bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral energy distributions and high-energy emission of BL Lac type objects
Authors: Troitsky Sergey
Published: June 2008

Based on identifications from the Véron and Quasars.org catalogues, we determine the optical-to-X-ray spectral indices for a sample of 201 BL Lac type objects (BLLs) and search for trends in the distribution of these indices of the sources detected in high-energy bands. We find that EGRET-detected sources are low-energy peaked and that the positional correlation with the arrival directions of ultrahigh-energy cosmic rays from the previously studied Akeno Giant Air-Shower Array, Yakutsk and High-Resolution Fly's Eye samples is dominated by low-energy-peaked BLLs.
Estimating Trends with Percentage of Smoothness Chosen by the User
Authors: Guerrero Victor M.
Published: June 2008

This work presents a method for estimating trends of economic time series that allows the user to fix at the outset the desired percentage of smoothness for the trend. The calculations are based on the Hodrick‐Prescott (HP) filter usually employed in business cycle analysis. The situation considered here is not related to that kind of analysis, but with describing the dynamic behaviour of the series by way of a smooth curve. To apply the filter, the user has to specify a smoothing constant that determines the dynamic behaviour of the trend. A new method that formalizes the concept of trend smoothness is proposed here to choose that constant. Smoothness of the trend is measured in percentage terms with the aid of an index related to the underlying statistical model of the HP filter. Empirical illustrations are provided using data on Mexico's GDP.
Homicide Arrest Clearances: A Review of the Literature
Authors: Riedel Marc
Published: June 2008

This is a review of the research literature on homicide arrest clearances or homicides for which no offender is arrested. The article describes the decline in the percent of homicides resulting in arrests and charges from over 90 pecent in 1960 to 61 percent in 2006. Research is reviewed on the reasons for the lack of public attention and concern and the low homicide clearance rates in the USA in comparison with other countries. Research on the extent to which homicides are uncleared because they involve low‐status persons and those economically disadvantaged is compared with research suggesting that it is the characteristics of the homicide event that make clearance difficult. It seems that such factors as age, gender, and race/ethnicity play a role in whether the homicide is cleared by arrest. Characteristics of homicides that increase clearances include occurrence in private residences, domestic homicides, and homicide with weapons other than firearms. Research on what police can do to increase clearances is examined. Suggestions on how to increase access to information on how homicide investigations are carried out are also discussed.
Streambank Soil and Phosphorus Losses Under Different Riparian Land‐Uses in Iowa1
Authors: Zaimes George N. , Schultz Richard C. , Isenhart Thomas M.
Published: June 2008

Abstract:  Phosphorus and sediment are major nonpoint source pollutants that degrade water quality. Streambank erosion can contribute a significant percentage of the phosphorus and sediment load in streams. Riparian land‐uses can heavily influence streambank erosion. The objective of this study was to compare streambank erosion along reaches of row‐cropped fields, continuous, rotational and intensive rotational grazed pastures, pastures where cattle were fenced out of the stream, grass filters and riparian forest buffers, in three physiographic regions of Iowa. Streambank erosion was measured by surveying the extent of severely eroding banks within each riparian land‐use reach and randomly establishing pin plots on subsets of those eroding banks. Based on these measurements, streambank erosion rate, erosion activity, maximum pin plot erosion rate, percentage of streambank length with severely eroding banks, and soil and phosphorus losses per unit length of stream reach were compared among the riparian land‐uses. Riparian forest buffers had the lowest streambank erosion rate (15‐46 mm/year) and contributed the least soil (5‐18 tonne/km/year) and phosphorus (2‐6 kg/km/year) to stream channels. Riparian forest buffers were followed by grass filters (erosion rates 41‐106 mm/year, soil losses 22‐47 tonne/km/year, phosphorus losses 9‐14 kg/km/year) and pastures where cattle were fenced out of the stream (erosion rates 22‐58 mm/year, soil losses 6‐61 tonne/km/year, phosphorus losses 3‐34 kg/km/year). The streambank erosion rates for the continuous, rotational, and intensive rotational pastures were 101‐171, 104‐122, and 94‐170 mm/year, respectively. The soil losses for the continuous, rotational, and intensive rotational pastures were 197‐264, 94‐266, and 124‐153 tonne/km/year, respectively, while the phosphorus losses were 71‐123, 37‐122, and 66 kg/km/year, respectively. The only significant differences for these pasture practices were found among the percentage of severely eroding bank lengths with intensive rotational grazed pastures having the least compared to the continuous and rotational grazed pastures. Row‐cropped fields had the highest streambank erosion rates (239 mm/year) and soil losses (304 tonne/km/year) and very high phosphorus losses (108 kg/km/year).
Hydrology of Clay Settling Areas and Surrounding Landscapes in the Phosphate Mining District, Peninsular Florida1
Authors: Murphy Kathryn E. , Rains Mark C. , Kittridge Michael G. , Stewart Mark T. , Ross Mark A.
Published: June 2008

