015-01-01

    The current study aimed to investigate the prevalence of vancomycin-resistant Enterococcus in E. faecalis and E. faecium and antimicrobial susceptibility patterns, then dominant genes responsible for vancomycin resistance were determined. For this propose, 180 clinical isolates of Enterococcus were subjected for identification and antibiotic susceptibility assay. Then, the gene responsible vancomycin resistant strains were determined. The results demonstrated the E. faecalis as a dominant Enterococcus. Resistance to erythromycin was dominant and multidrug resistance strains observed in E. faecalis. vanA was responsible for vancomycin resistance. In conclusion, a high rate of resistance to antibiotics in Enterococcus is clearly problematic, and a novel strategy is needed to decrease resistance in Enterococcus.

  4. Strong in vitro activities of two new rifabutin analogs against multidrug-resistant Mycobacterium tuberculosis.

    Science.gov (United States)

    García, Ana-Belén; Palacios, Juan J; Ruiz, María-Jesús; Barluenga, José; Aznar, Fernando; Cabal, María-Paz; García, José María; Díaz, Natalia

    2010-12-01

    Two new rifabutin analogs, RFA-1 and RFA-2, show high in vitro antimycobacterial activities against Mycobacterium tuberculosis. MIC values of RFA-1 and RFA-2 were ≤0.02 μg/ml against rifamycin-susceptible strains and 0.5 μg/ml against a wide selection of multidrug-resistant strains, compared to ≥50 μg/ml for rifampin and 10 μg/ml for rifabutin. Molecular dynamic studies indicate that the compounds may exert tighter binding to mutants of RNA polymerase that have adapted to the rifamycins.

  5. Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily

    Directory of Open Access Journals (Sweden)

    Sanath Kumar

    2013-01-01

    Full Text Available Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS.

  6. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia

    Science.gov (United States)

    Morales-López, Soraya E.; Parra-Giraldo, Claudia M.; Ceballos-Garzón, Andrés; Martínez, Heidys P.; Rodríguez, Gerson J.; Álvarez-Moreno, Carlos A.

    2017-01-01

    Candida auris is an emerging multidrug-resistant fungus that causes a wide range of symptoms. We report finding 17 cases of C. auris infection that were originally misclassified but correctly identified 27.5 days later on average. Patients with a delayed diagnosis of C. auris had a 30-day mortality rate of 35.2%. PMID:27983941

  7. Pharmacokinetics of ertapenem in patients with multidrug-resistant tuberculosis

    NARCIS (Netherlands)

    van Rijn, Sander P; van Altena, Richard; Akkerman, Onno W; van Soolingen, Dick; van der Laan, Tridia; de Lange, Wiel C M; Kosterink, Jos G W; van der Werf, Tjip S; Alffenaar, Jan-Willem C

    2016-01-01

    Treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is becoming more challenging because of increased levels of drug resistance against second-line TB drugs. One promising group of antimicrobial drugs is carbapenems. Ertapenem is an attractive carbapenem for

  8. Multidrug-resistant tuberculosis and leprosy: An unsolved mystery

    Directory of Open Access Journals (Sweden)

    Robin Gupta

    2017-01-01

    Full Text Available Tuberculosis (TB and leprosy are two age-old infections, which we are facing even today. With drug-resistant TB on the rise, we report a case of multidrug-resistant TB with leprosy, which has never been reported previously. The peculiar course of this case forces us to rethink about the upcoming challenges due to their cooccurrence.

  9. Multidrug-Resistant Pathogens in Hospitalized Syrian Children

    Science.gov (United States)

    Kassem, Diana Faour; Hoffmann, Yoav; Shahar, Naama; Ocampo, Smadar; Salomon, Liora; Zonis, Zeev

    2017-01-01

    Since 2013, wounded and ill children from Syria have received treatment in Israel. Screening cultures indicated that multidrug-resistant (MDR) pathogens colonized 89 (83%) of 107 children. For 58% of MDR infections, the pathogen was similar to that identified during screening. MDR screening of these children is valuable for purposes of isolation and treatment. PMID:27618479

  10. Confronting multidrug-resistant Acinetobacter baumannii: a review.

    Science.gov (United States)

    Neonakis, Ioannis K; Spandidos, Demetrios A; Petinaki, Efthimia

    2011-02-01

    Multidrug-resistant Acinetobacter baumannii (MDR-AB) infections are difficult to treat owing to the extremely limited armamentarium. The present review reports all available treatment options against MDR-AB, including single molecules, combination schemes, and alternative modes of antimicrobial administration. Additionally, a group of recently reported peptides with anti-MDR-AB activity is described.

  11. Multidrug-resistant tuberculosis and leprosy: An unsolved mystery.

    Science.gov (United States)

    Gupta, Robin; Garg, Kranti; Bhalla, Mala; Janmeja, Ashok K

    2017-01-01

    Tuberculosis (TB) and leprosy are two age-old infections, which we are facing even today. With drug-resistant TB on the rise, we report a case of multidrug-resistant TB with leprosy, which has never been reported previously. The peculiar course of this case forces us to rethink about the upcoming challenges due to their cooccurrence.

  12. Multidrug-resistant tuberculosis in Europe, 2010-2011

    NARCIS (Netherlands)

    Gunther, G.; Leth, F. van; Alexandru, S.; Altet, N.; Avsar, K.; Bang, D.; Barbuta, R.; Bothamley, G.; Ciobanu, A.; Crudu, V.; Davilovits, M.; Dedicoat, M.; Duarte, R.; Gualano, G.; Kunst, H.; Lange, W. de; Leimane, V.; Magis-Escurra Ibanez, C.; McLaughlin, A.M.; Muylle, I.; Polcova, V.; Pontali, E.; Popa, C; Rumetshofer, R.; Skrahina, A.; Solodovnikova, V.; Spinu, V.; Tiberi, S.; Viiklepp, P.; Lange, C.

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with

  13. Multidrug-Resistant Tuberculosis in Europe, 2010-2011

    NARCIS (Netherlands)

    Guenther, Gunar; van Leth, Frank; Alexandru, Sofia; Altet, Neus; Avsar, Korkut; Bang, Didi; Barbuta, Raisa; Bothamley, Graham; Ciobanu, Ana; Crudu, Valeriu; Danilovits, Manfred; Dedicoat, Martin; Duarte, Raquel; Gualano, Gina; Kunst, Heinke; de Lange, Wiel; Leimane, Vaira; Magis-Escurra, Cecile; McLaughlin, Anne-Marie; Muylle, Inge; Polcova, Veronika; Pontalli, Emanuele; Popa, Christina; Rumetshofer, Rudolf; Skrahina, Alena; Solodovnikova, Varvara; Spinu, Victor; Tiberi, Simon; Viiklepp, Piret; Lange, Christoph

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with

  14. Infection by multidrug-resistant Elizabethkingia meningoseptica: case reports

    Directory of Open Access Journals (Sweden)

    Jailton Lobo da Costa Lima

    2014-12-01

    Full Text Available We report two cases of sepsis in critically ill patients in two tertiary care hospitals in Recife-PE, Brazil. The first case is an 87-year-old patient with chronic myeloid leukemia and sepsis; and the second case is a 93-year-old patient with prostate cancer and septic shock caused by multidrug-resistant (MDR Elizabethkingia meningoseptica.

  15. Epidemiology of Primary Multidrug-Resistant Tuberculosis, Vladimir Region, Russia.

    Science.gov (United States)

    Ershova, Julia V; Volchenkov, Grigory V; Kaminski, Dorothy A; Somova, Tatiana R; Kuznetsova, Tatiana A; Kaunetis, Natalia V; Cegielski, J Peter; Kurbatova, Ekaterina V

    2015-11-01

    We studied the epidemiology of drug-resistant tuberculosis (TB) in Vladimir Region, Russia, in 2012. Most cases of multidrug-resistant TB (MDR TB) were caused by transmission of drug-resistant strains, and >33% were in patients referred for testing after mass radiographic screening. Early diagnosis of drug resistance is essential for preventing transmission of MDR TB.

  16. Multidrug-resistant tuberculosis, Somalia, 2010-2011.

    Science.gov (United States)

    Sindani, Ireneaus; Fitzpatrick, Christopher; Falzon, Dennis; Suleiman, Bashir; Arube, Peter; Adam, Ismail; Baghdadi, Samiha; Bassili, Amal; Zignol, Matteo

    2013-03-01

    In a nationwide survey in 2011, multidrug-resistant tuberculosis (MDR TB) was found in 5.2% and 40.8% of patients with new and previously treated TB, respectively. These levels of drug resistance are among the highest ever documented in Africa and the Middle East. This finding presents a serious challenge for TB control in Somalia.

  17. Characterization of a multidrug-resistant, novel Bacteroides genomospecies.

    Science.gov (United States)

    Salipante, Stephen J; Kalapila, Aley; Pottinger, Paul S; Hoogestraat, Daniel R; Cummings, Lisa; Duchin, Jeffrey S; Sengupta, Dhruba J; Pergam, Steven A; Cookson, Brad T; Butler-Wu, Susan M

    2015-01-01

    Metronidazole- and carbapenem-resistant Bacteroides fragilis are rare in the United States. We isolated a multidrug-resistant anaerobe from the bloodstream and intraabdominal abscesses of a patient who had traveled to India. Whole-genome sequencing identified the organism as a novel Bacteroides genomospecies. Physicians should be aware of the possibility for concomitant carbapenem- and metronidazole-resistant Bacteroides infections.

  18. Multidrug transporters and antibiotic resistance in Lactococcus lactis

    NARCIS (Netherlands)

    Poelarends, GJ; Mazurkiewicz, P; Konings, WN

    2002-01-01

    The Gram-positive bacterium Lactococcus lactis produces two distinct multidrug transporters, designated LmrA and LmrP, that both confer resistance to a wide variety of cationic lipophilic cytotoxic compounds as well as to many clinically relevant antibiotics. While LmrP is a proton/drug antiporter

  19. Bedaquiline in the multidrug-resistant tuberculosis treatment: Belarus experience

    Directory of Open Access Journals (Sweden)

    Alena Skrahina

    2016-01-01

    Conclusion: Our interim results on safety and effectiveness of bedaquiline-containing regimens in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB patients are encouraging. They will add value to understanding role and place of this new anti-TB drug in M/XDR-TB treatment.

  20. Multidrug transporters and antibiotic resistance in Lactococcus lactis

    NARCIS (Netherlands)

    Poelarends, GJ; Mazurkiewicz, P; Konings, WN

    2002-01-01

    The Gram-positive bacterium Lactococcus lactis produces two distinct multidrug transporters, designated LmrA and LmrP, that both confer resistance to a wide variety of cationic lipophilic cytotoxic compounds as well as to many clinically relevant antibiotics. While LmrP is a proton/drug antiporter t

  1. Multidrug-resistant tuberculosis in Europe, 2010-2011

    DEFF Research Database (Denmark)

    Günther, Gunar; van Leth, Frank; Alexandru, Sofia

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients wi...

  2. Genome evolution and plasticity of Serratia marcescens, an important multidrug-resistant nosocomial pathogen.

    Science.gov (United States)

    Iguchi, Atsushi; Nagaya, Yutaka; Pradel, Elizabeth; Ooka, Tadasuke; Ogura, Yoshitoshi; Katsura, Keisuke; Kurokawa, Ken; Oshima, Kenshiro; Hattori, Masahira; Parkhill, Julian; Sebaihia, Mohamed; Coulthurst, Sarah J; Gotoh, Naomasa; Thomson, Nicholas R; Ewbank, Jonathan J; Hayashi, Tetsuya

    2014-08-01

    Serratia marcescens is an important nosocomial pathogen that can cause an array of infections, most notably of the urinary tract and bloodstream. Naturally, it is found in many environmental niches, and is capable of infecting plants and animals. The emergence and spread of multidrug-resistant strains producing extended-spectrum or metallo beta-lactamases now pose a threat to public health worldwide. Here we report the complete genome sequences of two carefully selected S. marcescens strains, a multidrug-resistant clinical isolate (strain SM39) and an insect isolate (strain Db11). Our comparative analyses reveal the core genome of S. marcescens and define the potential metabolic capacity, virulence, and multidrug resistance of this species. We show a remarkable intraspecies genetic diversity, both at the sequence level and with regards genome flexibility, which may reflect the diversity of niches inhabited by members of this species. A broader analysis with other Serratia species identifies a set of approximately 3,000 genes that characterize the genus. Within this apparent genetic diversity, we identified many genes implicated in the high virulence potential and antibiotic resistance of SM39, including the metallo beta-lactamase and multiple other drug resistance determinants carried on plasmid pSMC1. We further show that pSMC1 is most closely related to plasmids circulating in Pseudomonas species. Our data will provide a valuable basis for future studies on S. marcescens and new insights into the genetic mechanisms that underlie the emergence of pathogens highly resistant to multiple antimicrobial agents.

  3. Prevalence of Multidrug Resistant Mycobacterium tuberculosis by Mycobacteria growth

    Directory of Open Access Journals (Sweden)

    Livani S

    2012-01-01

    Full Text Available Background and objectives: Identification and monitoring ofmultidrugresistant Mycobacterium tuberculosis strains (MDR ishighlighted by the high risk of their spreading in different areas.Prevalence of these strains was evaluated in Golestan province innortheast of Iran.Material and Methods: Drug susceptibility testing to Isoniazid andrifampin was carried out for 148 clinical samples that had grown inMycobacteria growth indicator tube (MGIT system, according to themanufacturer's instructions (Becton-Dickinson, USA. The associationof drug resistance frequency with demographic characteristics andgrowth time were investigated. The appropriate statistical tests, X2 andstudent Ttest were performed for comparison of these variants. A pvalue>0.05 was considered significant in all cases.Results: The turnaround time required for growth of Mycobacteriumtuberculosis in MGIT system was between 2 to 55 days (mean16.3±10.4 days. Of all samples studied, 17.6% and 3.4% wereresistant to Isoniazid and rifampin, respectively, and 3.4% (5 sampleswere MDR (CI 95%; 1- 6%. The turnaround time required fordetermining MDR cases was 9.6 days. No statistically significantassociation was found between the resistance to the drugs and none ofthe factors including sex, age, type of clinical sample, and positivity ofthe smear.Conclusion: The prevalence of MDR in the studied region wasdetermined to be 3.4% which is similar to the country-wideevaluations. The turnaround time for Mycobacterium growth and antidrug susceptibility result can be shortened by MGIT method.Key words: Mycobacterium tuberculosis, Mycobacterium GrowthIndicator Tube, Multidrug Resistant

  4. Reconnecting Actions and Consequences

    DEFF Research Database (Denmark)

    Petersen, Marianne Graves; Ludvigsen, Martin; Krogh, Peter

    2009-01-01

    In this paper we present a brief critique of the current approach to the design of pervasive computing artifacts; claiming that this in itself promotes solutions that prevent end-users from accessing and understanding the consequences of their actions in terms of energy sustainability, specifical...

  5. Acromegaly : irreversible clinical consequences

    NARCIS (Netherlands)

    Wassenaar, Monica Johanna Elisabeth

    2010-01-01

    This thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the considerable prevalence of diverse morbidity in these patients, during the active phase of the disease but even

  6. Acromegaly : irreversible clinical consequences

    NARCIS (Netherlands)

    Wassenaar, Monica Johanna Elisabeth

    2010-01-01

    This thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the considerable prevalence of diverse morbidity in these patients, during the active phase of the disease but even

  7. Hepatic steatosis : metabolic consequences

    NARCIS (Netherlands)

    Boer, Adriana Maria den

    2006-01-01

    In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism

  8. Reconnecting Actions and Consequences

    DEFF Research Database (Denmark)

    Ludvigsen, Martin; Krogh, Peter; Petersen, Marianne Graves

    2009-01-01

    In this paper we present a brief critique of the current approach to the design of pervasive computing artifacts; claiming that this in itself promotes solutions that prevent end-users from accessing and understanding the consequences of their actions in terms of energy sustainability, specifically...

  9. Hepatic steatosis : metabolic consequences

    NARCIS (Netherlands)

    Boer, Adriana Maria den

    2006-01-01

    In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism unde

  10. Normal modal preferential consequence

    CSIR Research Space (South Africa)

    Britz, K

    2012-12-01

    Full Text Available of necessitation holds for the corresponding consequence relations, as one would expect it to. We present a representation result for this tightened framework, and investigate appropriate notions of entailment in this context|normal entailment, and a rational...

  11. Innate aminoglycoside resistance of Achromobacter xylosoxidans is due to AxyXY-OprZ, an RND-type multidrug efflux pump.

    Science.gov (United States)

    Bador, Julien; Amoureux, Lucie; Blanc, Emmanuel; Neuwirth, Catherine

    2013-01-01

    Achromobacter xylosoxidans is an innately multidrug-resistant pathogen which is emerging in cystic fibrosis (CF) patients. We characterized a new resistance-nodulation-cell division (RND)-type multidrug efflux pump, AxyXY-OprZ. This system is responsible for the intrinsic high-level resistance of A. xylosoxidans to aminoglycosides (tobramycin, amikacin, and gentamicin). Furthermore, it can extrude cefepime, carbapenems, some fluoroquinolones, tetracyclines, and erythromycin. Some of the AxyXY-OprZ substrates are major components widely used to treat pulmonary infections in CF patients.

  12. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria

    OpenAIRE

    Sun, Wei; Weingarten, Rebecca A.; Xu, Miao; Southall, Noel; Dai, Sheng; Shinn, Paul; Sanderson, Philip E.; Williamson, Peter R.; Frank, Karen M.; Zheng,Wei

    2016-01-01

    Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pne...

  13. Antibacterial efficacy of Syzygium aromaticum extracts on multi-drug resistant Streptococcus mutans isolated from dental plaque samples

    OpenAIRE

    Dhamodhar Prakash; Sreenivasa murthy BV; Channa rayappa; Karthik Ramesh; Neha Gopinath; Shantha Kumar SS; George John Varuvelil

    2012-01-01

    Over the last few decades there has been a remarkable increase in the prevalence rate of Dental Caries. Streptococcus mutans has been implicated as major cariogenic bacteria because they produce high levels of lactic acid and extracellular polysaccharide. In the present study, 38 % of S. mutans was recovered from the dental plaque samples collected from patients. Antibiotic sensitivity tests revealed the emergence of Multi-Drug Resistance (MDR) with all the isolates being completely resista...

  14. Genomic definition of hypervirulent and multidrug-resistant Klebsiella pneumoniae clonal groups.

    Science.gov (United States)

    Bialek-Davenet, Suzanne; Criscuolo, Alexis; Ailloud, Florent; Passet, Virginie; Jones, Louis; Delannoy-Vieillard, Anne-Sophie; Garin, Benoit; Le Hello, Simon; Arlet, Guillaume; Nicolas-Chanoine, Marie-Hélène; Decré, Dominique; Brisse, Sylvain

    2014-11-01

    Multidrug-resistant and highly virulent Klebsiella pneumoniae isolates are emerging, but the clonal groups (CGs) corresponding to these high-risk strains have remained imprecisely defined. We aimed to identify K. pneumoniae CGs on the basis of genome-wide sequence variation and to provide a simple bioinformatics tool to extract virulence and resistance gene data from genomic data. We sequenced 48 K. pneumoniae isolates, mostly of serotypes K1 and K2, and compared the genomes with 119 publicly available genomes. A total of 694 highly conserved genes were included in a core-genome multilocus sequence typing scheme, and cluster analysis of the data enabled precise definition of globally distributed hypervirulent and multidrug-resistant CGs. In addition, we created a freely accessible database, BIGSdb-Kp, to enable rapid extraction of medically and epidemiologically relevant information from genomic sequences of K. pneumoniae. Although drug-resistant and virulent K. pneumoniae populations were largely nonoverlapping, isolates with combined virulence and resistance features were detected.

  15. A Novel SERCA Inhibitor Demonstrates Synergy with Classic SERCA Inhibitors and Targets Multidrug-Resistant AML

    Science.gov (United States)

    Bleeker, Nicholas P.; Cornea, Razvan L.; Thomas, David D.; Xing, Chengguo

    2013-01-01

    Drug resistance exists as a major obstacle in the treatment of cancer and drug molecules that retain effectiveness against resistant cancers are a high clinical priority. Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) was recently identified as a promising lead for the treatment of multidrug-resistant leukemia, which elicits its cytotoxic effect, in part, through inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Herein initial experiments with SERCA1a, CXL017 demonstrated no significant effect on calcium affinity, competed with ATP, and induced a dose-dependent decrease in ATPase activity. Among all CXLs tested, (−)-CXL017 exhibited the greatest SERCA inhibition with an IC50 = 13.5 ± 0.5 μM. Inhibitor combination studies were used to assess potential interactions between (−)-CXL017 and well-known SERCA inhibitors: thapsigargin, cyclopiazonic acid, and 2, 5-di-tert-butylhydroquinone. Surprisingly, (−)-CXL017 exhibited marked synergy with each of the known SERCA inhibitors whereas all combinations of the known inhibitors yielded additive effects, indicating that (−)-CXL017 may bind at a unique allosteric site. Treatment of parental (HL60) and multidrug-resistant (HL60/MX2) acute myeloid leukemia cells with the known SERCA inhibitors revealed that all of these inhibitors demonstrate selective cytotoxicity (7.7 to 400 fold) for the resistant cell line. Within the CXL series, a positive correlation exists between SERCA inhibition and cytotoxicity in HL60/MX2 but not HL60. (−)-CXL017 was also shown to enhance the cytotoxicity of thapsigargin in HL60/MX2 cells. Given the elevated SERCA levels and ER calcium content in HL60/MX2, SERCA likely plays a significant role in the collateral sensitivity of this multidrug-resistance cell line to CXL molecules as well as known SERCA inhibitors. PMID:24079514

  16. In vitro antimicrobial potential of Terminalia chebula fruit extracts against multidrug-resistant uropathogens

    Institute of Scientific and Technical Information of China (English)

    Anwesa Bag; Subir Kumar Bhattacharyya; Nishith Kumar Pal; Rabi Ranjan Chattopadhyay

    2012-01-01

    Objective: Terminalia chebula Retz. (combretaceae) is called the “King of Medicine” in Tibet and is always listed at the top of the list of “Ayurvedic Materia Medica” because of its extraordinary power of healing. The present study was carried out to evaluate the possible in vitro antibacterial potential of different solvent extracts of T. chebula fruit against multidrug-resistant uropathogens. Methods: A total of 52 multidrug-resistant uropathogenic bacteria were used in this study. Successive extractions of T. chebula fruits were performed with solvents of different polarities. Agar well diffusion and microbroth dilution assay methods were used for antibacterial susceptibility testing. Kill-kinetics study was done to know the rate and extent of bacterial killing. Qualitative phytochemical screening was done to know the major phytoconstituents present in the plant material. Acute oral toxicity study in mice was performed to evaluate the toxic potential of the plant material, if any. Results:The ethanol extract of T. chebula fruits demonstrated a strong antimicrobial activity against all the test isolates and found to be most effective over others. Kill-kinetics study showed dose and time dependent antibacterial activity of ethanol extract. Phytochemical analysis revealed the presence of high concentration of phenolics and low concentration of flavonoids and terpenoids. In acute oral toxicity study, no gross behavioral changes were observed in mice at recommended dosage level and 24 h LD50 of ethanol extract was found to be >4 g/kg, p.o. in mice. Conclusions: The results provide justification for the use of Terminalia chebula fruit in folk medicine to treat various infectious diseases and could be useful for the development of alternative/ complementary medicine for multidrug-resistant uropathogens.

  17. Consequences of removing the flattening filter from linear accelerators in generating high dose rate photon beams for clinical applications: A Monte Carlo study verified by measurement

    Energy Technology Data Exchange (ETDEWEB)

    Ishmael Parsai, E. [Department of Radiation Oncology, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614 (United States)]. E-mail: Ishmael.parsai@utoledo.edu; Pearson, David [Department of Radiation Oncology, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614 (United States); Department of Physics and Astronomy, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614 (United States); Kvale, Thomas [Department of Physics and Astronomy, University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614 (United States)

    2007-08-15

    An Elekta SL-25 medical linear accelerator (Elekta Oncology Systems, Crawley, UK) has been modelled using Monte Carlo simulations with the photon flattening filter removed. It is hypothesized that intensity modulated radiation therapy (IMRT) treatments may be carried out after the removal of this component despite it's criticality to standard treatments. Measurements using a scanning water phantom were also performed after the flattening filter had been removed. Both simulated and measured beam profiles showed that dose on the central axis increased, with the Monte Carlo simulations showing an increase by a factor of 2.35 for 6 MV and 4.18 for 10 MV beams. A further consequence of removing the flattening filter was the softening of the photon energy spectrum leading to a steeper reduction in dose at depths greater than the depth of maximum dose. A comparison of the points at the field edge showed that dose was reduced at these points by as much as 5.8% for larger fields. In conclusion, the greater photon fluence is expected to result in shorter treatment times, while the reduction in dose outside of the treatment field is strongly suggestive of more accurate dose delivery to the target.

  18. Characterization of integrons and resistance genes in multidrug-resistant Salmonella enterica isolated from meat and dairy products in Egypt.

    Science.gov (United States)

    Ahmed, Ashraf M; Shimamoto, Toshi; Shimamoto, Tadashi

    2014-10-17

    Foodborne pathogens are a leading cause of illness and death, especially in developing countries. The problem is exacerbated if bacteria attain multidrug resistance. Little is currently known about the extent of antibiotic resistance in foodborne pathogens and the molecular mechanisms underlying this resistance in Africa. Therefore, the current study was carried out to characterize, at the molecular level, the mechanism of multidrug resistance in Salmonella enterica isolated from 1600 food samples (800 meat products and 800 dairy products) collected from different street venders, butchers, retail markets and slaughterhouses in Egypt. Forty-seven out of 69 isolates (68.1%) showed multidrug resistance phenotypes to at least three classes of antimicrobials. The incidence of multidrug-resistant isolates was higher in meat products (37, 69.8%) than in dairy products (10, 62.5%). The multidrug-resistant serovars included, S. enterica serovar Typhimurium (24 isolates, 34.8%), S. enterica serovar Enteritidis, (15 isolates, 21.8%), S. enterica serovar Infantis (7 isolates, 10.1%) and S. enterica non-typable serovar (1 isolate, 1.4%). The highest resistance was to ampicillin (95.7%), then to kanamycin (93.6%), spectinomycin (93.6%), streptomycin (91.5%) and sulfamethoxazole/trimethoprim (91.5%). PCR and DNA sequencing were used to screen and characterize integrons and antibiotic resistance genes and 39.1% and 8.7% of isolates were positive for class 1 and class 2 integrons, respectively. β-lactamase-encoding genes were identified in 75.4% of isolates and plasmid-mediated quinolone resistance genes were identified in 27.5% of isolates. Finally, the florphenicol resistance gene, floR, was identified in 18.8% of isolates. PCR screening identified S. enterica serovar Typhimurium DT104 in both meat and dairy products. This is the first study to report many of these resistance genes in dairy products. This study highlights the high incidence of multidrug-resistant S. enterica in

  19. Reversal of MRP7 (ABCC10-mediated multidrug resistance by tariquidar.

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    Yue-Li Sun

    Full Text Available Multidrug resistance protein 7 (MRP7, ABCC10 is a recently discovered member of the ATP-binding cassette (ABC family which are capable of conferring resistance to a variety of anticancer drugs, including taxanes and nucleoside analogs, in vivo. MRP7 is highly expressed in non-small cell lung cancer cells, and Mrp7-KO mice are highly sensitive to paclitaxel, making MRP7 an attractive chemotherapeutic target of non-small cell lung cancer. However, only a few inhibitors of MRP7 are currently identified, with none of them having progressed to clinical trials. We used MRP7-expressing cells to investigate whether tariquidar, a third generation inhibitor of P-glycoprotein, could inhibit MRP7-mediated multidrug resistance (MDR. We found that tariquidar, at 0.1 and 0.3 µM, significantly potentiated the sensitivity of MRP7-transfected HEK293 cells to MRP7 substrates and increased the intracellular accumulation of paclitaxel. We further demonstrated that tariquidar directly impaired paclitaxel efflux and could downregulate MRP7 protein expression in a concentration- and time-dependent manner after prolonged treatment. Our findings suggest that tariquidar, at pharmacologically achievable concentrations, reverses MRP7-mediated MDR through inhibition of MRP7 protein expression and function, and thus represents a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.

  20. Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment

    Science.gov (United States)

    Gomez, James E; Kaufmann-Malaga, Benjamin B; Wivagg, Carl N; Kim, Peter B; Silvis, Melanie R; Renedo, Nikolai; Ioerger, Thomas R; Ahmad, Rushdy; Livny, Jonathan; Fishbein, Skye; Sacchettini, James C; Carr, Steven A; Hung, Deborah T

    2017-01-01

    Antibiotic resistance arising via chromosomal mutations is typically specific to a particular antibiotic or class of antibiotics. We have identified mutations in genes encoding ribosomal components in Mycobacterium smegmatis that confer resistance to several structurally and mechanistically unrelated classes of antibiotics and enhance survival following heat shock and membrane stress. These mutations affect ribosome assembly and cause large-scale transcriptomic and proteomic changes, including the downregulation of the catalase KatG, an activating enzyme required for isoniazid sensitivity, and upregulation of WhiB7, a transcription factor involved in innate antibiotic resistance. Importantly, while these ribosomal mutations have a fitness cost in antibiotic-free medium, in a multidrug environment they promote the evolution of high-level, target-based resistance. Further, suppressor mutations can then be easily acquired to restore wild-type growth. Thus, ribosomal mutations can serve as stepping-stones in an evolutionary path leading to the emergence of high-level, multidrug resistance. DOI: http://dx.doi.org/10.7554/eLife.20420.001 PMID:28220755

  1. Reversing multidrug resistance by RNA interference through the suppression of MDR1 gene in human hepatoma cells

    Institute of Scientific and Technical Information of China (English)

    Xiao-Ping Chen; Qi wang; Jian Guan; Zhi-Yong Huang; Wan-Guang Zhang; Bi-Xiang Zhang

    2006-01-01

    AIM: To reverse the multidrug resistance (MDR) by RNA interference (RNAi)-mediated MDR1 suppression in hepatoma cells.METHODS: For reversing MDR by RNAi technology, two different short hairpin RNAs (shRNAs) were designed and constructed into pGenSil-1 plasmid, respectively. They were then transfected into a highly adriamycin-resistant HepG2 hepatoma cell line (HepG2/ADM). The RNAi effect on MDR was evaluated by real-time PCR, cell cytotoxicity assay and rhodamine 123 (Rh123) efflux assy.RESULTS: The stably-transfected clones showed various degrees of reversal of MDR phenotype. Surprisingly, the MDR phenotype was completely reversed in two transfected clones.CONCLUSION: MDR can be reversed by the shRNAmediated MDRI suppression in HepG2/ADM cells, which provides a valuable clue to make multidrug-resistant hepatoma cells sensitive to anti-cancer drugs.

  2. Which strategies follow from the surveillance of multidrug-resistant bacteria to strengthen the control of their spread? A French experience.

