bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing the Relationship Between HIV‐1 Genotype and Phenotype: Prediction‐Based Classification
Authors: Foulkes A. S. , Gruttola V. De
Published: May 2004

Summary. This paper establishes a framework for understanding the complex relationships between HIV‐1 genotypic markers of resistance to antiretroviral drugs and clinical measures of disease progression. A new classification scheme based on the probabilities of how new patients will respond to antiretroviral therapy given the available data is proposed as a method for distinguishing among groups of viral sequences. This approach draws from existing cluster analysis, discriminant analysis, and recursive partitioning techniques and requires a model relating genotypic characteristics to phenotypic response. A data set of 2746 sequences and the corresponding Indinavir 50% inhibitory concentrations are described and used for illustrative purposes.
The DN A Database Search Controversy
Authors: Balding David J.
Published: May 2004

Summary.A recent article inBiometrics(Stockmarr, 1999,55, 671–677) has generated correspondence (56, 1274–1277;57, 976–980) reigniting a controversy started by a 1996 report on DNA profile evidence issued by the U.S. National Research Council (NRC). The issue concerns the evidential weight of a DNA profile match when the match results from a search through a profile database. The views of both Stockmarr and the NRC report conflict with those of many statisticians working in the area, and the differing viewpoints lead to dramatically different assessments of evidence. I outline reasons why Stockmarr and the NRC report are wrong. I also briefly discuss possible reasons why forensic applications tend to be problematic for statisticians.
Evaluating alternative gait strategies using evolutionary robotics
Authors: Sellers William I. , Dennis Louise A. , W.‐J. Wang , Crompton Robin H.
Published: May 2004

Evolutionary robotics is a branch of artificial intelligence concerned with the automatic generation of autonomous robots. Usually the form of the robot is predefined and various computational techniques are used to control the machine's behaviour. One aspect is the spontaneous generation of walking in legged robots and this can be used to investigate the mechanical requirements for efficient walking in bipeds. This paper demonstrates a bipedal simulator that spontaneously generates walking and running gaits. The model can be customized to represent a range of hominoid morphologies and used to predict performance parameters such as preferred speed and metabolic energy cost. Because it does not require any motion capture data it is particularly suitable for investigating locomotion in fossil animals. The predictions for modern humans are highly accurate in terms of energy cost for a given speed and thus the values predicted for other bipeds are likely to be good estimates. To illustrate this the cost of transport is calculated forAustralopithecus afarensis. The model allows the degree of maximum extension at the knee to be varied causing the model to adopt walking gaits varying from chimpanzee‐like to human‐like. The energy costs associated with these gait choices can thus be calculated and this information used to evaluate possible locomotor strategies in early hominids.
Mechanisms for the acquisition of habitual bipedality: are there biomechanical reasons for the acquisition of upright bipedal posture?
Authors: Preuschoft Holger
Published: May 2004

Morphology and biomechanics are linked by causal morphogenesis (‘Wolff's law’) and the interplay of mutations and selection (Darwin's ‘survival of the fittest’). Thus shape‐based selective pressures can be determined. In both cases we need to know which biomechanical factors lead to skeletal adaptation, and which ones exert selective pressures on body shape. Each bone must be able to sustain the greatest regularly occurring loads. Smaller loads are unlikely to lead to adaptation of morphology. The highest loads occur primarily in posture and locomotion, simply because of the effect of body weight (or its multiple). In the skull, however, it is biting and chewing that result in the greatest loads. Body shape adapted for an arboreal lifestyle also smooths the way towards bipedality. Hindlimb dominance, length of the limbs in relation to the axial skeleton, grasping hands and feet, mass distribution (especially of the limb segments), thoracic shape, rib curvatures, and the position of the centre of gravity are the adaptations to arboreality that also pre‐adapt for bipedality. Five divergent locomotor/morphological types have evolved from this base: arm‐swinging in gibbons, forelimb‐dominated slow climbing in orang‐utans, quadrupedalism/climbing in the African apes, an unknown mix of climbing and bipedal walking in australopithecines, and the remarkably endurant bipedal walking of humans. All other apes are also facultative bipeds, but it is the biomechanical characteristics of bipedalism in orang‐utans, the most arboreal great ape, which is closest to that in humans. If not evolutionary accident, what selective factor can explain why two forms adopted bipedality? Most authors tend to connect bipedal locomotion with some aspect of progressively increasing distance between trees because of climatic changes. More precise factors, in accordance with biomechanical requirements, include stone‐throwing, thermoregulation or wading in shallow water. Once bipedality has been acquired, development of typical human morphology can readily be explained as adaptations for energy saving over long distances. A paper in this volume shows that load‐carrying ability was enhanced from australopithecines to Homo ergaster (early African H. erectus), supporting an earlier proposition that load‐carrying was an essential factor in human evolution.
X‐ray omni microscopy
Authors: PAGANIN D. , GUREYEV T. E. , MAYO S. C. , STEVENSON A. W. , NESTERETS YA. I. , WILKINS S. W.
Published: May 2004

