bluuebunny/crossref_metadata_2025 huggingface dataset:
Vancomycin-Resistant
Enterococcus faecium
: Catheter Colonization,
esp
Gene, and Decreased Susceptibility to Antibiotics in Biofilm
Authors: Raad Issam I. , Hanna Hend A. , Boktour Maha , Chaiban Gassan , Hachem Ray Y. , Dvorak Tanya , Lewis Russell , Murray Barbara E.
Published: November 2005

To evaluate the molecular characteristics and antibiotic susceptibility in biofilm of vancomycin-resistant
Enterococcus faecium
(VREF) organisms that had caused catheter-related VREF bacteremia (VREF-CRB), we compared 22 isolates causing bacteremia obtained from patients with VREF-CRB with 30 isolates from control patients with gastrointestinal colonization by VREF. Using pulsed-field gel electrophoresis, we identified 17 unique strains among the 22 VREF-CRB isolates and 23 strains among the gastrointestinal isolates. The
esp
gene was detected in 53% (9 of 17) of the VREF-CRB and 61% (14 of 23) of the control strains (
P
= 0.6). VREF-CRB produced heavier biofilm colonization of silicone disks than did control organisms (
P
< 0.001). Daptomycin, minocycline, and quinupristin-dalfopristin were each independently more active than linezolid in reducing biofilm colonization by VREF-CRB (
P
< 0.01), with daptomycin being the most active, followed by minocycline. In conclusion, the
esp
gene in VREF is not associated with heavy biofilm colonization or catheter-related bacteremia. In biofilm, daptomycin and minocycline were the most active antibiotics against VREF, and linezolid was the least active.
Erythromycin Resistance and Genetic Elements Carrying Macrolide Efflux Genes in
Streptococcus agalactiae
Authors: Marimón José María , Valiente Adoración , Ercibengoa María , García-Arenzana José M. , Pérez-Trallero Emilio
Published: November 2005

The macrolide resistance determinants and genetic elements carrying the
mef
(A) and
mef
(E) subclasses of the
mef
gene were studied with
Streptococcus agalactiae
isolated in 2003 and 2004 from 7,084 vaginorectal cultures performed to detect carrier pregnant women. The prevalence of carriage was 18% (1,276 isolates), and that of erythromycin resistance 11.0% (129 of the 1,171 isolates studied).
erm
(B),
erm
(A) subclass
erm
(TR), and the
mef
gene, either subclass
mef
(A) or
mef
(E), were found in 72 (55.8%), 41 (31.8%), and 12 (9.3%) erythromycin-resistant isolates, while 4 isolates had more than 1 erythromycin resistance gene. Of the 13 M-phenotype
mef
-containing erythromycin-resistant
S. agalactiae
isolates, 11 had the
mef
(E) subclass gene alone, one had both the
mef
(E) and the
erm
(TR) subclass genes, and one had the
mef
(A) subclass gene.
mef
(E) subclass genes were associated with the carrying element mega in 10 of the 12
mef
(E)-containing strains, while the single
mef
(A) subclass gene found was associated with the genetic element Tn
1207.3
. The nonconjugative nature of the mega element and the clonal diversity of
mef
(E)-containing strains determined by pulsed-field gel electrophoresis suggest that transformation is the main mechanism through which this resistance gene is acquired.
In Vivo Measurement of Levofloxacin Penetration into Lung Tissue after Cardiac Surgery
Authors: Hutschala Doris , Skhirtladze Keso , Zuckermann Andreas , Wisser Wilfried , Jaksch Peter , Mayer-Helm Bernhard Xaver , Burgmann Heinz , Wolner Ernst , Müller Markus , Tschernko Edda M.
Published: November 2005

Nosocomial pneumonia is a severe complication after cardiac surgery (CS). Levofloxacin, a fluoroquinolone, qualifies for the therapy of postoperative pneumonia. However, penetration properties of levofloxacin into the lung tissue could be substantially affected by CS: atelectasis, low cardiac output after CS, high volume loads, and inflammatory capillary leak potentially influence drug distribution. The aim of our study was to gain information on interstitial antibiotic concentrations in lung tissue in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Therefore, six patients undergoing elective CS participated in this prospective study. A dose of 500 mg of levofloxacin was administered intravenously in addition to standard antibiotic prophylaxis immediately after the end of surgery. Time versus concentration profiles of levofloxacin in the interstitial lung tissue and plasma were determined. A microdialysis technique was used for lung interstitial concentration measurements. The microdialysis procedure was well tolerated in all patients and no adverse events were observed. The median area under the concentration curve (AUC) of levofloxacin in interstitial lung fluid was 18.6 μg · h/ml (range, 10.1 to 33.6). The median AUC for tissue (AUC
tissue
) of unbound levofloxacin/AUC
total
in plasma was 0.6 (range, 0.4 to 0.9). The median unbound AUC
tissue
/MIC was 2.4 (range, 1.3 to 4.2) for
Pseudomonas aeruginosa
. Our study demonstrated the feasibility and safety of microdialysis in human lung tissue in vivo after CS. The unbound AUC/MIC ratio revealed that levofloxacin used in the described manner was borderline sufficient for the treatment of nosocomial pneumonia caused by
Klebsiella pneumoniae
and insufficient for the treatment of pneumonia caused by
Pseudomonas aeruginosa
, because the breakpoint of 30 to 40 for AUC/MIC could not be reached by the conventionally used dosage schema in our post-CS setting. Penetration was lower than in previous reports.
Moxifloxacin and Azithromycin but not Amoxicillin Protect Human Respiratory Epithelial Cells against
Streptococcus pneumoniae
In Vitro when Administered up to 6 Hours after Challenge
Authors: Ulrich Martina , Albers Cordula , Möller Jan-Georg , Dalhoff Axel , Korfmann Gisela , Künkele Frank , Döring Gerd
Published: November 2005

