bluuebunny/crossref_metadata_2025 huggingface dataset:
Heat Exchanger Design for the Process Industries
Authors: Bell Kenneth J.
Published: January 2005

The design process for heat exchangers in the process industries and for similar applications in the power and large-scale environmental control industries is described. Because of the variety of substances (frequently multicomponent, of variable and uncertain composition, and changing phase) to be processed under wide ranges of temperatures, pressures, flow rates, chemical compatibility, and fouling propensity, these exchangers are almost always custom-designed and constructed. Many different exchanger configurations are commercially available to meet special conditions, with design procedures of varying degrees of reliability. A general design logic can be applied, with detailed procedures specific to the type of exchanger. The basis of the design process is first a careful and comprehensive specification of the range of conditions to be satisfied, and second, organized use of a fundamentally valid and extrapolatable rating method. The emphasis in choosing a design method is upon rational representation of the physical processes, rather than upon high accuracy. Finally, the resultant design must be vetted in detail by the designer and the process engineer for operability, flexibility, maintainability, and safety.
Submicron Heat Transport Model in Silicon Accounting for Phonon Dispersion and Polarization
Authors: Narumanchi Sreekant V. J. , Murthy Jayathi Y. , Amon Cristina H.
Published: January 2005

In recent years, the Boltzmann transport equation (BTE) has begun to be used for predicting thermal transport in dielectrics and semiconductors at the submicron scale. However, most published studies make a gray assumption and do not account for either dispersion or polarization. In this study, we propose a model based on the BTE, accounting for transverse acoustic and longitudinal acoustic phonons as well as optical phonons. This model incorporates realistic phonon dispersion curves for silicon. The interactions among the different phonon branches and different phonon frequencies are considered, and the proposed model satisfies energy conservation. Frequency-dependent relaxation times, obtained from perturbation theory, and accounting for phonon interaction rules, are used. In the present study, the BTE is numerically solved using a structured finite volume approach. For a problem involving a film with two boundaries at different temperatures, the numerical results match the analogous exact solutions from radiative transport literature for various acoustic thicknesses. For the same problem, the transient thermal response in the acoustically thick limit matches results from the solution to the parabolic Fourier diffusion equation. In the acoustically thick limit, the bulk experimental value of thermal conductivity of silicon at different temperatures is recovered from the model. Experimental in-plane thermal conductivity data for silicon thin films over a wide range of temperatures are also matched satisfactorily.
The Dynamics of Two-Dimensional Buoyancy Driven Convection in a Horizontal Rotating Cylinder
Authors: Hasan Nadeem , Sanghi Sanjeev
Published: January 2005

The present study involves a numerical investigation of buoyancy induced two-dimensional fluid motion in a horizontal, circular, steadily rotating cylinder whose wall is subjected to a periodic distribution of temperature. The axis of rotation is perpendicular to gravity. The governing equations of mass, momentum and energy, for a frame rotating with the enclosure, subject to Boussinesq approximation, have been solved using the Finite Difference Method on a Cartesian colocated grid utilizing a semi-implicit pressure correction approach. The problem is characterized by four dimensionless parameters: (1) Gravitational Rayleigh number Rag; (2) Rotational Rayleigh number RaΩ; (3) Taylor number Ta; and (4) Prandtl number Pr. The investigations have been carried out for a fixed Pr=0.71 and a fixed Rag=105 while RaΩ is varied from 102 to 107. From the practical point of view, RaΩ and Ta are not independent for a given fluid and size of the enclosure. Thus they are varied simultaneously. Further, an observer attached to the rotating cylinder, is stationary while the “g” vector rotates resulting in profound changes in the flow structure and even the flow direction at low enough flow rates RaΩ<105 with phase “ϕg” of the “g” vector. For RaΩ⩾105, the global spatial structure of the flow is characterized by two counter-rotating rolls in the rotating frame while the flow structure does not alter significantly with the phase of the rotating “g” vector. The frequency of oscillation of Nusselt number over the heated portion of the cylinder wall is found to be very close to the rotation frequency of the cylinder for RaΩ⩽105 whereas multiple frequencies are found to exist for RaΩ>105. The time mean Nusselt number for the heated portion of the wall undergoes a nonmonotonic variation with RaΩ, depending upon the relative magnitudes of the different body forces involved.
Donald Q. Kern Lecture Award Paper: Odyssey of the Enhanced Boiling Surface
Authors: Webb Ralph L.
Published: January 2005

This paper traces the evolution of enhanced boiling surfaces. Early work was highly empirical and done in industrial research. The 1968 Milton patent [“Heat Exchange System,” U.S. Patent 3,696,861] described the first porous coated surface, and the 1972 Webb patent [“Heat Transfer Surface Having a High Boiling Heat Transfer Coefficient,” U.S. Patent 3,521,708] described a “structured” tube surface geometry. The first fundamental understanding of the “pore-and-tunnel” geometry was published by Nakayama in 1980 [Nakayama, W., Daikoku, T., Kuwahara, H., and Nakajima, T. 1980, “Dynamic Model of Enhanced Boiling Heat Transfer on Porous Surfaces Part I: Experimental Investigation,” J. Heat Transfer, 102, pp. 445–450]. Webb and Chien’s flow visualization allowed observation of the evaporation in the subsurface tunnels [Chien, L.-H., and Webb, R. L., 1998, “Visualization of Pool Boiling on Enhanced Surfaces,” Exp. Fluid Thermal Sci., 16b, pp. 332–341]. They also performed an experimental parametric study that defines the effect of pore diameter and pitch on the boiling performance. The progression of work on analytical boiling models is also reviewed.
Entropy Generation Extrema and Their Relationship With Heat Exchanger Effectiveness—Number of Transfer Unit Behavior for Complex Flow Arrangements
Authors: Shah Ramesh K. , Skiepko Teodor
Published: January 2005

