bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Martensitic Transformation on the Evolution of Residual Stresses and Identification of the Critical Linear Mass Density in Direct Laser Metal Deposition–Based Repair
Authors: Vundru Chaitanya , Singh Ramesh , Yan Wenyi , Karagadde Shyamprasad 
Published: April 2020

Abstract
Direct laser metal deposition (DLMD) is a promising additive manufacturing technique which has a huge potential in remanufacturing and restoration of high-value dies/molds and aerospace components. The residual stresses developed in the material deposited via DLMD affect the structural integrity of the restored components. The service life of the restored component will be compromised if tensile residual stresses are present in the deposited layer. The residual stresses originate due to differential thermal expansion/contraction and martensitic transformation-driven volumetric dilation and transformation-induced plasticity. The influence of martensitic transformation and processing conditions on the residual stresses of DLMD-processed components needs to be understood and modeled for sustainable repair. Hence, a finite element model has been developed to capture the coupled effect of thermomechanics and martensitic transformation on the evolution of residual stresses in DLMD. In this study, the individual and coupled effects of strains due to volume dilation and transformation-induced plasticity on residual stress evolution have been analyzed for the deposition of crucible particle metallurgy (CPM) 9 V on H-13 tool steel. The finite element model has been experimentally validated using X-ray and neutron diffractions. The inclusion of both transformation strains in the residual stress decreases the prediction errors of peak tensile residual stress from ∼48% to ∼15%. The fully coupled thermomechanical and metallurgical model has been used to obtain a critical linear mass density (m˙/v) corresponding to the onset of a fully compressive longitudinal residual stress state in the deposited layer to ensure sustainable repair.
Aminoglycoside 6′-
N
-Acetyltransferase Variants of the Ib Type with Altered Substrate Profile in Clinical Isolates of
Enterobacter cloacae
and
Citrobacter freundii
Authors: Casin Isabelle , Bordon Florence , Bertin Philippe , Coutrot Anne , Podglajen Isabelle , Brasseur Robert , Collatz Ekkehard 
Published: April 2020

ABSTRACT

Three clinical isolates,
Enterobacter cloacae
EC1562 and EC1563 and
Citrobacter freundii
CFr564, displayed an aminoglycoside resistance profile evocative of low-level 6′-
N
acetyltransferase type II [AAC(6′)-II] production, which conferred reduced susceptibility to gentamicin but not to amikacin or isepamicin. Aminoglycoside acetyltransferase assays suggested the synthesis in the three strains of an AAC(6′) which acetylated amikacin practically as well as it acetylated gentamicin in vitro. Both compounds, however, as well as isepamicin, retained good bactericidal activity against the three strains. The
aac
genes were borne by conjugative plasmids (pLMM562 and pLMM564 of ca. 100 kb and pLMM563 of ca. 20 kb). By PCR mapping and nucleotide sequence analysis, an
aac(6′)-Ib
gene was found in each strain upstream of an
ant
(3")-I gene in a
sulI
-type integron. The size of the AAC(6′)-Ib variant encoded by pLMM562 and pLMM564, AAC(6′)-Ib
7
, was deduced to be 184 (or 177) amino acids long, whereas in pLMM563 a 21-bp duplication allowing the recruitment of a start codon resulted in the translation of a variant, AAC(6′)-Ib
8
, of 196 amino acids, in agreement with size estimates obtained by Western blot analysis. Both variants had at position 119 a serine instead of the leucine typical for the AAC(6′)-Ib variants conferring resistance to amikacin. By using methods that predict the secondary structure, these two amino acids appear to condition an α-helical structure within a putative aminoglycoside binding domain of AAC(6′)-Ib variants.
Detection of
grlA
and
gyrA
Mutations in 344
Staphylococcus aureus
Strains
Authors: Wang Tong , Tanaka Mayumi , Sato Kenichi 
Published: April 2020