We determined the protective effect of moxifloxacin, azithromycin, and amoxicillin against
Streptococcus pneumoniae
infection of respiratory cells. Moxifloxacin and azithromycin effectively killed intracellular
S. pneumoniae
strains and protected respiratory epithelial cells significantly even when given 6 h after
S. pneumoniae
challenge. Amoxicillin was less effective.
Efficacy of Caspofungin against
Aspergillus terreus
Authors: Barchiesi Francesco , Spreghini Elisabetta , Santinelli Alfredo , Fothergill Annette W. , Fallani Stefania , Manso Esther , Pisa Eleonora , Giannini Daniele , Novelli Andrea , Cassetta Maria I. , Mazzei Teresita , Rinaldi Michael G. , Scalise Giorgio
Published: November 2005

We investigated the in vitro and in vivo activities of caspofungin against
Aspergillus terreus
. The drug increased survival and reduced tissue fungal burden in neutropenic mice. Therefore, our data support the role of caspofungin in treating systemic infections due to this emerging pathogen.
Horizontal Transfer of Erythromycin Resistance from
Clostridium difficile
to
Butyrivibrio fibrisolvens
Authors: Spigaglia Patrizia , Barbanti Fabrizio , Mastrantonio Paola
Published: November 2005

This study demonstrates for the first time the in vitro transfer of the erythromycin resistance gene
erm
(B) between two obligate anaerobes, the human spore-forming pathogen
Clostridium difficile
and the rumen commensal
Butyrivibrio fibrisolvens
, suggesting that this event might occur also in the natural environment.
Variants of the
Klebsiella pneumoniae
OKP Chromosomal Beta-Lactamase Are Divided into Two Main Groups, OKP-A and OKP-B
Authors: Fevre Cindy , Passet Virginie , Weill François-Xavier , Grimont Patrick A. D. , Brisse Sylvain
Published: November 2005

Two
bla
OKP
subgroups were found, diverging by 4.2%. Subgroups
bla
OKP-A
(10 enzyme variants, pIs from 7.1 to 8.3) and
bla
OKP-B
(11 variants, pI 7.1) showed similar antibiotic susceptibilities. Sequencing of
rpoB
,
gyrA
, and
mdh
demonstrated a concordant subdivision of
Klebsiella pneumoniae
phylogenetic group KpII into two subgroups, KpII-A and KpII-B.
In Vitro Synergy of Daptomycin plus Rifampin against
Enterococcus faecium
Resistant to both Linezolid andVancomycin
Authors: Pankey George , Ashcraft Deborah , Patel Nalini
Published: November 2005

In
vitro synergy testing of daptomycin plus rifampin was performed against
24 unique isolates of
Enterococcus faecium
resistant to both
linezolid and vancomycin. Synergy testing showed that 21/24 (88%) were
synergistic and 3/24 (12%) were indifferent by the Etest method.
Time-kill assays revealed synergy for 18/24 (75%) and indifference for
6/24
(25%).
Interaction of Monobenzamidine-Linked Trypanocides with the
Trypanosoma brucei
P2 Aminopurine Transporter
Authors: Stewart Mhairi L. , Boussard Cyrille , Brun Reto , Gilbert Ian H. , Barrett Michael P.
Published: November 2005

Single benzamidine group-carrying compounds were shown to interact with the
Trypanosoma brucei
P2 aminopurine transporter. Replacement of the amidine with a guanidine group decreased affinity. Trypanocidal activity was evident, but compounds were equally toxic against trypanosomes lacking the P2 transporter, which indicates additional uptake routes for monobenzamidine-derived compounds.
Novel Rearrangement of a Class 2 Integron in Two Non-Epidemiologically Related Isolates of
Acinetobacter baumannii
Authors: Ramírez María Soledad , Quiroga Cecilia , Centrón Daniela
Published: November 2005

Tn
7
::In2-8 contains
sat2
-
aadB
-
catB2
(
ΔattC
)-
dfrA1
-
sat2
-
aadA1
-
orfX
in the variable region of a class 2 integron embedded in the Tn
7
-like transposon. This novel transposon was inserted in its preferred site downstream of the
glms
gene in
Acinetobacter baumannii
. Acquisition of the pseudocassette
catB2
could have arisen by a secondary-site integrase-mediated intermolecular recombination event.
Antipneumococcal Activity of Dalbavancin Compared to Other Agents
Authors: Lin Gengrong , Smith Kathy , Ednie Lois M. , Appelbaum Peter C.
Published: November 2005

