bluuebunny/crossref_metadata_2025 huggingface dataset:
Faith‐Based Social Service Organizations and Government Funding: Data from a National Survey*
Authors: Ebaugh Helen Rose , Saltzman Chafetz Janet , Pipes Paula F.
Published: April 2005

Objective. The objective of the research reported in this article is to test four hypotheses concerning government funding among faith‐based social service coalitions: that it is positively related to size and organizational professionalism; positively related to attitudes toward government funding; positively related to social activism; and negatively related to organizational religiosity.

Method. Our method is the application of OLS and probit analysis to data from a national survey of 656 such organizations.

Results. Using three measures of government funding and 12 predictor variables, results are mixed in their support of the size and professionalization hypothesis and generally support the remaining hypotheses. These findings are replicated when we compare coalitions that had and had not applied for government funding.

Conclusions. Our findings emphasize that greater religious expressiveness dissuades coalitions from both seeking and receiving government funding, but higher levels of social activism expedite both.
Welfare Reform and Teenage Girls*
Authors: Offner Paul
Published: April 2005

Objectives. Although the problems of teenage girls figured prominently in the passage of welfare reform legislation in 1996, there has been relatively little research on the effects of the new law on this population. This article attempts to fill this gap.

Methods. The article employs a difference‐in‐difference methodology to assess program impacts, making use of data from the March Current Population Survey for the years 1989–2001.

Results. The main findings are that the 1996 legislation increased school attendance among all teenage girls and reduced the rate of teenage childbearing.

Conclusion. These are important behavioral changes that should positively affect the program's long‐term success.
Private and Public Displays of Affection Among Interracial and Intra‐Racial Adolescent Couples*
Authors: Vaquera Elizabeth , Kao Grace
Published: April 2005

Objective. This article examines variation in displays of affection between interracial and intra‐racial adolescent couples.

Method. Using the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents in the United States, we estimate hierarchical linear models to compare characteristics of interracial and intra‐racial relationships among white, African‐American, Hispanic, Asian American, and Native American adolescents. In our comparisons we highlight three dimensions of relationship attributes: public display, private display, and intimate physical contact.

Results. Our findings suggest that interracial couples are less likely than intra‐racial couples to exhibit public and private displays of affection, but are not different from intra‐racial couples in intimate displays of affection.

Conclusions. Social barriers against interracial dating still exist such that even though interracial couples are similar to intra‐racial couples in their levels of intimacy in private, they are less comfortable displaying their feelings in public.
Visual experience during cataract surgery: a nation‐wide survey on the knowledge of optometry students*
Authors: Tan Colin S. H. , Tang Wilfred , Tan Say Beng , Eong Kah‐Guan Au
Published: April 2005

Purpose:  Many patients experience a variety of visual sensations during cataract surgery under local anaesthesia. Up to 16.2% of patients are frightened by their intraoperative visual experience. This study aimed to determine the knowledge and beliefs of optometry students on this subject.

Methods:  A nationwide survey using a standardised, self‐administered questionnaire was conducted on all optometry students in Singapore.

Results:  For cataract surgery under regional anaesthesia, 38.9% of the respondents believed that patients might experience no light perception while 68.5% felt that patients were likely to be able to perceive light. Overall, 70.4% felt that patients might be frightened by their visual experiences and 88.0% believed that preoperative counselling of patients would serve to reduce the fear experienced during the surgery. For cataract surgery under topical anaesthesia, 37.0% of the respondents believed that patients would perceive no light and 74.1% believed that patients would retain light perception. Overall, 67.6% believed that patients may be frightened and 86.1% felt that preoperative counselling would help.

Conclusion:  Many optometry students correctly believed that patients might experience a variety of visual sensations during cataract surgery under local anaesthesia. The majority were also aware that patients might be frightened by this and felt that preoperative counselling would be helpful.
In vivo corneal confocal microscopy in keratoconus
Authors: Hollingsworth Joanna G. , Efron Nathan , Tullo Andrew B.
Published: April 2005

Purpose:  To evaluate the corneas of keratoconic subjects using in vivo confocal microscopy.

Methods:  Slit scanning confocal microscopy was used to evaluate the central cornea of one eye of each of 29 keratoconic subjects (mean age 31 ± 10 years; range 16–49 years). Quantitative aspects of corneal morphology were compared against data from control subjects.

Results:  Compared with normal control corneas, epithelial wing cell nuclei were larger (p < 0.0001) and epithelial basal cell diameter was larger (p < 0.05) in the keratoconic cornea. Many of the keratoconic corneas investigated showed increased levels of stromal haze and reflectivity, which appeared to be related to the presence of apical scarring on slit lamp examination. A grading scale was devised to quantify the levels of haze. This scale was shown to provide a measure of the level of scarring present. The anterior keratocyte density (AKD) and posterior keratocyte density were 19% lower (p < 0.0001) and 10% lower (p = 0.004) than in controls, respectively. The reduction in AKD was significantly associated with three factors: a history of atopy, eye rubbing and the presence of corneal staining. The mean endothelial cell density in keratoconus was 6% greater than that of normal controls (p = 0.05). The level of endothelial polymegethism was shown not to be different between keratoconic subjects and matched controls (paired t‐test: t = 1.82, p = 0.08).

