bluuebunny/crossref_metadata_2025 huggingface dataset:
Chain-Terminating Dinucleoside Tetraphosphates Are Substrates for DNA Polymerization by Human Immunodeficiency Virus Type 1 Reverse Transcriptase with Increased Activity against Thymidine Analogue-Resistant Mutants
Authors: Meyer Peter R. , Smith Anthony J. , Matsuura Suzanne E. , Scott Walter A.
Published: October 2006

Nucleoside reverse transcriptase inhibitors are an important class of drugs for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Resistance to these drugs is often the result of mutations that increase the transfer of chain-terminating nucleotides from blocked DNA termini to a nucleoside triphosphate acceptor, resulting in the generation of an unblocked DNA chain and synthesis of a dinucleoside polyphosphate containing the chain-terminating deoxynucleoside triphosphate analogue. We have synthesized and purified several dinucleoside tetraphosphates (ddAp
4
ddA, ddCp
4
ddC, ddGp
4
ddG, ddTp
4
ddT, Ap
4
ddG, 2′(3′)-
O
-(
N
-methylanthraniloyl)-Ap
4
ddG, and AppNHppddG) and show that these compounds can serve as substrates for DNA chain elongation and termination resulting in inhibition of DNA synthesis. Thymidine analogue-resistant mutants of reverse transcriptase are up to 120-fold more sensitive to inhibition by these compounds than is wild-type enzyme. Drugs based on the dinucleoside tetraphosphate structure could delay or prevent the emergence of mutants with enhanced primer unblocking activity. In addition, such drugs could suppress the resistance phenotype of mutant HIV-1 that is present in individuals infected with resistant virus.
Peptide Deformylase Inhibitors as Potent Antimycobacterial Agents
Authors: Teo Jeanette W. P. , Thayalan Pamela , Beer David , Yap Amelia S. L. , Nanjundappa Mahesh , Ngew Xinyi , Duraiswamy Jeyaraj , Liung Sarah , Dartois Veronique , Schreiber Mark , Hasan Samiul , Cynamon Michael , Ryder Neil S. , Yang Xia , Weidmann Beat , Bracken Kathryn , Dick Thomas , Mukherjee Kakoli
Published: October 2006

Peptide deformylase (PDF) catalyzes the hydrolytic removal of the N-terminal formyl group from nascent proteins. This is an essential step in bacterial protein synthesis, making PDF an attractive target for antibacterial drug development. Essentiality of the
def
gene, encoding PDF from
Mycobacterium tuberculosis
, was demonstrated through genetic knockout experiments with
Mycobacterium bovis
BCG. PDF from
M. tuberculosis
strain H37Rv was cloned, expressed, and purified as an N-terminal histidine-tagged recombinant protein in
Escherichia coli
. A novel class of PDF inhibitors (PDF-I), the
N
-alkyl urea hydroxamic acids, were synthesized and evaluated for their activities against the
M. tuberculosis
PDF enzyme as well as their antimycobacterial effects. Several compounds from the new class had 50% inhibitory concentration (IC
50
) values of <100 nM. Some of the PDF-I displayed antibacterial activity against
M. tuberculosis
, including MDR strains with MIC
90
values of <1 μM. Pharmacokinetic studies of potential leads showed that the compounds were orally bioavailable. Spontaneous resistance towards these inhibitors arose at a frequency of ≤5 × 10
−7
in
M. bovis
BCG. DNA sequence analysis of several spontaneous PDF-I-resistant mutants revealed that half of the mutants had acquired point mutations in their formyl methyltransferase gene (
fmt
), which formylated Met-tRNA. The results from this study validate
M. tuberculosis
PDF as a drug target and suggest that this class of compounds have the potential to be developed as novel antimycobacterial agents.
Complete DNA Sequence, Comparative Genomics, and Prevalence of an IncHI2 Plasmid Occurring among Extraintestinal Pathogenic
Escherichia coli
Isolates
Authors: Johnson Timothy J. , Wannemeuhler Yvonne M. , Scaccianoce Jennifer A. , Johnson Sara J. , Nolan Lisa K.
Published: October 2006

We have sequenced a large plasmid that occurs among avian pathogenic
Escherichia coli
isolates. This plasmid, pAPEC-O1-R, is a 241,387-bp IncHI2 plasmid which is cotransmissible via bacterial conjugation with a ColBM virulence plasmid, encodes resistance to eight antimicrobial agents, and appears to occur at low rates among extraintestinal
E. coli
isolates.
Effects of Various Media on the Activity of NXL103 (Formerly XRP 2868), a New Oral Streptogramin, against
Haemophilus influenzae
Authors: Pankuch Glenn A. , Hoellman Dianne , Bryskier André , Lowther John , Appelbaum Peter C.
Published: October 2006

The activity of NXL103 against 108 strains of
Haemophilus influenzae
was tested using
Haemophilus
test media (HTM) obtained from various sources. With the exception of those obtained with stored HTM, MICs did not differ significantly, with MIC
50
and MIC
90
values of 0.5 and 0.5 to 1 μg/ml, respectively, in each medium.
Synergy between Efflux Pump CmeABC and Modifications in Ribosomal Proteins L4 and L22 in Conferring Macrolide Resistance in
Campylobacter jejuni
and
Campylobacter coli
Authors: Cagliero Cédric , Mouline Christian , Cloeckaert Axel , Payot Sophie
Published: October 2006