Against 307 pneumococci of various resistotypes, dalbavancin MICs were 0.008 to 0.125 μg/ml. All strains were susceptible to vancomycin, teicoplanin, linezolid, and quinupristin-dalfopristin. Dalbavancin at 2× MIC was bactericidal against all 10 pneumococci tested after 24 h. Vancomycin and teicoplanin killed 10 and 8 strains, respectively, at 2× MIC after 24 h.
Human Immunodeficiency Virus Type 1 Latency Model for High-Throughput Screening
Authors: Micheva-Viteva Sofiya , Pacchia Annmarie L. , Ron Yacov , Peltz Stuart W. , Dougherty Joseph P.
Published: November 2005

Human immunodeficiency virus type 1 (HIV-1) is not eliminated from patients even after years of antiretroviral therapy, apparently due to the presence of latently infected cells. Here we describe the development of a cell-based system of latency that can be used for high-throughput screening aimed at novel drug discovery to eradicate HIV-1 infection.
LOWER SPECTRAL BRANCHES OF A PARTICLE COUPLED TO A BOSE FIELD
Authors: ANGELESCU NICOLAE , MINLOS ROBERT A. , ZAGREBNOV VALENTIN A.
Published: November 2005

The structure of the lower part (i.e. ε-away below the two-boson threshold) spectrum of Fröhlich's polaron Hamiltonian in the weak coupling regime is obtained in spatial dimension d ≥ 3. It contains a single polaron branch defined for total momentum p ∈ G(0), where G(0) ⊂ ℝd is a bounded domain, and, for any p ∈ ℝd, a manifold of polaron + one-boson states with boson momentum q in a bounded domain depending on p. The polaron becomes unstable and dissolves into the one-boson manifold at the boundary of G(0). The dispersion laws and generalized eigenfunctions are calculated.
CONVOLUTION AND CENTRAL LIMIT THEOREM ARISING FROM ADDITION OF FIELD OPERATORS IN ONE-MODE TYPE INTERACTING FOCK SPACES
Authors: KRYSTEK ANNA DOROTA , WOJAKOWSKI ŁUKASZ JAN
Published: November 2005

In Ref. 2 the authors introduced field operators in one-mode type Interacting Fock Spaces whose spectral measures have common symmetric Jacobi recurrence coefficients but differ in the nonsymmetric ones. We show that the convolution of measures arising from addition of such field operators is the universal convolution of Accardi and Bożejko. We also present the associated central limit theorem in a more general form than in Ref. 2 and give it a proof based on the properties of the convolution.
A d-DEFORMATION OF FREE GAUSSIAN RANDOM VARIABLES
Authors: WYSOCZAŃSKI JANUSZ
Published: November 2005

We define a deformation of free creations (and annihilations), given by operators on the full Fock space, acting nontrivially only between the vacuum subspace ℂΩ and the twofold tensor product [Formula: see text]. Then we study the distribution of the deformed free gaussian operators, with the deformation containing also a real parameter d. The recurrence formula for moments is shown, and the Cauchy transform of the distribution measure is computed. This yields the description of the measure: absolutely continuous part and the atomic part. The existence of atoms depends on the parameter d. The special case d =1 is studied with all details, with the formula for moments is given as values of the hypergeometric series. Finally we show the formula for computing the mixed moments of the deformed operators.
LARGE AND MODERATE DEVIATIONS FOR OCCUPATION TIMES OF IMMIGRATION SUPERPROCESSES
Authors: HONG WENMING , LI ZENGHU
Published: November 2005

Large and moderate deviation principles are proved for the occupation time process of a subcritical branching superprocess with immigration.
FINGERPRINT MINUTIAE RELATIONSHIP REPRESENTATION AND MATCHING BASED ON CURVE COORDINATE SYSTEM
Authors: ZHU EN , YIN JIAN-PING , ZHANG GUO-MIN , HU CHUN-FENG
Published: November 2005

A minutiae relationship representation and matching method based on curve coordinate system is proposed. For each minutia, a curve coordinate system is established, and the coordinates of other minutiae in this coordinate system is computed. Thus, the coordinate relationship between each pair of minutiae can be evaluated. These relationships are used for pairing minutiae between the template fingerprint and the query fingerprint by means of transferring reference minutiae. The algorithm is tested on FVC2004DBs which include many highly distorted fingerprints. Results have shown that the proposed algorithm achieves improved matching accuracy and is able to cope with highly distorted fingerprints.
HUMAN POSTURE RECOGNITION: EIGENSPACE TUNING BY A MEAN EIGENSPACE
Authors: RAHMAN M. MASUDUR , ISHIKAWA SEIJI
Published: November 2005

This paper investigates an appearance-change issue due to various human body shapes in an eigenspace analysis, which is responsible for generating person-based eigenspaces employing a conventional eigenspace method. We call this a figure effect in this study for this phenomenon. As a consequence, an appearance-based eigenspace method cannot be effective for recognizing human postures with its present available formulation. We propose to employ a generalized eigenspace for avoiding this problem, which is developed by calculating a mean of some selected eigenspaces. We also investigate a dress effect due to human wearing clothes in this paper. The study proposes image pre-processing by Laplacian of Gaussian (LoG) filter for reducing the dress problem. Since the proposed method tunes a conventional eigenspace as an appropriate method for human posture recognition, the proposed scheme is known as an eigenspace tuning. An eigenspace called a tuned eigenspace is obtained from this tuning scheme and it is used for further recognition of unfamiliar postures. We have tested the proposed approach employing a number of human models wearing various clothes along with their different body shapes, and the significance of the method to human posture recognition has been demonstrated.
In Vivo Quantitative Measurement of Intact Fibrous Cap and Lipid-Rich Necrotic Core Size in Atherosclerotic Carotid Plaque
Authors: Cai Jianming , Hatsukami Thomas S. , Ferguson Marina S. , Kerwin William S. , Saam Tobias , Chu Baocheng , Takaya Norihide , Polissar Nayak L. , Yuan Chun
Published: November 2005

