144 research outputs found
Convergence of Staphylococcus aureus Persister and Biofilm Research: Can Biofilms Be Defined as Communities of Adherent Persister Cells?
P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice
The ATP-binding cassette transporters P-glycoprotein (ABCB1, MDR1) and multidrug resistance protein 4 (MRP4) efflux irinotecan and its active metabolite SN-38 in vitro, and thus may contribute to system clearance of these compounds. Mdr1a/b(-/-), Mrp4(-/-), and wild-type mice were administered 20 or 40 mg/kg irinotecan, and plasma samples were collected for 6 hours. Irinotecan and SN-38 lactone and carboxylate were quantitated and data were analyzed with nonlinear mixed-effects modeling. Mdr1a/b genotype was a significant covariate for the clearance of both irinotecan lactone and SN-38 lactone. Exposures to irinotecan lactone and SN-38 lactone after a 40 mg/kg dose were 1.6-fold higher in Mdr1a/b(-/-) mice compared to wild-type mice. Plasma concentrations of irinotecan lactone, irinotecan carboxylate, and SN-38 lactone in Mrp4(-/-) mice were similar to the wild-type controls. These results suggest that P-gp plays a role in irinotecan and SN-38 elimination, but Mrp4 does not affect irinotecan or SN-38 plasma pharmacokinetics.Fil: Tagen, Michael. St. Jude Children's Research Hospital; Estados UnidosFil: Zhuang, Yanli. St. Jude Children's Research Hospital; Estados UnidosFil: Zhang, Fan. St. Jude Children's Research Hospital; Estados UnidosFil: Harstead, K. Elaine. St. Jude Children's Research Hospital; Estados UnidosFil: Shen, Jun. St. Jude Children's Research Hospital; Estados UnidosFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentina. St. Jude Children's Research Hospital; Estados UnidosFil: Fraga, Charles H.. St. Jude Children's Research Hospital; Estados UnidosFil: Panetta, John C.. St. Jude Children's Research Hospital; Estados UnidosFil: Waters, Christopher M.. St. Jude Children's Research Hospital; Estados UnidosFil: Stewart, Clinton F.. St. Jude Children's Research Hospital; Estados Unido
Redeploying ÎČ-lactam antibiotics as a novel antivirulence strategy for the treatment of methicillin-resistant <i>Staphylococcus aureus</i> infections
Innovative approaches to the use of existing antibiotics is an important strategy in efforts to address the escalating antimicrobial resistance crisis. We report a new approach to the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections by demonstrating that oxacillin can be used to significantly attenuate the virulence of MRSA despite the pathogen being resistant to this drug. Using mechanistic in vitro assays and in vivo models of invasive pneumonia and sepsis, we show that oxacillin-treated MRSA strains are significantly attenuated in virulence. This effect is based primarily on the oxacillin-dependent repression of the accessory gene regulator quorum-sensing system and altered cell wall architecture, which in turn lead to increased susceptibility to host killing of MRSA. Our data indicate that beta-lactam antibiotics should be included in the treatment regimen as an adjunct antivirulence therapy for patients with MRSA infections. This would represent an important change to current clinical practice for treatment of MRSA infection, with the potential to significantly improve patient outcomes in a safe, cost-effective manner
A High-Resolution Multimode Digital Microscope System
In this chapter we describe the development of a high-resolution, multimode digital imaging
system based on a wide-field epifluorescent and transmitted light microscope and a cooled
charge-coupled device (CCD) camera. Taylor and colleagues (Farkas et al., 1993; Taylor et
al., 1992) have reviewed the advantages of using multiple optical modes to obtain
quantitative information about cellular processes and described instrumentation they have
developed for multimode digital imaging. The instrument described here is somewhat
specialized for our microtubule and mitosis studies, but it is also applicable to a variety of
problems in cellular imaging including tracking proteins fused to the green fluorescent
protein (GFP) in live cells (Cubitt et al., 1995; Heim and Tsien, 1996; Olson et al., 1995).
For example, the instrument has been valuable for correlating the assembly dynamics of
individual cytoplasmic microtubules (labeled by conjugating X-rhodamine to tubulin) with
the dynamics of membranes of the endoplasmic reticulum (ER, labeled with DiOC6) and the
dynamics of the cell cortex [by differential interference contrast (DIC)] in migrating
vertebrate epithelial cells (Waterman-Storer and Salmon, 1997). The instrument has also
been important in the analysis of mitotic mutants in the powerful yeast genetic system
Saccharo-myces cerevisiae. Yeast cells are a major challenge for high-resolution imaging of
nuclear or microtubule dynamics because the preanaphase nucleus is only about 2 ÎŒm wide
in a cell about 6 ÎŒm wide. We have developed methods for visualizing nuclear and spindle
dynamics during the cell cycle using high-resolution digitally enhanced DIC (DE-DIC)
imaging (Yang et al., 1997; Yeh et al., 1995). Using genetic and molecular techniques.