Macrolide-resistant mutants of
Campylobacter jejuni
and
Campylobacter coli
were selected in vitro using erythromycin and tylosin. These mutants exhibited modifications in the ribosomal proteins L4 (G74D) and L22 (insertions at position 86 or 98). A synergy between the CmeABC efflux pump and these modifications in conferring macrolide resistance was observed.
Amino Acid Substitutions in Mosaic Penicillin-Binding Protein 2 Associated with Reduced Susceptibility to Cefixime in Clinical Isolates of
Neisseria gonorrhoeae
Authors: Takahata Sho , Senju Nami , Osaki Yumi , Yoshida Takuji , Ida Takashi
Published: October 2006

The molecular mechanisms of reduced susceptibility to cefixime in clinical isolates of
Neisseria gonorrhoeae
, particularly amino acid substitutions in mosaic penicillin-binding protein 2 (PBP2), were examined. The complete sequence of
ponA
,
penA
, and
por
genes, encoding, respectively, PBP1, PBP2, and porin, were determined for 58 strains isolated in 2002 from Japan. Replacement of leucine 421 by proline in PBP1 and the mosaic-like structure of PBP2 were detected in 48 strains (82.8%) and 28 strains (48.3%), respectively. The presence of mosaic PBP2 was the main cause of the elevated cefixime MIC (4- to 64-fold). In order to identify the mutations responsible for the reduced susceptibility to cefixime in isolates with mosaic PBP2,
penA
genes with various mutations were transferred to a susceptible strain by genetic transformation. The susceptibility of partial recombinants and site-directed mutants revealed that the replacement of glycine 545 by serine (G545S) was the primary mutation, which led to a two- to fourfold increase in resistance to cephems. Replacement of isoleucine 312 by methionine (I312M) and valine 316 by threonine (V316T), in the presence of the G545S mutation, reduced susceptibility to cefixime, ceftibuten, and cefpodoxime by an additional fourfold. Therefore, three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in
N. gonorrhoeae
.
In Vitro Antianaerobic Activity of DX-619, a New Des-Fluoro(6)Quinolone
Authors: Tanaka Kaori , Mikamo Hiroshige , Nakao Ken'ichi , Watanabe Kunitomo
Published: October 2006

The
in vitro activity of DX-619, a new des-F(6) quinolone, against
anaerobic bacteria was evaluated. DX-619 showed potent activity against
Bacteroides
,
Prevotella
,
Fusobacterium
,
Micromonas
,
Actinomyces
, and
Clostridium
spp., with MIC
50
s/MIC
90
s of ≤0.03 to
0.25/≤0.03 to 1 μg/ml, respectively. DX-619 was also
active against imipenem-resistant
Bacteroides
spp., with
MIC
50
s/MIC
90
s of 0.25/1 μg/ml,
respectively.
Studies on the Mode of Action of the Antifungal Hexapeptide PAF26
Authors: Muñoz Alberto , López-García Belén , Marcos Jose F.
Published: October 2006

The small antimicrobial peptide PAF26 (Ac-RKKWFW-NH
2
) has been identified by a combinatorial approach and shows preferential activity toward filamentous fungi. In this work, we investigated the mode of action and inhibitory effects of PAF26 on the fungus
Penicillium digitatum
. The dye Sytox Green was used to demonstrate that PAF26 induced cell permeation. However, microscopic observations showed that sub-MIC concentrations of PAF26 produced both alterations of hyphal morphology (such as altered polar growth and branching) and chitin deposition in areas of no detectable permeation. Analysis of dose-response curves of inhibition and permeation suggested that growth inhibition is not solely a consequence of permeation. In order to shed light on the mode of PAF26 action, its antifungal properties were compared with those of melittin, a well-known pore-forming peptide that kills through cytolysis. While the 50% inhibitory concentrations and MICs of the two peptides against
P. digitatum
mycelium were comparable, they differed markedly in their fungicidal activities toward conidia and their hemolytic activities toward human red blood cells. Kinetic studies showed that melittin quickly induced
Penicillium
cell permeation, while PAF26-induced Sytox Green uptake was significantly slower and less efficient. Therefore, the ultimate growth inhibition and morphological alterations induced by PAF26 for
P. digitatum
are not likely a result of conventional pore formation. Fluorescently labeled PAF26 was used to demonstrate its specific in vivo interaction and translocation inside germ tubes and hyphal cells, at concentrations as low as 0.3 μM (20 times below the MIC), at which no inhibitory, morphological, or permeation effects were observed. Interestingly, internalized PAF26 could bind to cellular RNAs, since in vitro nonspecific RNA binding activity of PAF26 was demonstrated by electrophoretic mobility shift assays. We propose that PAF26 is a short, de novo-designed penetratin-type peptide that has multiple detrimental effects on target fungi, which ultimately result in permeation and killing.
In Vitro Activities of Tritrpticin Alone and in Combination with Other Antimicrobial Agents against
Pseudomonas aeruginosa
Authors: Cirioni Oscar , Giacometti Andrea , Silvestri Carmela , Della Vittoria Agnese , Licci Alberto , Riva Alessandra , Scalise Giorgio
Published: October 2006