Conclusions:  Confocal microscopy demonstrates significant quantitative alterations of corneal morphology in keratoconus.
Microbiological analysis of chronic dacryocystitis
Authors: Sun Xuguang , Liang Qingfeng , Luo Shiyun , Wang Zhiqun , Li Ran , Jin Xiuying
Published: April 2005

Aims:  To investigate the microbiology of specimens from patients with chronic dacryocystitis.

Methods:  A total of 100 samples were obtained from the contents of the lacrimal duct in 91 consecutive patients with chronic dacryocystitis, including nine bilateral cases. These samples were cultured for aerobic and anaerobic bacteria and fungi with a routine microbiological technique. Positive cultured isolates were identified.

Results:  A total of 180 strains were isolated from the 85 bacterial samples, including 150 strains of aerobic bacteria and 30 strains of anaerobic bacteria. Fungi were found in eight samples and actinomyces in three samples. The bacterial species that were most frequently found were Staphylococcus species, representing 34.5% of all strains, followed by Corynebacterium diphtheroides (15.5%). The sensitivity tests revealed that levo‐ofloxacin and amikacin were the most effective antibiotics.

Conclusions:  Gram positive cocci was the predominant pathogen of chronic dacryocystitis. Levo‐ofloxacin and amikacin had the best effect in vitro.
TURBIDIMETRIC LIPID ASSAY IN SEED FLOURS
Authors: DROCHIOIU GABI
Published: April 2005

A simple, fast, sensitive and accurate turbidimetric assay of lipids in the milled seeds was developed. The procedure is based on the extraction of lipids into acetone followed by their turbidimetric reaction with a 1.5% solution of sulfosalicylic acid and turbidimetric measurements. The spectral measurement was made at 440 nm against a blank of the reagents. A standard curve was constructed using raw fat extracted from the species being analyzed. For analysis of a large number of solvents, the standardization of the turbidimetric method may be accomplished using Soxhlet values for a few representative samples. A negative relationship between the hardness of maize particles and their content of raw fat was observed.
COMPARISON OF SELECTED ADSORBENTS FOR ADSORPTION AND DESORPTION OF VITAMIN E FROM PALM FATTY ACID DISTILLATE
Authors: CHU B.S. , BAHARIN B.S. , CHE MAN Y.B. , QUEK S.Y.
Published: April 2005

Performance of four selected adsorbents, namely silica gel (SG), aluminum oxide (AO), synthetic brominated polyaromatic SP 207(SP) and functionalized polyaromatic Dowex Optipore L‐285 (DO), for adsorption/desorption of vitamin E from palm fatty acid distillate (PFAD) was compared. Vitamin E from PFAD was preconcentrated and dissolved in hexane. Batch mode adsorption experiments were carried out by reacting the vitamin E solution with the adsorbents separately in an orbital shaker under controlled conditions. It appeared that increasing initial vitamin E concentration favored adsorption process as indicated by an increase in adsorption capacity and percentage of vitamin E uptake. Results showed that the adsorption process was exothermic for all adsorbents. Isopropanol was used to recover vitamin E from the adsorbents. It was found that increasing reaction temperature resulted in a higher vitamin E recovery. SG was the most suitable adsorbent for separation of vitamin E as it possessed the highest adsorption capacity and recovery among adsorbents under experimental conditions employed.
ANTIOXIDANT POTENTIAL OF EEL (ANGUILLA JAPONICA AND CONGER MYRIASTER) FLESH AND SKIN
Authors: EKANAYAKE PRASHANI MUDIKA , PARK GEUN TAE , LEE YOUNG DON , KIM SE JAE , JEONG SANG CHUL , LEE JEHEE
Published: April 2005

The flesh and skin of Anguilla japonica and Conger myriaster were investigated for their antioxidant activity. Ethyl acetate and diethyl ether extracts (4 mg/mL) after extracting with methanol were tested for 2,2‐diphenyl‐1‐picrylhidrazyl (DPPH) free radical scavenging (FRS) activity for flesh and skin of each eel species. The values were compared with α‐tocopherol and butylated hydroxytoluene (BHT). Extracts showing positive results, when tested for DPPH FRS, were examined for dose effect, hydrogen peroxide (H2O2), hydroxyl radical and superoxide scavenging assays and heat stability. All extracts of A. japonica showed a dose‐dependent DPPH FRS and significant hydroxyl radical scavenging activities (>65%). The diethyl ether extract of the flesh of A. japonica showed the highest superoxide scavenging activity. Diethyl ether extracts of A. japonica were heat stable, and ethyl acetate extracts were stable up to 75C. Thus, it can be concluded that A. japonica is rich with heat stable and nonpolar antioxidants.
PALM OIL AND SUNFLOWER OIL: EFFECT OF BLEND COMPOSITION AND STIRRER TYPES DURING FRACTIONATION ON THE YIELD AND PHYSICOCHEMICAL PROPERTIES OF THE OLEINS
Authors: NOR AINI I. , HASMADI M. , MAMOT S. , RADZUAN J.
Published: April 2005