The science of wave‐field phase retrieval and phase measurement is sufficiently mature to permit the routine reconstruction, over a given plane, of the complex wave‐function associated with certain coherent forward‐propagating scalar wave‐fields. This reconstruction gives total knowledge of the information that has been encoded in the complex wave‐field by passage through a sample of interest. Such total knowledge is powerful, because it permits the emulation in software of the subsequent action of an infinite variety of coherent imaging systems. Such ‘virtual optics’, in which software forms a natural extension of the ‘hardware optics’ in an imaging system, may be useful in contexts such as quantitative atom and X‐ray imaging, in which optical elements such as beam‐splitters and lenses can be realized in software rather than optical hardware. Here, we develop the requisite theory to describe such hybrid virtual‐physical imaging systems, which we term ‘omni optics’ because of their infinite flexibility. We then give an experimental demonstration of these ideas by showing that a lensless X‐ray point projection microscope can, when equipped with the appropriate software, emulate an infinite variety of optical imaging systems including those which yield interferograms, Zernike phase contrast, Schlieren imaging and diffraction‐enhanced imaging.
FIB‐induced damage in silicon
Authors: RUBANOV S. , MUNROE P. R.
Published: May 2004

The damage created in silicon transmission electron microscope specimens prepared using a focused ion beam miller is assessed using cross‐sections of trenches milled under different beam conditions. Side‐wall damage consists of an amorphous layer formed by direct interaction with the energetic gallium ion beam; a small amount of implanted gallium is also detected. By contrast, bottom‐wall damage layers are more complex and contain both amorphous films and crystalline regions that are richer in implanted gallium. More complex milling sequences show that redeposition of milled material, enriched in gallium, can occur depending on the geometry of the mill employed. The thickness of the damage layers depends strongly on beam energy, but is independent of beam current. Monte Carlo modelling of the damage formed indicates that recoil silicon atoms contribute significantly to the damaged formed in the specimen.
Robust incremental compensation of the light attenuation with depth in 3D fluorescence microscopy
Authors: KERVRANN C. , LEGLAND D. , PARDINI L.
Published: May 2004

Fluorescent signal intensities from confocal laser scanning microscopes (CLSM) suffer from several distortions inherent to the method. Namely, layers which lie deeper within the specimen are relatively dark due to absorption and scattering of both excitation and fluorescent light, photobleaching and/or other factors. Because of these effects, a quantitative analysis of images is not always possible without correction. Under certain assumptions, the decay of intensities can be estimated and used for a partial depth intensity correction. In this paper we propose an original robust incremental method for compensating the attenuation of intensity signals. Most previous correction methods are more or less empirical and based on fitting a decreasing parametric function to the section mean intensity curve computed by summing all pixel values in each section. The fitted curve is then used for the calculation of correction factors for each section and a new compensated sections series is computed. However, these methods do not perfectly correct the images. Hence, the algorithm we propose for the automatic correction of intensities relies on robust estimation, which automatically ignores pixels where measurements deviate from the decay model. It is based on techniques adopted from the computer vision literature for image motion estimation. The resulting algorithm is used to correct volumes acquired in CLSM. An implementation of such a restoration filter is discussed and examples of successful restorations are given.
Using microscopic techniques to reveal the mechanism of anion exchange in crystalline co‐ordination polymers
Authors: THOMPSON C. , CHAMPNESS N. R. , KHLOBYSTOV A. N. , ROBERTS C. J. , SCHRÖDER M. , TENDLER S. J. B. , WILKINSON M. J.
Published: May 2004

Co‐ordination polymers are currently attracting extensive interest due to their potential applications as supramolecular hosts, vessels, and frameworks for storage and separations. Many applications rely on the ion exchange capabilities of these compounds, and considerable debate surrounds the mechanism by which ion exchange occurs in co‐ordination polymers. Here AFM and SEM were applied, for the first time, to investigate this class of materials. In situ AFM studies revealed the mechanism by which anion exchange and the subsequent structural transformations of the crystalline co‐ordination polymers {[Ag(4,4′‐bipy)]BF4}∞ and {[Ag(4,4′‐bipy)]NO3}∞ occur. The process is initiated by the dissolution of the metastable crystalline polymer, followed by the subsequent crystallization of the new stable phase on the surface of the original crystal. The formation of deep clefts in the metastable polymer crystal during the transformation allows the solution to access the successive crystalline layers. Thus, the entire process can be viewed as a self‐perpetuating cascade of dissolution and recrystallization throughout the macroscopic crystal. SEM data consolidate the findings of AFM. These techniques collectively illustrate that the anion exchange, and subsequent structural transformation, proceeds via a solvent‐mediated mechanism, rather than a purely solid‐state one.
Computerized Task‐Based Exposure, Explicitness, Type of Feedback, and Spanish L2 Development
Authors: Rosa Elena M. , Leow Ronald P.
Published: May 2004

This study examined whether exposure to second/foreign language (L2) data under different computerized task conditions had a differential impact on learners' ability to recognize and produce the target structure immediately after exposure to the input and over time. Learners' L2 development was assessed through recognition and controlled‐production tests containing old and new exemplars of the target structure. Adult learners of Spanish were exposed to past conditional sentences under 1 of 6 conditions premised on different degrees of explicitness. The degree of explicitness was manipulated by combining 3 features: (a) a pretask providing explicit grammatical information, (b) feedback concurrent to input processing, and (c) variation in the nature (i.e., implicit or explicit) of the feedback in those cases in which it was provided. The advantages of processing input under explicit conditions were evident (a) in production more than in recognition and (b) in new exemplars more than in old exemplars.
Trends in Labor Induction in the United States: Is It True That What Goes Up Must Come Down?
Authors: Kirby Russell S.
Published: May 2004

Commentary on: Zhang J, Yancey MK, Henderson CE. U.S. national trends in labor induction, 1989–1998. J Reprod Med 2002;47:120–124.

 MacDorman MF, Mathews TJ, Martin JA, Malloy MH. Trends and characteristics of induced labour in the United States, 1989–98. Paediatr Perinat Epidemiol 2002;16:263–273.

