bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple-Dose Pharmacokinetic Behavior of Elvucitabine, a Nucleoside Reverse Transcriptase Inhibitor, Administered over 21 Days with Lopinavir-Ritonavir in Human Immunodeficiency Virus Type 1-Infected Subjects
Authors: Colucci Philippe , Pottage John C. , Robison Heather , Turgeon Jacques , Schürmann Dirk , Hoepelman I. M. , Ducharme Murray P. 
Published: November 2008

ABSTRACT
The purpose of this study was to describe the plasma pharmacokinetics (PK) of elvucitabine at different doses when administered daily or every other day for 21 days with lopinavir-ritonavir (Kaletra) in human immunodeficiency virus (HIV)-infected subjects. Three different dosing regimens of elvucitabine were administered with lopinavir-ritonavir to 24 subjects with moderate levels of HIV. Plasma samples were collected over 35 days. Elvucitabine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK of elvucitabine was determined using both noncompartmental and compartmental analyses. Models were developed and tested using ADAPT II, while a population analysis was performed using IT2S. The PK behavior of elvucitabine was best described by a two-compartment linear model using two absorption rates and an increase in the bioavailability after day 1. The augmentation in the bioavailability after day 1 was variable, with some subjects demonstrating a major increase while others had little or no increase. Elvucitabine has a long half-life of approximately 100 h. The increase in elvucitabine bioavailability may be due to ritonavir inhibiting an efflux gut transporter with activity present in various levels between subjects. The proposed PK model may be utilized and improved further by linking the PK behavior of elvucitabine to various markers of efficacy.
Variations in Amino Acid Composition of Antisense Peptide-Phosphorodiamidate Morpholino Oligomer Affect Potency against
Escherichia coli
In Vitro and In Vivo
Authors: Mellbye Brett L. , Puckett Susan E. , Tilley Luke D. , Iversen Patrick L. , Geller Bruce L. 
Published: November 2008

ABSTRACT

The potency of antisense peptide-phosphorodiamidate morpholino oligomers (PPMOs) was improved by varying the peptide composition. An antisense phosphorodiamidate morpholino oligomer (PMO) complementary to the mRNA of the essential gene
acpP
(which encodes the acyl carrier protein required for lipid biosynthesis) in
Escherichia coli
was conjugated to the 5′ ends of various cationic membrane-penetrating peptides. Each peptide had one of three repeating sequence motifs: C-N-N (motif 1), C-N (motif 2), or C-N-C (motif 3), where C is a cationic residue and N is a nonpolar residue. Variations in the cationic residues included arginine, lysine, and ornithine (O). Variations in the nonpolar residues included phenylalanine, valine, β-alanine (B), and 6-aminohexanoic acid (X). The MICs of the PPMOs varied from 0.625 to >80 μM (about 3 to 480 μg/ml). Three of the most potent were the (RX)
6
B-, (RXR)
4
XB-, and (RFR)
4
XB-AcpP PMOs, which were further tested in mice infected with
E. coli
. The (RXR)
4
XB-AcpP PMO was the most potent of the three conjugates tested in mice. The administration of 30 μg (1.5 mg/kg of body weight) (RXR)
4
XB-AcpP PMO at 15 min postinfection reduced CFU/ml in blood by 10
2
to 10
3
within 2 to 12 h compared to the numbers in water-treated controls. All mice treated with 30 μg/dose of (RXR)
4
XB-AcpP PMO survived infection, whereas all water-treated mice died 12 h postinfection. The reduction in CFU/ml in blood was proportional to the dose of PPMO from 30 to 300 μg/ml. In summary, the C-N-C motif was more effective than the other two motifs, arginine was more effective than lysine or ornithine, phenylalanine was more effective than 6-aminohexanoic acid in vitro but not necessarily in vivo, and (RXR)
4
XB-AcpP PMO reduced bacterial infection and promoted survival at clinically relevant doses.
Comparison of the Performances of Two In-House Rapid Methods for Antitubercular Drug Susceptibility Testing
Authors: de la Iglesia Agustina I. , Stella Emma J. , Morbidoni Héctor R. 
Published: November 2008

