bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluctuating selection on reproductive timing in Digitalis purpurea
Authors: Sletvold Nina , M. Grindeland John
Published: October 2006

Despite recent, strong interest in the modelling of monocarpic perennial flowering strategies, little is known about how variation in demographic rates affects selection on optimal timing of flowering. Temporal variation may yield fluctuating selective pressures, or, if individuals experience time trends, selection for phenotypic plasticity. Here we report the results of a 3‐year study in a large field population of the facultative biennial herb Digitalis purpurea, where we use field data on size‐dependent growth, survival and fecundity to parameterize an existing optimisation model. We compare results from models using either deterministic or individually varying demographic rates to address the degree of fluctuating selection on the flowering strategy. In addition, we explore whether recent growing conditions influence the size‐specific liability to flower. Model results differed widely between years; immediate onset of reproduction was predicted in 1999, strongly delayed reproduction in 2000. This reflected large differences in both growth and survival rates between years. Observed flowering sizes also varied between years, but were larger in 1999 than in 2000, contrary to model predictions. Incorporating individual variation in growth increased predicted optimal flowering sizes compared to models using deterministic growth, whereas the inclusion of individual survival variation had little effect. There was no significant effect of recent growth rate on flowering probability. Taken together, these results indicate highly fluctuating selection on the flowering strategy in D. purpurea, but no evidence of adaptive plasticity in response to current growing conditions. Fluctuating selection may contribute to maintain genetic variation for threshold size for flowering, and may partly explain the large within‐season size‐variation in flowering individuals found in natural populations of D. purpurea.
The role of spatial scale and area in determining richness‐altitude gradients in Swedish lake phytoplankton communities
Authors: Jankowski Thomas , A. Weyhenmeyer Gesa
Published: October 2006

Lake phytoplankton richness data were analyzed to reveal the effects of area and scale on the richness‐elevation relationship. Lakes provide a unique opportunity to accomplish this because of their well‐defined boundaries, which clearly define local communities and their habitat area. Local phytoplankton richness (alpha diversity) was found to decrease with increasing elevation, even when the effect of lake area was accounted for. This decrease coincided with a decrease in lake productivity with increasing elevation. Additionally, pairwise dissimilarity calculations suggested that isolation by distance was less important in structuring local phytoplankton richness than isolation by either elevation or environmental distance. In contrast, phytoplankton richness calculated for elevation bands (gamma diversity) showed a hump‐shaped dependence on elevation, with a mid‐elevation maximum, consistent with the predictions of a mid‐domain null model. Moreover, mean pairwise dissimilarity within elevation bands shows compositional dissimilarity to be highest at high elevations and low environmental distances, emphasizing the isolated character of high‐elevation lakes. We suggest that the form of the phytoplankton richness‐elevation relationship is scale‐dependent, and that geometric constraints, differences in the possibility of horizontal and vertical dispersal, environmental heterogeneity and an underlying monotonic trend in productivity, are likely to be responsible for the patterns in alpha and gamma diversity observed along elevation gradients.
Local population dynamics and the impact of scale and isolation: a study on different little owl populations
Authors: Schaub Michael , Ullrich Bruno , Knötzsch Gerhard , Albrecht Patrick , Meisser Christian
Published: October 2006

The understanding of how variation of demographic rates translates into variation of population growth is a central aim in population ecology. Besides stochastic and deterministic factors, the spatial extent and the isolation of a local population may have an impact on the contribution of the different demographic components. Using long‐term demographic data we performed retrospective population analyses of four little owl (Athene noctua) populations with differential spatial extent and degree of isolation to assess the contribution of demographic rates to the variation of the growth rate (λ) of each local population and to the difference of λ among populations. In all populations variation of fecundity contributed least to variation of λ, and variation of adult survival contributed most to variation of λ in three of four populations. Between population comparisons revealed that differences mainly stem from differences of immigration and juvenile local survival. The relative importance of immigration to λ tended to decrease with increasing spatial extent and isolation of the local populations. None of the four local populations was self‐sustainable. Because the local populations export and import individuals, they can be considered as open recruitment systems in which part of the recruited breeding birds are not produced locally. The spatial extent and the degree of isolation of a local population have an impact on local population dynamics; hence these factors need to be considered in studies about local population dynamics and for deriving conservation measures.
The Biosphere Reserve Program in the United States
Authors: Franklin Jerry F.
Published: October 2006

The objective of the biosphere reserve program is to identify and protect representative and unique segments of the world's biotic provinces as major centers for biotic and genetic preservation, ecological and environmental research, education, and demonstration. It is intended to be more than simply another program of preservation layered onto existing parks and reserves. The success of the program will depend in large measure on the overall significance of the selected reserves and the degree to which they are active sites for scientific research and monitoring.
Delaware River: Evidence for Its Former Extension to Wilmington Submarine Canyon
Authors: Twichell David C. , Knebel Harley J. , Folger David W.
Published: October 2006

