bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effective Antimicrobial Regimens for Use in Humans for Therapy ofBacillus anthracisInfections and Postexposure Prophylaxis
Authors: Deziel Mark R. , Heine Henry , Louie Arnold , Kao Mark , Byrne William R. , Basset Jennifer , Miller Lynda , Bush Karen , Kelly Michael , Drusano G. L. 
Published: November 2005

ABSTRACTExpanded options for treatments directed against pathogens that can be used for bioterrorism are urgently needed. Treatment regimens directed against such pathogens can be identified only by using data derived from in vitro and animal studies. It is crucial that these studies reliably predict the efficacy of proposed treatments in humans. The objective of this study was to identify a levofloxacin treatment regimen that will serve as an effective therapy forBacillus anthracisinfections and postexposure prophylaxis. An in vitro hollow-fiber infection model that replicates the pharmacokinetic profile of levofloxacin observed in humans (half-life [t1/2], 7.5 h) or in animals, such as the mouse or the rhesus monkey (t1/2, ∼2 h), was used to evaluate a proposed indication for levofloxacin (500 mg once daily) for the treatment ofBacillus anthracisinfections. The results obtained with the in vitro model served as the basis for the doses and the dose schedules that were evaluated in the mouse inhalational anthrax model. The effects of levofloxacin and ciprofloxacin treatment were compared to those of no treatment (untreated controls). The main outcome measure in the in vitro hollow-fiber infection model was a persistent reduction of culture density (≥4 log10reduction) and prevention of the emergence of levofloxacin-resistant organisms. In the mouse inhalational anthrax model the main outcome measure was survival. The results indicated that levofloxacin given once daily with simulated human pharmacokinetics effectively sterilizedBacillus anthraciscultures. By using a simulated animal pharmacokinetic profile, a once-daily dosing regimen that provided a human-equivalent exposure failed to sterilize the cultures. Dosing regimens that “partially humanized” levofloxacin exposures within the constraints of animal pharmacokinetics reproduced the antimicrobial efficacy seen with human pharmacokinetics. In a mouse inhalational anthrax model, once-daily dosing was significantly inferior (survival end point) to regimens of dosing every 12 h or every 6 h with identical total daily levofloxacin doses. These results demonstrate the predictive value of the in vitro hollow-fiber infection model with respect to the success or the failure of treatment regimens in animals. Furthermore, the model permits the evaluation of treatment regimens that “humanize” antibiotic exposures in animal models, enhancing the confidence with which animal models may be used to reliably predict the efficacies of proposed antibiotic treatments in humans in situations (e.g., the release of pathogens as agents of bioterrorism or emerging infectious diseases) where human trials cannot be performed. A treatment regimen effective in rhesus monkeys was identified.
Pitfalls in Estimating Piperaquine Elimination
Authors: Tarning Joel , Lindegårdh Niklas , Annerberg Anna , Singtoroj Thida , Day Nicholas P. J. , Ashton Michael , White Nicholas J. 
Published: November 2005

ABSTRACT
By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a healthy volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs.
Attenuation of the Activity of Caspofungin at High Concentrations against
Candida albicans
: Possible Role of Cell Wall Integrity and Calcineurin Pathways
Authors: Wiederhold Nathan P. , Kontoyiannis Dimitrios P. , Prince Randall A. , Lewis Russell E. 
Published: November 2005

ABSTRACT

Caspofungin had diminished activity in vitro against
Candida albicans
at concentrations of 8 to 32 μg/ml. This phenomenon was markedly attenuated in a Δ
mkc1
/Δ
mkc1
deletion mutant and by the addition of cyclosporine to the wild type. Short exposure to these caspofungin concentrations resulted in
MKC1
up-regulation, suggesting roles of cell wall integrity and calcineurin pathways.
VIM-12, a Novel Plasmid-Mediated Metallo-β-Lactamase from
Klebsiella pneumoniae
That Resembles a VIM-1/VIM-2 Hybrid
Authors: Pournaras Spyros , Ikonomidis Alexandros , Tzouvelekis Leonidas S. , Tokatlidou Despoina , Spanakis Nicholas , Maniatis Antonios N. , Legakis Nicholas J. , Tsakris Athanassios 
Published: November 2005