While the concept of minimum irreversibility is associated with the maximum energy efficiency for energy conversion processes in thermal systems, we have found that it is not quite applicable to the heat exchanger analysis. We have shown that the heat exchanger effectiveness can be maximum, having an intermediate value or minimum at the maximum irreversibility operating point depending on the flow arrangement of the two fluids. Similarly, the heat exchanger effectiveness can be minimum or maximum at the minimum irreversibility operating point. The objective of this paper is to illustrate and discuss such heat exchanger performance and irreversibility trends by combining the temperature difference irreversibility with the P-NTU results for complex flow arrangements.
Alterations in DNA Gyrase and Topoisomerase IV in Resistant Mutants of
Clostridium perfringens
Found after In Vitro Treatment with Fluoroquinolones
Authors: Rafii Fatemeh , Park Miseon , Novak John S.
Published: January 2005

To compare mutations in the DNA gyrase (
gyrA
and
gyrB
) and topoisomerase IV (
parC
and
parE
) genes of
Clostridium perfringens
, which are associated with in vitro exposure to fluoroquinolones, resistant mutants were selected from eight strains by serial passage in the presence of increasing concentrations of norfloxacin, ciprofloxacin, gatifloxacin, or trovafloxacin. The nucleotide sequences of the entire
gyrA
,
gyrB
,
parC
, and
parE
genes of 42 mutants were determined. DNA gyrase was the primary target for each fluoroquinolone, and topoisomerase IV was the secondary target. Most mutations appeared in the quinolone resistance-determining regions of
gyrA
(resulting in changes of Asp-87 to Tyr or Gly-81 to Cys) and
parC
(resulting in changes of Asp-93 or Asp-88 to Tyr or Ser-89 to Ile); only two mutations were found in
gyrB
, and only two mutations were found in
parE
. More mutants with multiple
gyrA
and
parC
mutations were produced with gatifloxacin than with the other fluoroquinolones tested. Allelic diversity was observed among the resistant mutants, for which the drug MICs increased 2- to 256-fold. Both the structures of the drugs and their concentrations influenced the selection of mutants.
Potent Plasmodicidal Activity of a Heat-Induced Reformulation of Deoxycholate-Amphotericin B (Fungizone) against
Plasmodium falciparum
Authors: Hatabu Toshimitsu , Takada Tsuyoshi , Taguchi Nao , Suzuki Mamoru , Sato Kumiko , Kano Shigeyuki
Published: January 2005

The emergence and spread of drug-resistant
Plasmodium falciparum
continue to pose problems in malaria chemotherapy. Therefore, it is necessary to identify new antimalarial drugs and therapeutic strategies. In the present study, the activity of a heat-treated form of amphotericin B (HT-AMB) against
P. falciparum
was evaluated. The efficacy and toxicity of HT-AMB were also compared with those of the standard formulation (AMB). HT-AMB showed significant activity against a chloroquine-resistant strain (strain K-1) and a chloroquine-susceptible strain (strain FCR-3) in vitro. The 50% inhibitory concentrations of HT-AMB were 0.32 ± 0.03 μg/ml for strain K-1 and 0.33 ± 0.03 μg/ml for strain FCR-3. In the presence of 1.0 μg of HT-AMB per ml, only pyknotic parasites were observed after 24 h of incubation of early trophozoites (ring forms). However, when late trophozoites and schizonts were cultured with 1.0 μg of HT-AMB per ml, those forms multiplied to ring forms but the number of infected erythrocytes did not increase. These results indicate that HT-AMB possesses potent antiplasmodial activity and that the drug is more effective against the ring-form stage than against the late trophozoite and schizont stages. HT-AMB was observed to have little cytotoxic effect against a human liver cell line (Chang liver cells). In conclusion, the results suggest that HT-AMB has promising properties and merits further in vivo investigations as a treatment for falciparum malaria.
Efficacy of Micafungin in Combination with Other Drugs in a Murine Model of Disseminated Trichosporonosis
Authors: Serena Carolina , Pastor F. Javier , Gilgado Félix , Mayayo Emilio , Guarro Josep
Published: January 2005

Using a murine model of disseminated infection caused by
Trichosporon asahii
, we have evaluated the efficacies of amphotericin B (AMB; 1 mg/kg of body weight/day), fluconazole (FLC; 20 mg/kg/twice a day), and micafungin (MFG; 5 mg/kg/twice a day). We tested these drugs alone and in combination (MFG with AMB and MFG with FLC). MFG with AMB showed a synergistic effect and demonstrated a higher degree of efficacy in prolonging survival and reducing the kidney fungal burden than either agent alone. The combination MFG with FLC was able to reduce significantly the kidney fungal burden in comparison to that achieved with either drug administered alone.
Antifungal Susceptibilities of Clinical Isolates of
Candida
Species,
Cryptococcus neoformans
, and
Aspergillus
Species from Taiwan: Surveillance of Multicenter Antimicrobial Resistance in Taiwan Program Data from 2003
Authors: Hsueh Po-Ren , Lau Yeu-Jun , Chuang Yin-Ching , Wan Jen-Hsien , Huang Wen-Kuei , Shyr Jainn-Ming , Yan Jing-Jou , Yu Kwok-Woon , Wu Jiunn-Jong , Ko Wen-Chien , Yang Yi-Chueh , Liu Yung-Ching , Teng Lee-Jene , Liu Cheng-Yi , Luh Kwen-Tay
Published: January 2005