The in vitro activity of the cathelicidin tritrpticin was investigated against multidrug-resistant
Pseudomonas aeruginosa
. The isolates were susceptible to the peptide at concentrations of 0.50 to 8 mg/liter. Tritrpticin completely inhibits lipopolysaccharide procoagulant activity at a 10 μM concentration. Fractionary inhibitory concentration indexes (0.385, 0.312, and 0.458) demonstrated synergy between the peptide and β-lactams.
Unexpected Link between Iron and Drug Resistance of
Candida
spp.: Iron Depletion Enhances Membrane Fluidity and Drug Diffusion, Leading to Drug-SusceptibleCells
Authors: Prasad Tulika , Chandra Aparna , Mukhopadhyay Chinmay K. , Prasad Rajendra
Published: October 2006

Inthis study, we show that iron depletion in
Candida
albicans
with bathophenanthrolene disulfonic acid and
ferrozine as chelators enhanced its sensitivity to several drugs,
including the most common antifungal, fluconazole (FLC). Several other
species of
Candida
also displayed increased sensitivity to FLC
because of iron restriction. Iron uptake mutations, namely,Δ
ftr1
and Δ
ftr2
, as well as the
copper transporter mutation Δ
ccc2
, which affects
high-affinity iron uptake in
Candida
, produced increased
sensitivity to FLC compared to that of the wild type. The effect of
iron depletion on drug sensitivity appeared to be independent of the
efflux pump proteins Cdr1p and Cdr2p. We found that iron deprivation
led to lowering of membrane ergosterol by 15 to 30%. Subsequently,
fluorescence polarization measurements also revealed that
iron-restricted
Candida
cells displayed a 29 to 40% increase
in membrane fluidity, resulting in enhanced passive diffusion of the
drugs. Northern blot assays revealed that the
ERG11
gene was
considerably down regulated in iron-deprived cells, which might account
for the lowered ergosterol content. Our results show a close
relationship between cellular iron and drug susceptibilities of
C. albicans
. Considering that multidrug resistance is
a manifestation of multifactorial phenomena, the influence of cellular
iron on the drug susceptibilities of
Candida
suggests iron as
yet another novel determinant of multidrug
resistance.
Novel
Pseudomonas aeruginosa
Quorum-Sensing Inhibitors Identified in an Ultra-High-Throughput Screen
Authors: Müh Ute , Schuster Martin , Heim Roger , Singh Ashvani , Olson Eric R. , Greenberg E. Peter
Published: October 2006

The opportunistic pathogen
Pseudomonas aeruginosa
has two complete acyl-homoserine lactone (acyl-HSL) signaling systems, LasR-LasI and RhlR-RhlI. LasI catalyzes the synthesis of
N
-3-oxododecanoyl homoserine lactone (3OC12-HSL), and LasR is a transcription factor that requires 3OC12-HSL as a ligand. RhlI catalyzes the synthesis of
N
-butanoyl homoserine lactone (C
4
), and RhlR is a transcription factor that responds to C
4
. LasR and RhlR control the transcription of hundreds of
P. aeruginosa
genes, many of which are critical virulence determinants, and LasR is required for RhlR function. We developed an ultra-high-throughput cell-based assay to screen a library of approximately 200,000 compounds for inhibitors of LasR-dependent gene expression. Although the library contained a large variety of chemical structures, the two best inhibitors resembled the acyl-homoserine lactone molecule that normally binds to LasR. One compound, a tetrazole with a 12-carbon alkyl tail designated PD12, had a 50% inhibitory concentration (IC
50
) of 30 nM. The second compound, V-06-018, had an IC
50
of 10 μM and is a phenyl ring with a 12-carbon alkyl tail. A microarray analysis showed that both compounds were general inhibitors of quorum sensing, i.e., the expression levels of most LasR-dependent genes were affected. Both compounds also inhibited the production of two quorum-sensing-dependent virulence factors, elastase and pyocyanin. These compounds should be useful for studies of LasR-dependent gene regulation and might serve as scaffolds for the identification of new quorum-sensing modulators.
Search for Cyclodextrin-Based Inhibitors of Anthrax Toxins: Synthesis, Structural Features, and Relative Activities
Authors: Karginov Vladimir A. , Nestorovich Ekaterina M. , Yohannes Adiamseged , Robinson Tanisha M. , Fahmi Nour Eddine , Schmidtmann Frank , Hecht Sidney M. , Bezrukov Sergey M.
Published: October 2006