ABSTRACT

Resistance to rifampin (rifampicin), isoniazid, and streptomycin of 69
Mycobacterium tuberculosis
isolates was analyzed by an in-house method based on mycobacteriophage D29 and a colorimetric micromethod. Both methods showed sensitivity and specificity values ranging from 93% to 100%. These simple methods offer an option for drug resistance assessment of
M. tuberculosis
.
Reconstruction of the Phenotypes of Methicillin-Resistant
Staphylococcus aureu
s by Replacement of the Staphylococcal Cassette Chromosome
mec
with a Plasmid-Borne Copy of
Staphylococcus sciuri pbpD
Gene
Authors: Antignac Aude , Tomasz Alexander 
Published: November 2008

ABSTRACT

The
mecA
gene, the central determinant of methicillin (meticillin)-resistant
Staphylococcus aureus
(MRSA), is not native to this bacterial species but may have originated in the animal commensal species
Staphylococcus sciuri
. All
S. sciuri
strains carry a close homologue of
mecA
in the form of
pbpD
, the genetic determinant of penicillin binding protein 4 (PBP 4) of
S. sciuri
. Here we describe an experimental system that could be used for additional tests for this proposition. The
S. sciuri pbpD
gene was cloned into a shuttle plasmid and introduced into methicillin-susceptible
S. aureus
strain COL-S derived from parental MRSA strain COL from which the resistance cassette staphylococcal cassette chromosome
mec
was excised. The
S. sciuri pbpD
determinant was transcribed and translated in the
S. aureus
transductants producing large amounts of the 84-kDa
S. sciuri
PBP 4 and was then deposited in the plasma membrane of the host bacterium. Transductants carrying the heterologous
S. sciuri pbpD
gene exhibited properties typical of those of parental MRSA strain COL, including broad-spectrum, high-level, and homogeneous resistance to structurally different β-lactams. Antibiotic resistance was dependent on the functioning of
S. aureus
PBP 2 and was suppressed by the specific regulatory genes
mecI
and
mecR
and by inhibitors of an early step in cell wall biosynthesis.
S. sciuri
PBP 4 was also able to replace the essential physiological function(s) of the native PBP 2 of
S. aureus
and produce peptidoglycan typical of that of parental MRSA strain COL. Our results provide further support for the proposition that the resistance determinant
mecA
of MRSA strains has evolved from
S. sciuri pbpD
.
Variety of Antiprion Compounds Discovered through an In Silico Screen Based on Cellular-Form Prion Protein Structure: Correlation between Antiprion Activity and Binding Affinity
Authors: Hosokawa-Muto Junji , Kamatari Yuji O. , Nakamura Hironori K. , Kuwata Kazuo 
Published: November 2008

ABSTRACT

Transmissible spongiform encephalopathies are associated with the conformational conversion of the prion protein from the cellular form (PrP
C
) to the scrapie form. This process could be disrupted by stabilizing the PrP
C
conformation, using a specific ligand identified as a chemical chaperone. To discover such compounds, we employed an in silico screen that was based on the nuclear magnetic resonance structure of PrP
C
. In combination, we performed ex vivo screening using the Fukuoka-1 strain-infected neuronal mouse cell line at a compound concentration of 10 μM and surface plasmon resonance. Initially, we selected 590 compounds according to the calculated docked energy and finally discovered 24 efficient antiprion compounds, whose chemical structures are quite diverse. Surface plasmon resonance studies showed that the binding affinities of compounds for PrP
C
roughly correlated with the compounds' antiprion activities, indicating that the identification of chemical chaperones that bind to the PrP
C
structure and stabilize it is one efficient strategy for antiprion drug discovery. However, some compounds possessed antiprion activities with low affinities for PrP
C
, indicating a mechanism involving additional modulation factors. We classified the compounds roughly into five categories: (i) binding and effective, (ii) low binding and effective, (iii) binding and not effective, (iv) low binding and not effective, and (v) acceleration. In conclusion, we found a spectrum of compounds, many of which are able to modulate the pathogenic conversion reaction. The appropriate categorization of these diverse compounds would facilitate antiprion drug discovery and help to elucidate the pathogenic conversion mechanism.
Identification of a Novel Trimethoprim Resistance Gene,
dfrK
, in a Methicillin-Resistant
Staphylococcus aureus
ST398 Strain and Its Physical Linkage to the Tetracycline Resistance Gene
tet
(L)
Authors: Kadlec Kristina , Schwarz Stefan 
Published: November 2008