The susceptibilities of nonduplicate isolates to six antifungal agents were determined for 391 blood isolates of seven
Candida
species, 70 clinical isolates (from blood or cerebrospinal fluid) of
Cryptococcus neoformans
, and 96 clinical isolates of four
Aspergillus
species, which were collected in seven different hospitals in Taiwan (as part of the 2003 program of the study group Surveillance of Multicenter Antimicrobial Resistance in Taiwan). All isolates of
Candida
species other than
C. glabrata
and
C. krusei
were susceptible to fluconazole. Among the 59
C. glabrata
isolates, 16 (27%) were not susceptible to fluconazole, and all were dose-dependently susceptible or resistant to itraconazole. For three (5.1%)
C. glabrata
isolates, voriconazole MICs were 2 to 4 μg/ml, and for all other
Candida
species isolates, voriconazole MICs were ≤0.5 μg/ml. The proportions of isolates for which amphotericin B MICs were ≥2 μg/ml were 100% (3 isolates) for
C. krusei
, 11% (23 of 207 isolates) for
Candida albicans
, 3.0% (2 of 67 isolates) for
Candida tropicalis
, 20% (12 of 59 isolates) for
C. glabrata
, and 0% for both
Candida parapsilosis
and
Candida lusitaniae
. For three (4%)
Cryptococcus neoformans
isolates, fluconazole MICs were ≥16 μg/ml, and two (3%) isolates were not inhibited by 1 μg of amphotericin B/ml. For four (4.2%) of the
Aspergillus
isolates, itraconazole MICs were 8 μg/ml.
Aspergillus flavus
was less susceptible to amphotericin B, with the MICs at which 50% (1 μg/ml) and 90% (2 μg/ml)
nsrsid417869\delrsid7301351
of isolates were inhibited being twofold greater than those for
Aspergillus fumigatus
and
Aspergillus niger
. All
Aspergillus
isolates were inhibited by ≤1 μg of voriconazole/ml, including isolates with increased resistance to amphotericin B and itraconazole. This study revealed the emergence in Taiwan of decreased susceptibilities of
Candida
species to amphotericin B and of
C. neoformans
to fluconazole and amphotericin B. Voriconazole was the most potent agent against the fungal isolates tested, including fluconazole- and amphotericin B-nonsusceptible strains.
Cholesterol Import by
Aspergillus fumigatus
and Its Influence on Antifungal Potency of Sterol Biosynthesis Inhibitors
Authors: Xiong Quanbo , Hassan Saad A. , Wilson William K. , Han Xiang Y. , May Gregory S. , Tarrand Jeffrey J. , Matsuda Seiichi P. T.
Published: January 2005

High mortality rates from invasive aspergillosis in immunocompromised patients are prompting research toward improved antifungal therapy and better understanding of fungal physiology. Herein we show that
Aspergillus fumigatus
, the major pathogen in aspergillosis, imports exogenous cholesterol under aerobic conditions and thus compromises the antifungal potency of sterol biosynthesis inhibitors. Adding serum to RPMI medium led to enhanced growth of
A. fumigatus
and extensive import of cholesterol, most of which was stored as ester. Growth enhancement and sterol import also occurred when the medium was supplemented with purified cholesterol instead of serum. Cells cultured in RPMI medium with the sterol biosynthesis inhibitors itraconazole or voriconazole showed retarded growth, a dose-dependent decrease in ergosterol levels, and accumulation of aberrant sterol intermediates. Adding serum or cholesterol to the medium partially rescued the cells from the drug-induced growth inhibition. We conclude that cholesterol import attenuates the potency of sterol biosynthesis inhibitors, perhaps in part by providing a substitute for membrane ergosterol. Our findings establish significant differences in sterol homeostasis between filamentous fungi and yeast. These differences indicate the potential value of screening aspergillosis antifungal agents in serum or other cholesterol-containing medium. Our results also suggest an explanation for the antagonism between itraconazole and amphotericin B, the potential use of
Aspergillus
as a model for sterol trafficking, and new insights for antifungal drug development.
Bayesian Parameter Estimates of Nelfinavir and Its Active Metabolite, Hydroxy-tert-Butylamide, in Infants Perinatally Infected with Human Immunodeficiency Virus Type 1
Authors: Payen Salomé , Faye Albert , Compagnucci Alexandra , Giaquinto Carlo , Gibbs Diana , Gomeni Roberto , Bressolle Françoise , Jacqz-Aigrain Evelyne
Published: January 2005

The objective of the present study was to develop a population pharmacokinetic model for nelfinavir mesylate (NFV) and nelfinavir hydroxy-tert-butylamide (M8), the most abundant metabolite of NFV, in infants vertically infected with human immunodeficiency virus type 1 and participating in the Paediatric European Network for Treatment of AIDS 7 study. Plasma NFV concentrations were determined during repeated NFV administrations (two to three times a day). Eighteen infants younger that age 2 years participated in this study. The doses administered ranged from 71 to 203 mg/kg of body weight/day. Pharmacokinetic parameter estimates were obtained by a compartmental approach by using a kinetic model to simultaneously fit NFV and M8 (active metabolite) concentrations. M8 was shown to be formation rate limited and was characterized by first-order rate constants of formation and elimination. Body weight was found to be a more appropriate predictor than age of the changes in (i) the rate of metabolism, (ii) the elimination rate constant of NFV, and (iii) NFV clearance. Population parameters were computed to account for the relationship between the rate of metabolism and body weight. The estimated NFV and M8 elimination half-lives were 4.3 and 2.04 h, respectively. The estimated NFV clearance was 2.13 liters/h/kg. The M8 concentration-to-NFV concentration ratio was 0.64 ± 0.44. In conclusion, the population pharmacokinetic model describing the dispositions of NFV and M8 should facilitate the design of future studies to elucidate the relative contributions of the parent compound and M8 to the pharmacological and toxic effects of NFV therapy.
Mutations in
folP
Associated with Elevated Sulfonamide MICs for
Neisseria meningitidis
Clinical Isolates from Five Continents
Authors: Fiebelkorn K. R. , Crawford S. A. , Jorgensen J. H.
Published: January 2005