Seismic-reflection profiles indicate that during the Pleistocene the Delaware River flowed across the continental shelf east of Delaware Bay and emptied into Wilmington Submarine Canyon. The ancestral valley (width, 3 to 8 kilometers; relief, 10 to 30 meters) is buried, is not reflected in the surface topography, and probably predates the formation of the present canyon head.
Excitation of the Venus Night Airglow
Authors: Lawrence G. M. , Barth C. A. , Argabright V.
Published: October 2006

The strongest spectral features in the Venus night airglow between 3000 and 8000 angstroms are identified as the Herzberg II (c
1
σ
-
u
- X
3
σ
-
g
) bands of molecular oxygen. These bands have been produced in a laboratory afterglow by the recombination of oxygen atoms in the presence of carbon dioxide molecules. It is hypothesized that the same mechanism produces this emission in the upper atmosphere of Venus.
Pleistocene Avifaunas and the Overkill Hypothesis
Authors: Grayson Donald K.
Published: October 2006

At the end of the North American Pleistocene, birds and mammals suffered comparable degrees of generic extinction. Both the magnitude and pattern of avian extinction are incompatible with the hypothesis that humans played a major role in causing the demise of numerous North American mammalian genera at this time.
Remote-Sensing of Crop Yields
Authors: Idso Sherwood B. , Jackson Ray D. , Reginato Robert J.
Published: October 2006

Our research efforts with durum wheat have led to the development of the SDD concept. Its application makes possible crop yield estimates from remotely acquired canopy temperatures and auxiliary air temperature measurements obtained during the period from head emergence to the cessation of head growth. Canopy albedo measurements appear adequate to delineate this critical period, making the technique potentially adaptable to predictions of crop yields by remote-sensing. The trifactor nomograms produced from combinations of the linear regression equations also suggest that the SDD concept may be used for scheduling irrigations by remote-sensing.
Wood Versus Fossil Fuel as a Source of Excess Carbon Dioxide in the Atmosphere: A Preliminary Report
Authors: Adams J. A. S. , Mantovani M. S. M. , Lundell L. L.
Published: October 2006

If the amounts of wood consumed in deforestation to increase agricultural land and as firewood in underindustrialized countries are added to the amount consumed by the money economies as forest products, the estimates of the net amount of wood removed from the biosphere in this century should be revised upward. The per capita ratio of the weight of carbon from net wood burned to the weight of carbon from fossil fuel burned in this century has been at least 0.1 and may have approached 1.0.
Searching for Extraterrestrial Civilizations
Authors: Kuiper T. B. H. , Morris M.
Published: October 2006

We have argued that planning for a search for extraterrestrial intelligence should involve a minimum number of assumptions. In view of the feasibility (at our present level of understanding) of using nuclear fusion to effect interstellar travel at a speed of 0.1
c
, it appears unwarranted (at this time) to assume that it would not occur for at least some technologically advanced civilizations. One cannot even conclude that humans would not attempt this within the next few centuries. On the contrary, the most likely future situation, given the maintenance of technological growth and the absence of extraterrestrial interference, is that our civilization will explore and colonize our galactic neighborhood.

A comparison of the time scales of galactic evolution and interstellar travel leads to the conclusion that the galaxy is either essentially empty with respect to technological civilizations or extensively colonized. In the former instance, a SETI would be unproductive. In the latter, a SETI could be fruitful if a signal has been deliberately directed at the earth or at an alien outpost, probe, or communication relay station in our solar system. In the former case, an existing antenna would probably be sufficient to detect the signal. In the latter case, success would depend on the way in which the communications were coded.

Failure to detect a signal could permit any of the following conclusions: (i) the galaxy is devoid of technological civilizations, advanced beyond our own, (ii) such civilizations exist, but cannot (for some reason which is presently beyond our ken) engage in interstellar colonization, or (iii) such civilizations are not attempting overt contact with terrestrial civilizations and their intercommunications, if present, are not coded in a simple way. To plan at this time for a high-cost, large-array SETI based on the last two possibilities appears to be rather premature.
Estimate of the Contribution of Biologically Produced Dimethyl Sulfide to the Global Sulfur Cycle
Authors: Maroulis Peter J. , Bandy Alan R.
Published: October 2006

Atmospheric dimethyl sulfide (DMS) measurements were made on the Atlantic Coast of the United States at Wallops Island and Cape Henry, Virginia, during June 1975. The very low concentrations, typically less than 30 parts per trillion observed at the Cape Henry site, were thought to result from the smog chemistry associated with the Norfolk metropolitan area. Atmospheric DMS concentrations at the Wallops Island site were much higher, having a geometric mean of 58 parts per trillion and a geometric standard deviation of 2.1. At this site the DMS source strength was estimated to be 6 milligrams of sulfur per square meter per year. Because of wind conditions during this experiment, the DMS source strength is thought to be representative of the DMS source strength of the ocean in the Wallops Island area and is much less than the 130 milligrams of sulfur per square meter per year needed to balance the ocean-atmosphere portion of the global sulfur budget.
Galilean Satellites of Jupiter: 12.6-Centimeter Radar Observations
Authors: Campbell D. B. , Chandler J. F. , Pettengill G. H. , Shapiro I. I.
Published: October 2006