ABSTRACT

A novel trimethoprim resistance gene, designated
dfrK
, was detected in close proximity to the tetracycline resistance gene
tet
(L) on the ca. 40-kb plasmid pKKS2187 in a porcine methicillin (meticillin)-resistant
Staphylococcus aureus
isolate of sequence type 398. The
dfrK
gene encodes a 163-amino-acid dihydrofolate reductase that differs from all so-far-known dihydrofolate reductases.
In Vitro Evaluation of the Antimicrobial Activity of Ceftaroline against Cephalosporin-Resistant Isolates of
Streptococcus pneumoniae
Authors: McGee Lesley , Biek Donald , Ge Yigong , Klugman Magderie , du Plessis Mignon , Smith Anthony M. , Beall Bernard , Whitney Cynthia G. , Klugman Keith P. 
Published: November 2008

ABSTRACT

Increasing pneumococcal resistance to extended-spectrum cephalosporins warrants the search for novel agents with activity against such resistant strains. Ceftaroline, a parenteral cephalosporin currently in phase 3 clinical development, has demonstrated potent in vitro activity against resistant gram-positive organisms, including penicillin-resistant
Streptococcus pneumoniae.
In this study, the activity of ceftaroline was evaluated against highly cefotaxime-resistant isolates of pneumococci from the Active Bacterial Core surveillance program of the Centers for Disease Control and Prevention and against laboratory-derived cephalosporin-resistant mutants of
S. pneumoniae
. The MICs of ceftaroline and comparators were determined by broth microdilution. In total, 120 U.S. isolates of cefotaxime-resistant (MIC ≥ 4 μg/ml)
S. pneumoniae
were tested along with 18 laboratory-derived R6 strains with known penicillin-binding protein (PBP) mutations. Clinical isolates were characterized by multilocus sequence typing, and the DNAs of selected isolates were sequenced to identify mutations affecting
pbp
genes. Ceftaroline (MIC
90
= 0.5 μg/ml) had greater in vitro activity than penicillin, cefotaxime, or ceftriaxone (MIC
90
= 8 μg/ml for all comparators) against the set of highly cephalosporin-resistant clinical isolates of
S. pneumoniae
. Ceftaroline was also more active against the defined R6 PBP mutant strains, which suggests that ceftaroline can overcome common mechanisms of PBP-mediated cephalosporin resistance. These data indicate that ceftaroline has significant potency against
S. pneumoniae
strains resistant to existing parenteral cephalosporins and support its continued development for the treatment of infections caused by resistant
S. pneumoniae
strains.
Mycoplasma suis
Invades Porcine Erythrocytes
Authors: Groebel K. , Hoelzle K. , Wittenbrink M. M. , Ziegler U. , Hoelzle L. E. 
Published: November 2008

ABSTRACT

Mycoplasma suis
belongs to the hemotrophic mycoplasma group and causes infectious anemia in pigs. According to the present state of knowledge, this organism adheres to the surface of erythrocytes but does not invade them. We found a novel
M. suis
isolate that caused severe anemia in pigs with a fatal disease course. Interestingly, only marginal numbers of the bacteria were visible on and between the erythrocytes in acridine orange-stained blood smears for acutely diseased pigs, whereas very high loads of
M. suis
were detected in the same blood samples by quantitative PCR. These findings indicated that
M. suis
is capable of invading erythrocytes. By use of fluorescent labeling of
M. suis
and examination by confocal laser scanning microscopy, as well as scanning and transmission electron microscopy, we proved that the localization of
M. suis
was intracellular. This organism invades erythrocytes in an endocytosis-like process and is initially surrounded by two membranes, and it was also found floating freely in the cytoplasm. In conclusion, we were able to prove for the first time that a member of the hemotrophic mycoplasma group is able to invade the erythrocytes of its host. Such colonization should protect the bacterial cells from the host's immune response and hamper antibiotic treatment. In addition, an intracellular life cycle may explain the chronic nature of hemotrophic mycoplasma infections and should serve as the foundation for novel strategies in hemotrophic mycoplasma research (e.g., treatment or prophylaxis).
Effect of a different caeruloplasmin assay method on the relationship between serum copper and caeruloplasmin
Authors: Twomey P J 
Published: November 2008

Abstract

Background
The assessment of copper status is difficult. When investigating excess and deficient copper states, healthcare professionals usually assume that the locally available caeruloplasmin and copper assay results are comparable to data from the literature.

Objective
To investigate the effect of different caeruloplasmin assays on the relationship between copper and caeruloplasmin.