Recently, using structure-inspired drug design, we demonstrated that aminoalkyl derivatives of β-cyclodextrin inhibited anthrax lethal toxin action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. In the present study, we evaluate a series of new β-cyclodextrin derivatives with the goal of identifying potent inhibitors of anthrax toxins. Newly synthesized hepta-6-thioaminoalkyl and hepta-6-thioguanidinoalkyl derivatives of β-cyclodextrin with alkyl spacers of various lengths were tested for the ability to inhibit cytotoxicity of lethal toxin in cells as well as to block ion conductance through PA channels reconstituted in planar bilayer lipid membranes. Most of the tested derivatives were protective against anthrax lethal toxin action at low or submicromolar concentrations. They also blocked ion conductance through PA channels at concentrations as low as 0.1 nM. The activities of the derivatives in both cell protection and channel blocking were found to depend on the length and chemical nature of the substituent groups. One of the compounds was also shown to block the edema toxin activity. It is hoped that these results will help to identify a new class of drugs for anthrax treatment, i.e., drugs that block the pathway for toxin translocation into the cytosol, the PA channel.
Variant
Salmonella
Genomic Island 1-L Antibiotic Resistance Gene Cluster in
Salmonella enterica
Serovar Newport
Authors: Cloeckaert Axel , Praud Karine , Doublet Benoît , Demartin Marie , Weill François-Xavier
Published: October 2006

We report a new
Salmonella
genomic island 1 variant antibiotic resistance gene cluster called SGI1-L in a
Salmonella enterica
serovar Newport isolate containing a
dfrA15
gene cassette conferring resistance to trimethoprim. The isolate carried another class 1 integron containing the
aacC5
and
aadA7
gene cassettes conferring resistance to gentamicin and streptomycin/spectinomycin, respectively.
Integration of Pharmacokinetic and Pharmacodynamic Indices of Marbofloxacin in Turkeys
Authors: Haritova Aneliya Milanova , Rusenova Nikolina Velizarova , Parvanov Parvan Rusenov , Lashev Lubomir Dimitrov , Fink-Gremmels Johanna
Published: October 2006

Fluoroquinolones are extensively used in the treatment of systemic bacterial infections in poultry, including systemic
Escherichia coli
bacillosis, which is a common disease in turkey flocks. Marbofloxacin has been licensed for use in various mammalian species, but not as yet for turkeys, although its kinetic properties distinguish it from other fluoroquinolones. For example, the longer half-life of marbofloxacin in many animal species has been appreciated in veterinary practice. It is generally accepted that, for fluoroquinolones, the optimal dose should be estimated on the basis of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the drug under consideration. Knowledge of these specific data for the target animal species allows the establishment of an integrated PK-PD model that is of high predictive value. In the present study, the antibacterial efficacy (PD indices) against a field isolate of
Escherichia coli
O78/K80 was investigated ex vivo following oral and intravenous administration of marbofloxacin to turkeys (breed BUT 9; six animals per group) at a dose of 2 mg/kg of body weight (BW). At the same time, the serum concentrations of marbofloxacin were measured at different time intervals by a standardized high-performance liquid chromatography method, allowing the calculation of the most relevant kinetic parameters (PK parameters). The in vitro serum inhibitory activity of marbofloxacin against the selected
E. coli
strain, O78/K80, was 0.5 μg/ml in the blood serum of turkeys, and the ratio of the maximum concentration of the drug in serum to the serum inhibitory activity was 1.34. The lowest ratio of the measured serum concentration multiplied by the incubation period of 24 h to the serum inhibitory activity required for bacterial elimination was lower than the ratio of the area under the serum concentration-time curve (AUC) to the serum inhibitory activity. These first results suggested that the recommended dose of 2 mg/kg BW of marbofloxacin is sufficient to achieve a therapeutic effect in diseased animals. However, considering the risk of resistance induction, the applied dose should be equal to an AUC/MIC of >125, the generally recommended dose for all fluoroquinolones. According to the PK-PD results presented here, a dose of 3.0 to 12.0 mg/kg BW per day would be needed to meet this criterion. In conclusion, the results of the present study provide the rationale for an optimal dose regimen for marbofloxacin in turkeys and hence should form the basis for dose selection in forthcoming clinical trials.
Postantibiotic Effect of Ceftobiprole against 12 Gram-Positive Organisms
Authors: Pankuch G. A. , Appelbaum P. C.
Published: October 2006

The in vitro postantibiotic effects (PAEs), postantibiotic sub-MIC effects (PA-SMEs), and sub-MIC effects of ceftobiprole were determined for 12 gram-positive organisms. Pneumococcal, staphylococcal, and enterococcal PAEs were 1.4 to 3.1 h, 0 to 1.8 h, and 0 to 0.9 h, respectively. The PA-SMEs (0.4 times the MIC) for pneumococci, staphylococci, and enterococci were 4.8 to >10.3 h, 1.5 to 9.6 h, and 3.8 to >10.7 h, respectively.
Prevalence of Mutations Associated with Higher Levels of Sulfadoxine-Pyrimethamine Resistance in
Plasmodium falciparum
Isolates from Car Nicobar Island and Assam, India
Authors: Ahmed Anwar , Lumb Vanshika , Das Manoj K. , Dev Vas , Wajihullah  , Sharma Yagya D.
Published: October 2006