The effect of blend composition of refined, bleached and deodorized (RBD) palm oil and sunflower oil and that of different types of stirrers during fractionation on the yield and physicochemical characteristics of the oleins was investigated. Blends of 80% palm oil with 20% sunflower oil, and 60% palm oil with 40% sunflower oil were fractionated at 21C, and the oil samples were agitated with stirrers 1, 2, 3 and 4. The results showed that the highest yield was obtained with 60% palm oil and 40% sunflower oil blend when stirrer 2 was used to agitate the sample. There was a significant difference in iodine value (IV) of samples agitated with stirrers 3 and 4. The difference was not significant when stirrers 1 and 2 were used. Blending palm oil with sunflower oil followed by fractionation produced oleins of much higher IV than either commercially available regular palm olein or superolein. The major fatty acids in the oleins obtained after fractionating blend of 80% palm oil and 20% sunflower oil were palmitic (31.8–33.2%), oleic (38.1–39.3%) and linoleic (21.6–24.1%) acids. With higher amount of sunflower oil of 40% in the oil blend, the amount of palmitic acid significantly decreased (25.1–26.3%). After fractionation, the blend containing 60% palm oil and 40% sunflower oil produced liquid fractions which were lower in dipalmitoyl‐oleoyl‐glycerol (POP), palmitoyl‐oleoyl‐stearoyl‐glycerol (POS), palmitoyl‐dioleoyl‐glycerol (POO) and dipalmitoyl‐linoleoyl‐glycerol (PLP) compared to the blend containing 80% palm oil and 20% sunflower oil. The blend with a higher level of sunflower oil at 40% produced oleins of much lower cloud point (3.5–3.7C) than the blend containing only 20% sunflower oil. The type of stirrer did not have any significant effect on the cloud point.
STRUCTURED TRIACYLGLYCEROLS CONTAINING BEHENIC ACID: PREPARATION AND PROPERTIES
Authors: TYNEK MARIA , LEDÓCHOWSKA ELEONORA
Published: April 2005

Low‐calorie structured lipids (SL) containing behenic and oleic acids were prepared using interesterification of olive oil with hydrogenated high erucic acid rapeseed oil and acidolysis of olive oil with behenic acid. The reactions were catalyzed by the Lipozyme RM IM enzyme. Triacylglycerols (TAGs), obtained by interesterification (TAG

SLHE

), contained 20.9 and 45.3% of behenic and oleic acids, respectively, whereas those obtained by acidolysis (TAG

SLB

) contained 34.6 and 49.6% of these acids, respectively. In both cases, behenic acid was mainly incorporated in the sn‐1,3 positions of the TAG molecules (∼93%). The distribution of oleic acid in the individual positions was different for each product. The content of oleic acid in the sn‐2 position of TAG was 50.2 and 80.3% for TAGSLHEand TAGSLB, respectively. The melting temperature of TAGSLHE(45.5%) was higher than that of TAGSLB(37.5%). Because of the suitable solid fat content characteristics of TAGSLBas a function of temperature, it is possible to use TAGSLBin bakery and in confectionery industries for production of margarines and blends, among others.
REDUCTION IN MICROBIAL GROWTH AND IMPROVEMENT OF STORAGE QUALITY IN FRESH‐CUT PINEAPPLE AFTER METHYL JASMONATE TREATMENT
Authors: MARTÍNEZ‐FERRER MAGALY , HARPER CAROL
Published: April 2005

Maintaining the quality of a fresh‐cut fruit or vegetable product is a major concern and a priority in the development and in the production of fresh‐cut produce products of the industry. The industry has been searching for alternative methods to protect fresh‐cut produce from decay and to prolong shelf life. The objective of this research is to enhance the quality and the shelf life of fresh‐cut pineapple by exposure to methyl jasmonate (MJ). The exposure of the diced pineapple to a MJ emulsion at a concentration of 10

−4
 M for 5 min in a sealed container decreased microbiological growth by 3 logs after 12 days of storage at 7C, compared with the control pineapple. Methyl jasmonate as vapor or as dip did not affect the firmness or the color of the fruit. Methyl jasmonate may be a practical treatment to ensure the safety and the quality of fresh‐cut pineapple and other fruits and vegetables.
PHYSICAL AND SENSORY CHARACTERISTICS OF LOW‐FAT ITALIAN SAUSAGE PREPARED WITH HYDRATED OAT
Authors: KERR W.L. , WANG X. , CHOI S.G.
Published: April 2005

Low‐fat Italian sausage was prepared with hydrated oat flakes at 10, 20 and 30% (w/w), and precook times of 0, 2 and 4 min. Cook loss and expressible moisture, cutting force and texture profile analysis, color and consumer sensory analysis were analyzed by response‐surface methodology. Minimum cook loss occurred at 16.3% of the hydrated oat and 0.76 min precook time, while expressible moisture decreased with increasing oat levels and decreasing precook time. In general, both cutting force and hardness decreased with hydrated oat level. Measurements of L*, a* and b* showed a slightly lighter product and a shift to more red and yellow cooked product at intermediate oat levels and precook times. For sensory attributes, both oat level and precook time were significant. Greatest flavor and texture likeability were attained with hydrated oat levels of 3–12%, and precook times of 1.5–3 min. Greatest overall likeability occurred over a region of 0–14% hydrated oat, and 1.1–3.3 min precook time.
INFLUENCE OF CELL SIZE AND CELL WALL VOLUME FRACTION ON FAILURE PROPERTIES OF POTATO AND CARROT TISSUE
Authors: ZDUNEK ARTUR , UMEDA MIKIO
Published: April 2005