Bloom and coworkers (Shaw et al., 1997a,b) have been able to label the cytoplasmic astral
microtubules in dividing yeast cells by expression of cytoplasmic dynein fused to GFP.
Overlays of GFP and DIC images of dividing cells have provided the opportunity to see for
the first time the dynamics of cytoplasmic microtubules in live yeast cells and how these
dynamics and microtubule interactions with the cell cortex change with mitotic cell cycle
events in wild-type and in mutant strains (Shaw et al., 1997a,b)
Concepts émergents dans le référentiel de compétences CanMEDS pour les médecins
Background: The CanMEDS physician competency framework will be updated in 2025. The revision occurs during a time of disruption and transformation to society, healthcare, and medical education caused by the COVID-19 pandemic and growing acknowledgement of the impacts of colonialism, systemic discrimination, climate change, and emerging technologies on healthcare and training. To inform this revision, we sought to identify emerging concepts in the literature related to physician competencies.
Methods: Emerging concepts were defined as ideas discussed in the literature related to the roles and competencies of physicians that are absent or underrepresented in the 2015 CanMEDS framework. We conducted a literature scan, title and abstract review, and thematic analysis to identify emerging concepts. Metadata for all articles published in five medical education journals between October 1, 2018 and October 1, 2021 were extracted. Fifteen authors performed a title and abstract review to identify and label underrepresented concepts. Two authors thematically analyzed the results to identify emerging concepts. A member check was conducted.
Results: 1017 of 4973 (20.5%) of the included articles discussed an emerging concept. The thematic analysis identified ten themes: Equity, Diversity, Inclusion, and Social Justice; Anti-racism; Physician Humanism; Data-Informed Medicine; Complex Adaptive Systems; Clinical Learning Environment; Virtual Care; Clinical Reasoning; Adaptive Expertise; and Planetary Health. All themes were endorsed by the authorship team as emerging concepts.
Conclusion: This literature scan identified ten emerging concepts to inform the 2025 revision of the CanMEDS physician competency framework. Open publication of this work will promote greater transparency in the revision process and support an ongoing dialogue on physician competence. Writing groups have been recruited to elaborate on each of the emerging concepts and how they could be further incorporated into CanMEDS 2025.Contexte : Le rĂ©fĂ©rentiel de compĂ©tences CanMEDS pour les mĂ©decins sera mis Ă jour en 2025. Cette rĂ©vision intervient Ă un moment oĂč la sociĂ©tĂ©, les soins de santĂ© et lâenseignement mĂ©dical sont bouleversĂ©s et en pleine mutation Ă cause de la pandĂ©mie de la COVID-19; on est aussi Ă lâheure oĂč lâon reconnaĂźt de plus en plus les effets du colonialisme, de la discrimination systĂ©mique, des changements climatiques et des nouvelles technologies sur les soins de santĂ© et la formation des mĂ©decins. Pour Ă©clairer cette rĂ©vision, nous avons tentĂ© dâextraire de la littĂ©rature scientifique les concepts Ă©mergents se rapportant aux compĂ©tences des mĂ©decins.
MĂ©thodes : Les concepts Ă©mergents ont Ă©tĂ© dĂ©finis comme des idĂ©es ayant trait aux rĂŽles et aux compĂ©tences des mĂ©decins qui sont dĂ©battues dans la littĂ©rature, mais qui sont absentes ou sous-reprĂ©sentĂ©es dans le cadre CanMEDS 2015. Nous avons rĂ©alisĂ© une recherche documentaire, un examen des titres et des rĂ©sumĂ©s, et une analyse thĂ©matique pour repĂ©rer les concepts Ă©mergents. Les mĂ©tadonnĂ©es de tous les articles publiĂ©s dans cinq revues dâĂ©ducation mĂ©dicale entre le 1er octobre 2018 et le 1er octobre 2021 ont Ă©tĂ© extraites. Quinze auteurs ont effectuĂ© un examen des titres et des rĂ©sumĂ©s pour relever et Ă©tiqueter les concepts sous-reprĂ©sentĂ©s. Deux auteurs ont procĂ©dĂ© Ă une analyse thĂ©matique des rĂ©sultats pour dĂ©gager les concepts Ă©mergents. Une vĂ©rification a Ă©tĂ© faite par les membres de lâĂ©quipe.
