bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence of chytrid‐mediated population declines in common midwife toad in Serra da Estrela, Portugal
Authors: Rosa G. M. , Anza I. , Moreira P. L. , Conde J. , Martins F. , Fisher M. C. , Bosch J.
Published: November 2012

The emergence of a novel infectious disease, chytridiomycosis, is now widely recognized as a major cause of amphibian declines and biodiversity loss across local and global scales. Amphibian mortalities caused by the pathogenic chytrid fungus, Batrachochytrium dendrobatidis (Bd) were first recorded in Iberia, Europe over a decade ago. In August 2009, hundreds of post‐metamorphic common midwife toads (Alytes obstetricans) were found dead in the water and margins of a pond in the Serra da Estrela Natural Park, north‐central Portugal. Histological and genetic analyses confirmed their infection with Bd. Given the likelihood of a new outbreak of chytridiomycosis, we evaluated the possible impacts of this disease on populations of A. obstetricans within the Park by conducting field surveys during 2010 and 2011. We compared the present distribution and abundance of A. obstetricans with historical records, and quantified the present prevalence and intensity of infection by Bd. Results showed that (1) A. obstetricans disappeared from 67% of the 1 × 1 km squares where it was recorded in the past, (2) breeding is currently limited to 16% of the confirmed breeding sites in the past, and that (3) larvae are now less abundant, as well as are highly infected by Bd in the remaining sites. These effects were most pronounced at altitudes above 1200 m. Our findings suggest that an outbreak of chytridiomycosis is responsible for the rapid decline of A. obstetricans in Serra da Estrela, and we believe that urgent conservation measures are needed to prevent local extinction of the species.
Radicalizing electoral system effects on support for nationalist hardliners inSerbia
Authors: Bochsler Daniel
Published: November 2012

This paper investigates electoral outcomes produced by the two‐round majority system in ethnically divided societies. Earlier studies, focused mainly on the SouthernAmerican states, have revealed that in ethnically mixed environments, competitors with radical positions on ethnic issues perform particularly well. This paper extends this idea to municipal elections inSerbia, showing how radical majority nationalist parties exhibit particularly strong performances in ethnically mixed municipalities. While this effect is also apparent under proportional representation, we argue that it is much stronger when a two‐round majority vote system is employed.
Direct evidence of nonadherence to antiepileptic medication in refractory focal epilepsy
Authors: Carpentier Nicolas , Jonas Jacques , Frismand Solène , Vignal Jean‐Pierre , Rikir Estelle , Baumann Cédric , Lapicque Françoise , Saint‐Marcoux Franck , Vespignani Hervé , Maillard Louis
Published: November 2012

The adherence to medication in drug‐resistant focal epilepsy (RFE) remains largely unknown. The present work aimed to assess the frequency of recent adherence to antiepileptic drugs (AEDs) in patients with RFE. This prospective observational study screened all patients with RFE, admitted to the Nancy University Hospital between April 2006 and September 2008, for a 5‐day hospitalization without AED tapering. The adherence to AEDs was assessed by measuring serum drug levels on day 1 (reflecting the recent “at home” adherence) and day 5 (reflecting the individual reference concentration when drug ingestion was supervised). A patient was considered nonadherent if at least one of their serum drug levels was different between days 1 and 5. The day‐1 value was considered different from day 5 when it was at least 30% lower (underdosed) or 30% higher (overdosed). Nonadherent patients were classified as under‐consumers in the case of one or more underdosed day‐1 values, over‐consumers in the case of one or more overdosed day‐1 values, or undefined if they exhibited both underdosed and overdosed day‐1 values. Forty‐four of the 48 screened patients were included. Eighteen (40.9%) of 44 patients were nonadherent. Among them, 12 (66.7%) were over‐consumers, 4 (22.2%) were under‐consumers, and 2 (11.1%) were undefined nonadherents. The study indicates that recent adherence to antiepileptic medication in this group of patients with RFE is poor. Overconsumption is the most frequent form of nonadherence in this population and should be specifically assessed to prevent its possible consequences in terms of AEDs dose‐dependent adverse events.
Efficiency Through Proximity
Authors: Metson Geneviève , Aggarwal Rimjhim , Childers Daniel L.
Published: November 2012

In tightly coupled socioecological systems, such as cities, the interactions between socio‐economic and biophysical characteristics of an area strongly influence ecosystem function. Very often the effects of socioeconomic activities on ecosystem function are unintended, but can impact the sustainability of a city and can have irreversible effects. The food system in its entirety, from production to treatment of human waste, is one of the most important contributors to the way phosphorus (P) cycles through cities. In this article we examined the changes in P dynamics at the urban–agricultural interface of the Phoenix, Arizona, USA, metropolitan area between 1978 and 2008. We found that the contribution of cotton to harvested P decreased while the contribution of alfalfa, which is used as feed for local dairy cows, increased over the study period. This change in cropping pattern was accompanied by growth in the dairy industry and increased internal recycling of P due to dairy cow manure application to alfalfa fields and the local recycling of biosolids and treated wastewater. The proximity of urban populations with dairies and feed production and low runoff in this arid climate have facilitated this serendipitous recycling. Currently P is not strongly regulated or intentionally managed in this system, but farmers' behaviors, shaped largely by market forces and policies related to water recycling, unintentionally affect P cycling. This underscores the need to move from unintentional to deliberate and holistic management of P dynamics through collaborations between practitioners and researchers in order to enhance urban sustainability.
Faster? Cheaper? Better? Using ADR to Resolve Federal Sector EEO Complaints
Authors: Nabatchi Tina , Stanger Anya
Published: November 2012