Background—

Previous studies with contrast-enhanced magnetic resonance imaging (CEMRI) have shown that the fibrous cap (FC) in atherosclerotic carotid plaques enhances with gadolinium-based contrast agents. Conversely, the lipid-rich necrotic core (LR-NC), lacking both vasculature and matrix, shows no or only slight enhancement. The goal of this study was to assess whether CEMRI can be used to accurately measure the dimensions of the intact FC and LR-NC.

Methods and Results—

Twenty-one patients scheduled for carotid endarterectomy were imaged with a 1.5-T scanner. Precontrast images and CEMRI were obtained. One hundred eight locations with an intact FC were matched between MRI and the excised histology specimens. Quantitative measurements of FC length along the lumen circumference, FC area, and LR-NC area were collected from CEMRI images and histology sections. Blinded comparison of corresponding MR images and histology slices showed moderate to good correlation for length (
r
=0.73,
P
<0.001) and area (
r
=0.80,
P
<0.001) of the intact FC. The mean percentage LR-NC areas (LR-NC area/wall area) measured by CEMRI and histology were 30.1% and 32.7%, respectively, and were strongly correlated across locations (
r
=0.87,
P
<0.001).

Conclusions—

In vivo high-resolution CEMRI is capable of quantitatively measuring the dimensions of the intact FC and LR-NC. These new parameters may be useful to evaluate plaque vulnerability and provide continuous variables for characterizing the intact FC and LR-NC in progression and regression studies.
Effect of Thalidomide on Cardiac Remodeling in Chronic Heart Failure
Authors: Gullestad Lars , Ueland Thor , Fjeld Jan G. , Holt Even , Gundersen Torstein , Breivik Kjell , Følling Magne , Hodt Anders , Skårdal Rita , Kjekshus John , Andreassen Arne , Kjekshus Elin , Wergeland Ragnhild , Yndestad Arne , Frøland Stig S. , Semb Anne Grete , Aukrust Pål
Published: November 2005

Background—

Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD).

Methods and Results—

Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (&7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-α, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage.

Conclusions—

Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.
A Barotropic Envelope Rossby Soliton Model for Block–Eddy Interaction. Part III: Wavenumber Conservation Theorems for Isolated Blocks and Deformed Eddies
Authors: Luo Dehai
Published: November 2005

In a series of previous papers, an envelope Rossby soliton theory was formulated to investigate the interaction between a preexisting planetary wave and synoptic-scale eddies leading to a typical blocking flow. In this paper, numerical and analytical studies are presented in order to examine the interactive relationship between an isolated vortex pair block and deformed synoptic-scale eddies during their interaction. The deformed blocked flow and eddies are found to satisfy the wavenumber conservation theorem. It is shown that the feedback by a blocked flow on the preexisting synoptic eddies gives rise to two types of eddies: one is the Z-type eddies with a meridional monopole structure that appears at the middle of the channel and the other is the M-type eddies with a meridional tripole structure that have long wavelength and large amplitude. Both the total wavenumber of the blocked flow and M-type eddies and the total wavenumber of the Z- and M-type eddies are conserved. The M- and Z-type eddies are compressed and elongated, respectively, as the blocked flow is elongated zonally during its onset phase, but the reverse is observed during the decay phase. The zonally elongated Z-type eddies are found to counteract the compressed M-type eddies in the blocking region, but strengthen the M-type eddies upstream, causing the split of eddies around the blocking region.

In addition, it is also verified theoretically that the blocked flow and synoptic-eddy activity are symbiotically dependent upon one another. The deformed (Z and M type) eddies also display a low-frequency oscillation in amplitude, wavenumber, group velocity, and phase speed, consistent with the blocked flow by the eddy forcing. Thus, it appears that the low-frequency eddy forcing is responsible for the low-frequency variability of the blocked flow and synoptic-eddy activity.
Dynamic Instabilities of Simulated Hurricane-like Vortices and Their Impacts on the Core Structure of Hurricanes. Part I: Dry Experiments
Authors: Kwon Young C. , Frank William M.
Published: November 2005

A series of numerical simulations of dry, axisymmetric hurricane-like vortices is performed to examine the growth of barotropic and baroclinic eddies and their potential impacts on hurricane core structure and intensity. The numerical experiments are performed using the fifth-generation Pennsylvania State University–National Center for Atmospheric Research (PSU–NCAR) Mesoscale Model (MM5) with a 6-km horizontal grid. To examine internal effects on the stability of vortices, all external forcings are eliminated. Axisymmetric vortices that resemble observed hurricane structures are constructed on an f plane, and the experiments are performed without moist and boundary layer processes.