Sulfonamide resistance in meningococci is associated with mutations in the chromosomal gene
folP
, which encodes dihydropteroate synthase. Several mutations associated with resistance have been previously described, including amino acid substitutions at codons 31 and 194, a glycine-serine insertion at codons 195 and 196, and, recently, an additional mutation at nucleotide 682 (C682A). In this study, sulfisoxazole MICs were determined for 424 geographically diverse clinical isolates of
Neisseria meningitidis
, including all major subtypes. A subset of 134 isolates with MICs ranging from 0.5 to >64 μg/ml were assayed for the C682A mutation by real-time PCR, and 25 isolates were selected for
folP
gene sequencing. All isolates for which the sulfisoxazole MIC was ≥8 possessed the C682A mutation by real-time PCR or
folP
sequencing, and 34 of 35 isolates with a MIC of ≤2 lacked this mutation. Of 16 sequenced isolates for which the sulfisoxazole MIC was ≥4, 15 possessed previously described mutations, including 10 at codon 31, 1 at codon 194, and 4 with the 2-amino-acid insertion codons 195 and 196; all 16 possessed the C682A mutation. The C682A mutation predicted elevated sulfonamides MICs for a large number of geographically diverse clinical isolates of meningococci. Detection of this mutation by real-time PCR or other methods may allow more wide-scale detection of meningococcal isolates with for which the sulfonamide MICs are elevated without resorting to multiple assays or
folP
gene sequencing, providing a simple, high-throughput screening method for use in public health and epidemiologic settings.
Genetic Analysis of a Unique Bacteriocin, Smb, Produced by
Streptococcus mutans
GS5
Authors: Yonezawa Hideo , Kuramitsu Howard K.
Published: January 2005

A dipeptide lantibiotic, named Smb, in
Streptococcus mutans
GS5 was characterized by molecular genetic approaches. The Smb biosynthesis gene locus is encoded by a 9.5-kb region of chromosomal DNA and consists of seven genes in the order
smbM1
, -
T
, -
F
, -
M2
, -
G
, -
A
, -
B
. This operon is not present in some other strains of
S. mutans
, including strain UA159. The genes encoding Smb were identified as
smbA
and
smbB
. Inactivation of
smbM1
,
smbA
, or
smbB
attenuated the inhibition of the growth of the indicator strain RP66, confirming an essential role for these genes in Smb expression. Mature Smb likely consists of the 30-amino-acid SmbA together with the 32-amino-acid SmbB. SmbA exhibited similarity with the mature lantibiotic lacticinA2 from
Lactococcus lactis
, while SmbB was similar to the mersacidin-like peptides from
Bacillus halodurans
and
L. lactis
. We also demonstrated that Smb expression is induced by the competence-stimulating peptide (CSP) and that a com box-like sequence is located in the
smb
promoter region. These results suggest that Smb belongs to the class I bacteriocin family, and its expression is dependent on CSP-induced quorum sensing.
Generation and Characterization of Recombinant Influenza A (H1N1) Viruses Harboring Amantadine Resistance Mutations
Authors: Abed Yacine , Goyette Nathalie , Boivin Guy
Published: January 2005

The emergence of resistance to amantadine in influenza A viruses has been shown to occur rapidly during treatment as a result of single-amino-acid substitutions at position 26, 27, 30, 31, or 34 within the transmembrane domain of the matrix-(M)-2 protein. In this study, reverse genetics was used to generate and characterize recombinant influenza A (H1N1) viruses harboring L26F, V27A, A30T, S31N, G34E, and V27A/S31N mutations in the M2 gene. In plaque reduction assays, all mutations conferred amantadine resistance, with drug concentrations resulting in reduction of plaque number by 50% (IC
50
s) 154- to 3,300-fold higher than those seen for the wild type (WT). M2 mutants had no impairment in their replicative capacities in vitro on the basis of plaque size and replication kinetics experiments. In addition, all mutants were at least as virulent as the WT in experimentally infected mice, with the highest mortality rate being obtained with the recombinant harboring a double V27A/S31N mutation. These findings could help explain the frequent emergence and transmission of amantadine-resistant influenza viruses during antiviral pressure in the clinical setting.
Pharmacokinetics of the Antiviral Agent β-
l
-3′-Fluoro-2′,3′-Didehydro-2′,3′-Dideoxycytidine in Rhesus Monkeys
Authors: Asif Ghazia , Hurwitz Selwyn J. , Gumina Giuseppe , Chu Chung K. , McClure Harold M. , Schinazi Raymond F.
Published: January 2005

β-
l
-3′-Fluoro-2′,3′-didehydro-2′,3′-dideoxycytidine (
l
-3′-Fd4C) is a potent and selective antiretroviral nucleoside with activity against lamivudine-resistant human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. The pharmacokinetics of
l
-3′-Fd4C were characterized in three rhesus monkeys given single intravenous and oral doses. A two-compartment open model was fitted to the plasma and urine data. Plasma concentrations declined in a biexponential fashion with an average beta half-life of 12.45 h and central and steady-state volumes of distribution of 0.43 and 1.90 liters/kg, respectively. The average systemic and renal clearance values were 0.23 and 0.08 liters/kg, respectively, and the apparent mean terminal half-life of the oral dose was 12.5 h. The serum concentrations exceeded the 90% effective concentration value for lamivudine-resistant and wild-type HIV-1 after oral administrations. A large variation was observed in the oral bioavailability, which ranged from 15 to 31%. To determine whether the bioavailability may be improved by using a basic buffer solution, the oral dose was repeated to the same animals in a sodium bicarbonate solution. The bioavailability of
l
-3′-Fd4C administered with sodium bicarbonate was not significantly different from the bioavailability when the oral dose was administered in the absence of buffer (
P
= 0.49), suggesting that further development of this compound may warrant other approaches, such as development of a prodrug to improve its oral absorption.
Use of an Efflux Pump Inhibitor To Determine the Prevalence of Efflux Pump-Mediated Fluoroquinolone Resistance and Multidrug Resistance in
Pseudomonas aeruginosa
Authors: Kriengkauykiat Jane , Porter Edith , Lomovskaya Olga , Wong-Beringer Annie
Published: January 2005