    Science.gov (United States)

    Lepelletier, Didier; Perron, Stéphanie; Huguenin, Hélène; Picard, Monique; Bemer, Pascale; Caillon, Jocelyne; Juvin, Marie-Emmanuelle; Drugeon, Henri Bernard

    2004-02-01

    Efforts to enhance standard precautions and to isolate patients with positive routine clinical cultures during 3 years were insufficient to decrease multidrug-resistant bacteria infection rates. Routine screening for carriage in high-risk patients may be necessary to halt transmission and control the hospital reservoir.

  3. Genome Sequence of a Multidrug-Resistant Strain of Klebsiella pneumoniae, BAMC 07-18, Isolated from a Combat Injury Wound.

    Science.gov (United States)

    Van Laar, Tricia A; Chen, Tsute; Childers, Brandon M; Chen, Ping; Abercrombie, Johnathan J; Leung, Kai P

    2014-11-26

    Klebsiella pneumoniae is an important infectious agent of surgical sites and combat wounds. Antibiotic resistance and tolerance are common impediments to the healing of chronic infections. Here, we report the genome sequence of a highly multidrug-resistant strain of K. pneumoniae, BAMC 07-18, isolated from a combat wound of a soldier.

  4. Genetic knockdown and pharmacological inhibition of parasite multidrug resistance transporters disrupts egg production in Schistosoma mansoni.

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    Ravi S Kasinathan

    2011-12-01

    Full Text Available P-glycoprotein (Pgp and multidrug resistance-associated proteins (MRPs are ATP-dependent transporters involved in efflux of toxins and xenobiotics from cells. When overexpressed, these transporters can mediate multidrug resistance (MDR in mammalian cells, and changes in Pgp expression and sequence are associated with drug resistance in helminths. In addition to the role they play in drug efflux, MDR transporters are essential components of normal cellular physiology, and targeting them may prove a useful strategy for development of new therapeutics or of compounds that enhance the efficacy of current anthelmintics. We previously showed that expression of Schistosoma mansoni MDR transporters increases in response to praziquantel (PZQ, the current drug of choice against schistosomiasis, and that reduced PZQ sensitivity correlates with higher levels of these parasite transporters. We have also shown that PZQ inhibits transport by SMDR2, a Pgp orthologue from S. mansoni, and that PZQ is a likely substrate of SMDR2. Here, we examine the physiological roles of SMDR2 and SmMRP1 (the S. mansoni orthologue of MRP1 in S. mansoni adults, using RNAi to knock down expression, and pharmacological agents to inhibit transporter function. We find that both types of treatments disrupt parasite egg deposition by worms in culture. Furthermore, administration of different MDR inhibitors to S. mansoni-infected mice results in a reduction in egg burden in host liver. These schistosome MDR transporters therefore appear to play essential roles in parasite egg production, and can be targeted genetically and pharmacologically. Since eggs are responsible for the major pathophysiological consequences of schistosomiasis, and since they are also the agents for transmission of the disease, these results suggest a potential strategy for reducing disease pathology and spread.

  5. Magnitude and consequences of undertreatment of high-risk patients with non-ST segment elevation acute coronary syndromes: insights from the DESCARTES Registry.

    Science.gov (United States)

    Heras, M; Bueno, H; Bardají, A; Fernández-Ortiz, A; Martí, H; Marrugat, J

    2006-11-01

    To analyse intensity of treatment of high-risk patients with non-ST elevation acute coronary syndromes (NSTEACS) included in the DESCARTES (Descripción del Estado de los Sindromes Coronarios Agudos en un Registro Temporal Español) registry. Patients with NSTEACS (n = 1877) admitted to 45 randomly selected Spanish hospitals in April and May 2002 were studied. Patients with ST segment depression and troponin rise were considered high risk (n = 478) and were compared with non-high risk patients (n = 1399). 46.9% of high-risk patients versus 39.5% of non-high-risk patients underwent angiography (p = 0.005), 23.2% versus 18.8% (p = 0.038) underwent percutaneous revascularisation, and 24.9% versus 7.4% (p or = 4, 2-3 and or = 4 (OR 2.87, 95% CI 1.27 to 6.52, p = 0.012). Class I recommended treatments were underused in high-risk patients in the DESCARTES registry. This undertreatment was an independent predictor of death of patients with an acute coronary syndrome.

  6. ACTION OF NEWER DISINFECTANTS ON MULTIDRUG RESISTANT BACTERIA

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    Bipasa

    2014-03-01

    Full Text Available BACKGROUND: Current procedures for infection control in hospital environments have not been successful in curbing the rise in infections by multi-drug-resistant (MDR pathogens. Emergence of resistance to chemical disinfectants is increasing steadily and has been reported worldwide. So prevention of multidrug-resistant health care associated infections (HAI has become a priority issue and great challenge to clinicians. This requires appropriate sterilization and disinfection procedures and strict adherence to protocol in infection control policy. There is a need to evaluate the efficacy of newer disinfectants which have come into the market for better control of HAI. AIMS AND OBJECTIVES: The aim of this study was to evaluate and compare disinfection efficacy of three newer disinfectants– Novacide (didecyldimethylammonium chloride and polyhexamethylene biguanide, Silvicide a strong oxidizing agent (hydrogen peroxide and silver nitrate and Virkon, a powerful oxidizing agent (a stabilized blend of peroxygen compounds and potassium salts, pitting them against two time-honored conventional disinfectants phenol and lysol and testing them against common MDR clinical isolates, reference strains and spores. MATERIALS AND METHODS: All the disinfectants at different dilutions were tested for bactericidal efficacy by liquid suspension time-kill tests. A heavy initial microbial load was simulated by preparing bacterial inoculum. Numbers of viable cells were counted and reduction in microbial colony counts before and after disinfectant exposure was expressed as log reduction. RESULTS: Among the disinfectants, Novacide was most effective. All clinical MDR bacterial isolates and reference strains were killed within 30 seconds of exposure at 0.156% solution, whereas spores got killed after 30 minutes of exposure at 2.5% solution which is the recommended concentration. For Silvicide all vegetative bacteria were killed at 5% solution after 20 minutes contact time

  7. Molecular characterization of multidrug-resistant Klebsiella pneumoniae isolates.

    Science.gov (United States)

    Hou, Xiang-hua; Song, Xiu-yu; Ma, Xiao-bo; Zhang, Shi-yang; Zhang, Jia-qin

    2015-01-01

    Klebsiella pneumoniae is an important cause of healthcare-associated infections worldwide. Selective pressure, the extensive use of antibiotics, and the conjugational transmission of antibiotic resistance genes across bacterial species and genera facilitate the emergence of multidrug-resistant (MDR) K. pneumoniae. Here, we examined the occurrence, phenotypes and genetic features of MDR K. pneumoniae isolated from patients in intensive care units (ICUs) at the First Affiliated Hospital of Xiamen University in Xiamen, China, from January to December 2011. Thirty-eight MDR K. pneumoniae strains were collected. These MDR K. pneumoniae isolates possessed at least seven antibiotic resistance determinants, which contribute to the high-level resistance of these bacteria to aminoglycosides, macrolides, quinolones and β-lactams. Among these isolates, 24 strains were extended-spectrum β-lactamase (ESBL) producers, 2 strains were AmpC producers, and 12 strains were both ESBL and AmpC producers. The 38 MDR isolates also contained class I (28/38) and class II integrons (10/38). All 28 class I-positive isolates contained aacC1, aacC4, orfX, orfX' and aadA1 genes. β-lactam resistance was conferred through bla SHV (22/38), bla TEM (10/38), and bla CTX-M (7/38). The highly conserved bla KPC-2 (37/38) and bla OXA-23(1/38) alleles were responsible for carbapenem resistance, and a gyrAsite mutation (27/38) and the plasmid-mediated qnrB gene (13/38) were responsible for quinolone resistance. Repetitive-sequence-based PCR (REP-PCR) fingerprinting of these MDR strains revealed the presence of five groups and sixteen patterns. The MDR strains from unrelated groups showed different drug resistance patterns; however, some homologous strains also showed different drug resistance profiles. Therefore, REP-PCR-based analyses can provide information to evaluate the epidemic status of nosocomial infection caused by MDR K. pneumoniae; however, this test lacks the power to discriminate some

  8. Molecular characterization of multidrug-resistant Klebsiella pneumoniae isolates

    Directory of Open Access Journals (Sweden)

    Xiang-hua Hou

    2015-09-01

    Full Text Available Klebsiella pneumoniae is an important cause of healthcare-associated infections worldwide. Selective pressure, the extensive use of antibiotics, and the conjugational transmission of antibiotic resistance genes across bacterial species and genera facilitate the emergence of multidrug-resistant (MDR K. pneumoniae. Here, we examined the occurrence, phenotypes and genetic features of MDR K. pneumoniae isolated from patients in intensive care units (ICUs at the First Affiliated Hospital of Xiamen University in Xiamen, China, from January to December 2011. Thirty-eight MDR K. pneumoniae strains were collected. These MDR K. pneumoniae isolates possessed at least seven antibiotic resistance determinants, which contribute to the high-level resistance of these bacteria to aminoglycosides, macrolides, quinolones and β-lactams. Among these isolates, 24 strains were extended-spectrum β-lactamase (ESBL producers, 2 strains were AmpC producers, and 12 strains were both ESBL and AmpC producers. The 38 MDR isolates also contained class I (28/38 and class II integrons (10/38. All 28 class I-positive isolates contained aacC1, aacC4, orfX, orfX’ and aadA1 genes. β-lactam resistance was conferred through blaSHV (22/38, blaTEM (10/38, and blaCTX-M (7/38. The highly conserved blaKPC-2 (37/38 and blaOXA-23(1/38 alleles were responsible for carbapenem resistance, and a gyrAsite mutation (27/38 and the plasmid-mediated qnrB gene (13/38 were responsible for quinolone resistance. Repetitive-sequence-based PCR (REP-PCR fingerprinting of these MDR strains revealed the presence of five groups and sixteen patterns. The MDR strains from unrelated groups showed different drug resistance patterns; however, some homologous strains also showed different drug resistance profiles. Therefore, REP-PCR-based analyses can provide information to evaluate the epidemic status of nosocomial infection caused by MDR K. pneumoniae; however, this test lacks the power to discriminate some

  9. Multidrug-Resistant Enterococci Lack CRISPR-cas

    OpenAIRE

    Palmer, Kelli L.; Michael S Gilmore

    2010-01-01

    Clustered, regularly interspaced short palindromic repeats (CRISPR) provide bacteria and archaea with sequence-specific, acquired defense against plasmids and phage. Because mobile elements constitute up to 25% of the genome of multidrug-resistant (MDR) enterococci, it was of interest to examine the codistribution of CRISPR and acquired antibiotic resistance in enterococcal lineages. A database was built from 16 Enterococcus faecalis draft genome sequences to identify commonalities and polymo...

  10. Multidrug-Resistant Escherichia fergusonii: a Case of Acute Cystitis▿

    Science.gov (United States)

    Savini, Vincenzo; Catavitello, Chiara; Talia, Marzia; Manna, Assunta; Pompetti, Franca; Favaro, Marco; Fontana, Carla; Febbo, Fabio; Balbinot, Andrea; Di Berardino, Fabio; Di Bonaventura, Giovanni; Di Zacomo, Silvia; Esattore, Francesca; D'Antonio, Domenico

    2008-01-01

    We report a case in which Escherichia fergusonii, an emerging pathogen in various types of infections, was associated with cystitis in a 52-year-old woman. The offending strain was found to be multidrug resistant. Despite in vitro activity, beta-lactam treatment failed because of a lack of patient compliance with therapy. The work confirms the pathogenic potential of E. fergusonii. PMID:18256229

  11. Multidrug-Resistant Tuberculosis: Treatment and Outcomes of 93 Patients

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    Sarah K Brode

    2015-01-01

    Full Text Available BACKGROUND: Tuberculosis (TB remains a leading cause of death worldwide and the emergence of multidrug-resistant TB (MDR TB poses a threat to its control. There is scanty evidence regarding optimal management of MDR TB. The majority of Canadian cases of MDR TB are diagnosed in Ontario; most are managed by the Tuberculosis Service at West Park Healthcare Centre in Toronto. The authors reviewed 93 cases of MDR TB admitted from January 1, 2000 to December 31, 2011.

  12. Chromosomal Instability Confers Intrinsic Multi-Drug Resistance

    Science.gov (United States)

    Lee, Alvin J X; Endesfelder, David; Rowan, Andrew J; Walther, Axel; Birkbak, Nicolai J; Futreal, P Andrew; Downward, Julian; Szallasi, Zoltan; Tomlinson, Ian P M; Kschischo, Maik; Swanton, Charles

    2011-01-01

    Aneuploidy is associated with poor prognosis in solid tumours. Spontaneous chromosome mis-segregation events in aneuploid cells promote Chromosomal Instability (CIN) that may contribute to the acquisition of multi-drug resistance in vitro and heighten risk for tumour relapse in animal models. Identification of distinct therapeutic agents that target tumour karyotypic complexity has important clinical implications. In order to identify distinct therapeutic approaches to specifically limit the growth of CIN tumours we focussed on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally-unstable (CIN+) or diploid/near-diploid (CIN−), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle and trans-membrane receptor signalling pathways. CIN+ cell lines displayed significant intrinsic multi-drug resistance compared to CIN− cancer cell lines and this appeared to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multi-drug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity, and isogenic cell line models of CIN+ displayed multi-drug resistance relative to their CIN− parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse progression-free or disease-free survival relative to patients with CIN− disease. Our results suggest that stratifying tumour responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumour CIN status on drug sensitivity. PMID:21363922

  13. Multidrug-resistant tuberculosis in the Amazonas State, Brazil, 2000-2011.

    Science.gov (United States)

    Garrido, M da S; Bührer-Sékula, S; Souza, A B; de Oliveira, G P; Antunes, I A; Mendes, J M; Saraceni, V; Martinez-Espinosa, F E; Ramasawmy, R

    2015-05-01

    Amazonas is facing increasing challenges in tuberculosis (TB) control, with nearly 3000 cases per year, and multidrug-resistant TB (MDR-TB) may jeopardise the TB control programme. To assess the number of MDR-TB cases in the Amazonas and to improve estimates of the burden of TB. The Brazilian National Mandatory Disease Reporting System (SINAN) and the Brazilian Epidemiological Surveillance System of Multidrug Resistance (TBMR) were searched for MDR-TB cases in the State of Amazonas from 2000 to 2011. Eighty-one MDR-TB cases were notified. The rates of primary MDR-TB, initial MDR-TB during the first treatment regimen and acquired MDR-TB were respectively 3.8%, 13.7% and 82.7%; 26.9% of previously treated patients had ⩾ 4 treatment cycles. The MDR-TB cases reported 263 contacts, only 35.0% of whom were examined. The cure and death rates among the 81 patients with MDR-TB were respectively 45.7% and 25.9%. The number of MDR-TB cases seems incompatible with the high TB prevalence in the Amazonas. Most patients were unaware of contact with TB patients. TB is endemic in the Amazonas. This highlights the need for improving resistance investigation among all TB cases.

  14. Antimicrobial activity of octenidine against multidrug-resistant Gram-negative pathogens.

    Science.gov (United States)

    Alvarez-Marin, R; Aires-de-Sousa, M; Nordmann, P; Kieffer, N; Poirel, L

    2017-08-19

    Multidrug-resistant (MR) Gram-negative (GN) pathogens pose a major and growing threat for healthcare systems, as therapy of infections is often limited due to the lack of available systemic antibiotics. Well-tolerated antiseptics, such as octenidine dihydrochloride (OCT), may be a very useful tool in infection control to reduce the dissemination of MRGN. This study aimed to investigate the bactericidal activity of OCT against international epidemic clones of MRGN. A set of five different species (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii, and Pseudomonas aeruginosa) was studied to prove OCT efficacy without organic load, under "clean conditions" (0.3 g/L albumin) and under "dirty conditions" (3 g/L albumin + 3 mL/L defibrinated sheep blood), according to an official test norm (EN13727). We used five clonally unrelated isolates per species, including a susceptible wild-type strain, and four MRGN isolates, corresponding to either the 3MRGN or 4MRGN definition of multidrug resistance. A contact time of 1 min was fully effective for all isolates by using different OCT concentrations (0.01% and 0.05%), with a bacterial reduction factor of >5 log10 systematically observed. Growth kinetics were determined with two different wild-type strains (A. baumannii and K. pneumoniae), proving a time-dependent efficacy of OCT. These results highlight that OCT may be extremely useful to eradicate emerging highly resistant Gram-negative pathogens associated with nosocomial infections.

  15. Chloramphenicol - A Potent Armament Against Multi-Drug Resistant (MDR) Gram Negative Bacilli?

    Science.gov (United States)

    Sood, Smita

    2016-02-01

    Multidrug-resistant gram-negative bacteria cause infections which are hard to treat and cause high morbidity and mortality. Due to limited therapeutic options there is a renewed interest upon older antimicrobials which had fallen into disuse as a result of toxic side effects. One such antibiotic is chloramphenicol which was sidelined due to reports linking its use with the development of aplastic anaemia. A study was conducted to evaluate the susceptibility of chloramphenicol in light of the emerging problem of multi-drug resistant gram negative bacteria (MDR GNB). A total of 483 MDR GNB of the 650 consecutive Gram Negative Bacteria isolated from various clinical samples of patients admitted at a tertiary care hospital in Jaipur between January-June 2014 were screened for chloramphenicol susceptibility by the disc diffusion method as per CLSI guidelines. The MDR GNB isolates were obtained from 217 (45%) urine, 163 (34%) from respiratory samples, 52(11%) from pus, 42 (9%) from blood and 9 (2%) from body fluids. A 68% of the MDR GNB isolates were found to be sensitive to chloramphenicol. Clinicians should always check for the local susceptibility of Gram-negative bacteria to chloramphenicol. This antibiotic has a potential to play a role in the therapeutic management of infections due to MDR GNB pathogens.

  16. Phenotypic and molecular characterization of multidrug resistant Klebsiella pneumoniae isolated from a university teaching hospital, China.

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    Jikun Du

    Full Text Available The multidrug-resistant rate of Klebsiella pneumoniae has risen rapidly worldwide. To better understand the multidrug resistance situation and molecular characterization of Klebsiella pneumoniae, a total of 153 Klebsiella pneumoniae isolates were collected, and drug susceptibility test was performed to detect its susceptibility patterns to 13 kinds of antibiotics. Phenotypic tests for carbapenemases ESBLs and AmpC enzyme-producing strains were performed to detect the resistance phenotype of the isolates. Then PCR amplification and sequencing analysis were performed for the drug resistance determinants. The results showed that 63 strains harbored bla CTX-M gene, and 14 strains harbored bla DHA gene. Moreover, there were 5 strains carrying bla KPC gene, among which 4 strains carried bla CTX-M, bla DHA and bla KPC genes, and these 4 strains were also resistant to imipenem. Our data indicated that drug-resistant Klebsiella pneumoniae were highly prevalent in the hospital. Thus it is warranted that surveillance of epidemiology of those resistant isolates should be a cause for concern, and appropriate drugs should be chosen.

  17. Novel nanostructured enoxaparin sodium-PLGA hybrid carriers overcome tumor multidrug resistance of doxorubicin hydrochloride.

    Science.gov (United States)

    Wang, Jia; Wu, Lei; Kou, Longfa; Xu, Meng; Sun, Jin; Wang, Yongjun; Fu, Qiang; Zhang, Peng; He, Zhonggui

    2016-11-20

    Novel enoxaparin sodium-PLGA hybrid nanocarries (EPNs) were successfully designed for sustained delivery of hydrophilic cationic doxorubicin hydrochloride (DOX) and to overcome multidrug resistance (MDR). By incorporation of the negative polymer of enoxaparin sodium (ES), DOX was highly encapsulated into EPNs with an encapsulation efficiency of 92.49%, and ES effectively inhibited the proliferation of HUVEC cell lines. The in vivo pharmacokinetics study after intravenous injection indicated that DOX-loaded EPNs (DOX-EPNs) exhibited a higher area under the curve (AUC) and a longer half-life (t1/2) in comparison with DOX solution (DOX-Sol). The biodistribution study demonstrated that DOX-EPNs increased the DOX level in plasma and decreased the accumulation of DOX in liver and spleen. Compared with DOX-Sol, DOX-EPNs increased the cytotoxicity in P-gp over-expressing MCF-7/Adr cells, attributed to the higher intracellular efficiency of DOX produced by the EPNs. DOX-EPNs entered into resistant tumor cells by multiple endocytosis pathways, which resulted in overcoming the multidrug resistance of MCF-7/Adr cells by escaping the efflux induced by P-gp transporters. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Phenotypic and molecular characterization of multidrug resistant Klebsiella pneumoniae isolated from a university teaching hospital, China.

    Science.gov (United States)

    Du, Jikun; Li, Peipei; Liu, Helu; Lü, Dongyue; Liang, Hong; Dou, Yuhong

    2014-01-01

    The multidrug-resistant rate of Klebsiella pneumoniae has risen rapidly worldwide. To better understand the multidrug resistance situation and molecular characterization of Klebsiella pneumoniae, a total of 153 Klebsiella pneumoniae isolates were collected, and drug susceptibility test was performed to detect its susceptibility patterns to 13 kinds of antibiotics. Phenotypic tests for carbapenemases ESBLs and AmpC enzyme-producing strains were performed to detect the resistance phenotype of the isolates. Then PCR amplification and sequencing analysis were performed for the drug resistance determinants. The results showed that 63 strains harbored bla CTX-M gene, and 14 strains harbored bla DHA gene. Moreover, there were 5 strains carrying bla KPC gene, among which 4 strains carried bla CTX-M, bla DHA and bla KPC genes, and these 4 strains were also resistant to imipenem. Our data indicated that drug-resistant Klebsiella pneumoniae were highly prevalent in the hospital. Thus it is warranted that surveillance of epidemiology of those resistant isolates should be a cause for concern, and appropriate drugs should be chosen.

  19. Chloramphenicol – A Potent Armament Against Multi-Drug Resistant (MDR) Gram Negative Bacilli?

    Science.gov (United States)

    2016-01-01

    Introduction Multidrug-resistant gram-negative bacteria cause infections which are hard to treat and cause high morbidity and mortality. Due to limited therapeutic options there is a renewed interest upon older antimicrobials which had fallen into disuse as a result of toxic side effects. One such antibiotic is chloramphenicol which was sidelined due to reports linking its use with the development of aplastic anaemia. Aim A study was conducted to evaluate the susceptibility of chloramphenicol in light of the emerging problem of multi-drug resistant gram negative bacteria (MDR GNB). Materials and Methods A total of 483 MDR GNB of the 650 consecutive Gram Negative Bacteria isolated from various clinical samples of patients admitted at a tertiary care hospital in Jaipur between January-June 2014 were screened for chloramphenicol susceptibility by the disc diffusion method as per CLSI guidelines. Results The MDR GNB isolates were obtained from 217 (45%) urine, 163 (34%) from respiratory samples, 52(11%) from pus, 42 (9%) from blood and 9 (2%) from body fluids. A 68% of the MDR GNB isolates were found to be sensitive to chloramphenicol. Conclusion Clinicians should always check for the local susceptibility of Gram-negative bacteria to chloramphenicol. This antibiotic has a potential to play a role in the therapeutic management of infections due to MDR GNB pathogens. PMID:27042458

  20. Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system.

    Science.gov (United States)

    Sarkadi, Balázs; Homolya, László; Szakács, Gergely; Váradi, András

    2006-10-01

    In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the "chemoimmunity" network, which has a number of features reminiscent of classical immunology.

  1. Emergence of a Potent Multidrug Efflux Pump Variant That Enhances Campylobacter Resistance to Multiple Antibiotics

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    Hong Yao

    2016-09-01

    Full Text Available Bacterial antibiotic efflux pumps are key players in antibiotic resistance. Although their role in conferring multidrug resistance is well documented, the emergence of “super” efflux pump variants that enhance bacterial resistance to multiple drugs has not been reported. Here, we describe the emergence of a resistance-enhancing variant (named RE-CmeABC of the predominant efflux pump CmeABC in Campylobacter, a major zoonotic pathogen whose resistance to antibiotics is considered a serious antibiotic resistance threat in the United States. Compared to the previously characterized CmeABC transporters, RE-CmeABC is much more potent in conferring Campylobacter resistance to antibiotics, which was shown by increased MICs and reduced intracellular accumulation of antibiotics. Structural modeling suggests that sequence variations in the drug-binding pocket of CmeB possibly contribute to the enhanced efflux function. Additionally, RE-CmeABC expands the mutant selection window of ciprofloxacin, enhances the emergence of antibiotic-resistant mutants, and confers exceedingly high-level resistance to fluoroquinolones, an important class of antibiotics for clinical therapy of campylobacteriosis. Furthermore, RE-CmeABC is horizontally transferable, shifts antibiotic MIC distribution among clinical isolates, and is increasingly prevalent in Campylobacter jejuni isolates, suggesting that it confers a fitness advantage under antimicrobial selection. These findings reveal a new mechanism for enhanced multidrug resistance and an effective strategy utilized by bacteria for adaptation to selection from multiple antibiotics.

  2. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations.

    Science.gov (United States)

    Sun, Jingjing; Deng, Ziqing; Yan, Aixin

    2014-10-17

    Multidrug resistance (MDR) refers to the capability of bacterial pathogens to withstand lethal doses of structurally diverse drugs which are capable of eradicating non-resistant strains. MDR has been identified as a major threat to the public health of human being by the World Health Organization (WHO). Among the four general mechanisms that cause antibiotic resistance including target alteration, drug inactivation, decreased permeability and increased efflux, drug extrusion by the multidrug efflux pumps serves as an important mechanism of MDR. Efflux pumps not only can expel a broad range of antibiotics owing to their poly-substrate specificity, but also drive the acquisition of additional resistance mechanisms by lowering intracellular antibiotic concentration and promoting mutation accumulation. Over-expression of multidrug efflux pumps have been increasingly found to be associated with clinically relevant drug resistance. On the other hand, accumulating evidence has suggested that efflux pumps also have physiological functions in bacteria and their expression is subject tight regulation in response to various of environmental and physiological signals. A comprehensive understanding of the mechanisms of drug extrusion, and regulation and physiological functions of efflux pumps is essential for the development of anti-resistance interventions. In this review, we summarize the development of these research areas in the recent decades and present the pharmacological exploitation of efflux pump inhibitors as a promising anti-drug resistance intervention.

  3. Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

    Science.gov (United States)

    Arendrup, Maiken Cavling; Patterson, Thomas F

    2017-08-15

    Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  4. Linezolid susceptibility in Helicobacter pylori, including strains with multidrug resistance.

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    Boyanova, Lyudmila; Evstatiev, Ivailo; Gergova, Galina; Yaneva, Penka; Mitov, Ivan

    2015-12-01

    Only a few studies have evaluated Helicobacter pylori susceptibility to linezolid. The aim of the present study was to assess linezolid susceptibility in H. pylori, including strains with double/multidrug resistance. The susceptibility of 53 H. pylori strains was evaluated by Etest and a breakpoint susceptibility testing method. Helicobacter pylori resistance rates were as follows: amoxicillin, 1.9%; metronidazole, 37.7%; clarithromycin, 17.0%; tetracycline, 1.9%; levofloxacin, 24.5%; and linezolid (>4 mg/L), 39.6%. The linezolid MIC50 value was 31.2-fold higher than that of clarithromycin and 10.5-fold higher than that of levofloxacin; however, 4 of 11 strains with double/multidrug resistance were linezolid-susceptible. The MIC range of the oxazolidinone agent was larger (0.125-64 mg/L) compared with those in the previous two reports. The linezolid resistance rate was 2.2-fold higher in metronidazole-resistant strains and in strains resistant to at least one antibiotic compared with the remaining strains. Briefly, linezolid was less active against H. pylori compared with clarithromycin and levofloxacin, and linezolid resistance was linked to resistance to metronidazole as well as to resistance to at least one antibiotic. However, linezolid activity against some strains with double/multidrug resistance may render the agent appropriate to treat some associated H. pylori infections following in vitro susceptibility testing of the strains. Clinical trials are required to confirm this suggestion.

  5. The importance of high-level predators in marine protected area management: Consequences of their decline and their potential recovery in the Mediterranean context

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    Giulia Prato

    2013-11-01

    Full Text Available High-level predators have been depleted in the oceans worldwide following centuries of selective fishing. There is widespread evidence that high-level predators’ extirpation may trigger trophic cascades leading to the degradation of marine ecosystems. Restoration of large carnivores to former levels of abundance might lead to ecosystem recovery, but very few pristine ecosystems are left as baselines for comparison. Marine protected areas (MPAs can trigger initial rapid increases of high-level predator abundance and biomass. Nevertheless, long term protection is needed before the ecosystem's carrying capacity for large carnivores is approached and indirect effects on lower trophic levels are observed. The Mediterranean is probably very far from its pristine condition, due to a long history of fishing. Today small to medium-sized consumers (e.g. sea breams are the most abundant predators shaping coastal benthic communities, while historical reconstructions depict abundant populations of large piscivores and sharks inhabiting coastal areas. Mediterranean MPAs are following a promising trajectory of ecosystem recovery, as suggested by a strong gradient of fish biomass increase. Consistent monitoring methods to assess relative variations of high-level predators, together with food-web models aimed at disentangling the indirect effects of their recovery, could be useful tools to help set up appropriate management strategies of MPAs.

  6. Failure to Respond to Food Resource Decline Has Catastrophic Consequences for Koalas in a High-Density Population in Southern Australia.

    Science.gov (United States)

    Whisson, Desley A; Dixon, Victoria; Taylor, Megan L; Melzer, Alistair

    2016-01-01

    Understanding the ability of koalas to respond to changes in their environment is critical for conservation of the species and their habitat. We monitored the behavioural response of koalas to declining food resources in manna gum (Eucalyptus viminalis) woodland at Cape Otway, Victoria, Australia, from September 2011 to November 2013. Over this period, koala population density increased from 10.1 to 18.4 koalas.ha-1. As a result of the high browsing pressure of this population, manna gum canopy condition declined with 71.4% manna gum being completely or highly defoliated in September 2013. Despite declining food resources, radio collared koalas (N = 30) exhibited high fidelity to small ranges (0.4-1.2 ha). When trees became severely defoliated in September 2013, koalas moved relatively short distances from their former ranges (mean predicted change in range centroid = 144 m) and remained in areas of 0.9 to 1.0 ha. This was despite the high connectivity of most manna gum woodland, and close proximity of the study site (koalas with 71% (15/21) of radio collared koalas dying from starvation or being euthanased due to their poor condition between September and November 2013.

