bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deformable mesh registration for the validation of automatic target localization algorithms
Authors: Robertson Scott , Weiss Elisabeth , Hugo Geoffrey D. 
Published: June 2013

Purpose:To evaluate deformable mesh registration (DMR) as a tool for validating automatic target registration algorithms used during image‐guided radiation therapy.Methods:DMR was implemented in a hierarchical model, with rigid, affine, and B‐spline transforms optimized in succession to register a pair of surface meshes. The gross tumor volumes (primary tumor and involved lymph nodes) were contoured by a physician on weekly CT scans in a cohort of lung cancer patients and converted to surface meshes. The meshes from weekly CT images were registered to the mesh from the planning CT, and the resulting registered meshes were compared with the delineated surfaces. Known deformations were also applied to the meshes, followed by mesh registration to recover the known deformation. Mesh registration accuracy was assessed at the mesh surface by computing the symmetric surface distance (SSD) between vertices of each registered mesh pair. Mesh registration quality in regions within 5 mm of the mesh surface was evaluated with respect to a high quality deformable image registration.Results:For 18 patients presenting with a total of 19 primary lung tumors and 24 lymph node targets, the SSD averaged 1.3 ± 0.5 and 0.8 ± 0.2 mm, respectively. Vertex registration errors (VRE) relative to the applied known deformation were 0.8 ± 0.7 and 0.2 ± 0.3 mm for the primary tumor and lymph nodes, respectively. Inside the mesh surface, corresponding average VRE ranged from 0.6 to 0.9 and 0.2 to 0.9 mm, respectively. Outside the mesh surface, average VRE ranged from 0.7 to 1.8 and 0.2 to 1.4 mm. The magnitude of errors generally increased with increasing distance away from the mesh.Conclusions:Provided that delineated surfaces are available, deformable mesh registration is an accurate and reliable method for obtaining a reference registration to validate automatic target registration algorithms for image‐guided radiation therapy, specifically in regions on or near the target surfaces.
Evaluation of Initial and Steady-State Gatifloxacin Pharmacokinetics and Dose in Pulmonary Tuberculosis Patients by Using Monte Carlo Simulations
Authors: Smythe Wynand , Merle Corinne S. , Rustomjee Roxana , Gninafon Martin , Lo Mame Bocar , Bah-Sow Oumou , Olliaro Piero L. , Lienhardt Christian , Horton John , Smith Peter , McIlleron Helen , Simonsson Ulrika S. H. 
Published: June 2013

ABSTRACT

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of ≥125 for the area under the concentration time curve to infinity (AUC
0–∞
) for the free fraction of gatifloxacin over the MIC (
f
AUC/MIC) was investigated using Monte Carlo simulations. The median AUC
0–∞
of 41.2 μg · h/ml decreased on average by 14.3% (90% confidence interval [CI], −90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an
f
AUC/MIC of ≥125 only when the MIC was <0.125 μg/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.)
Noncompetitive Inhibition of Hepatitis B Virus Reverse Transcriptase Protein Priming and DNA Synthesis by the Nucleoside Analog Clevudine
Authors: Jones Scott A. , Murakami Eisuke , Delaney William , Furman Phillip , Hu Jianming 
Published: June 2013