This article presents the influence of cell size and cell wall volume fraction on the failure parameters of potato tuber and carrot tissue. Confocal scanning laser microscope was used for obtaining images of the cell structure of the tissues. The mean cell face area and the cell wall volume fraction obtained from the images was compared with work to failure, failure stress, failure strain and secant modulus obtained in a compression test of potato and carrot tissue at two strain rates. Bigger cells and less amount of cell wall material weakened the tissue, which was visible as a linear decrease in the parameters: work to failure, failure stress and failure strain. There were differences between potato and carrot in the secant modulus. For carrot, the secant modulus changed with microstructural parameters, whereas for potato, the secant modulus did not depend on these values. The strain rate decreases all the failure properties for potato. For carrot, only the work to failure was affected by the strain rate.
DEVELOPMENT OF DYNAMIC MODULUS AND CELL OPENING OF DOUGH DURING BAKING
Authors: SINGH AJAY PAL , BHATTACHARYA MRINAL
Published: April 2005

The dynamic shear modulus (elastic and viscous modulus) development of dough during baking was studied. Flooded parallel plate geometry was used to monitor the rheological changes of commercially available canned doughs (bread dough, bun dough and biscuit dough). The normal force exerted on the upper plate by the expanding dough was measured to study the cell‐opening event. The dough‐baking process was simulated in a rheometer oven. The morphology of baked dough was studied using a scanning electron microscope to elucidate the effect of ingredients and process parameters on the properties of the final baked product. Three stages of modulus development were observed during the baking process: bubble growth and packing, rapid expansion/starch gelatinization and final curing. The cell opening coincided with the sudden rise in modulus caused by starch gelatinization. The rate at which starch gelatinization takes place controls the temperature of the cell opening. The type and concentration of various ingredients have a greater effect on the modulus and on the cell opening than the heating rates. Frequency dependence was observed during baking, but the effect on modulus development diminished at higher frequencies.
On a Novel Tool Life Relation for Precision Cutting Tools
Authors: Mamalis A. G. , Kundra´k J. , Horva´th M.
Published: April 2005

When using new, very expensive superhard tool materials (diamond or CBN) for precision and ultraprecision machining of parts made, very often, from expensive materials, exact knowledge of the tool wear process (considering, of-course, its stochastic character) is absolutely necessary. It means, that we need new tool-life equations for these new tools. In the present paper, a new tool life relation is proposed based on machining experiments. It reflects the two-extremum form of tool life curves and is valid for a wide range of cutting conditions.
Topology of Spade Drills for Wood Drilling Operations Part 2: Spade Drill Point Cutting Geometry Analysis
Authors: Zhao Hanxin , Ehmann Kornel F.
Published: April 2005

Based on the spade drill point’s mathematical models established in Part 1 of this paper, a detailed methodology for the analysis of the cutting edges and angle distributions along these edges is given. The analysis addresses the most important geometric elements of the bit including the tip, major cutting edge, and the chisel edge profiles, as well as the rake and clearance angle distribution along these cutting edges. In unison, the geometric model of the spade bit and the analysis procedure described in this part of the paper have laid the foundation for a methodology and a software package for a detailed geometric analysis of all relevant cutting mechanics related geometric entities of the drill. This, in turn, constitutes the first prerequisite for assessing the cutting performance of these tools.
Modeling of Cutting Forces Under Hard Turning Conditions Considering Tool Wear Effect
Authors: Huang Yong , Liang Steven Y.
Published: April 2005

Quantitative understanding of cutting forces under hard turning conditions is important for thermal modeling, tool life estimation, chatter prediction, and tool condition monitoring purposes. Although significant research has been documented on the modeling of forces in the turning operation in general, turning of hardened materials involves several distinctive process conditions, including negative tool rake angle, large tool nose radius, and rapid tool wear. These process conditions warrant specific treatment in the analysis of cutting forces. This paper first addresses these issues by formulating an oblique chip formation force model through the extension of a two-dimensional (2D) mechanistic force model while considering the effect of tool geometry complexities. The coefficients of the mechanistic force model are estimated by applying a genetic algorithm in overcoming the lack of explicit normal equations. Then the forces occurring due to flank wear are modeled by extending a 2D worn tool force modeling approach into a three-dimensional analysis to accommodate the effect of low feed rate, small depth of cut, and relatively large tool nose radius in hard turning. The total cutting forces are the linear summation of forces due to chip formation and forces due to flank wear. The model-predicted forces match well with experimental results in the turning of hardened 52100 bearing steel under practical cutting conditions (low feed rate, small depth of cut, and gentle cutting speed) using cubic boron nitride (CBN) tools under the progressive tool flank wear conditions.
New Insight Into the Flow Around a Wind Turbine Airfoil Section1
Authors: Bertagnolio F. , Sørensen N. N. , Rasmussen F.
Published: April 2005

The objective of this paper is an improved understanding of the physics of the aeroelastic motion of wind turbine blades in order to improve the numerical models used for their design. Two- and three-dimensional Navier–Stokes calculations of the flow around a wind turbine airfoil using the k−ω SST and Detached Eddy Simulation (DES) turbulence models, as well as an engineering semiempirical dynamic stall model, are conducted. The computational results are compared to the experimental results that are available for both the static airfoil and the pitching airfoil. It is shown that the Navier–Stokes simulations can reproduce the main characteristic features of the flow. The DES model seems to be able to reproduce most of the details of the unsteady aerodynamics. Aerodynamic work computations indicate that a plunging motion of the airfoil can become unstable.
Analysis of the Cutting Force Components and Friction in High Speed Machining
Authors: Sutter G. , Molinari A.
Published: April 2005