This article examines the Equal Employment Opportunity Commission's Management Directive 110, which requires all federal agencies to offer alternative dispute resolution (ADR) to employees with equal employment opportunity (EEO) complaints. Specifically, the article examines federal sector EEO complaint processing before and after the passage of Management Directive 110 and compares the traditional EEO procedure with the use of ADR on several indicators of case processing and case outcomes. Findings are reported in three sections: an overall analysis, an analysis of the informal stage of the process, and an analysis of the formal stage of the process. The article concludes with a discussion and directions for future research.
The Effect of School‐Specific Parenting Processes on Academic Achievement in Adolescence and Young Adulthood
Authors: Gordon Mellissa S. , Cui Ming
Published: November 2012

There is inconsistency in the current literature regarding the association between dimensions of parenting processes and academic achievement for adolescents. Further, few studies have extended such an association into young adulthood. In this study, we examined the effect of three dimensions of parenting processes, including school‐specific involvement, general parental support, and parental expectations, on academic achievement in adolescence and in young adulthood. Using a large, nationally representative, and longitudinal sample, we found that results from regression analyses suggested that all three dimensions of parenting processes had a significant effect on adolescents' academic success. In particular, school‐specific involvement had a stronger effect than general parental support and parental expectations. Further, parenting processes were indirectly associated with academic achievement later in young adulthood, partially through academic achievement in adolescence. Implications of the findings are also discussed.
The Relationship Between Parent‐Infant Bed Sharing and Marital Satisfaction for Mothers of Infants
Authors: Messmer Rosemary , Miller Lynn D. , Yu Christine M.
Published: November 2012

This study investigated the relationship between marital satisfaction and time spent bed sharing with infants in a community sample of 81 bed sharing mothers. Time spent bed sharing did not significantly predict variance in marital satisfaction when considering bed sharers as a whole. Moderation analysis, however, showed the interaction between time spent bed sharing and group classification either as “intentional,” defined as parents who endorse the ideology of bed sharing, or “reactive,” defined as parents who do not plan to bed share but bed share as a reaction to infant nighttime problems, explained a significant increase in variance in marital satisfaction, ΔR2 = .075, F(1, 75) = 7.31, p = .008. None of the intended mediator variables (satisfaction with bed sharing, fatigue, and sexual satisfaction) were significantly correlated with time spent bed sharing. Results highlight the importance of recognizing the differences between intentional bed sharers and reactive bed sharers.
Educational Differences in Marital Dissolution: Comparison of White and African American Women
Authors: Kim Jeounghee
Published: November 2012

Although the trend of marital dissolution has diverged by education in recent decades, literature was not clear about whether African Americans experienced a significant educational difference in marital dissolution. This study hypothesized that educational differences within the African American community have emerged and that the growth in this difference was larger for African Americans than for Whites in the 1990–1994 and 1995–1999 marriage cohorts. Using the Wave 2 Topical Modules of the 2001, 2004, and 2008 panels of the Survey of Income and Program Participation, this study analyzed a series of discrete time‐logit models but failed to find significant evidence to support the 2 hypotheses. Similar to the experience of White women in recent years, however, the probability of marital dissolution has been on the steady decline among African Americans regardless of their educational attainment since the 1990s.
Effect of Sea‐Level Rise on Salt Water Intrusion near a Coastal Well Field in Southeastern Florida
Authors: Langevin Christian D. , Zygnerski Michael
Published: November 2012

A variable‐density groundwater flow and dispersive solute transport model was developed for the shallow coastal aquifer system near a municipal supply well field in southeastern Florida. The model was calibrated for a 105‐year period (1900 to 2005). An analysis with the model suggests that well‐field withdrawals were the dominant cause of salt water intrusion near the well field, and that historical sea‐level rise, which is similar to lower‐bound projections of future sea‐level rise, exacerbated the extent of salt water intrusion. Average 2005 hydrologic conditions were used for 100‐year sensitivity simulations aimed at quantifying the effect of projected rises in sea level on fresh coastal groundwater resources near the well field. Use of average 2005 hydrologic conditions and a constant sea level result in total dissolved solids (TDS) concentration of the well field exceeding drinking water standards after 70 years. When sea‐level rise is included in the simulations, drinking water standards are exceeded 10 to 21 years earlier, depending on the specified rate of sea‐level rise.
Compositional and Mechanical Properties of Peanuts Roasted to Equivalent Colors using Different Time/Temperature Combinations
Authors: McDaniel Kristin A. , White Brittany L. , Dean Lisa L. , Sanders Timothy H. , Davis Jack P.
Published: November 2012