  7. In vitro and in vivo analysis of antimicrobial agents alone and in combination against multi-drug resistant Acinetobacter baumannii

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    Songzhe eHE

    2015-05-01

    Full Text Available Objective To investigate the in vitro and in vivo antibacterial activities of tigecycline and other 13 common antimicrobial agents, alone or in combination, against multi-drug resistant Acinetobacter baumannii.MethodsAn in vitro susceptibility test of 101 Acinetobacter baumannii was used to detect minimal inhibitory concentrations (MICs. A mouse lung infection model of multi-drug resistant Acinetobacter baumannii,established by the ultrasonic atomization method, was used to define in vivo antimicrobial activities.Results Multi-drug resistant Acinetobacter baumannii showed high sensitivity to tigecycline (98% inhibition, polymyxin B (78.2% inhibition, and minocycline (74.2% inhibition. However, the use of these antimicrobial agents in combination with other antimicrobial agents produced synergistic or additive effects. In vivo data showed that white blood cell (WBC counts in drug combination groups C (minocycline + amikacin and D (minocycline + rifampicin were significantly higher than in groups A (tigecycline and B (polymyxin B (P < 0.05, after administration of the drugs 24h post-infection. Lung tissue inflammation gradually increased in the model group during the first 24h after ultrasonic atomization infection; vasodilation, congestion with hemorrhage were observed 48h post infection. After three days of anti-infective therapy in groups A, B, C and D, lung tissue inflammation in each group gradually recovered with clear structures. The mortality rates in drug combination groups (groups C and D were much lower than in groups A and B.ConclusionThe combination of minocycline with either rifampicin or amikacin is more effective against multidrug-resistant Acinetobacter baumannii than single-agent tigecycline or polymyxin B. In addition, the mouse lung infection by ultrasonic atomization is a suitable model for drug screening and analysis of infection mechanism.

  8. Antimicrobial activity of some essential oils against oral multidrug-resistant Enterococcus faecalis in both planktonic and biofilm state

    Institute of Scientific and Technical Information of China (English)

    Fethi Benbelad; Abdelmounam Khadir; Mohamed Amine Abdoune; Mourad Bendahou; Alain Muselli; Jean Costa

    2014-01-01

    Objective: To evaluate some essential oils in treatment of intractable oral infections, principally caused by biofilm of multidrug-resistant Enterococcus faecalis (E. faecalis), such as persistent endodontic infections in which their treatment exhibits a real challenge for dentists.Methods:were evaluated for antimicrobial activity against sensitive and resistant clinical strains of E. faecalis in both planktonic and biofilm state using two methods, disk diffusion and broth micro-dilution.Results:Studied essential oils showed a good antimicrobial activity and high ability in E. Ten chemically analyzed essential oils by gas chromatography-mass spectrometry faecalis biofilm eradication, whether for sensitive or multidrug-resistant strains, especially those of Origanum glandulosum and Thymbra capitata with interesting minimum inhibitory concentration, biofilm inhibitory concentration, and biofilm eradication concentration values which doesn’t exceed 0.063%, 0.75%, and 1.5%, respectively.Conclusions:Findings of this study indicate that essential oils extracted from aromatic plants can be used in treatment of intractable oral infections, especially caused by biofilm of multidrug-resistant E. faecalis.

  9. In vitro characterization and inhibition of the interaction between ciprofloxacin and berberine against multidrug-resistant Klebsiella pneumoniae.

    Science.gov (United States)

    Zhou, Xiao-Yuan; Ye, Xiao-Guang; He, Li-Ting; Zhang, Su-Rong; Wang, Ruo-Lun; Zhou, Jun; He, Zhuo-Shan

    2016-10-01

    Ciprofloxacin is a quinolone antibiotic used to treat Klebsiella pneumoniae infections in the clinic. Previous studies have demonstrated that berberine exhibits antibacterial activity and less acquired resistance related to efflux pumps. The multidrug efflux pump acrAB-tolC can be stimulated to expel as much toxic material as possible from the cells, but a detrimental effect can be produced owing to an overcrowded periplasm with excess expression products, which inhibits bacterial growth. In this study, the in vitro antibacterial activities of ciprofloxacin in combination with berberine were evaluated and compared with those of ciprofloxacin and berberine alone by evaluating the MIC, MBC and summation fractional IC against 20 clinical multidrug-resistant K. pneumoniae isolates, 1 quality control bacterium and 1 induced-resistance bacterium. Susceptibility tests showed that the MIC for the combination of berberine and ciprofloxacin was 1/2 that of the individual agents or less. Antimicrobial activities of 18.18% synergy and 77.27% additivity were found. Furthermore, synergism was verified through a time-kill assay, which suggested that the synergistic antibacterial effect of the two-drug combination may, to some extent, be related to the high expression of the acrAB-tolC and acrR multidrug efflux pumps. Indeed, the expression of these genes was increased >14-fold in the isolates affected by ciprofloxacin-berberine combination synergism.

  10. Potassium-bearing Iron-Nickel Sulfides in Nature and High-Pressure Experiments: Geochemical Consequences of Potassium in the Earth's Core

    Science.gov (United States)

    Keshav, S.; Corgne, A.; McDonough, W. F.; Fei, Y.

    2005-01-01

    Introduction: Potassium (K) as a large ion lithophile element has dominantly been concentrated in the Earth s crust and the mantle through differentiation, and in the form of K-40 contributes to the planet s heat budget. However, whether or not K also enters core-forming phases, has been debated for over three decades. Arguments favoring entry of K in the core are based on: (1) K-sulfide (with Fe, Ni, Cu, Na, and Cl; djerfisherite) found in highly reduced enstatite chondrites (or aubrites, enstatite achondrites); (2) demonstration that K, owing to an s-d electronic switch at high-pressure, exhibits transition- element like character, (3) solubility of measurable K in Fe-Ni-S liquids at high pressure, temperature conditions, and (4) models of cooling of the core that seem to require, besides convection, some form of radioactivity, and thus lending support to the experimental work. In this contribution, we assess the effect of sequestering K in the core, as it is perhaps an element that is a key to reconciling geochemistry, paleomagnetism, accretion, and thermal evolution models for the planet.

  11. Real time high frequency monitoring of water quality in river streams using a UV-visible spectrometer: interest, limits and consequences for monitoring strategies

    Science.gov (United States)

    Faucheux, Mikaël; Fovet, Ophélie; Gruau, Gérard; Jaffrézic, Anne; Petitjean, Patrice; Gascuel-Odoux, Chantal; Ruiz, Laurent

    2013-04-01

    Stream water chemistry is highly variable in space and time, therefore high frequency water quality measurement methods are likely to lead to conceptual advances in the hydrological sciences. Sub-daily data on water quality improve the characterization of pollutant sources and pathways during flood events as well as during long-term periods [1]. However, real time, high frequency monitoring devices needs to be properly calibrated and validated in real streams. This study analyses data from in situ monitoring of a stream water quality. During two hydrological years (2010-11, 2011-12), a submersible UV-visible spectrometer (Scan Spectrolyser) was used for surface water quality measurement at the outlet of a headwater catchment located at Kervidy-Naizin, Western France (AgrHys long-term hydrological observatory, http://www.inra.fr/ore_agrhys/). The spectrometer is reagentless and equipped with an auto-cleaning system. It allows real time, in situ and high frequency (20 min) measurements and uses a multiwavelengt spectral (200-750 nm) for simultaneous measurement of nitrate, dissolved organic carbon (DOC) and total suspended solids (TSS). A global calibration based on a PLS (Partial Least Squares) regression is provided by the manufacturer as default configuration of the UV-visible spectrometer. We carried out a local calibration of the spectrometer based on nitrates and DOC concentrations analysed in the laboratory from daily manual sampling and sub-daily automatic sampling of flood events. TSS results are compared with 15 min turbidity records from a continuous turdidimeter (Ponsel). The results show a good correlation between laboratory data and spectrometer data both during basis flows periods and flood events. However, the local calibration gives better results than the global one. Nutrient fluxes estimates based on high and different low frequency time series (daily to monthly) are compared to discuss the implication for environmental monitoring strategies. Such

  12. Chemical consequences of cutaneous photoageing

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    Thurstan Sarah A

    2012-04-01

    Full Text Available Abstract Human skin, in common with other organs, ages as a consequence of the passage of time, but in areas exposed to solar ultraviolet radiation, the effects of this intrinsic ageing process are exacerbated. In particular, both the severity and speed of onset of age-related changes, such as wrinkle formation and loss of elasticity, are enhanced in photoaged (also termed extrinsically aged as compared with aged, photoprotected, skin. The anatomy of skin is characterised by two major layers: an outer, avascular, yet highly cellular and dynamic epidermis and an underlying vascularised, comparatively static and cell-poor, dermis. The structural consequences of photoageing are mainly evident in the extracellular matrix-rich but cell-poor dermis where key extracellular matrix proteins are particularly susceptible to photodamage. Most investigations to date have concentrated on the cell as both a target for and mediator of, ultraviolet radiation-induced photoageing. As the main effectors of dermal remodelling produced by cells (extracellular proteases generally have low substrate specificity, we recently suggested that the differential susceptibility of key extracellular matrix proteins to the processes of photoageing may be due to direct, as opposed to cell-mediated, photodamage. In this review, we discuss the experimental evidence for ultraviolet radiation (and related reactive oxygen species-mediated differential degradation of normally long lived dermal proteins including the fibrillar collagens, elastic fibre components, glycoproteins and proteoglycans. Whilst these components exhibit highly diverse primary and hence macro- and supra-molecular structures, we present evidence that amino acid composition alone may be a useful predictor of age-related protein degradation in both photoexposed and, as a consequence of differential oxidation sensitivity, photoprotected, tissues.

  13. U-Pb SHRIMP zircon dating of high-grade rocks from the Upper Allochthonous Terrane of Bragança and Morais Massifs (NE Portugal); geodynamic consequences

    Science.gov (United States)

    Mateus, A.; Munhá, J.; Ribeiro, A.; Tassinari, C. C. G.; Sato, K.; Pereira, E.; Santos, J. F.

    2016-04-01

    Bragança and Morais Massifs are part of the mega-klippen ensemble of NW Iberia, comprising a tectonic pile of four allochthonous units stacked above the Central-Iberian Zone autochthon. On top of this pile, the Upper Allochthonous Terrane (UAT) includes different high-grade metamorphic series whose age and geodynamic meaning are controversial. Mafic granulites provided U-Pb zircon ages at 399 ± 7 Ma, dating the Variscan emplacement of UAT. In contrast, U-Pb zircon ages of ky- and hb-eclogites, felsic/intermediate HP/HT-granulites and orthogneisses (ca. 500-480 Ma) are identical to those of gabbros (488 ± 10 Ma) and Grt-pyroxenites (495 ± 8 Ma) belonging to a mafic/ultramafic igneous suite that records upper mantle melting and mafic magma crustal underplating at these times. Gabbros intrude the high-grade units of UAT and did not underwent the HP metamorphic event experienced by eclogites and granulites. These features and the zircon dates resemblance among different lithologies, suggest that extensive age resetting of older events may have been correlative with the igneous suite emplacement/crystallisation. Accordingly, reconciliation of structural, petrological and geochronological evidence implies that the development and early deformation of UAT high-grade rocks should be ascribed to an orogenic cycle prior to ≈ 500 Ma. Undisputable dating of this cycle is impossible, but the sporadic vestiges of Cadomian ages cannot be disregarded. The ca. 500-480 Ma time-window harmonises well with the Lower Palaeozoic continental rifting that trace the Variscan Wilson Cycle onset and the Rheic Ocean opening. Subsequent preservation of the high heat-flow regime, possibly related to the Palaeotethys back-arc basin development (ca. 450-420 Ma), would explain the 461 ± 10 Ma age yielded by some zircon domains in felsic granulites, conceivably reflecting zircon dissolution/recrystallisation till Ordovician times, long before the Variscan paroxysm (ca. 400-390 Ma). This

  14. Land cover trajectory in the Caatinga biome: analysing trends, drivers and consequences with high resolution satellite time series in Paraiba, Brazil

    Science.gov (United States)

    Rufino, Iana; Cunha, John; Carlos, Galvão; Nailson, Silva

    2017-04-01

    The Caatinga Biome is a unique Earth ecosystem with only 1% of conserved and protected areas (Oliveira et al, 2012). Human activities pressures high threaten Caatinga Biodiversity. Along the last decades, native green areas are changed by crops, livestock or those areas are reached by urban areas (Oliveira et al 2012; Fiaschi e Pianni, 2009; Sivakumar, 2007; Castelleti et al, 2004; Pereira et al, 2013; le Polain de Waroux & Lambin, 2012; Apgaua et al, 2013). Precipitation rates have high variability in space and time. High temperatures with small inter annual variability drives evapotranspiration up and turns the water scarcity the main challenge for sustainable life in rural areas. Sánchez-Azofeifa et al., (2005) try establishing research priorities for tropical dry forests and they recommend Scientific Community to focus on ecology and social aspects and possibilities of remote sensing techniques in those studies. Specific algorithms to produce estimates of energy balance and evapotranspiration of water to the atmosphere can process satellite images derived from several sensors. These estimates, combined with the analysis of historical time-series, allow the detection of changes in the terrestrial plant systems and can be used to discriminate the influences from human occupation and those from climate variability and/or change on energy fluxes and land cover. The algorithms have to be calibrated and validated using ground-based data. Thus, a large multiple source set of satellite and ground data has to be processed and comparatively analyzed. However, the high computational cost for image processing introduce further processing challenges. In order to face those challenges, this research explores the possibilities of using these medium resolution remote sensing products (30 meters), presenting a multitemporal long term analysis (24 months) to identify the land trajectory of one Semi-arid area (pilot) in the Caatinga biome. All processing steps use the

  15. Classification of refractory ceramic fibres and repercussions on high temperature insulation; La classification des fibres ceramiques refractaires et ses consequences sur l'isolation haute temperature

    Energy Technology Data Exchange (ETDEWEB)

    Class, Ph. [Thermal Ceramics de France (France)

    2000-09-01

    1999 saw the implementation of the European directive 97/69/CE on the classification of man made vitreous (silicate) fibres. This major change and its extent may be difficult to understand but is of great importance to all industries using such materials. The author, expert in Health, Safety and Environment at Thermal Ceramics Europe and representative of the European Ceramic Fibre Industry Association (ECFIA), develops this classification here, giving emphasis to the repercussions it will have on refractory ceramic fibres and high temperature insulating wools. (author)

  16. Unintended Consequences of Remittance

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    Adediran Daniel Ikuomola

    2015-09-01

    Full Text Available Research on migrants’ remittance in Nigeria has largely focused on the contribution to national development and economic well-being of family members. In contrast, this article explores the way in which remittance serves as potential sources of conflict within migrant households. The article investigates intra-household conflicts related to migrant remittances, revealing the contradictory and unintended consequences of remittances destabilizing cordial relationships between migrants and family members. Within the family (mainly extended families, the sharing of remittance is often accompanied with envy, distrust, and accusation of witch hunt. While improper utilization and accountability of remittances strain relationships, migrants are forced to re-strategize on how remittances get to their relatives and sometimes cut off communication and remittances with family members. Based on the qualitative data collected in Benin City (Edo State in Nigeria, the article investigates intra-household conflicts emanating from migrant remittances, from the perspectives of migrants on holidays.

  17. Medical consequences of obesity.

    Science.gov (United States)

    Lawrence, Victor J; Kopelman, Peter G

    2004-01-01

    The obese are subject to health problems directly relating to the carriage of excess adipose tissue. These problems range from arthritis, aches and pains, sleep disturbance, dyspnea on mild exertion, and excessive sweating to social stigmatization and discrimination, all of which may contribute to low quality of life and depression (Table 1). The most serious medical consequences of obesity are a result of endocrine and metabolic changes, most notably type 2 diabetes mellitus, cardiovascular disease, and increased risk of cancer. Not all obesity comorbidities are fully reversed by weight loss. The degree and duration of weight loss required may not be achievable by an individual patient. Furthermore, "weight cycling" may be more detrimental to both physical and mental health than failure to achieve weight loss targets with medical and lifestyle advice.

  18. Characterization of the folding energy landscapes of computer generated proteins suggests high folding free energy barriers and cooperativity may be consequences of natural selection.

    Science.gov (United States)

    Scalley-Kim, Michelle; Baker, David

    2004-04-30

    To determine the extent to which protein folding rates and free energy landscapes have been shaped by natural selection, we have examined the folding kinetics of five proteins generated using computational design methods and, hence, never exposed to natural selection. Four of these proteins are complete computer-generated redesigns of naturally occurring structures and the fifth protein, called Top7, has a computer-generated fold not yet observed in nature. We find that three of the four redesigned proteins fold much faster than their naturally occurring counterparts. While natural selection thus does not appear to operate on protein folding rates, the majority of the designed proteins unfold considerably faster than their naturally occurring counterparts, suggesting possible selection for a high free energy barrier to unfolding. In contrast to almost all naturally occurring proteins of less than 100 residues but consistent with simple computational models, the folding energy landscape for Top7 appears to be quite complex, suggesting the smooth energy landscapes and highly cooperative folding transitions observed for small naturally occurring proteins may also reflect the workings of natural selection.

  19. Consequences of the armed conflict in the urban social order. Te case of the high ground of San Cristobal locality. Bogotá 1990-2010.

    Directory of Open Access Journals (Sweden)

    Angie Catherine Callejas Téllez

    2016-11-01

    Full Text Available This article considers the period understood between 1990 and  2010, when the actions of armed groups in the high ground of  San Cristóbal were clearer in order to keep territorial control,  especially over the routes of  communication with other municipalities. Here, elements that make possible the comprehension  of the current context of  the observed territory stand out, for  which a sketch of the history of  the locality was made, and three  key points in which the armed groups had an impact were developed: the configuration of the space, the social relations and the  political participation

  20. A Substrate Mimic Allows High-Throughput Assay of the FabA Protein and Consequently the Identification of a Novel Inhibitor of Pseudomonas aeruginosa FabA.

    Science.gov (United States)

    Moynié, Lucile; Hope, Anthony G; Finzel, Kara; Schmidberger, Jason; Leckie, Stuart M; Schneider, Gunter; Burkart, Michael D; Smith, Andrew D; Gray, David W; Naismith, James H

    2016-01-16

    Eukaryotes and prokaryotes possess fatty acid synthase (FAS) biosynthetic pathways that comprise iterative chain elongation, reduction, and dehydration reactions. The bacterial FASII pathway differs significantly from human FAS pathways and is a long-standing target for antibiotic development against Gram-negative bacteria due to differences from the human FAS, and several existing antibacterial agents are known to inhibit FASII enzymes. N-Acetylcysteamine (NAC) fatty acid thioesters have been used as mimics of the natural acyl carrier protein pathway intermediates to assay FASII enzymes, and we now report an assay of FabV from Pseudomonas aeruginosa using (E)-2-decenoyl-NAC. In addition, we have converted an existing UV absorbance assay for FabA, the bifunctional dehydration/epimerization enzyme and key target in the FASII pathway, into a high-throughput enzyme coupled fluorescence assay that has been employed to screen a library of diverse small molecules. With this approach, N-(4-chlorobenzyl)-3-(2-furyl)-1H-1,2,4-triazol-5-amine (N42FTA) was found to competitively inhibit (pIC50=5.7±0.2) the processing of 3-hydroxydecanoyl-NAC by P. aeruginosa FabA. N42FTA was shown to be potent in blocking crosslinking of Escherichia coli acyl carrier protein and FabA, a direct mimic of the biological process. The co-complex structure of N42FTA with P. aeruginosa FabA protein rationalises affinity and suggests future design opportunities. Employing NAC fatty acid mimics to develop further high-throughput assays for individual enzymes in the FASII pathway should aid in the discovery of new antimicrobials.

  1. Predictors and dietary consequences of frequent intake of high-sugar, low-nutrient foods in 1-year-old children participating in the ABIS study.

    Science.gov (United States)

    Brekke, Hilde K; van Odijk, Jenny; Ludvigsson, Johnny

    2007-01-01

    Foods rich in sugar have been suggested to contribute to the increasing prevalence of obesity in children. The aim of this report is to investigate the dietary pattern in 1-year-old children who frequently receive foods rich in sugar but low in nutrients and to study associated demographic and parental factors. During 1977-9, 21,700 infants were invited to participate in this prospective, population-based, longitudinal cohort study. Screening questionnaires were completed for 16,070 infants after delivery. Follow-up questionnaires from 10,762 children at 1 year of age are included in the analysis. It was found that 24% of the children received sweets/pastries more often than one or two times per week. They had a higher intake of French fries, potato crisps and cream as well as a lower intake of fruit and vegetables. A frequent intake of sugar-rich, low-nutrient foods was significantly associated with several maternal factors (high intake of sweets/pastries during pregnancy, young age, mother living alone) as well as presence of older siblings. Maternal smoking during pregnancy and maternal overweight were of borderline significance. Parental education level was inversely associated with the frequency of intake of sweets/pastries in the child. Children who frequently receive sweets/pastries also have an otherwise unfavourable dietary pattern. Several parental and demographic factors were associated with this feeding pattern, especially high intake of sweets/pastries during pregnancy. Screening of pregnant women for risk predictors like consumption of sweets/pastries, young age and smoking could be possible ways of identifying children at future risk for low dietary quality.

  2. Physiological consequences : Cardiopulmonary, vestibular, and sensory aspects

    NARCIS (Netherlands)

    Welsch, H.; Albery, W.; Banks, R.D.; Bles, W.

    2000-01-01

    Discussing the physiological consequences of enhanced fighter manoeuvrability (EFM), aspects of cardiopulmonary reactions will be seen during high G manoeuvres, especially the combination of negative G-load followed by high G-onset manoeuvres ("push-pull"). The aircraft's capability to reach high al

  3. Clinical Management of an Increasing Threat: Outpatient Urinary Tract Infections Due to Multidrug-Resistant Uropathogens.

    Science.gov (United States)

    Walker, Emily; Lyman, Alessandra; Gupta, Kalpana; Mahoney, Monica V; Snyder, Graham M; Hirsch, Elizabeth B

    2016-10-01

    Urinary tract infections (UTIs) are among the most commonly treated bacterial infections. Over the past decade, antimicrobial resistance has become an increasingly common factor in the management of outpatient UTIs. As treatment options for multidrug-resistant (MDR) uropathogens are limited, clinicians need to be aware of specific clinical and epidemiological risk factors for these infections. Based on available literature, the activity of fosfomycin and nitrofurantoin remain high for most cases of MDR Escherichia coli UTIs. Trimethoprim-sulfamethoxazole retains clinical efficacy, but resistance rates are increasing internationally. Beta-lactam agents have the highest rates of resistance and lowest rates of clinical success. Fluoroquinolones have high resistance rates among MDR uropathogens and are being strongly discouraged as first-line agents for UTIs. In addition to accounting for local resistance rates, consideration of patient risk factors for resistance and pharmacological principles will help guide optimal empiric treatment of outpatient UTIs.

  4.  Pressure-induced Fe↔Cu cationic valence exchange and its structural consequences: High-pressure studies of delafossite CuFeO2

    Science.gov (United States)

    Xu, W. M.; Rozenberg, G. Kh.; Pasternak, M. P.; Kertzer, M.; Kurnosov, A.; Dubrovinsky, L. S.; Pascarelli, S.; Munoz, M.; Vaccari, M.; Hanfland, M.; Jeanloz, R.

    2010-03-01

    The present high-pressure studies of CuFeO2 to 30 GPa using x-ray diffraction, along with F57e Mössbauer and Fe and CuK -edge x-ray absorption spectroscopy methods, reveal a sequence of intricate structural/electronic-magnetic pressure-induced transitions. The low-pressure R3¯m structure (0-18 GPa) is composed of sheets of FeS=5/23+ ions alternating with layers of O-CuS=01+-O dumbbells, the latter oriented along the c axis. This structure is characterized by an unusual positive d(c/a)/dP . At 18 GPa a structural transition takes place to a more isotropic C2/c structure with the O-CuS=01+-O axis tilted 28° from the c axis and with negative d(c/a)/dP . This transition corroborates with the onset of long-range antiferromagnetic order. Starting at ˜23GPa , with an initial volume reduction in ˜|ΔV/V0|=0.16 , the Cu-Fe bands overlap and this leads to a (CuS=01+FeS=5/23+)→(CuS=1/22+FeS=22+) interionic valence exchange in about 1/3 of the C2/c-CuFeO2 at 27 GPa. As a result: (i) the Cu2+-O becomes fourfold coordinated and is in a new crystallographic structure with space group P3¯m , and (ii) the Néel temperature increases above twofold [TN(CuS=1/22+FeS=22+)≈2.2TN(CuS=01+FeS=5/23+)] . This sequence of transitions is reversible with minimal hysteresis.

  5. Lifecycle Problems in Consequence Estimation

    Directory of Open Access Journals (Sweden)

    Lehman William

    2016-01-01

    Full Text Available The United States Army Corps of Engineers (USACE guidance documents require economists and planners to meet a very high standard when evaluating consequences resulting from flood events. The guidance documents require analysts to evaluate how government action changes the consequences over time, in addition to evaluating how government inaction changes consequences over time as well. Corps guidance (Engineering Regulation 1105-2-100, Section 2-3.c.4 and Engineering Regulation 1105-2-100, Section 2-3.b respectively require the evaluation of direct and indirect economic impacts, life risk impacts, and agricultural impacts for both current conditions and future most likely conditions across a range of alternatives. Evaluating the potential for impacts from flooding across time, and how time impacts their existence or vulnerability, is considered a “lifecycle approach”. Little to no guidance is available on the process of calculating this “lifecycle approach” regarding changes in the value and number of assets within the floodplain over time. Performing a lifecycle analysis of a project over durations from 30 to 100 years, depending on the project purpose, requires evaluation of the changes in human behavior caused by changes in the floodplain such as reconstruction of structures, maintenance of structures, construction of new structures, population growth, and what type of structures are being built within the study area. This type of evaluation is not fully supported by most of the software programs utilized for flood risk management in the planning context. This paper is intended to describe pros and cons of economic lifecycle evaluation techniques to address the needs stated by policy, and tools that are being developed to support this analysis.

  6. Conditional probability analysis of multidrug resistance in Gram-negative bacilli isolated from tertiary medical institutions in South Korea during 1999-2009.

    Science.gov (United States)

    Kim, Yong-Hak

    2016-01-01

    Multidrug resistance of Gram-negative bacilli is a major problem globally. However, little is known about the combined probability of resistance to various antibiotics. In this study, minimum inhibitory concentrations of widely used antibiotics were determined using clinical isolates of Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, randomly chosen from strain collections created during 1999-2009 in tertiary medical institutions in Seoul, South Korea. To analyze combined efficacy of antibiotics against a subgroup of isolates, conditional probabilities were determined based on arbitrary, non-independent patterns of antimicrobial susceptibility and resistance. Multidrug resistance, defined as resistance to three or more classes of antibiotics, was observed in the following order: A. baumannii (96%), P. aeruginosa (65%), E. coli (52%), and K. pneumoniae (7%). A. baumannii strains resistant to gentamicin were found to be resistant to a number of antibiotics, except for colistin and polymyxin B. Resistance to gentamicin following exposure to this antibiotic was highly likely to lead to multidrug resistance in all four microbes. This study shows a causal relationship between gentamicin resistance and the prevalence of multidrug resistance in clinical isolates of Gramnegative bacilli in South Korea during 1999-2009 and suggests the importance of prudent use of gentamicin in hospitals.

  7. Seismic Consequence Abstraction

    Energy Technology Data Exchange (ETDEWEB)

    M. Gross

    2004-10-25

    The primary purpose of this model report is to develop abstractions for the response of engineered barrier system (EBS) components to seismic hazards at a geologic repository at Yucca Mountain, Nevada, and to define the methodology for using these abstractions in a seismic scenario class for the Total System Performance Assessment - License Application (TSPA-LA). A secondary purpose of this model report is to provide information for criticality studies related to seismic hazards. The seismic hazards addressed herein are vibratory ground motion, fault displacement, and rockfall due to ground motion. The EBS components are the drip shield, the waste package, and the fuel cladding. The requirements for development of the abstractions and the associated algorithms for the seismic scenario class are defined in ''Technical Work Plan For: Regulatory Integration Modeling of Drift Degradation, Waste Package and Drip Shield Vibratory Motion and Seismic Consequences'' (BSC 2004 [DIRS 171520]). The development of these abstractions will provide a more complete representation of flow into and transport from the EBS under disruptive events. The results from this development will also address portions of integrated subissue ENG2, Mechanical Disruption of Engineered Barriers, including the acceptance criteria for this subissue defined in Section 2.2.1.3.2.3 of the ''Yucca Mountain Review Plan, Final Report'' (NRC 2003 [DIRS 163274]).

  8. Legal consequences of kleptomania.

    Science.gov (United States)

    Grant, Jon E; Odlaug, Brian L; Davis, Andrew A; Kim, Suck Won

    2009-12-01

    Although studies have examined clinical characteristics of kleptomania, no previous studies have examined the legal consequences of kleptomania. From 2001 to 2007, 101 adult subjects (n = 27 [26.7%] males) with DSM-IV kleptomania were assessed on sociodemographics and clinical characteristics including symptom severity, comorbidity, and legal repercussions. Of 101 subjects with kleptomania, 73.3% were female. Mean age of shoplifting onset was 19.4 +/- 12.0 years, and subjects shoplifted a mean of 8.2 +/- 11.0 years prior to meeting full criteria for kleptomania. Co-occurring depressive, substance use, and impulse control disorders were common. Sixty-nine subjects with kleptomania (68.3%) had been arrested, 36.6% had been arrested but not convicted, 20.8% had been convicted and incarcerated after conviction, while only 10.9% had been convicted and not incarcerated after conviction. Kleptomania is associated with significant legal repercussions. The findings emphasize the need for rigorous treatment approaches to target kleptomania symptoms and prevent re-offending.

  9. CONSEQUENCES OF THE DEMOGRAPHIC CRISIS

    Directory of Open Access Journals (Sweden)

    LIVIU RADU

    2014-11-01

    Full Text Available Major dysfunctionalities can arise from the demographic decline, both on a social level and from the perspective of the economic-financial evolution of the world’s states. The obvious aging of the industrialized states’ population overlapping the import of cheap workforce in the developing countries can start mutations whose consequences are somewhat predictable but discouraging. An accelerated urbanization of the states is foreseen, as well as the decrease of birthrates, negative external migration, increase of mortality and its stagnation in a larger value than that of the birthrate, and not least the population’s aging will hinder a part of the developing countries to sustain a high rhythm of long-term economical increase. The socialeconomic consequences will be reflected in the labor market, the householders’ amount of income as well as in the education’s level. All of these aspects call for a rethinking of the public politics, especially of the social insurance’s system and of the education, a reorientation of the economy based on the increase of specializing in production and productivity, as well as a financial stability unburdened by the politics’ interference in the business environment.

  10. Epidemiologic analysis: Prophylaxis and multidrug-resistance in surgery.

    Science.gov (United States)

    Solís-Téllez, H; Mondragón-Pinzón, E E; Ramírez-Marino, M; Espinoza-López, F R; Domínguez-Sosa, F; Rubio-Suarez, J F; Romero-Morelos, R D

    Surgical site infection is defined as an infection related to the surgical procedure in the area of manipulation occurring within the first 30 postoperative days. The diagnostic criteria include: purulent drainage, isolation of microorganisms, and signs of infection. To describe the epidemiologic characteristics and differences among the types of prophylactic regimens associated with hospital-acquired infections at the general surgery service of a tertiary care hospital. The electronic case records of patients that underwent general surgery at a tertiary care hospital within the time frame of January 1, 2013 and December 31, 2014 were reviewed. A convenience sample of 728 patients was established and divided into the following groups: Group 1: n=728 for the epidemiologic study; Group 2: n=638 for the evaluation of antimicrobial prophylaxis; and Group 3: n=50 for the evaluation of multidrug-resistant bacterial strains in the intensive care unit. The statistical analysis was carried out with the SPSS 19 program, using the Mann-Whitney U test and the chi-square test. A total of 728 procedures were performed (65.9% were elective surgeries). Three hundred twelve of the patients were males and 416 were females. Only 3.98% of the patients complied with the recommended antimicrobial prophylaxis, and multidrug-resistant bacterial strains were found in the intensive care unit. A single prophylactic dose is effective, but adherence to this recommendation was not adequate. The prophylactic guidelines are not strictly adhered to in our environment. There was a significant association between the development of nosocomial infections from multidrug-resistant germs and admission to the intensive care unit. Copyright © 2016 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.