To assess sulfadoxine and pyrimethamine resistance (SPR), we describe here the dihydropteroate synthetase (DHPS) mutations among the
Plasmodium falciparum
isolates in which dihydrofolate reductase (DHFR) mutations had recently been described by us (A. Ahmed, M. K. Das, V. Dev, M. A. Saifi, Wajihullah, and Y. D. Sharma, Antimicrob. Agents Chemother. 50:1546-1549, 2006). A majority of isolates from Car Nicobar island showed double DHPS mutations, whereas a majority of isolates from Uttar Pradesh (U.P.) and Assam contained the wild-type DHPS. Based on DHFR-DHPS mutations, the expected level of SPR was lowest in U.P., higher in Assam, and highest in Car Nicobar, suggesting that a region-wise drug policy is needed in India.
Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years
Authors: Jullien Vincent , Urien Saïk , Hirt Déborah , Delaugerre Constance , Rey Elisabeth , Teglas Jean-Paul , Vaz Paula , Rouzioux Christine , Chaix Marie-Laure , Macassa Eugenia , Firtion Ghislaine , Pons Gérard , Blanche Stéphane , Tréluyer Jean-Marc
Published: October 2006

The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (
V
/
F
) and plasma clearance (CL/
F
) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir
V
/
F
and CL/
F
were both related to body weight (BW), with an important increase in weight-normalized CL/
F
for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/
F
. The lopinavir CL/
F
was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/
F
for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.
A Small Subpopulation of Blastospores in
Candida albicans
Biofilms Exhibit Resistance to Amphotericin B Associated with Differential Regulation of Ergosterol and
β
-1,6-Glucan Pathway Genes
Authors: Khot Prasanna D. , Suci Peter A. , Miller R. Lance , Nelson Raoul D. , Tyler Bonnie J.
Published: October 2006

The resistance of
Candida albicans
biofilms to a broad spectrum of antimicrobial agents has been well documented. Biofilms are known to be heterogeneous, consisting of microenvironments that may induce formation of resistant subpopulations. In this study we characterized one such subpopulation.
C. albicans
biofilms were cultured in a tubular flow cell (TF) for 36 h. The relatively large shear forces imposed by draining the TF removed most of the biofilm, which consisted of a tangled mass of filamentous forms with associated clusters of yeast forms. This portion of the biofilm exhibited the classic architecture and morphological heterogeneity of a
C. albicans
biofilm and was only slightly more resistant than either exponential- or stationary-phase planktonic cells. A submonolayer fraction of blastospores that remained on the substratum was resistant to 10 times the amphotericin B dose that eliminated the activity of the planktonic populations. A comparison between planktonic and biofilm populations of transcript abundance for genes coding for enzymes in the ergosterol (
ERG1
, -
3
, -
5
, -
6
, -
9
, -
11
, and -
25
) and β-1,6-glucan (
SKN
and
KRE1
, -
5
, -
6
, and -
9
) pathways was performed by quantitative RT-PCR. The results indicate a possible association between the high level of resistance exhibited by the blastospore subpopulation and differential regulation of
ERG1
,
ERG25
,
SKN1
, and
KRE1
. We hypothesize that the resistance originates from a synergistic effect involving changes in both the cell membrane and the cell wall.
Methodological Issues in the Assessment of Antimalarial Drug Treatment: Analysis of 13 Studies in Eight African Countries from 2001 to 2004
Authors: Guthmann Jean-Paul , Pinoges Loretxu , Checchi Francesco , Cousens Simon , Balkan Suna , van Herp Michel , Legros Dominique , Olliaro Piero
Published: October 2006

The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).
Maximal lipidic power in high competitive level triathletes and cyclists
Authors: González-Haro C , Galilea P A , González-de-Suso J M , Drobnic F , Escanero J F
Published: October 2006

Objective:To describe the fat-oxidation rate in triathlon and different modalities of endurance cycling.

Methods:34 endurance athletes (15 male triathletes, 4 female triathletes, 11 road cyclists and 4 male mountain bikers) underwent a progressive cycloergometer test until exhaustion. Relative work intensity (VO2max), minimal lactate concentration (La−min), lactic threshold, individual lactic threshold (ILT), maximal fat-oxidation rate (Fatmax, Fatmaxzone) and minimal fat-oxidation rate (Fatmin) were determined in each of the groups and were compared by means of one-way analysis of variance.

Results:No significant differences were found for Fatmax, Fatminor for the Fatmaxzone expressed as fat oxidation rate (g/min). Intensities −20%, −10% and −5% Fatmaxwere significantly lower for mountain bikers with respect to road cyclists and female triathletes, expressed as % VO2max. Intensities 20%, 10% and 5% Fatmaxwere significantly lower for mountain bikers with respect to male triathletes and female triathletes, and for male triathletes in comparison with female triathletes, expressed as % VO2max. Lactic threshold and La−mindid not show significant differences with respect to Fatmax. Lactic threshold was found at the same VO2maxwith respect to the higher part of the Fatmaxzone, and La−minat the same VO2maxwith respect to the lower part of the Fatmaxzone.

Conclusions:The VO2maxof Fatmaxand the Fatmaxzone may explain the different endurance adaptations of the athletes according to their sporting discipline. Lactic threshold and La−minwere found at different relative work intensities with respect to those of Fatmaxeven though they belonged to the Fatmaxzone.
Blood tests in tired elite athletes: expectations of athletes, coaches and sport science/sports medicine staff
Authors: Fallon K E
Published: October 2006

Background:The issue of the expectations of elite athletes, their coaches and non-medically qualified athlete support staff of consultations with sports physicians has not been previously dealt with in the sports medicine literature. As fulfilment of expectations of the content of a consultation may influence patient’s satisfaction and clinical outcome, it is important to assess the expectations of athletes and, most importantly, coaches.