Abstract:  Peanuts in North America and Europe are primarily consumed after dry roasting. Standard industry practice is to roast peanuts to a specific surface color (Hunter L‐value) for a given application; however, equivalent surface colors can be attained using different roast temperature/time combinations, which could affect product quality. To investigate this potential, runner peanuts from a single lot were systematically roasted using 5 roast temperatures (147, 157, 167, 177, and 187 °C) and to Hunter L‐values of 53 ± 1, 48.5 ± 1, and 43 ± 1, corresponding to light, medium, and dark roasts, respectively. Moisture contents (MC) ranged from 0.41% to 1.70% after roasting. At equivalent roast temperatures, MC decreased as peanuts became darker; however, for a given color, MC decreased with decreasing roast temperature due to longer roast times required for specified color formation. Initial total tocopherol contents of expressed oils ranged from 164 to 559 μg/g oil. Peanuts roasted at lower temperatures and darker colors had higher tocopherol contents. Glucose content was roast color and temperature dependent, while fructose was only temperature dependent. Soluble protein was lower at darker roast colors, and when averaged across temperatures, was highest when samples were roasted at 187 °C. Lysine content decreased with increasing roast color but was not dependent on temperature. MC strongly correlated with several components including tocopherols (R2 = 0.67), soluble protein (R2 = 0.80), and peak force upon compression (R2 = 0.64). The variation in characteristics related to roast conditions is sufficient to suggest influences on final product shelf life and consumer acceptability.

Practical Application:  Peanuts are typically dry roasted to a specified surface color for a given food application; however, it is possible to obtain equivalent colors using different temperatures. This simple observation led to the overall goal of this research which was to determine if peanuts roasted to equivalent surface colors using different temperatures are equivalent from a quality perspective. Several compositional and textural measurements important to product quality differed based on the temperature used to achieve a given roast color. Overall, this study suggests there is good potential to optimize peanut quality by simply adjusting the time/temperature profiles during roasting.
A general model of detectability using species traits
Authors: Garrard Georgia E. , McCarthy Michael A. , Williams Nicholas S. G. , Bekessy Sarah A. , Wintle Brendan A.
Published: November 2012

Imperfect detectability is a critical source of variation that limits ecological progress and frustrates effective conservation management. Available modelling methods provide valuable detectability estimates, but these are typically species‐specific.

We present a novel application of time‐to‐detection modelling in which detectability of multiple species is a function of plant traits and observer characteristics. The model is demonstrated for plants in a temperate grassland community in south‐eastern Australia.

We demonstrate that detectability can be estimated using observer experience, species population size and likelihood of flowering. The inclusion of flower colour and species distinctiveness improves the capacity of the model to predict detection rates for new species.

We demonstrate the application of the general model to plants in a temperate grassland community, but this modelling method may be extended to other communities or taxa for which time‐to‐detection models are appropriate.

Detectability is influenced by traits of the species and the observer. General models can be used to derive detectability estimates where repeat survey data, point counts or mark‐recapture data are not available. As these data are almost always absent for species of conservation concern, general models such as ours will be useful for informing minimum survey requirements for monitoring and impact assessment, without the delays and costs associated with data collection.
Factors affecting the (in)accuracy of mammalian mesocarnivore scat identification in South‐western Europe
Authors: Monterroso P. , Castro D. , Silva T. L. , Ferreras P. , Godinho R. , Alves P. C.
Published: November 2012

Research on terrestrial carnivore ecology frequently relies on scat identification and analysis. However, species assignment is commonly based on scat morphology. Potential errors in scat identification are rarely accounted for and might contribute to substantial bias of the final results. Using molecular methods, we evaluate the accuracy of species identification based on morphological characteristics of mammalian mesocarnivore scats collected in two areas in the Iberian Peninsula. Our results revealed that error rates in species assignment of scats based on morphology were highly variable, ranging from 14%, for putative red fox Vulpes vulpes samples, to 88%, for putative wildcats Felis silvestris. The developed models revealed that putative species, season, study area and target species abundance are among the factors involved in identification accuracy. However, the low variability explained suggests that unaccounted factors also had significant effects on accuracy rates. The error rates in scat species assignment constitute a potential source of bias in ecological studies, with serious consequences for the management of threatened species, as unrealistic estimates of status and distribution are prone to occur. Our results suggest that scat identification accuracy rates are circumstance‐specific and therefore should not be transferred or extrapolated. We suggest that scat‐based studies should implement measures (molecular or others) that allow researchers to determine their own circumstance‐specific error rates in scat identification, which should be incorporated in subsequent analyses, ensuring reliable ecological inferences.
PomZ, a ParA‐like protein, regulates Z‐ring formation and cell division in Myxococcus xanthus
Authors: Treuner‐Lange Anke , Aguiluz Kryssia , van der Does Chris , Gómez‐Santos Nuria , Harms Andrea , Schumacher Dominik , Lenz Peter , Hoppert Michael , Kahnt Jörg , Muñoz‐Dorado José , Søgaard‐Andersen Lotte
Published: November 2012