ABSTRACT

A transferable plasmid from
Klebsiella pneumoniae
carried a class 1 integron containing
bla
VIM-12
, a novel
bla
VIM
-type gene, flanked by two copies of
aacA7. bla
VIM-12
was clustered between
bla
VIM-1
and
bla
VIM-2
and differed from
bla
VIM-1
by 18 nucleotides that were all located at the 3′ end and matched the corresponding nucleotides in
bla
VIM-2
. The
bla
VIM-12
-associated 59-base element was identical to that described in
bla
VIM-2
alleles.
Effect of Voriconazole Combined with Micafungin against
Candida
,
Aspergillus
, and
Scedosporium
spp. and
Fusarium solani
Authors: Heyn Kathrin , Tredup Antje , Salvenmoser Stefanie , Müller Frank-Michael C. 
Published: November 2005

ABSTRACT

Effects of voriconazole combined with micafungin against 101 isolates of
Candida
spp. and 100 isolates of filamentous fungi have been evaluated by in vitro checkerboard analysis. The combination was indifferent for 97% of the
Candida
isolates and synergistic for 64% of the filamentous fungi (79% for
Aspergillus fumigatus
).
CONSTRUCTIVE UNIVERSAL CENTRAL LIMIT THEOREMS BASED ON INTERACTING FOCK SPACES
Authors: ACCARDI L. , CRISMALE V. , LU Y. G. 
Published: November 2005

Cabana-Duvillard and lonescu11have proved that any symmetric probability measure with moments of any order can be obtained as central limit theorem of self-adjoint, weakly independent and symmetrically distributed (in a quantum souse) random variables. Results of this type will be called "universal central limit theorem".Using Interacting Fock Space (IFS) techniques we extend this result in two directions: (i) we prove that the random variables can be taken to be generalized Gaussian in the sense of Accardi and Bożejko3and we give a realization of such random variables as sums of creation, annihilation and preservation operators acting on an appropriate IFS; (ii) we extend the above-mentioned result to the nonsymmetric case. The nontrivial difference between the symmetric and the nonsymmetric case is explained at the end of the introduction below.
Estimating Cloud Optical Depth from Surface Radiometric Observations: Sensitivity to Instrument Noise and Aerosol Contamination
Authors: Beaulne Alain , Barker Howard W. , Blanchet Jean-Pierre 
Published: November 2005

Abstract
The spectral-difference algorithm of Barker and Marshak for inferring optical depth τ of broken clouds has been shown numerically to be potentially useful. Their method estimates cloud-base reflectance and τ using spectral radiometric measurements made at the surface at two judiciously chosen wavelengths. Here it is subject to sensitivity tests that address the impacts of two ubiquitous sources of potential error: instrument noise and presence of aerosol. Experiments are conducted using a Monte Carlo photon transport model, cloud-resolving model data, and surface albedo data from satellite observations. The objective is to analyze the consistency between inherent and retrieved values of τ. Increasing instrument noise, especially if uncorrelated at both wavelengths, decreases retrieved cloud fraction and increases retrieved mean τ. As with all methods that seek to infer τ using passive radiometry, the presence of aerosol requires that threshold values be set in order to discriminate between cloudy and cloud-free columns. A technique for estimating thresholds for cloudy columns is discussed and demonstrated. Finally, it was found that surface type and mean inherent τ play major roles in defining retrieval accuracy.
Radiative Effects of Cloud Horizontal Inhomogeneity and Vertical Overlap Identified from a Monthlong Cloud-Resolving Model Simulation
Authors: Wu Xiaoqing , Liang Xin-Zhong 
Published: November 2005