ABSTRACT
All currently approved antiviral drugs for the treatment of chronic hepatitis B virus (HBV) infection are nucleos(t)ide reverse transcriptase inhibitors (NRTI), which inhibit the DNA synthesis activity of the HBV polymerase. The polymerase is a unique reverse transcriptase (RT) that has a novel protein priming activity in which HP initiates viral DNA synthesis using itself as a protein primer. We have determined the ability of NRTI-triphosphates (TP) to inhibit HBV protein priming and their mechanisms of action. While entecavir-TP (a dGTP analog) inhibited protein priming initiated specifically with dGTP, clevudine-TP (a TTP analog) was able to inhibit protein priming independently of the deoxynucleoside triphosphate (dNTP) substrate and without being incorporated into DNA. We next investigated the effect of NRTIs on the second stage of protein priming, wherein two dAMP nucleotides are added to the initial deoxyguanosine nucleotide. The obtained results indicated that clevudine-TP as well as tenofovir DF-DP strongly inhibited the second stage of protein priming. Tenofovir DF-DP was incorporated into the viral DNA primer, whereas clevudine-TP inhibited the second stage of priming without being incorporated. Finally, kinetic analyses using the HBV endogenous polymerase assay revealed that clevudine-TP inhibited DNA chain elongation by HP in a noncompetitive manner. Thus, clevudine-TP appears to have the unique ability to inhibit HBV RT via binding to and distorting the HP active site, sharing properties with both NRTIs and nonnucleoside RT inhibitors.
HIV-Positive Nigerian Adults Harbor Significantly Higher Serum Lumefantrine Levels than HIV-Negative Individuals Seven Days after Treatment for Plasmodium falciparum Infection
Authors: Chijioke-Nwauche Ifeyinwa , van Wyk Albert , Nwauche Chijioke , Beshir Khalid B. , Kaur Harparkash , Sutherland Colin J. 
Published: June 2013

ABSTRACT

Management of coinfection with malaria and HIV is a major challenge to public health in developing countries, and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both infections. Each of the constituent components of artemether-lumefantrine, the first-line regimen for malaria treatment in Nigeria, and nevirapine, a major component of highly active antiretroviral therapy, are drugs metabolized by the cytochrome P450 3A4 isoenzyme system, which is also known to be induced by nevirapine. We examined potential interactions between lumefantrine and nevirapine in 68 HIV-positive adults, all of whom were diagnosed with asymptomatic
Plasmodium falciparum
infections by microscopy.
Post hoc
PCR analysis confirmed the presence of
P. falciparum
in only a minority of participants. Day 7 capillary blood levels of lumefantrine were significantly higher in HIV-positive participants than in 99 HIV-negative controls (
P
= 0.0011). Associations between day 7 levels of lumefantrine and risk of persistent parasitemia could not be evaluated due to inadequate power. Further investigations of the impact of nevirapine on
in vivo
malaria treatment outcomes in HIV-infected patients are thus needed.
Group B Streptococcus and Streptococcus suis Capsular Polysaccharides Induce Chemokine Production by Dendritic Cells via Toll-Like Receptor 2- and MyD88-Dependent and -Independent Pathways
Authors: Calzas Cynthia , Goyette-Desjardins Guillaume , Lemire Paul , Gagnon Fleur , Lachance Claude , Van Calsteren Marie-Rose , Segura Mariela 
Published: June 2013

ABSTRACTStreptococcus agalactiae(also known as group BStreptococcus[GBS]) andStreptococcus suisare encapsulated streptococci causing severe septicemia and meningitis. Bacterial capsular polysaccharides (CPSs) are poorly immunogenic, but anti-CPS antibodies are essential to the host defense against encapsulated bacteria. The mechanisms underlying anti-CPS antibody responses are not fully elucidated, but the biochemistry of CPSs, particularly the presence of sialic acid, may have an immunosuppressive effect. We investigated the ability of highly purifiedS. suisand GBS native (sialylated) CPSs to activate dendritic cells (DCs), which are crucial actors in the initiation of humoral immunity. The influence of CPS biochemistry was studied using CPSs extracted from different serotypes within these two streptococcal species, as well as desialylated CPSs. No interleukin-1β (IL-1β), IL-6, IL-12p70, tumor necrosis factor alpha (TNF-α), or IL-10 production was observed inS. suisor GBS CPS-stimulated DCs. Moreover, these CPSs exerted immunosuppressive effects on DC activation, as a diminution of gamma interferon (IFN-γ)-induced B cell-activating factor of the tumor necrosis factor family (BAFF) expression was observed in CPS-pretreated cells. However,S. suisand GBS CPSs induced significant production of CCL3, via partially Toll-like receptor 2 (TLR2)- and myeloid differentiation factor 88 (MyD88)-dependent pathways, and CCL2, via TLR-independent mechanisms. No major influence of CPS biochemistry was observed on the capacity to induce chemokine production by DCs, indicating that DCs respond to these CPSs in a patterned way rather than a structure-dedicated manner.
Interleukin-17 Protects against the Francisella tularensis Live Vaccine Strain but Not against a Virulent F. tularensis Type A Strain
Authors: Skyberg Jerod A. , Rollins MaryClare F. , Samuel Joshua W. , Sutherland Marjorie D. , Belisle John T. , Pascual David W. 
Published: June 2013

ABSTRACT

Francisella tularensis
is a highly infectious intracellular bacterium that causes the zoonotic infection tularemia. While much literature exists on the host response to
F. tularensis
infection, the vast majority of work has been conducted using attenuated strains of
Francisella
that do not cause disease in humans. However, emerging data indicate that the protective immune response against attenuated
F. tularensis
versus
F. tularensis
type A differs. Several groups have recently reported that interleukin-17 (IL-17) confers protection against the live vaccine strain (LVS) of
Francisella
. While we too have found that IL-17Rα
−/−
mice are more susceptible to
F. tularensis
LVS infection, our studies, using a virulent type A strain of
F. tularensis
(SchuS4), indicate that IL-17Rα
−/−
mice display organ burdens and pulmonary gamma interferon (IFN-γ) responses similar to those of wild-type mice following infection. In addition, oral LVS vaccination conferred equivalent protection against pulmonary challenge with SchuS4 in both IL-17Rα
−/−
and wild-type mice. While IFN-γ was found to be critically important for survival in a convalescent model of SchuS4 infection, IL-17 neutralization from either wild-type or IFN-γ
−/−
mice had no effect on morbidity or mortality in this model. IL-17 protein levels were also higher in the lungs of mice infected with the LVS rather than
F. tularensis
type A, while IL-23p19 mRNA expression was found to be caspase-1 dependent in macrophages infected with LVS but not SchuS4. Collectively, these results demonstrate that IL-17 is dispensable for host immunity to type A
F. tularensis
infection, and that induced and protective immunity differs between attenuated and virulent strains of
F. tularensis
.
Characterization of Streptococcal Platelet-Activating Factor Acetylhydrolase Variants That Are Involved in Innate Immune Evasion
Authors: Liu Guanghui , Liu Mengyao , Xie Gang , Lei Benfang 
Published: June 2013

ABSTRACTHuman pathogen group A streptococcus (GAS) has developed mechanisms to subvert innate immunity. We recently reported that the secreted esterase produced by serotype M1 GAS (SsEM1) reduces neutrophil recruitment by targeting platelet-activating factor (PAF). SsEM1and SsE produced by serotype M28 GAS (SsEM28) have a 37% sequence difference. This study aims at determining whether SsEM28is also a PAF acetylhydrolase and participates in innate immune evasion. We also examined whether SsE evolved to target PAF by characterizing the PAF acetylhydrolase (PAF-AH) activity and substrate specificity of SsEM1, SsEM28, SeE, the SsE homologue inStreptococcus equi, and human plasma PAF-AH (hpPAF-AH). PAF incubated with SsEM28or SeE was converted into lyso-PAF. SsEM1and SsEM28hadkcatvalues of 373 s−1and 467 s−1, respectively, that were ≥30-fold greater than that of hpPAF-AH (12 s−1). The comparison of SsEM1, SsEM28, and hpPAF-AH inkcatandKmin hydrolyzing triglycerides, acetyl esters, and PAF indicates that the SsE proteins are more potent hydrolases against PAF and have high affinity for PAF. SsEM28possesses much lower esterase activities against triglycerides and other esters than SsEM1but have similar potency with SsEM1in PAF hydrolysis. Deletion ofsseM28in acovSdeletion mutant of GAS increased neutrophil recruitment and reduced skin infection, whereas intransexpression of SsEM28in GAS reduced neutrophil infiltration and increased skin invasion in subcutaneous infection of mice. These results suggest that the SsE proteins evolved to target PAF for enhancing innate immune evasion and skin invasion.
Stenotrophomonas maltophilia Encodes a Type II Protein Secretion System That Promotes Detrimental Effects on Lung Epithelial Cells
Authors: Karaba Sara M. , White Richard C. , Cianciotto Nicholas P. 
Published: June 2013