Three vortices are designed for this study. A balanced control vortex is built based on the results of a full-physics simulation of Hurricane Floyd (1999). Then, two other axisymmetric vortices, EXP-1 and EXP-2, are constructed by modifying the wind and mass fields of the control vortex. The EXP-1 vortex is designed to satisfy the necessary condition of baroclinic instability, while the EXP-2 vortex satisfies the necessary condition of barotropic instability. These modified vortices are thought to lie within the natural range of structural variability of hurricanes.

The EXP-1 and EXP-2 vortices are found to be unstable with respect to small imposed perturbations, while the control vortex is stable. Small perturbations added to the EXP-1 and EXP-2 vortices grow exponentially at the expense of available potential energy and kinetic energy of the primary vortex, respectively. The most unstable normal modes of both vortices are obtained via a numerical method. The most unstable mode of the EXP-1 (baroclinically unstable) vortex vertically tilts against shear, and the maximum growth occurs near a height of 14 km and a radius of 20 km. On the other hand, the most unstable normal mode of the EXP-2 (barotropically unstable) vortex has horizontal tilting against the mean angular velocity shear, and the maximum perturbations are located at a lower altitude (around 4 km) and at larger radius (around 100 km). Despite these differences, the normal modes of both vortices have a wavenumber-1 structure.

The energy budget analysis shows that the growing baroclinic and barotropic perturbations have opposite effects on the vortex intensity in terms of kinetic energy. Baroclinic eddies strengthen, whereas barotropic eddies weaken, the primary vortex. It is hypothesized that fluctuations in hurricane core structure and intensity can occur due to eddy processes triggered by alternating periods of barotropic and baroclinic eddy growth in the core. Once formed, these eddies may interact with the intense diabatic energy sources in real hurricanes. A similar study of eddy behaviors in a more realistic hurricane, which includes moist and boundary layer processes and uses a finer grid mesh, will be the topic of Part II.
Study of the Aerosol Indirect Effect by Large-Eddy Simulation of Marine Stratocumulus
Authors: Lu Miao-Ling , Seinfeld John H.
Published: November 2005

A total of 98 three-dimensional large-eddy simulations (LESs) of marine stratocumulus clouds covering both nighttime and daytime conditions were performed to explore the response of cloud optical depth (τ) to various aerosol number concentrations (Na = 50–2500 cm−3) and the covarying meteorological conditions (large-scale divergence rate and SST). The idealized First International Satellite Cloud Climatology Project (ISCCP) Regional Experiment (FIRE) and the Atlantic Stratocumulus Transition Experiment (ASTEX) Lagrangian 1 sounding profiles were used to represent the lightly and heavily drizzling cases, respectively. The first and second aerosol indirect effects are identified. Through statistical analysis, τ is found be to both positively correlated with Na and cloud liquid water path (LWP) with a higher correlation associated with LWP, which is predominantly regulated by large-scale subsidence and SST. Clouds with high LWP occur under low SST or weak large-scale subsidence. Introduction of a small amount of giant sea salt aerosol into the simulation lowers the number of cloud droplets activated, results in larger cloud droplets, and initiates precipitation for nondrizzling polluted clouds or precedes the precipitation process for drizzling clouds. However, giant sea salt aerosol is found to have a negligible effect on τ for lightly precipitating cases, while resulting in a relative reduction of τ of 3%–77% (increasing with Na, for Na = 1000–2500 cm−3) for heavily precipitating cases, suggesting that the impact of giant sea salt is only important for moist and potentially convective clouds. Finally, a regression analysis of the simulations shows that the second indirect effect is more evident in clear than polluted cases. The second indirect effect is found to enhance (reduce) the overall aerosol indirect effect for heavily (lightly) drizzling clouds; that is, τ is larger (smaller) for the same relative change in Na than considering the Twomey (first indirect) effect alone. The aerosol indirect effect (on τ) is lessened in the daytime afternoon conditions and is dominated by the Twomey effect; however, the effect in the early morning is close but slightly smaller than that in the nocturnal run. Diurnal variations of the aerosol indirect effect should be considered to accurately assess its magnitude.
Supplying Local Microphysics Parameterizations with Information about Subgrid Variability: Latin Hypercube Sampling
Authors: Larson Vincent E. , Golaz Jean-Christophe , Jiang Hongli , Cotton William R.
Published: November 2005

One problem in computing cloud microphysical processes in coarse-resolution numerical models is that many microphysical processes are nonlinear and small in scale. Consequently, there are inaccuracies if microphysics parameterizations are forced with grid box averages of model fields, such as liquid water content. Rather, the model needs to determine information about subgrid variability and input it into the microphysics parameterization.

One possible solution is to assume the shape of the family of probability density functions (PDFs) associated with a grid box and sample it using the Monte Carlo method. In this method, the microphysics subroutine is called repeatedly, once with each sample point. In this way, the Monte Carlo method acts as an interface between the host model’s dynamics and the microphysical parameterization. This avoids the need to rewrite the microphysics subroutines.

A difficulty with the Monte Carlo method is that it introduces into the simulation statistical noise or variance, associated with the finite sample size. If the family of PDFs is tractable, one can sample solely from cloud, thereby improving estimates of in-cloud processes. If one wishes to mitigate the noise further, one needs a method for reduction of variance. One such method is Latin hypercube sampling, which reduces noise by spreading out the sample points in a quasi-random fashion.