 Kozak LJ, Weeks JD. U.S. trends in obstetric procedures, 1990–2000. Birth 2002;29:157–161.

Abstract:  Three recent studies examined the national trend in labor induction in the United States. All show a doubling in the rate of induction during the 1990s, although vital statistics data show a consistently higher trend than that obtained from national hospital discharge data. Neither data source adequately documents the full range of indications for induction, its timing, hospital staffing considerations, and other factors that may play a role. Although rates of induction of labor may be leveling off, despite a lack of scientific evidence for its widespread use, rates are likely to remain at current levels for the next few years.
Carbonic anhydrase and C4 photosynthesis: a transgenic analysis
Authors: VON CAEMMERER S. , QUINN V. , HANCOCK N. C. , PRICE G. D. , FURBANK R. T. , LUDWIG M.
Published: May 2004

Carbonic anhydrase (CA, EC 4.2.1.1) catalyses the first reaction in the C4 photosynthetic pathway, the conversion of atmospheric CO2 to bicarbonate in the mesophyll cytosol. To examine the importance of the enzyme to the functioning of the C4 photosynthetic pathway, Flaveria bidentis (L.) Kuntze, a C4 dicot, was genetically transformed with an antisense construct in which the cDNA encoding a putative cytosolic CA (CA3) was placed under the control of a constitutive promoter. Some of the primary transformants had impaired CO2 assimilation rates and required high CO2 for growth. The T1 progeny of four primary transformants were used to examine the quantitative relationship between leaf CA activity and CO2 assimilation rate. CA activity was determined in leaf extracts with a mass spectrometric technique that measured the rate of 18O exchange from doubly labelled 13C18O2. Steady‐state CO2 assimilation rates were unaffected by a decrease in CA activity until CA activity was less than 20% of wild type when they decreased steeply. Transformants with less than 10% of wild‐type CA activity had very low CO2 assimilation rates and grew poorly at ambient CO2 partial pressure. Reduction in CA activity also increased the CO2 partial pressure required to saturate CO2 assimilation rates. The present data show that CA activity is essential for the functioning of the C4 photosynthetic pathway.
Vegetation‐induced sedimentary structures from fossil forests in the Pennsylvanian Joggins Formation, Nova Scotia
Authors: Rygel Michael C. , Gibling Martin R. , Calder John H.
Published: May 2004

Vegetation‐induced sedimentary structures (VISS) are primary structures formed by the interaction of detrital sediment within situplants. VISS provide physical evidence of vegetation's fundamental role in mediating sediment accumulation and erosion in clastic depositional systems. Despite the abundance of modern VISS, descriptions from the ancient record are surprisingly rare. Analysis of fossil forests in floodplain strata of the Pennsylvanian Joggins Formation has identified seven types of VISS. Five hydrodynamic types comprise simple forms developed around a single plant (centroclinal cross‐strata, scratch circles, upturned beds) and complex forms where structures have amalgamated between several plants (coalesced scour fills, scour‐and‐mound beds). Two types (mudstone‐filled hollows, downturned beds) form by the decay of an entombed plant and represent infilling of an empty hollow and/or soft‐sediment deformation. Hydrodynamic types are present in both dryland and wetland settings, whereas decay‐related types occur only in dryland settings where the water table was perennially or periodically low. VISS represent significant accumulations of sediment and are present in a high proportion of Joggins Formation strata. The paucity of descriptions from the ancient record suggests that these structures have been overlooked or misinterpreted as strictly hydrodynamic. Recognition of VISS in early to middle Palaeozoic strata may provide an important insight into the distribution of early land plants in oxidizing environments where organic material was not preserved.
Changes in clay mineral content of tidal flat sediments resulting from dike construction along the Lower Saxony coast of the North Sea, Germany
Authors: Brockamp Olaf , Zuther Michael
Published: May 2004

The clay mineral content of the < 2 µm fraction in tidal flat sediments in the former Harle Bay on the Lower Saxony coast has changed considerably since the thirteenth century up to the present time. The proportion of smectite has decreased from 29 to 11 wt%, whereas the proportion of illite has increased by about 10 wt% and those of chlorite and kaolinite by about 3 wt% each. The chemical composition of the major clay mineral illite has also changed: Al2O3 has decreased by about 2 wt%, K2O by about 1·5 wt% and SiO2 by about 3 wt%. It can be concluded that the changes in the clay mineral content are mainly influenced by dike construction and sea level rise, modifying flow pattern, submarine morphology, sedimentation and tidal range. These processes cause smectite to settle less rapidly because of its small grain size and low density resulting from interlayer water, so that the sediment becomes impoverished in this mineral.
Tectonic controls on drainage evolution and development of terminal alluvial fans, southern Pyrenees, Spain
Authors: Jones Stuart J.
Published: May 2004

An understanding of how drainage patterns respond to tectonics can provide an insight into past deformational events within mountain belts and where sediment flux is supplied to depositional basins. The transverse rivers draining the Spanish Pyrenees show sudden diversions to axial courses and the capture of lateral systems producing large trunk rivers that break through the thrust front at structurally controlled points. The drainage reorganization from the initial regularly spaced pattern in the Late Eocene caused by the growth of thrust‐controlled topography influenced the location of outlets into the Ebro basin. The headward capture and merger of rivers as a result of structural diversion formed two large terminal fan systems during the Oligo‐Miocene along the Pyrenean thrust front. The early structural topographic controls on drainage evolution will have long‐term effects on sedimentation and stratigraphic architecture of foreland basins. This will only be maintained as long as there is tectonic uplift and the river systems strive to re‐attain a regular drainage spacing across the orogenic belt as partly achieved in the Pyrenees.
Intergranular diamonds derived from partial melting of crustal rocks at ultrahigh‐pressure metamorphic conditions
Authors: Korsakov Andrey V. , Theunissen Karel , Smirnova Larissa V.
Published: May 2004