Fluoroquinolone-resistance in
Pseudomonas aeruginosa
may be due to efflux pump overexpression (EPO) and/or target mutations. EPO can result in multidrug resistance (MDR) due to broad substrate specificity of the pumps. MC-04,124, an efflux pump inhibitor (EPI) shown to significantly potentiate activity of levofloxacin in
P. aeruginosa
, was used to examine the prevalence of EPO in clinical isolates. MICs were determined for ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin with or without EPI and for other antipseudomonal agents by using broth microdilution against
P. aeruginosa
isolates from adults (
n
= 119) and children (
n
= 24). The prevalence of the EPO phenotype (≥8-fold MIC decrease when tested with EPI) was compared among subgroups with different resistance profiles. The EPO phenotype was more prevalent among levofloxacin-resistant than levofloxacin-sensitive strains (61%, 48/79 versus 9%, 6/64). EPO was present in 60% of fluoroquinolone-resistant strains without cross-resistance, while it was present at variable frequencies among strains with cross-resistance to other agents: piperacillin-tazobactam (86%), ceftazidime (76%), cefepime (65%), imipenem (56%), gentamicin (55%), tobramycin (48%), and amikacin (27%). The magnitude of MIC decrease with an EPI paralleled the frequency of which the EPO phenotype was observed in different subgroups. EPI reduced the levofloxacin MIC by as much as 16-fold in eight strains for which MICs were 128 μg/ml. Efflux-mediated resistance appears to contribute significantly to fluoroquinolone resistance and MDR in
P. aeruginosa
. Our data support the fact that increased fluoroquinolone usage can negatively impact susceptibility of
P. aeruginosa
to multiple classes of antipseudomonal agents.
Tetracycline-Resistant ClinicalHelicobacter pyloriIsolates with and without Mutations in 16S rRNA-Encoding Genes
Authors: Wu Jeng Yih , Kim Jae J. , Reddy Rita , Wang W. M. , Graham David Y. , Kwon Dong H.
Published: January 2005

Tetracycline-resistantHelicobacter pyloristrains have been increasingly reported worldwide. However, only a small number of tetracycline-resistant strains have been studied with regard to possible mechanisms of resistance and those studies have focused on mutations in the tetracycline binding sites of 16S rRNA-encoding genes. We here report studies of 41 tetracycline-resistantH. pyloristrains (tetracycline MICs, 4 to 32 μg/ml) from North America (n= 12) and from East Asia (n= 29). DNA sequence analyses of 16S rRNA-encoding genes revealed that 22 (54%) of the resistant isolates carried one of five different single-nucleotide substitutions (CGA, GGA, TGA, AGC, or AGT) at the putative tetracycline binding site (AGA965-967). Single-nucleotide substitutions were associated with reduced ribosomal binding and with slightly increased tetracycline MICs (1 to 2 μg/ml). The 19 tetracycline-resistant isolates with no detectable mutations in the tetracycline binding site had normal tetracycline-ribosome binding. All tetracycline-resistant isolates, including those with and those without mutations in the tetracycline binding site, showed decreased accumulation of tetracycline. These results suggest that tetracycline resistance is multifactorial, involving alterations both in ribosomal binding and in membrane permeability.
Antiviral Treatment with Alpha Interferon Up-Regulates CD14 on Liver Macrophages and Its Soluble Form in Patients with Chronic Hepatitis B
Authors: Carotenuto Patrizia , van Riel Debby , Artsen André , Bruijns Sven , Uytdehaag Fons G. , Laman Jon D. , van Nunen Andeltje B. , Zondervan Pieter E. , De Man Robert A. , Osterhaus Albert D. , Pontesilli Oscar
Published: January 2005

To investigate whether therapy with alpha interferon (IFN-α) induces changes in intrahepatic antigen-presenting cells (APCs), we obtained liver biopsy specimens before, during, and after therapy with IFN-α from chronic hepatitis B patients whose viral load had already been reduced by at least 8 weeks of treatment with lamivudine. HLA-DR, CD1a, and CD83 were not modified by the therapy. The intralobular expression of CD68 on Kupffer cells remained stable, denoting no changes in the number of resident macrophages during IFN-α treatment. In contrast, CD14 was weakly expressed in the absence of IFN-α and was significantly up-regulated during therapy. At the same time, the levels of soluble CD14 and interleukin-10 in plasma increased significantly. In vitro, monocytes maintained in the presence of IFN-α differentiated into macrophages or dendritic cells with higher levels of expression of CD14 than that for the control cultures. During therapy with IFN-α, T-cell infiltration in the portal spaces was reduced, mainly due to a significant decrease in the number of CD8+T cells. These findings show that IFN-α is biologically active on APCs in vivo and in vitro and suggest that this newly described regulatory function, together with the already known inhibitory effects on lymphocytes, may cooperate to reduce inflammation and consequent tissue damage in patients with chronic viral hepatitis.
Structure-Activity Relationships of Different β-Lactam Antibiotics against a Soluble Form of
Enterococcus faecium
PBP5, a Type II Bacterial Transpeptidase
Authors: Hujer Andrea M. , Kania Malgosia , Gerken Thomas , Anderson Vernon E. , Buynak John D. , Ge Xiaoxia , Caspers Patrick , Page Malcolm G. P. , Rice Louis B. , Bonomo Robert A.
Published: January 2005

Penicillin-binding proteins (PBPs) catalyze the essential reactions in the biosynthesis of cell wall peptidoglycan from glycopeptide precursors. β-Lactam antibiotics normally interfere with this process by reacting covalently with the active site serine to form a stable acyl-enzyme. The design of novel β-lactams active against penicillin-susceptible and penicillin-resistant organisms will require a better understanding of the molecular details of this reaction. To that end, we compared the affinities of different β-lactam antibiotics to a modified soluble form of a resistant
Enterococcus faecium
PBP5 (Δ1-36 rPBP5). The soluble protein, Δ1-36 rPBP5, was expressed in
Escherichia coli
and purified, and the NH
2
-terminal protein sequence was verified by amino acid sequencing. Using β-lactams with different R1 side chains, we show that azlocillin has greater affinity for Δ1-36 rPBP5 than piperacillin and ampicillin (apparent