Abstract:  The objective of this study was to use applied and naturally occurring geochemical tracers to study the hydrology of clay settling areas (CSAs) and the hydrological connectivity between CSAs and surrounding hydrological landscapes. The study site is located on the Fort Meade Mine in Polk County, Florida. The CSA has a well‐developed, subangular‐blocky, clay‐rich surface layer with abundant desiccation cracks and other macropores, and a massive, clay‐rich sublayer that is saturated below ∼1.0‐2.5 m. A bromide tracer was applied to study hydrological processes in the upper part of the CSA. Bromide infiltrated rapidly and perched on a massive, clay‐rich sublayer. Bromide concentrations decreased in the upper part of the profile without being transported vertically down through the lower part of the profile suggesting that bromide was lost to lateral rather than to vertical transport. Infiltration and lateral flow were rapid suggesting that preferential flow through desiccation cracks and other macropores likely dominates flow in the upper part of the CSA. Naturally occurring solute and stable isotope tracers were used to study the hydrological connectivity between the CSA and the surrounding hydrological landscape. Three‐end mass‐balance mixing model results indicate that shallow and/or deep CSA water can be found in all downgradient waters and must be as much as ∼50% of some downgradient waters. Discharge from the CSA to the surrounding surface water‐bodies and surficial aquifer occurs laterally through the berms and/or vertically through the massive, clay‐rich sublayer. However, the precise flow paths from the CSA to the surrounding hydrological landscape are unclear and the fluxes remain unquantified, so the precise effects of CSAs on the hydrology of the surrounding hydrological landscape also remain unquantified.
Dose Proportionality of Fentanyl Buccal Tablet in Healthy Japanese Volunteers
Authors: Darwish Mona , Tempero Kenneth , Jiang John G. , Thompson Jeffrey , Simonson Philip G.
Published: June 2008

Objective.  This study was conducted to assess the dose proportionality, safety, and tolerability of fentanyl buccal tablet (FBT) in Japanese volunteers.

Methods.  Healthy, opioid‐naive Japanese adults received single‐dose FBT 100, 200, 400, and 800 µg in a randomized, open‐label, crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Peak serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum fentanyl concentration‐time curve (AUC) from time 0 to infinity (AUC0–∞), and AUC from 0 to the last quantifiable concentration (AUC0–last) were summarized using descriptive statistics. Dose proportionality was claimed if the ln‐ln plots of Cmax, AUC0–∞, and AUC0–last vs. dose were linear and the 90% confidence intervals (CI) of the slopes were within 0.8927 and 1.1073. The safety population comprised volunteers who received ≥1 FBT.

Results.  Twenty‐five volunteers were enrolled, 23 were included in the safety population (mean age 35.3 years), and 19 completed the study. The assessment of dose proportionality did not meet the statistical criteria (slope [90% CI]: 0.9118 [0.8601, 0.9635] for Cmax, 1.0756 [1.0377, 1.1136] for AUC0–∞, and 1.0992 [1.0677, 1.1307] for AUC0–last). However, the increase in systemic exposure with dose appeared linear, and a post hoc analysis of partial AUCs from time 0 to 8, 12, 18, and 24 hours supported dose proportionality. Median tmax of 90 minutes (range 30–180 minutes) was independent of dose. Adverse events (AEs) were mild or moderate. The most frequent AEs were nausea (N = 9), dizziness (N = 8), headache (N = 6), somnolence (N = 6), dyspepsia (N = 5), and vomiting (N = 3). No application‐site or serious AEs were reported.

Conclusions.  Systemic exposure to FBT was approximately dose proportional across the range 100 µg to 800 µg in healthy Japanese adults. Adverse events were mild or moderate.
Extent of Fentanyl Accumulation Following Multiple Doses of Fentanyl Buccal Tablet 400 µg in Healthy Japanese Volunteers
Authors: Darwish Mona , Tempero Kenneth , Jiang John G. , Simonson Philip G.
Published: June 2008

Objective.  This study was conducted to characterize the pharmacokinetics, including extent of accumulation, and safety and tolerability of fentanyl following multiple doses of fentanyl buccal tablet (FBT) in healthy Japanese volunteers.

Methods.  Healthy Japanese adults received 10 successive doses of open‐label FBT 400 µg at 6‐hour intervals. Naltrexone was given to minimize the opioid effects of fentanyl. FBT was placed above a molar tooth between the gum and cheek. Peak serum fentanyl concentration (Cmax), time to Cmax (tmax), and area under the serum fentanyl concentration‐time curve from 0 to 6 hours (AUC0–6) were summarized using descriptive statistics. Accumulation ratio was calculated as Cmax for dose 10/Cmax for dose 1, and was calculated similarly for AUC0–6.