ABSTRACT

Mutations in the
grlA
and
gyrA
genes of 344 clinical strains of
Staphylococcus aureus
isolated in 1994 in Japan were identified by combinations of single-strand conformation polymorphism analysis, restriction fragment length analysis, and direct sequencing to identify possible relationships to fluoroquinolone resistance. Five types of single-point mutations and four types of double mutations were observed in the
grlA
genes of 204 strains (59.3%). Four types of single-point mutations and four types of double mutations were found in the
gyrA
genes of 188 strains (54.7%). Among them, the
grlA
mutation of TCC→TTC or TAC (Ser-80→Phe or Tyr) and the
gyrA
mutation of TCA→TTA (Ser-84→Leu) were principal, being detected in 137 (39.8%) and 121 (35.9%) isolates, respectively. The
grlA
point mutations of CAT→CAC (His-77 [silent]), TCA→CCA (Ser-81→Pro), and ATA→ATT (Ile-100 [silent]) were novel, as was the GAC→GGC (Asp-73→Gly) change in
gyrA
. A total of 15 types of mutation combinations within both genes were related to ciprofloxacin resistance (MIC ≥ 3.13 μg/ml) and were present in 193 mutants (56.1%). Strains containing mutations in both genes were highly resistant to ciprofloxacin (MIC at which 50% of the isolates are inhibited [MIC
50
] = 50 μg/ml). Those with the Ser-80→Phe or Tyr alteration in
grlA
but wild-type
gyrA
showed a lower level of ciprofloxacin resistance (MIC
50
≤ 12.5 μg/ml). Levofloxacin was active against 68 of 193 isolates (35.2%) with mutations at codon 80 of
grlA
in the presence or absence of a concomitant mutation at codon 73, 84, or 88 in
gyrA
(MIC ≤ 6.25 μg/ml). The new fluoroquinolone DU-6859a showed good activity with 186 of 193 isolates (96.4%) for which the MIC was ≤6.25 μg/ml.
Pharmacokinetics and Absolute Bioavailability of Oral Foscarnet in Human Immunodeficiency Virus-Seropositive Patients
Authors: Noormohamed Faruq H. , Youle Michael S. , Higgs Christopher J. , Martin-Munley Sarah , Gazzard Brian G. , Lant Ariel F. 
Published: April 2020

ABSTRACT

The pharmacokinetics, absolute bioavailability, accumulation, and tolerability over 8 days of an oral formulation of foscarnet (90 mg/kg of body weight once daily [QD] [
n
= 6], 90 mg/kg twice daily [BID] [
n
= 6], and 180 mg/kg QD [
n
= 3]) were investigated in 15 asymptomatic, human immunodeficiency virus-seropositive male patients free of active cytomegalovirus infection and with normal upper gastrointestinal function. Peak plasma drug concentrations were (mean ± standard deviation) 46.4 ± 10.8 μM (90 mg/kg QD), 45.7 ± 6.9 μM (90 mg/kg BID), and 64.9 ± 31.7 μM (180 mg/kg QD) on day 1 and rose to 86.2 ± 35.8, 78.7 ± 35.2, and 86.4 ± 25.0 μM, respectively, on day 8. The mean peak concentration in plasma following the intravenous administration of foscarnet (90 mg/kg) was 887.3 ± 102.7 μM (
n
= 13). The terminal half-life in plasma remained unchanged, averaging 5.5 ± 2.2 h on day 1 (
n
= 15) and 6.6 ± 1.9 h on day 8 (
n
= 13), whereas it was 5.7 ± 0.7 h following intravenous dosing. Oral bioavailabilities were 9.1% ± 2.2% (90 mg/kg QD), 9.5% ± 1.7% (90 mg/kg BID), and 7.6% ± 3.7% (180 mg/kg QD); the accumulation ratios on the 8th day of dosing were 2.1 ± 1.1, 1.8 ± 0.4, and 1.7 ± 0.7, respectively. The overall 24-h urinary excretion of oral foscarnet averaged 7.8% ± 2.6% (day 1) and 13.4% ± 6.0% (day 8), whereas it was 95.0% ± 4.9% after intravenous dosing. The glomerular filtration rate and creatinine clearance remained constant, and the mean 24-h renal clearances of foscarnet for the entire study group were 96 ± 18 ml/min (day 1), 88 ± 13 ml/min (day 8), and 103 ± 16 ml/min after intravenous dosing. Adverse effects were largely confined to gastrointestinal disturbances, with all subjects experiencing diarrhea that was dose dependent in its severity. The results suggest that the formulation studied would require significant improvement with respect to tolerability and bioavailability to gain clinical acceptance.
Synthesis and Evaluation of Dinitroanilines for Treatment of Cryptosporidiosis
Authors: Benbow John W. , Bernberg Erin L. , Korda Anna , Mead Jan R. 
Published: April 2020