Abstract
The representation of subgrid horizontal and vertical variability of clouds in radiation schemes remains a major challenge for general circulation models (GCMs) due to the lack of cloud-scale observations and incomplete physical understanding. The development of cloud-resolving models (CRMs) in the last decade provides a unique opportunity to make progress in this area of research. This paper extends the study of Wu and Moncrieff to quantify separately the impacts of cloud horizontal inhomogeneity (optical property) and vertical overlap (geometry) on the domain-averaged shortwave and longwave radiative fluxes at the top of the atmosphere and the surface, and the radiative heating profiles. The diagnostic radiation calculations using the monthlong CRM-simulated tropical cloud optical properties and cloud fraction show that both horizontal inhomogeneity and vertical overlap of clouds are equally important for obtaining accurate radiative fluxes and heating rates. This study illustrates an objective approach to use long-term CRM simulations to separate cloud overlap and inhomogeneity effects, based on which GCM representation (such as mosaic treatment) of subgrid cloud–radiation interactions can be evaluated and improved.
Influences of Asymmetric Heating on Hurricane Evolution in the MM5
Authors: Möller J. Dominique , Shapiro Lloyd J. 
Published: November 2005

Abstract
While previous idealized studies have demonstrated the importance of asymmetric atmospheric features in the intensification of a symmetric tropical cyclone vortex, the role of convectively generated asymmetries in creating changes in the azimuthally averaged cyclone is not well understood. In the present study the full-physics nonhydrostatic fifth-generation Pennsylvania State University–National Center for Atmospheric Research (PSU–NCAR) Mesoscale Model (MM5) is used to evaluate the influence of such asymmetries. Rather than adding winds and temperatures in balance with a specified potential vorticity (PV) asymmetry, or temperature perturbations themselves, to a symmetric vortex as in previous studies, a diabatic heating asymmetry is imposed on a spunup model hurricane. The impact of short-duration eyewall-scale monochromatic azimuthal wavenumber diabatic heating on the short- and long-term evolution of the azimuthally averaged vortex is evaluated, and a tangential wind budget is made to determine the mechanisms responsible for the short-term impact.
It is found that the small eddy kick created by the additional diabatic heating asymmetry leads to a substantially amplified long-term change in the azimuthally averaged vortex, with episodes of strong relative weakening and strengthening following at irregular intervals. This behavior is diabatically controlled. It is also found that the symmetric secondary circulation can be active in creating short-term changes in the vortex, and is not simply a passive response as in previous studies with dry physics. A central conclusion of the study is that the structure of the spunup hurricane vortex, in particular preexisting asymmetric features, can have a substantial influence on the character of the response to an additional diabatic heating asymmetry. The results also imply that a small change in the factors that control convective activity will have a substantial lasting consequence for the intensification of a hurricane.
Observations and Analysis of Uncorrelated Rain
Authors: Larsen Michael L. , Kostinski Alexander B. , Tokay Ali 
Published: November 2005

Abstract
Most microphysical models in precipitation physics and radar meteorology assume (at least implicitly) that raindrops are completely uncorrelated in space and time. Yet, several recent studies have indicated that raindrop arrivals are often temporally and spatially correlated. Resolution of this conflict must begin with observations of perfectly uncorrelated rainfall, should such “perfectly steady rain” exist at all. Indeed, it does. Using data with high temporal precision from a two-dimensional video disdrometer and the pair-correlation function, a scale-localized statistical tool, several ∼10–20-min rain episodes have been uncovered where no clustering among droplet arrival times is found. This implies that (i) rain events exist where current microphysical models can be tested in an optimal manner and (ii) not all rain can be properly described using fractals.
Teleconnections from Tropics to Northern Extratropics through a Southerly Conveyor
Authors: Wang Zhuo , Chang C-P. , Wang Bin , Jin Fei-Fei 
Published: November 2005