Observations of the Galilean satellites with the radar system at the Arecibo Observatory, Puerto Rico, show that their surfaces are highly diffuse scatterers of radio waves of length 12.6 centimeters; spectra of the radar echoes are asymmetric and broad. The geometric radar albedos for the outer three satellites—0.42 ± 0.10, 0.20 ± 0.05, and 0.09 ± 0.02 for Europa, Ganymede, and Callisto, respectively—show about the same relative decreases as do the optical albedos, although the latter presumably bear only on material much nearer the surface. Radii of 1420 ± 30, 2640 ± 80, and 2360 ± 70 kilometers for Europa, Ganymede, and Callisto were determined from the radar data and are in good agreement with the corresponding optically derived values. Io, observed successfully only once, appears to have an albedo comparable to Ganymede's, but no radius was estimated for it.
Determining the General Circulation of the Oceans: A Preliminary Discussion
Authors: Wunsch Carl
Published: October 2006

The classical oceanographic problem of deducing the unknown constant in the dynamic method—the problem of the "level of no motion"—may be treated as a geophysical inverse problem. The unknown "barotropic" velocity may be chosen to satisfy an arbitrary number of conservation laws, subject to perfect geostrophic balance and with explicit use made of the relative errors in the observations. The solution obtained is one of minimum energy. A western North Atlantic region is used to demonstrate the power of the method.
Competition Between Seed-Eating Rodents and Ants in Desert Ecosystems
Authors: Brown James H. , Davidson Diane W.
Published: October 2006

Three kinds of evidence indicate that desert rodents and ants compete for seeds: (i) extensive overlaps in diet, (ii) reciprocal increases when one taxon is experimentally excluded, and (iii) complementary patterns of diversity and biomass in geographic gradients of productivity. The effect on seed resources and annual plants seems to be similar whether rodents, ants, or both are foraging.
Moonquakes: Mechanisms and Relation to Tidal Stresses
Authors: Toksöz M. Nafi , Goins Neal R. , Cheng C. H.
Published: October 2006

Observed features of moonquakes are combined with theoretical calculations of the tidal stresses to interpret the moonquake mechanisms. Tidal stresses, together with a postulated ambient tectonic stress, are sufficient to explain the depth, periodicity, and polarity reversal of moonquakes. Both of these stresses are small (on the order of 1 bar) and consistent with the small magnitudes of moonquakes.
Chainlike Formation of Particle Deposits in Fluid-Particle Separation
Authors: Tien Chi , Wang Chiu-Sen , Barot D. T.
Published: October 2006

A theory is proposed for the formation and growth of particle dendrites on a collector placed in an aerosol or hydrosol stream. It is based on the interplay of two intrinsic properties of suspended particles: (i) their finite size and (ii) the randomness of the location of individual particles in the fluid stream. The results of simulations based on this theory resemble those obtained from experiments.
Polyelectrolytes: Potential Chloroform Precursors
Authors: Kaiser Klaus L. E. , Lawrence John
Published: October 2006

Chloroform residues in potable water are generally thought to be derived only from the organic matter in the raw water upon chlorination. However, formation of chloroform at concentrations of a few micrograms per liter from widely used polyelectrolyte coagulants and coagulant aids has now been observed. Most of the ten commercial polyelectrolyte formulations tested reacted with chlorine to form chloroform under thermal conditions. This reaction was found to be strongly activated by ultraviolet irradiation. Since the chemical composition of polyelectrolytes and their impurities are little known, further studies are required before a full assessment of their benefits and potential harm can be made.
North Atlantic Ice-Rafting: A Major Change at 75,000 Years Before the Present
Authors: Ruddiman W. F.
Published: October 2006

During the last interglacial-to-glacial climatic cycle [127,000 to 10,000 years before the present (B.P.)], the fundamental geographic shift in the main axis of ice-rafting deposition occurred at 75,000 years B.P. An earlier meridional depositional maximum along the Greenland-Newfoundland coasts was superseded by a nearly zonal and much stronger axis some 1500 kilometers to the south along 40°N to 50°N. Both depositional patterns are best explained by cyclonic flow in the subpolar gyre, with the depositional shift related to the retreat of warm, ice-melting North Atlantic drift water from the northwestern half of the gyre. Similar shifts must have characterized preceding interglacial-glacial cycles.
Stink of Stinkpot Turtle Identified: ω-Phenylalkanoic Acids
Authors: Eisner Thomas , Conner William E. , Hicks Karen , Dodge Kenneth R. , Rosenberg Herbert I. , Jones Tappey H. , Cohen Marcia , Meinwald Jerrold
Published: October 2006

The exocrine secretion of the "stinkpot turtle,"
Sternotherus odoratus
, discharged by the animals in response to disturbance, contains four ω-phenylalkanoic acids (phenylacetic, 3-phenylpropionic, 5-phenylpentanoic, and 7-phenylheptanoic). The last two of these are new natural products. The first two are powerfully malodorous and responsible for the stench of the fluid. Lesser components, including several aliphatic acids, are also present. Only a few milligrams of secretion are discharged by a turtle at any one time. Although bioassays with fish suggest that the secretion has the potential to serve as a feeding deterrent to predators, it is argued that
Sternotherus
does not ordinarily discharge enough fluid to effect this action and may employ its secretion only as an aposematic signal that warns predators of its more generalized undesirability.
Herbivore-Plant Interactions: Mixed-Function Oxidases and Secondary Plant Substances
Authors: Brattsten L. B. , Wilkinson C. F. , Eisner T.
Published: October 2006