RĂ©sultats : Parmi les 4973 articles dĂ©pouillĂ©s, 1017 (20,5 %) abordaient un concept Ă©mergent. Les dix thĂšmes suivants sont ressortis de lâanalyse thĂ©matique : lâĂ©quitĂ©, la diversitĂ©, lâinclusion et la justice sociale; lâantiracisme; humanisme des mĂ©decin; la mĂ©decine fondĂ©e sur les donnĂ©es; les systĂšmes adaptatifs complexes; lâenvironnement de lâapprentissage clinique; les soins virtuels; le raisonnement clinique; lâexpertise adaptative; et la santĂ© planĂ©taire. Lâensemble de ces thĂšmes ont Ă©tĂ© approuvĂ©s comme concepts Ă©mergents par lâĂ©quipe de rĂ©daction.
Conclusion : Cet examen de la littĂ©rature a permis de relever dix concepts Ă©mergents qui peuvent servir Ă Ă©clairer la rĂ©vision du rĂ©fĂ©rentiel de compĂ©tences CanMEDS pour les mĂ©decins qui aura lieu en 2025. La publication en libre accĂšs de ce travail favorisera la transparence du processus de rĂ©vision et le dialogue continu sur les compĂ©tences des mĂ©decins. Des groupes de rĂ©daction ont Ă©tĂ© recrutĂ©s pour dĂ©velopper chacun des concepts Ă©mergents et pour examiner la façon dont ils pourraient ĂȘtre intĂ©grĂ©s dans la version du rĂ©fĂ©rentiel CanMEDS de 2025
Evolutionary trade-offs associated with loss of PmrB function in host-adapted <i>Pseudomonas aeruginosa</i>
Pseudomonas aeruginosa colonises the upper airway of cystic fibrosis (CF) patients, providing a reservoir of host-adapted genotypes that subsequently establish chronic lung infection. We previously experimentally-evolved P. aeruginosa in a murine model of respiratory tract infection and observed early-acquired mutations in pmrB, encoding the sensor kinase of a two-component system that promoted establishment and persistence of infection. Here, using proteomics, we show downregulation of proteins involved in LPS biosynthesis, antimicrobial resistance and phenazine production in pmrB mutants, and upregulation of proteins involved in adherence, lysozyme resistance and inhibition of the chloride ion channel CFTR, relative to wild-type strain LESB65. Accordingly, pmrB mutants are susceptible to antibiotic treatment but show enhanced adherence to airway epithelial cells, resistance to lysozyme treatment, and downregulate host CFTR expression. We propose that P. aeruginosa pmrB mutations in CF patients are subject to an evolutionary trade-off, leading to enhanced colonisation potential, CFTR inhibition, and resistance to host defences, but also to increased susceptibility to antibiotics.</p
Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons: Effects on Gastroschisis among Offspring in the National Birth Defects Prevention Study
Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted
International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999
Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the âconditionalityâ terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd
Airborne dust and high temperatures are risk factors for invasive bacterial disease
Background The Sahel region of West Africa has the highest bacterial meningitis attack and case fatality rate in the world. The effect of climatic factors on patterns of invasive respiratory bacterial disease is not well documented. Objective We aimed to assess the link between climatic factors and occurrence of invasive respiratory bacterial disease in a Sahel region of Niger. Methods We conducted daily disease surveillance and climatic monitoring over an 8-year period between January 1, 2003, and December 31, 2010, in Niamey, Niger, to determine risk factors for bacterial meningitis and invasive bacterial disease. We investigated the mechanistic effects of these factors on Streptococcus pneumoniae infection in mice. Results High temperatures and low visibility (resulting from high concentrations of airborne dust) were identified as significant risk factors for bacterial meningitis. Dust inhalation or exposure to high temperatures promoted progression of stable asymptomatic pneumococcal nasopharyngeal carriage to pneumonia and invasive disease. Dust exposure significantly reduced phagocyte-mediated bacterial killing, and exposure to high temperatures increased release of the key pneumococcal toxin pneumolysin through increased bacterial autolysis. Conclusion Our findings show that climatic factors can have a substantial influence on infectious disease patterns, altering density of pneumococcal nasopharyngeal carriage, reducing phagocytic killing, and resulting in increased inflammation and tissue damage and consequent invasiveness. Climatic surveillance should be used to forecast invasive bacterial disease epidemics, and simple control measures to reduce particulate inhalation might reduce the incidence of invasive bacterial disease in regions of the world exposed to high temperatures and increased airborne dust
Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study
There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring
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