Methods
Caeruloplasmin and copper results were obtained retrospectively from the laboratory information system before and after a change in the caeruloplasmin assay method. The central tendencies and population confidence intervals for copper and caeruloplasmin were compared. Linear regression analysis was carried out to determine the exact relationship (slope and intercept) between caeruloplasmin and copper. The graph of copper versus caeruloplasmin was also examined to see if the confidence intervals overlapped or not. Finally, the χ2 test was used to determine if there was a difference with respect to the lower reference intervals for the caeruloplasmin assays.

Results
There were 338 and 461 patients in the first and second methods, respectively. None of the patients had Wilson disease. There was no difference between the central tendency copper concentrations or the 95% confidence intervals for the population copper concentrations for the two periods. However, there were differences between the two caeruloplasmin assay methods for both the central tendencies and the population confidence intervals. The data show a statistically significant difference in the relationship between caeruloplasmin and copper associated with the change in the caeruloplasmin assay. There were seven and 100 patients with caeruloplasmin concentrations &lt;200 mg/l with the first and second methods, respectively, which was a significant difference (χ2 test; p&lt;&lt;0.001).

Conclusions
This study shows that that the relationship between copper and caeruloplasmin depends on the caeruloplasmin assay used. A caeruloplasmin assay that reads too high may miss cases of Wilson disease (false negatives), and an assay that reads too low (false positives) may result in further investigations to exclude Wilson disease. Assay-based cut-offs are essential for the investigation of copper excess and deficiency states in the absence of proper assay standardisation. Each laboratory should verify their caeruloplasmin assay reference interval to avoid false positives and/or false negative results.
Cardiovascular risk in South Asians
Authors: Ramaraj R , Chellappa P 
Published: November 2008

Abstract
Cardiovascular disease (CVD) has become a major clinical and public health problem. South Asian countries, namely India, Pakistan, Sri Lanka, Bangladesh and Nepal, not only represent a quarter of the world's population but also contribute to the highest proportion of CVD burden when compared with any other regions globally. This population carries the increased risk even if they migrate to other countries and have increased mortality due to CVD at a younger age in comparison to the local population. In this review, the risk factors and reasons for the higher rate of CVD in South Asians are discussed.
Exercise induced bronchoconstriction and sports
Authors: Billen A , Dupont L 
Published: November 2008

Abstract
Exercise induced bronchoconstriction (EIB) describes the acute transient airway narrowing that occurs during and most often after exercise, and is prevalent in elite athletes. Prolonged hyperventilation of dry or cold air and increased inhalation of pollutants or allergens could account for the bronchoconstrictive reaction. The subsequent airway inflammation seems to differ from typical asthma. Objective measures of lung function and provocation tests should be used for an accurate and reliable diagnosis. EIB is currently treated with inhalation of β2-agonists or, as second choice, sodium cromoglycate approximately 15 min before exercise. If this proves to be insufficient then inhaled steroids should be added. Leukotriene receptor antagonists can be used in patients whose symptoms do not respond to inhaled steroids. The screening of high risk populations such as swimmers, cyclists, rowers and winter athletes is recommended by some authors. Drug doping regulations and practical recommendations for competitive athletes and their health care providers are explained.
Recent advances in the management of type 2 diabetes mellitus: a review
Authors: Srinivasan B T , Jarvis J , Khunti K , Davies M J 
Published: November 2008

Abstract
Type 2 diabetes mellitus (T2DM) is a progressive disorder caused by a combination of insulin resistance and β cell dysfunction. It is associated with an increased and premature risk of cardiovascular disease as well as specific microvascular complications such as retinopathy, nephropathy and neuropathy. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched, such as the glucagon-like peptide (GLP-1) agonists (exenatide) and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and vildagliptin. This review looks at these new agents in terms of their mode of action, pharmacokinetics and use in clinical practice. This review also includes new agents in the area of weight loss that may have a positive effect for glucose management—for example, rimonabant.
Pseudo-hypertriglyceridaemia: a measurement artefact due to glycerol kinase deficiency
Authors: Walmsley T A , Potter H C , George P M , Florkowski C M 
Published: November 2008