This paper formulates a sampling interface based on the Latin hypercube method. The associated family of PDFs is assumed to be a joint normal/lognormal (i.e., Gaussian/lognormal) mixture. This method of variance reduction has a couple of advantages. First, the method is general: the same interface can be used with a wide variety of microphysical parameterizations for various processes. Second, the method is flexible: one can arbitrarily specify the number of hydrometeor categories and the number of calls to the microphysics parameterization per grid box per time step.

This paper performs a preliminary test of Latin hypercube sampling. As a prototypical microphysical formula, this paper uses the Kessler autoconversion formula. The PDFs that are sampled are extracted diagnostically from large-eddy simulations (LES). Both stratocumulus and cumulus boundary layer cases are tested. In this diagnostic test, the Latin hypercube can produce somewhat less noisy time-averaged estimates of Kessler autoconversion than a traditional Monte Carlo estimate, with no additional calls to the microphysics parameterization. However, the instantaneous estimates are no less noisy. This paper leaves unanswered the question of whether the Latin hypercube method will work well in a prognostic, interactive cloud model, but this question will be addressed in a future manuscript.
Biology and Management of Histologic Transformation of Indolent Lymphoma
Authors: Freedman Arnold S.
Published: November 2005

The evolution of indolent lymphomas to aggressive histologies, known as histologic transformation (HT), is a frequent occurrence for all subtypes of low grade B cell lymphoproliferative disorders. The risk of developing HT is approximately 3% per year for patients with indolent lymphoma. Clinically these present with a rapid change in the behavior of the disease, with evidence of a highly proliferative malignancy with a propensity to involve extranodal sites. The prognosis of patients following transformation is generally poor, with median survival of about 12 months. Recent studies suggest that the development of HT is very complex with the acquisition of multiple cytogenetic abnormalities in the low-grade lymphoma cells prior to HT. To date, there are no biologic or genetic parameters predictive of the development of HT. A myriad of genetic lesions have been identified in HT, and provide insight into its pathogenesis. These include genes regulating proliferation (C-MYC and C-MYC-regulated genes); control of the cell cycle (CDKN2a and CDKN2B); and programmed cell death (TP53, C-MYC, and BCL2). Gene expression profiling has been applied to the study of HT and has increased our understanding of the transformation process. There has been limited progress in the treatment of patients with HT. Conventional chemotherapy is generally of limited benefit, although a subset of patients are long-term survivors following high-dose therapy and autologous stem cell transplantation. The use of radioimmunotherapy and new agents targeting specific lesions or aberrant pathways may impact on the management of these aggressive diseases.
Umbilical Cord Blood Transplantation: A New Alternative Option
Authors: Tse William , Laughlin Mary J.
Published: November 2005

Allogeneic hematopoietic stem cell transplantation is a life-saving procedure for hematopoietic malignancies, marrow failure syndromes, and hereditary immunodeficiency disorders. However, wide application of this procedure is limited by availability of suitably HLA-matched adult donors. Umbilical cord blood (UCB) has being increasingly used as an alternative hematopoietic stem cell source for these patients. To date, over 6000 UCB transplant procedures in children and adults have been performed worldwide using UCB donors. Broader use of UCB for adult patients is however limited by the available infused cell dose. This has prompted intensive research on ex vivo expansion of UCB stem cells and UCB graft-engineering including accessory cells able to improve UCB engraftment and reconstitution and for tissue regenerative potential. Recently, two large European and North American retrospective studies demonstrated that UCB is an acceptable alternative source of hematopoietic stem cells for adult recipients who lack HLA-matched adult donors. UCB is anticipated to address needs in both transplantation and regenerative medicine fields. It has advantages of easy procurement, no risk to donors, low risk of transmitting infections, immediate availability and immune tolerance allowing successful transplantation despite HLA disparity.
Haploidentical Stem Cell Transplantation: The Always Present but Overlooked Donor
Authors: Spitzer Thomas R.
Published: November 2005

Haploidentical stem cell transplantation is a treatment option for the approximately 70% of patients who do not have an HLA-identical sibling donor. The availability of a haploidentical donor in most families is a potential advantage, both for avoiding the need to find an alternative unrelated donor, and for the potentially more potent graft-versus-tumor effect that can be induced. The early complications of severe graft-versus-host disease (GVHD) following T-cell replete stem cell transplantation (SCT), and graft failure and recurrent malignancy (after T-cell depleted SCT) have limited the applications of this approach. Newer strategies employing T-cell depletion of the graft, using either very high-dose peripheral blood stem cells and/or more intensive conditioning therapy have overcome some of the problems of conventional transplantation. Nonmyeloablative SCT approaches have overcome some of the morbidity and mortality associated with the early complications of SCT and have been associated with favorable engraftment and GVHD profiles. Induction of mixed lymphohematopoietic chimerism as a platform for adoptive cellular immunotherapy (via delayed donor lymphocyte infusions) may have important application in avoiding early GVHD, while ultimately capturing a very potent graft-versus-tumor effect. Current strategies are focusing on improvement of immune reconstitution and prevention of recurrence of the underlying malignancy.
Platelets and Thrombosis in Myeloproliferative Diseases
Authors: Harrison Claire N.
Published: November 2005