ABSTRACT

The efficacy of a series of dinitroaniline herbicide derivatives for the treatment of
Cryptosporidium parvum
infections has been studied. The lead compounds oryzalin (compound 1) and trifluralin (compound 2) have low water solubility (<3 ppm) which was alleged to be a major contributor to their poor pharmacokinetic availability. Derivatives of compounds 1 and 2 were synthesized. In these derivatives the functionality at the C-1 amine position or the C-4 position was substituted with groups with various hydrophilicities to determine if a direct relation existed between water solubility and overall activity. The chlorinated precursors of these derivatives were also examined and were found to be less active in the
C. parvum
assays, a result in direct contrast to earlier work with
Leishmania
. Enhanced water solubility alone did not overcome the drug availability problem; however, several candidates with similar activities but with toxicities lower than those of the lead compounds were produced.
Green Fluorescent Protein Reporter Microplate Assay for High-Throughput Screening of Compounds against
Mycobacterium tuberculosis
Authors: Collins L. A. , Torrero M. N. , Franzblau S. G. 
Published: April 2020

ABSTRACT

An optimal assay for high-throughput screening for new antituberculosis agents would combine the microplate format and low cost of firefly luciferase reporter assays and redox dyes with the ease of kinetic monitoring inherent in the BACTEC system. The green fluorescent protein (GFP) of the jellyfish
Aequorea victoria
is a useful reporter molecule which requires neither substrates nor cofactors due to the intrinsically fluorescent nature of the protein. The gene encoding a red-shifted, higher-intensity GFP variant was introduced by electroporation into
Mycobacterium tuberculosis
H
37
Ra and
M. tuberculosis
H
37
Rv on expression vector pFPV2. A microplate-based fluorescence assay (GFP microplate assay [GFPMA]) was developed and evaluated by determining the MICs of existing antimycobacterial agents. The MICs of isoniazid, rifampin, ethambutol, streptomycin, amikacin, ofloxacin, ethionamide, thiacetazone, and capreomycin, but not cycloserine, determined by GFPMA were within 1 log
2
dilution of those determined with the BACTEC 460 system and were available in 7 days. Equivalent MICs of antituberculosis agents in the BACTEC 460 system for both the reporter and parent strains suggested that introduction of pFPV2 did not influence drug susceptibility, in general. GFPMA provides a unique tool with which the dynamic response of
M. tuberculosis
to the existing and potential antituberculosis agents can easily, rapidly, and inexpensively be monitored.
A Novel Peptide-Grafted Liposomal Delivery System Targeted to Macrophages
Authors: Banerjee Goutam , Medda Swapna , Basu Mukul K. 
Published: April 2020

ABSTRACTThe interaction of chemotactic peptide (e.g., fMet-Leu-Phe)-grafted liposomes with macrophages is noted to be rapid and specific. At a grafted peptide concentration of 100 nmol, internalization of the peptide-grafted liposomes by the macrophages is found to reach equilibrium in 30 min. The peptide alone and the peptide-grafted empty liposomes are found to show moderate antileishmanial activity in vitro. Primaquine, which is known to generate O2−in phagocytic cells, showed leishmanicidal properties when it was tested in vitro against parasite-infected macrophages over a certain range of concentrations. It showed much better efficacy against experimental leishmaniasis when it was used in the fMet-Leu-Phe-grafted liposomal form in comparison with its efficacy when it was either in the free form or encapsulated in ungrafted liposomes. The conventional toxicity parameters (e.g., blood pathology and tissue histology-specific enzyme levels related to normal liver function) are found to be very close to normal when fMet-Leu-Phe-grafted liposomal primaquine is used. The biodegradabilities of both the drug and the delivery systems are also found to be very satisfactory. Thus, this delivery system may have possible applications for the treatment of leishmaniasis as well as other macrophage-associated disorders.
Mathematical Modeling of the Interrelationship of CD4 Lymphocyte Count and Viral Load Changes Induced by the Protease Inhibitor Indinavir
Authors: Drusano George L. , Stein Daniel S. 
Published: April 2020

ABSTRACT

While CD4 cell counts are widely used to predict disease progression in human immunodeficiency virus (HIV)-infected patients, they are poorly explanatory of the progression to AIDS or death after the introduction of chemotherapy. Changes in HIV load (as measured by RNA PCR) have been shown to be a much better predictor of the risk of disease progression. Since the interrelationship of these markers is of great clinical interest, we modeled the time-averaged return of CD4 cell count and change in viral load subsequent to therapy with the HIV protease inhibitor indinavir. We found that CD4 cell return was significantly related to both the baseline CD4 count (
r
2
= 0.86,
P
< 0.001) and the decline in HIV RNA PCR-determined viral load (also referred to in this work as the HIV RNA PCR decline) (
r
2
= 0.60,
P
< 0.01). Simultaneously modeling both influences in a linked nonlinear model (
r
2
= 0.93,
P
< 0.001) demonstrated that (i) the starting number of CD4 cells accounted for the majority of the change in CD4 cell return and (ii) the return of CD4 cells attributable to viral load decrease was 50% of maximal with only a decrease of approximately 0.2 log of HIV RNA as modeled from the first 12 weeks of therapy. Much greater viral inhibition beyond that necessary for maximal CD4 cell return is possible. Given that HIV RNA PCR decline is more strongly linked to ultimate clinical course in HIV disease, our findings indicate that CD4 return is potentially misleading as an indicator of antiviral effect, since it is determined more by the starting CD4 value than by viral load decline and since near-maximal changes occur with minimal antiviral effect.
Doxycycline Hyclate Treatment of Experimental Canine Ehrlichiosis Followed by Challenge Inoculation with TwoEhrlichia canisStrains
Authors: Breitschwerdt Edward B. , Hegarty Barbara C. , Hancock Susan I. 
Published: April 2020