Abstract
Rossby wave propagation theory predicts that Rossby waves in a tropical easterly flow cannot escape from the Tropics to the extratropics. Here the authors show that a southerly flow component in the basic state (a southerly conveyor) may transfer a Rossby wave source northward; thus, a forcing embedded in the deep tropical easterlies may excite a Rossby wave response in the extratropical westerlies. It is shown that the southerly conveyor determines the location of the effective Rossby wave source and that the extratropical response is relatively insensitive to the location of the tropical forcing, provided that the tropical response can reach the southerly conveyor. A stronger southerly flow favors a stronger extratropical response, and the spatial structure of the extratropical response is determined by the extratropical westerly basic flows.
The Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia
Authors: DeAngelo Daniel J. 
Published: November 2005

Abstract
Intensive chemotherapy regimens for children with acute lymphoblastic leukemia (ALL) have greatly improved, and the majority of children with precursor B-cell ALL are able to achieve a complete remission (CR), with an induction rate approaching 98% and a 5-year estimated event-free survival rate (EFS) of approximately 80%. Although there have been dramatic improvements over the last several decades in both the EFS and overall survival (OS) rates in young children with ALL, the results in adult clinical trials have not kept pace. Current adult treatment regimens result in CR rates in the 80% range, with EFS at 5 years of only 30%–40%. Adolescents and young adults represent a minority of patients enrolled onto either adult or pediatric clinical trials. As a result, little information is available regarding CR, EFS, and OS rates for this age group, and the appropriate treatment regimen for this group of patients remains elusive. Recent studies suggest that young adult patients have far superior outcomes when treated on more intensive pediatric regimens. In addition, new insights into the molecular pathogenesis of T cell ALL have led to new therapeutic strategies.
Management of Polycythemia Vera and Essential Thrombocythemia
Authors: Campbell Peter J. , Green Anthony R. 
Published: November 2005

Abstract
The optimal management of patients with polycythemia vera (PV) and essential thrombocythemia (ET) continues to be controversial. Both diseases present diagnostic challenges and there is a paucity of data from randomized clinical trials to guide therapeutic decisions. However, the past two years have seen major advances in our understanding of these myeloproliferative disorders (MPD). First, the ECLAP study demonstrated the anti-thrombotic efficacy of aspirin in patients with PV.1 Second, the PT-1 trial, the largest randomized study of any MPD, has provided much needed guidance on the optimal management of patients with ET.2 Third, the identification of a single JAK2 mutation in most patients with PV, and in some of those with ET, illuminates the pathogenesis of these diseases and raises questions about the boundary between them.3–7 For the purpose of management decisions, it remains appropriate to consider them as separate entities for the time being. However, as we learn more about the clinical significance of the JAK2 mutation, it seems likely that the coming years will see major changes in the way we classify and manage these disorders.
The Ubiquitin Proteasome Pathway from Bench to Bedside
Authors: Orlowski Robert Z. 
Published: November 2005

Abstract
The validation of the ubiquitin-proteasome pathway as a target for therapy of hematological malignancies stands out as one salient example of the ability to translate laboratory-based findings from the bench to the bedside. Preclinical studies showed that proteasome inhibitors had significant activity against models of non-Hodgkin lymphoma and multiple myeloma, and identified some of the relevant mechanisms of action. These led to phase I through III trials of the first clinically available proteasome inhibitor, bortezomib, which confirmed its activity as a single agent in these diseases. Modulation of proteasome function was then found to be a rational approach to achieve both chemosensitization in vitro and in vivo, as well as to overcome chemotherapy resistance. Based on these findings, first-generation bortezomib-based regimens incorporating traditional chemotherapeutics such as alkylating agents, anthracyclines, immunomodulatory agents, or steroids have been evaluated, and many show promise of enhanced clinical anti-tumor efficacy. Further studies of the pro-and anti-apoptotic actions of proteasome inhibitors, and of their effects on gene and protein expression profiles, suggest that novel agents, such as those targeting the heat shock protein pathways, are exciting candidates for incorporation into these combinations. Phase I trials to test these concepts are just beginning, but have already shown some encouraging results. Finally, novel proteasome inhibitors are being developed with unique properties that may also have therapeutic applications. Taken together, these studies demonstrate the power of rational drug design and development to provide novel, effective therapies for patients with hematological malignancies.
Chronic Lymphocytic Leukemia (CLL): First-Line Treatment
Authors: Hallek Michael ,   On Behalf Of The German CLL Study Group
Published: November 2005