Results.  Fourteen volunteers (mean age 33 years) were enrolled, and 13 completed the study. After doses 1 and 10, respectively, mean (SD) Cmax was 1.70 (0.49) ng/mL and 1.97 (0.42) ng/mL, AUC0–6 was 4.46 (1.14) ng·h/mL and 6.81 (0.90) ng·h/mL, and median (range) tmax was 50 (30–110) minutes and 30 (15–120) minutes. Following 10 successive doses, systemic exposure (AUC0–6) was 55% higher than after dose 1, and Cmax was 23% higher. Steady state was achieved within 3 days of dosing at 6‐hour intervals, i.e., prior to dose 10. The most frequent adverse events (AEs) were somnolence (N = 9), decreased oxygen saturation (N = 4), headache (N = 3), application‐site pain (N = 8), application‐site erythema (N = 6), and application‐site reaction (N = 5). All AEs were mild or moderate.

Conclusions.  Following administration of FBT at 6‐hour intervals to healthy Japanese volunteers, at steady state, fentanyl exposure was higher by 55% (AUC0–6) and 23% (Cmax) than after a single dose of FBT. Adverse events were mild or moderate.
Photodynamic therapy with verteporfin in age‐related macular degeneration: a systematic review of efficacy, safety, treatment modifications and pharmacoeconomic properties
Authors: Cruess Alan F. , Zlateva Gergana , Pleil Andreas M. , Wirostko Barbara
Published: June 2008

Photodynamic therapy (PDT) with verteporfin has been used less comprehensively in the treatment of exudative age‐related macular degeneration (AMD), and specifically of choroidal neovascularization (CNV), since the advent of antiangiogenic therapies. Recently, there has been a renewed interest in PDT as an adjunct to these and other agents in the treatment of neovascular AMD. In light of this new development and the European Medicines Evaluation Agency’s (EMEA) recent labelling decision to rescind approval for the use of PDT in occult CNV lesions, the present systematic review was undertaken to revisit the evidence supporting its clinical application. Photodynamic therapy provided the first pharmacological treatment for patients suffering from subfoveal CNV, the major cause of severe vision loss in AMD. Key clinical trials evaluating efficacy and safety have examined patients with all lesion subtypes, with the primary labelled indication (i.e. lesions containing a classic component of ≥ 50% ) deriving from the results of the Treatment of Age‐related Macular Degeneration with Photodynamic Therapy (TAP) Study. The subsequent TAP Study Group post hoc categorization of lesions as predominantly classic is open to question, however, as it appears that the overall efficacy in this group only may have reflected the especially strong response in 100% classic lesions. Based on a subgroup analysis of the Verteporfin in Photodynamic Therapy Study, the indication for PDT subsequently was expanded in some jurisdictions, including that of the EMEA, to include occult lesions with no classic component. However, the subsequent Visudyne in Occult Study found no benefit in 100% occult lesions, resulting in the EMEA rescinding its approval for this indication.
Glaucomatous retinal nerve fibre layer defects may be identified in Stratus OCT images classified as normal
Authors: Hougaard Jesper Leth , Heijl Anders , Bengtsson Boel
Published: June 2008

Purpose:  We aimed to compare the retinal nerve fibre layer (RNFL) in different Stratus optical coherence tomography (OCT) images in glaucoma eyes with RNFL thickness values within normal limits.

Methods:  We studied the Stratus OCT high‐resolution standard protocol for assessment of peripapillary RNFL thickness. The four glaucoma eyes presented (with reproducible visual field defects, mean deviations from − 3.49 dB to − 0.49 dB and structural loss on RNFL and/or disc photography) had results within the 95% normal limits for all OCT parameters (full circle, quadrant or clock hour mean RNFL thickness). We qualitatively compared the RNFL in pseudo‐colour and grey‐scale images defined by the Stratus OCT software with what appeared to be the RNFL when not defined automatically (and in raw data OCT images).

Results:  A localized RNFL defect was identified in conventional 495‐nm RNFL photographs in all four patients. Obviously, in these selected eyes, the atrophy was not picked up by the OCT RNFL border algorithm, and at the corresponding location a localized RNFL atrophy (narrowing of the high signal intensity RNFL) was either not or just barely detectable in pseudo‐colour OCT. However, defects seemed to be present in OCT grey‐scale and raw data images in all four eyes.

Conclusions:  Our observations suggest that OCT images obtained in glaucoma eyes that are misclassified by the standard statistical analyses of Stratus OCT may contain information indicating RNFL defects. Thus, the current diagnostic ability of OCT in glaucoma can probably be extended.
A case of adrenal rest tumor of the liver: Radiological imaging and immunohistochemical study of steroidogenic enzymes
Authors: Baba Yoshifumi , Beppu Toru , Imai Katsunori , Masuda Toshiro , Iyama Ken‐ichi , Sasano Hironobu , Baba Hideo
Published: June 2008