K
i

= 7 ± 0.3 μM, compared to 36 ± 3 and 51 ± 10 μM, respectively). Azlocillin also exhibits the most rapid acylation rate (apparent

k
2

= 15 ± 4 M
−1
s
−1
). Meropenem demonstrates an affinity for Δ1-36 rPBP5 comparable to that of ampicillin (apparent

K
i

= 51 ± 15 μM) but is slower at acylating (apparent

k
2

= 0.14 ± 0.02 M
−1
s
−1
). This characterization defines important structure-activity relationships for this clinically relevant type II transpeptidase, shows that the rate of formation of the acyl-enzyme is an essential factor determining the efficacy of a β-lactam, and suggests that the specific side chain interactions of β-lactams could be modified to improve inactivation of resistant PBPs.
Conservation of Amino Acids in Human Rhinovirus 3C Protease Correlates with Broad-Spectrum Antiviral Activity of Rupintrivir, a Novel Human Rhinovirus 3C Protease Inhibitor
Authors: Binford S. L. , Maldonado F. , Brothers M. A. , Weady P. T. , Zalman L. S. , Meador J. W. , Matthews D. A. , Patick A. K.
Published: January 2005

The picornavirus 3C protease is required for the majority of proteolytic cleavages that occur during the viral life cycle. Comparisons of published amino acid sequences from 6 human rhinoviruses (HRV) and 20 human enteroviruses (HEV) show considerable variability in the 3C protease-coding region but strict conservation of the catalytic triad residues. Rupintrivir (formerly AG7088) is an irreversible inhibitor of HRV 3C protease with potent in vitro activity against all HRV serotypes (48 of 48), HEV strains (4 of 4), and untyped HRV field isolates (46 of 46) tested. To better understand the relationship between in vitro antiviral activity and 3C protease-rupintrivir binding interactions, we performed nucleotide sequence analyses on an additional 21 HRV serotypes and 11 HRV clinical isolates. Antiviral activity was also determined for 23 HRV clinical isolates and four additional HEV strains. Sequence comparison of 3C proteases (n= 58) show that 13 and 11 of the 14 amino acids that are involved in side chain interactions with rupintrivir are strictly conserved among HRV and HEV, respectively. These sequence analyses are consistent with the comparable in vitro antiviral potencies of rupintrivir against all HRV serotypes, HRV isolates, and HEV strains tested (50% effective concentration range, 3 to 183 nM;n= 125). In summary, the conservation of critical amino acid residues in 3C protease and the observation of potent, broad-spectrum antipicornavirus activity of rupintrivir highlight the advantages of 3C protease as an antiviral target.
Provitamin B
5
(Pantothenol) Inhibits Growth of the Intraerythrocytic Malaria Parasite
Authors: Saliba Kevin J. , Ferru Isabelle , Kirk Kiaran
Published: January 2005

Pantothenic acid, a precursor of the crucial enzyme cofactor coenzyme A, is one of a relatively few nutrients for which the intraerythrocytic parasite has an absolute and acute requirement from the external medium. In some organisms the provitamin pantothenol can serve as a source of pantothenic acid; however, this was not the case for the human malaria parasite
Plasmodium falciparum
. Instead, pantothenol inhibited the in vitro growth of
P. falciparum
via a mechanism that involves competition with pantothenate and which can be attributed to inhibition of the parasite's pantothenate kinase. Oral administration of pantothenol to mice infected with the murine parasite
Plasmodium vinckei vinckei
resulted in a significant inhibition of parasite proliferation. This study highlights the potential of the coenzyme A biosynthesis pathway in general, and pantothenate kinase in particular, as an antimalarial drug target.
Pharmacokinetics and Pharmacodynamics of Cefpirome in Subcutaneous Adipose Tissue of Septic Patients
Authors: Sauermann Robert , Delle-Karth Georg , Marsik Claudia , Steiner Ilka , Zeitlinger Markus , Mayer-Helm Bernhard X. , Georgopoulos Apostolos , Müller Markus , Joukhadar Christian
Published: January 2005

The objective of the present study was to evaluate whether cefpirome, a member of the latest class of broad-spectrum cephalosporins, sufficiently penetrates subcutaneous adipose tissue in septic patients. After the administration of the drug at 2 g, tissue cefpirome concentrations in septic patients (
n
= 11) and healthy controls (
n
= 7) were determined over a period of 4 h by means of microdialysis. To assess the antibacterial effect of cefpirome at the target site, the measured pharmacokinetic profiles were simulated in vitro with select strains of
Staphylococcus aureus
and
Pseudomonas aeruginosa
. The tissue penetration of cefpirome was significantly impaired in septic patients compared with that in healthy subjects. For subcutaneous adipose tissue, the area under the concentration-versus-time curve values from 0 to 240 min were 13.11 ± 5.20 g · min/liter in healthy subjects and 6.90 ± 2.56 g · min/liter in septic patients (
P
< 0.05). Effective bacterial growth inhibition was observed in all in vitro simulations. This was attributed to the significantly prolonged half-life in tissue (
P
< 0.05), which kept the tissue cefpirome levels above the MICs for relevant pathogens for extended periods in the septic group. By consideration of a dosing interval of 8 h, the values for the time above MIC (
T
> MIC) in tissue were greater than 60% for pathogens for which the MIC was ≤4 mg/liter in all septic patients. The present data indicate that cefpirome is an appropriate agent for the treatment of soft tissue infections in septic patients. However, due to the high interindividual variability of the pharmacokinetics of cefpirome in tissue, dosing intervals of not more than 8 h should be preferred to ensure that susceptible bacterial strains are killed in each patient.
Comparison of the Antiviral Activities of Alkoxyalkyl and Alkyl Esters of Cidofovir against Human and Murine Cytomegalovirus Replication In Vitro
Authors: Wan William B. , Beadle James R. , Hartline Caroll , Kern Earl R. , Ciesla Stephanie L. , Valiaeva Nadejda , Hostetler Karl Y.
Published: January 2005