An original experimental device is used to reproduce conditions of orthogonal cutting for a wide range of cutting speeds (from 15 to about 100 m/s) (Sutter et al.). Improvement of the initial device (Sutter et al.) makes it possible to record both values of normal and tangential forces in orthogonal cutting. An analysis of the tool–chip friction is then possible for a large range of cutting speeds. The evolution of cutting force components as well as the evolution of the friction coefficient are presented and analyzed. In addition, the process of chip formation during high speed machining is illustrated by photographic recording with a high speed camera.
Frequency Shift in Drilling due to Margin Engagement
Authors: Dilley D. N. , Stephenson D. A. , Bayly P. V. , Schaut A. J.
Published: April 2005

Drill chatter degrades hole roundness, hole size, and tool life. This wastes time and money in tools, scrap, and hole rework. Chatter prediction in milling and turning has shown significant benefit to industry; however, researchers have been unable to accurately predict chatter in drilling applications. In the past, the drill, including the chisel edge, was modeled as either a fixed-fixed or fixed-pinned beam (Tekinalp, O., and Ulsoy, A. G., 1989, “Modeling and Finite Element Analysis of Drill Bit Vibrations,” ASME J. Eng. Indust. 111, pp. 148–154), but more recent research (Dilley, D. N., Bayly, P. V., and Schaut, A. J., 2005, “Effects of the Chisel Edge on the Chatter Frequency in Drilling,” J. Sound Vib., 281, pp. 423–428) has shown that a fixed-embedded model using springs improves frequency matching. The effects of the drill margins on dynamics have not been studied. The fixed-fixed or fixed-pinned model will be shown to be inappropriate for modeling the effects of margin engagement, while the spring-end boundary condition can better approximate the frequency increase observed experimentally as the drill margins engage deeper into the hole. In addition, the shifted frequency is well below the frequency found from an analytical fixed-fixed or fixed-pinned beam. Evidence that the margins cause the frequency shift is seen in three-dimensional waterfall plots that show this shift for pilot hole drilling (in which the margins are engaged), but not for tube drilling (in which margins are not engaged).
A Finite Element Analysis For Stiffness of Fixture Units
Authors: Zheng, Y. , Rong, and Y. , Hou Z.
Published: April 2005

This paper presents a systematic finite element model to predict the fixture unit stiffness by introducing nonlinear contact elements on the contact surface between fixture components. The contact element includes three independent springs: two in tangential directions and one in the normal direction of the contact surface. Strong nonlinearity is caused by possible separation and sliding between two fixture components. The problem is formulated by the penalty function method and is solved by the Newton-Raphson procedure. The model was validated by two cases of analysis of a linear cantilever beam and a simple fixture unit with two components. The results are in agreement with the corresponding analytical solution of beams and the previous experimental results for fixture in the literature.
Should We Use
N
-Acetyltransferase Type 2 Genotyping To Personalize Isoniazid Doses?
Authors: Kinzig-Schippers Martina , Tomalik-Scharte Dorota , Jetter Alexander , Scheidel Bernhard , Jakob Verena , Rodamer Michael , Cascorbi Ingolf , Doroshyenko Oxana , Sörgel Fritz , Fuhr Uwe
Published: April 2005

Isoniazid is metabolized by the genetically polymorphic arylamine
N
-acetyltransferase type 2 (NAT2). A greater number of high-activity alleles are related to increased acetylation capacity and in some reports to low efficacy and toxicity of isoniazid. The objective of this study was to assess individual isoniazid exposure based on NAT2 genotype to predict a personalized therapeutic dose. Isoniazid was administered to 18 healthy Caucasians (age 30 ± 6 years, body weight 74 ± 10 kg, five women) in random order as a 200-mg infusion, a 100-mg oral, and a 300-mg oral single dose. For the assessment of NAT2 genotype, common single nucleotide polymorphisms identifying 99.9% of variant alleles were characterized. Noncompartmental pharmacokinetics and compartmental population pharmacokinetics were estimated from isoniazid plasma concentrations until 24 h postdose by high-pressure liquid chromatography. The influence of NAT2 genotype, drug formulation, body weight, and sex on dose-normalized isoniazid pharmacokinetics was assessed by analysis of variance from noncompartmental data and confirmed by population pharmacokinetics. Eight high-activity NAT2*4 alleles were identified. Sex had no effect; the other factors explained 93% of the variability in apparent isoniazid clearance (analysis of variance). NAT2 genotype alone accounted for 88% of variability. Individual isoniazid clearance could be predicted as clearance (liters/hour) = 10 + 9 × (number of NAT2*4 alleles). To achieve similar isoniazid exposure, current standard doses presumably appropriate for patients with one high-activity NAT2 allele may be decreased or increased by approximately 50% for patients with no or two such alleles, respectively. Prospective clinical trials are required to assess the merits of this approach.
Inhibitory Effect of Aureobasidin A on
Toxoplasma gondii
Authors: Sonda Sabrina , Sala Giusy , Ghidoni Riccardo , Hemphill Andrew , Pieters Jean
Published: April 2005

The apicomplexan parasite
Toxoplasma gondii
is a leading opportunistic pathogen associated with AIDS and congenital birth defects. Due to the need for identifying new parasite-specific treatments, the possibility of targeting sphingolipid biosynthesis in the parasite was investigated. Aureobasidin A, an inhibitor of the enzyme synthesizing the sphingolipid inositol phosphorylceramide, which is present in fungi, plants, and some protozoa but absent in mammalian cells, was found to block in vitro
T. gondii
replication without affecting host cell metabolism. Aureobasidin A treatment did not induce tachyzoite to bradyzoite stage conversion in
T. gondii
but resulted in a loss of intracellular structures and vacuolization within the parasite. In addition, aureobasidin A inhibited sphingolipid synthesis in
T. gondii
. Sphingolipid biosynthetic pathways may therefore be considered targets for the development of anti-
T. gondii
agents.
Incidence of Class 1 Integrons in a Quaternary Ammonium Compound-Polluted Environment
Authors: Gaze W. H. , Abdouslam N. , Hawkey P. M. , Wellington E. M. H.
Published: April 2005