ABSTRACTDogs were experimentally inoculated withEhrlichia canisFlorida to assess the efficacy of doxycycline hyclate for the treatment of acute ehrlichiosis. Treatment with doxycycline eliminated infection in eight of eight dogs. Untreated infected control dogs appeared to eliminate the infection or, alternatively, suppress the degree of ehrlichiemia to a level not detectable by tissue culture isolation or PCR or by transfusion of blood into recipient dogs. Prior infection did not infer protection against homologous (strain Florida) or heterologous (strain NCSU Jake) strains ofE. canis. We conclude that doxycycline hyclate is an effective treatment for acuteE. canisinfection; however, these results may not be applicable to chronic infections in nature. Spontaneous resolution of infection, induced by the dog’s innate immune response, provides evidence that anE. canisvaccine, once developed, might potentially confer protective immunity against the organism.
Comparison of Pharmacodynamics of Azithromycin and Erythromycin In Vitro and In Vivo
Authors: den Hollander Jan G. , Knudsen Jenny D. , Mouton Johan W. , Fuursted Kurt , Frimodt-Møller Niels , Verbrugh Henri A. , Espersen Frank 
Published: April 2020

ABSTRACT

In this study, we determined the efficacy of various dosing regimens for erythromycin and azithromycin against four pneumococci with different susceptibilities to penicillin in an in vitro pharmacokinetic model and in a mouse peritonitis model. The MIC was 0.03 μg/ml, and the 50% effective doses (determined after one dose) of both drugs were comparable for the four pneumococcal strains and were in the range of 1.83 to 6.22 mg/kg. Dosing experiments with mice, using regimens for azithromycin of one to eight doses/6 h, showed the one-dose regimen to give the best result; of the pharmacodynamic parameters tested (the maximum drug concentration in serum [
C
max
], the times that the drug concentration in serum remained above the MIC and above the concentration required for maximum killing, and the area under the concentration time curve),
C
max
was the best predictor of outcome. The bacterial counts in mouse blood or peritoneal fluid during the first 24 h after challenge were not correlated to survival of the mice. The serum concentration profiles obtained with mice for the different dosing regimens were simulated in the in vitro pharmacokinetic model. Here as well, the one-dose regimen of azithromycin showed the best result. However, the killing curves in vivo in mouse blood and peritoneal fluid and in the vitro pharmacokinetic model were not similar. The in vitro killing curves showed a decrease of 2 log
10
within 2 and 3 h for azithromycin and erythromycin, respectively, whereas the in vivo killing curves showed a bacteriostatic effect for both drugs. It is concluded that the results in terms of predictive pharmacodynamic parameters are comparable for the in vitro and in vivo models and that high initial concentrations of azithromycin favor a good outcome.
Intrinsic Resistance to Inhibitors of Fatty Acid Biosynthesis in
Pseudomonas aeruginosa
Is Due to Efflux: Application of a Novel Technique for Generation of Unmarked Chromosomal Mutations for the Study of Efflux Systems
Authors: Schweizer Herbert P. 
Published: April 2020

ABSTRACT

Many strains of
Pseudomonas aeruginosa
are resistant to the antibiotics cerulenin and thiolactomycin, potent inhibitors of bacterial fatty acid biosynthesis. A novel yeast Flp recombinase-based technique was used to isolate an unmarked
mexAB-oprM
deletion encoding an efflux system mediating resistance to multiple antibiotics in
P. aeruginosa
. The experiments showed that the MexAB-OprM system is responsible for the intrinsic resistance of this bacterium to cerulenin and thiolactomycin. Whereas thiolactomycin was not a substrate of the MexCD-OprJ pump expressed in a Δ(
mexAB-oprM
)
nfxB
mutant, cerulenin was efficiently effluxed by the MexCD-OprJ system. It was also found that the MexAB-OprM system is capable of efflux of irgasan, a broad-spectrum antimicrobial compound used in media selective for
Pseudomonas.
In Vitro Activities of Y-688, a New 7-Substituted Fluoroquinolone, against Anaerobic Bacteria
Authors: MacGowan A. P. , Bowker K. E. , Wootton M. , Holt H. A. , Reeves D. S. 
Published: April 2020