Accurate positioning of the division site is essential to generate appropriately sized daughter cells with the correct chromosome number. In bacteria, division generally depends on assembly of the tubulin homologue FtsZ into the Z‐ring at the division site. Here, we show that lack of the ParA‐like protein PomZ in Myxococcus xanthus resulted in division defects with the formation of chromosome‐free minicells and filamentous cells. Lack of PomZ also caused reduced formation of Z‐rings and incorrect positioning of the few Z‐rings formed. PomZ localization is cell cycle regulated, and PomZ accumulates at the division site at midcell after chromosome segregation but prior to FtsZ as well as in the absence of FtsZ. FtsZ displayed cooperative GTP hydrolysis in vitro but did not form detectable filaments in vitro. PomZ interacted with FtsZ in M. xanthus cell extracts. These data show that PomZ is important for Z‐ring formation and is a spatial regulator of Z‐ring formation and cell division. The cell cycle‐dependent localization of PomZ at midcell provides a mechanism for coupling cell cycle progression and Z‐ring formation. Moreover, the data suggest that PomZ is part of a system that recruits FtsZ to midcell, thereby, restricting Z‐ring formation to this position.
FadD3 is an acyl‐CoA synthetase that initiates catabolism of cholesterol rings C and D in actinobacteria
Authors: Casabon Israël , Crowe Adam M. , Liu Jie , Eltis Lindsay D.
Published: November 2012

The cholesterol catabolic pathway occurs in most mycolic acid‐containing actinobacteria, such as Rhodococcus jostii RHA1, and is critical for Mycobacterium tuberculosis (Mtb) during infection. FadD3 is one of four predicted acyl‐CoA synthetases potentially involved in cholesterol catabolism. A ΔfadD3 mutant of RHA1 grew on cholesterol to half the yield of wild‐type and accumulated 3aα‐H‐4α(3′‐propanoate)‐7aβ‐methylhexahydro‐1,5‐indanedione (HIP), consistent with the catabolism of half the steroid molecule. This phenotype was rescued by fadD3 of Mtb. Moreover, RHA1 but not ΔfadD3 grew on HIP. Purified FadD3Mtb catalysed the ATP‐dependent CoA thioesterification of HIP and its hydroxylated analogues, 5α‐OH HIP and 1β‐OH HIP. The apparent specificity constant (kcat/Km) of FadD3Mtb for HIP was 7.3 ± 0.3 × 105 M−1 s−1, 165 times higher than for 5α‐OH HIP, while the apparent Km for CoASH was 110 ± 10 μM. In contrast to enzymes involved in the catabolism of rings A and B, FadD3Mtb did not detectably transform a metabolite with a partially degraded C17 side‐chain. Overall, these results indicate that FadD3 is a HIP‐CoA synthetase that initiates catabolism of steroid rings C and D after side‐chain degradation is complete. These findings are consistent with the actinobacterial kstR2 regulon encoding ring C/D degradation enzymes.
Evolutionarily conserved differences in pallial and thalamic short‐term synaptic plasticity in striatum
Authors: Ericsson Jesper , Stephenson‐Jones Marcus , Kardamakis Andreas , Robertson Brita , Silberberg Gilad , Grillner Sten
Published: November 2012

Key points

Recent studies have shown that the striatum and the basal ganglia are to a remarkable degree conserved throughout the vertebrate phylum.

As the basic organization of the neural machinery for action selection is present in the lamprey, it is essential to understand how the striatum is activated.

In this study we characterize the pharmacology and synaptic dynamics from the lateral pallium (LPal; cortex) and thalamus (Th), the main excitatory input to the striatum.

We show that, as in mammals, the LPal and Th provide glutamatergic excitation to the striatum, but with completely opposite short‐term synaptic plasticity due to differences in presynaptic properties.

These synaptic differences are also characteristic of the mammalian striatum, suggesting that these are fundamental components of the vertebrate mechanisms for action selection.

Abstract  The striatum of the basal ganglia is conserved throughout the vertebrate phylum. Tracing studies in lamprey have shown that its afferent inputs are organized in a manner similar to that of mammals. The main inputs arise from the thalamus (Th) and lateral pallium (LPal; the homologue of cortex) that represents the two principal excitatory glutamatergic inputs in mammals. The aim here was to characterize the pharmacology and synaptic dynamics of afferent fibres from the LPal and Th onto identified striatal neurons to understand the processing taking place in the lamprey striatum. We used whole‐cell current‐clamp recordings in acute slices of striatum with preserved fibres from the Th and LPal, as well as tract tracing and immunohistochemistry. We show that the Th and LPal produce monosynaptic excitatory glutamatergic input through NMDA and AMPA receptors. The synaptic input from the LPal displayed short‐term facilitation, unlike the Th input that instead displayed strong short‐term synaptic depression. There was also an activity‐dependent recruitment of intrastriatal oligosynaptic inhibition from both inputs. These results indicate that the two principal inputs undergo different activity‐dependent short‐term synaptic plasticity in the lamprey striatum. The difference observed between Th and LPal (cortical) input is also observed in mammals, suggesting a conserved trait throughout vertebrate evolution.
Dampened dopamine‐mediated neuromodulation in prefrontal cortex of fragile X mice
Authors: Paul Kush , Venkitaramani Deepa V. , Cox Charles L.
Published: November 2012