Objective:To assess the expectations and beliefs about fatigue, particularly in relation to blood tests, of athletes, their coaches and support staff in the specific context of tiredness of <7 days’ duration.

Subjects:28 senior sports science or non-medically qualified sports medicine staff, 22 elite coaches and 62 elite athletes from the Australian Institute of Sport were included in this study.

Methods:A single questionnaire.

Results:The expectation for a blood test at the initial consultation for short-term fatigue was particularly high among athletes (81%) and coaches (91%). This expectation increased in athletes if their performance was worsening. All groups unanimously suggested that a blood test be performed in cases of more prolonged fatigue. Increase in total training load was perceived to be the most important cause of fatigue, but issues relating to sleep were also thought to be highly relevant. All groups suggested that blood tests provide some degree of reassurance, and all groups suggested that the most important blood tests that might be performed related to exclusion of iron deficiency, anaemia and infection.

Conclusion:Athletes and their coaches generally expect that blood tests will be performed even when fatigue has been present for <1 week. This is at odds with currently available evidence of the diagnostic utility of these tests. Despite the current evidence base, individual factors in the athletes, coaches and doctors need to be considered when deciding on whether such testing has to be performed.
Gold prospectivity maps of the Red Lake greenstone belt: application of GIS technology
Authors: Harris J R , Sanborn-Barrie M , Panagapko D A , Skulski T , Parker J R
Published: October 2006

Recent advances in the use of Geographic Information Systems (GIS) software and analysis can be used in conjunction with traditional geoscience data sets to determine effective predictors for gold mineralization, from which mineral prospectivity maps can be generated that highlight potential exploration targets on a regional scale. In this paper, key components of the Archean lode gold deposit model for the Red Lake belt are selected and modeled using weights of evidence (WofE) analysis and logistic regression, leading to the creation of gold prospectivity maps. The best predictors for past and present gold producers in the Red Lake camp, according to WofE analysis include (1) elevated trace elements, Au, As, and Sb; (2) a number of alteration indices calculated from oxide geochemical data; (3) alteration characterized by pervasive and vein-style ferroan carbonate and elevated Au, As, Sb, and S anomalies; (4) proximity to the Mackenzie Island stock and diorite phases of the Dome stock; and, (5) tholeiitic basaltic flows and associated gabbroic rocks of the Balmer assemblage. Gold prospectivity maps produced by logistic regression using binary evidence maps highlight anomalous localities within known and highly prospective areas in the district (Madsen – Red Lake corridor, Balmertown – Cochenour – East Bay). In addition, a number of localities not known to contain significant deposits were also identified as prospective.
Stratigraphy, structure, and geochronology of the 3.02.7 Ga Wallace Lake greenstone belt, western Superior Province, southeast Manitoba, Canada
Authors: Sasseville C , Tomlinson K Y , Hynes A , McNicoll V
Published: October 2006

In western Superior province, the North Caribou terrane (NCT) constitutes a Mesoarchean proto-continent heavily overprinted by Neoarchean magmatism and deformation resulting from the western Superior Province accretion. Locally, along the southern margin of the NCT, Mesoarchean (~3.0 Ga) rift sequences are preserved. These sequences are of key importance to our understanding of the early tectonic evolution of continental crust. The Wallace Lake greenstone belt is located at the southern margin of the NCT and includes the Wallace Lake assemblage, the Big Island assemblage, the Siderock Lake assemblage, and the French Man Bay assemblage. The Wallace Lake assemblage exposes one of the best-preserved Mesoarchean rift sequences along the southern margin of the NCT. The volcano-sedimentary assemblage (3.02.92 Ga) exposes arkoses derived from the uplift of a tonalite basement in a subaqueous environment, capped by carbonate and iron formation. Mafic to ultramafic volcanic rocks exhibiting crustal contamination and derived from plume magmatism cap this rift sequence. The Wallace Lake assemblage exhibits D1 Mesoarchean deformation. The Big Island assemblage comprises mafic volcanic rocks of oceanic affinity that were docked to the Wallace Lake assemblage along northwest-trending D2 shear zones. The timing of volcanism and docking of the Big Island assemblage remain uncertain. The Siderock Lake and French Man Bay assemblages were deposited in strike-slip basins related to D3 and D4 stages of movement of the transcurrent Wanipigow fault (<2.709 Ga). Regionally, the Wallace Lake assemblage correlates with the LewisStory Rift assemblage observed in Lake Winnipeg, whereas the Big Island assemblage appears to correlate with the Black Island assemblage observed in the Lake Winnipeg area. Thus, the North Caribou terrane appears to preserve vestiges of a Mesoarchean rifted succession together with overlying Neoarchean allochthonous, juvenile, volcanic successions over a considerable distance along its present-day southern margin.
Geological evolution of the northwestern Superior Province: Clues from geology, kinematics, and geochronology in the Gods Lake Narrows area, Oxford–Stull terrane, Manitoba
Authors: Lin S , Davis D W , Rotenberg E , Corkery M T , Bailes A H
Published: October 2006