The mixed-function oxidases of a polyphagous insect larva (the southern armyworm,
Spodoptera eridania
) were found to be induced by a diversity of secondary plant substances. The induction proceeds rapidly and in response to a small quantity of secondary substance. Following induction, the larva is less susceptible to dietary poisoning. It is argued that mixed-function oxidases play a major role in protecting herbivores against chemical stress from secondary plant substances.
Vision in Annelid Worms
Authors: Wald George , Rayport Stephen
Published: October 2006

In a first electrophysiological study of worm vision, electroretinograms were measured in two alciopid worms:
Torrea
, taken at the surface, and deep-sea
Vanadis
. Both forms possess a primary retina in the focal plane of the lens, and accessory retinas lying beside the lens. Such accessory retinas occur also in deep-sea fishes and cephalopods. In
Torrea
the primary retina peaks in sensitivity at 400 nanometers, the secondary retina at 560 nanometers. Both together could serve as a depth gauge, since 560 nanometers attenuates much faster in seawater than 400 nanometers. The
Vanadis
eyes peaked in sensitivity at 460 to 480 nanometers, a property shared with deep-sea forms of other phyla; and appropriate, since these wavelengths penetrate seawater most deeply, and also are the wavelengths of maximum bioluminescence.
Female-Female Pairing in Western Gulls (
Larus occidentalis
) in Southern California
Authors: Hunt George L. , Hunt Molly Warner
Published: October 2006

Pairs of females that remain together from one year to the next are associated with the presence of supernormal clutches in western gull nests. Intervals between laying of eggs in supernormal clutches are less than those found in normal clutches, a result indicating both females in a pair contribute to the clutch. Most eggs in supernormal clutches are infertile. The pairs of females occupy territories that are not shared with a resident male. In three homosexual pairs one of the females exhibited behaviors normally ascribed only to males.
Selective Vocal Learning in a Sparrow
Authors: Marler Peter , Peters Susan
Published: October 2006

Male swamp sparrows learn their songs; they fail to learn songs of the sympatric song sparrow. Syllables from tape recordings of both species of sparrow were spliced into an array of swamp sparrow-like and song sparrow-like temporal patterns. Swamp sparrows learned only those songs made of swamp sparrow syllables. They did so irrespective of whether the temporal pattern was swamp sparrow-like or song sparrow-like. Selectivity was retained by birds reared in total isolation from adult conspecific sounds.
Telithromycin-Nonsusceptible Clinical Isolates of
Streptococcus pneumoniae
from Europe
Authors: Al-Lahham Adnan , Appelbaum Peter C. , van der Linden Mark , Reinert Ralf René
Published: October 2006

Telithromycin-nonsusceptible pneumococcal clinical isolates (
n
= 17) were analyzed for their antimicrobial susceptibility, macrolide resistance mechanisms, and genetic relatedness. All strains showed the
erm
(B) genotype and showed a wide range of combinations of macrolide resistance mechanisms. The predominant clone (
n
= 7) was serotype 14, sequence type 143.
Hyaluronic Acid Binding Peptides Prevent Experimental Staphylococcal Wound Infection
Authors: Zaleski Kathleen J. , Kolodka Tadeusz , Cywes-Bentley Colette , McLoughlin Rachel M. , Delaney Mary L. , Charlton Bernard T. , Johnson Wendy , Tzianabos Arthur O.
Published: October 2006

Staphylococcus aureus
is a major cause of surgical wound infections. The development of mechanisms of antimicrobial resistance by this and other bacterial pathogens has prompted the search for new approaches to treat infectious diseases. Hyaluronic acid binding peptides have been shown to modulate cellular trafficking during host responses and were assessed for their ability to treat and possibly prevent experimental surgical wound infections caused by
S. aureus
. Treatment with these peptides was highly efficacious in reducing the number of
S. aureus
cells at the wound site and ameliorated the inflammatory host response associated with these infections. These data suggest a novel approach for the treatment and prophylaxis of staphylococcal wound infections in the clinical setting.
Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection
Authors: Colombo Sara , Buclin Thierry , Cavassini Matthias , Décosterd Laurent A. , Telenti Amalio , Biollaz Jérôme , Csajka Chantal
Published: October 2006

Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1(CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.
Novel Streptomycin Resistance Gene from
Mycobacterium fortuitum
Authors: Ramón-García Santiago , Otal Isabel , Martín Carlos , Gómez-Lus Rafael , Aínsa José A.
Published: October 2006