The myeloproliferative disorders have been the “poor cousins” in the family of hematological malignancies for some time. Recently this field has advanced considerably with the description of a mutation in the JAK2 kinase detectable in the majority of patients and the publication of two landmark clinical trials—ECLAP and MRC PT1. But although both ECLAP and MRC PT1 inform clinical management and allude to the complexities of thrombosis we still lack fundamental knowledge, and our understanding of thrombosis in these conditions has not paralleled advances in the field of thrombosis and vascular biology. The predominant clinical complications of essential thrombocythemia and polycythemia vera are thrombotic and hemorrhagic; these significantly impact upon prognosis and quality of life. Here the current status of our knowledge is reviewed with specific emphasis upon the role of the platelet in the pathogenesis of thrombosis as well as the impact of recent data from ECLAP and MRC PT1.
Acquired Risk Factors for Venous Thromboembolism in Medical Patients
Authors: Prandoni Paolo
Published: November 2005

Acute venous thromboembolism (VTE) is a serious and potentially fatal disorder, which often complicates the course of hospitalized patients, but may also affect ambulatory and otherwise healthy people. While the introduction of thromboprophylactic measures is expected to have reduced the occurrence of postoperative VTE, there is an increasing awareness of the importance of medical conditions in determining thromboembolic events. Among the conditions that predispose patients to VTE are increasing age, cancer and its treatment, prolonged immobility, stroke or paralysis, previous VTE, congestive heart failure, acute infection, pregnancy or puerperium, dehydration, hormonal treatment, varicose veins, long air travel, acute inflammatory bowel disease, rheumatologic disease, and nephrotic syndrome. Other factors that have recently been associated with an increased risk of VTE disorders include persistent elevation of D-dimer and atherosclerotic disease. Recognition of the incidence and clinical importance of thrombosis will most likely encourage more widespread use of antithrombotic prophylaxis in medical patients.
Efficient gene-driven germ-line point mutagenesis of C57BL/6J mice
Authors: Michaud Edward J , Culiat Cymbeline T , Klebig Mitchell L , Barker Paul E , Cain KT , Carpenter Debra J , Easter Lori L , Foster Carmen M , Gardner Alysyn W , Guo ZY , Houser Kay J , Hughes Lori A , Kerley Marilyn K , Liu Zhaowei , Olszewski Robert E , Pinn Irina , Shaw Ginger D , Shinpock Sarah G , Wymore Ann M , Rinchik Eugene M , Johnson Dabney K
Published: November 2005

Background

Analysis of an allelic series of point mutations in a gene, generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, is a valuable method for discovering the full scope of its biological function. Here we present an efficient gene-driven approach for identifying ENU-induced point mutations in any gene in C57BL/6J mice. The advantage of such an approach is that it allows one to select any gene of interest in the mouse genome and to go directly from DNA sequence to mutant mice.

Results

We produced the Cryopreserved Mutant Mouse Bank (CMMB), which is an archive of DNA, cDNA, tissues, and sperm from 4,000 G1 male offspring of ENU-treated C57BL/6J males mated to untreated C57BL/6J females. Each mouse in the CMMB carries a large number of random heterozygous point mutations throughout the genome. High-throughput Temperature Gradient Capillary Electrophoresis (TGCE) was employed to perform a 32-Mbp sequence-driven screen for mutations in 38 PCR amplicons from 11 genes in DNA and/or cDNA from the CMMB mice. DNA sequence analysis of heteroduplex-forming amplicons identified by TGCE revealed 22 mutations in 10 genes for an overall mutation frequency of 1 in 1.45 Mbp. All 22 mutations are single base pair substitutions, and nine of them (41%) result in nonconservative amino acid substitutions. Intracytoplasmic sperm injection (ICSI) of cryopreserved spermatozoa into B6D2F1 or C57BL/6J ova was used to recover mutant mice for nine of the mutations to date.

Conclusions

The inbred C57BL/6J CMMB, together with TGCE mutation screening and ICSI for the recovery of mutant mice, represents a valuable gene-driven approach for the functional annotation of the mammalian genome and for the generation of mouse models of human genetic diseases. The ability of ENU to induce mutations that cause various types of changes in proteins will provide additional insights into the functions of mammalian proteins that may not be detectable by knockout mutations.
Functional inaccessibility of quiescent herpes simplex virus genomes
Authors: Minaker Rebecca L , Mossman Karen L , Smiley James R
Published: November 2005

Background

Newly delivered herpes simplex virus genomes are subject to repression during the early stages of infection of human fibroblasts. This host defence strategy can limit virus replication and lead to long-term persistence of quiescent viral genomes. The viral immediate-early protein ICP0 acts to negate this negative regulation, thereby facilitating the onset of the viral replication cycle. Although few mechanistic details are available, the host repression machinery has been proposed to assemble the viral genome into a globally inaccessible configuration analogous to heterochromatin, blocking access to most or all trans-acting factors. The strongest evidence for this hypothesis is that ICP0-deficient virus is unable to reactivate quiescent viral genomes, despite its ability to undergo productive infection given a sufficiently high multiplicity of infection. However, recent studies have shown that quiescent infection induces a potent antiviral state, and that ICP0 plays a key role in disarming such host antiviral responses. These findings raise the possibility that cells containing quiescent viral genomes may be refractory to superinfection by ICP0-deficient virus, potentially providing an alternative explanation for the inability of such viruses to trigger reactivation. We therefore asked if ICP0-deficient virus is capable of replicating in cells that contain quiescent viral genomes.