ABSTRACT

The in vitro activities of Y-688, a new 7-substituted fluoroquinolone derivative, against 317 nonduplicate anaerobic isolates were determined. Eighty-five percent of the
Bacteroides fragilis
group (
n
= 89) were inhibited by ≤2 mg of Y-688 per liter, while 78, 100, 89, and 98% of gram-negative bacilli (
n
= 135), gram-positive cocci (
n
= 59), and non-spore-forming (
n
= 58) and spore-forming (
n
= 51) gram-positive bacilli, respectively, were inhibited by ≤1 mg of Y-688 per liter.
Nucleotide and Amino Acid Sequences of the Metallo-β-Lactamase, ImiS, from
Aeromonas veronii
bv. sobria
Authors: Walsh T. R. , Neville W. A. , Haran M. H. , Tolson D. , Payne D. J. , Bateson J. H. , Macgowan A. P. , Bennett P. M. 
Published: April 2020

ABSTRACT

The
Aeromonas veronii
bv. sobria metallo-β-lactamase gene,
imiS
, was cloned. The
imiS
open reading frame extends for 762 bp and encodes a protein of 254 amino acids with a secreted modified protein of 227 amino acids and a predicted pI of 8.1. To confirm the predicted sequence, purified ImiS was digested and the resulting peptides were identified, yielding an identical sequence for ImiS, with 98% identity to CphA. Both possessed the putative active-site sequence Asn-Tyr-His-Thr-Asp at positions 88 to 92, which is unique to the
Aeromonas
metallo-β-lactamases.
In Vitro Comparative Efficacy of Voriconazole and Itraconazole against Fluconazole-Susceptible and -Resistant
Cryptococcus neoformans
Isolates
Authors: Nguyen M. Hong , Yu Christine Y. 
Published: April 2020

ABSTRACT

In vitro susceptibility testing for 50 clinical isolates of fluconazole-susceptible or -resistant
Cryptococcus neoformans
was performed with itraconazole and voriconazole. Voriconazole was more potent than itraconazole for fluconazole-susceptible isolates and as potent as itraconazole for fluconazole-susceptible dose-dependent isolates and for fluconazole-resistant isolates. For fluconazole-resistant isolates, the voriconazole and itraconazole MICs ranged from 1 to 2 μg/ml.
Extent and consequences of lymphadenectomy in oesophageal cancer surgery: case vignette survey
Authors: de Gouw Didi JJM , Scholte Mirre , Gisbertz Suzanne S , Wijnhoven Bas P L , Rovers Maroeska M , Klarenbeek Bastiaan R , Rosman Camiel 
Published: April 2020

ObjectivesLymph node dissection (LND) is part of the standard operating procedure in patients with resectable oesophageal cancer after neoadjuvant chemoradiotherapy regardless of lymph node (LN) status. The aims of this case vignette survey were to acquire expert opinions on the current practice of LND and to determine potential consequences of non-invasive LN staging on the extent of LND and postoperative morbidity.DesignAn online survey including five short clinical cases (case vignettes) was sent to 272 oesophageal surgeons worldwide.Participants86 oesophageal surgeons (median experience in oesophageal surgery of 15 years) participated in the survey (response rate 32%).Main outcome measuresExtent of standard LND, potential changes in LND based on accurate LN staging and consequences for postoperative morbidity were evaluated.ResultsStandard LND varied considerably between experts; for example, pulmonary ligament, splenic artery, aortopulmonary window and paratracheal LNs are routinely dissected in less than 60%. The omission of (parts of) LND is expected to decrease the number of chyle leakages, pneumonias, and laryngeal nerve pareses and to reduce operating time. In order to guide surgical treatment decisions, a diagnostic test for LN staging after neoadjuvant therapy requires a minimum sensitivity of 92% and a specificity of 90%.ConclusionsThis expert case vignette survey study shows that there is no consensus on the extent of standard LND. Oesophageal surgeons seem more willing to extend LND rather than omit LND, based on accurate LN staging. The majority of surgeons expect that less extensive LND can reduce postoperative morbidity.