We have isolated the
aph
(
3
")
-Ic
gene, encoding an aminoglycoside 3"-
O
-phosphotransferase [APH(3")-Ic], from a genomic library of an environmental
Mycobacterium fortuitum
strain, selecting for streptomycin resistance. APH(3")-Ic phosphorylates and inactivates streptomycin. Similar genes have been described in
Streptomyces griseus
and plasmid RSF1010. It is also present in some
M. fortuitum
clinical isolates.
Macrolide and Azithromycin Use Are Linked to Increased Macrolide Resistance in
Streptococcus pneumoniae
Authors: Bergman Miika , Huikko Solja , Huovinen Pentti , Paakkari Pirkko , Seppälä Helena ,   Finnish Study Group for Antimicrobial Resistance (FiRe Network)
Published: October 2006

The connection between regional rates of antimicrobial resistance in
Streptococcus pneumoniae
and regional antimicrobial use in Finland was investigated. During the 6-year study period of 1997 to 2002, a total of 31,609
S. pneumoniae
isolates were tested for penicillin resistance and a total of 23,769 isolates were tested for macrolide resistance in 18 central hospital districts in Finland. The regional macrolide resistance rates were compared with the local use of (i) all macrolides pooled and (ii) azithromycin. The penicillin resistance levels were compared with the consumption data for (i) penicillins, (ii) cephalosporins, (iii) all beta-lactams pooled, and (iv) all macrolides pooled. A statistically significant association between macrolide resistance and total use of macrolides and the use of azithromycin was found. Moreover, total use of beta-lactams and total use of cephalosporins were significantly connected to low-level penicillin resistance. A statistically significant association between penicillin-nonsusceptible isolates and penicillin or total macrolide consumption was not found. In conclusion, total macrolide use and azithromycin use are associated with increased macrolide resistance, and beta-lactam use and cephalosporin use are connected to increased low-level penicillin resistance in
S. pneumoniae
. Unnecessary prescribing of macrolides and cephalosporins should be avoided.
Randomized, Open-Label, Comparative Study of Piperacillin-Tazobactam Administered by Continuous Infusion versus Intermittent Infusion for Treatment of Hospitalized Patients with Complicated Intra-Abdominal Infection
Authors: Lau William K. , Mercer David , Itani Kamal M. , Nicolau David P. , Kuti Joseph L. , Mansfield Debra , Dana Adrian
Published: October 2006

The purpose of this randomized, multicenter, open-label study was to compare the continuous infusion of piperacillin-tazobactam with the standard intermittent infusion in 262 hospitalized patients with complicated intra-abdominal infections. Within 1 day of surgical intervention, eligible patients were randomized (1:1) to piperacillin-tazobactam 12 g/1.5 g administered continuously over 24 h or 3 g/0.375 g administered over 30 min intermittently every 6 h for 4 to 14 days. The demographics of the patients in the groups were similar, with a median APACHE II score of 7 and a median length of hospitalization of 7 days. Among 167 clinically evaluable patients, 86.4% and 88.4% of the patients treated with the continuous infusion and the intermittent infusion, respectively, were clinically cured or improved at the test-of-cure visit (
P
= 0.817). Bacteriological success was observed in 83.9% and 87.9% of patients (
P
= 0.597) in the two groups, respectively, and no differences in bacteriological response by pathogen were noted. Defervesence and white blood cell count normalization occurred in the majority of patients within 3 days and were similar between patients receiving the continuous infusion and those receiving the intermittent infusion. Drug-related adverse events were generally mild and were reported in similar numbers of patients in each arm of the trial. The results of this study support continuous infusion as a safe and reasonable alternate mode of administration of piperacillin-tazobactam for the treatment of complicated intra-abdominal infection.
Derivation of an In Vivo Drug Exposure Breakpoint for Flucytosine againstCandida albicansand Impact of the MIC, Growth Rate, and Resistance Genotype on the Antifungal Effect
Authors: Hope William W. , Warn Peter A. , Sharp Andrew , Howard Susan , Kasai Miki , Louie Arnold , Walsh Thomas J. , Drusano George L. , Denning David W.
Published: October 2006

Drug exposure or pharmacodynamic breakpoints refer to a magnitude of drug exposure which separates a population into groups with high and low probabilities of attaining a desired outcome. We used a pharmacodynamic model of disseminated candidiasis to define an in vivo drug exposure breakpoint for flucytosine (5FC) againstCandida albicans. The results were bridged to humans by using population pharmacokinetics and Monte Carlo simulation. An in vivo drug exposure breakpoint for 5FC was apparent when serum levels were above the MIC for 45% of the dosing interval. The Monte Carlo simulations suggested that using a human dose of 100 mg/kg of body weight/day in four divided doses, 5FC resistance was defined at an MIC of 32 mg/liter. Target attainment rates following administration of 25, 50, and 100 mg/kg/day were similar, suggesting that the use of a lower dose of 5FC is possible. Using six isolates ofC. albicanswith MICs ranging from 0.06 to >64 mg/liter, we also explored the influence that the MIC, the fraction of the dosing interval that the serum levels of 5FC remained above the MIC (T>MIC), the 5FC resistance genotype, and the in vivo growth rate had on the response to 5FC. The MIC and T>MIC were both critical measures affecting the generation of a drug effect but had no bearing on the magnitude of the maximal kill induced by 5FC. The in vivo growth rate was a critical additional determinant of the exposure-response relationship. There was a relationship between the 5FC resistance genotype and the exposure-response relationship.
In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells
Authors: Vidal Francesc , Domingo Joan Carles , Guallar Jordi , Saumoy Maria , Cordobilla Begoña , Sánchez de la Rosa Rainel , Giralt Marta , Álvarez Maria Luisa , López-Dupla Miguel , Torres Ferran , Villarroya Francesc , Cihlar Tomas , Domingo Pere
Published: October 2006

We assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P= 0.002) and TFV (P= 0.0001). The combination of 10 μM RTV and 40 μM LPV significantly reduced RPTEC viability (P< 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs.
Urinary Bactericidal Activity of Extended-Release Ciprofloxacin (1,000 Milligrams) versus Levofloxacin (500 Milligrams) in Healthy Volunteers Receiving a Single Oral Dose
Authors: Wagenlehner Florian M. E. , Kinzig-Schippers Martina , Tischmeyer Uwe , Wagenlehner Christine , Sörgel Fritz , Naber Kurt G.
Published: October 2006

Twelve volunteers received a single oral dose of 1,000 mg extended-release (XR) ciprofloxacin versus 500 mg levofloxacin to assess urinary bactericidal titers (UBTs) against common uropathogens. Areas under UBT-time curves were significantly larger for
Proteus mirabilis
with XR ciprofloxacin and for staphylococci with levofloxacin.
Enhancement of Antimicrobial Activity against
Pseudomonas aeruginosa
by Coadministration of G10KHc and Tobramycin
Authors: Eckert Randal , Brady Keith M. , Greenberg E. Peter , Qi Fengxia , Yarbrough Daniel K. , He Jian , McHardy Ian , Anderson Maxwell H. , Shi Wenyuan
Published: October 2006

Pseudomonas aeruginosa
is a common opportunistic human pathogen that is associated with life-threatening acute infections and chronic airway colonization during cystic fibrosis. Previously, we converted the wide-spectrum antimicrobial peptide novispirin G10 into a
s
electively-
t
argeted
a
nti
m
icrobial
p
eptide (STAMP), G10KHc. Compared to novispirin G10, the STAMP had an enhanced ability to kill
Pseudomonas mendocina
. In this study, we explored the activity of G10KHc against
P. aeruginosa
. G10KHc was found to be highly active (as active as tobramycin) against
P. aeruginosa
clinical isolates. Most interestingly, we observed a synergistic-like enhancement in killing activity when biofilms and planktonic cultures of
P. aeruginosa
were cotreated with G10KHc and tobramycin. The data indicate that the mechanism of enhanced activity may involve increased tobramycin uptake due to G10KHc-mediated cell membrane disruption. These results suggest that G10KHc may be useful against
P. aeruginosa
during acute and chronic infection states, especially when it is coadministered with tobramycin.
In Vitro Pharmacodynamics of Anidulafungin and Caspofungin against
Candida glabrata
Isolates, Including Strains with Decreased Caspofungin Susceptibility
Authors: Cota Jason , Carden Michael , Graybill John R. , Najvar Laura K. , Burgess David S. , Wiederhold Nathan P.
Published: October 2006

The activities of anidulafungin and caspofungin against
Candida glabrata
were evaluated. MICs, 50% inhibitory concentrations (IC
50
values), and IC
90
values for anidulafungin were lower than those for caspofungin for 16 of 18 strains tested. Anidulafungin has potent in vitro activity against
C. glabrata
that is maintained against isolates with elevated caspofungin MICs.
Multiple Genetic Elements Carry the Tetracycline Resistance Gene
tet
(W) in the Animal Pathogen
Arcanobacterium pyogenes
Authors: Billington Stephen J. , Jost B. Helen
Published: October 2006

The
tet
(W) gene is associated with tetracycline resistance in a wide range of bacterial species, including obligately anaerobic rumen bacteria and isolates from the human gut and oral mucosa. However, little is known about how this gene is disseminated and the types of genetic elements it is carried on. We examined tetracycline-resistant isolates of the animal commensal and opportunistic pathogen
Arcanobacterium pyogenes
, all of which carried
tet
(W), and identified three genetic elements designated ATE-1, ATE-2, and ATE-3. These elements were found in 25%, 35%, and 60% of tetracycline-resistant isolates, respectively, with some strains carrying both ATE-2 and ATE-3. ATE-1 shows characteristics of a mobilizable transposon, and the
tet
(W) genes from strains carrying this element can be transferred at low frequencies between
A. pyogenes
strains. ATE-2 has characteristics of a simple transposon, carrying only the resistance gene and a transposase, while in ATE-3, the
tet
(W) gene is associated with a streptomycin resistance gene that is 100% identical at the DNA level with the
aadE
gene from the
Campylobacter jejuni
plasmid pCG8245. Both ATE-2 and ATE-3 show evidence of being carried on larger genetic elements, but conjugation to other strains was not observed under the conditions tested. ATE-1 was preferentially associated with
A. pyogenes
strains of bovine origin, while ATE-2 and ATE-3 elements were primarily found in porcine isolates, suggesting that these elements may circulate in different environments. In addition, four alleles of the
tet
(W) gene, primarily associated with different elements, were detected among
A. pyogenes
isolates.
Adaptive Resistance and Differential Protein Expression ofSalmonella entericaSerovar Enteritidis Biofilms Exposed to Benzalkonium Chloride
Authors: Mangalappalli-Illathu Anil K. , Korber Darren R.
Published: October 2006