The study of lithology, geochronology, and structure in the Oxford–Stull terrane, in particular in the Gods Lake Narrows area, has led to the recognition of three distinct supracrustal sequences: ~2.8–2.9 Ga volcanic rocks; a ~2720 Ma fault-bounded package of volcanics and sandstones; and ~2705 Ma conglomerate and alkaline volcanic rocks of the Oxford Lake Group. Detrital zircon as old as 3647 Ma is present in the Oxford Lake Group. An early generation of folding and shearing occurred prior to deposition of the Oxford Lake Group and was probably synchronous with emplace ment of 2721 Ma tonalite dykes. The second generation of deformation caused south-over-north thrusting of volcanic rocks over the Oxford Lake Group. The youngest fabric resulted from east-southeast-trending, dextral, south-over-north shearing. The youngest rock dated in the area is the 2668 ± 1 Ma Magill Lake pluton, which records crustal melting following deformation. The pattern of sedimentation and deformation in this area is similar to but slightly older than that found in the southern half of the Superior Province, which shows a southward-younging diachroneity. The south-dipping north-vergent shear zones observed in the area contrast with dominantly north-dipping south-vergent structures observed and interpreted south of the North Caribou superterrane (NCS). The limited size of the study area precludes any strongly based large-scale tectonic interpretation; however, data and observations from the Gods Lake Narrows area are most easily accommodated in a model where the NCS served as a nucleus onto which other terranes were accreted and both the northern and southern margins of the NCS were Andean-type continental margins with opposite subduction polarities.
Invasive potential of common carp (Cyprinus carpio) and Nile tilapia (Oreochromis niloticus) in American freshwater systems
Authors: Zambrano Luis , Martínez-Meyer Enrique , Menezes Naercio , Peterson A Townsend
Published: October 2006

Nonnative fish introductions disrupt ecosystem processes and can drive native species to local extinction. Two of the most widespread, introduced species are the common carp (Cyprinus carpio) from Eurasia and the Nile tilapia (Oreochromis niloticus) from Africa. In North and South America, these introductions stem from aquaculture facilities, as well as historical introductions for recreational angling. An emergent field of ecological niche modeling provides robust predictions of the geographic potential of alien species to better understand their capacity to become established at broad scales. We used this modeling approach to produce spatially explicit predictions of the invasive potential of common carp and Nile tilapia in the Americas. Model predictions were tested using occurrence data for established populations in their native area and in the Americas. Results indicated that predictive power of niche models was high. Distributional potential of common carp in the Americas covers most temperate regions and high mountain tropical aquatic systems, whereas that of Nile tilapia is focused in the tropics and coast areas. The consequences of the potential establishment of these exotic species can be profound on native aquatic faunas, particularly on highly diverse regions such as the Amazon Basin and central Mexico.
The catchability of large American lobsters (Homarus americanus) from diving and trapping studies off Grand Manan Island, Canadian Maritimes
Authors: Tremblay M J , Smith S J , Robichaud D A , Lawton P
Published: October 2006

Catchability (q) in traps was estimated for American lobsters (Homarus americanus) in Flagg Cove, off Grand Manan Island (New Brunswick, Canada), where large females (>100 mm carapace length (CL)) aggregate in late summer and early fall. In 2001 and 2002, diver surveys were used to estimate lobster density, and traps were then deployed to obtain catch rates. Bayesian generalized linear models were fit to the densities of different size groups (81–100, 101–130, 131–160, and >160 mm CL) of ovigerous females, non-ovigerous females, and males. Catchability was strongly affected by year. Differences in q due to sex and size for ovigerous females, non-ovigerous females, and males were apparent but were not consistent between years. Size was not an important factor for the catchability of lobsters between 81 and 160 mm CL. In comparison with lobsters of a similar size in other areas, Flagg Cove lobsters in the size range of 81–100 mm CL were less catchable. We hypothesize that this resulted from the high densities and larger sizes of lobsters in Flagg Cove, which likely lead to increased agonistic interactions and reduced entry of lobsters into traps.
Are there hot spots for Elliptio complanata in the shallow littoral zone of a large Canadian Shield lake?
Authors: Griffiths Natalie A , Cyr Hélène
Published: October 2006

The variability in habitat conditions in large lake basins may provide areas favourable for unionid recruitment and growth. Here we test whether the distribution, body size, and growth rate of Elliptio complanata differ between upwind and downwind sites in a 5.8 km long lake basin. We measured density and morphological characteristics of E. complanata at nine upwind and nine downwind sites. We also measured growth rates and stable isotope (δ13C, δ15N) signatures at three upwind and three downwind sites. We found no difference in density or body size of E. complanata between upwind and downwind sites, despite clear differences in water temperature and food availability. Contrary to our expectations, the growth rate of E. complanata was higher (by 62%) at upwind sites. The reason for this difference is uncertain, but higher shell erosion and a negative relationship between δ13C and C/N ratio suggest that E. complanata may be more stressed at downwind sites. The δ15N of E. complanata did not differ systematically between upwind and downwind sites, but increased with increasing body size. It would therefore be prudent to standardize the size of E. complanata used to measure the baseline of lake food webs.
Diatom reference communities in Québec (Canada) streams based on Kohonen self-organizing maps and multivariate analyses
Authors: Grenier Martine , Campeau Stéphane , Lavoie Isabelle , Park Young Seuk , Lek Sovan
Published: October 2006