Alkoxyalkyl esters of cidofovir (CDV) have substantially greater antiviral activity and selectivity than unmodified CDV against herpesviruses and orthopoxviruses in vitro. Enhancement of antiviral activity was also noted when cyclic CDV was esterified with alkoxyalkanols. In vitro antiviral activity of the most active analogs against human cytomegalovirus (HCMV) and orthopoxviruses was increased relative to CDV up to 1,000- or 200-fold, respectively. Alkyl chain length and linker structure are important potential modifiers of antiviral activity and selectivity. In this study, we synthesized a series of alkoxyalkyl esters of CDV or cyclic CDV with alkyl chains from 8 to 24 atoms and having linker moieties of glycerol, propanediol, and ethanediol. We also synthesized alkyl esters of CDV which lack the linker to determine if the alkoxyalkyl linker moiety is required for activity. The new compounds were evaluated in vitro against HCMV and murine CMV (MCMV). CDV or cyclic CDV analogs both with and without linker moieties were highly active against HCMV and MCMV, and their activities were strongly dependent on chain length. The most active compounds had 20 atoms esterified to the phosphonate of CDV. Both alkoxypropyl and alkyl esters of CDV provided enhanced antiviral activities against CMV in vitro. Thus, the oxypropyl linker moiety is not required for enhanced activity. CDV analogs having alkyl ethers linked to glycerol or ethanediol linker groups also demonstrated increased activity against CMV.
Prevalence and Subtypes of Ciprofloxacin-Resistant
Campylobacter
spp. in Commercial Poultry Flocks before, during, and after Treatment with Fluoroquinolones
Authors: Humphrey Tom J. , Jørgensen Frieda , Frost Jennifer A. , Wadda Haddy , Domingue Gil , Elviss Nicola C. , Griggs Deborah J. , Piddock Laura J. V.
Published: January 2005

Five commercial broiler chicken flocks were treated with either difloxacin or enrofloxacin for a clinically relevant infection, as instructed by a veterinarian. Campylobacters were isolated from individual fecal samples and from samples associated with the broiler environment before, during, and after treatment. Ciprofloxacin-resistant
Campylobacter jejuni
and/or
C. coli
strains were detected pretreatment in four flocks, but they constituted a very small proportion of the campylobacters present. When the broilers were treated with a fluoroquinolone, a rapid increase in the proportion of ciprofloxacin-resistant campylobacters was observed. During treatment nearly 100% of campylobacters were resistant, and in some flocks a high proportion of resistant strains persisted for up to 4 weeks after treatment. Prior to treatment a variety of campylobacter subtypes were present. During and after treatment considerable changes in both species and subtype prevalence were observed, but no single fluoroquinolone-resistant clone became dominant. Instead, resistant
C. coli
strains or a mixture of resistant
C. coli
and
C. jejuni
strains became dominant, whereas susceptible
C. jejuni
strains had usually been dominant prior to treatment. The resistant subtypes which emerged and became dominant were not always the same as those detected pretreatment. The persistence of resistant strains for up to 4 weeks posttreatment has important implications for any strategy designed to avoid the introduction of such strains into the food chain.
Altered NADH/NAD
+
Ratio Mediates Coresistance to Isoniazid and Ethionamide in Mycobacteria
Authors: Vilchèze Catherine , Weisbrod Torin R. , Chen Bing , Kremer Laurent , Hazbón Manzour H. , Wang Feng , Alland David , Sacchettini James C. , Jacobs William R.
Published: January 2005

The front-line antituberculosis drug isoniazid (INH) and the related drug ethionamide (ETH) are prodrugs that upon activation inhibit the synthesis of mycolic acids, leading to bactericidal activity. Coresistance to INH and ETH can be mediated by dominant mutations in the target gene
inhA
, encoding an enoyl-ACP reductase, or by recessive mutations in
ndh
, encoding a type II NADH dehydrogenase (NdhII). To address the mechanism of resistance mediated by the latter, we have isolated novel
ndh
mutants of
Mycobacterium smegmatis
and
Mycobacterium bovis
BCG. The
M. smegmatis ndh
mutants were highly resistant to INH and ETH, while the
M. bovis
BCG mutants had low-level resistance to INH and ETH. All mutants had defects in NdhII activity resulting in an increase in intracellular NADH/NAD
+
ratios. Increasing NADH levels were shown to protect InhA against inhibition by the INH-NAD adduct formed upon INH activation. We conclude that
ndh
mutations mediate a novel mechanism of resistance by increasing the NADH cellular concentration, which competitively inhibits the binding of INH-NAD or ETH-NAD adduct to InhA.
Caspofungin Inhibits
Rhizopus oryzae
1,3-β-
d
-Glucan Synthase, Lowers Burden in Brain Measured by Quantitative PCR, and Improves Survival at a Low but Not a High Dose during Murine Disseminated Zygomycosis
Authors: Ibrahim Ashraf S. , Bowman Joel C. , Avanessian Valentina , Brown Keturah , Spellberg Brad , Edwards John E. , Douglas Cameron M.
Published: January 2005

Rhizopus oryzae
is the most common cause of zygomycosis, a life-threatening infection that usually occurs in patients with diabetic ketoacidosis. Despite standard therapy, the overall rate of mortality from zygomycosis remains >50%, and new strategies for treatment are urgently needed. The activities of caspofungin acetate (CAS) and other echinocandins (antifungal inhibitors of the synthesis of 1,3-β-
d
-glucan synthase [GS]) against the agents of zygomycosis have remained relatively unexplored, especially in animal models of infection. We found that
R. oryzae
has both an
FKS
gene, which in other fungi encodes a subunit of the GS synthesis complex, and CAS-susceptible, membrane-associated GS activity. Low-dose but not high-dose CAS improved the survival of mice with diabetic ketoacidosis infected with a small inoculum but not a large inoculum of
R. oryzae
. Fungal burden, assessed by a novel quantitative PCR assay, correlated with increasing inocula and progression of disease, particularly later in the infection, when CFU counts did not. CAS decreased the brain burden of
R. oryzae
when it was given prophylactically but not when therapy was started after infection. These results indicate that CAS has significant but limited activity against
R. oryzae
in vivo and demonstrates an inverse dose-response effect. The potential for CAS to play a role in combination therapy against zygomycosis merits further investigation.
Multiechinocandin- and Multiazole-ResistantCandida parapsilosisIsolates Serially Obtained during Therapy for Prosthetic Valve Endocarditis
Authors: Moudgal Varsha , Little Tania , Boikov Dina , Vazquez Jose A.
Published: January 2005