Abstract
A man presented with elevated plasma triglycerides and was commenced on fibrate treatment. The triglycerides did not fall and compliance was questioned. The triglyceride elevation was inconsistent with the observed lack of turbidity in the plasma sample. Triglyceride elevation was not confirmed by a different analytical method and lipoprotein electrophoresis showed a normal very low density lipoprotein (VLDL) band pattern. Glycerol kinase deficiency was suspected and was supported by elevated urine glycerol, and confirmed by reduced leucocyte enzyme activity and mutational analysis of the GK gene which showed a novel three base pair deletion. Demonstration of a point mutation also excludes a contiguous gene deletion syndrome.
Lower Silurian subduction-related volcanic rocks in the Chaleurs Group, northern New Brunswick, CanadaGeological Survey of Canada, Contribution No. 2008-0166.Contribution to Natural Resources Canada’s Targeted Geoscience Initiative 3 (2005–2010).
Authors: Wilson R. A. , van Staal C. R. , Kamo S. 
Published: November 2008

Early Silurian volcanic and subvolcanic rocks are preserved in the lower part of the Chaleurs Group at two locations in northern New Brunswick. At Quinn Point, mafic to intermediate rocks are hosted by sedimentary rocks of the Weir Formation, and at Pointe Rochette, a bed of felsic tuff occurs near the base of the Weir. These rocks are interpreted as the first evidence in New Brunswick of magmatism associated with Late Ordovician – Early Silurian subduction of Tetagouche–Exploits back-arc oceanic crust. At Quinn Point, mafic rocks include a thick basaltic flow or sill and intermediate to mafic cobbles in overlying conglomerate beds. The in situ mafic rocks and the conglomerate clasts are chemically alike and display subduction-related affinities on tectonic discrimination diagrams. At Pointe Rochette, fine-grained felsic tuff contains elevated Th and U and depleted high-field-strength elements, consistent with a subduction-influenced setting, although rare-earth element (REE) abundances are low and the REE profile is relatively flat. A U–Pb (zircon) age of 429.2 ± 0.5 Ma was obtained from the tuff, consistent with the late Llandovery to early Wenlock age of the overlying La Vieille Formation and coinciding with the latter stages of development of the Brunswick subduction complex. Volcanic rocks were emplaced in the arc to arc-trench gap region, probably reflecting local step-back of the magmatic axis due to accretion of continental back-arc ribbons. The low volume of Early Silurian subduction-influenced rocks is probably related to the relatively narrow width of the back-arc basin and the young, “warm” character of back-arc crust.
ON COSMIC RAY ACCELERATION IN RELATIVISTIC JETS
Authors: OSTROWSKI MICHAL 
Published: November 2008

We review the theoretical progress in the field of cosmic-ray first-order Fermi acceleration at relativistic shock fronts, showing that recent results change our knowledge about these processes substantially. In particular, relativistic shocks are unlikely to form particle distributions extending to very high energies. Instead, recent simulations give particle distributions where a shock-compressed injected component is followed by a more or less extended high energy tail. An increase of the Lorentz factor of the shock usually leads to steepening and a decrease of the energetic tail, so that fitted spectral indices to the high energy part can substantially deviate from the "universal power law index" σ ≈ 2.2. We report on observational findings from the hot spots in Cygnus A, showing that the derived electron spectra (with a very flat, σ ≈ 1.5, low energy part up to ~ 1 GeV, followed by a much steeper, σ > 3, part at higher energies) indeed deviate from the standard expectation for relativistic shocks. We conclude with a short discussion of some qualitative features of shear and second-order Fermi acceleration in turbulent relativistic plasmas.
Semantic Priming in a Cortical Network Model
Authors: Brunel Nicolas , Lavigne Frédéric 
Published: November 2008

Abstract
Contextual recall in humans relies on the semantic relationships between items stored in memory. These relationships can be probed by priming experiments. Such experiments have revealed a rich phenomenology on how reaction times depend on various factors such as strength and nature of associations, time intervals between stimulus presentations, and so forth. Experimental protocols on humans present striking similarities with pair association task experiments in monkeys. Electrophysiological recordings of cortical neurons in such tasks have found two types of task-related activity, “retrospective” (related to a previously shown stimulus), and “prospective” (related to a stimulus that the monkey expects to appear, due to learned association between both stimuli). Mathematical models of cortical networks allow theorists to understand the link between the physiology of single neurons and synapses, and network behavior giving rise to retrospective and/or prospective activity. Here, we show that this type of network model can account for a large variety of priming effects. Furthermore, the model allows us to interpret semantic priming differences between the two hemispheres as depending on a single association strength parameter.