Abstract
For the past ten years, there has been a dynamic development of new therapeutic compounds and prognostic parameters for chronic lymphocytic leukemia (CLL). Hematologists and oncologists are challenged to use these new possibilities for an optimized, risk- and fitness-adapted treatment strategy, with the goal of achieving long-term remissions and preserving a good quality of life. This review is intended to summarize the current knowledge on first-line treatment of CLL.
Management of Bleeding Disorders in Children
Authors: Manno Catherine S. 
Published: November 2005

Abstract
Diagnosis and management of congenital and acquired bleeding disorders in children requires not only an understanding of the unique characteristics of pediatric hemostasis but also the natural course of bleeding disorders in children, which may differ substantially from the course observed in adult patients. In this article, three bleeding disorders of great importance to the pediatric hematologist are reviewed: neonatal alloimmune thrombocytopenia (NAIT), hemophilia and immune-mediated thrombocytopenic purpura (ITP). Current aspects of management are outlined. The unique physiology of transplacental transfer of maternally derived anti-platelet antibodies can result in neonatal immune thrombocytopenia, a significant cause of morbidity and mortality from bleeding in affected infants. For patients with hemophilia, approaches to treatment have shifted over the past decade from on-demand therapy to prophylaxis, either primary of secondary, resulting in delay of onset or complete avoidance of hemophilic arthropathy. Hemophilic inhibitors often develop in young children, prompting the need for a thorough understanding of the use of bypassing agents as well as immune tolerance induction in the young child. Finally, although several management strategies for ITP of childhood have been shown to improve the platelet count, side effects associated with corticosteroids, IVIg, anti-D and splenectomy force the practitioner to also consider the option of carefully observing, but not treating, the child with ITP.
New Perspectives in Hemophilia Treatment
Authors: Kessler Craig M. 
Published: November 2005

Abstract
A variety of factor concentrates are currently available for replacement therapy for patients with hemophilia. These differ by several parameters, including source (pooled from pooled blood vs recombinant), purity, pathogen inactivation, and by the presence or absence of extraneous proteins such as albumin. The choice of replacement product reflects both safety issues of pathogen transmission or inhibitor development, and personal preferences of the patient and the physician. In general, currently available products are viral pathogen-free, although there is debate about the risk of transmission of parvovirus B19 and prion pathogens. Because of this very small risk, recombinant factor is the treatment of choice in previously untreated patients. In addition, a subset of concentrates contain factor that is activated during manufacture, yielding activated products that can be used in the treatment of patients with inhibitors. Such activated products, especially recombinant factor VIIa (rFVIIa), have also acquired several off-label indications in the management of bleeding in non-hemophiliac patients. The management of hemophilia patients with inhibitors is an ongoing challenge. Immune tolerance induction using a desensitization technique is successful in up to 90% of patients with alloantibodies against factor VIII, with greatest success seen in patients with low titer inhibitors who are treated soon after detection of an alloantibody and in whom treatment includes administration of immunosuppression along with repeated infusions of high titer concentrates. Such therapy is less successful in patients with factor IX alloantibodies. Non-hemophiliac patients with acquired inhibitors represent a unique patient population that requires special management. These patients have a mortality rate that approaches 25% because of the association of acquired inhibitors with severe bleeding complications, occurrence in a largely elderly population, and the frequent presence of an underlying, often serious, primary medical condition. Treatment consists of immunosuppression with steroids, chemotherapy, or intravenous immunoglobulin. Recent studies using rituximab for selective B-cell depletion in these patients have been very promising, although prospective controlled studies have not yet been performed. Finally, although hemophilia A and B appear to be ideal diseases to target with gene therapy approaches, the promise of this therapy remains to be realized.