A case of adrenal rest tumor in the liver of a 67‐year‐old female was reported. The tumor appeared on diagnostic imaging as a hypervascular and fat‐containing mass at the periphery of right hepatic lobe and required differential diagnosis from hepatocellular carcinoma (HCC). Pathological diagnosis of the intraoperative frozen section taken under laparoscopic liver biopsy could not exclude fat‐containing HCC. Therefore, she underwent partial resection of the right hepatic lobe. A yellowish‐brown mass, 17 × 14 × 11 mm in a diameter, was located in the subcapsular portion. Histologically, the mass presented features similar to those of the adrenal cortex and was composed of pale cells. Immunohistochemically, the mass expressed the adrenal 4‐binding protein and several enzymes involved in the synthesis of adrenocortical steroids. Based on these findings, the hepatic mass was finally diagnosed as an adrenal rest tumor of the liver.
Living donor liver transplantation for fulminant hepatic failure
Authors: Matsui Yucihi , Sugawara Yasuhiko , Yamashiki Noriyo , Kaneko Junichi , Tamura Sumihito , Togashi Junichi , Makuuchi Masatoshi , Kokudo Norihiro
Published: June 2008

Aim:  The aim of this study was to investigate the safety of living donor liver transplantation (LDLT) for fulminant hepatic failure (FHF) patients.

Methods:  We reviewed the clinical indications, operative procedures and prognosis of LDLT performed on patients with FHF at the University of Tokyo. From January 1996 to August 2007, 96 patients were referred to our department due to severe acute hepatitis or FHF. Of these, 36 underwent LDLT and were the subjects of this study. Of the 36 patients who underwent LDLT, 32 were over 18 years old. The etiologies of FHF included non‐A, non‐B hepatitis in 23, hepatitis B virus in 11, Wilson's disease in one, and auto‐immune hepatitis in one. Graft type included right liver in 18, left liver in 16 and right paramedian sector in two.

Results:  Patient and graft survival rates at 5 years were 87% and 82%, respectively. Twenty‐three patients had postoperative complications: acute cellular rejection in 12, biliary stricture in eight, bile leakage in six, peritoneal hemorrhage in six and hepatic arterial thrombosis in four.

Conclusion:  The LDLT procedure provided satisfactory survival rates for FHF patients.
Overexpression of hepatic inducible nitric oxide synthase in biliary atresia
Authors: Vejchapipat Paisarn , Poomsawat Sopee , Imvised Tawan , Chongsrisawat Voranush , Chittmittrapap Soottiporn , Poovorawan Yong
Published: June 2008

Aims:  Biliary atresia (BA) is a rare and serious liver disease in infants characterized by progressive inflammatory cholangiopathy. The aims of this study were to investigate hepatic expression of inducible nitric oxide synthase (iNOS) in BA and to associate the iNOS expression with their early therapeutic outcome.

Methods:  Hepatic iNOS expression was determined using immunohistochemistry from liver biopsies of 24 BA patients, and 16 non‐BA patients whose liver tissues were needed in the treatment process. Six months after surgery, the BA patients were categorized into two groups;good and poor outcome. The iNOS expression of hepatocyte areas was evaluated based on its intensity using ImageJ software. Unpaired t‐tests were used for the comparisons of iNOS expression between groups.

Results:  Hepatic iNOS expression of BA patients was significantly stronger than that of non‐BA patients (P < 0.0001). The largest area of hepatic iNOS expression was the area of hepatocytes. Subgroup analysis of BA patients at 6 months post‐op revealed that there was no difference in iNOS expression between the patients with good outcome and those with poor outcome (P = 0.732).

Conclusions:  Overexpression of hepatic iNOS in BA patients was demonstrated. Within liver tissues, hepatocytes were the major source of hepatic iNOS production. However, the expression was not associated with the early therapeutic outcome. These results suggest that iNOS plays a role in the liver pathology of BA but its expression cannot be used as a predictor for therapeutic outcome.
Interior Design at a Crossroads: Embracing Specificity through Process, Research, and Knowledge
Authors: Poldma Tiiu
Published: June 2008

Tiiu Poldma is Vice Dean of Graduate Studies and Research in the Faculty of Environmental Design, and associate professor at the School of Industrial Design at the University of Montreal. Tiiu Poldma received a BID at Ryerson in 1982 (Toronto), MA in Culture and Values in Education in 1999 and Doctor of Philosophy in 2003, both from McGill University in Montreal, Canada. She teaches interior design studio and theory within the Bachelor of Interior Design program at the University of Montreal, and advanced research methodologies in the Masters of Science and Ph.D. programs at the Faculty of Environmental Design. She is currently the Director of the Research Group GRID(Group for Research in Illumination and Design) and heads up the Colour, Light and Form Lab (Laboratoire Forme*couleur*lumiere) at the faculty. She accredits design programs as a site evaluator for CIDAboth in Canada and the United States, and is also a member of the Editorial Board of Inderscience where she is the Regional Editor of the Journal of Design Research (JDR), and serves on the Editorial Board of Design/Science/Planning (Techne Press, Amsterdam).
Rebuttal of the Report by the Institute for Justice Entitled Designing Cartels: How Industry Insiders Cut Out Competition
Authors: Martin Caren S.
Published: June 2008

In September 2006, the Institute for Justice published a report entitled Designing Cartels: How Industry Insiders Cut Out Competition (Carpenter). The stated purpose was to examine “titling laws, using the interior design industry as the focus, to stimulate further research in this area and to illustrate what titling laws are and how they function” (p. 1). However, the focus of the report, in concert with the Institute for Justice's lawsuits against existing interior design regulation in New Mexico and Texas, appears to be an attack on the interior design profession.

This paper is a research–supported rebuttal that analyzes Carpenter's findings within two major constructs: 1) interior decoration is not interior design, and 2) the purpose of regulation. The evidence of the Institute for Justice report is examined via principal topics that include the definition of interior design; the relationship of interior design to the health, safety, and welfare of the public; the framework of interior design regulation; the ideology of consumerism; the function of the Better Business Bureau (BBB) as a measurement tool of industry quality; and the idea of “profession” as a construct.

This rebuttal found that Designing Cartels has not succeeded in presenting findings and conclusions that support its intended purpose. It is unfortunate for the public and the interior design profession that this report has been so widespread and used as a way to bolster litigation against the public interest without being examined more closely. Suggestions of the Institute for Justice, if implemented, could compromise the public's health, safety, and welfare.
Designing Cognitive Stimulating Environments for Infants and Toddlers
Authors: Kopec David , LaCapra Damon
Published: June 2008

The purpose of the study was to review existing literature on the development of cognitive functioning and subsequent interpretations of environmental stimuli to develop an evidence–based hypothetical design for a prototype nursery to enhance the perception and cognition of infants and toddlers. To this end, literature on the cognitive development of both humans and animals was analyzed as it relates to the evolution of neurobiological processes to identify specific developmental capacities of infants and toddlers in the perception and detection of environmental stimuli. From this evidence–based knowledge, the researchers developed hypothetical designs as a starting point for further study.

The methodology used for the study centered on a review of existing literature about biological and neurological development of sensory perception and the detection of stimuli. More specifically, the researchers looked at the neurobiological processes that enable infants and toddlers to detect sensation, and at the ways in which environmental sensations may be enhanced in order to strengthen neural connections. As part of this analysis, the researchers considered evolutionary perspectives, particularly as they relate to elements found in nature, and analyzed literature pertaining to children who were denied access to sensory stimulation during their formative years.

The result was the development of a hypothetical prototype interior environment that could replicate the variations of basic stimulation patterns found within nature. The subsequent data were then analyzed and cross–referenced with existing research to form suppositions on safety and feasibility. The end result was the development of a prototype nursery as a hypothetical solution to enhancing sensory stimulation of children in their formative years, one that can now be implemented and studied further to determine its efficacy and impact on the development of infants and toddlers.
On the Use of Momentum Balance and the Assumed Modes Method in Transverse Impact Problems
Authors: Palas H. , Hsu W. C. , Shabana A. A.
Published: June 2008

The objective of this investigation is to examine the validity of applying the assumed modes method and the generalized impulse momentum approach that involves the coefficient of restitution in the analysis of transverse impact in constrained elastic systems. A simple impact model that consists of a rotating beam which is subjected to a transverse impact by a mass (impact hammer) moving with a constant velocity is used. For the purpose of comparison and in order to check the validity of using the proposed technique, the transverse deformation of the beam with respect to the beam coordinate system is described using three different assumed sets of orthogonal functions. The different sets of modes are the clamped-free modes, pin-free modes, and a set of assumed harmonic functions. The system mass matrix that accounts for the coupling between the rigid body motion and the elastic deformation is identified and used with the Jacobian matrix of the kinematic constraints and the coefficient of restitution to define the algebraic generalized impulse momentum equations that describe the transverse impact. The series solution obtained using the generalized impulse momentum equations is used to define the generalized impulse, the jump discontinuity in the system reference and modal velocities, and the jump discontinuities in the generalized joint reaction forces. It is shown in this investigation, that by increasing the number of elastic degrees of freedom, the jump discontinuity in the angular velocity of the rod as well as the generalized impulse converge to zero regardless of the assumed complete set of modes used. The effect of the coefficient of restitution and the mass ratio on the jump in the system velocities and the generalized reaction forces is also examined.
An Active Control Strategy for Achieving Weak Radiator Structures
Authors: Naghshineh K. , Koopmann G. H.
Published: June 2008

A general control strategy is presented for active suppression of total radiated sound power from harmonically excited structures based on the measurement of their response. Using the measured response of the structure together with knowledge of its structural mobility, an equivalent primary excitation force is found at discrete points along the structure. Using this equivalent primary force and performing a quadratic optimization of the power radiated from the structure, a set of control forces is found at selected points on the structure that results in minimum radiated sound power. A numerical example of this strategy is presented for a simply supported beam in a rigid baffle excited by a harmonic plane wave incident at an oblique angle. A comparison of the response of the beam with and without control forces shows a large reduction in the controlled response displacement magnitude. In addition, as the result of the action of the control forces, the magnitude of the wave number spectrum of the beam’s response in the supersonic region is decreased substantially. The effect of the number and location of the actuators on reductions in sound power level is also studied. The actuators located at the anti-nodes of structural modes within the supersonic region together with those lcoated near boundaries are found to be the most effective in controlling the radiation of sound from a structure.
Dynamic Characteristics of a Constrained String Translating Across an Elastic Foundation
Authors: Tan C. A. , Zhang L.
Published: June 2008

The free and forced linear response of a constrained string translating across an elastic foundation is examined in this paper. The transfer function method is used in the analysis. For the general problem, three subsystems are identified. The subsystems are coupled by physical constraints imposed at the subsystem interfaces. Free vibration analysis shows that eigenvalue loci exhibit veering characteristics and vibration modes are localized. These phenomena are due to the coupling of the subsystems. A third-order perturbation solution is also derived to examine the local characteristics of regions of curve veering. Studies on the wave propagation aspects show that the string/foundation medium can have propagating and amplitude-attenuating free vibration waves depending on the stiffness, location, and size of the elastic foundation. Moreover, the amount of shape distortion of a propagating wave at the constraint discontinuity depends also on the foundation stiffness.
Molecular Characterization of Ofloxacin-ResistantMycobacterium tuberculosisStrains from Russia
Authors: Mokrousov Igor , Otten Tatiana , Manicheva Olga , Potapova Yulia , Vishnevsky Boris , Narvskaya Olga , Rastogi Nalin
Published: June 2008

In this work, we studied the variation in thegyrAandgyrBgenes in ofloxacin- and multidrug-resistantMycobacterium tuberculosisstrains circulating in northwest Russia. Comparison with spoligotyping data suggested that similar to the spread of multidrug-resistant tuberculosis, the spread of fluoroquinolone-resistant tuberculosis in Russia may be due, at least partly, to the prevalence of the Beijing genotype in a local population ofM. tuberculosis.
Pharmacokinetics and Tolerability of Oseltamivir Combined with Probenecid
Authors: Holodniy Mark , Penzak Scott R. , Straight Timothy M. , Davey Richard T. , Lee Kelvin K. , Goetz Matthew Bidwell , Raisch Dennis W. , Cunningham Francesca , Lin Emil T. , Olivo Noemi , Deyton Lawrence R.
Published: June 2008

Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (
P
< 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 ± 76 and 81 ± 54 ng/ml, respectively;
P
= 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 ± 26 and 81 ± 54 ng/ml, respectively;
P
= 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.
The Antimalarial Trioxaquine DU1301 Alkylates Heme in Malaria-Infected Mice
Authors: Bousejra-El Garah Fatima , Claparols Catherine , Benoit-Vical Françoise , Meunier Bernard , Robert Anne
Published: June 2008

The in vivo alkylation of heme by the antimalarial trioxaquine DU1301 afforded covalent heme-drug adducts that were detected in the spleens of
Plasmodium
sp.-infected mice. This result indicates that the alkylation capacities of trioxaquines in mammals infected with
Plasmodium
strains are similar to that of artemisinin, a natural antimalarial trioxane-containing drug.
Kinetic Characterization of VIM-7, a Divergent Member of the VIM Metallo-β-Lactamase Family
Authors: Samuelsen Ørjan , Castanheira Mariana , Walsh Timothy R. , Spencer James
Published: June 2008

Purified recombinant VIM-7 possesses efficient penicillinase and carbapenemase activities comparable to those of VIM-2. Cephalosporinase activity was variable and generally lower than those of VIM-1 and VIM-2. A homology model suggests that the VIM-7 Tyr-218 Phe substitution may be responsible for the reduced catalytic efficiency against certain cephalosporins, including ceftazidime and cefepime.
Molecular Mechanism of Hepatitis C Virus Replicon Variants with Reduced Susceptibility to a Benzofuran Inhibitor, HCV-796
Authors: Howe Anita Y. M. , Cheng Huiming , Johann Stephen , Mullen Stanley , Chunduru Srinivas K. , Young Dorothy C. , Bard Joel , Chopra Rajiv , Krishnamurthy Girija , Mansour Tarek , O'Connell John
Published: June 2008

HCV-796 selectively inhibits hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In hepatoma cells containing a genotype 1b HCV replicon, HCV-796 reduced HCV RNA levels by 3 to 4 log
10
HCV copies/μg total RNA (the concentration of the compound that inhibited 50% of the HCV RNA level was 9 nM). Cells bearing replicon variants with reduced susceptibility to HCV-796 were generated in the presence of HCV-796, followed by G418 selection. Sequence analysis of the NS5B gene derived from the replicon variants revealed several amino acid changes within 5 Å of the drug-binding pocket. Specifically, mutations were observed at Leu314, Cys316, Ile363, Ser365, and Met414 of NS5B, which directly interact with HCV-796. The impacts of the amino acid substitutions on viral fitness and drug susceptibility were examined in recombinant replicons and NS5B enzymes with the single-amino-acid mutations. The replicon variants were 10- to 1,000-fold less efficient in forming colonies in cells than the wild-type replicon; the S365L variant failed to establish a stable cell line. Other variants (L314F, I363V, and M414V) had four- to ninefold-lower steady-state HCV RNA levels. Reduced binding affinity with HCV-796 was demonstrated in an enzyme harboring the C316Y mutation. The effects of these resistance mutations were structurally rationalized using X-ray crystallography data. While different levels of resistance to HCV-796 were observed in the replicon and enzyme variants, these variants retained their susceptibilities to pegylated interferon, ribavirin, and other HCV-specific inhibitors. The combined virological, biochemical, biophysical, and structural approaches revealed the mechanism of resistance in the variants selected by the potent polymerase inhibitor HCV-796.
Role of Porins for Uptake of Antibiotics by
Mycobacterium smegmatis
Authors: Danilchanka Olga , Pavlenok Mikhail , Niederweis Michael
Published: June 2008

The outer membrane of mycobacteria presents an effective permeability barrier for many antibiotics. Transport pathways across this membrane are unknown for most drugs. Here, we examined which antibiotics utilize the porin pathway across the outer membrane of the model organism
Mycobacterium smegmatis
. Deletion of the porins MspA and MspC drastically increased the resistance of
M. smegmatis
ML10 to β-lactam antibiotics, while its β-lactamase activity remained unchanged. These results are consistent with the ninefold-reduced outer membrane permeability of the
M. smegmatis
porin mutants for cephaloridine and strongly indicate that β-lactam antibiotics rely on the porin pathway. The porin mutant ML10 accumulated less chloramphenicol and norfloxacin and was less susceptible to these antibiotics than wild-type
M. smegmatis
. These results demonstrated that small and hydrophilic antibiotics use the Msp porins for entering the cell. In contrast to norfloxacin, the hydrophobic moxifloxacin was 32-fold more effective in inhibiting the growth of
M. smegmatis
, presumably because it was able to diffuse through the lipid membrane. Structural models indicated that erythromycin, kanamycin, and vancomycin are too large to move through the MspA channel. This study presents the first experimental evidence that hydrophilic fluoroquinolones and chloramphenicol diffuse through porins in mycobacteria. Thus, mutations resulting in less efficient porins or lower porin expression levels are likely to represent a mechanism for the opportunistic pathogens
M. avium
,
M. chelonae
, and
M. fortuitum
, which have Msp-like porins, to acquire resistance to fluoroquinolones.
Rifampin and Rifaximin Resistance in Clinical Isolates of
Clostridium difficile
Authors: O'Connor Jennifer R. , Galang Minerva A. , Sambol Susan P. , Hecht David W. , Vedantam Gayatri , Gerding Dale N. , Johnson Stuart
Published: June 2008

Rifaximin, a poorly absorbed rifamycin derivative, is a promising alternative for the treatment of
Clostridium difficile
infections. Resistance to this agent has been reported, but no commercial test for rifaximin resistance exists and the molecular basis of this resistance has not been previously studied in
C. difficile
. To evaluate whether the rifampin Etest would be a suitable substitute for rifaximin susceptibility testing in the clinical setting, we analyzed the in vitro rifaximin susceptibilities of 80 clinical isolates from our collection by agar dilution and compared these results to rifampin susceptibility results obtained by agar dilution and Etest. We found rifaximin susceptibility data to agree with rifampin susceptibility; the MICs of both antimicrobials for all isolates were either very low or very high. Fourteen rifaximin-resistant (MIC, ≥32 μg/ml) unique isolates from patients at diverse locations in three countries were identified. Molecular typing analysis showed that nine (64%) of these isolates belonged to the epidemic BI/NAP1/027 group that is responsible for multiple outbreaks and increased disease severity in the United Kingdom, Europe, and North America. The molecular basis of rifaximin and rifampin resistance in these isolates was investigated by sequence analysis of
rpoB
, which encodes the β subunit of RNA polymerase, the target of rifamycins. Resistance-associated
rpoB
sequence differences that resulted in specific amino acid substitutions in an otherwise conserved region of RpoB were found in all resistant isolates. Seven different RpoB amino acid substitutions were identified in the resistant isolates, which were divided into five distinct groups by restriction endonuclease analysis typing. These results suggest that the amino acid substitutions associated with rifamycin resistance were independently derived rather than disseminated from specific rifamycin-resistant clones. We propose that rifaximin resistance in
C. difficile
results from mutations in RpoB and that rifampin resistance predicts rifaximin resistance for this organism.
Evaluation of Etest Method for Determining Isavuconazole MICs against
Cryptococcus gattii
and
Cryptococcus neoformans
Authors: Thompson George R. , Fothergill Annette W. , Wiederhold Nathan P. , Vallor Ana C. , Wickes Brian L. , Patterson Thomas F.
Published: June 2008

We compared Etest with broth microdilution testing for isavuconazole activity against 92
Cryptococcus
isolates. A 97.8% agreement was found between these methods, without major discrepancies (>2-well dilution difference). Our findings support the use of the Etest methodology as a reliable method for the determination of MICs against
Cryptococcus
spp.
First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone
Authors: Nagelschmitz Johannes , Voith Barbara , Wensing Georg , Roemer Axel , Fugmann Burkhard , Haynes Richard K. , Kotecka Barbara M. , Rieckmann Karl H. , Edstein Michael D.
Published: June 2008

In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (
t
1/2
) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short
t
1/2
, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant
Plasmodium falciparum
lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's
t
1/2
is well suited for artemisinin-based combination therapy for the treatment of
P. falciparum
malaria.
Comparative Evaluation of Virus Transmission Inhibition by Dual-Acting Pyrimidinedione Microbicides Using the Microbicide Transmission and Sterilization Assay
Authors: Watson Karen M. , Buckheit Christa E. , Buckheit Robert W.
Published: June 2008

In the absence of a fully effective human immunodeficiency virus (HIV) vaccine, topical microbicides represent an important strategy for preventing the transmission of HIV through sexual intercourse, the predominant mode of HIV transmission worldwide. Although a comprehensive understanding of HIV transmission has not yet emerged in the microbicide field, it is likely the result of rapid infection of monocyte-derived cells in the vaginal mucosa by CCR5-tropic viruses. Inhibition of HIV transmission requires agents that prevent entry, fusion, reverse transcription, or other preintegrative replication events or agents which directly inactivate HIV or modulate the target cells to render them uninfectible. In vitro assays typically used to evaluate the ability of a microbicide to prevent virus transmission use epithelial or human osteosarcoma-derived cells or immune cells more relevant to the development of anti-HIV therapeutic agents and quantify virus production at short time intervals following infection. We have developed a microbicide transmission and sterilization assay (MTSA) to more sensitively and quantitatively evaluate virus transmission in cell culture in the presence of microbicidal compounds. Results obtained with the MTSA demonstrate that the inhibitory capacity of microbicides is often overestimated in short-term transmission inhibition assays, while some compounds yield equivalent inhibitory results, indicating a biological relevance for the MTSA-based evaluations to identify superior potent microbicides. The MTSA defines the concentration of the microbicide required to totally suppress the transmission of virus in cell culture and may thus help define the effective concentration of the microbicide required in a formulated microbicide product.
Inhibition of OXA-1 β-Lactamase by Penems
Authors: Bethel Christopher R. , Distler Anne M. , Ruszczycky Mark W. , Carey Marianne P. , Carey Paul R. , Hujer Andrea M. , Taracila Magda , Helfand Marion S. , Thomson Jodi M. , Kalp Matthew , Anderson Vernon E. , Leonard David A. , Hujer Kristine M. , Abe Takao , Venkatesan Aranapakam M. , Mansour Tarek S. , Bonomo Robert A.
Published: June 2008

The partnering of a β-lactam with a β-lactamase inhibitor is a highly effective strategy that can be used to combat bacterial resistance to β-lactam antibiotics mediated by serine β-lactamases (EC 3.2.5.6). To this end, we tested two novel penem inhibitors against OXA-1, a class D β-lactamase that is resistant to inactivation by tazobactam. The

K
i

of each penem inhibitor for OXA-1 was in the nM range (

K
i

of penem 1, 45 ± 8 nM;

K
i

of penem 2, 12 ± 2 nM). The first-order rate constant for enzyme and inhibitor complex inactivation of penems 1 and 2 for OXA-1 β-lactamase were 0.13 ± 0.01 s
−1
and 0.11 ± 0.01 s
−1
, respectively. By using an inhibitor-to-enzyme ratio of 1:1, 100% inactivation was achieved in ≤900 s and the recovery of OXA-1 β-lactamase activity was not detected at 24 h. Covalent adducts of penems 1 and 2 (changes in molecular masses, +306 ± 3 and +321 ± 3 Da, respectively) were identified by electrospray ionization mass spectrometry (ESI-MS). After tryptic digestion of OXA-1 inactivated by penems 1 and 2, ESI-MS and matrix-assisted laser desorption ionization-time-of-flight MS identified the adducts of 306 ± 3 and 321 ± 3 Da attached to the peptide containing the active-site Ser67. The base hydrolysis of penem 2, monitored by serial
1
H nuclear magnetic resonance analysis, suggested that penem 2 formed a linear imine species that underwent 7-endo-trig cyclization to ultimately form a cyclic enamine, the 1,4-thiazepine derivative. Susceptibility testing demonstrated that the penem inhibitors at 4 mg/liter effectively restored susceptibility to piperacillin. Penem β-lactamase inhibitors which demonstrate high affinities and which form long-lived acyl intermediates may prove to be extremely useful against the broad range of inhibitor-resistant serine β-lactamases present in gram-negative bacteria.