By reporting for the first time intergranular diamond in quartz–feldspar (Qtz–Kfs) aggregates, the processes of metamorphic diamond formation have to be reconsidered. Based on their Kfs/Qtz ratio, the texture of these aggregates are proposed to result from ‘granitic’ melt with a calculated composition that corresponds well with that of experimental data for the pelitic system. Taking into account experiments on CO2 solubility in silicate melt under ultrahigh‐pressure conditions, a granitic melt is further suggested to act as a crystallization medium as well as a transport medium for producing metamorphic diamond.
Fast Ca2+‐dependent inactivation of the store‐operated Ca2+ current (ISOC) in liver cells: a role for calmodulin
Authors: Litjens Tom , Harland M. Lyn , Roberts Michael L. , Barritt Gregory J. , Rychkov Grigori Y.
Published: May 2004

Store‐operated Ca2+ channels (SOCs) provide a major pathway for Ca2+ entry in non‐excitable cells. SOCs in immortalized liver cells are highly selective for Ca2+ over other cations and are similar to well‐studied Ca2+ release activated Ca2+ (CRAC) channels in haematopoietic cell lines. In the present work, employing H4IIE liver cells, we investigated fast inactivation of SOC current (ISOC), which occurs at membrane potentials below −60 mV. This inactivation was significantly reduced when BAPTA, a faster Ca2+ buffer, was used instead of EGTA, and was completely abolished if  Na+ was used as a charge carrier in the absence of divalent cations in the external medium. These results suggested that fast inactivation of SOCs in H4IIE cells was Ca2+ dependent and was similar to the fast inactivation of CRAC channels. Experiments showing that the fast inactivation of ISOC was not affected by the disruption of actin by latrunculin B indicate that the cytoskeleton is unlikely to be involved. To elucidate the mechanism of Ca2+ dependence, a possible role of calmodulin (CaM) in SOCs' fast inactivation was investigated. The CaM inhibitors Mas‐7 and calmidazolium failed to affect ISOC fast inactivation, whereas over‐expression of a CaM inhibitor peptide or a mutant CaM lacking functional EF hands significantly altered the inactivation of ISOC. Out of two exponential components normally required to approximate kinetics of ISOC fast inactivation, the faster component was reduced in amplitude by 30%, compared to the control. The results presented suggest that CaM is responsible for at least part of Ca2+‐dependent fast inactivation of ISOC in liver cells. It is hypothesized that CaM is tethered to the channel itself and therefore protected from chemical inhibitors.
tcaA
Inactivation Increases Glycopeptide Resistance in
Staphylococcus aureus
Authors: Maki Hideki , McCallum Nadine , Bischoff Markus , Wada Akihito , Berger-Bächi Brigitte
Published: May 2004

The experimental deletion of the
tcaRAB
region has been shown to increase teicoplanin resistance in
Staphylococcus aureus
. By sequential genetic complementation of a
tcaRAB
mutant, we identified
tcaA
as the key gene within
tcaRAB
that is responsible for changes in glycopeptide resistance levels. Northern blot analysis of the
tcaRAB
region showed that the
tcaA
gene is expressed only weakly over the growth cycle and is strongly inducible by teicoplanin. Among some clinical isolates tested, glycopeptide-intermediate-resistant (GISA) strains Michigan and SA137/93G were found to have truncated
tcaA
genes. While the former carries a nucleotide insertion that creates a premature stop codon, the latter was found to harbor an IS
256
insertion. Complementation of these two GISA strains with a functional
tcaA
allele reduced their levels of teicoplanin and vancomycin resistance five- to eightfold and twofold, respectively. The data presented here indicate that inactivation of
tcaA
contributes to and plays a relevant role in glycopeptide resistance in
S. aureus
clinical isolates.
Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001
Authors: Christiansen K. J. , Bell J. M. , Turnidge J. D. , Jones R. N.
Published: May 2004

Between 1999 and 2001, 16,731 isolates from the Asia-Pacific Region were tested in the SENTRY Program for susceptibility to six fluoroquinolones including garenoxacin. Garenoxacin was four- to eightfold less active against
Enterobacteriaceae
than ciprofloxacin, although both drugs inhibited similar percentages at 1 μg/ml. Garenoxacin was more active against gram-positive species than all other fluoroquinolones except gemifloxacin. For
Staphylococcus aureus
, oxacillin resistance was high in many participating countries (Japan, 67%; Taiwan, 60%; Hong Kong, 55%; Singapore, 52%), with corresponding high levels of ciprofloxacin resistance (57 to 99%) in oxacillin-resistant
S. aureus
(ORSA). Of the ciprofloxacin-resistant ORSA isolates, the garenoxacin MIC was >4 μg/ml for only 9% of them. For
Streptococcus pneumoniae
, penicillin nonsusceptibility and macrolide resistance were high in many countries. No relationship was seen between penicillin and garenoxacin susceptibility, with all isolates being susceptible at <2 μg/ml. There was, however, a partial correlation between ciprofloxacin and garenoxacin MICs. For ciprofloxacin-resistant isolates for which garenoxacin MICs were 0.25 to 1 μg/liter, mutations in both the ParC and GyrA regions of the quinolone resistance-determining region could be demonstrated. No mutations conferring high-level resistance were detected. Garenoxacin shows useful activity against a wide range of organisms from the Asia-Pacific region. In particular, it has good activity against
S. aureus
and
S. pneumoniae
, although there is evidence that low-level resistance is present in those organisms with ciprofloxacin resistance.
Comparative Activities of the Triterpene Saponin Maesabalide III and Liposomal Amphotericin B (AmBisome) againstLeishmania donovaniin Hamsters
Authors: Maes Louis , Germonprez Nils , Quirijnen Ludo , Van Puyvelde Luc , Cos Paul , Vanden Berghe Dirk
Published: May 2004