Samples of effluent and soil were collected from a reed bed system used to remediate liquid waste from a wool finishing mill with a high use of quaternary ammonium compounds (QACs) and were compared with samples of agricultural soils. Resistance quotients of aerobic gram-negative and gram-positive bacteria to ditallowdimethylammomium chloride (DTDMAC) and cetyltrimethylammonium bromide (CTAB) were established by plating onto nutrient agar containing 5 μg/ml or 50 μg/ml DTDMAC or CTAB. Approximately 500 isolates were obtained and screened for the presence of theintI1(class 1 integrase),qacE(multidrug efflux), andqacEΔ1(attenuatedqacE) genes. QAC resistance was higher in isolates from reed bed samples, and class 1 integron incidence was significantly higher for populations that were preexposed to QACs. This is the first study to demonstrate that QAC selection in the natural environment has the potential to coselect for antibiotic resistance, as class 1 integrons are well-established vectors for cassette genes encoding antibiotic resistance.
Phase 1 Safety and Pharmacokinetic Study of Chimeric Murine-Human Monoclonal Antibody cαStx2 Administered Intravenously to Healthy Adult Volunteers
Authors: Dowling Thomas C. , Chavaillaz Pierre A. , Young David G. , Melton-Celsa Angela , O'Brien Alison , Thuning-Roberson Claire , Edelman Robert , Tacket Carol O.
Published: April 2005

Hemolytic-uremic syndrome (HUS) is a serious complication of infection by Shiga toxin-producing
Escherichia coli
. Shiga toxin type 2 (Stx2) is responsible for the renal toxicity that can follow intestinal infection and hemorrhagic colitis due to
E. coli
. A chimeric mouse-human antibody, designated cαStx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, cαStx2 was generally well tolerated. Pharmacokinetic studies indicated that clearance was stable over the dose range of 1.0 to 10 mg/kg of body weight (0.249 ± 0.023 ml/kg/h) but was higher for the 0.1-mg/kg dose (0.540 ± 0.078 ml/kg/h), suggesting saturable elimination. A similar nonlinear trend was observed for the volume of distribution, where average values ranged from 0.064 ± 0.015 liter/kg for the 1.0- to 10-mg/kg doses and 0.043 ± 0.005 for the 0.01-mg/kg dose. The relatively small volume of distribution suggests that the antibody is limited to the vascular (plasma) compartment. The mean half-life was 165 ± 66 h, with lowest values observed for the 0.1-mg/kg dose (56.2 ± 9.7 h) and the highest values reported for the 10.0-mg/kg dose (206.4 ± 12.4 h). Future studies are needed to confirm the safety of this cαStx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.
Clinical Pharmacokinetics of Alamifovir and Its Metabolites
Authors: Chan Clark , Abu-Raddad Eyas , Golor Georg , Watanabe Hikari , Sasaki Akira , Yeo Kwee Poo , Soon Danny , Sinha Vikram P. , Flanagan Shawn D. , He Minxia M. , Wise Stephen D.
Published: April 2005

Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclincal efficacy activity against wild-type and lamivudine-resistant hepatitis B virus. Two studies were conducted to examine the single- and multiple-dose alamifovir pharmacokinetics after oral administration in healthy males. In study 1, subjects were given single doses (0.2 to 80 mg), with a subset receiving 20 mg in a fed state. Study 2 subjects were dosed with 2.5 to 15 mg twice daily for 15 days. Plasma samples were collected over 72 h in study 1 and over 24 h on days 1 and 15 in study 2. Concentrations of alamifovir and its major metabolites were determined using liquid chromatography/tandem mass spectrometry methods. The data were analyzed using a noncompartmental technique. Although alamifovir was rapidly absorbed, there was limited systemic exposure due to its rapid hydrolysis and formation of at least three metabolites, suggesting that alamifovir acts as a prodrug. The major metabolites detected were 602074 and 602076, with 602075 detectable only in higher-dose groups. Maximum 602074 plasma concentration was achieved at approximately 0.5 h (
T
max
) and declined with a 1- to 2-h terminal half-life (
t
1/2
). Maximum concentrations of 602076 (
C
max
) averaged 10% of the 602074
C
max
and reached
T
max
in 2.5 h with a 4-h
t
1/2
. Food appeared to decrease the extent of absorption of the compound. Multiple dosing resulted in minimal accumulation, and the concentrations following multiple doses could be predicted using the single-dose data. Alamifovir was well tolerated and the pharmacokinetics were characterized in these studies.
Imidazole Antibiotics Inhibit the Nitric Oxide Dioxygenase Function of Microbial Flavohemoglobin
Authors: Helmick Ryan A. , Fletcher Arin E. , Gardner Anne M. , Gessner Christopher R. , Hvitved Angela N. , Gustin Michael C. , Gardner Paul R.
Published: April 2005