Key points

Activation of D1 receptors produces an initial suppression followed by facilitation of evoked inhibitory postsynaptic currents (IPSCs) in layer II pyramidal neurons of mouse prefrontal cortex.

In Fmr1 knockout (KO) mice, the D1‐mediated facilitation of evoked IPSCs is absent whereas the initial suppression is unaltered.

Downstream mechanisms of the D1‐mediated facilitation (i.e. cAMP‐dependent facilitation) persists in Fmr1 KO neurons; however, there is a decrease in D1 receptor protein in the Fmr1 KO tissues.

These results indicate the dopamine‐dependent modulation of inhibition is dampened in Fmr1 KO animals, which could produce a relative hyperexcitability of neural circuitry within decision‐making regions of the prefrontal cortex in fragile X syndrome.

Abstract  Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive‐compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long‐lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1‐type receptors seen in wild‐type mice; however, such enhancement is absent in the Fmr1 knock‐out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.
Laser Light Transmission Through Thermoplastics as a Function of Thickness and Laser Incidence Angle: Experimental and Modeling
Authors: Azhikannickal Elizabeth , Bates Philip J. , Zak Gene
Published: November 2012

It is important to accurately measure and predict the laser light transmission through unreinforced and reinforced thermoplastics if candidate materials are to be assessed for laser transmission welding (LTW) applications. This paper presents the results of laser transmission measurements through unreinforced polyamide 6 (PA6) and 10% glass fiber reinforced polycarbonate of various thicknesses and corresponding to various laser incidence angles (angle between the incident laser beam and the normal to the transparent part). A novel transmission measurement method, developed by the authors, was employed. A model, utilizing the Fresnel specular surface reflection conditions as well as accounting for refraction, absorption and reflection of the laser light through the bulk material, was used to predict transmission as a function of thickness and laser incidence angle. Results of transmission tests on both materials showed that, for a given thickness, the transmission decreases as the laser angle of incidence increases. In addition, at any given laser incidence angle, the transmission decreases as the thickness increases. The advantage of the model is that it requires only one experimentally determined constant for a given material. Good agreement existed between the experimentally measured transmission and the model prediction for the range of thicknesses and laser incidence angles studied.
Ultrasonic Vibration-Assisted Pelleting of Wheat Straw: A Designed Experimental Investigation on Pellet Quality and Sugar Yield
Authors: Zhang P. F. , Zhang Q. , Deines T. W. , Pei Z. J. , Wang D. H.
Published: November 2012

Increasing demands and concerns for reliable supply of liquid transportation fuels make it important to find alternative sources to petroleum-based fuels. One such alternative is cellulosic ethanol. However, several technical barriers have hindered large-scale, cost-effective manufacturing of cellulosic ethanol, such as low density of cellulosic feedstocks (causing high transportation and storage costs) and low efficiency of enzymatic hydrolysis (causing longer processing time and low sugar yield). Ultrasonic vibration-assisted (UV-A) pelleting can increase the density of cellulosic materials and sugar yield in enzymatic hydrolysis. At present, effects of process variables in UV-A pelleting on pellet quality (density, durability, and spring-back) and sugar yield have not been adequately investigated. This paper reports an experimental investigation on UV-A pelleting of wheat straw. A 24 factorial design is employed to evaluate effects of process variables (moisture content, sieve size, pelleting pressure, and ultrasonic power) on output variables (pellet density, durability, spring-back, and sugar yield).
Wound Healing and Immunity
Authors: Mueller Kristen L.
Published: November 2012

Tagging adenovirus with a serum protein prompts an immune response when the virus enters cells.
To Die For
Authors: Hurtley Stella M.
Published: November 2012

Protein misfolding stimulates the destruction of microRNAs and the synthesis of an enzyme that promotes cell death.
Vancomycin Treatment's Association with Delayed Intestinal Tissue Injury, Clostridial Overgrowth, and Recurrence of Clostridium difficile Infection in Mice
Authors: Warren Cirle A. , van Opstal Edward J. , Riggins Mary S. , Li Yuesheng , Moore John H. , Kolling Glynis L. , Guerrant Richard L. , Hoffman Paul S.
Published: November 2012