The development of adaptive resistance ofSalmonella entericaserovar Enteritidis ATCC 4931 biofilms following exposure to benzalkonium chloride (BC) either continuously (1 μg ml−1) or intermittently (10 μg ml−1for 10 min daily) was examined. Biofilms adapted to BC over a 144-h period could survive a normally lethal BC challenge (500 μg ml−1for 10 min) and then regrow, as determined by increases in biofilm thickness, total biomass, and the ratio of the viable biomass to the nonviable biomass. Exposure of untreated control biofilms to the lethal BC challenge resulted in biofilm erosion and cell death. Proteins found to be up-regulated following BC adaptation were those involved in energy metabolism (TpiA and Eno), amino acid and protein biosynthesis (WrbA, TrxA, RplL, Tsf, Tuf, DsbA, and RpoZ), nutrient binding (FruB), adaptation (CspA), detoxification (Tpx, SodB, and a probable peroxidase), and degradation of 1,2-propanediol (PduJ and PduA). A putative universal stress protein (YnaF) was also found to be up-regulated. Proteins involved in proteolysis (DegQ), cell envelope formation (RfbH), adaptation (UspA), heat shock response (DnaK), and broad regulatory functions (Hns) were found to be down-regulated following adaptation. An overall increase in cellular protein biosynthesis was deduced from the significant up-regulation of ribosomal subunit proteins, translation elongation factors, and amino acid biosynthesis protein and down-regulation of serine endoprotease. The cold shock response, stress response, and detoxification are suggested to play roles in the adaptive resistance ofSalmonellaserovar Enteritidis biofilms to BC.
Genes Involved in Intrinsic Antibiotic Resistance of
Acinetobacter baylyi
Authors: Gomez Maria J. , Neyfakh Alexander A.
Published: October 2006

Bacterial genes defining intrinsic resistance to antibiotics encode proteins that can be targeted by antibiotic potentiators. To find such genes, a transposon insertion library of
Acinetobacter baylyi
was screened with subinhibitory concentrations of various antibiotics to find supersusceptible mutants. A DNA microarray printer was used to replica plate 10,000 individual library clones to select mutants unable to grow at 1/10 the MICs of 12 different antibiotics. Transposon insertions in 11 genes were found to cause an eightfold or higher hypersusceptibility to at least one antibiotic. Most of the mutants identified exhibited hypersusceptibility to β-lactam antibiotics. These included mutants with disruptions of genes encoding proteins involved in efflux (
acrB
and
oprM
) as well as genes pertaining to peptidoglycan synthesis and modification (
ampD
,
mpl
, and
pbpG
). However, disruptions of genes encoding proteins with seemingly unrelated functions (
gph
,
argH
,
hisF, and ACIAD0795
) can also render cells hypersusceptible to β-lactam antibiotics. A knockout of
gshA
, involved in glutathione biosynthesis, enhanced the susceptibility to metronidazole, while a knockout of
recD
, involved in recombination and repair, made the bacteria hypersusceptible to ciprofloxacin. Disruption of
acrB
in
Escherichia coli
rendered the cells hypersusceptible to several antibiotics. However, knockout mutants of other homologous genes in
E. coli
showed no significant changes in antibiotic MICs, indicating that the intrinsic resistance genes are species specific.
In Vitro Activity of Ceftobiprole against Aerobic and Anaerobic Strains Isolated from Diabetic Foot Infections
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni , Warren Yumi A. , Tyrrell Kerin L. , Fernandez Helen T.
Published: October 2006

Against 443 aerobic and anaerobic bacteria isolated from diabetic foot infections, ceftobiprole MICs (μg/ml) at which 90% of the isolates tested were inhibited were as follows: methicillin-resistant
Staphylococcus aureus
, 1; methicillin-susceptible
S. aureus
and
Staphylococcus lugdunensis
, 0.5;
Anaerococcus prevotii
, 0.125;
Finegoldia magna
, 0.5;
Peptoniphilus asaccharolyticus
, 1;
Peptostreptococcus anaerobius
, 4;
Escherichia coli
and
Enterobacter
species, 0.125;
Klebsiella
species, 2; and
Pseudomonas aeruginosa
, 8.
Prevalence in the United States of
aac(6
′
)
-
Ib
-
cr
Encoding a Ciprofloxacin-Modifying Enzyme
Authors: Park Chi Hye , Robicsek Ari , Jacoby George A. , Sahm Daniel , Hooper David C.
Published: October 2006