Maesabalide III (MB-III), an oleane triterpene saponin isolated from the Vietnamese plantMaesa balansae, is a new antileishmanial lead compound whose activity againstLeishmania donovani(MHOM/ET/67/L82) in groups of five golden hamsters was evaluated after administration of a single subcutaneous dose on either day 1 (prophylactic treatment) or day 28 (curative treatment) after infection. Liposomal amphotericin B (AmBisome), administered intravenously at 5 mg/kg of body weight, was used as the reference drug. Amastigote burdens in liver, spleen, and bone marrow were determined either 7 days (early effects) or 56 days (late effects) after treatment. Prophylactic administration of MB-III at 0.2 mg/kg reduced liver amastigote burdens by 99.8 and 83% within 7 and 56 days after treatment, respectively. In the latter group, however, all animals became ill and some died. Both MB-III at 0.8 mg/kg and liposomal amphotericin B were 100% effective against liver stages, but clearance from the spleen and bone marrow was not achieved. Curative administration of MB-III at 0.2 and 0.4 mg/kg was not protective, as no survivors were left at the termination of the experiment on day 84. Despite the high level of reduction of the liver amastigote burden after treatment with MB-III at 0.8 mg/kg (94.2%) or liposomal amphotericin B (99.4%), clinical protection could not be obtained in either group, with two deaths occurring and the residual liver burdens persisting. It is concluded that administration of a single dose of MB-III at 0.8 mg/kg has efficacy potential comparable to that of a single dose of liposomal amphotericin B at 5 mg/kg and is therefore considered a promising new antileishmanial lead compound. However, multiple-dose pharmacological, toxicological, and pharmacokinetic studies are still needed before it can become a valid drug candidate for development.
Spread of Novel Aminoglycoside Resistance Gene
aac
(
6
′)-
Iad
among
Acinetobacter
Clinical Isolates in Japan
Authors: Doi Yohei , Wachino Jun-ichi , Yamane Kunikazu , Shibata Naohiro , Yagi Tetsuya , Shibayama Keigo , Kato Haru , Arakawa Yoshichika
Published: May 2004

A novel aminoglycoside resistance gene,
aac
(
6
′)-
Iad
, encoding aminoglycoside 6′-
N
-acetyltransferase, was identified in
Acinetobacter
genospecies 3 strain A-51. The gene encoded a 144-amino-acid protein, which shared modest identity (up to 36.7%) with some of the aminoglycoside 6′-
N
-acetyltransferases. The results of high-pressure liquid chromatography assays confirmed that the protein is a functional aminoglycoside 6′-
N
-acetyltransferase. The enzyme conferred resistance to amikacin, tobramycin, sisomicin, and isepamicin but not to gentamicin. The prevalence of this gene among
Acinetobacter
clinical isolates in Japan was then investigated. Of 264
Acinetobacter
sp. strains isolated from geographically diverse areas in Japan in 2002, 16 were not susceptible to amikacin, and
aac
(
6
′)
-Iad
was detected in 7. Five of the producers of aminoglycoside 6′-
N
-acetyltransferase type Iad were identified as
Acinetobacter baumannii
, and two were identified as
Acinetobacter
genospecies 3. These results suggest that
aac
(
6
′)-
Iad
plays a substantial role in amikacin resistance among
Acinetobacter
spp. in Japan.
Antibacterial Activities of the Cathelicidins Prophenin (Residues 62 to 79) and LL-37 in the Presence of a Lung Surfactant Preparation
Authors: Wang Yuqin , Walter Gabi , Herting Egbert , Agerberth Birgitta , Johansson Jan
Published: May 2004

The antibacterial activities of the cathelicidin peptides LL-37 and an 18-residue C-terminal fragment of prophenin, corresponding to positions 62 to 79 of native prophenin (PF-18), were analyzed in the presence of a modified surfactant preparation isolated from minced porcine lungs. At low micromolar concentrations, both LL-37 and PF-18 showed significant activities against different serotypes of group B streptococci, with LL-37 being more active on a molar basis. The surfactant preparation at a concentration of 10 mg/ml partly blocked the antibacterial activity of 9 μM LL-37 and completely blocked the antibacterial activity of 9 μM PF-18. However, 10 mg of the surfactant preparation per ml had only minor inhibitory effects on LL-37 and PF-18 at 90 μM. Addition of up to 900 μM PF-18 did not affect the surface properties of the surfactant preparation. These data suggest that surfactant preparations containing antimicrobial peptides could be useful for the local treatment of pulmonary infections.
Efficacies of Amphotericin B (AMB) Lipid Complex, AMB Colloidal Dispersion, Liposomal AMB, and Conventional AMB in Treatment of Murine Coccidioidomycosis
Authors: González Gloria M. , Tijerina Rolando , Najvar Laura K. , Bocanegra Rosie , Rinaldi Michael G. , Graybill John R.
Published: May 2004