ABSTRACT

The Gram-negative bacterium
Stenotrophomonas maltophilia
is increasingly identified as a multidrug-resistant pathogen, being associated with pneumonia, among other infections. Despite this increasing clinical problem, the genetic and molecular basis of
S. maltophilia
virulence is quite minimally defined. We now report that strain K279a, the first clinical isolate of
S. maltophilia
to be sequenced, encodes a functional type II protein secretion (T2S) system. Indeed, mutants of K279a that contain a mutation in the
xps
locus exhibit a loss of at least seven secreted proteins and three proteolytic activities. Unlike culture supernatants from the parental K279a, supernatants from multiple
xps
mutants also failed to induce the rounding, detachment, and death of A549 cells, a human lung epithelial cell line. Supernatants of the
xps
mutants were also unable to trigger a massive rearrangement in the host cell's actin cytoskeleton that was associated with K279a secretion. In all assays, a complemented
xpsF
mutant behaved as the wild type did, demonstrating that Xps T2S is required for optimal protein secretion and the detrimental effects on host cells. The activities that were defined as being Xps dependent in K279a were evident among other respiratory isolates of
S. maltophilia
. Utilizing a similar type of genetic analysis, we found that a second T2S system (Gsp) encoded by the K279a genome is cryptic under all of the conditions tested. Overall, this study represents the first examination of T2S in
S. maltophilia
, and the data obtained indicate that Xps T2S likely plays an important role in
S. maltophilia
pathogenesis.
Diagnostic, therapeutic and economic consequences of a positive urinary antigen test forLegionellaspp. in patients admitted with community-acquired pneumonia: a 7-year retrospective evaluation
Authors: Engel M F , van Manen L , Hoepelman A I M , Thijsen S , Oosterheert J J 
Published: June 2013

AimsA positive urinary antigen test forLegionellaspp. (Legionella urinary antigen test; LUAT) allows an early switch from empiric to targeted treatment (TT) in hospitalised, community-acquired pneumonia (CAP) patients. We aimed to evaluate the diagnostic, therapeutic and economic consequences of this frequently used test 7 years after its implementation.MethodsWe retrospectively evaluated LUATs performed between 2005 and 2011 in two teaching hospitals. All tests performed in hospitalised CAP patients were used in the economic evaluation and positive tests were included in the treatment evaluation. Data on patient characteristics, admission and outcome were retrieved from the patients’ files. The number of days gained by making a rapid aetiological diagnosis, the number of days TT could be provided and their costs were calculated.ResultsOf 4485 LUATs, 2504 (56%) were performed for CAP including 55 (1%) positive tests (€1041/positive test). In 26 (60%) of the 43 included positive tests, LUAT was the only test showingLegionellaspp. Subsequently, earlier TT was possible in the remaining cases during 209 cumulative admission days (€274/TT day). LUAT led to detection ofLegionellaspp. 13 days earlier per case (€203/day) as compared with culture/serology alone.ConclusionsTimely LUAT use in accordance with current guidelines allows early detection and treatment of CAP caused byLegionellaspp. at considerable expense.
Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma
Authors: Frei E , Visco C , Xu-Monette Z Y , Dirnhofer S , Dybkær K , Orazi A , Bhagat G , Hsi E D , van Krieken J H , Ponzoni M , Go R S , Piris M A , Møller M B , Young K H , Tzankov A 
Published: June 2013

BackgroundHigh levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the ‘rituximab (R)-era’ are lacking.MethodsTo test reproducibility and applicability of observations from the ‘pre-R era’ to the ‘R era’, we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP.Results1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0–85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, andBCL2-orC-MYCrearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance.ConclusionsAddition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the ‘R era’ without proper scientific studies.
Improving equity by removing healthcare fees for children in Burkina Faso
Authors: Ridde V , Haddad S , Heinmüller R 
Published: June 2013