Echinocandins are approved for the treatment of candidal infections. In vitro they have been shown to be less potent against strains ofCandida parapsilosisthan against otherCandidaspp. This is the first case report describing the development of a secondary multidrug (echinocandin-azole)-resistantCandidastrain during therapy.
Detection of KPC Carbapenem-Hydrolyzing Enzymes in
Enterobacter
spp. from Brooklyn, New York
Authors: Bratu Simona , Landman David , Alam Maqsood , Tolentino Elaine , Quale John
Published: January 2005

Enterobacter
spp. are rarely resistant to carbapenems. In this report, one
Enterobacter
sp. isolate possessed
bla
KPC-3
and two possessed
bla
KPC-2
. For all three strains, the imipenem MICs were dependent on the inoculum and testing method; two were reported by the clinical laboratories to be carbapenem susceptible. Improved detection methods will be necessary to identify these enzymes.
Interspecies Recombination in Type II Topoisomerase Genes Is Not a Major Cause of Fluoroquinolone Resistance in Invasive
Streptococcus pneumoniae
Isolates in the United States
Authors: Pletz Mathias W. R. , McGee Lesley , Beall Bernard , Whitney Cynthia G. , Klugman Keith P.
Published: January 2005

Mutations in the topoisomerase type II enzymes account for fluoroquinolone resistance in
Streptococcus pneumoniae
. These mutations can arise spontaneously or be transferred by intraspecies or interspecies recombination, primarily with viridans streptococci. We analyzed the nucleotide sequences of the quinolone resistance-determining regions of 49 invasive levofloxacin-resistant pneumococcal isolates and did not find any evidence for interspecies recombination.
The Biocide Triclosan Selects
Stenotrophomonas maltophilia
Mutants That Overproduce the SmeDEF Multidrug Efflux Pump
Authors: Sanchez Patricia , Moreno Eduardo , Martinez Jose L.
Published: January 2005

The possibility that triclosan selects
Stenotrophomonas maltophilia
mutants overexpressing the multidrug resistance pump SmeDEF is analyzed. Five out of 12 triclosan-selected mutants were less susceptible to antibiotics than the wild-type strain and overproduced SmeDEF. Results are discussed in relation to current debates on the potential selection of antibiotic-resistant bacteria by household biocides.
Rapid Acquisition of Stable Azole Resistance by
Candida glabrata
Isolates Obtained before the Clinical Introduction of Fluconazole
Authors: Borst Annemarie , Raimer Maria T. , Warnock David W. , Morrison Christine J. , Arthington-Skaggs Beth A.
Published: January 2005

Five azole-susceptible
Candida glabrata
isolates obtained before 1975 became resistant to fluconazole, itraconazole, and voriconazole within 4 days of in vitro fluconazole exposure. This cross-resistance was stable for at least 4 months after removal of fluconazole and was associated with increased
CgCDR1
and
CgCDR2
expression.
The
aadB
Gene Cassette Is Associated with
bla
SHV
Genes in
Klebsiella
Species Producing Extended-Spectrum β-Lactamases
Authors: Jones Louisa A. , McIver Christopher J. , Kim Mi-Jurng , Rawlinson William D. , White Peter A.
Published: January 2005

Integrons were detected in 37 (72.5%) of 51
Klebsiella
spp. producing extended-spectrum beta-lactamases by PCR with primers that targeted integrase genes and cassette regions. PCR and amplicon sequencing of the cassette regions revealed
aadB
and
aadA2
gene cassettes that confer resistance to a range of aminoglycosides.
aadB
was associated with a class 1 integron on a 28-kb plasmid, pES1, that also contained
bla
SHV-12
and IS
26
.
In Vitro Antileishmanial Activity of Nicotinamide
Authors: Sereno D. , Alegre A. Monte , Silvestre R. , Vergnes B. , Ouaissi A.
Published: January 2005

Our study represents the first report demonstrating the antileishmanial activity of nicotinamide (NAm), a form of vitamin B
3
. A 5 mM concentration of NAm significantly inhibited the intracellular growth of
Leishmania
amastigotes and the NAD-dependent deacetylase activity carried by parasites overexpressing
Leishmania major
SIR2 (LmSIR2). However, the transgenic parasites were as susceptible as the wild-type parasites to NAm-induced cell growth arrest. Therefore, we conclude that NAm inhibits leishmanial growth and that overexpression of LmSIR2 does not overcome this inhibition. The mechanism of the inhibition is not defined but may include other in vivo targets. NAm may thus represent a new antileishmanial agent which could potentially be used in combination with other drugs during therapy.
Antibiotic Resistance in Diarrheagenic
Escherichia coli
and
Shigella
Strains Isolated from Children in Hanoi, Vietnam
Authors: Nguyen Trung Vu , Le Phung Van , Le Chinh Huy , Weintraub Andrej
Published: January 2005

The MICs for 162 diarrheagenic
Escherichia coli
strains and 28
Shigella
strains were determined on the basis of NCCLS guidelines. More than 75% of the strains were resistant to ampicillin, chloramphenicol (53.6% of
Shigella
strains), and trimethoprim-sulfamethoxazole. Multiresistance was detected in 89.5% of
E. coli
strains and 78.6% of
Shigella
strains.