The therapeutic efficacy of three lipid formulations of amphotericin B was compared with that of conventional amphotericin B in treatment of murine coccidioidomycosis. All treatments prolonged survival compared with the no-treatment group (
P
< 0.0001). Although conventional amphotericin B was more active than lipid formulations on reducing quantitative fungal load on a milligram-per-kilogram basis (
P
< 0.003 to 0.0002), the lipid preparations could be administered at higher doses, sterilizing liver and spleen tissues. The efficacies of the lipid preparations were similar in this murine model of coccidioidomycosis.
In Vitro Activities of the New Semisynthetic Glycopeptide Telavancin (TD-6424), Vancomycin, Daptomycin, Linezolid, and Four Comparator Agents against Anaerobic Gram-Positive Species and
Corynebacterium
spp
Authors: Goldstein Ellie J. C. , Citron Diane M. , Merriam C. Vreni , Warren Yumi A. , Tyrrell Kerin L. , Fernandez Helen T.
Published: May 2004

Telavancin
is a new semisynthetic glycopeptide anti-infective with multiple
mechanisms of action, including inhibition of bacterial membrane
phospholipid synthesis and inhibition of bacterial cell wall synthesis.
We determined the in vitro activities of telavancin, vancomycin,
daptomycin, linezolid, quinupristin-dalfopristin, imipenem,
piperacillin-tazobactam, and ampicillin against 268 clinical isolates
of anaerobic gram-positive organisms and 31
Corynebacterium
strains using agar dilution methods according to National Committee for
Clinical Laboratory Standards procedures. Plates with daptomycin were
supplemented with Ca
2+
to 50 mg/liter. The MICs at
which 90% of isolates tested were inhibited (MIC
90
s)
for telavancin and vancomycin were as follows:
Actinomyces
spp. (
n
= 45), 0.25 and 1 μg/ml, respectively;
Clostridium difficile
(
n
= 14), 0.25 and 1μ
g/ml, respectively;
Clostridium ramosum
(
n
=
16), 1 and 4 μg/ml, respectively;
Clostridium
innocuum
(
n
= 15), 4 and 16 μg/ml,
respectively;
Clostridium clostridioforme
(
n
=
15), 8 and 1 μg/ml, respectively;
Eubacterium
group (
n
= 33), 0.25 and 2μ
g/ml, respectively;
Lactobacillus
spp. (
n
=
26), 0.5 and 4 μg/ml, respectively;
Propionibacterium
spp. (
n
= 34), 0.125 and
0.5 μg/ml, respectively;
Peptostreptococcus
spp.
(
n
= 52), 0.125 and 0.5 μg/ml, respectively;
and
Corynebacterium
spp. (
n
= 31), 0.03 and
0.5 μg/ml, respectively. The activity of TD-6424 was similar to
that of quinupristin-dalfopristin for most strains except
C.
clostridioforme
and
Lactobacillus casei
, where
quinupristin-dalfopristin was three- to fivefold more active.
Daptomycin had decreased activity (MIC > 4 μg/ml)
against 14 strains of
Actinomyces
spp. and all
C.
ramosum
,
Eubacterium lentum
, and
Lactobacillus plantarum
strains. Linezolid showed decreased
activity (MIC > 4 μg/ml) against
C. ramosum
,
two strains of
C. difficile
, and 15 strains of
Lactobacillus
spp. Imipenem and piperacillin-tazobactam were
active against >98% of strains. The MICs of ampicillin
for eight
Clostridium
spp. and three strains of
L.
casei
were >1 μg/ml. The MIC
90
of
TD-6424 for all strains tested was ≤2 μg/ml. TD-6424
has potential for use against infections with gram-positive anaerobes
and deserves further clinical
evaluation.
Pharmacokinetics and Safety of Intravenous Voriconazole in Children after Single- or Multiple-Dose Administration
Authors: Walsh Thomas J. , Karlsson Mats O. , Driscoll Timothy , Arguedas Adriano G. , Adamson Peter , Saez-Llorens Xavier , Vora Ajay J. , Arrieta Antonio C. , Blumer Jeffrey , Lutsar Irja , Milligan Peter , Wood Nolan
Published: May 2004

We conducted a multicenter study of the safety, tolerability, and plasma pharmacokinetics of the parenteral formulation of voriconazole in immunocompromised pediatric patients (2 to 11 years old). Single doses of 3 or 4 mg/kg of body weight were administered to six and five children, respectively. In the multiple-dose study, 28 patients received loading doses of 6 mg/kg every 12 h on day 1, followed by 3 mg/kg every 12 h on day 2 to day 4 and 4 mg/kg every 12 h on day 4 to day 8. Standard population pharmacokinetic approaches and generalized additive modeling were used to construct the structural pharmacokinetic and covariate models used in this analysis. In contrast to that in adult healthy volunteers, elimination of voriconazole was linear in children following doses of 3 and 4 mg/kg every 12 h. Body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics. Elimination capacity correlated with the CYP2C19 genotype. Exposures were similar at 4 mg/kg every 12 h in children (median area under the concentration-time curve (AUC), 14,227 ng · h/ml) and 3 mg/kg in adults (median AUC, 13,855 ng · h/ml). Visual disturbances occurred in 5 (12.8%) of the 39 patients and were the only drug-related adverse events that occurred more than once. No withdrawals from the study were related to voriconazole. We conclude that pediatric patients have a higher capacity for elimination of voriconazole per kilogram of body weight than do adult healthy volunteers and that dosages of 4 mg/kg may be required in children to achieve exposures consistent with those in adults following dosages of 3 mg/kg.
Short- and Long-Term Effects of Pneumococcal Conjugate Vaccination of Children on Penicillin Resistance
Authors: Temime L. , Guillemot D. , Boëlle P. Y.
Published: May 2004