Flavohemoglobins metabolize nitric oxide (NO) to nitrate and protect bacteria and fungi from NO-mediated damage, growth inhibition, and killing by NO-releasing immune cells. Antimicrobial imidazoles were tested for their ability to coordinate flavohemoglobin and inhibit its NO dioxygenase (NOD) function. Miconazole, econazole, clotrimazole, and ketoconazole inhibited the NOD activity of
Escherichia coli
flavohemoglobin with apparent

K
i

values of 80, 550, 1,300, and 5,000 nM, respectively.
Saccharomyces cerevisiae
,
Candida albicans
, and
Alcaligenes eutrophus
enzymes exhibited similar sensitivities to imidazoles. Imidazoles coordinated the heme iron atom, impaired ferric heme reduction, produced uncompetitive inhibition with respect to O
2
and NO, and inhibited NO metabolism by yeasts and bacteria. Nevertheless, these imidazoles were not sufficiently selective to fully mimic the NO-dependent growth stasis seen with NOD-deficient mutants. The results demonstrate a mechanism for NOD inhibition by imidazoles and suggest a target for imidazole engineering.
Multidrug Resistance in
Staphylococcus aureus
Due to Overexpression of a Novel Multidrug and Toxin Extrusion (MATE) Transport Protein
Authors: Kaatz Glenn W. , McAleese Fionnuala , Seo Susan M.
Published: April 2005

Efflux is an important mechanism of multidrug resistance (MDR) in bacteria. The multidrug and toxin extrusion (MATE) family is the most recently described group of MDR efflux proteins, none of which have previously been identified in
Staphylococcus aureus
. Two independently derived
S. aureus
mutants having efflux-related MDR phenotypes were studied using microarray technology and a marked overexpression of an open reading frame (ORF;
mepA
) encoding a protein homologous with MATE family proteins was observed in both. There was concomitant overexpression of ORFs in close proximity to
mepA
(∼100 bp) encoding a MarR-type regulator (
mepR
, upstream of
mepA
) and a protein of unknown function (
mepB
, downstream). Experiments in which
mepA
was overexpressed or disrupted revealed that the encoded protein has a broad substrate profile that includes several monovalent and divalent biocides and the fluoroquinolone antimicrobial agents norfloxacin and ciprofloxacin. The function of MepB is obscure, it does not contribute to the MDR phenotype conferred by MepA. MepR overexpression reversed the MDR phenotypes of both mutants by repressing
mepA
transcription. All three ORFs are preferentially transcribed as a single
mepRAB
unit, suggesting that the three genes form an operon.
Plasmid-Encoded Tet B Tetracycline Resistance in
Haemophilus parasuis
Authors: Lancashire John F. , Terry Tamsin D. , Blackall P. J. , Jennings Michael P.
Published: April 2005

The complete sequence of two plasmids, pHS-Tet (5.1 kb) and pHS-Rec (9.5 kb), isolated from
Haemophilus parasuis
strain HS1543 has been obtained. Plasmid pHS-Tet contains four open reading frames including a
tet
(B) tetracycline resistance gene which unusually did not have an associated
tetR
repressor gene. From a total of 45
H. parasuis
isolates surveyed (15 international reference strains, 15 field isolates selected for their genetic diversity, and 15 recent Australian field isolates), 2 tetracycline-resistant field isolates (HS226 and HS1859) were identified. Analysis of three additional isolates from the same disease outbreak as strain HS1859 revealed a further tetracycline-resistant
H. parasuis
strain (HS1857, serovar 8) and a tetracycline-resistant
Actinobacillus pleuropneumoniae
strain (HS1861). An approximately 10.6-kb plasmid was identified in field isolate HS226 and outbreak strains HS1857, HS1859, and HS1861. Southern hybridization analysis of these plasmids showed that the Tet B determinant was present, and restriction digest comparisons suggest that these plasmids are related. This is believed to be the first report of native
H. parasuis
plasmids and Tet B-mediated tetracycline resistance in this microorganism.
Antipneumococcal Activity of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin
Authors: Kosowska Klaudia , Hoellman Dianne B. , Lin Gengrong , Clark Catherine , Credito Kim , McGhee Pamela , Dewasse Bonifacio , Bozdogan Bülent , Shapiro Stuart , Appelbaum Peter C.
Published: April 2005

Ceftobiprole
(previously known as BAL9141), an
anti-methicillin-resistant
Staphylococcus aureus
cephalosporin, was very highly active against a panel of 299
drug-susceptible and -resistant pneumococci, with MIC
50
and
MIC
90
values (μg/ml) of 0.016 and 0.016 (penicillin
susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0
(penicillin resistant). Ceftobiprole, imipenem, and
ertapenem had lower MICs against all pneumococcal
strains than amoxicillin, cefepime, ceftriaxone, cefotaxime,
cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally
varied in parallel, whereas fluoroquinolone MICs did not correlate with
penicillin or macrolide susceptibility or resistance.
All strains were susceptible to linezolid, quinupristin-dalfopristin,
daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that
at 1× and 2× the MIC, ceftobiprole was bactericidal
against 10/12 and 11/12 strains, respectively. Levofloxacin,
moxifloxacin, vancomycin, and teicoplanin were each bactericidal
against 10 to 12 strains at 2× the MIC. Azithromycin and
clarithromycin were slowly bactericidal, and telithromycin was
bactericidal against only 5/12 strains at 2× the MIC. Linezolid
was mainly bacteriostatic, whereas quinupristin-dalfopristin and
daptomycin showed marked killing at early time periods. Prolonged
serial passage in the presence of subinhibitory concentrations of
ceftobiprole failed to yield mutants with high MICs towards this
cephalosporin, and single-passage selection showed very low frequencies
of spontaneous mutants with breakthrough MICs towards
ceftobiprole.
Geographical and Ecological Analysis of Resistance, Coresistance, and Coupled Resistance to Antimicrobials in Respiratory Pathogenic Bacteria in Spain
Authors: Pérez-Trallero Emilio , García-de-la-Fuente Celia , García-Rey César , Baquero Fernando , Aguilar Lorenzo , Dal-Ré Rafael , García-de-Lomas Juan
Published: April 2005