BackgroundThis study evaluated the effects on healthcare access inequities of an intervention exempting children under 5 years from user fees in Burkina Faso.MethodsThe design consisted of two complementary studies. The first was an interrupted time series (56 months before and 12 months after) study of daily curative consultations according to distance (<5, 5–9 and ≥10 km) in a stratified random sample of 18 health centres: 12 with the intervention and 6 without. The second was a household panel survey (n=1214) assessing the evolution of health-seeking behaviours. Multilevel regression was used throughout.ResultsAttendance doubled under the intervention, after adjusting forCentres de Santé et de Promotion Socialesize, districts, secular trend and seasonal variation. Utilisation increased for all distance ranges and in all of the 12 health centres of the intervention area. The exemption benefited all children (rate ratios (RR)=1.52 (1.23 to 1.88)), whether their health needs were high (RR=1.69 (1.22 to 2.32)) or not (RR=1.46 (1.10 to 1.93)) and whether the children lived near (RR=1.42 (1.09 to 1.85)) or far from a health centre (RR=1.79 (1.31 to 2.43)). The exemption benefited the children of poor families when health need was high and services near (RR=5.23; (1.30 to 20.99)). The amount saved for a child's treatment by the exemption was on average and median 2500 F CFA (≈US$5).ConclusionsExempting children under five from user fees is effective and helps reduce inequities of access. It benefits vulnerable populations, although their service utilisation remains constrained by limitations in geographic accessibility of services.
Phosphotyrosine‐Protein‐Phosphatase and Diabetic Disorders. Further Studies on the Relationship between Low Molecular Weight Acid Phosphatase Genotype and Degree of Glycemic Control
Authors: Lucarini N. , Antonacci E. , Bottini N. , Borgiani P. , Faggioni G. , Gloria-Bottini F. 
Published: June 2013

We have studied a new sample of 276 NIDDM patients from the population of Penne (Italy). Comparison of the new data with those of 214 diabetic pregnant women from the population of Rome reported in a previous paper has shown that the pattern of association between low molecular weight acid phosphatase genotype and degree of glycemic control is similar in the two classes of diabetic patients.Among nonobese subjects the proportion of ACP1*A (the allele showing the lowest enzymatic activity) is lower in diabetic patients with high glycemic levels (mean value greater than 8.9 mmol/l) than in diabetic patients with a low glycemic level (mean value less than 8.9 mmol/l). Among obese subjects no significant association is observed between glycemic levels and ACP1. Among nonobese subjects the concentration of f isoform of ACP1 is higher in patients showing a high glycemic level than in patients showing a low glycemic level. No significant difference is observed for s isoform.
Large Number of Polymorphic Nucleotides and a Termination Codon in the env Gene of the Endogenous Human Retrovirus ERV3
Authors: Rasmussen H. B. , Clausen J. 
Published: June 2013

The terminal portion of the pol gene and the entire env gene of the human endogenous retrovirus ERV3 was screened for polymorphic nucleotides. For this purpose fragments amplified from the desired regions of ERV3 were subjected to single strand conformational analysis (SSCP analysis). Using this approach, we detected 13 polymorphic nucleotides, namely four in the pol gene and nine in the env gene. Three of the nucleotide substitutions were synonymous (not affecting the amino acid code). One of the non‐synonymous nucleotide substitutions changed an arginine codon to a termination codon. The alleles at the different polymorphic sites could be arranged into five ERV3 haplotypes, two of which were new.To evaluate the possible significance of the termination codon, which precludes expression of a putative immunoregulatory factor, we examined samples of DNA from patients with multiple sclerosis, a demyelinating disease of presumed autoimmune etiology. We did not find an association between the ERV3 allele with the termination codon and this disease.Perhaps the presence of a stop codon combined with the high number of non‐synonymous nucleotide substitutions in the reading frame of the env gene reflects absence of selective constraints during evolution. Obviously, our findings contradict the assumption that the reading frame of the ERV3 env gene has been conserved throughout evolution.