Antibiotic treatment, including vancomycin, for
Clostridium difficile
infection (CDI) has been associated with recurrence of disease in up to 25% of infected persons. This study investigated the effects of vancomycin on the clinical outcomes, intestinal histopathology, and anaerobic community during and after treatment in a murine model of CDI. C57BL/6 mice were challenged with
C. difficile
strain VPI 10463 after pretreatment with an antibiotic cocktail. Twenty-four hours after infection, mice were treated daily with vancomycin, nitazoxanide, fidaxomicin, or metronidazaole for 5 days. Mice were monitored for either 6 or 12 days postinfection. Clinical, diarrhea, and histopathology scores were measured. Cecal contents or stool samples were assayed for clostridial or
Bacteroides
DNA and
C. difficile
toxins A and B. Vancomycin treatment of infected mice was associated with improved clinical, diarrhea, and histopathology scores and survival during treatment. However, after discontinuation of the drug, clinical scores and histopathology were worse in treated mice than in untreated infected controls. At the end of the study, 62% of the vancomycin-treated mice succumbed to recurrence, with an overall mortality rate equivalent to that of the untreated infected control group. Fidaxomicin-treated mice had outcomes similar to those of vancomycin-treated mice.
C. difficile
predominated over
Bacteroides
in cecal contents of vancomycin-treated mice, similar to findings for untreated infected mice. Decreasing the duration of vancomycin treatment from 5 days to 1 day decreased recurrence and deaths. In conclusion, vancomycin improved clinical scores and histopathology acutely but was associated with poor outcome posttreatment in
C. difficile
-infected mice. Decreasing vancomycin exposure may decrease relapse and improve survival in CDI.
A Rationally Engineered Anti-HIV Peptide Fusion Inhibitor with Greatly Reduced Immunogenicity
Authors: Brauer Frances , Schmidt Kerstin , Zahn Roland C. , Richter Cornelia , Radeke Heinfried H. , Schmitz Jörn E. , von Laer Dorothee , Egerer Lisa
Published: November 2012

Peptides derived from the C-terminal heptad repeat 2 (HR2) region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very efficient HIV-1 fusion inhibitors. We previously developed innovative gene therapeutic approaches aiming at the directin vivoproduction of C peptides from genetically modified host cells and found that T cells expressing membrane-anchored or secreted C peptides are protected from HIV-1 infection. However, an unwanted immune response against such antiviral peptides may significantly impair clinical efficacy and pose safety risks to patients. To overcome this problem, we engineered a novel C peptide, V2o, with greatly reduced immunogenicity and excellent antiviral activity. V2o is based on the chimeric C peptide C46-EHO, which is derived from the HR2 regions of HIV-2EHOand HIV-1HxB2and has broad anti-HIV and anti-simian immunodeficiency virus activity. Antibody and major histocompatibility complex class I epitopes within the C46-EHO peptide sequence were identified byin silicoandin vitroanalyses. Using rational design, we removed these epitopes by amino acid substitutions and thus minimized antigenicity and immunogenicity considerably. At the same time, the antiviral activity of the deimmunized peptide V2o was preserved or even enhanced compared to that of the parental C46-EHO peptide. Thus, V2o is an ideal candidate, especially for those novel therapeutic approaches for HIV infection that involve directin vivoproduction of antiviral C peptides.
Effects of Obesity and Sex on Antimicrobial Pharmacokinetics and Acute Kidney Injury: Validation of a Preclinical Model
Authors: Pai Manjunath P. , Chen Wen Zhen , Garba Adinoyi , Cui Huadong , Zaffo Barbara , El-Fawal Hassan A. N. , Mousa Shaker A.
Published: November 2012

Obese patients may be at a greater risk for acute kidney injury (AKI) with the use of certain antimicrobial agents that are dosed by weight. Current preclinical models of AKI utilize the male rat within a narrow weight range that limits extrapolation of the generated results. We evaluated the pharmacokinetics and AKI potential of gentamicin in 14-week-old diet-induced obesity-prone (n= 40) and obesity-resistant (n= 40) rats of both sexes. Single daily doses of gentamicin (12.5, 18.75, or 25 mg/kg of body weight) or saline (control) were administered intraperitoneally for 14 doses. Blood samples were collected after doses 1, 7, and 14, assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and analyzed using a nonparametric population pharmacokinetic approach for gentamicin. Urine was collected after doses 1, 3, and 5 and assayed for kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) and normalized to creatinine (Cr) values. Histology was performed on all animals, and the degree of proximal tubular injury was graded. The mean (minimum, maximum) weight of the rats was 330 (136, 580) g. NGAL/Cr predicted AKI better than did KIM-1/Cr and was detectable in male rats after dose 1 and in obesity-prone female rats after dose 5. Proximal tubular injury by histology was significantly higher in male than in female rats. A significant relationship between the gentamicin area under the curve from zero to 24 hours (AUC0–24) estimates and the maximum NGAL/Cr ratio was observed. This preclinical model has the potential to aid with dose extrapolation for body size and improve assessment of the toxicology potential of antimicrobials in development.
Population Pharmacokinetics of Fusidic Acid: Rationale for Front-Loaded Dosing Regimens Due to Autoinhibition of Clearance
Authors: Bulitta Jürgen B. , Okusanya Olanrewaju O. , Forrest Alan , Bhavnani Sujata M. , Clark Kay , Still J. Gordon , Fernandes Prabhavathi , Ambrose Paul G.
Published: November 2012