Recent observations have shown that wide-scale vaccination with pneumococcal conjugate vaccines was associated with a reduction in invasive disease, supporting the expectation that vaccination could help reduce carriage of
Streptococcus pneumoniae
and control the spread of resistant strains. However, it is too early to assess whether these effects can be sustained in the long term. Here, we used mathematical modeling to investigate time changes in pneumococcal colonization and resistance induced by conjugate vaccination in an environment where antibiotic exposure is high and resistance is widespread. According to model predictions, vaccination induced a decrease in carriage of vaccine-type pneumococci to very low levels, typically in 10 to 15 years under epidemiologically realistic conditions. Almost simultaneously, non-vaccine-type pneumococci spread in the community. Consequently, while there was a short-term decrease in the overall carriage rate, it was followed after a few years by a renewed, although limited, increase. Vaccination with a heptavalent vaccine did not affect the extent to which antibiotic resistance was selected: in all cases, the distribution of resistance levels peaked at high levels (MIC > 2 μg/ml) after 20 years. With a vaccine optimally designed to include all serotypes currently exhibiting decreased susceptibility to penicillin G, the selection of resistance was slowed down, although not prevented. These results suggest that because of serotype replacement, the effects of vaccination observed today may not be sustained in the long term. As a consequence, vaccination alone may not be successful in controlling selection for resistance in
S. pneumoniae
.
Sulfadoxine Resistance in
Plasmodium vivax
Is Associated with a Specific Amino Acid in Dihydropteroate Synthase at the Putative Sulfadoxine-Binding Site
Authors: Korsinczky Michael , Fischer Katja , Chen Nanhua , Baker Joanne , Rieckmann Karl , Cheng Qin
Published: May 2004

Sulfadoxine is predominantly used in combination with pyrimethamine, commonly known as Fansidar, for the treatment of
Plasmodium falciparum
. This combination is usually less effective against
Plasmodium vivax
, probably due to the innate refractoriness of parasites to the sulfadoxine component. To investigate this mechanism of resistance by
P. vivax
to sulfadoxine, we cloned and sequenced the
P. vivax dhps
(
pvdhps
) gene. The protein sequence was determined, and three-dimensional homology models of dihydropteroate synthase (DHPS) from
P. vivax
as well as
P. falciparum
were created. The docking of sulfadoxine to the two DHPS models allowed us to compare contact residues in the putative sulfadoxine-binding site in both species. The predicted sulfadoxine-binding sites between the species differ by one residue, V585 in
P. vivax
, equivalent to A613 in
P. falciparum
. V585 in
P. vivax
is predicted by energy minimization to cause a reduction in binding of sulfadoxine to DHPS in
P. vivax
compared to
P. falciparum
. Sequencing
dhps
genes from a limited set of geographically different
P. vivax
isolates revealed that V585 was present in all of the samples, suggesting that V585 may be responsible for innate resistance of
P. vivax
to sulfadoxine. Additionally, amino acid mutations were observed in some
P. vivax
isolates in positions known to cause resistance in
P. falciparum
, suggesting that, as in
P. falciparum
, these mutations are responsible for acquired increases in resistance of
P. vivax
to sulfadoxine.
Mechanism of Action at the Molecular Level of the Antiviral Drug 3(2H)-Isoflavene against Type 2 Poliovirus
Authors: Salvati Anna L. , De Dominicis Alessandra , Tait Sabrina , Canitano Andrea , Lahm Armin , Fiore Lucia
Published: May 2004

The mechanism of action of the antiviral compound 3(2H)-isoflavene against Sabin type 2 poliovirus has been studied, and interference with virus uncoating was demonstrated. Isolation and sequencing of drug-resistant variants revealed single amino acid substitutions (I194M or D131V) in the VP1 capsid protein. While M194 is located in a hydrophobic pocket and should partially fill the space occupied by the isoflavene ring, V131 is exposed on the VP1 surface, forming a contact with VP4. The D131V mutation most likely induces local conformational changes in VP1 and/or VP4 that affect viral flexibility. Two dependent variants, N53S of VP1 and K58E of VP4, both located on the inner surface of the capsid, near the threefold axis of symmetry, were also selected. Both mutations affected viral stability, allowing the transition to 135S particles in the absence of drug, without the involvement of the viral receptor.
Complete Sequences of Six Penicillin-Binding Protein Genes from 40
Streptococcus pneumoniae
Clinical Isolates Collected in Japan
Authors: Sanbongi Yumiko , Ida Takashi , Ishikawa Midori , Osaki Yumi , Kataoka Hiroshi , Suzuki Takahisa , Kondo Kumiko , Ohsawa Fukuichi , Yonezawa Minoru
Published: May 2004