  11. Recurrence after treatment for pulmonary multidrug-resistant tuberculosis.

    Science.gov (United States)

    Becerra, Mercedes C; Appleton, Sasha C; Franke, Molly F; Chalco, Katiuska; Bayona, Jaime; Murray, Megan B; Mitnick, Carole D

    2010-09-15

    We estimated the proportion of recurrence within 2 years among adults cured by individualized multidrug-resistant tuberculosis regimens in Peru. Among 310 individuals with at least 24 months of follow-up, 16 experienced an episode of recurrent tuberculosis. If we assume the worst for treatment effectiveness-that all 16 episodes were caused by the original tuberculosis strain-then 5.2% (95% confidence interval, 3.0%-8.2%) experienced true relapse. This is an upper-bound estimate of relapse on which new regimens must improve.

  12. Overcoming multidrug resistance(MDR) in cancer by nanotechnology

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The emerging nanotechnology-based drug delivery holds tremendous potential to deliver chemotherapeutic drugs for treatment of multidrug resistance(MDR) cancer.This drug delivery system could improve the pharmacokinetic behavior of antitumor drugs,deliver chemotherapeutic drugs to target sites,control release of drugs,and reduce the systemic toxicity of drugs in MDR cancer.This review addresses the use of nanotechnology to overcome MDR classified on the bases of the fundamental mechanisms of MDR and various approaches to deliver drugs for treatment of MDR cancer.

  13. Human Multidrug Resistance 1 gene polymorphisms and Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Martinelli, Marcella; Scapoli, Luca; Pacilli, Angela Maria Grazia; Carbonara, Paolo; Girardi, Ambra; Mattei, Gabriella; Rodia, Maria Teresa; Solmi, Rossella

    2015-01-01

    Background: For the first time we tested an association between the human multidrug resistance gene 1 (MDR1) polymorphisms (SNPs) and idiopathic pulmonary fibrosis (IPF). Several MDR1 polymorphisms are associated with pathologies in which they modify the drug susceptibility and pharmacokinetics. Materials and Methods: We genotyped three MDR1 polymorphisms of 48 IPF patients and 100 control subjects with Italian origins. Results: No evidence of association was detected. Conclusion: There are 50 known MDR1 SNPs, and their role is explored in terms of the effectiveness of drug therapy. We consider our small-scale preliminary study as a starting point for further research. PMID:25767528

  14. [Multidrug-resistant tuberculosis: current epidemiology, therapeutic regimens, new drugs].

    Science.gov (United States)

    Gómez-Ayerbe, C; Vivancos, M J; Moreno, S

    2016-09-01

    Multidrug and extensively resistant tuberculosis are especially severe forms of the disease for which no efficacious therapy exists in many cases. All the countries in the world have registered cases, although most of them are diagnosed in resource-limited countries from Asia, Africa and South America. For adequate treatment, first- and second-line antituberculosis drugs have to be judiciously used, but the development of new drugs with full activity, good tolerability and little toxicity is urgently needed. There are some drugs in development, some of which are already available through expanded-access programs.

  15. Expression of multidrug resistance-related markers in primary neuroblastoma

    Institute of Scientific and Technical Information of China (English)

    吕庆杰; 董芳; 张锦华; 李晓晗; 马颖; 姜卫国

    2004-01-01

    Background Multidrug resistance is associated with a poor prognosis in various human cancers. However, the clinical significance of the expression of multidrug resistance-related markers in neuroblastoma is still on debate. In this study, the effect of the expression of p-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance protein (LRP) in neuroblastoma was evaluated. Methods The streptavidin-biotin immunoperoxidase (SP) technique was used to evaluate the expression of P-gp, MRP, and LRP in 70 cases of untreated primary neuroblastoma. Results The frequencies of the expression of P-gp, MRP, and LRP were 61.4%, 38.6%, and 24.3%, respectively. A significant positive correlation was observed between P-gp and MRP expression (P=0.001), as well as between LRP and MRP expression (P=0.01). The rates of expression of P-gp and MRP were higher in tumors from patients aged greater than one year old than in tumors from patients aged less than 1 year old at time of diagnosis (P=0.01 and 0.018, respectively). MRP expression in tumors that had metastasized was significantly more frequent than in tumors that had not metastasized (P=0.015). The expression of all tested proteins showed a significant relationship with whether or not the tumor had differentiated (P=0.006, 0.000 or 0.001, respectively). MRP expression was significantly associated with a reduction in both median survival time and 2-year cumulative survival (P=0.02). By contrast, P-gp and MRP expression did not correlate with survival. According to Cox regression analysis, only the co-expression of P-gp and MRP had significant prognostic value (relative hazard, 3.513, P=0.033). Conclusions The intrinsic, multidrug resistance of neuroblastoma involves the combined effects of P-gp, MRP, and LRP. MRP expression may be an important factor determining prognosis in neuroblastoma.

  16. The lactococcal secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines

    NARCIS (Netherlands)

    Putman, M; van Veen, HW; Degener, JE; Konings, WN

    2001-01-01

    The active efflux of toxic compounds by (multi)drug transporters is one of the mechanisms that bacteria have developed to resist cytotoxic drugs. The authors describe the role of the lactococcal secondary multidrug transporter LmrP in the resistance to a broad range of clinically important antibioti

  17. Natural History of Multi-Drug Resistant Organisms in a New Military Medical Facility

    Science.gov (United States)

    2013-12-01

    Staphylococcus saprophyticus 14 (3) Enterococcus (faecium and faecalis) 11 (2) The remaining 11 species each comprised less than 2% of total 169 (32...environment plays in the transmission of multidrug-resistant Gram-negative bacteria and methicillin-resistant Staphylococcus aureus (MDRO) is increasingly...Pseudomonas aeruginosa, methicillin- resistant Staphylococcus aureus (MRSA); Klebsiella pneumoniea; and Clostridium difficile. Multidrug- resistance (MDR

  18. Safety assessment of high consequence robotics system

    Energy Technology Data Exchange (ETDEWEB)

    Robinson, D.G.; Atcitty, C.B.

    1996-08-01

    This paper outlines the use of a failure modes and effects analysis for the safety assessment of a robotic system being developed at Sandia National Laboratories. The robotic system, the weigh and leak check system, is to replace a manual process for weight and leakage of nuclear materials at the DOE Pantex facility. Failure modes and effects analyses were completed for the robotics process to ensure that safety goals for the systems have been met. Due to the flexible nature of the robot configuration, traditional failure modes and effects analysis (FMEA) were not applicable. In addition, the primary focus of safety assessments of robotics systems has been the protection of personnel in the immediate area. In this application, the safety analysis must account for the sensitivities of the payload as well as traditional issues. A unique variation on the classical FMEA was developed that permits an organized and quite effective tool to be used to assure that safety was adequately considered during the development of the robotic system. The fundamental aspects of the approach are outlined in the paper.

  19. Dynamic visualization techniques for high consequence software

    Energy Technology Data Exchange (ETDEWEB)

    Pollock, G.M.

    1998-02-01

    This report documents a prototype tool developed to investigate the use of visualization and virtual reality technologies for improving software surety confidence. The tool is utilized within the execution phase of the software life cycle. It provides a capability to monitor an executing program against prespecified requirements constraints provided in a program written in the requirements specification language SAGE. The resulting Software Attribute Visual Analysis Tool (SAVAnT) also provides a technique to assess the completeness of a software specification. The prototype tool is described along with the requirements constraint language after a brief literature review is presented. Examples of how the tool can be used are also presented. In conclusion, the most significant advantage of this tool is to provide a first step in evaluating specification completeness, and to provide a more productive method for program comprehension and debugging. The expected payoff is increased software surety confidence, increased program comprehension, and reduced development and debugging time.

  20. Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation

    Directory of Open Access Journals (Sweden)

    C. Sharma

    2016-09-01

    Full Text Available Candida auris is an emerging multidrug resistant yeast that causes nosocomial fungaemia and deep-seated infections. Notably, the emergence of this yeast is alarming as it exhibits resistance to azoles, amphotericin B and caspofungin, which may lead to clinical failure in patients. The multigene phylogeny and amplified fragment length polymorphism typing methods report the C. auris population as clonal. Here, using whole genome sequencing analysis, we decipher for the first time that C. auris strains from four Indian hospitals were highly related, suggesting clonal transmission. Further, all C. auris isolates originated from cases of fungaemia and were resistant to fluconazole (MIC >64 mg/L.

  1. Thiocarbamates from Moringa oleifera Seeds Bioactive against Virulent and Multidrug-Resistant Vibrio Species

    Science.gov (United States)

    de Sousa, Oscarina Viana; Hofer, Ernesto; Mafezoli, Jair; Barbosa, Francisco Geraldo

    2017-01-01

    Prospect of antibacterial agents may provide an alternative therapy for diseases caused by multidrug-resistant bacteria. This study aimed to evaluate the in vitro bioactivity of Moringa oleifera seed extracts against 100 vibrios isolated from the marine shrimp Litopenaeus vannamei. Ethanol extracts at low (MOS-E) and hot (MOS-ES) temperature are shown to be bioactive against 92% and 90% of the strains, respectively. The most efficient Minimum Inhibitory Concentration (MIC) levels of MOS-E and MOS-ES against a high percentage of strains were 32 µg mL−1. Bioguided screening of bioactive compounds showed that the ethyl acetate fraction from both extracts was the only one that showed antibacterial activity. Vibriocidal substances, niazirine and niazimicine, were isolated from the aforementioned fraction through chromatographic fractionation. PMID:28770224

  2. Survival and evolution of a large multidrug resistance plasmid in new clinical bacterial hosts

    DEFF Research Database (Denmark)

    Porse, Andreas; Schønning, Kristian; Munck, Christian

    2016-01-01

    of these plasmids within pathogenic hosts are poorly understood. Here we study plasmid-host adaptations following transfer of a 73 kb conjugative multidrug resistance plasmid to naïve clinical isolates of Klebsiella pneumoniae and Escherichia coli We use experimental evolution, mathematical modelling and population...... sequencing to show that the long-term persistence and molecular integrity of the plasmid is highly influenced by multiple factors within a 25 kb plasmid region constituting a host-dependent burden. In the E. coli hosts investigated here, improved plasmid stability readily evolves via IS26 mediated deletions...... of plasmid adaptation. While insertion sequences are well known to supply plasmids with adaptive traits, our findings suggest that they also play an important role in plasmid evolution by maintaining the plasticity necessary to alleviate plasmid-host constrains. Further, the observed evolutionary strategy...

  3. Studying health consequences of microchimerism

    DEFF Research Database (Denmark)

    Olsen, J.; Campi, Rita; Frydenberg, Morten;

    2003-01-01

    Abstract. A pregnancy requires a reasonably good health and may have positive as well as negative health consequences for the woman. Part of these health effects may depend on the immune response to the exchange of fetal cells (microchimerism). The number of biological fathers to a woman’s children...... may thus have a health effect beyond the parity effect. A possible design for studying this is to compare health effects for women with or without multiple partners but with the same parity. We compared total and cause specific mortality in these two groups in order to estimate their comparability...... one partner had a higher relative mortality rate, which was even higher if she had more than two partners. This finding persisted after excluding unnatural deaths and did not depend on time from exposure. Although some of the findings were adjusted for parity, age and social factors, it is highly...

  4. STUDIES ON ANTIBACTERIAL EFFECT OF APAMARGA (ACHYRANTHES ASPERA ON MULTI-DRUG RESISTANT CLINICAL ISOLATES

    Directory of Open Access Journals (Sweden)

    Patil Usha

    2013-04-01

    Full Text Available Recent reports on emergence of multidrug resistant bacteria are cause of concern in medical world. Several ayurvedic drugs have been proved to contain the antimicrobial activity. Literature on effect of ayurvedic drugs on multidrug resistant bacterial pathogens is limited. Present study reports the antimicrobial effect of Achyranthes aspera (Apamarga crude extracts on the clinical isolates of multidrug resistant bacteria. The drug was evaluated by using phytochemical tests. Crude extracts of aqueous, methanol, ethanol and chloroform was prepared. Antibacterial activity against clinically isolated multidrug resistant bacteria belonging to groups of bacillus, citrobacter, E.coli, klebsiella, proteus and salmonella was tested. The drug showed highest efficacy against Bacillus organism while least effectiveness on Proteus spp bacteria. Results of the study conclude that the medicinal plant A. aspera might be useful against multidrug resistance in pathogens of clinical importance.

  5. In-vitro activity of polymyxin B in combination with imipenem, rifampicin and azithromycin versus multidrug resistant strains of Acinetobacter baumannii producing OXA-23 carbapenemases

    Directory of Open Access Journals (Sweden)

    Bean David C

    2006-04-01

    Full Text Available Abstract Background Acinetobacter baumannii has emerged as a major nosocomial pathogen worldwide. Many of the circulating strains exhibit multi-drug resistance remaining consistently susceptible only to polymyxins. In-vitro studies have reported that polymyxins combined with carbapenems, rifampicin or azithromycin are synergistic against these strains despite in-vitro resistance to these agents alone. The use of antimicrobial combinations have therefore been advocated for the treatment of severe A. baumannii infection in man. In order to determine whether such combinations are synergistic against the prevalent clones of multi-drug resistant A. baumannii causing infection in the UK, we performed synergy testing against representative isolates using two rapid Etest methods. Methods The activity of polymyxin in combination with imipenem, azithromycin or rifampicin was assessed against five strains of multi-drug resistant A. baumannii encoding OXA-23 carbapenemases. Synergy studies were performed by Etest-agar dilution and a combined Etest strip method. Synergy was defined as a FICI of ≤ 0.5. Results All strains were resistant to β-lactams, carbapenems, quinolones and aminoglycosides but susceptible to polymyxins. Marked synergy was not seen with polymyxin in combination with imipenem, rifampicin or azithromycin against any of the strains. Borderline synergy (FICI = 0.5 was seen against one strain belonging to OXA-23 clonal group 2, using the Etest-agar dilution method only. Conclusion In-vitro synergy with polymxyin in combination with imipenem, rifampicin or azithromycin is highly strain and method dependent. As reliable synergy could not be demonstrated against the prevalent UK multi-drug resistant strains, use of such combinations should not be used for empirical treatment of these infections in the UK. The optimal treatment for serious multi-drug A. baumannii infection and the role of combination therapy should be addressed in a prospective

  6. The demise of multidrug-resistant HIV-1: the national time trend in Portugal

    Science.gov (United States)

    Vercauteren, Jurgen; Theys, Kristof; Carvalho, Ana Patricia; Valadas, Emília; Duque, Luis Miguel; Teófilo, Eugénio; Faria, Telo; Faria, Domitília; Vera, José; Águas, Maria João; Peres, Susana; Mansinho, Kamal; Vandamme, Anne-Mieke; Camacho, Ricardo Jorge; Mansinho, Kamal; Cláudia Miranda, Ana; Aldir, Isabel; Ventura, Fernando; Nina, Jaime; Borges, Fernando; Valadas, Emília; Doroana, Manuela; Antunes, Francisco; João Aleixo, Maria; João Águas, Maria; Botas, Júlio; Branco, Teresa; Vera, José; Vaz Pinto, Inês; Poças, José; Sá, Joana; Duque, Luis; Diniz, António; Mineiro, Ana; Gomes, Flora; Santos, Carlos; Faria, Domitília; Fonseca, Paula; Proença, Paula; Tavares, Luís; Guerreiro, Cristina; Narciso, Jorge; Faria, Telo; Teófilo, Eugénio; Pinheiro, Sofia; Germano, Isabel; Caixas, Umbelina; Faria, Nancy; Paula Reis, Ana; Bentes Jesus, Margarida; Amaro, Graça; Roxo, Fausto; Abreu, Ricardo; Neves, Isabel

    2013-01-01

    Objectives Despite a decreasing mortality and morbidity in treated HIV-1 patients, highly active antiretroviral treatment (HAART) can still fail due to the development of drug resistance. Especially, multidrug-resistant viruses pose a threat to efficient therapy. We studied the changing prevalence of multidrug resistance (MDR) over time in a cohort of HIV-1-infected patients in Portugal. Patients and methods We used data of 8065 HIV-1-infected patients followed from July 2001 up to April 2012 in 22 hospitals located in Portugal. MDR at a specific date of sampling was defined as no more than one fully active drug (excluding integrase and entry inhibitors) at that time authorized by the Portuguese National Authority of Medicines and Health Products (INFARMED), as interpreted with the Rega algorithm version 8.0.2. A generalized linear mixed model was used to study the time trend of the prevalence of MDR. Results We observed a statistically significant decrease in the prevalence of MDR over the last decade, from 6.9% (95% CI: 5.7–8.4) in 2001–03, 6.0% (95% CI: 4.9–7.2) in 2003–05, 3.7% (95% CI: 2.8–4.8) in 2005–07 and 1.6% (95% CI: 1.1–2.2) in 2007–09 down to 0.6% (95% CI: 0.3–0.9) in 2009–12 [OR = 0.80 (95% CI: 0.75–0.86); P < 0.001]. In July 2011 the last new case of MDR was seen. Conclusions The prevalence of multidrug-resistant HIV-1 is decreasing over time in Portugal, reflecting the increasing efficiency of HAART and the availability of new drugs. Therefore, in designing a new drug, safety and practical aspects, e.g. less toxicity and ease of use, may need more attention than focusing mainly on efficacy against resistant strains. PMID:23228933

  7. New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline

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    Leibert E

    2014-07-01

    Full Text Available Eric Leibert, Mauricio Danckers, William N Rom Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, NY, USA Abstract: Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB. New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug–drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase

  8. Strategies for decreasing multidrug antibiotic resistance: role of ototopical agents for treatment of middle ear infections.

    Science.gov (United States)

    Klein, Jerome O

    2002-10-01

    Change in the susceptibility of bacterial pathogens to antimicrobial agents is constant. The efficacy of a new drug may change as it is used in clinical settings, and resistant bacterial clones result from the encounter of drug and organism. Soon after the introduction of the sulfonamides in the mid-1930s, the first effective agents of the antimicrobial era, resistance of pneumococci and group A streptococci was evident. In each of the following decades, a different problem in multidrug resistance occurred among common bacterial pathogens: beta-lactamase-producing staphylococci in the 1950s; highly resistant gram-negative enteric bacteria in the 1960s; beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis in the 1970s; and multidrug-resistant pneumococci in the 1980s. Antimicrobial resistance among respiratory pathogens is now a common clinical problem throughout the world, and its management is a part of routine office practice. Currently in the United States, about 25% of pneumococci are resistant to penicillin, and 25% of H influenzae and 90% of M catarrhalis produce beta-lactamase and would be inactivated by organisms producing the enzyme. The emergence of penicillin and multidrug-resistant pneumococci and beta-lactamase-producing strains of H influenzae and M catarrhalis have special importance for the management of infections of the middle ear. The widespread use of oral and parenteral antimicrobial drugs for appropriate and inappropriate uses has driven the emergence and spread of resistant organisms. This article discusses current susceptibility patterns of organisms involved in middle ear infections, risk factors associated with development of resistant strains, strategies for limiting the incidence and spread of resistant organisms and, as part of the strategy, use of ototopical rather than systemic antimicrobial drugs for chronic suppurative otitis media (CSOM) and acute otitis media (AOM) in children with tympanostomy tubes. Although

  9. Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals.

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    Gullberg, Erik; Albrecht, Lisa M; Karlsson, Christoffer; Sandegren, Linus; Andersson, Dan I

    2014-10-07

    How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments. Importance: Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to

  10. Genotyping and serotyping of macrolide and multidrug resistant Streptococcus pneumoniae isolated from carrier children

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    S F Swedan

    2016-01-01

    Full Text Available Aims: Streptococcus pneumoniae, an opportunistic pathogen commonly carried asymptomatically in the nasopharynx of children, is associated with increasing rates of treatment failures due to a worldwide increase in drug resistance. We investigated the carriage of S. pneumoniae in children 5 years or younger, the identity of prevalent serotypes, the rates of resistance to macrolides and other antimicrobial agents and the genotypes responsible for macrolide resistance. Materials and Methods: Nasopharyngeal swabs were collected from 157 children under 5 years for cultural isolation of S. pneumoniae. Antibiogram of isolates  was determined using the disk diffusion test, and the minimal inhibitory concentration to macrolides was determined using the E-test. Isolate serotypes and macrolide resistance genes, erm(B and mef(E, were identified using multiplex polymerase chain reactions. Results: S. pneumoniae was recovered from 33.8% of children; 41.9% among males and 21.9% among females (P = 0.009. The highest carriage rate occurred among age groups 7-12 months and 49-60 months. Most frequent serotypes were 19F, 6A/B, 11A, 19A, 14 and 15B/C.  Resistance to macrolides was 60.4%. Resistance to oxacillin, trimethoprim/sulfamethoxazole and clindamycin was present among 90.6%, 54.7% and 32.1% of isolates, respectively. All isolates were susceptible to chloramphenicol, levofloxacin and vancomycin. Isolates resistant to one or more macrolide drugs were more likely to be multidrug resistant. Resistance to clindamycin or oxacillin coexisted with macrolide resistance. Among the erythromycin-resistant isolates, erm(B, mef(E and erm(B and mef(E genes were present at rates of 43.8%, 37.5% and 6.3%, respectively. Erm(B and mef(E were associated with very high level and moderate-to-high level resistance to macrolides, respectively. Conclusion: A significant proportion of children harboured macrolide and multidrug-resistant S. pneumoniae.

  11. Leprosy in French Polynesia. The possible impact of multidrug therapy on epidemiological trends.

    Science.gov (United States)

    Cartel, J L; Spiegel, A; Nguyen Ngoc, L; Moulia-Pelat, J P; Martin, P M; Grosset, J H

    1992-09-01

    In 1982, following the recommendations of a WHO study group, multidrug therapy (MDT) was introduced into French Polynesia to treat all patients suffering from active leprosy, and--only on request--those still on dapsone monotherapy. After 5 years, a clear-cut decrease of prevalence and mean annual detection rates for leprosy (except for detection rates among children aged less than 15 years, many of such cases being detected early by increased household contact training) has been observed. There was also a decrease in the proportion of newly detected cases with disabilities. During the 21-year period preceding the introduction of MDT into the control programme, mean annual detection rates for leprosy had remained stable, and this led to the consideration that such a decrease was due neither to the natural decline of the disease nor to the economic improvement of the country. Our results, together with the fact that, to date, the relapse rate was nil in the Polynesian patients put on MDT, strongly suggest that the implementation of MDT has resulted in a decrease of detection rates for leprosy which may be a consequence of a decrease in the transmission of the disease.

  12. Multidrug Efflux Pumps in Staphylococcus aureus: an Update.

    Science.gov (United States)

    Costa, Sofia Santos; Viveiros, Miguel; Amaral, Leonard; Couto, Isabel

    2013-01-01

    The emergence of infections caused by multi- or pan-resistant bacteria in the hospital or in the community settings is an increasing health concern. Albeit there is no single resistance mechanism behind multiresistance, multidrug efflux pumps, proteins that cells use to detoxify from noxious compounds, seem to play a key role in the emergence of these multidrug resistant (MDR) bacteria. During the last decades, experimental data has established their contribution to low level resistance to antimicrobials in bacteria and their potential role in the appearance of MDR phenotypes, by the extrusion of multiple, unrelated compounds. Recent studies suggest that efflux pumps may be used by the cell as a first-line defense mechanism, avoiding the drug to reach lethal concentrations, until a stable, more efficient alteration occurs, that allows survival in the presence of that agent. In this paper we review the current knowledge on MDR efflux pumps and their intricate regulatory network in Staphylococcus aureus, a major pathogen, responsible from mild to life-threatening infections. Particular emphasis will be given to the potential role that S. aureus MDR efflux pumps, either chromosomal or plasmid-encoded, have on resistance towards different antimicrobial agents and on the selection of drug - resistant strains. We will also discuss the many questions that still remain on the role of each specific efflux pump and the need to establish appropriate methodological approaches to address all these questions.

  13. Effect of methylglyoxal on multidrug-resistant Pseudomonas aeruginosa

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    Katsuhiko eHayashi

    2014-04-01

    Full Text Available Honey has a complex chemistry, and its broad-spectrum antimicrobial activity varies with floral source, climate, and harvesting conditions. Methylglyoxal was identified as the dominant antibacterial component of manuka honey. Although it has been known that methylglyoxal has antibacterial activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, there is not much information describing its activity against gram-negative bacteria. In this study, we report the effect of methylglyoxal against multidrug-resistant Pseudomonas aeruginosa (MDRP using 53 clinically isolated strains. We also assessed the effect of deleting the five multidrug efflux systems in P. aeruginosa, as well as the efflux systems in Escherichia coli and Salmonella enterica serovar Typhimurium, on MICs of methylglyoxal. Our results indicate that methylglyoxal inhibits the growth of MDRP at concentrations of 128–512 µg/ml (1.7–7.1 mM and is not recognized by drug efflux systems.

  14. Horizontal gene transfer—emerging multidrug resistance in hospital bacteria

    Institute of Scientific and Technical Information of China (English)

    SenkaDZIDIC; VladimirBEDEKOVIC

    2003-01-01

    The frequency and spectrum of antibiotic resistant infections have increased worldwide during the past few decades. This increase has been attributed to a combination of microbial characteristics, the selective pressure of antimicrobial use, and social and technical changes that enhance the transmission of resistant organisms. The resistance is acquired by mutational changer or by the acquisition of resistance-encoding genetic material which is transfered from another bacteria. The spread of antibiotic resistance genes may be causally related to the overuse of antibiotics in human health care and in animal feeds, increased use of invasive devices and procedures, a greater number of susceptible hosts, and lapses in infection control practices leading to increased transmission of resistant organisms. The resistance gene sequences are integrated by recombination into several classes of naturally occurring gene expression cassettes and disseminated within the microbial population by horizontal gene transfer mechanisms: transformation, conjugation or transduction. In the hospital, widespread use of antimicrobials in the intensive care units (ICU) and for immunocompromised patients has resulted in the selection of multidrug-resistant organisms. Methicilin-resistant Staphylococci, vancomycin resistant Enterococci and extended-spectrum betalactamase(ESBL) producing Gram negative bacilli are identified as major phoblem in nosocomial infections. Recent surveillance studies have demonstrated trend towares more seriously ill patients suffering from multidrug-resistant nosocomial infections. Emergence of multiresistant bacteria and spread of resistance genes should enforce the aplication of strict prevention strategies, including changes in antibiotic treatment regimens, hygiene measures, infection prevention and control of horizontal nosocomial transmission of organisms.

  15. MexXY multidrug efflux system of Pseudomonas aeruginosa

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    Yuji eMorita

    2012-11-01

    Full Text Available Anti-pseudomonas aminoglycosides, such as amikacin and tobramycin, are used in the treatment of Pseudomonas aeruginosa infections. However, their use is linked to the development of resistance. During the last decade, the MexXY multidrug efflux system has been comprehensively studied, and numerous reports of laboratory and clinical isolates have been published. This system has been increasingly recognized as one of the primary determinants of aminoglycoside resistance in P. aeruginosa. In P. aeruginosa cystic fibrosis isolates, upregulation of the pump is considered the most common mechanism of aminoglycoside resistance. Non-fermentative Gram-negative pathogens possessing very close MexXY orthologues such as Achromobacter xylosoxidans and various Burkholderia species [e.g., B. pseudomallei and B. cepacia complexes], but not B. gladioli, are intrinsically resistant to aminoglycosides. Here, we summarize the properties (e.g., discovery, mechanism, gene expression, clinical significance of the P. aeruginosa MexXY pump and other aminoglycoside efflux pumps such as AcrD of Escherichia coli, AmrAB-OprA of B. pseudomallei, and AdeABC of Acinetobacter baumannii. MexXY inducibility of the PA5471 gene product, which is dependent on ribosome inhibition or oxidative stress, is noteworthy. Moreover, the discovery of the cognate outer membrane component (OprA of MexXY in the multidrug-resistant clinical isolate PA7, serotype O12 deserves special attention.

  16. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients

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    Katharina Göhring

    2015-01-01

    Full Text Available In pediatric and adult patients after stem cell transplantation (SCT disseminated infections caused by human cytomegalovirus (HCMV can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV, foscarnet (PFA and cidofovir (CDV are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97 and the polymerase-gene (UL54. Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against all three drugs is associated to mutations in the UL54-gene. Monitoring of drug resistance by genotyping is mostly done by PCR-based Sanger sequencing. For phenotyping with cell culture the isolation of HCMV is a prerequisite. The development of multidrug resistance with mutation in both genes is rare, but it is often associated with a fatal outcome. The manifestation of multidrug resistance is mostly associated with combined UL97/UL54-mutations. Normally, mutations in the UL97 gene occur initially followed by UL54 mutation after therapy switch. The appearance of UL54-mutation alone without any detection of UL97-mutation is rare. Interestingly, in a number of patients the UL97 mutation could be detected in specific compartments exclusively and not in blood.

  17. Photoexcited quantum dots for killing multidrug-resistant bacteria

    Science.gov (United States)

    Courtney, Colleen M.; Goodman, Samuel M.; McDaniel, Jessica A.; Madinger, Nancy E.; Chatterjee, Anushree; Nagpal, Prashant

    2016-05-01

    Multidrug-resistant bacterial infections are an ever-growing threat because of the shrinking arsenal of efficacious antibiotics. Metal nanoparticles can induce cell death, yet the toxicity effect is typically nonspecific. Here, we show that photoexcited quantum dots (QDs) can kill a wide range of multidrug-resistant bacterial clinical isolates, including methicillin-resistant Staphylococcus aureus, carbapenem-resistant Escherichia coli, and extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Salmonella typhimurium. The killing effect is independent of material and controlled by the redox potentials of the photogenerated charge carriers, which selectively alter the cellular redox state. We also show that the QDs can be tailored to kill 92% of bacterial cells in a monoculture, and in a co-culture of E. coli and HEK 293T cells, while leaving the mammalian cells intact, or to increase bacterial proliferation. Photoexcited QDs could be used in the study of the effect of redox states on living systems, and lead to clinical phototherapy for the treatment of infections.

  18. Molecular Pathways: Regulation and Therapeutic Implications of Multidrug Resistance

    Science.gov (United States)

    Chen, Kevin G.; Sikic, Branimir I.

    2012-01-01

    Multidrug transporters constitute major mechanisms of multidrug resistance (MDR) in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs, and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex, and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that govern ABCB1 expression and the development of MDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e.g., mutant p53) that guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insignts provide additional translational targets and potential strategies to deal with clinical MDR. PMID:22344233

  19. An examination of the causes, consequences, and policy responses to the migration of highly trained health personnel from the Philippines: the high cost of living/leaving-a mixed method study.