Among 313
Enterobacteriaceae
from the United States with a ciprofloxacin MIC of ≥0.25 μg/ml and reduced susceptibility to ceftazidime,
aac(6
′
)-Ib
was present in 50.5% of isolates, and of these, 28% carried the
cr
variant responsible for low-level ciprofloxacin resistance.
aac(6
′
)-Ib-cr
was geographically widespread, stable over time, most common in
Escherichia coli
, equally prevalent in ciprofloxacin-susceptible and -resistant strains, and not associated with
qnr
genes.
Population Pharmacokinetics of Tigecycline in Patients with Complicated Intra-Abdominal or Skin and Skin Structure Infections
Authors: Van Wart S. A. , Owen J. S. , Ludwig E. A. , Meagher A. K. , Korth-Bradley J. M. , Cirincione B. B.
Published: October 2006

Tigecycline, a first-in-class expanded glycylcycline antimicrobial agent, has demonstrated efficacy in the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal (cIAI) infections. A population pharmacokinetic (PK) model for tigecycline was developed for patients with cSSSI or cIAI enrolled in two phase 2 clinical trials, and the influence of selected demographic factors and clinical laboratory measures was investigated. Tigecycline was administered as an intravenous loading dose followed by a 0.5- or 1-h infusion every 12 h for up to 14 days. Blood samples were collected the day before or the day of hospital discharge for the determination of serum tigecycline concentrations. Patient covariates were evaluated using stepwise forward (α = 0.05) and backward (α = 0.001) procedures. The predictive performance of the model was assessed separately using pooled data from either two phase 3 studies for patients with cSSSI or two phase 3 studies for patients with cIAI. A two-compartment model with zero-order input and first-order elimination adequately described the steady-state tigecycline concentration-time data. Tigecycline clearance was shown to increase with increasing weight, increasing creatinine clearance, and male gender (
P
< 0.001). The final model provided a relatively unbiased fit to each data set. Individual predicted values of the area under the concentration-time curve from 0 to 12 h (AUC
0-12
) were generally unbiased (median prediction error, −1.60% to −3.78%) and were similarly precise (median absolute prediction error, <4%) when compared across data sets. The population PK model provided the basis to obtain individual estimates of steady-state AUC
0-12
in later exposure-response analyses of tigecycline safety and efficacy in patients with cSSSI or cIAI.
Rocky shoreline deposits in the Lower Silurian (upper Llandovery, Telychian) Chicotte Formation, Anticosti Island, Quebec
Authors: Desrochers André
Published: October 2006

The upper Llandovery (Telychian) Chicotte Formation is a regionally extensive crinoid-rich unit exposed in the south-central part of Anticosti Island in the Gulf of St. Lawrence. The Chicotte encrinites represent an inner ramp, crinoidal sand-shoal complex (about 80 m thick) that prograded over deeper middle to outer ramp facies of the underlying Jupiter Formation in response to a long-term sea-level fall. The typical depositional unit in the Chicotte Formation is a metre-scale subtidal cycle indicating that higher frequency sea-level changes were also present. Metre-scale cycles are typically characterized by coarsening-upward, locally cross-bedded encrinitic material capped by a sharp erosional surface. These bounding surfaces change progressively upsection from simple planar to low-relief scalloped erosional surfaces to complex polyphase surfaces formed by distinct but superimposed erosional events. Three-dimensional paleomorphological features with local relief up to 50 m associated with erosional surfaces are exposed along coastal and river sections and in places have been partially exhumed by modern erosion along coastal exposures to expose a prominent intraformational unconformity. Paleolandforms include large-scale irregular sea stacks and shallow cliffs, similar to those present along modern rocky shorelines. Reefal limestones with small pockets of well-washed crinoidal sand and brachiopod banks form a narrow shoreline sediment wedge piled against the intra-Chicotte unconformity. The sea-level lowstand recorded within the Chicotte Formation coincides with a major sea-level lowstand recognized elsewhere on several continents during the early to middle Telychian time, indicating a eustatic rather than tectonic origin.
Glacial and rocky-shore dynamics of the Karlebotn monadnocks: late Neoproterozoic of northern Norway
Authors: Levine Rebekah , Baarli B Gudveig , Johnson Markes E
Published: October 2006

Located near the village of Karlebotn in East Finnmark, Norway, a cluster of six gneissic monadnocks is unconformably surrounded by weakly metamorphosed sandstone strata of late Neoproterozoic age in the Smalfjord Formation. Differentiated by faults, the monadnocks were further sculpted by a glacier that flowed through a coastal valley concordant with the present-day Varangerfjorden. The largest of the monadnocks is 337 m long and 167 m wide. There remains ample evidence of glacial activity associated with this feature. Relict lodgement tillites are preserved on the west side of the monadnock, flowtillites on the steep surfaces of the north and southwest sides, and a small esker directly on top. The valley was later inundated due to glacial eustacy, and the Karlebotn monadnocks became an archipelago in a shallow estuary of a broad fjord. Interpretation of exposed versus sheltered rocky shores on opposite sides of the largest monadnock island is supported by mineralogical variations in basal strata along the unconformity and evidence of paleocurrents. Greater water energy was concentrated on the southeast side, where a small sandy beach developed. Water energy must have been minimal on the north side because of a general lack of reworking and winnowing of till when the rocky shore was inundated.