The identification of biological reference conditions specific to each type of water body is essential for the development of sound biological indicators and criteria. The purpose of the present study was to establish the reference conditions of each stream type sampled in southern Québec (Canada) using benthic diatoms and environmental variables characterizing streams and watersheds. First, stream reaches were classified as a function of their natural watershed and habitat characteristics. Second, diatom communities were classified based solely on taxa abundance data. Resulting groups were graphically presented on ordinations to interpret, a posteriori, the environmental gradients associated with diatom groups and to identify the diatom communities representing the reference conditions of each of the stream reach groups. A final classification based solely on diatom reference communities found pH and conductivity to be the main discriminating factors, regardless of ecoregion and stream type. Although a specific diatom reference community may be identified for each stream group, our results suggest that many of these communities exhibit strong similarities. Only two reference communities may therefore be used, one for circumneutral conditions and one for alkaline conditions. These reference communities represent the baseline for biocriteria development.
Patterns of hydrogen peroxide among lakes of the Mackenzie Delta, western Canadian Arctic
Authors: Febria Catherine M , Lesack Lance FW , Gareis Jolie AL , Bothwell Max L
Published: October 2006

Dissolved organic carbon (DOC) in Mackenzie Delta lakes varies in composition and concentration, ranging from low concentrations and high colour in frequently flooded lakes to high concentrations in clear lakes that are infrequently flooded. DOC is a precursor to the photochemical production of hydrogen peroxide (H2O2) in lake waters. Here we assessed the patterns of H2O2using three approaches: (i) H2O2levels were tracked in 40 lakes during the open water season from the Arctic summer solstice (24 h sunlight) to late summer; (ii) diurnal dynamics of in situ H2O2were tracked in a pair of lakes with contrasting DOC regimes (coloured vs. noncoloured DOC); and (iii) buildup of H2O2was tracked in experimental microcosms of lake water exposed to manipulated UV levels. H2O2levels were highest at the solstice and in intermittently flooded lakes. During 24 h daylight, lakes with contrasting DOC regimes showed cumulative build up of H2O2during multiple cloudless days. Cumulatively, H2O2was highest in the Delta lake with a higher DOC concentration and low in colour. H2O2buildup in lake water shielded from UVB exposure was not significantly lower from microcosms under full sunlight. UVA was the most important in coloured DOC photobleaching and H2O2production.
Ultraviolet vision and foraging in juvenile bluegill (Lepomis macrochirus)
Authors: Leech Dina M , Johnsen Sönke
Published: October 2006

Ultraviolet (UV) photoreceptors have been reported in a wide variety of freshwater and marine organisms, suggesting that UV vision is prominent in aquatic ecosystems. However, its adaptive significance remains speculative. The present study tested whether the foraging of juvenile bluegill (Lepomis macrochirus) is enhanced in the presence of UV radiation (UVR). Laboratory feeding trials were conducted in a laminar flow tank in which L. macrochirus juveniles between 2.3 and 3.5 cm standard length were fed the cladoceran Daphnia magna. Sighting and striking distances, as well as capture success, were measured in the presence and absence of UVR. Mean sighting and striking distances and capture success did not differ significantly between the two light treatments. There were also no significant differences in the frequency distributions of sighting and striking distance. These results suggest that UV vision may not be used to enhance foraging in L. macrochirus on Daphnia within the size class tested.
Performance of time-varying catchability estimators in statistical catch-at-age analysis
Authors: Wilberg Michael J , Bence James R
Published: October 2006

We used Monte Carlo simulations to evaluate how different methods of estimating fishery catchability within statistical catch-at-age analysis (SCA) performed when fishery catchability changed over time. Data-generating models included cases where catchability changed abruptly or gradually over time and where catchability was explicitly a function of population abundance, and we considered corresponding estimation models. In many cases, including fishery effort data in the estimation model and allowing catchability to follow a random walk provided the best (or nearly best) estimates of biomass in the last year as measured by the median of the absolute value of the relative error. Exceptions were cases where fishing mortality was low and catchability trended over time. The estimation model that ignored fishery effort data performed well in cases with a good survey, but performance degraded as survey precision decreased. The white noise estimation model performed poorly in situations where catchability trended over time. No estimation model was best for all underlying models of catchability, but the random walk estimation model performed well under most circumstances and should be used as a starting point for SCAs.
The cost of overfishing and management strategies for new fisheries on slow-growing fish: orange roughy (Hoplostethus atlanticus) in New Zealand
Authors: Hilborn Ray , Annala John , Holland Daniel S
Published: October 2006

The history of orange roughy (Hoplostethus atlanticus) stocks, primarily in New Zealand and Australia, is commonly used as an example of the inability to manage fisheries resources. We review the history and status of the New Zealand orange roughy fishery and show that the total loss of potential biological yield from overfishing is no more than 8.3% (1260 tonnes (t)·year1) of the potential yield. The losses from underfishing are estimated to be 810 t·year1. We consider the biological and economic consequences of alternative management approaches to the New Zealand orange roughy fishery. We suggest that given the uncertainty in stock abundance and productivity and market and processing capacity limits, the management of New Zealand orange roughy stocks has been close to economically optimal and has produced near maximum sustainable yield from the resource.