    Science.gov (United States)

    Castro-Palaganas, Erlinda; Spitzer, Denise L; Kabamalan, Maria Midea M; Sanchez, Marian C; Caricativo, Ruel; Runnels, Vivien; Labonté, Ronald; Murphy, Gail Tomblin; Bourgeault, Ivy Lynn

    2017-03-31

    Dramatic increases in the migration of human resources for health (HRH) from developing countries like the Philippines can have consequences on the sustainability of health systems. In this paper, we trace the outflows of HRH from the Philippines, map out its key causes and consequences, and identify relevant policy responses. This mixed method study employed a decentered, comparative approach that involved three phases: (a) a scoping review on health workers' migration of relevant policy documents and academic literature on health workers' migration from the Philippines; and primary data collection with (b) 37 key stakeholders and (c) household surveys with seven doctors, 329 nurses, 66 midwives, and 18 physical therapists. Filipino health worker migration is best understood within the context of macro-, meso-, and micro-level factors that are situated within the political, economic, and historical/colonial legacy of the country. Underfunding of the health system and un- or underemployment were push factors for migration, as were concerns for security in the Philippines, the ability to practice to full scope or to have opportunities for career advancement. The migration of health workers has both negative and positive consequences for the Philippine health system and its health workers. Stakeholders focused on issues such as on brain drain, gain, and circulation, and on opportunities for knowledge and technology transfer. Concomitantly, migration has resulted in the loss of investment in human capital. The gap in the supply of health workers has affected the quality of care delivered, especially in rural areas. The opening of overseas opportunities has commercialized health education, compromised its quality, and stripped the country of skilled learning facilitators. The social cost of migration has affected émigrés and their families. At the household level, migration has engendered increased consumerism and materialism and fostered dependency on overseas

  20. Epidemiological status of multidrug-resistant tuberculosis%耐多药肺结核流行现状分析

    Institute of Scientific and Technical Information of China (English)

    谭明伟; 刘晞照; 郭晓华; 饶俊莉; 李兴挺; 熊德场

    2014-01-01

    OBJECTIVE To understand the epidemiological status of multidrug-resistant tuberculosis in Chongqing area so as to further adjust the screening strategies and control the spread of the epidemic .METHODS The medical records were collected from the patients with multidrug-resistant tuberculosis who were treated in the appointed hospitals from Mar 2010 to Feb 2012 ,then the incidence of disease and epidemiological characteristics were ana-lyzed ,and the statistical analysis was performed with the use of SPSS19 .0 software .RESULTS Of 554 patients with suspected multidrug-resistant tuberculosis who were positive for smear from Mar 2010 to Feb 2012 ,37 were confirmed with multidrug-resistant tuberculosis ,including 2 cases of pandrug-resistant tuberculosis ,the multi-drug-resistant rate of the tuberculosis patients with positive smear was 6 .68% ,and most of the patients with mul-tidrug-resistant tuberculosis came from Wanzhou area ,there was no significant difference between the rural and urban area .The average age of the patients was (43 .57 ± 2 .65) years old ,the ratio of the male and female was 2 . 36∶1 ,and the mortality rate of the patients with multidrug-resistant tuberculosis was 21 .62% .The detection rate of multidrug-resistant tuberculosis was 24 .51% in 6 highly-risk populations .The multidrug-resistant rate of the tuberculosis patients with positive smear was 3 .04% in the primary treatment ,24 .47% in the retreatment .Among the patients with 7 types of positive smears ,the multidrug-resistant rate was the highest (66 .67% ) in the patients who failed the retreatment .CONCLUSION The incidence of multidrug-resistant tuberculosis is as comparable in Chongqing area as in the whole country and tends to increase in the young population ,the condition is severe ,the mortality rate is high ,and the patients who fail the retreatment are the population at high risk of multidrug-resist-ant tuberculosis .The screening strategies tend to be reasonable and still

  1. The serum resistome of a globally disseminated multidrug resistant uropathogenic Escherichia coli clone.

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    Minh-Duy Phan

    Full Text Available Escherichia coli ST131 is a globally disseminated, multidrug resistant clone responsible for a high proportion of urinary tract and bloodstream infections. The rapid emergence and successful spread of E. coli ST131 is strongly associated with antibiotic resistance; however, this phenotype alone is unlikely to explain its dominance amongst multidrug resistant uropathogens circulating worldwide in hospitals and the community. Thus, a greater understanding of the molecular mechanisms that underpin the fitness of E. coli ST131 is required. In this study, we employed hyper-saturated transposon mutagenesis in combination with multiplexed transposon directed insertion-site sequencing to define the essential genes required for in vitro growth and the serum resistome (i.e. genes required for resistance to human serum of E. coli EC958, a representative of the predominant E. coli ST131 clonal lineage. We identified 315 essential genes in E. coli EC958, 231 (73% of which were also essential in E. coli K-12. The serum resistome comprised 56 genes, the majority of which encode membrane proteins or factors involved in lipopolysaccharide (LPS biosynthesis. Targeted mutagenesis confirmed a role in serum resistance for 46 (82% of these genes. The murein lipoprotein Lpp, along with two lipid A-core biosynthesis enzymes WaaP and WaaG, were most strongly associated with serum resistance. While LPS was the main resistance mechanism defined for E. coli EC958 in serum, the enterobacterial common antigen and colanic acid also impacted on this phenotype. Our analysis also identified a novel function for two genes, hyxA and hyxR, as minor regulators of O-antigen chain length. This study offers novel insight into the genetic make-up of E. coli ST131, and provides a framework for future research on E. coli and other Gram-negative pathogens to define their essential gene repertoire and to dissect the molecular mechanisms that enable them to survive in the bloodstream and

  2. Risk factors for nosocomial burn wound infection caused by multidrug resistant Acinetobacter baumannii.

    Science.gov (United States)

    Tekin, Recep; Dal, Tuba; Bozkurt, Fatma; Deveci, Ozcan; Palanc, Ylmaz; Arslan, Eyüp; Selçuk, Caferi Tayyar; Hoşoğlu, Salih

    2014-01-01

    Acinetobacter baumannii infections in burn patients may lead to delays in wound healing, graft losses, and development of sepsis. Determining the risk factors for multidrug resistant A. baumannii (MDR-AB) infections is essential for infection control. In the present study, the authors aimed to evaluate risk factors for wound infections caused by A. baumannii in burn patients. The study was conducted at Dicle University Hospital Burn Center, from April 2011 to July 2012, to investigate the risk factors for MDR-AB infections. The data of both the case and control group patients and the result of wound cultures were recorded on a daily basis, on individual forms given for each patient, and analyzed. A total of 30 cases infected with MDR-AB, and 60 uninfected control patients, were included in the study. The mean age (±SD) was 7.7 ± 15.4 years in infected patients and 11.4 ± 16.5 years in uninfected patients. The mean total burn surface area was 13.5 ± 10.9% in uninfected patients and 34.7 ± 16.2% in infected patients. The mean total burn surface area, the abbreviated burn severity index, acute physiological and chronic health evaluation II score, day of admission to hospital, length of hospital stay, first excision day, prior usage of third-generation cephalosporins, and stay in intensive care unit of the infected patients were significantly higher (P infection. Univariate analysis found that high acute physiological and chronic health evaluation II score, first excision time of wound, invasive device usage, admission day to hospital, and prior usage of broad-spectrum antibiotics were risk factors for nosocomial infections. This study showed that multiple factors contribute to multidrug resistance in A. baumannii. A combination of an early diagnosis of wound infections, appropriate antimicrobial treatments, surgical debridement, and early wound closure may be effective in the management.

  3. Multidrug-resistant organisms in neonatal sepsis in two tertiary neonatal ICUs, Egypt.

    Science.gov (United States)

    Awad, Hesham A; Mohamed, Maha H; Badran, Nabil F; Mohsen, Manal; Abd-Elrhman, Al-Sayed A

    2016-03-01

    Neonatal sepsis remains a serious problem in any neonatal intensive care unit (NICU). Bacterial organisms have developed increased resistance to commonly used antibiotics. Because not enough data are available from Egypt, the aim of the present study was to determine the causative bacteria and the level of their resistance to commonly used antibiotics in tertiary NICUs in Cairo, Egypt. A 3.5-year retrospective study was carried out at NICUs of the Children's Hospital of Ain Shams University and that of El-Hussein Hospital, Al-Azhar University, Egypt. Records of neonates were reviewed. All neonates with culture-proven sepsis were included in the study. Almost one-third of the admitted neonates (33.4%) were diagnosed as having neonatal sepsis, 32.25% of them culture-proven. Early/late onset sepsis was found in 35.4 and 64.6%, respectively. Gram-negative/gram-positive bacteria was found in 68 to 25.6%. Fungal infection was detected in 9% of the isolates. Escherichia coli was the main pathogen isolated in both early-onset sepsis (41.2%) and late-onset sepsis (24.5%). Overall, 77% of the isolates were multidrug-resistant (60% of gram-positive bacteria and 83.4% of gram-negative bacteria). Nearly 80% (79%) of mortality was caused by multidrug-resistant organisms. Gram-positive and gram-negative bacteria showed high resistance against commonly used antibiotics such as ampicillin, amoxicillin, cefotaxime, ceftriaxone, and gentamicin. There is an alarming increase in antibiotic resistance to the commonly used antibiotics. Continuous surveillance for antibiotic susceptibility is needed to ensure proper empirical therapy. Improvement of infection control practices, avoidance of irrational use of antibiotics, and revision of the protocols are mandatory in the prevention of neonatal sepsis.

  4. Diversity of multi-drug resistant Acinetobacter baumannii population in a major hospital in Kuwait

    Directory of Open Access Journals (Sweden)

    Leila eVali

    2015-07-01

    Full Text Available Acinetobacter baumannii is one of the most important opportunistic pathogens that causes serious health care associated complications in critically ill patients. In the current study we report on the diversity of the clinical multi-drug resistant A. baumannii in Kuwait by molecular characterization. One hundred A. baumannii were isolated from one of the largest governmental hospitals in Kuwait. Following the identification of the isolates by molecular methods, the amplified blaOXA-51-like gene product of one isolate (KO-12 recovered from blood showed the insertion of the ISAba19 at position 379 in blaOXA-78. Of the 33 multi-drug resistant isolates, 28 (85% contained blaOXA-23, 2 (6% blaOXA-24 and 6 (18% blaPER-1 gene. We did not detect blaOXA-58, blaVIM, blaIMP, blaGES, blaVEB and blaNDM genes in any of the tested isolates. In 3 blaPER-1 positive isolates the genetic environment of blaPER-1 consisted of two copies of ISPa12 (tnpiA1 surrounding the blaPER-1 gene on a highly stable plasmid of ca. 140-kb. MLST analysis of the 33 A. baumannii isolates identified 20 different STs, of which 6 (ST-607, ST-608, ST-609, ST-610, ST-611 and ST-612 were novel. Emerging STs such as ST15 (identified for the first time in the Middle East, ST78 and ST25 were also detected. The predominant clonal complex was CC2. PFGE and MLST defined the MDR isolates as multi-clonal with diverse lineages. Our results lead us to believe that A. baumannii is diverse in clonal origins and / or is undergoing clonal expansion continuously while multiple lineages of MDR A. baumannii circulate in hospital wards simultaneously.

  5. Green synthesized silver nanoparticles destroy multidrug resistant bacteria via reactive oxygen species mediated membrane damage

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    Balaram Das

    2017-09-01

    Full Text Available The growing need of antimicrobial agent for novel therapies against multi-drug resistant bacteria has drawn researchers to green nanotechnology. Especially, eco-friendly biosynthesis of silver nanoparticles (Ag NPs has shown its interesting impact against bacterial infection in laboratory research. In this study, a simple method was developed to form Ag NPs at room temperature, bio-reduction of silver ions from silver nitrate salt by leaf extract from Ocimum gratissimum. The Ag NPs appear to be capped with plant proteins, but are otherwise highly crystalline and pure. The Ag NPs have a zeta potential of −15 mV, a hydrodynamic diameter of 31 nm with polydispersity index of 0.65, and dry sizes of 18 ± 3 nm and 16 ± 2 nm, based on scanning and transmission electron microscopy respectively. The minimum inhibitory concentration (MIC of the Ag NPs against a multi-drug resistant Escherichia coli was 4 μg/mL and the minimum bactericidal concentration (MBC was 8 μg/mL, while the MIC and MBC against a resistant strain of Staphylococcus aureus were slightly higher at 8 μg/mL and 16 μg/mL respectively. Further, the Ag NPs inhibited biofilm formation by both Escherichia coli and S. aureus at concentrations similar to the MIC for each strain. Treatment of E. coli and S. aureus with Ag NPs resulted in damage to the surface of the cells and the production of reactive oxygen species. Both mechanisms likely contribute to bacterial cell death. In summary, this new method appears promising for green biosynthesis of pure Ag NPs with potent antimicrobial activity.

  6. Structural and biochemical analyses of alanine racemase from the multidrug-resistant Clostridium difficile strain 630.

    Science.gov (United States)

    Asojo, Oluwatoyin A; Nelson, Sarah K; Mootien, Sara; Lee, Yashang; Rezende, Wanderson C; Hyman, Daniel A; Matsumoto, Monica M; Reiling, Scott; Kelleher, Alan; Ledizet, Michel; Koski, Raymond A; Anthony, Karen G

    2014-07-01

    Clostridium difficile, a Gram-positive, spore-forming anaerobic bacterium, is the leading cause of infectious diarrhea among hospitalized patients. C. difficile is frequently associated with antibiotic treatment, and causes diseases ranging from antibiotic-associated diarrhea to life-threatening pseudomembranous colitis. The severity of C. difficile infections is exacerbated by the emergence of hypervirulent and multidrug-resistant strains, which are difficult to treat and are often associated with increased mortality rates. Alanine racemase (Alr) is a pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes the reversible racemization of L- and D-alanine. Since D-alanine is an essential component of the bacterial cell-wall peptidoglycan, and there are no known Alr homologs in humans, this enzyme is being tested as an antibiotic target. Cycloserine is an antibiotic that inhibits Alr. In this study, the catalytic properties and crystal structures of recombinant Alr from the virulent and multidrug-resistant C. difficile strain 630 are presented. Three crystal structures of C. difficile Alr (CdAlr), corresponding to the complex with PLP, the complex with cycloserine and a K271T mutant form of the enzyme with bound PLP, are presented. The structures are prototypical Alr homodimers with two active sites in which the cofactor PLP and cycloserine are localized. Kinetic analyses reveal that the K271T mutant CdAlr has the highest catalytic constants reported to date for any Alr. Additional studies are needed to identify the basis for the high catalytic activity. The structural and activity data presented are first steps towards using CdAlr for the development of structure-based therapeutics for C. difficile infections.

  7. Epidemiology and molecular characterization of multidrug-resistant Gram-negative bacteria in Southeast Asia

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    Nuntra Suwantarat

    2016-05-01

    Full Text Available Abstract Background Multidrug-resistant Gram-negative bacteria (MDRGN, including extended-spectrum β-lactamases (ESBLs and multidrug-resistant glucose-nonfermenting Gram-negative bacilli (nonfermenters, have emerged and spread throughout Southeast Asia. Methods We reviewed and summarized current critical knowledge on the epidemiology and molecular characterization of MDRGN in Southeast Asia by PubMed searches for publications prior to 10 March 2016 with the term related to “MDRGN definition” combined with specific Southeast Asian country names (Thailand, Singapore, Malaysia, Vietnam, Indonesia, Philippines, Laos, Cambodia, Myanmar, Brunei. Results There were a total of 175 publications from the following countries: Thailand (77, Singapore (35, Malaysia (32, Vietnam (23, Indonesia (6, Philippines (1, Laos (1, and Brunei (1. We did not find any publications on MDRGN from Myanmar and Cambodia. We did not include publications related to Shigella spp., Salmonella spp., and Vibrio spp. and non-human related studies in our review. English language articles and abstracts were included for analysis. After the abstracts were reviewed, data on MDRGN in Southeast Asia from 54 publications were further reviewed and included in this study. Conclusions MDRGNs are a major contributor of antimicrobial-resistant bacteria in Southeast Asia. The high prevalence of ESBLs has been a major problem since 2005 and is possibly related to the development of carbapenem resistant organisms in this region due to the overuse of carbapenem therapy. Carbapenem–resistant Acinetobacter baumannii is the most common pathogen associated with nosocomial infections in this region followed by carbapenem-resistant Pseudomonas aeruginosa. Although Southeast Asia is not an endemic area for carbapenem-resistant Enterobacteriaceae (CRE, recently, the rate of CRE detection has been increasing. Limited infection control measures, lack of antimicrobial control, such as the presence of

  8. New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline.

    Science.gov (United States)

    Leibert, Eric; Danckers, Mauricio; Rom, William N

    2014-01-01

    Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB). New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug-drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase III trial is being reorganized. While bedaquiline is an exciting drug and marks a dramatic moment in the history of TB treatment, its ultimate place in the anti-TB drug armamentarium is unclear pending the Phase III trial and

  9. Immunization against multidrug-resistant Acinetobacter baumannii effectively protects mice in both pneumonia and sepsis models.

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    Weiwei Huang

    Full Text Available OBJECTIVE: Acinetobacter baumannii is considered the prototypical example of a multi- or pan- drug-resistant bacterium. It has been increasingly implicated as a major cause of nosocomial and community-associated infections. This study proposed to evaluate the efficacy of immunological approaches to prevent and treat A. baumannii infections. METHODS: Mice were immunized with outer membrane vesicles (OMVs prepared from a clinically isolated multidrug-resistant strain of A. baumannii. Pneumonia and sepsis models were used to evaluate the efficacy of active and passive immunization with OMVs. The probable effective mechanisms and the protective potential of clonally distinct clinical isolates were investigated in vitro using an opsonophagocytic assay. RESULTS: Intramuscular immunization with OMVs rapidly produced high levels of OMV-specific IgG antibodies, and subsequent intranasal challenge with A. baumannii elicited mucosal IgA and IgG responses. Both active and passive immunization protected the mice from challenges with homologue bacteria in a sepsis model. Bacterial burden in bronchoalveolar lavage fluids (BALF, lung, and spleen, inflammatory cell infiltration in BALF and lung, and inflammatory cytokine accumulation in BALF was significantly suppressed in the pneumonia model by both active and passive immunization strategies. The antisera from immunized mice presented with significant opsonophagocytic activities in a dose-dependent manner against not only homologous strains but also five of the other six clonally distinct clinical isolates. CONCLUSIONS: Utilizing immunological characteristics of outer membrane proteins to elevate protective immunity and circumvent complex multidrug-resistance mechanisms might be a viable approach to effectively control A. baumannii infections.

  10. Antimicrobial hydrogels: a new weapon in the arsenal against multidrug-resistant infections.

    Science.gov (United States)

    Ng, Victor W L; Chan, Julian M W; Sardon, Haritz; Ono, Robert J; García, Jeannette M; Yang, Yi Yan; Hedrick, James L

    2014-11-30

    The rapid emergence of antibiotic resistance in pathogenic microbes is becoming an imminent global public health problem. Treatment with conventional antibiotics often leads to resistance development as the majority of these antibiotics act on intracellular targets, leaving the bacterial morphology intact. Thus, they are highly prone to develop resistance through mutation. Much effort has been made to develop macromolecular antimicrobial agents that are less susceptible to resistance as they function by microbial membrane disruption. Antimicrobial hydrogels constitute an important class of macromolecular antimicrobial agents, which have been shown to be effective in preventing and treating multidrug-resistant infections. Advances in synthetic chemistry have made it possible to tailor molecular structure and functionality to impart broad-spectrum antimicrobial activity as well as predictable mechanical and rheological properties. This has significantly broadened the scope of potential applications that range from medical device and implant coating, sterilization, wound dressing, to antimicrobial creams for the prevention and treatment of multidrug-resistant infections. In this review, advances in both chemically and physically cross-linked natural and synthetic hydrogels possessing intrinsic antimicrobial properties or loaded with antibiotics, antimicrobial polymers/peptides and metal nanoparticles are highlighted. Relationships between physicochemical properties and antimicrobial activity/selectivity, and possible antimicrobial mechanisms of the hydrogels are discussed. Approaches to mitigating toxicity of metal nanoparticles that are encapsulated in hydrogels are reviewed. In addition, challenges and future perspectives in the development of safe and effective antimicrobial hydrogel systems especially involving co-delivery of antimicrobial polymers/peptides and conventional antimicrobial agents for eventual clinical applications are presented.

  11. Genetic characterisation of multidrug-resistant Salmonella enterica serotypes isolated from poultry in Cairo, Egypt

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    Mohammed Abdel-Maksoud

    2015-05-01

    Full Text Available Background: Food-borne diseases pose serious health problems, affecting public health and economic development worldwide.Methods: Salmonella was isolated from samples of chicken parts, skin samples of whole chicken carcasses, raw egg yolks, eggshells and chicken faeces. Resulting isolates were characterised by serogrouping, serotyping, antimicrobial susceptibility testing and detection of extended-spectrum β-lactamase (ESBL production. Antibiotic resistance genes and integrons were identified by polymerase chain reaction (PCR.Results: The detection rates of Salmonella were 60%, 64% and 62% in chicken parts, skin, and faeces, respectively, whereas the egg yolks and eggshells were uniformly negative. Salmonella Kentucky and S. Enteritidis serotypes comprised 43.6% and 2.6% of the isolates, respectively, whilst S. Typhimurium was absent. Variable resistance rates were observed against 16 antibiotics; 97% were resistant to sulfamethoxazole, 96% to nalidixic acid and tetracycline and 76% to ampicillin. Multidrug resistance was detected in 82% (64/78 of the isolates and ESBL production was detected in 8% (6/78. The β-lactamase blaTEM-1 gene was detected in 57.6% and blaSHV-1 in 6.8% of the isolates, whilst the blaOXA gene was absent. The sul1gene was detected in 97.3% and the sul2 gene in 5.3% of the isolates. Sixty-four of the 78 isolates (82% were positive for the integrase gene (int I from class 1 integrons, whilst int II was absent.Conclusion: This study reveals the presence of an alarming number of multidrug-resistant Salmonella isolates in the local poultry markets in Cairo. The high levels of drug resistance suggest an emerging problem that could impact negatively on efforts to prevent and treat poultry and poultry-transmitted human diseases in Egypt.

  12. Effect of multidrug resistance 1/P-glycoprotein on the hypoxia-induced multidrug resistance of human laryngeal cancer cells.

    Science.gov (United States)

    Li, Dawei; Zhou, Liang; Huang, Jiameng; Xiao, Xiyan

    2016-08-01

    In a previous study, it was demonstrated that hypoxia upregulated the multidrug resistance (MDR) of laryngeal cancer cells to chemotherapeutic drugs, with multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp) expression also being upregulated. The present study aimed to investigate the role and mechanism of MDR1/P-gp on hypoxia-induced MDR in human laryngeal carcinoma cells. The sensitivity of laryngeal cancer cells to multiple drugs and cisplatin-induced apoptosis was determined by CCK-8 assay and Annexin-V/propidium iodide staining analysis, respectively. The accumulation of rhodamine 123 (Rh123) in the cells served as an estimate of drug accumulation and was evaluated by flow cytometry (FCM). MDR1/P-gp expression was inhibited using interference RNA, and the expression of the MDR1 gene was analyzed using reverse transcription-quantitative polymerase chain reaction and western blotting. As a result, the sensitivity to multiple chemotherapeutic agents and the apoptosis rate of the hypoxic laryngeal carcinoma cells increased following a decrease in MDR1/P-gp expression (PP-gp markedly increased intracellular Rh123 accumulation (PP-gp serves an important role in regulating hypoxia-induced MDR in human laryngeal carcinoma cells through a decrease in intracellular drug accumulation.

  13. Phenotypic and genotypic characterization of multidrug-resistant Bacteroides, Parabacteroides spp., and Pseudoflavonifractor from a Costa Rican hospital.

    Science.gov (United States)

    Molina, José; Barrantes, Gloriana; Quesada-Gómez, Carlos; Rodríguez, César; Rodríguez-Cavallini, Evelyn

    2014-10-01

    Multidrug resistance in Bacteroides spp. and related genera is uncommon and has not been described in Latin America until now. We studied phenotypically and genotypically the multidrug resistance of 10 clinical strains of Bacteroides, two of Parabacteroides distasonis, and one of Pseudoflavonifractor capillosus recovered in a national hospital between 2006 and 2010. To this end, we determined minimum inhibitory concentrations (MICs) of amoxicillin, amoxicillin-clavulanic acid, cefotaxime, imipenem, clindamycin, ciprofloxacin, tetracycline, and metronidazole using E-tests, evaluated the isolates for β-lactamases with nitrocefin hydrolysis tests, performed a polymerase chain reaction (PCR)-based screening of erm, tet, and nim genes, obtained partial gyrA sequences, and studied the effect of tazobactam and efflux pump inhibitors (EPI) on the MIC of cefotaxime, clindamycin, and ciprofloxacin. Three isolates were resistant to four different classes of antibiotics and 10 were resistant to three. β-lactam resistance was in most cases due to β-lactamases susceptible of partial inhibition by tazobactam. Ten isolates were cfxA-positive and two isolates had cepA. Twelve isolates were highly resistant to clindamycin and nine were highly resistant to ciprofloxacin. However, these phenotypes were not linked to ermA, ermB, ermF, and ermG or mutations in gyrA. Addition of EPI lowered the MICs of clindamycin and ciprofloxacin of one and four isolates, respectively. Twelve isolates had tetQ and four were positive for tetM. In both cases, genes of the two-component system RteAB accompanied tet genes. Although metronidazole susceptibility was universal, nim genes were not present. To our knowledge, this is the first report of multidrug resistance due to less commonly identified or alternative mechanisms in strains of Bacteroides and related species from a developing country.

  14. Multidrug resistance mediated by ABC transporters in osteosarcoma cell lines: mRNA analysis and functional radiotracer studies

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Celia Maria Freitas [Department of Pathology, Leiden University Medical Center, 2300 RC Leiden (Netherlands); Faculty of Medicine, Institute of Biophysics/Biomathematics, IBILI, 3000-354 Coimbra (Portugal)]. E-mail: cgomes@ibili.uc.pt; van Paassen, Heidi [Department of Pathology, Leiden University Medical Center, 2300 RC Leiden (Netherlands); Romeo, Salvatore [Department of Pathology, Leiden University Medical Center, 2300 RC Leiden (Netherlands); Welling, Mick M. [Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, 2300 RC Leiden (Netherlands); Feitsma, R.I.J. [Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, 2300 RC Leiden (Netherlands); Abrunhosa, Antero J. [Faculty of Medicine, Institute of Biophysics/Biomathematics, IBILI, 3000-354 Coimbra (Portugal); Botelho, M. Filomena [Faculty of Medicine, Institute of Biophysics/Biomathematics, IBILI, 3000-354 Coimbra (Portugal); Hogendoorn, Pancras C.W. [Department of Pathology, Leiden University Medical Center, 2300 RC Leiden (Netherlands); Pauwels, Ernest [Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, 2300 RC Leiden (Netherlands); Cleton-Jansen, Anne Marie [Department of Pathology, Leiden University Medical Center, 2300 RC Leiden (Netherlands)

    2006-10-15

    Drug resistance remains a significant impediment to successful chemotherapy and constitutes a major prognostic factor in osteosarcoma (OS) patients. This study was designed to identify the role and prognostic significance of multidrug-resistance (MDR)-related transporters, such as multidrug resistance protein 1 (MDR1), multidrug-resistance-associated protein (MRP1) and breast-cancer-related protein (BCRP), in OS using cationic lipophilic radiotracers. We evaluated the chemosensitivity of four OS cell lines (Saos-2, 143B, MNNG/HOS and U-2OS) to doxorubicin (DOX), cisplatin (CIS) and methotrexate. The expression of MDR-related transporters was analyzed at mRNA level by quantitative polymerase chain reaction and at functional level by {sup 99m}Tc sestamibi and {sup 99m}Tc tetrofosmin. The effectiveness of MDR modulators [cyclosporin A (CsA) and imatinib] on transporter inhibition and on the reversal of resistance was also assessed. MNNG/HOS and U-2OS cells expressing high levels of MDR1 were highly resistant to DOX and showed reduced accumulation and higher efflux for radiotracers. Although MRP1 was uniformly expressed in all cells, only U-2OS was resistant to CIS. CsA restored sensitivity to DOX and CIS, and enhanced the accumulation and efflux half-life of radiotracers in MDR1-expressing cell lines. The chemosensitivity of OS cells to DOX was strongly dependent on mRNA MDR1 expression and could be circumvented by adding CsA. The kinetic parameters of radiotracers correlated with MDR1 expression levels, hence predicting DOX resistance. We concluded that sensitivity to chemotherapy is strongly dependent on the expression of MDR1 transporter and that radiotracer studies could prove clinically useful in predicting chemotherapy response and in evaluating the efficacy of MDR-reversing agents.

  15. Multidrug resistance reversal in human gastric carcinoma cells by neferine

    Institute of Scientific and Technical Information of China (English)

    Jian-Guo Cao; Xiao-Qing Tang; Shu-Hong Shi

    2004-01-01

    AIM: To investigate the reversal effect of neferine on multidrug resistance in human gastric carcinoma cell line.METHODS: Cells of a human gastric cancer cells line, SGC7901,and its vincristine (VCR) -resistant variant, SGC7901/VCR,were cultivated with or without neferine and/or VCR. The cytotoxic effect of VCR was evaluated by the MTT assay. Cell apoptosis induced by VCR was determined by flow cytometry (FCM). The expression of P-glycoprotein (P-gp) and a multidrug-resistance-associated protein (MRP) in cells was examined by immunofluorescence and FCM.RESULTS: Neferine at the concentration from 2.5 μmol/L to 10 μmol/L had no cytotoxicity to SGC7901 cells, and its variant SGC7901/VCR cells. The IC50 of VCR against SGC7901 and SGC7901/VCR cells was 0.059 μg/mL and 2.32 μg/mL,respectively, indicating that SGC7901/VCR cells were 39 times more resistant to VCR than its parent SGC7 901 cells. After treatment with neferine at concentrations of 2.5, 5 and 10 μmol/L, the IC50 of VCR to SGC7901/VCR cell line decreased to 0.340, 0.128 and 0.053 μg/mL, respectively,thus, increased the chemosensitivity by 6.8-, 18.1- and 43.8-fold, respectively. SGC7901/VCR cells were apoptosis resistant to VCR. Neferine (2.5, 5 and 10 μmol/L) promoted the VCR-induced apoptosis of SGC7901/VCR cells in a dosedependent manner. The expressions of P-gp and MRP were strongly positive in SGC7901/VCR cells, which were significantly down-regulated after treatment with neferine (10 μmol/L)for 24 h.CONCLUSION: Neferine reverses multidrug resistance of human gastric carcinoma SGC7901/VCR cells, which may be associated with the down-regulations of P-gp and MRP expression in SGC701/VCR cells.

  16. Vagueness, truth and permissive consequence

    NARCIS (Netherlands)

    Cobreros, P.; Egré, P.; Ripley, D.; van Rooij, R.; Achourioti, D.; Galinon, H.; Martínez Fernández, J.; Fujimoto, K.