The objectives of this analysis were to develop a population pharmacokinetic (PK) model to describe the absorption and disposition of fusidic acid after single and multiple doses and to determine the effect of food on the rate and extent of bioavailability. Plasma PK data from three phase 1 studies (
n
= 75;
n
= 14 with and without food) in which healthy subjects received sodium fusidate (500 to 2,200 mg) as single or multiple oral doses every 8 h (q8h) or q12h for up to 7 days were modeled using S-ADAPT (MCPEM algorithm). Accumulation of fusidic acid after multiple doses was more than that predicted based on single-dose data. The PK of fusidic acid was best described using a time-dependent mixed-order absorption process, two disposition compartments, and a turnover process to describe the autoinhibition of clearance. The mean total clearance (% coefficient of variation) was 1.28 liters/h (33%) and the maximum extent of autoinhibition was 71.0%, with a 50% inhibitory concentration (IC
50
) of 46.3 mg/liter (36%). Food decreased the extent of bioavailability by 18%. As a result of the autoinhibition of clearance, steady state can be achieved earlier with dosing regimens that contain higher doses (after 8 days for 750 mg q12h and 1 day for 1,500 mg q12h on day 1 followed by 600 mg q12h versus 3 weeks for 500 mg q12h). Given that large initial doses autoinhibit the clearance of fusidic acid, this characteristic provides a basis for the administration of front-loaded dosing regimens of sodium fusidate which would allow for effective concentrations to be achieved early in therapy.
Inhibition of Streptococcus pneumoniae Penicillin-Binding Protein 2x and Actinomadura R39 DD-Peptidase Activities by Ceftaroline
Authors: Zervosen Astrid , Zapun André , Frère Jean-Marie
Published: November 2012

Although the rate of acylation of a penicillin-resistant form of
Streptococcus pneumoniae
penicillin-binding protein 2x (PBP2x) by ceftaroline is 80-fold lower than that of its penicillin-sensitive counterpart, it remains sufficiently high (

k
2
/K

= 12,600 M
−1
s
−1
) to explain the sensitivity of the penicillin-resistant strain to this new cephalosporin. Surprisingly, the
Actinomadura
R39 DD-peptidase is not very sensitive to ceftaroline.
Both Fidaxomicin and Vancomycin Inhibit Outgrowth of Clostridium difficile Spores
Authors: Allen Charlotte A. , Babakhani Farah , Sears Pam , Nguyen Ly , Sorg Joseph A.
Published: November 2012

Fidaxomicin (FDX) is approved to treat
Clostridium difficile
-associated diarrhea and is superior to vancomycin in providing a sustained clinical response (cure without recurrence in the subsequent 25 days). The mechanism(s) behind the low recurrence rate of FDX-treated patients could be multifactorial. Here, we tested effects of FDX, its metabolite OP-1118, and vancomycin on spore germination and determined that none affected the initiation of spore germination but all inhibited outgrowth of vegetative cells from germinated spores.
Chlorhexidine and Mupirocin Susceptibilities of Methicillin-Resistant Staphylococcus aureus from Colonized Nursing Home Residents
Authors: McDanel Jennifer S. , Murphy Courtney R. , Diekema Daniel J. , Quan Victor , Kim Diane S. , Peterson Ellena M. , Evans Kaye D. , Tan Grace L. , Hayden Mary K. , Huang Susan S.
Published: November 2012

Chlorhexidine and mupirocin are used in health care facilities to eradicate methicillin-resistant
Staphylococcus aureus
(MRSA) carriage. The objective of this study was to assess the frequency of chlorhexidine and mupirocin resistance in isolates from nares carriers in multiple nursing homes and to examine characteristics associated with resistance. Nasal swab samples were collected from approximately 100 new admissions and 100 current residents in 26 nursing homes in Orange County, CA, from October 2008 to May 2011. MRSA isolates were tested for susceptibility by using broth microdilution, disk diffusion, and Etest; for genetic relatedness using pulsed-field gel electrophoresis; and for
qac
gene carriage by PCR. Characteristics of the nursing homes and their residents were collected from the Medicare Minimum Data Set and Long-Term Care Focus. A total of 829 MRSA isolates were obtained from swabbing 3,806 residents in 26 nursing homes. All isolates had a chlorhexidine MIC of ≤4 μg/ml. Five (0.6%) isolates harbored the
qacA
and/or
qacB
gene loci. Mupirocin resistance was identified in 101 (12%) isolates, with 78 (9%) isolates exhibiting high-level mupirocin resistance (HLMR). HLMR rates per facility ranged from 0 to 31%. None of the isolates with HLMR displayed
qacA
or
qacB
, while two isolates carried
qacA
and exhibited low-level mupirocin resistance. Detection of HLMR was associated with having a multidrug-resistant MRSA isolate (odds ratio [OR], 2.69;
P
= 0.004), a history of MRSA (OR, 2.34;
P
< 0.001), and dependency in activities of daily living (OR, 1.25;
P
= 0.004). In some facilities, HLMR was found in nearly one-third of MRSA isolates. These findings may have implications for the increasingly widespread practice of MRSA decolonization using intranasal mupirocin.
Mupirocin and Chlorhexidine Resistance in Staphylococcus aureus in Patients with Community-Onset Skin and Soft Tissue Infections
Authors: Fritz Stephanie A. , Hogan Patrick G. , Camins Bernard C. , Ainsworth Ali J. , Patrick Carol , Martin Madeline S. , Krauss Melissa J. , Rodriguez Marcela , Carey-Ann Burnham D.
Published: November 2012