All six penicillin-binding protein (PBP) genes, namely,
pbp1a
,
pbp1b
,
pbp2a
,
pbp2b
,
pbp2x
, and
pbp3
, of 40
Streptococcus pneumoniae
clinical isolates, including penicillin-resistant
S. pneumoniae
isolates collected in Japan, were completely sequenced. The MICs of penicillin for these strains varied between 0.015 and 8 μg/ml. In PBP 2X, the Thr550Ala mutation close to the KSG motif was observed in only 1 of 40 strains, whereas the Met339Phe mutation in the STMK motif was observed in six strains. These six strains were highly resistant (MICs ≧ 2 μg/ml) to cefotaxime. The MICs of cefotaxime for 27 strains bearing the Thr338Ala mutation tended to increase, but the His394Leu mutation next to the SSN motif did not exist in these strains. In PBP 2B, the Thr451Ala/Phe/Ser and Glu481Gly mutations close to the SSN motif were observed in 24 strains, which showed penicillin resistance and intermediate resistance, and the Thr624Gly mutation close to the KTG motif was observed in 2 strains for which the imipenem MIC (0.5 μg/ml) was the highest imipenem MIC detected. In PBP 1A, the Thr371Ser/Ala mutation in the STMK motif was observed in all 13 strains for which the penicillin MICs were ≧1 μg/ml. In PBP 2A, the Thr411Ala mutation in the STIK motif was observed in one strain for which with the cefotaxime MIC (8 μg/ml) was the highest cefotaxime MIC detected. On the other hand, in PBPs 1B and 3, no mutations associated with resistance were observed. The results obtained here support the concept that alterations in PBPs 2B, 2X, and 1A are mainly involved in
S. pneumoniae
resistance to β-lactam antibiotics. Our findings also suggest that the Thr411Ala mutation in PBP 2A may be associated with β-lactam resistance.
Enhanced Production of Farnesol by
Candida albicans
Treated with Four Azoles
Authors: Hornby Jacob M. , Nickerson Kenneth W.
Published: May 2004

The dimorphic fungus
Candida albicans
excretes farnesol, which is produced enzymatically from the sterol biosynthetic intermediate farnesyl pyrophosphate. Inhibition of
C. albicans
by four azole antifungals, fluconazole, ketoconazole, miconazole, and clotrimazole, caused elevated farnesol production (10- to 45-fold). Furthermore, farnesol production occurs in both laboratory strains and clinical isolates (J. M. Hornby et al., Appl. Environ. Microbiol. 67:2982-2992, 2001) of
C. albicans
.
Immunopharmacology of CpG Oligodeoxynucleotides and Ribavirin
Authors: Vollmer Jörg , Rankin Robert , Hartmann Hanna , Jurk Marion , Samulowitz Ulrike , Wader Tanja , Janosch Andrea , Schetter Christian , Krieg Arthur M.
Published: May 2004

To investigate their potential mechanisms of action, the nucleoside analogue ribavirin and a TLR9 agonist were compared. The CpG oligodeoxynucleotides (ODN) demonstrated strong TLR9-related Th1-type effects, and ribavirin appeared only to mediate signaling in TLR-transfected cells. CpG ODN represent a promising new type of therapeutic drug for hepatitis C or other infectious diseases.
Mountain bike injuries and clipless pedals: a review of three cases: Figure 1
Authors: Patel N D
Published: May 2004

The cases are reported of three off road cyclists with isolated soft tissue injuries to the right lower leg, caused by the chain ring as they struggled to release their feet from clipless pedals. Correct adjustment of the pedals to facilitate quick release of the feet is required to prevent such injuries.
Effect of massage of the hamstring muscle group on performance of the sit and reach test
Authors: Barlow A , Clarke R , Johnson N , Seabourne B , Thomas D , Gal J
Published: May 2004

Objective:To investigate if a single massage of the hamstring muscle group would alter the performance of the sit and reach test.

Methods:Before treatment, each of 11 male subjects performed the sit and reach test. The treatment consisted of either massage of the hamstring muscle group (both legs, total time about 15 minutes) or supine rest with no massage. Performance of the sit and reach test was repeated after treatment. Each subject returned the subsequent week to perform the tests again, receiving the alternative treatment relative to their initial visit. Mean percentage changes in sit and reach scores after treatment were calculated for the massage and no massage treatments, and analysed using Student’sttests.

Results:Mean (SD) percentage changes in sit and reach scores after massage and no massage were small (6.0 (4.3)% and 4.6 (4.8)% respectively) and not significantly different for subjects with relatively high (15 cm and above) values before treatment. Mean percentage changes in sit and reach scores for subjects with relatively low values before treatment (below 15 cm) were large (18.2 (8.2)% and 15.5 (16.2)% respectively), but no significant differences were found between the massage and no massage groups.

Conclusions:A single massage of the hamstring muscle group was not associated with any significant increase in sit and reach performance immediately after treatment in physically active young men.
Do physical leisure time activities prevent fatigue? A 15 month prospective study of nurses’ aides
Authors: Eriksen W , Bruusgaard D
Published: May 2004

Objective:To test the hypothesis that physical leisure time activities reduce the risk of developing persistent fatigue.

Methods:The hypothesis was tested in a sample that was homogeneous with respect to sex and occupation, with a prospective cohort design. Of 6234 vocationally active, female, Norwegian nurses’ aides, not on leave because of illness or pregnancy when they completed a mailed questionnaire in 1999, 5341 (85.7%) completed a second questionnaire 15 months later. The main outcome measure was the prevalence of persistent fatigue—that is, always or usually feeling fatigued in the daytime during the preceding 14 days.

Results:In participants without persistent fatigue at baseline, reported engagement in physical leisure time activities for 20 minutes or more at least once a week during the three months before baseline was associated with a reduced risk of persistent fatigue at the follow up (odds ratio  =  0.70; 95% confidence interval 0.55 to 0.89), after adjustments for age, affective symptoms, sleeping problems, musculoskeletal pain, long term health problems of any kind, smoking, marital status, tasks of a caring nature during leisure time, and work factors at baseline.

Conclusion:The study supports the hypothesis that physical leisure time activities reduce the risk of developing persistent fatigue.