    2015-01-01

    We say that a sentence A is a permissive consequence of a set of premises Γ whenever, if all the premises of Γ hold up to some standard, then A holds to some weaker standard. In this paper, we focus on a three-valued version of this notion, which we call strict-to-tolerant consequence, and discuss

  17. The draft genome sequence of multidrug-resistant Pseudomonas aeruginosa strain CCBH4851, a nosocomial isolate belonging to clone SP (ST277) that is prevalent in Brazil

    Science.gov (United States)

    Silveira, Melise; Albano, Rodolpho; Asensi, Marise; Assef, Ana Paula Carvalho

    2014-01-01

    The high occurrence of nosocomial multidrug-resistant (MDR) microorganisms is considered a global health problem. Here, we report the draft genome sequence of a MDR Pseudomonas aeruginosa strain isolated in Brazil that belongs to the endemic clone ST277. The genome encodes important resistance determinant genes and consists of 6.7 Mb with a G+C content of 66.86% and 6,347 predicted coding regions including 60 RNAs. PMID:25466623

  18. Complete Genome Sequences of Three Multidrug-Resistant Clinical Isolates of Streptococcus pneumoniae Serotype 19A with Different Susceptibilities to the Myxobacterial Metabolite Carolacton

    Science.gov (United States)

    Bunk, Boyke; Schober, Isabel; Spröer, Cathrin; Bergmann, Simone; Jarek, Michael; Overmann, Jörg; Wagner-Döbler, Irene

    2017-01-01

    ABSTRACT The full-genome sequences of three drug- and multidrug-resistant Streptococcus pneumoniae clinical isolates of serotype 19A were determined by PacBio single-molecule real-time sequencing, in combination with Illumina MiSeq sequencing. A comparison to the genomes of other pneumococci indicates a high nucleotide sequence identity to strains Hungary19A-6 and TCH8431/19A. PMID:28209832

  19. The draft genome sequence of multidrug-resistant Pseudomonas aeruginosa strain CCBH4851, a nosocomial isolate belonging to clone SP (ST277 that is prevalent in Brazil

    Directory of Open Access Journals (Sweden)

    Melise Silveira

    2014-12-01

    Full Text Available The high occurrence of nosocomial multidrug-resistant (MDR microorganisms is considered a global health problem. Here, we report the draft genome sequence of a MDR Pseudomonas aeruginosa strain isolated in Brazil that belongs to the endemic clone ST277. The genome encodes important resistance determinant genes and consists of 6.7 Mb with a G+C content of 66.86% and 6,347 predicted coding regions including 60 RNAs.

  20. 多药耐药铜绿假单胞菌医院感染的高危因素及药物敏感性分析%High risk factors of nosocomial infection caused by multidrug-resistant Pseudomonas aeruginosa and analysis of drug sensitivity

    Institute of Scientific and Technical Information of China (English)

    曹利君; 王春萍

    2011-01-01

    OBJECTIVE To investigate the risk factors for nosocomial infection caused by multidrug-resistant Pseudomonas aeruginosa and analyze the drug sensitivity. METHODS A total of 98 cases of patients with P. Aeruginosa infection in our hospital from Jan 2007 to May 2011 were selected in this study and divided them into control group (sensitive group) with 48 cases and observation group (multi-drug resistant group) with 50 patients. The age, length of stay, mechanical ventilation rate associated with lung-based diseases, APACHE TJ score and so on for the two groups were compared, and statistics and analysis for the observation group of departments and MIC distribution were performed. RESULTS The age of the observed group (60. 25±5. 66)years was older than the control group (53. 14±6. 13)years, length of stay (35. 28±6. 89)d was longer than the control group (26. 52±6. 37)d, mechanical ventilation rate (50. 0%) was higher than control group (25. 0%) , associated with lung disease (28.0%) was proportion (12. 5%} higher than the control group, APACHE II score (20. 5± 3.1) points was (15. 4i2, 9) points higher than the control group. The highest proportion in distributed departments were ICU and neurology, and they were 24. 0% and 20. 0% respectively, There were significantly different (P<0. 05). CONCLUSION There are characteristics of the nosocomial infection in risk factors and drug sensitivity of multi-drug resistant P. Aeruginosa, which are is worthy of the attention in clinic.%目的 探讨分析多药耐药性铜绿假单胞菌医院感染的高危因素及药物敏感性.方法 选取2007年1月-2011年5月检测出的98例铜绿假单胞菌感染患者为研究对象,将其分为对照组(敏感组)48例和观察组(多药耐药组)50例,对两组年龄、住院时间、机械通气率、伴有肺部基础疾病、APACHEⅡ评分等进行统计及比较,并对观察组的科室分布及MIC进行统计及分析.结果 观察组平均年龄(60.25±5.66)

  1. Natural product modulators to overcome multidrug resistance in cancer.

    Science.gov (United States)

    Cort, Aysegul; Ozben, Tomris

    2015-01-01

    Multidrug resistance (MDR) is a condition that makes cells simultaneously unresponsive to different drugs, unrelated to their chemical structure and mechanism of action. MDR caused by the presence and overexpression of ABC transporters makes obstacles in cancer treatment and lower the effectiveness of chemotherapy. Natural products are investigated by many researchers as MDR modulators for their low toxicity and potent, selective behavior. When coadministered, MDR modulators compete with cytotoxic agents for binding to the active site of the membrane transporters and reduce drug efflux. Natural product-based drugs are important in struggling against drug resistance during cancer therapy. This review is focused on the potential mechanisms against drug resistance, the development of inhibitors for ABC drug transporters, natural product modulators, and nanoparticle drug delivery.

  2. [Leprosy situation in Myanmar before and after multidrug therapy].

    Science.gov (United States)

    Ishii, Norihisa; Mori, Shuichi

    2005-09-01

    We introduced history of leprosy in Myanmar based on the book of Myanmar Academy of Medical Science published entitled "CONQUEST OF SCOURGES IN MYANMAR (Complied and Edited by Ko Ko, Kyaw and U Thaung) at 2002. "Leprosy Elimination Programme in Myanmar (Kyaw Lwin and Kyaw Nyunt Stein)" was appeared at chapter III in it. After dapsone treatment appeared, leprosy control program has started. Health system and service were developed and leprosy control program was also included in them. The integration of the elimination activities into basic health workers, such as midwives and health volunteers, has enabled the participation of a wide range of people in the community. After 1990s, multidrug therapy (MDT) was covered whole area of Myanmar, and task force for leprosy elimination was formed at Sate/Division, District and Township level. Finally Myanmar achieved the elimination of leprosy in January in 2003.

  3. How to Measure Export via Bacterial Multidrug Resistance Efflux Pumps

    Directory of Open Access Journals (Sweden)

    Jessica M. A. Blair

    2016-07-01

    Full Text Available Bacterial multidrug resistance (MDR efflux pumps are an important mechanism of antibiotic resistance and are required for many pathogens to cause infection. They are also being harnessed to improve microbial biotechnological processes, including biofuel production. Therefore, scientists of many specialties must be able to accurately measure efflux activity. However, myriad methodologies have been described and the most appropriate method is not always clear. Within the scientific literature, many methods are misused or data arising are misinterpreted. The methods for measuring efflux activity can be split into two groups, (i those that directly measure efflux and (ii those that measure the intracellular accumulation of a substrate, which is then used to infer efflux activity. Here, we review the methods for measuring efflux and explore the most recent advances in this field, including single-cell or cell-free technologies and mass spectrometry, that are being used to provide more detailed information about efflux pump activity.

  4. Preparation of silver nanoparticles fabrics against multidrug-resistant bacteria

    Science.gov (United States)

    Hanh, Truong Thi; Thu, Nguyen Thi; Hien, Nguyen Quoc; An, Pham Ngoc; Loan, Truong Thi Kieu; Hoa, Phan Thi

    2016-04-01

    The silver nanoparticles (AgNPs)/peco fabrics were prepared by immobilization of AgNPs on fabrics in which AgNPs were synthesized by γ-irradiation of the 10 mM AgNO3 chitosan solution at the dose of 17.6 kGy. The AgNPs size has been estimated to be about 11 nm from TEM image. The AgNPs content onto peco fabrics was of 143±6 mg/kg at the initial AgNPs concentration of 100 ppm. The AgNPs colloidal solution was characterized by UV-vis spectroscopy and TEM image. The antibacterial activity of AgNPs/peco fabrics after 60 washings against Staphylococcus aureus and Klebsiella pneumoniae was found to be over 99%. Effects of AgNPs fabics on multidrug-resistant pathogens from the clinical specimens were also tested.

  5. A plausible worst-case scenario of increasing multidrug resistance as a tool for assessing societal risks and capabilities in Sweden.

    Science.gov (United States)

    Roffey, Roger; Lindberg, Anna; Molin, Lena; Wikman-Svahn, Per

    2015-01-01

    A "plausible worst-case scenario" of a gradually increasing level of multidrug-resistant bacteria (carbapenem-resistant E. coli) in the human population was developed and used to study how Swedish authorities would manage this situation and to identify preventive measures that could be taken. Key findings include: (1) a scenario in which 5% of the population in southern Sweden become carriers of carbapenem-resistant E. coli is possible or even likely in 10 to 15 years; (2) it is not clear when and how the increase of E. coli resistant to carbapenems as in the scenario would be detected in the general human population; (3) identified negative consequences of the scenario on society were primarily due to increased demands on the healthcare system and potential consequences for food-producing animals, food safety, and environmental health; and (4) a number of preventive and mitigation measures were suggested, including initiating long-term screening programs for public and animal health as well as for food and water production to monitor increasing levels of carbapenem resistance. Strategies and plans to prevent and handle future increasing prevalence of multidrug-resistant bacteria need to be developed.

  6. Multidrug-resistant pathogens in the food supply.

    Science.gov (United States)

    Doyle, Marjorie E

    2015-04-01

    Antimicrobial resistance, including multidrug resistance (MDR), is an increasing problem globally. MDR bacteria are frequently detected in humans and animals from both more- and less-developed countries and pose a serious concern for human health. Infections caused by MDR microbes may increase morbidity and mortality and require use of expensive drugs and prolonged hospitalization. Humans may be exposed to MDR pathogens through exposure to environments at health-care facilities and farms, livestock and companion animals, human food, and exposure to other individuals carrying MDR microbes. The Centers for Disease Control and Prevention classifies drug-resistant foodborne bacteria, including Campylobacter, Salmonella Typhi, nontyphoidal salmonellae, and Shigella, as serious threats. MDR bacteria have been detected in both meat and fresh produce. Salmonellae carrying genes coding for resistance to multiple antibiotics have caused numerous foodborne MDR outbreaks. While there is some level of resistance to antimicrobials in environmental bacteria, the widespread use of antibiotics in medicine and agriculture has driven the selection of a great variety of microbes with resistance to multiple antimicrobials. MDR bacteria on meat may have originated in veterinary health-care settings or on farms where animals are given antibiotics in feed or to treat infections. Fresh produce may be contaminated by irrigation or wash water containing MDR bacteria. Livestock, fruits, and vegetables may also be contaminated by food handlers, farmers, and animal caretakers who carry MDR bacteria. All potential sources of MDR bacteria should be considered and strategies devised to reduce their presence in foods. Surveillance studies have documented increasing trends in MDR in many pathogens, although there are a few reports of the decline of certain multidrug pathogens. Better coordination of surveillance programs and strategies for controlling use of antimicrobials need to be implemented in

  7. Detection of multidrug resistance using molecular nuclear technique

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Tae; Ahn, Byeong Cheol [School of Medicine, Kyungpook National Univ., Daegu (Korea, Republic of)

    2004-04-01

    Although the outcome of cancer patients after cytotoxic chemotherapy is related diverse mechanisms, multidrug resistance (MDR) for chemotherapeutic drugs due to cellular P-glycoprotein (Pgp) or multidrug-resistance associated protein (MRP) is most important factor in the chemotherapy failure to cancer. A large number of pharmacologic compounds, including verapamil, quinidine, tamoxifen, cyclosporin A and quinolone derivatives have been reported to overcome MDR. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transporter. {sup 99}m-Tc-MIBI and other {sup 99}m-Tc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with {sup 11}C have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N-({sup 11}C)acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. SPECT and PET pharmaceuticals have successfully used to evaluate pharmacologic effects of MDR modulators. Imaging of MDR and reversal of MDR with bioluminescence in a living animal is also evaluated for future clinical trial. We have described recent advances in molecular imaging of MDR and reviewed recent publications regarding feasibility of SPECT and PET imaging to study the functionality of MDR transporters in vivo.

  8. Functional study of the novel multidrug resistance gene HA117 and its comparison to multidrug resistance gene 1

    Directory of Open Access Journals (Sweden)

    Chen Tingfu

    2010-07-01

    Full Text Available Abstract Background The novel gene HA117 is a multidrug resistance (MDR gene expressed by all-trans retinoic acid-resistant HL-60 cells. In the present study, we compared the multidrug resistance of the HA117 with that of the classical multidrug resistance gene 1 (MDR1 in breast cancer cell line 4T1. Methods Transduction of the breast cancer cell line 4T1 with adenoviral vectors encoding the HA117 gene and the green fluorescence protein gene (GFP (Ad-GFP-HA117, the MDR1 and GFP (Ad-GFP-MDR1 or GFP (Ad-GFP was respectively carried out. The transduction efficiency and the multiplicity of infection (MOI were detected by fluorescence microscope and flow cytometry. The transcription of HA117 gene and MDR1 gene were detected by reverse transcription polymerase chain reaction (RT-PCR. Western blotting analysis was used to detect the expression of P-glycoprotein (P-gp but the expression of HA117 could not be analyzed as it is a novel gene and its antibody has not yet been synthesized. The drug-excretion activity of HA117 and MDR1 were determined by daunorubicin (DNR efflux assay. The drug sensitivities of 4T1/HA117 and 4T1/MDR1 to chemotherapeutic agents were detected by Methyl-Thiazolyl-Tetrazolium (MTT assay. Results The transducted efficiency of Ad-GFP-HA117 and Ad-GFP-MDR1 were 75%-80% when MOI was equal to 50. The transduction of Ad-GFP-HA117 and Ad-GFP-MDR1 could increase the expression of HA117 and MDR1. The drug resistance index to Adriamycin (ADM, vincristine (VCR, paclitaxel (Taxol and bleomycin (BLM increased to19.8050, 9.0663, 9.7245, 3.5650 respectively for 4T1/HA117 and 24.2236, 11.0480, 11.3741, 0.9630 respectively for 4T1/MDR1 as compared to the control cells. There were no significant differences in drug sensitivity between 4T1/HA117 and 4T1/MDR1 for the P-gp substrates (ADM, VCR and Taxol (P Conclusions These results confirm that HA117 is a strong MDR gene in both HL-60 and 4T1 cells. Furthermore, our results indicate that the MDR

  9. Global consequences of unsafe abortion.

    Science.gov (United States)

    Singh, Susheela

    2010-11-01

    Unsafe abortion is a significant cause of death and ill health in women in the developing world. A substantial body of research on these consequences exists, although studies are of variable quality. However, unsafe abortion has a number of other significant consequences that are much less widely recognized. These include the economic consequences, the immediate costs of providing medical care for abortion-related complications, the costs of medical care for longer-term health consequences, lost productivity to the country, the impact on families and the community, and the social consequences that affect women and families. This article will review the scientific evidence on the consequences of unsafe abortion, highlight gaps in the evidence base, suggest areas where future research efforts are needed, and speculate on the future situation regarding consequences and evidence over the next 5-10 years. The information provided is useful and timely given the current heightened interest in the issue of unsafe abortion, growing from the recent focus of national and international agencies on reducing maternal mortality by 75% by 2015 (as one of the Millennium Development Goals established in 2000).

  10. [Efficiency of the use of peppermint (Mentha piperita L) essential oil inhalations in the combined multi-drug therapy for pulmonary tuberculosis].

    Science.gov (United States)

    Shkurupiĭ, V A; Kazarinova, N V; Ogirenko, A P; Nikonov, S D; Tkachev, A V; Tkachenko, K G

    2002-01-01

    The essential oil of peppermint (Mentha piperita L.) has been found to have an in vitro pronounced and equal antimycobacterial effect in doses of 300 and 600 micrograms/ml, respectively. The use of its inhalations (upon 20-min heat evaporation into the room atmosphere for 2 months) as a supplement to combined multidrug therapy for pulmonary tuberculosis has indicated their significantly high positive effect in terms of abacillation (by 26.8 and 58.5% with doses of 0.01 and 0.005 ml/m3, respectively). This was followed by earlier positive X-ray changes in the lung and by attenuation of the intoxication syndrome. The findings suggest that peppermint essential oil may be used in combined multidrug therapy in patients with disseminated and infiltrative pulmonary tuberculosis.

  11. Dissemination of multidrug-resistant, class 1 integron-carrying Acinetobacter baumannii isolates in Taiwan

    National Research Council Canada - National Science Library

    Huang, L.-Y; Chen, T.-L; Lu, P.-L; Tsai, C.-A; Cho, W.-L; Chang, F.-Y; Fung, C.-P; Siu, L. K

    2008-01-01

    In this study, 283 multidrug-resistant Acinetobacter baumannii (MDR-AB) bloodstream isolates were collected between 1996 and 2004, from three teaching hospitals located in different regions of Taiwan...

  12. Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs.

    Science.gov (United States)

    Fluman, Nir; Bibi, Eitan

    2014-09-23

    Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner.

  13. Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs

    Directory of Open Access Journals (Sweden)

    Nir Fluman

    2014-09-01

    Full Text Available Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner.

  14. Manipulating the drug/proton antiport stoichiometry of the secondary multidrug transporter MdfA.

    Science.gov (United States)

    Tirosh, Osnat; Sigal, Nadejda; Gelman, Amir; Sahar, Nadav; Fluman, Nir; Siemion, Shira; Bibi, Eitan

    2012-07-31

    Multidrug transporters are integral membrane proteins that use cellular energy to actively extrude antibiotics and other toxic compounds from cells. The multidrug/proton antiporter MdfA from Escherichia coli exchanges monovalent cationic substrates for protons with a stoichiometry of 1, meaning that it translocates only one proton per antiport cycle. This may explain why transport of divalent cationic drugs by MdfA is energetically unfavorable. Remarkably, however, we show that MdfA can be easily converted into a divalent cationic drug/≥ 2 proton-antiporter, either by random mutagenesis or by rational design. The results suggest that exchange of divalent cationi c drugs with two (or more) protons requires an additional acidic residue in the multidrug recognition pocket of MdfA. This outcome further illustrates the exceptional promiscuous capabilities of multidrug transporters.

  15. Multidrug transporters from bacteria to man : similarities in structure and function

    NARCIS (Netherlands)

    van Veen, HW; Konings, WN

    1997-01-01

    Organisms ranging from bacteria to man possess transmembrane transporters which confer resistance to toxic corn pounds. Underlining their biological significance, prokaryotic and eukaryotic multidrug transport proteins are very similar in structure and function. Therefore, a study of the factors whi

  16. Impact of fungal drug transporters on fungicide sensitivity, multidrug resistance and virulence

    NARCIS (Netherlands)

    Waard, de M.A.; Andrade, A.C.; Hayashi, K.; Schoonbeek, H.; Stergiopoulos, I.; Zwiers, L.H.

    2006-01-01

    Drug transporters are membrane proteins that provide protection for organisms against natural toxic products and fungicides. In plant pathogens, drug transporters function in baseline sensitivity to fungicides, multidrug resistance (MDR) and virulence on host plants. This paper describes drug transp

  17. Multidrug transporters from bacteria to man : similarities in structure and function

    NARCIS (Netherlands)

    van Veen, HW; Konings, WN

    Organisms ranging from bacteria to man possess transmembrane transporters which confer resistance to toxic corn pounds. Underlining their biological significance, prokaryotic and eukaryotic multidrug transport proteins are very similar in structure and function. Therefore, a study of the factors

  18. Biofilm formation in clinical isolates of nosocomial Acinetobacter baumannii and its relationship with multidrug resistance

    Directory of Open Access Journals (Sweden)

    Ebrahim Babapour

    2016-06-01

    Conclusions: Since most of the multidrug resistant strains produce biofilm, it seems necessary to provide continuous monitoring and determination of antibiotic susceptibility of clinical A. baumannii. This would help to select the most appropriate antibiotic for treatment.

  19. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

    DEFF Research Database (Denmark)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia

    2014-01-01

    Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated...

  20. Phenotypic and genotypic analysis of multidrug-resistant tuberculosis in Ethiopia.

    NARCIS (Netherlands)

    Agonafir, M.; Lemma, E.; Wolde-Meskel, D.; Goshu, S.; Santhanam, A.; Girmachew, F.; Demissie, D.; Getahun, M.; Gebeyehu, M.; Soolingen, D. van

    2010-01-01

    SETTING: National Tuberculosis Reference Laboratory, Addis Ababa, Ethiopia. OBJECTIVES: To determine the drug susceptibility pattern of Mycobacterium tuberculosis isolates and to genetically characterise multidrug-resistant tuberculosis (MDR-TB) isolates. DESIGN: A total of 107 M. tuberculosis isola

  1. Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium

    DEFF Research Database (Denmark)

    Bryant, Josephine M; Grogono, Dorothy M; Rodriguez-Rincon, Daniela

    2016-01-01

    Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality....

  2. Ontogeny, aging, and gender-related changes in hepatic multidrug resistant protein genes in rats.

    Science.gov (United States)

    Zhu, Qiong-Ni; Hou, Wei-Yu; Xu, Shang-Fu; Lu, Yuan-Fu; Liu, Jie

    2017-02-01

    Multidrug resistance proteins (Mrps) are efflux transporters playing important roles in endogenous substances and xenobiotics transport out of the liver. Children, elderly, gender and physio-pathological conditions could influence their expression and result in changes in drug disposition.

  3. Lipoteichoic acid synthesis inhibition in combination with antibiotics abrogates growth of multidrug-resistant Enterococcus faecium

    NARCIS (Netherlands)

    Paganelli, Fernanda L.|info:eu-repo/dai/nl/357297849; van de Kamer, Tim; Brouwer, Ellen C.|info:eu-repo/dai/nl/304815667; Leavis, Helen L.|info:eu-repo/dai/nl/304820717; Woodford, Neil; Bonten, Marc J M|info:eu-repo/dai/nl/123144337; Willems, Rob J L|info:eu-repo/dai/nl/106866370; Hendrickx, Antoni P A|info:eu-repo/dai/nl/304820741

    Enterococcus faecium is a multidrug-resistant (MDR) nosocomial pathogen causing significant morbidity in debilitated patients. New antimicrobials are needed to treat antibiotic-resistant E. faecium infections in hospitalised patients. E. faecium incorporates lipoteichoic acid (LTA)

  4. Genomic epidemiology of multidrug-resistant Mycobacterium tuberculosis during transcontinental spread.

    Science.gov (United States)

    Coscolla, Mireia; Barry, Pennan M; Oeltmann, John E; Koshinsky, Heather; Shaw, Tambi; Cilnis, Martin; Posey, Jamie; Rose, Jordan; Weber, Terry; Fofanov, Viacheslav Y; Gagneux, Sebastien; Kato-Maeda, Midori; Metcalfe, John Z

    2015-07-15

    The transcontinental spread of multidrug-resistant (MDR) tuberculosis is poorly characterized in molecular epidemiologic studies. We used genomic sequencing to understand the establishment and dispersion of MDR Mycobacterium tuberculosis within a group of immigrants to the United States. We used a genomic epidemiology approach to study a genotypically matched (by spoligotype, IS6110 restriction fragment length polymorphism, and mycobacterial interspersed repetitive units-variable number of tandem repeat signature) lineage 2/Beijing MDR strain implicated in an outbreak of tuberculosis among refugees in Thailand and consecutive cases within California. All 46 MDR M. tuberculosis genomes from both Thailand and California were highly related, with a median difference of 10 single-nucleotide polymorphisms (SNPs). The Wat Tham Krabok (WTK) strain is a new sequence type distinguished from all known Beijing strains by 55 SNPs and a genomic deletion (Rv1267c) associated with increased fitness. Sequence data revealed a highly prevalent MDR strain that included several closely related but distinct allelic variants within Thailand, rather than the occurrence of a single outbreak. In California, sequencing data supported multiple independent introductions of WTK with subsequent transmission and reactivation within the state, as well as a potential super spreader with a prolonged infectious period. Twenty-seven drug resistance-conferring mutations and 4 putative compensatory mutations were found within WTK strains. Genomic sequencing has substantial epidemiologic value in both low- and high-burden settings in understanding transmission chains of highly prevalent MDR strains.

  5. Modulation of multidrug resistance by flavonoids. Inhibitors of glutathione conjugation and MRP-mediated transport

    OpenAIRE

    Zanden, van, J.J.

    2005-01-01

    In this thesis, the use of flavonoids for inhibition of two important players in the glutathione related biotransformation system involved in multidrug resistance was investigated using several in vitro model systems. The enzymes of interest included the phase II glutathione S-transferase enzyme GSTP1-1, able to detoxify anticancer agents through conjugation with glutathione and the two multidrug resistance proteins MRP1 and MRP2 involved in glutathione mediated cellular efflux of, amongst ot...

  6. "Emergence of Multidrug Resistant Strains of Escherichia coli Isolated from Urinary Tract Infections"

    OpenAIRE

    R Moniri; Khorshidi, A; H Akbari

    2003-01-01

    The emergence of multidrug resistant strains of Escherichia coli has complicated treatment decision and may lead to treatment failures. From April to November 2001 we prospectively evaluated the prevalence of resistance to trimethoprim-sulfamethoxazole (SXT), gentamicin, cephalothin, ciprofloxacin, and nitrofurantoin in 220 Escherichia coli isolates from patients with urinary tract infections in kashan, Iran. To assess the current breadth of multidrug resistance among urinary isolates of E. c...

  7. Influence of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To evaluate the effect of efflux pump inhibitors (EPIs) on multidrug resistance of Helicobacter pylori (H. pylori).METHODS: H. pylori strains were isolated and cultured on Brucella agar plates with 10% sheep's blood. The multidrug resistant (MDR) H. pylori were obtained with the inducer chloramphenicol by repeated doubling of the concentration until no colony was seen, then the susceptibilities of the MDR strains and their parents to 9 antibiotics were assessed with agar dilution tests. The present stud...

  8. [Bioecological consequences of an accidental hydrocarbon discharge on the rocky shore of the high Normandy coast. Results one year after the oil pollution on the november 26th 1974].

    Science.gov (United States)

    Peltier, J C; Dupont, W; Dupont, J P

    1976-01-01

    We have followed, during one year, the ecological consequences of an accidental oil pollution on four rocky shores of the norman coast. In the shores where the detergents have not been used, the mussels have progressively excreted the hydrocarbons accumulated in their organism ; the other fixed animals have not been changed. In the shores where the detergents have been used their spreading had not only noxious demoecological consequences, but also synecological consequences with modifications of the fixed species which have colonized the rocks. These observations prove that the use of detergents to clean the polluted shores is not without care.

  9. Risk factors for nosocomial bloodstream infection caused by multidrug resistant gram-negative bacilli in pediatrics

    Directory of Open Access Journals (Sweden)

    Mariana V. Arnoni

    2007-04-01

    Full Text Available The aim of this study was to identify the risk factors for nosocomial bloodstream infections by multidrug resistant Gram-negative bacilli. From November 2001 to December 2003, in the Pediatric Department of the Santa Casa de São Paulo, a retrospective case-control study was developed concerning patients who had nosocomial bloodstream infection caused by Gram-negative bacilli. Patients with multidrug resistant infections were designated as case patients, and control patients were those with an infection that did not meet the criteria for multidrug resistance. Previous use of central venous catheter and previous use of vancomycin plus third generation cephalosporins were associated to a higher chance of infections by multidrug resistant Gram-negative bacilli (Odds ratio - 5.8 and 5.2, respectively. Regarding sensitivity of the isolated agents, 47.8% were multidrug resistant, 54.2% were Klebsiella spp. ESBL producers and 36.4% were imipenem resistant Pseudomonas aeruginosa. The lethality rate was 36.9% in the studied cases and this rate was significantly higher in the group of patients with multidrug resistant infections (p=0.013. Risk factor identification as well as the knowledge of the susceptibility of the nosocomial infectious agents gave us the possibility to perform preventive and control strategies to reduce the costs and mortality related to these infections.

  10. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  11. Metabolic consequences of craniopharyingioma and their management.

    Science.gov (United States)

    Lamas Oliveira, Cristina

    2013-11-01

    Most patients diagnosed with craniopharyngioma survive long-term, but suffer many consequences of the disease and its treatment. Among the metabolic consequences, there is a high prevalence of panhypopituitarism and diabetes insipidus, mainly due to the surgical treatment. Obesity is also more prevalent in these patients than in the general population, and gets worse with time. It is a consequence of a diminished basal metabolic rate and a lower physical activity compared to that of matched controls, with a similar or lower caloric intake. Many different hormonal alterations that could be responsible for those changes in the energy balance have been found. Patients whose tumor involved the hypothalamus are more prone to develop obesity and its consequences. Cardiovascular risk factors are also more prevalent in these patients, leading to a high cardiovascular morbidity and mortality. Sleep disturbances, dysfunction in thermoregulation and thirst and a lower bone mineral density can also be found. Although randomized clinical trials comparing different treatments are lacking, it looks like therapeutic strategies have a minor influence on the risk of long-term sequelae. Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.

  12. Pancreatic cancer cells express CD44 variant 9 and multidrug resistance protein 1 during mitosis.

    Science.gov (United States)

    Kiuchi, Shizuka; Ikeshita, Shunji; Miyatake, Yukiko; Kasahara, Masanori

    2015-02-01

    Pancreatic cancer is one of the most lethal cancers with high metastatic potential and strong chemoresistance. Its intractable natures are attributed to high robustness in tumor cells for their survival. We demonstrate here that pancreatic cancer cells (PCCs) with an epithelial phenotype upregulate cell surface expression of CD44 variant 9 (CD44v9), an important cancer stem cell marker, during the mitotic phases of the cell cycle. Of five human CD44(+) PCC lines examined, three cell lines, PCI-24, PCI-43 and PCI-55, expressed E-cadherin and CD44 variants, suggesting that they have an epithelial phenotype. By contrast, PANC-1 and MIA PaCa-2 cells expressed vimentin and ZEB1, suggesting that they have a mesenchymal phenotype. PCCs with an epithelial phenotype upregulated cell surface expression of CD44v9 in prophase, metaphase, anaphase and telophase and downregulated CD44v9 expression in late-telophase, cytokinesis and interphase. Sorted CD44v9-negative PCI-55 cells resumed CD44v9 expression when they re-entered the mitotic stage. Interestingly, CD44v9(bright) mitotic cells expressed multidrug resistance protein 1 (MDR1) intracellularly. Upregulated expression of CD44v9 and MDR1 might contribute to the intractable nature of PCCs with high proliferative activity.