Decolonization measures, including mupirocin and chlorhexidine, are often prescribed to prevent
Staphylococcus aureus
skin and soft tissue infections (SSTI). The objective of this study was to determine the prevalence of high-level mupirocin and chlorhexidine resistance in
S. aureus
strains recovered from patients with SSTI before and after mupirocin and chlorhexidine administration and to determine whether carriage of a mupirocin- or chlorhexidine-resistant strain at baseline precluded
S. aureus
eradication. We recruited 1,089 patients with community-onset SSTI with or without
S. aureus
colonization. In addition to routine care, 483 patients were enrolled in a decolonization trial: 408 received intranasal mupirocin (with or without antimicrobial baths), and 258 performed chlorhexidine body washes. Patients were followed for up to 12 months with repeat colonization cultures. All
S. aureus
isolates were tested for high-level mupirocin and chlorhexidine resistance. At baseline, 23/1,089 (2.1%) patients carried a mupirocin-resistant
S. aureus
strain and 10/1,089 (0.9%) patients carried chlorhexidine-resistant
S. aureus
. Of 4 patients prescribed mupirocin, who carried a mupirocin-resistant
S. aureus
strain at baseline, 100% remained colonized at 1 month compared to 44% of the 324 patients without mupirocin resistance at baseline (
P
= 0.041). Of 2 patients prescribed chlorhexidine, who carried a chlorhexidine-resistant
S. aureus
strain at baseline, 50% remained colonized at 1 month compared to 48% of the 209 patients without chlorhexidine resistance at baseline (
P
= 1.0). The overall prevalence of mupirocin and chlorhexidine resistance is low in
S. aureus
isolates recovered from outpatients, but eradication efforts were less successful in patients carrying a mupirocin-resistant
S. aureus
strain at baseline.
Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients
Authors: Goutelle Sylvain , Baudry Thomas , Gagnieu Marie-Claude , Boibieux André , Livrozet Jean-Michel , Peyramond Dominique , Chidiac Christian , Tod Michel , Ferry Tristan ,   on behalf of the Lyon HIV Cohort Study Group
Published: November 2012

Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h−1;P= 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24], 10.3 ± 2.1 versus 22.4 ± 11.2 mg · h · liter−1;P= 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.
Streptococcus pneumoniae Capsular Serotype Invasiveness Correlates with the Degree of Factor H Binding and Opsonization with C3b/iC3b
Authors: Hyams Catherine , Trzcinski Krzysztof , Camberlein Emilie , Weinberger Daniel M. , Chimalapati Suneeta , Noursadeghi Mahdad , Lipsitch Marc , Brown Jeremy S.
Published: November 2012

Different capsular serotypes of
Streptococcus pneumoniae
vary markedly in their ability to cause invasive infection, but the reasons why are not known. As immunity to
S. pneumoniae
infection is highly complement dependent, variations in sensitivity to complement between
S. pneumoniae
capsular serotypes could affect invasiveness. We have used 20 capsule-switched variants of strain TIGR4 to investigate whether differences in the binding of the alternative pathway inhibitor factor H (FH) could be one mechanism causing variations in complement resistance and invasive potential between capsular serotypes. Flow cytometry assays were used to assess complement factor binding and complement-dependent neutrophil association for the TIGR4 capsule-switched strains. FH binding varied with the serotype and inversely correlated with the results of factor B binding, C3b/iC3b deposition, and neutrophil association. Differences between strains in FH binding were lost when assays were repeated with
pspC
mutant strains, and loss of PspC also reduced differences in C3b/iC3b deposition between strains. Median FH binding was high in capsule-switched mutant strains expressing more invasive serotypes, and a principal component analysis demonstrated a strong correlation between serotype invasiveness, high FH binding, and resistance to complement and neutrophil association. Further data obtained with 33 clinical strains also demonstrated that FH binding negatively correlated with C3b/iC3b deposition and that median FH binding was high in strains expressing more invasive serotypes. These data suggest that variations in complement resistance between
S. pneumoniae
strains and the association of a serotype with invasiveness could be related to capsular serotype effects on FH binding.