Results

We found that ICP0-deficient herpes simplex virus is able to infect quiescently infected cells, leading to expression and replication of the superinfecting viral genome. Despite this productive infection, the resident quiescent viral genome was neither expressed nor replicated, unless ICP0 was provided in trans.

Conclusion

These data document that quiescent HSV genomes fail to respond to the virally modified host transcriptional apparatus or viral DNA replication machinery provided in trans by productive HSV infection in the absence of ICP0. These results point to global repression as the basis for HSV genome quiescence, and indicate that ICP0 induces reactivation by overcoming this global barrier to the access of trans-acting factors.
Stimulation of poliovirus RNA synthesis and virus maturation in a HeLa cell-free in vitro translation-RNA replication system by viral protein 3CDpro
Authors: Franco David , Pathak Harsh B , Cameron Craig E , Rombaut Bart , Wimmer Eckard , Paul Aniko V
Published: November 2005

Poliovirus protein 3CDpro possesses both proteinase and RNA binding activities, which are located in the 3Cpro domain of the protein. The RNA polymerase (3Dpol) domain of 3CDpro modulates these activities of the protein. We have recently shown that the level of 3CDpro in HeLa cell-free in vitro translation-RNA replication reactions is suboptimal for efficient virus production. However, the addition of either 3CDpro mRNA or of purified 3CDpro protein to in vitro reactions, programmed with viral RNA, results in a 100-fold increase in virus yield. Mutational analyses of 3CDpro indicated that RNA binding by the 3Cpro domain and the integrity of interface I in the 3Dpol domain of the protein are both required for function. The aim of these studies was to determine the exact step or steps at which 3CDpro enhances virus yield and to determine the mechanism by which this occurs. Our results suggest that the addition of extra 3CDpro to in vitro translation RNA-replication reactions results in a mild enhancement of both minus and plus strand RNA synthesis. By examining the viral particles formed in the in vitro reactions on sucrose gradients we determined that 3CDpro has only a slight stimulating effect on the synthesis of capsid precursors but it strikingly enhances the maturation of virus particles. Both the stimulation of RNA synthesis and the maturation of the virus particles are dependent on the presence of an intact RNA binding site within the 3Cpro domain of 3CDpro. In addition, the integrity of interface I in the 3Dpol domain of 3CDpro is required for efficient production of mature virus. Surprisingly, plus strand RNA synthesis and virus production in in vitro reactions, programmed with full-length transcript RNA, are not enhanced by the addition of extra 3CDpro. Our results indicate that the stimulation of RNA synthesis and virus maturation by 3CDpro in vitro is dependent on the presence of a VPg-linked RNA template.
Insulin induces a positive relationship between the rates of ATP and glycogen changes in isolated rat liver in presence of glucose; a 31P and 13C NMR study
Authors: Baillet-Blanco Laurence , Beauvieux Marie-Christine , Gin Henri , Rigalleau Vincent , Gallis Jean-Louis
Published: November 2005

Background

There is an emerging theory suggesting that insulin, which is known to be the predominant postprandial anabolic hormone, is also a major regulator of mitochondrial oxidative phosphorylation in human skeletal muscle. However, little is known about its effects in the liver. Since there is a theoretical relationship between glycogen metabolism and energy status, a simultaneous and continuous investigation of hepatic ATP and glycogen content was performed in intact and isolated perfused liver by 31P and 13C nuclear magnetic resonance (NMR) The hepatic rates of ATP and glycogen changes were evaluated with different concentrations of insulin and glucose during continuous and short-term supply.

Results

Liver from rats fed ad libitum were perfused with Krebs-Henseleit Buffer (KHB)(controls) or KHB containing 6 mM glucose, 30 mM glucose, insulin alone, insulin + 6 mM glucose, insulin + 30 mM glucose. In the control, glycogenolysis occurred at a rate of -0.53 ± 0.021 %·min-1 and ATP content decreased at a rate of -0.28 ± 0.029 %·min-1. In the absence of insulin, there was a close proportional relationship between the glycogen flux and the glucose concentration, whereas ATP rates never varied. With insulin + glucose, both glycogen and ATP rates were strongly related to the glucose concentration; the magnitude of net glycogen flux was linearly correlated to the magnitude of net ATP flux: fluxglycogen = 72.543(fluxATP) + 172.08, R2 = 0.98.

Conclusion

Only the co-infusion of 30 mM glucose and insulin led to (i) a net glycogen synthesis, (ii) the maintenance of the hepatic ATP content, and a strong positive correlation between their net fluxes. This has never previously been reported. The specific effect of insulin on ATP change is likely related to a rapid stimulation of the hepatic mitochondrial oxidative phosphorylation. We propose that variations in the correlation between rates of ATP and glycogen changes could be a probe for insulin resistance due to the action of substrates, drugs or pathologic situations. Consequently, any work evaluating insulin resistance on isolated organs or in vivo should determine both ATP and glycogen fluxes.
Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis
Authors: Esserman Laura J , Ozanne Elissa M , Dowsett Mitch , Slingerland Joyce M
Published: November 2005

Introduction

Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers.

Methods

BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate.

Results

If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%.

Conclusion

Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection.