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Waterloo
Waterloo was the last battle fought by Napoleon and the one which finally ended his imperial dreams. It involved huge armies and heavy losses on both sides. For those who fought in it - Dutch and Belgians, Prussians and Hanoverians as well as British and French troops - it was a murderous struggle. For all its ferocity, it was a battle that would be remembered very differently across Europe. In Britain it would be seen as an iconic battle whose memory would be enmeshed in British national identity across the following century. It failed to achieve this iconic status elsewhere. In Prussia it was overshadowed by the Battle of the Nations at Leipzig, while in Holland it was a simple appendage to the prestige of the House of Orange. And in France it was the epitome of a heroic defeat that served to sustain the romantic legend of the Napoleonic Wars and contributed to the growing cult of Napoleon himself. Whereas most works on the battle of Waterloo are only military in nature, Alan Forrest's outstanding work-the first in the Great Battles series -- describes every aspect of how the battle was fought but deals equally with the aftermath: how it has been commemorated, and its legacy. --Provided by publisher.
Book
Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing
An understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine response to antimicrobial therapy can provide the clinician with better-informed dosing regimens. Factors influential on antibiotic disposition and clinical outcome are presented, with a focus on the primary site of infection. Techniques to better understand antibiotic PK and optimize PD are acknowledged.
PubMed (inception–April 2016) was reviewed for relevant publications assessing antimicrobial exposures within different anatomic locations and clinical outcomes for various infection sites.
A limited literature base indicates variable penetration of antibiotics to different target sites of infection, with drug solubility and extent of protein binding providing significant PK influences in addition to the major clearing pathway of the agent. PD indices derived from in vitro studies and animal models determine the optimal magnitude and frequency of dosing regimens for patients. PK/PD modeling and simulation has been shown an efficient means of assessing these PD endpoints against a variety of PK determinants, clarifying the unique effects of infection site and patient characteristics to inform the adequacy of a given antibiotic regimen.
Appreciation of the PK properties of an antibiotic and its PD measure of efficacy can maximize the utility of these life-saving drugs. Unfortunately, clinical data remain limited for a number of infection site–antibiotic exposure relationships. Modeling and simulation can bridge preclinical and patient data for the prescription of optimal antibiotic dosing regimens, consistent with the tenets of personalized medicine.
Journal Article
Population Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients: Implications for Selection of Dosage Regimens
Background. Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. Methods. Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography—tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. Results. Twenty-four patients aged 21–87 years received intravenous polymyxin B (0.45–3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10–143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r2 = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. Conclusions. Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.
Journal Article
Expansion of the Pseudo-autosomal Region and Ongoing Recombination Suppression in the Silene latifolia Sex Chromosomes
There are two very interesting aspects to the evolution of sex chromosomes: what happens after recombination between these chromosome pairs stops and why suppressed recombination evolves. The former question has been intensively studied in a diversity of organisms, but the latter has been studied largely theoretically. To obtain empirical data, we used codominant genic markers in genetic mapping of the dioecious plant Silene latifolia, together with comparative mapping of S. latifolia sex-linked genes in S. vulgaris (a related hermaphrodite species without sex chromosomes). We mapped 29 S. latifolia fully sex-linked genes (including 21 newly discovered from transcriptome sequencing), plus 6 genes in a recombining pseudo-autosomal region (PAR) whose genetic map length is ∼25 cM in both male and female meiosis, suggesting that the PAR may contain many genes. Our comparative mapping shows that most fully sex-linked genes in S. latifolia are located on a single S. vulgaris linkage group and were probably inherited from a single autosome of an ancestor. However, unexpectedly, our maps suggest that the S. latifolia PAR region expanded through translocation events. Some genes in these regions still recombine in S. latifolia, but some genes from both addition events are now fully sex-linked. Recombination suppression is therefore still ongoing in S. latifolia, and multiple recombination suppression events have occurred in a timescale of few million years, much shorter than the timescale of formation of the most recent evolutionary strata of mammal and bird sex chromosomes.
Journal Article
Evolutionary Strata on the X Chromosomes of the Dioecious Plant Silene latifolia: Evidence From New Sex-Linked Genes
Despite its recent evolutionary origin, the sex chromosome system of the plant Silene latifolia shows signs of progressive suppression of recombination having created evolutionary strata of different X–Y divergence on sex chromosomes. However, even after 8 years of effort, this result is based on analyses of five sex-linked gene sequences, and the maximum divergence (and thus the age of this plant's sex chromosome system) has remained uncertain. More genes are therefore needed. Here, by segregation analysis of intron size variants (ISVS) and single nucleotide polymorphisms (SNPs), we identify three new Y-linked genes, one being duplicated on the Y chromosome, and test for evolutionary strata. All the new genes have homologs on the X and Y chromosomes. Synonymous divergence estimated between the X and Y homolog pairs is within the range of those already reported. Genetic mapping of the new X-linked loci shows that the map is the same in all three families that have been studied so far and that X–Y divergence increases with genetic distance from the pseudoautosomal region. We can now conclude that the divergence value is saturated, confirming the cessation of X–Y recombination in the evolution of the sex chromosomes at ∼10–20 MYA.
Journal Article
Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens
Polymyxins are often last-line therapeutic agents used to treat infections caused by multidrug-resistant
A. baumannii
. Recent reports of polymyxin-resistant
A. baumannii
highlight the urgent need for research into mechanisms of polymyxin resistance. This study employed genomic and transcriptomic analyses to investigate the mechanisms of polymyxin resistance in
A. baumannii
AB307-0294 using an
in vitro
dynamic model to mimic four different clinically relevant dosage regimens of polymyxin B and colistin over 96 h. Polymyxin B dosage regimens that achieved peak concentrations above 1 mg/L within 1 h caused significant bacterial killing (~5 log
10
CFU/mL), while the gradual accumulation of colistin resulted in no bacterial killing. Polymyxin resistance was observed across all dosage regimens; partial reversion to susceptibility was observed in 6 of 8 bacterial samples during drug-free passaging. Stable polymyxin-resistant samples contained a mutation in
pmrB
. The transcriptomes of stable and non-stable polymyxin-resistant samples were not substantially different and featured altered expression of genes associated with outer membrane structure and biogenesis. These findings were further supported
via
integrated analysis of previously published transcriptomics data from strain ATCC19606. Our results provide a foundation for understanding the mechanisms of polymyxin resistance following exposure to polymyxins and the need to explore effective combination therapies.
Journal Article
How a Drought-Resilient Water Delivery System Rose Out of the Desert: The Case of Tucson Water
Tucson (Ariz.) Water's complex jurisdictional experiences have demonstrated the importance of an open and consultative decision-making process - and demonstrated the benefits of collaboration with other utilities and jurisdictions and the value of sharing lessons learned.
Journal Article
THE RELEVANCE OF GENE FLOW IN METAPOPULATION DYNAMICS OF AN OCEANIC ISLAND ENDEMIC, OLEA EUROPAEA SUBSP. GUANCHICA
Theoretical and empirical studies suggest that geographical isolation and extinction-recolonization dynamics are two factors causing strong genetic structure in metapopulations, but their consequences in species with high dispersal abilities have not been tested at large scales. Here, we investigated the effect of population age structure and isolation by distance in the patterns of genetic diversity in a wind-pollinated, zoochorous tree (Olea europaea subsp. guanchica) sporadically affected by volcanic events across the Canarian archipelago. Genetic variation was assessed at six nuclear microsatellites (nDNA) and six chloroplast fragments (cpDNA) in nine subpopulations sampled on four oceanic islands. Subpopulations occurring on more recent substrates were more differentiated than those on older substrates, but within-subpopulation genetic diversity was not significantly different between age groups for any type of marker. Isolation-by-distance differentiation was observed for nDNA but not for cpDNA, in agreement with other metapopulation studies. Contrary to the general trend for island systems, between-island differentiation was extremely low, and lower than differentiation between subpopulations on the same island. The pollen-to-seed ratio was close to one, two orders of magnitude lower than the average estimated for other wind-pollinated, animal-dispersed plants. Our results showed that population turnover and geographical isolation increased genetic differentiation relative to an island model at equilibrium, but overall genetic structure was unexpectedly weak for a species distributed among islands. This empirical study shows that extensive gene flow, particularly mediated by seeds, can ameliorate population subdivision resulting from extinction-recolonization dynamics and isolation by distance.
Journal Article
Synergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-Resistant Pseudomonas aeruginosa
Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa . As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa . An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites ( q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B–enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B–enrofloxacin combination against XDR P. aeruginosa . The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level.
Journal Article