  13. Over-expressed CmbT multidrug resistance transporter improves the fitness of Lactococcus lactis

    Directory of Open Access Journals (Sweden)

    Filipić Brankica

    2013-01-01

    Full Text Available The influence of the over-expression of CmbT multidrug resistance transporter on the growth rate of Lactococcus lactis NZ9000 was studied. L. lactis is a lactic acid bacteria (LAB widely used as a starter culture in dairy industry. Recently characterized CmbT MDR transporter in L. lactis confers resistance to a wide variety of toxic compounds as well as to some clinically relevant antibiotics. In this study, the cmbT gene was over-expressed in the strain L. lactis NZ9000 in the presence of nisin inducer. Over-expression of the cmbT gene in L. lactis NZ9000 was followed by RT-PCR. The obtained results showed that the cmbT gene was successfully over-expressed by addition of sub-inhibitory amounts of nisin. Growth curves of L. lactis NZ9000/pCT50 over-expressing the cmbT gene and L. lactis NZ9000 control strain were followed in the rich medium as well as in the chemically defined medium in the presence solely of methionine (0.084 mM or mix of methionine and cysteine (8.4 mM and 8.2 mM, respectively. Resulting doubling times revealed that L. lactis NZ9000/pCT50 had higher growth rate comparing to the control strain. This could be a consequence of the CmbT efflux activity, which improves the fitness of the host bacterium through the elimination of toxic compounds from the cell.

  14. New Approaches With Natural Product Drugs for Overcoming Multidrug Resistance in Cancer.

    Science.gov (United States)

    Dinic, Jelena; Podolski-Renic, Ana; Stankovic, Tijana; Bankovic, Jasna; Pesic, Milica

    2015-01-01

    Resistance to chemotherapeutic drugs is one of the main obstacles to effective cancer treatment. Multidrug resistance (MDR) is defined as resistance to structurally and/or functionally unrelated drugs, and has been extensively investigated for the last three decades. There are two types of MDR: intrinsic and acquired. Tumor microenvironment selection pressure leads to the development of intrinsic MDR, while acquired resistance is a consequence of the administered chemotherapy. A central issue in chemotherapy failure is the existence of heterogeneous populations of cancer cells within one patient and patient-to-patient variability within each type of cancer. Numerous genes and pathways contribute to the development of MDR in cancer. Point mutations, gene amplification or other genetic or epigenetic changes all affect biological functions and may lead to the occurrence of MDR phenotype. Similar to the characteristics of cancerogenesis, the main features of MDR include abnormal tumor vasculature, regions of hypoxia, aerobic glycolysis, and a lower susceptibility to apoptosis. In order to achieve a lethal effect on cancer cells, drugs need to reach their intracellular target molecules. The overexpression of the efflux transporter P-glycoprotein (P-gp) in MDR cancer cells leads to decreased uptake of the drug and intracellular drug accumulation, minimising drug-target interactions. New agents being or inspired by natural products that successfully target these mechanisms are the main subject of this review. Two key approaches in combating MDR in cancer are discussed (i) finding agents that preserve cytotoxicity toward MDR cancer cells; (ii) developing compounds that restore the cytotoxic activity of classic anticancer drugs.

  15. Multidrug resistant commensal Escherichia coli in animals and its impact for public health

    Directory of Open Access Journals (Sweden)

    Ama eSzmolka

    2013-09-01

    Full Text Available After the era of plentiful antibiotics we are alarmed by the increasing number of antibiotic resistant strains. The genetic flexibility and adaptability of E. coli to constantly changing environments allows to acquire a great number of antimicrobial resistance mechanisms. Commensal strains of E. coli as versatile residents of the lower intestine are also repeatedly challenged by antimicrobial pressures during the lifetime of their host. As a consequence, commensal strains acquire the respective resistance genes, and/or develop resistant mutants in order to survive and maintain microbial homeostasis in the lower intestinal tract. Thus, commensal E. coli strains are regarded as indicators of antimicrobial load on their hosts. This chapter provides a short historic background of the appearance and presumed origin and transfer of antimicrobial resistance genes in commensal intestinal E. coli of animals with comparative information on their pathogenic counterparts. The dynamics, development and ways of evolution of resistance in the E. coli populations differ according to hosts, resistance mechanisms and antimicrobial classes used. The most frequent tools of E. coli against a variety of antimicrobials are the efflux pumps and mobile resistance mechanisms carried by plasmids and/or other transferable elements. The emergence of hybrid plasmids (both resistance and virulence among E. coli is of further concern. Co-existence and co-transfer of these bad genes in this huge and most versatile in vivo compartment may represent an increased public health risk in the future. Significance of multidrug resistant (MDR commensal E. coli seem to be highest in the food animal industry, acting as reservoir for intra- and interspecific exchange and a source for spread of MDR determinants through contaminated food to humans. Thus, public health potential of MDR commensal E. coli of food animals can be a concern and needs monitoring and more molecular analysis in the

  16. Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy.

    Science.gov (United States)

    Keppler, Dietrich

    2011-01-01

    The nine multidrug resistance proteins (MRPs) represent the major part of the 12 members of the MRP/CFTR subfamily belonging to the 48 human ATP-binding cassette (ABC) transporters. Cloning, functional characterization, and cellular localization of most MRP subfamily members have identified them as ATP-dependent efflux pumps with a broad substrate specificity for the transport of endogenous and xenobiotic anionic substances localized in cellular plasma membranes. Prototypic substrates include glutathione conjugates such as leukotriene C(4) for MRP1, MRP2, and MRP4, bilirubin glucuronosides for MRP2 and MRP3, and cyclic AMP and cyclic GMP for MRP4, MRP5, and MRP8. Reduced glutathione (GSH), present in living cells at millimolar concentrations, modifies the substrate specificities of several MRPs, as exemplified by the cotransport of vincristine with GSH by MRP1, or by the cotransport of GSH with bile acids or of GSH with leukotriene B(4) by MRP4.The role of MRP subfamily members in pathophysiology may be illustrated by the MRP-mediated release of proinflammatory and immunomodulatory mediators such as leukotrienes and prostanoids. Pathophysiological consequences of many genetic variants leading to a lack of functional MRP protein in the plasma membrane are observed in the hereditary MRP2 deficiency associated with conjugated hyperbilirubinemia in Dubin-Johnson syndrome, in pseudoxanthoma elasticum due to mutations in the MRP6 (ABCC6) gene, or in the type of human earwax and osmidrosis determined by single nucleotide polymorphisms in the MRP8 (ABCC8) gene. The hepatobiliary and renal elimination of many drugs and their metabolites is mediated by MRP2 in the hepatocyte canalicular membrane and by MRP4 as well as MRP2 in the luminal membrane of kidney proximal tubules. Therefore, inhibition of these efflux pumps affects pharmacokinetics, unless compensated by other ATP-dependent efflux pumps with overlapping substrate specificities.

  17. Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model.

    Science.gov (United States)

    Lazarowski, Alberto; Ramos, Alberto Javier; García-Rivello, Hernán; Brusco, Alicia; Girardi, Elena

    2004-02-01

    1. Failure of anticonvulsive drugs to prevent seizures is a common complication of epilepsy treatment known as drug-refractory epilepsy but their causes are not well understood. It is hypothesized that the multidrug resistance P-glycoprotein (Pgp-170), the product of the MDR-1 gene that is normally expressed in several excretory tissues including the blood brain barrier, may be participating in the refractory epilepsy. 2. Using two monoclonal antibodies against Pgp-170, we investigated the expression and cellular distribution of this protein in the rat brain during experimentally induced epilepsy. Repeated seizures were induced in male Wistar rats by daily administration of 3-mercaptopropionic acid (MP) 45 mg/kg i.p. for either 4 days (MP-4) or 7 days (MP-7). Control rats received an equivalent volume of vehicle. One day after the last injection, rats were sacrificed and brains were processed for immunohistochemistry for Pgp-170. As it was previously described, Pgp-170 immunostaining was observed in some brain capillary endothelial cells of animals from control group. 3. Increased Pgp-170 immunoreactivity was detected in MP-treated animals. Besides the Pgp-170 expressed in blood vessels, neuronal, and glial immunostaining was detected in hippocampus, striatum, and cerebral cortex of MP-treated rats. Pgp-170 immunolabeled neurons and glial cells were observed in a nonhomogeneous distribution. MP-4 animals presented a very prominent Pgp-170 immunostaining in the capillary endothelium, surrounding astrocytes and some neighboring neurons while MP-7 group showed increased neuronal labeling. 4. Our results demonstrate a selective increase in Pgp-170 immunoreactivity in the brain capillary endothelial cells, astrocytes, and neurons during repetitive MP-induced seizures. 5. The role for this Pgp-170 overexpression in endothelium and astrocytes as a clearance mechanism in the refractory epilepsy, and the consequences of neuronal Pgp-170 expression remain to be disclosed.

  18. Fluoroquinolone induction of phage-mediated gene transfer in multidrug-resistant Salmonella.

    Science.gov (United States)

    Bearson, Bradley L; Brunelle, Brian W

    2015-08-01

    Fluoroquinolones are broad-spectrum antibiotics that inhibit bacterial DNA gyrase and topoisomerase activity, which can cause DNA damage and result in bacterial cell death. In response to DNA damage, bacteria induce an SOS response to stimulate DNA repair. However, the SOS response may also induce prophage with production of infectious virions. Salmonella strains typically contain multiple prophages, and certain strains including phage types DT120 and DT104 contain prophage that upon induction are capable of generalised transduction. In this study, strains of multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium DT120 and DT104 were exposed to fluoroquinolones important for use in human and veterinary disease therapy to determine whether prophage(s) are induced that could facilitate phage-mediated gene transfer. Cultures of MDR S. Typhimurium DT120 and DT104 containing a kanamycin resistance plasmid were lysed after exposure to fluoroquinolones (ciprofloxacin, enrofloxacin and danofloxacin). Bacterial cell lysates were able to transfer the plasmid to a recipient kanamycin-susceptible Salmonella strain by generalised transduction. In addition, exposure of DT120 to ciprofloxacin induced the recA gene of the bacterial SOS response and genes encoded in a P22-like generalised transducing prophage. This research indicates that fluoroquinolone exposure of MDR Salmonella can facilitate horizontal gene transfer, suggesting that fluoroquinolone usage in human and veterinary medicine may have unintended consequences, including the induction of phage-mediated gene transfer from MDR Salmonella. Stimulation of gene transfer following bacterial exposure to fluoroquinolones should be considered an adverse effect, and clinical decisions regarding antibiotic selection for infectious disease therapy should include this potential risk. Published by Elsevier B.V.

  19. Ecotope-Based Entomological Surveillance and Molecular Xenomonitoring of Multidrug Resistant Malaria Parasites in Anopheles Vectors

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    Prapa Sorosjinda-Nunthawarasilp

    2014-01-01

    Full Text Available The emergence and spread of multidrug resistant (MDR malaria caused by Plasmodium falciparum or Plasmodium vivax have become increasingly important in the Greater Mekong Subregion (GMS. MDR malaria is the heritable and hypermutable property of human malarial parasite populations that can decrease in vitro and in vivo susceptibility to proven antimalarial drugs as they exhibit dose-dependent drug resistance and delayed parasite clearance time in treated patients. MDR malaria risk situations reflect consequences of the national policy and strategy as this influences the ongoing national-level or subnational-level implementation of malaria control strategies in endemic GMS countries. Based on our experience along with current literature review, the design of ecotope-based entomological surveillance (EES and molecular xenomonitoring of MDR falciparum and vivax malaria parasites in Anopheles vectors is proposed to monitor infection pockets in transmission control areas of forest and forest fringe-related malaria, so as to bridge malaria landscape ecology (ecotope and ecotone and epidemiology. Malaria ecotope and ecotone are confined to a malaria transmission area geographically associated with the infestation of Anopheles vectors and particular environments to which human activities are related. This enables the EES to encompass mosquito collection and identification, salivary gland DNA extraction, Plasmodium- and species-specific identification, molecular marker-based PCR detection methods for putative drug resistance genes, and data management. The EES establishes strong evidence of Anopheles vectors carrying MDR P. vivax in infection pockets epidemiologically linked with other data obtained during which a course of follow-up treatment of the notified P. vivax patients receiving the first-line treatment was conducted. For regional and global perspectives, the EES would augment the epidemiological surveillance and monitoring of MDR falciparum and

  20. Effects of indole alkaloids on multidrug resistance and labeling of P-glycoprotein by a photoaffinity analog of vinblastine.

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    Beck, W T; Cirtain, M C; Glover, C J; Felsted, R L; Safa, A R

    1988-06-30

    Multidrug resistant cells are characterized by decreased drug accumulation and retention, thought to be mediated by a high molecular weight glycoprotein, P-glycoprotein (P-gp). Agents such as verapamil have been shown to increase anticancer drug cytotoxicity and increase the amount of drug accumulated and retained by such cells. We show here that in addition to verapamil, reserpine, chloroquine, quinine, quinacrine, yohimbine, vindoline, and catharanthine also enhance the cytotoxicity of vinblastine (VLB) in a multidrug resistant, human leukemic cell line, CEM/VLB1K, described here for the first time. These cells express P-gp as a doublet that is photoaffinity labeled by the analog of VLB, N(p-azido-[3-125I]salicyl)-N'-beta-aminoethylvindesine ([125I]NASV). Both reserpine and, to a lesser extent, verapamil, compete with [125I]NASV for binding to P-gp. We also found that chloroquine, quinacrine, vindoline, and catharanthine, each of which enhanced VLB cytotoxicity in CEM/VLB1K cells by 10- to 15-fold, similarly inhibited [125I]NASV labeling of P-gp. However, neither quinine nor yohimbine inhibited this labeling, and the inhibition produced by catharanthine and vindoline was the greatest or exclusively on the lower band of the P-gp doublet. Our results suggest a complex relationship between the ability of a compound to modulate MDR and its ability to compete for binding to P-gp.

  1. The expression and significance of P-glycoprotein, lung resistance protein and multidrug resistance-associated protein in gastric cancer

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    Li Yan

    2009-11-01

    Full Text Available Abstract Background To detect the expression of multidrug resistance molecules P-glycoprotein (P-gp, Lung resistnce protein (LRP and Multidrug resistance-associated protein (MRP and analyze the relationship between them and the clinico-pathological features. Methods The expressions of P-gp, LRP and MRP in formalin-fixed paraffin-embedded tissue sections from 59 gastric cancer patients were determined by a labbelled Streptavidin-Peroxidase (SP immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery. Results The positive rates of P-gp, LRP, MRP were 86.4%, 84.7% and 27.1%, respectively. The difference between the positive rate of P-gp and MRP was significant statistically, as well as the difference between the expression of MRP and LRP. No significant difference was observed between P-gp and LRP, but the positively correlation between the expression of P-gp and LRP had been found. No significant correlation between the expression of P-gp, LRP, MRP and the grade of differentiation were observed. The expression of P-gp was correlated with clinical stages positively (r = 0.742, but the difference with the expression of P-gp in different stages was not significant. Conclusion The expressions of P-gp, LRP and MRP in patients with gastric cancer without prior chemotherapy are high, indicating that innate drug resistance may exist in gastric cancer.

  2. Evaluation of commercial multi-drug oral fluid devices to identify 39 new amphetamine-designer drugs.

    Science.gov (United States)

    Nieddu, Maria; Burrai, Lucia; Trignano, Claudia; Boatto, Gianpiero

    2014-03-01

    Recently, the diffusion on the black market of new psychoactive substances not controlled and often sold as 'legal highs', is exponentially increasing in Europe. Generally, the first analysis for these drugs involves an immunoassay screening in urine or plasma. Actually, there is growing interest in the use of oral fluid (OF) as alternative specimen over conventional biological fluids for drug testing, because of the significant advantages, as a non-invasive collection under direct observation without undue embarrassment or invasion of privacy, and a good correlation with plasma analytical data. Few assays have been developed for detection of new psychoactive compounds in biological samples, so it is important to investigate how they may or may not react in pre-existing commercial immunoassays. In this paper, two different multi-drugs oral fluid screen devices (OFDs) (Screen® Multi-Drug OFD and GIMA One Step Multi-Line Screen Test OFD) were evaluated to determine the cross-reactivity of thirty-nine new amphetamine designer drugs, including twelve substances officially recognized as illicit by italian legislation. Cross-reactivity towards most drugs analyzed was <1 in assays targeting amphetamine (AMP) or methamphetamine (MET). Only two (p-methoxyamphetamine and p-methoxymethamphetamine) of all tested amphetamines gave a positive result.

  3. Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma

    Institute of Scientific and Technical Information of China (English)

    Cheng-Jiang Li; Hua-Li Zhou; Jun Li; Hong-TianYao; Rong Su; Wen-Peng Li

    2011-01-01

    BACKGROUND: Sulfonylurea receptor 1 (SUR1) and multidrug resistance protein 1 (MRP1) are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormalinsulinsecretion. METHODS: Fasting glucose, insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients. Insulin content, SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS: Insulinoma patients presented the typical demons-trations of Whipple's triad. Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L, and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose. Immunohistochemistry and immunofluorescence staining showed that SUR1 increased, but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS: The hypersecretion of insulin in insulinomas might be, at least partially, due to the enrichment of SUR1. In contrast, MRP1, which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.

  4. Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.

    Science.gov (United States)

    Veiga, Maria Isabel; Osório, Nuno S; Ferreira, Pedro Eduardo; Franzén, Oscar; Dahlstrom, Sabina; Lum, J Koji; Nosten, Francois; Gil, José Pedro

    2014-12-01

    Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance.

  5. MULTIDRUG RESISTANT BACTERIA IN A TERTIARY CARE HOS PITAL.

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    Sujata

    2012-12-01

    Full Text Available ABSTRACT: BACKGROUND: Antibiotic resistance is a global problem in the hos pitals as well as in the community. Selection pressure exerted by over use of antimicrobial agents is the commonest predisposing factor of development of resist ance. Problems faced are especially with Methicillin Resistant Staphylococcus aureus (MR SA, Vancomycin Resistant Enterococci (VRE and Multidrug resistant Gram-negative bacilli (MDR-GNB. AIMS: A study was undertaken to find out the prevalence of all bacteri a isolated in this hospital from different specimens, which are resistant to first line antibio tics and their antimicrobial susceptibility pattern with higher antibiotics during a six-month pe riod. MATERIAL AND METHODS: All isolates from different specimens were processed by s tandard techniques and identified by standard biochemical tests. Antibiotic susceptibilit y was performed on Mueller Hinton Agar (MHA by Kirby-Bauer Disc Diffusion Method (KBDDM, according to CLSI guidelines. Those resistant to first line antibiotics were further te sted for higher antibiotics. For Extended Spectrum β -lactamse (ESBL detection, double disc synergy met hod was carried out for all Gram-negative bacilli. RESULTS: Out of 2987 bacteria grown, 904 (30.3% were multi drug resistant bacteria. Resistance to first line antib iotics was 83.4% and resistance to all higher antibiotics tested was 16.6%. Sixty percent of Staph ylococcus aureus was MRSA and all were sensitive to vancomycin. Prevalence of VRE was 5.3 %. Carbapenem resistant Pseudomonas aeruginosa and Acinetobacter species were 19.1% and 9.8% respectively and 10.1% of Klebsiella species was carbapenem resistant. CONCLUSIONS: This study highlights the extensive problem of antibiotic resistance encounter ed in this hospital. Thus, prudent and appropriate uses of antibiotics are required to reduce the emergence of resistance. Each hospital should also have its own antibiotic policy based on the susceptibility pattern of

  6. Evaluation of colistin susceptibility in multidrug-resistant clinical isolates from cystic fibrosis, France.

    Science.gov (United States)

    Biswas, S; Dubus, J-C; Reynaud-Gaubert, M; Stremler, N; Rolain, J-M

    2013-11-01

    The emergence of multidrug-resistant (MDR) bacteria in cystic fibrosis (CF) patients has led to the use of colistin drug and the emergence of colistin-resistant Gram-negative bacteria. The aim of this study was to compare the disk diffusion and Etest methods for colistin susceptibility testing on MDR bacteria associated with CF from Marseille, France. Forty-nine MDR clinical isolates (27 Stenotrophomonas maltophilia, 22 Achromobacter xylosoxidans) were used in this study. Disk diffusion and Etest assays were used to assess the reliability of these two techniques. For S. maltophilia, 25 out of 27 isolates had low minimum inhibitory concentrations (MICs, 0.125-0.75 mg/L), whereas two isolates displayed high MICs (32 mg/L). Similarly, 19 out of 22 A. xylosoxidans isolates had low MICs (0.75-3.0 mg/L), whereas three isolates had high MICs (32-256 mg/L). The diameters of zone inhibition with a 50-μg colistin disk displayed a good correlation with the MICs obtained by the Etest. Susceptible and resistant strains were eventually separated using a disk diffusion assay at a cut-off of ≤ 12 mm for a 50-μg disk. Colistin displayed excellent activity against S. maltophilia and A. xylosoxidans and the disk diffusion assay could be confidently used to determine the susceptibility to colistin for MDR Gram-negative bacteria in the context of CF.

  7. [Construction and analysis of subtractive cDNA library associated with multidrug resistance of acute leukemia].

    Science.gov (United States)

    Ji, Lei; Zhang, Wang-Gang; Liu, Jie; Liu, Xin-Ping; Yao, Li-Bo

    2004-08-01

    The study was aimed to construct subtractive cDNA library associated with multidrug resistance (MDR) of acute leukemia for screening genes related to MDR in leukemia. The improved PCR-based subtractive hybridization was performed to clone differential genes between HL-60/VCR and HL-60 cell line. The mRNA of HL-60/VCR and HL-60 cell line were isolated. Then the mRNA of HL-60/VCR group was reversely transcribed into cDNA by Cap-Finder method, and the mRNA of HL-60 was reversely transcribed into cDNA by ordinary method to be marked by biotin for the hybridization next with HL-60/VCR cDNA. After hybridizing, filtrating through the sephacryl S-400 column, absorbing by the magnetic beads, and amplifying by PCR method, the fragments were cloned by T-A method and the cDNA library was constructed. Then the quality of cDNA library was identified by dot-blotting hybridization method. The results showed that after constriction, the library demonstrated its good quality. There was a high proportion of large fragments in this library. From small amount of samples a large amount of candidate fragments could be screened rapidly at once by dot-blotting hybridization. It is concluded that a differentially-expressed subtractive cDNA library in MDR of leukemia with high quality and larger fragments can be efficiently constructed by improving subtractive hybridization and selective PCR method.

  8. Multidrug Resistance Protein-4 Influences Aspirin Toxicity in Human Cell Line

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    Isabella Massimi

    2015-01-01

    Full Text Available Overexpression of efflux transporters, in human cells, is a mechanism of resistance to drug and also to chemotherapy. We found that multidrug resistance protein-4 (MRP4 overexpression has a role in reducing aspirin action in patients after bypass surgery and, very recently, we found that aspirin enhances platelet MRP4 levels through peroxisome proliferator activated receptor-α (PPARα. In the present paper, we verified whether exposure of human embryonic kidney-293 cells (Hek-293 to aspirin modifies MRP4 gene expression and its correlation with drug elimination and cell toxicity. We first investigated the effect of high-dose aspirin in Hek-293 and we showed that aspirin is able to increase cell toxicity dose-dependently. Furthermore, aspirin effects, induced at low dose, already enhance MRP4 gene expression. Based on these findings, we compared cell viability in Hek-293, after high-dose aspirin treatment, in MRP4 overexpressing cells, either after aspirin pretreatment or in MRP4 transfected cells; in both cases, a decrease of selective aspirin cell growth inhibition was observed, in comparison with the control cultures. Altogether, these data suggest that exposing cells to low nontoxic aspirin dosages can induce gene expression alterations that may lead to the efflux transporter protein overexpression, thus increasing cellular detoxification of aspirin.

  9. Use of Genotype MTBDRplus Assay for Diagnosis of Multidrug-Resistant Tuberculosis in Nepal

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    Elina Maharjan

    2017-01-01

    Full Text Available The main aims of this study were to study the patterns of mutations in rpoB, katG, and inhA genes in Mycobacterium tuberculosis strains isolated from patients from Nepal and to evaluate the performance of genotype MTBDRplus assay, taking conventional drug susceptibility testing as gold standard for diagnosis of MDR-TB. A total of 69 Mycobacterium tuberculosis strains isolated from 73 smear positive sputum samples from patients suspected of suffering from multidrug-resistant tuberculosis were used in our study. The drug susceptibility pattern of Mycobacterium tuberculosis isolated from these sputum specimens was determined by using genotype MTBDRplus assay taking conventional drug susceptibility testing as reference. The sensitivity and specificity of the genotype MTBDRplus assay for the detection of MDR-TB were found to be 88.7% and 100%, respectively. 88.7% of the rifampicin resistant isolates had mutations in rpoB gene. Similarly, 79.7% and 9.4% of isoniazid resistant isolates had mutations in katG and inhA genes, respectively. Genotype MTBDRplus assay was found to be very rapid and highly sensitive and specific method for diagnosis of MDR-TB and will be very helpful for early diagnosis of MDR-TB in high tuberculosis burden countries.

  10. MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes.

    Science.gov (United States)

    Nath, S; Daneshvar, K; Roy, L D; Grover, P; Kidiyoor, A; Mosley, L; Sahraei, M; Mukherjee, P

    2013-06-17

    MUC1 (CD227), a membrane tethered mucin glycoprotein, is overexpressed in >60% of human pancreatic cancers (PCs), and is associated with poor prognosis, enhanced metastasis and chemoresistance. The objective of this study was to delineate the mechanism by which MUC1 induces drug resistance in human (BxPC3 and Capan-1) and mouse (KCKO, KCM) PC cells. We report that PC cells that express high levels of MUC1 exhibit increased resistance to chemotherapeutic drugs (gemcitabine and etoposide) in comparison with cells that express low levels of MUC1. This chemo resistance was attributed to the enhanced expression of multidrug resistance (MDR) genes including ABCC1, ABCC3, ABCC5 and ABCB1. In particular, levels of MRP1 protein encoded by the ABCC1 gene were significantly higher in the MUC1-high PC cells. In BxPC3 and Capan-1 cells MUC1 upregulates MRP1 via an Akt-dependent pathway, whereas in KCM cells MUC1-mediated MRP1 upregulation is via an Akt-independent mechanism. In KCM, BxPC3 and Capan-1 cells, the cytoplasmic tail motif of MUC1 associates directly with the promoter region of the Abcc1/ABCC1 gene, indicating a possible role of MUC1 acting as a transcriptional regulator of this gene. This is the first report to show that MUC1 can directly regulate the expression of MDR genes in PC cells, and thus confer drug resistance.

  11. Geographic predictors of primary multidrug-resistant tuberculosis cases in an endemic area of Lima, Peru.

    Science.gov (United States)

    Shah, L; Choi, H W; Berrang-Ford, L; Henostroza, G; Krapp, F; Zamudio, C; Heymann, S J; Kaufman, J S; Ciampi, A; Seas, C; Gotuzzo, E; Brewer, T F

    2014-11-01

    Peru reports among the highest multidrug-resistant tuberculosis (MDR-TB) rates in the Americas, with a growing proportion in previously untreated tuberculosis (TB) cases. The identification of clusters of primary MDR-TB compared with drug-susceptible TB (DS-TB) could help prioritize interventions. To examine the clustering of primary MDR-TB case residences and their proximity to high-risk locations in San Juan de Lurigancho District, Lima, Peru. Enrolled primary MDR-TB and primary DS-TB cases were interviewed and their primary residence was recorded using handheld Global Positioning System devices. Kuldorff's spatial scan statistic was used for cluster detection (SaTScan(TM), v. 9.1.1). Identified clusters were visualized in Quantum Geographic Information Systems software (v1.8.0). The following cluster centers were tested: a health centre with the highest TB and MDR-TB rates (Clinic X), a hospital and two prisons. Using regression analyses, we examined predictors of primary MDR-TB cases. A statistically significant cluster of primary MDR-TB cases was identified within a 2.29 km radius around Clinic X. Proximity to Clinic X remained a significant predictor of primary MDR-TB in adjusted regression analyses. We identified a hotspot of primary MDR-TB cases around Clinic X in a TB-endemic area. Causes of this clustering require investigation; targeted interventions for this high-risk area should be considered.

  12. Multidrug Resistance 1 Gene Variants, Pesticide Exposure, and Increased Risk of DNA Damage

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    Chun-Chieh Chen

    2014-01-01

    Full Text Available The P-glycoprotein, encoded by the multidrug resistance (MDR1 gene, extrudes fat-soluble compounds to the extracellular environment. However, the DNA damage of pesticides in subjects with genetic variation in MDR1 has not been investigated. In this study, the comet assay was applied to examine the extent of DNA damage in the peripheral blood of 195 fruit growers who had been exposed to pesticides and 141 unexposed controls. The MDR1 polymorphisms were identified. Questionnaires were administered to obtain demographic data and occupational history. Results showed subjects experiencing high (2.14 μm/cell, P<0.01 or low pesticide exposure (2.18 μm/cell, P<0.01 had a significantly greater DNA tail moment than controls (1.28 μm/cell. Compared to the MDR1 T-129C (rs3213619 TC/CC carriers, the TT carriers had increased DNA tail moment in controls (1.30 versus 1.12 μm/cell, P<0.01. Similar results were observed in the high and low pesticide-exposed groups. Combined analysis revealed that pesticide-exposed fruit growers with MDR1 -129 TT genotype had the greatest DNA damage in the subjects with the combinations of pesticide exposure and MDR1 -129 genotypes. In conclusion, pesticide exposed individuals with susceptible MDR1 -129 genotypes may experience increased risk of DNA damage.

  13. Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens

    Energy Technology Data Exchange (ETDEWEB)

    Zaborin, Alexander; Defazio, Jennifer; Kade, Matthew; Kaiser, Brooke LD; Belogortseva, Natalia; Camp, David G.; Smith, Richard D.; Adkins, Joshua N.; Kim, Sangman M.; Alverdy, Alexandria; Goldfeld, David; Firestone, Millicent; Collier, Joel; Jabri, Bana; Tirrell, Matthew; Zaborina, Olga; Alverdy, John C.

    2014-02-01

    The gastrointestinal tract is the primary site of colonization for multi-drug resistant healthcare associated pathogens (HAPs) that are the principal source and cause of life-threatening infections in critically ill patients. We previously identified a high molecular weight co-polymer (PEG15-20) with mucoadhesive and cytoprotective actions on the intestinal epithelium. In this report we covalently bonded phosphate (Pi) to PEG15-20 ( termed Pi-PEG15-20) to enhance its cytoprotective activity against microbial virulence activation and invasion based on our previous work showing that Pi is a key environmental cue regulating microbial virulence across pathogens of clinical importance to hospitalized patients. We demonstrated that Pi-PEG15-20 can suppress phosphate-, iron-, and quorum sensing signal- mediated activation of bacterial virulence as well as inhibit intestinal epithelial IL-8 release during lipopolysaccharide (LPS) exposure. Pi-PEG15-20 also prevented mortality in C. elegans and mice exposed to several highly virulent and antibiotic(?)-resistant health care acquired pathogens (HAPs) while preserving the normal microbiota. Intestinal application Pi-PEG 15-20 has the potential to be a useful agent to prevent the pathogenic activation of microbes during critical illness where exposure to HAPs is ubiquitous.