A multicenter susceptibility surveillance (the S.A.U.C.E. project) including 2,721
Streptococcus pneumoniae
, 3,174
Streptococcus pyogenes
, and 2,645
Haemophilus influenzae
consecutive isolates was carried out in 25 hospitals all over Spain from November 2001 to October 2002 to evaluate the current epidemiology of resistance of the main bacteria involved in community-acquired respiratory tract infections. Susceptibility testing was performed in a single centralized laboratory by a broth microdilution method. The prevalence of resistant
S. pneumoniae
strains was 0.4% for cefotaxime, 4.4% for amoxicillin and amoxicillin-clavulanic acid, 25.6% for cefuroxime-axetil, 34.5% for erythromycin, clarithromycin, and azithromycin, and 36.0% for cefaclor. Phenotypes of resistance to erythromycin were MLS
B
(macrolide-lincosamide-streptogramin B) in 89.9% (gene
ermB
) and M (macrolide) in 9.7% of cases (gene
mefA
). No strain harbored both genes simultaneously. Serotypes 19, 6, 23, 14, and 3 were the most prevalent, accounting for 54.6% of the total isolates. Resistance to macrolides seems to be the most alarming point, since among penicillin-susceptible isolates it reached 15.1% compared to 55.8% among penicillin-resistant strains. Geographically, a number of regions had rates of erythromycin resistance above 40% (even higher in children). Resistance to erythromycin was also high in
S. pyogenes
isolates: mean regional 33.2%, beta-lactamase-producing
H. influenzae
were 20%, whereas 4.4% had a beta-lactamase-negative, ampicillin-resistant phenotype. We highlight the importance of different geographical frequencies of coresistance (associations of resistance to different drugs within the same species) and coupled resistance (association of resistance between different species) probably resulting from different local coselective events.
Mechanism of Anti-Human Immunodeficiency Virus Activity of β-
d
-6-Cyclopropylamino-2′,3′-Didehydro-2′,3′-Dideoxyguanosine
Authors: Ray Adrian S. , Hernandez-Santiago Brenda I. , Mathew Judy S. , Murakami Eisuke , Bozeman Carey , Xie Meng-Yu , Dutschman Ginger E. , Gullen Elizabeth , Yang Zhenjun , Hurwitz Selwyn , Cheng Yung-Chi , Chu Chung K. , McClure Harold , Schinazi Raymond F. , Anderson Karen S.
Published: April 2005

To better understand the importance of the oxygen in the ribose ring of planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2′,3′-didehydro-2′,3′-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1 ± 0.1 μM while showing 50% inhibition of cell viability at 84.5 μM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-associated mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metabolism and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2′-deoxycoformycin, implying that the antiviral activity is due to its metabolism to the 2′-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chemical and potentially enzymatic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2′,3′-dideoxycytidine and 2′,3′-didehydro-3′-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability observed in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.
Inhibitory Effect of 2′-Substituted Nucleosides on Hepatitis C Virus Replication Correlates with Metabolic Properties in Replicon Cells
Authors: Tomassini Joanne E. , Getty Krista , Stahlhut Mark W. , Shim Sung , Bhat Balkrishen , Eldrup Anne B. , Prakash Thazha P. , Carroll Steven S. , Flores Osvaldo , MacCoss Malcolm , McMasters Daniel R. , Migliaccio Giovanni , Olsen David B.
Published: April 2005

Nucleosides have been widely used in the treatment of viral diseases, but relatively few have been identified as inhibitors of hepatitis C virus (HCV). The modified ribonucleosides, 2′-
C
-methyl-adenosine and 2′-
O
-methyl-cytidine, are potent inhibitors of HCV replication which specifically target the NS5B polymerase. Herein, a more extensive characterization of the effect of these compounds upon HCV replication in subgenomic replicons is reported. A highly selective antireplicative effect induced by the nucleosides in replicon-containing cell lines was maintained during an exponential growth period with potencies which paralleled the reduction of both positive- and negative-strand RNA replication. Moreover, the inhibitory effect closely correlated with the intrinsic metabolic properties of differing replicon clonal lines. Interestingly, while 2′-
C
-methyl-adenosine elicited similar inhibitory potencies in different cell lines, 2′-
O
-methyl-cytidine was found to be inactive in one replicon cell line tested, although the corresponding triphosphates comparably inhibited the in vitro activity of replication complexes isolated from these cells and the activity of NS5B polymerase using synthetic templates. The lack of antireplicative effect, attributed to poor intracellular conversion of the 2′-
O
-methyl-cytidine nucleoside to the active 5′-triphosphate, was reversed using a monophosphate prodrug. Thus, although replicon cells are useful for evaluating the effect of inhibitors upon HCV replication, these findings have important implications for their use in the identification and characterization of nucleosides and other chemotherapeutic agents requiring cellular metabolism.