  14. Multidrug resistant Escherichia coli strains isolated from urine sample, University of Gondar Hospital, Northwest Ethiopia

    Institute of Scientific and Technical Information of China (English)

    Setegn Eshetie; Fentahun Tarekegn; Gemechu Kumera; Feleke Mekonnen

    2016-01-01

    Objective: To assess multidrug resistant (MDR) Escherichia coli (E. coli) isolates from patients with urinary tract infection. Methods: From February to June 2014, a cross sectional study was conducted among urinary tract infection patients at the University of Gondar Hospital. Culture and disk diffusion method were used for E. coli isolation and to determine the antibiotic susceptibility patterns. Data were entered and analyzed using SPSS version 20. P Results: A total of 112 E. coli isolates were identified and the rate of isolation was higher among female participants (28.7%; P = 0.03). Of the isolates, 104 (92.9%) were MDR E. coli; and the isolates showed high resistance rates towards ampicillin (99%), cotrimoxazole (69%), chloramphenicol (58.7%), gentamycin (56.7%) and ceftazidime (55.8%). However, comparative isolates showed low resistance rates to ciprofloxacin (1%), cefepime (8.7%), and ceftriaxone (11.5%). Moreover, resistance rates of MDR E. coli isolates were significantly higher than non-MDR strains for ceftazidime (55.8% versus 12.5%; P = 0.015), and ampicillin (99% versus 87.5%; P = 0.018). Conclusions: High prevalence of MDR E. coli isolates was observed in this study. Regular monitoring of antibiotic resistance rates is necessarily required to improve and revise empirical antibiotic therapy protocols.

  15. Chernobyl accident and its consequences

    Energy Technology Data Exchange (ETDEWEB)

    Gittus, J.H.; Bonell, P.G.; Hicks, D.

    1987-01-01

    The USSR power reactor programme is first described. The reasons for the accident at the Chernobyl-4 RBMK nuclear reactor on 26 April 1986, the sequence of events that took place, and the immediate and long-term consequences are considered. A description of the RBMK-type reactors is given and the design changes resulting from the experience of the accident are explained. The source terms describing the details of the radioactivity release associated with the accident and the environmental consequences are covered in the last two sections of the report. Throughout the text comments referring to the UK Nuclear Installations Inspectorate Safety assessment principles have been inserted. (U.K.).

  16. Population consequences of reproductive decisions.

    Science.gov (United States)

    Smith, C; Reynolds, J D; Sutherland, W J

    2000-07-07

    Behaviour can be a key component of animal population ecology yet the population consequences of behavioural decisions are poorly understood. We conducted a behavioural and demographic study of the bitterling Rhodeus sericeus, a freshwater fish that spawns in live unionid mussels. We used a population model incorporating game theory decisions and measurements of demographic parameters in order to provide predictions of population size among 13 populations of this fish. Our model predicted that the observed behavioural spawning decisions, while maximizing individual fitness, cause a significant 6% reduction in population size compared with randomly distributed spawnings. We discuss our findings in the context of the population consequences of adaptive behaviour.

  17. Uncertainties in offsite consequence analysis

    Energy Technology Data Exchange (ETDEWEB)

    Young, M.L.; Harper, F.T.; Lui, C.H.

    1996-03-01

    The development of two new probabilistic accident consequence codes, MACCS and COSYMA, was completed in 1990. These codes estimate the consequences from the accidental releases of radiological material from hypothesized accidents at nuclear installations. In 1991, the U.S. Nuclear Regulatory Commission and the European Commission began co-sponsoring a joint uncertainty analysis of the two codes. The ultimate objective of this joint effort was to systematically develop credible and traceable uncertainty distributions for the respective code input variables using a formal expert judgment elicitation and evaluation process. This paper focuses on the methods used in and results of this on-going joint effort.

  18. Evaluation of health factors in high-rise buildings. 2. Bioclimatological consequences resulting from comparative measurements of the air ionisation in a high-rise building located in a heavily contaminated suburban area and at certain altitudes

    Energy Technology Data Exchange (ETDEWEB)

    Moese, J.R.; Fischer, G.

    1981-01-01

    According to accepted scientific theories inhaled small ions deliver their charges in the pulmonary alveoli and this leads to local recharges. This process stimulates structures of the central nervous system and the activity of the endocrine is excited, resulting in an enhancement of the general well-being. These possibilities of interpretation regarding a biological ionic effect are supported, with reservations by positive medical effects during and after a stay in a well-ventilated mountain climate or also in a sea-climate. Owing to their lower mobility the large ions are inhaled as small ions to an increasing extent. The chemical and physical noxa are delivered and deposited in the respiratory tract. They stick the epithelia in the trachea and in the bronchi as well as the endothelia in the lung vesicles. The number of the ciliary movements is reduced. Similar effects are known to be caused also by nicotine abuse. This results in a decreased ability of expectoration and a lower intake of oxygen by the alveoli. These facts could furnish an explanation for the increased vulnerability of city dwellers to infections diseases and to catarrh. The changed ionisation of air in urbanised areas definitely represents only one of the many risk factors. In addition to the attempt to characterize bioclimatically local weather conditions by means of the non-conventional parameter air ionisation our study has also been intended to establish biologically oriented criteria for the living in a high-rise building in a particularly unfavourable location. Under specific microclimatic conditions the uppermost storeys were at times bioclimatically favoured over the lowermost, especially when shallow air inversion is present. In such cases, small ions exclusively were registered in the upper storeys and large ions in the lower floors.

  19. Susceptibility of multidrug resistant clinical pathogens to a chlorhexidine formulation.

    Science.gov (United States)

    Günther, F; Kaiser, S J; Fries, T; Frank, U; Mutters, N T

    2015-01-01

    Multidrug resistant pathogens are a widespread problem in the hospital setting especially on intensive care units (ICU). This study evaluated the susceptibility of clinical isolates of gramnegative extensively drug resistant organisms (XDR), methicillinresistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) to a proprietary chlorhexidine digluconate (CHG) formulation used in one brand of CHG-impregnated cloths. Ten isolates each of XDR Pseudomonas aeruginosa, XDR Acinetobacter baumannii, XDR Klebsiella pneumoniae, XDR Escherichia coli, MRSA, and vancomycin-resistant Enterococcus faecium from our hospital were tested. All isolates were susceptible to the proprietary CHG formulation (0.5%, 1%, 2%), with 99% to 100% suppression of growth at the earliest time point in time kill assays (1 minute for gram-positive and 15 seconds for gram-negative organisms). Minimum inhibitory concentrations ranged from 1 : 4096 to 1 : 65536 for MRSA, 1 : 1024 to 1 : 2048 for VRE, 1 : 2048 to 1 : 4096 for XDR E. coli, 1 : 512 to 1 : 2048 for XDR A. baumannii, 1 : 512 to 1 : 1024 for XDR P. aeruginosa, and 1 : 512 to 1 : 1024 for XDR K. pneumoniae. Cloths impregnated with this CHG formulation provide effective protection against colonization and infection by many pathogens. This study provides in vitro evidence that the proprietary CHG formulation used in one brand of CHG-impregnated cloths is effective against XDR gram-negative organisms, MRSA, and VRE.

  20. Nanodrugs: optimism for emerging trend of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Khan AU

    2012-08-01

    Full Text Available Asad U KhanMedical Microbiology and Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, IndiaThis is with reference to an article published recently in your journal regarding the antibiotic activity of chitosan-coated silver nanoparticles.1 This is an inspiring move towards control of infection caused by multidrug-resistant bacteria which has become a serious problem for clinicians and physicians worldwide.2 At the moment, carbapenems are being used as the drugs of choice to combat infections. However, the emergence of carbapenem resistance has changed current remedial approaches in the management of serious infections. One of the latest enzymes, NDM-1 (New Delhi metallo-β-lactamase-1, first identified in a Swedish patient of Indian origin in 2008,3 has been key in the development of resistance to almost all antibiotics. Infection caused by NDM-1 producers is widespread on the Indian subcontinent,4 and is now emerging in the US and other countries throughout the world.5View original paper by Jena and colleagues.

  1. Tetracyclines for multidrug-resistant Acinetobacter baumannii infections.

    Science.gov (United States)

    Falagas, Matthew E; Vardakas, Konstantinos Z; Kapaskelis, Anastasios; Triarides, Nikolaos A; Roussos, Nikolaos S

    2015-05-01

    Multidrug-resistant (MDR) Acinetobacter baumannii infections have emerged as a serious threat worldwide. As novel agents have yet to be developed, understanding the effectiveness and safety of older antibiotics has become a priority. The purpose of this systematic review was to summarise the available clinical evidence on the use of tetracyclines for the treatment of A. baumannii infections. Ten retrospective studies regarding doxycycline and minocycline for the treatment of 185 A. baumannii infections (of which 65.4% were respiratory infections and 13% were bloodstream infections) in 156 patients were available. In most cases (86.4%), tetracyclines were administered in combination with another agent. The usual dosage of doxycycline or minocycline was 100mg intravenous or per os twice daily (usually with a 200mg loading dose for minocycline). Clinical success was achieved in 120 (76.9%) of 156 patients; in 87 (71.9%) of 121 respiratory infections and in 21 (87.5%) of 24 bloodstream infections. Twenty-two deaths occurred in 100 recorded cases. Microbiological eradication was attained in 72 (71.3%) of 101 available cases and documented microbiological eradication was reached in 59 (66.3%) of 89 available cases. Adverse events were noted in only 1 of 88 cases. Overall, although tetracycline-containing regimens showed encouraging results, more data from larger comparative trials are required to establish a role for these antibiotics in the treatment of MDR A. baumannii infections.

  2. Marine Natural Products as Models to Circumvent Multidrug Resistance.

    Science.gov (United States)

    Long, Solida; Sousa, Emília; Kijjoa, Anake; Pinto, Madalena M M

    2016-07-08

    Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

  3. Intracellular pH and the Control of Multidrug Resistance

    Science.gov (United States)

    Simon, Sanford; Roy, Deborshi; Schindler, Melvin

    1994-02-01

    Many anticancer drugs are classified as either weak bases or molecules whose binding to cellular structures is pH dependent. Accumulation of these drugs within tumor cells should be affected by transmembrane pH gradients. Indeed, development of multidrug resistance (MDR) in tumor cells has been correlated with an alkaline shift of cytosolic pH. To examine the role of pH in drug partitioning, the distribution of two drugs, doxorubicin and daunomycin, was monitored in fibroblasts and myeloma cells. In both cell types the drugs rapidly accumulated within the cells. The highest concentrations were measured in the most acidic compartments-e.g., lysosomes. Modifying the cellular pH in drug-sensitive cells to mimic reported shifts in MDR caused an immediate change in the cellular drug concentration. Drug accumulation was enhanced by acidic shifts and reversed by alkaline shifts. All of these effects were rapid and reversible. These results demonstrate that the alkaline shift observed in MDR is sufficient to prevent the accumulation of chemotherapeutic drugs independent of active drug efflux.

  4. Imaging multidrug resistance with 4-[18F]fluoropaclitaxel.

    Science.gov (United States)

    Kurdziel, Karen A; Kalen, Joseph D; Hirsch, Jerry I; Wilson, John D; Agarwal, Rakesh; Barrett, Daniel; Bear, Harry D; McCumiskey, James F

    2007-10-01

    Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[18F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.

  5. Imaging multidrug resistance with 4-[{sup 18}F]fluoropaclitaxel

    Energy Technology Data Exchange (ETDEWEB)

    Kurdziel, Karen A. [Department of Radiology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: kurdziel@vcu.edu; Kalen, Joseph D. [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: jdkalen@vcu.edu; Hirsch, Jerry I. [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: jihirsch@vcu.edu; Wilson, John D. [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: wilsonjd@hsc.vcu.edu; Agarwal, Rakesh [Surgical Oncology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: dbarrett@vcu.edu; Barrett, Daniel [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: ragarwal@vcu.edu; Bear, Harry D. [Surgical Oncology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: 9jmccumi@mail2.vcu.edu; McCumiskey, James F. [Department of Radiology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: hbear@hsc.vcu.edu

    2007-10-15

    Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[{sup 18}F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.

  6. Multidrug resistant Gram-negative bacilli in lower respiratory tract infections.

    Science.gov (United States)

    Vishwanath, Shashidhar; Chawla, Kiran; Gopinathan, Anusha

    2013-12-01

    Lower respiratory tract infections are among important causes of morbidity and mortality for all age groups. The emergence of multidrug resistant Gram-negative bacilli is an issue of increasing concern. A retrospective study including respiratory specimens (sputum and BAL) was conducted in our tertiary care centre. Samples were processed for microscopy, culture and susceptibility testing following standard methods. Multidrug resistant Gram-negative bacilli causing lower respiratory tract infections were studied for their causation of disease. The effect of appropriate treatment on clinical outcome was observed. A total of 472 Gram-negative pathogens were isolated from sputum and broncho-alveolar lavage fluid specimens during the study period. Among these Gram-negative pathogens 175 (37%) were found to be multidrug resistant. Klebsiella pneumoniae 85 (48.6%) and Acinetobacter spp. 59 (33.7%) were the predominant multidrug resistant Gram-negative bacilli isolated. Based on clinico-microbiological correlation, 138 (78.9%) multidrug resistant isolates were found to be pathogenic and the rest 37 (21.1%) were considered as colonizers. After initiating appropriate antibiotic therapy, clinical improvement was seen in 110 (79.7%) patients. In the patients who showed improvement, amikacin (34.3%) and cefoperazone-sulbactum (21.8%) were found to be the most effective drugs. A large majority of the isolated multidrug resistant Gram-negative bacilli were found to be pathogenic. Regular surveillance which directs appropriate empirical therapy; and good clinic-microbiological workup of each case of lower respiratory tract infection can reduce the morbidity and mortality associated with multidrug resistant organisms.

  7. [Fosfomycin--its significance for treatment of diseases due to multidrug-resistant bacteria].

    Science.gov (United States)

    Stock, Ingo

    2015-01-01

    Fosfomycin is a bactericidal phosphonic acid derivative, which engages by inhibiting pyruvyltransferase at an early stage in the peptidoglycan synthesis. It shows a broad spectrum of activity that includes many multidrug-resistant gram-negative and gram-positive bacteria. Fosfomycin is active against most strains of Pseudomonas aeruginosa and several multidrug-resistant Enterobacteriaceae, e.g., Escherichia coli strains expressing extended spectrum beta-lactamases (ESBL) and Klebsiella pneumoniae strains with decreased susceptibilities to carbapenems. Most methicillin-resistant Staphylococcus aureus (MRSA) strains as well as enterococci with and without vancomycin resistance are also sensitive to fosfomycin. During the last decade, a variety of studies showed that fosfomycin is not only suitable for treating uncomplicated urinary tract diseases, but also for the treatment of many other diseases caused by bacterial pathogens with and without multidrug resistance. However, large controlled studies demonstrating the efficacy of the drug to treat diseases caused by multidrug-resistant bacteria are still missing. Considering the low number of antibacterial agents with good activity against multidrug-resistant bacteria, fosfomycin should be evaluated as an important antibiotic for the treatment of several severe illnesses due to these pathogens. However, because some multidrug-resistant bacteria are also resistant to fosfomycin, this agent should only be applied if the pathogen is sensitive to this drug. In addition, because rapid development of resistance cannot be excluded if fosfomycin will be applied alone, this drug should only be given in combination with other effective drugs for the treatment of serious systemic diseases due to multidrug-resistant bacterial pathogens.

  8. Multidrug resistant Gram-negative bacilli in lower respiratory tract infections.

    Directory of Open Access Journals (Sweden)

    Shashidhar Vishwanath

    2013-12-01

    Full Text Available Lower respiratory tract infections are among important causes of morbidity and mortality for all age groups. The emergence of multidrug resistant Gram-negative bacilli is an issue of increasing concern.A retrospective study including respiratory specimens (sputum and BAL was conducted in our tertiary care centre. Samples were processed for microscopy, culture and susceptibility testing following standard methods. Multidrug resistant Gram-negative bacilli causing lower respiratory tract infections were studied for their causation of disease. The effect of appropriate treatment on clinical outcome was observed.A total of 472 Gram-negative pathogens were isolated from sputum and broncho-alveolar lavage fluid specimens during the study period. Among these Gram-negative pathogens 175 (37% were found to be multidrug resistant. Klebsiella pneumoniae 85 (48.6% and Acinetobacter spp. 59 (33.7% were the predominant multidrug resistant Gram-negative bacilli isolated. Based on clinico-microbiological correlation, 138 (78.9% multidrug resistant isolates were found to be pathogenic and the rest 37 (21.1% were considered as colonizers. After initiating appropriate antibiotic therapy, clinical improvement was seen in 110 (79.7% patients. In the patients who showed improvement, amikacin (34.3% and cefoperazone-sulbactum (21.8% were found to be the most effective drugs.A large majority of the isolated multidrug resistant Gram-negative bacilli were found to be pathogenic. Regular surveillance which directs appropriate empirical therapy; and good clinic-microbiological workup of each case of lower respiratory tract infection can reduce the morbidity and mortality associated with multidrug resistant organisms.

  9. Temporal fluctuation of multidrug resistant salmonella typhi haplotypes in the mekong river delta region of Vietnam.

    Directory of Open Access Journals (Sweden)

    Kathryn E Holt

    Full Text Available BACKGROUND: typhoid fever remains a public health problem in Vietnam, with a significant burden in the Mekong River delta region. Typhoid fever is caused by the bacterial pathogen Salmonella enterica serovar Typhi (S. Typhi, which is frequently multidrug resistant with reduced susceptibility to fluoroquinolone-based drugs, the first choice for the treatment of typhoid fever. We used a GoldenGate (Illumina assay to type 1,500 single nucleotide polymorphisms (SNPs and analyse the genetic variation of S. Typhi isolated from 267 typhoid fever patients in the Mekong delta region participating in a randomized trial conducted between 2004 and 2005. PRINCIPAL FINDINGS: the population of S. Typhi circulating during the study was highly clonal, with 91% of isolates belonging to a single clonal complex of the S. Typhi H58 haplogroup. The patterns of disease were consistent with the presence of an endemic haplotype H58-C and a localised outbreak of S. Typhi haplotype H58-E2 in 2004. H58-E2-associated typhoid fever cases exhibited evidence of significant geo-spatial clustering along the Sông H u branch of the Mekong River. Multidrug resistance was common in the established clone H58-C but not in the outbreak clone H58-E2, however all H58 S. Typhi were nalidixic acid resistant and carried a Ser83Phe amino acid substitution in the gyrA gene. SIGNIFICANCE: the H58 haplogroup dominates S. Typhi populations in other endemic areas, but the population described here was more homogeneous than previously examined populations, and the dominant clonal complex (H58-C, -E1, -E2 observed in this study has not been detected outside Vietnam. IncHI1 plasmid-bearing S. Typhi H58-C was endemic during the study period whilst H58-E2, which rarely carried the plasmid, was only transient, suggesting a selective advantage for the plasmid. These data add insight into the outbreak dynamics and local molecular epidemiology of S. Typhi in southern Vietnam.

  10. Evaluation of antibacterial efficacy of anise wastes against some multidrug resistant bacterial isolates

    Directory of Open Access Journals (Sweden)

    Mohamed Khaled Ibrahim

    2017-01-01

    Full Text Available Antibiotic resistance in bacteria is becoming a serious problem, especially after the emergence of multidrug-resistant strains. To overcome this problem, new and effective antibacterials or resistance modulators are highly needed and plant kingdom represents a valuable source of these compounds. In this study we investigated the antibacterial and resistance modulatory activity of Aniseeds waste Residue Extract (ASWRE and Star Anise Waste Residue Extract (SAWRE (post-distillation against 100 isolates belonging to two Gram positive (Streptococcus pneumoniae and Staphylococcus aureus and four Gram negative bacteria (Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa. Phenolic compounds of anise wastes were determined by HPLC. The antibacterial activity of anise waste extracts assays were performed by using inhibition zone diameters, MIC and MBC. Evaluation of synergy interaction between anise waste extracts and certain known antibacterial drugs like Cephradine, Chloramphenicol, Tetracycline and Amoxicillin was carried out using disc diffusion method, MIC and the fractional inhibitory concentrations (FIC. The results showed that HPLC method has been developed for the determination of 25 phenolic compounds from waste extracts. Both ASWRE and SAWRE have significant antibacterial activity against all of the test bacteria. SAWRE was found to have higher amounts of phenolic compounds contents that might be responsible for their comparatively higher antibacteria activity than ASWRE. Irradiation at 10 and 30 kGy did not significantly affect the antibacterial activity of both ASWRE and SAWRE. The combination of anise waste extracts and the tested antibiotics mostly showed synergistic effect. Synergistic interaction was most expressed against Streptococcus pneumoniae (Sp1 and Staphylococcus aureus (Sa1 by Tetracycline and chloramphenicol; Pseudomonas aeruginosa (P2, Klebsiella pneumoniae (K3, Acinetobacter baumannii

  11. Multidrug-resistant organisms in refugees: prevalences and impact on infection control in hospitals

    Science.gov (United States)

    Heudorf, Ursel; Albert-Braun, Sabine; Hunfeld, Klaus-Peter; Birne, Franz-Ulrich; Schulze, Jörg; Strobel, Klaus; Petscheleit, Knut; Kempf, Volkhard A. J.; Brandt, Christian

    2016-01-01

    Introduction: The refugee crisis is a great challenge to the social and healthcare system in European countries, especially in Germany. An abundance of data has been published on the refugees’ health problems (infections as well as physical diseases and psychiatric problems) and their prevention (i.e., sanitary and vaccination programs). However, data on prevalences of multidrug-resistant organisms (MDRO) in refugees are scarce, although it is known that most refugees are from or travelled through countries with high prevalences of MDRO. This paper presents current data on MDRO colonization of refugees admitted to hospitals, and the impact of screening upon admission and infection control in hospitals is discussed. Methods: Anonymous data obtained by screening upon hospital admission were reported by hospitals in the Rhine-Main region of Germany to the local public health department. Screening and microbiological analyses were performed from December 2015 to March 2016 according to standardized and validated methods. Results: 9.8% of the refugees screened (32/325) exhibited colonization with methicillin-resistant Staphylococcus aureus (MRSA), and 23.3% of the refugees (67/290) were colonized with Gram-negative bacteria with extended spectrum beta-lactamases, and/or enterobacteria with resistance against 3 or 4 groups of antibacterials, so-called 3MRGN (multidrug-resistant Gram-negative bacteria with resistance against penicillins, cephalosporins and quinolones) and 4MRGN (with additional resistance against carbapenems). Carbapenem-resistant Gram-negative bacteria (CRGN) were detected in 2.1% (6/290) of the refugees. Conclusion: The data confirms the studies published between 2014 and 2016, encompassing refugees tested in Germany, the Netherlands and Israel, with prevalences of MRSA and CRGN up to 13.5% and 5.6%. The MDRO prevalences are higher than those of “risk groups” for MRSA, such as hemodialysis patients and patients depending on outpatient home

  12. Literacy in Somali: Linguistic Consequences.

    Science.gov (United States)

    Biber, Douglas; Hared, Mohamed

    1991-01-01

    Linguistic consequences of literacy in Somalia are examined in a review of the literature and through a study of five dimensions of variation among Somali registers and the expansion of linguistic variation in Somali resulting from the introduction of written registers. (36 references) (LB)

  13. Sex differences in consequences of musculoskeletal pain.

    Science.gov (United States)

    Wijnhoven, Hanneke A H; de Vet, Henrica C W; Picavet, H Susan J

    2007-05-20

    Cross-sectional population-based study. To study sex differences in consequences of musculoskeletal pain (MP): limited functioning, work leave or disability, and healthcare use. MP is a major public health problem in developed countries due to high prevalence rates and considerable consequences. There are indications that consequences of MP differ for men and women. Data of a Dutch population-based study were used, limited to persons 25 to 64 years of age (n = 2517). Data were collected by a postal questionnaire. Women with any MP report more healthcare use for MP, i.e., contact with a medical caregiver and use of medicines than men, while men report more work disability (ever in life) due to low back pain only, irrespective of work status. None of the sex differences can be explained by age, household composition, educational level, smoking status, overweight, physical activity, and pain catastrophizing. Older age was related to more limited functioning due to MP (women), work disability due to MP (men), and healthcare use due to MP (men and women). A one-person household was associated with work disability (women) and use of medicines (men). Low educational level was associated with limited functioning (men), work leave (men), contact with a medical caregiver (men), and work disability (men and women). Smoking was associated with limited functioning (men), work leave (women), and healthcare use (women). Physical inactivity was associated with limited functioning due to MP in women. Pain catastrophizing was associated with limited functioning, work leave, and healthcare use (men and women) and work disability (men). Consequences of MP show a slightly different pattern for men and women. Women with any MPreport more healthcare use for MP, while men report more work disability due to low back pain only. These sex differences can not be explained by general risk factors, but associations between these factors and consequences of MP show some sex differences.

  14. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2)

    DEFF Research Database (Denmark)

    Litman, Thomas; Brangi, M; Hudson, E;

    2000-01-01

    known as ABCP1 or BCRP. The pharmacodynamics of mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines. We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR...... by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantrone......, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells. Thus...

  15. Multidrug resistance 1 gene polymorphisms may determine Crohn's disease behavior in patients from Rio de Janeiro

    Directory of Open Access Journals (Sweden)

    Ana Teresa P. Carvalho

    2014-01-01

    Full Text Available OBJECTIVES: Conflicting data from studies on the potential role of multidrug resistance 1 gene polymorphisms in inflammatory bowel disease may result from the analysis of genetically and geographically distinct populations. Here, we investigated whether multidrug resistance 1 gene polymorphisms are associated with inflammatory bowel diseases in patients from Rio de Janeiro. METHODS: We analyzed 123 Crohn's disease patients and 83 ulcerative colitis patients to determine the presence of the multidrug resistance 1 gene polymorphisms C1236T, G2677T and C3435T. In particular, the genotype frequencies of Crohn's disease and ulcerative colitis patients were analyzed. Genotype-phenotype associations with major clinical characteristics were established, and estimated risks were calculated for the mutations. RESULTS: No significant difference was observed in the genotype frequencies of the multidrug resistance 1 G2677T/A and C3435T polymorphisms between Crohn's disease and ulcerative colitis patients. In contrast, the C1236T polymorphism was significantly more common in Crohn's disease than in ulcerative colitis (p = 0.047. A significant association was also found between the multidrug resistance 1 C3435T polymorphism and the stricturing form of Crohn's disease (OR: 4.13; p = 0.009, whereas no association was found with penetrating behavior (OR: 0.33; p = 0.094. In Crohn's disease, a positive association was also found between the C3435T polymorphism and corticosteroid resistance/refractoriness (OR: 4.14; p = 0.010. However, no significant association was found between multidrug resistance 1 gene polymorphisms and UC subphenotypic categories. CONCLUSION: The multidrug resistance 1 gene polymorphism C3435T is associated with the stricturing phenotype and an inappropriate response to therapy in Crohn's disease. This association with Crohn's disease may support additional pathogenic roles for the multidrug resistance 1 gene in regulating gut

  16. Inhibition of the multidrug resistance P-glycoprotein: time for a change of strategy?

    Science.gov (United States)

    Callaghan, Richard; Luk, Frederick; Bebawy, Mary

    2014-04-01

    P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to "block" P-gp-mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application.

  17. International travel and acquisition of multidrug-resistant Enterobacteriaceae: a systematic review.

    Science.gov (United States)

    Hassing, Robert Jan; Alsma, Jelmer; Arcilla, Maris S; van Genderen, Perry J; Stricker, Bruno H; Verbon, Annelies

    2015-01-01

    International travel is considered to be an important risk factor for acquisition of multidrug-resistant Enterobacteriaceae (MRE). The aim of this systematic review was to determine the effect of international travel on the risk of post-travel faecal carriage of MRE. Secondary outcomes were risk factors for acquisition of MRE. A systematic search for relevant literature in seven international databases was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles needed to report on (i) foreign travel, (ii) screening of asymptomatic participants, (iii) antimicrobial susceptibility data and (iv) faecal Enterobacteriaceae carriage. Two researchers independently screened the abstracts, assessed the full article texts for eligibility and selected or rejected them for inclusion in the systematic review. In case of disagreement, a third researcher decided on inclusion. Eleven studies were identified. In all studies, a high prevalence (>20%) of carriage of MRE after international travel was found. The highest prevalence was observed in travellers returning from southern Asia. Foreign travel was associated with an increased risk of carriage of MRE. Further research is needed to assess if this leads to an increase in the number of infections with MRE. Systematic review registration number: PROSPERO CRD42015024973.

  18. Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance

    Science.gov (United States)

    Obolski, Uri; Stein, Gideon Y.; Hadany, Lilach

    2015-01-01

    High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used—mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists. PMID:26110266

  19. Carbapenemase Genes among Multidrug Resistant Gram Negative Clinical Isolates from a Tertiary Hospital in Mwanza, Tanzania

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    Martha F. Mushi

    2014-01-01

    Full Text Available The burden of antimicrobial resistance (AMR is rapidly growing across antibiotic classes, with increased detection of isolates resistant to carbapenems. Data on the prevalence of carbapenem resistance in developing countries is limited; therefore, in this study, we determined the prevalence of carbapenemase genes among multidrug resistant gram negative bacteria (MDR-GNB isolated from clinical specimens in a tertiary hospital in Mwanza, Tanzania. A total of 227 MDR-GNB isolates were analyzed for carbapenem resistance genes. For each isolate, five different PCR assays were performed, allowing for the detection of the major carbapenemase genes, including those encoding the VIM-, IMP-, and NDM-type metallo-beta-lactamases, the class A KPC-type carbapenemases, and the class D OXA-48 enzyme. Of 227 isolates, 80 (35% were positive for one or more carbapenemase gene. IMP-types were the most predominant gene followed by VIM, in 49 (21.59% and 28 (12% isolates, respectively. Carbapenemase genes were most detected in K. pneumoniae 24 (11%, followed by P. aeruginosa 23 (10%, and E. coli with 19 isolates (8%. We have demonstrated for the first time a high prevalence of MDR-GNB clinical isolates having carbapenem resistance genes in Tanzania. We recommend routine testing for carbapenem resistance among the MDR-GNB particularly in systemic infections.

  20. Evolution and Epidemiology of Multidrug-Resistant Klebsiella pneumoniae in the United Kingdom and Ireland

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    Danesh Moradigaravand

    2017-02-01

    Full Text Available Klebsiella pneumoniae is a human commensal and opportunistic pathogen that has become a leading causative agent of hospital-based infections over the past few decades. The emergence and global expansion of hypervirulent and multidrug-resistant (MDR clones of K. pneumoniae have been increasingly reported in community-acquired and nosocomial infections. Despite this, the population genomics and epidemiology of MDR K. pneumoniae at the national level are still poorly understood. To obtain insights into these, we analyzed a systematic large-scale collection of invasive MDR K. pneumoniae isolates from hospitals across the United Kingdom and Ireland. Using whole-genome phylogenetic analysis, we placed these in the context of previously sequenced K. pneumoniae populations from geographically diverse countries and identified their virulence and drug resistance determinants. Our results demonstrate that United Kingdom and Ireland MDR isolates are a highly diverse population drawn from across the global phylogenetic tree of K. pneumoniae and represent multiple recent international introductions that are mainly from Europe but in some cases from more distant countries. In addition, we identified novel genetic determinants underlying resistance to beta-lactams, gentamicin, ciprofloxacin, and tetracyclines, indicating that both increased virulence and resistance have emerged independently multiple times throughout the population. Our data show that MDR K. pneumoniae isolates in the United Kingdom and Ireland have multiple distinct origins and appear to be part of a globally circulating K. pneumoniae population.