bluuebunny/crossref_metadata_2025 huggingface dataset:
Social and existential alienation experienced by people with long‐term mental illness
Authors: Erdner Anette , Magnusson Annabella , Nyström Maria , Lützén Kim
Published: November 2005

The aim of this study was to explore how people suffering from long‐term mental illness and who live in the community experience their daily lives. The study was based on an ethnographic framework involving participant observations with 23 individuals from two rehabilitation centres and interviews with six women and two men. The observational notes and interviews were recorded, transcribed into the data and analysed based on the phases of hermeneutic interpretation. The process consisted of identifying tentative interpretations that highlighted various impediments that prevent people with long‐term mental illness from having an active life. The impediments can also be interpreted as a form of alienation, an interpersonal phenomenon and a consequence due to of the lack of social acceptance towards mental illness. The participants expressed concern about the future and lack of hope. Viewing themselves as being ‘odd’ is not a symptom of mental illness, but rather evidence of experiencing existential and social alienation not only as a consequence of other people's reactions but also their own negative attitudes towards mental illness and effects of their cognitive dysfunction.
CYLINDROSPERMOPSIS RACIBORSKII(CYANOBACTERIA) INVASION AT MID‐LATITUDES: SELECTION, WIDE PHYSIOLOGICAL TOLERANCE, ORGLOBALWARMING?1
Authors: Briand Jean‐François , Leboulanger Christophe , Humbert Jean‐François , Bernard Cécile , Dufour Philippe
Published: November 2005

The tropical bloom‐forming cyanobacteriumCylindrospermopsis raciborskii(Woloszynska) Seenaya et Subba Raju is causing increasing concern because of its potential toxicity and invasive behavior at mid‐latitudes. This species has recently been identified in several temperate areas and was first reported in France in 1994, but the mechanisms underlying this acclimation process remain to be elucidated. We performed a range of laboratory experiments in an attempt to identify the physiological characteristics that could account for this behavior. We investigated the three following hypotheses: 1) clones ofC. raciborskiiadapted to temperate climate have been selected as it advanced north, 2)C. raciborskiihas high physiological tolerance that allows it to prosper in a wide range of conditions, and 3) changes inclimate (global warming) have favored the development ofC. raciborskiiin mid‐latitudes. Ten strains ofC. raciborskiifrom Australia n=1), Brazil (2), France (2), Germany (1), Hungary (1), Mexico (1), and Senegal (2) were cultured at different temperatures and light intensities. Thein vitrogrowth parameters (μ and Topt) were the same for the tropical and temperate strains. All 10 strains displayed positive net growth in a wide range of temperatures (from 20 to 35°C) and light intensities (from 30 to 400 μmol photons·m−2·s−1), with maximum growth rates at around 30°C and 80 μmol photons·m−2·s−1. This suggests that the colonization of mid‐latitudes byC. raciborskiimay result from a combination of its ability to tolerate a rather wide range of climatic conditions and the global warming phenomenon, which provides this species with better environmental conditions for its growth.
THE DIATOM GENERA ELLERBECKIA And ACTINOCYCLUS: AN APPRAISAL OF KOCIOLEK AND SPAULDING1
Authors: Crawford Richard M.
Published: November 2005

The contention that the diatom genera Ellerbeckia and Actinocyclus are congeneric on the basis of images of valves of the latter lying inside those of the former is disputed. It is suggested that conclusive evidence is lacking and that too few questions were asked to allow for the possibility that the two genera, one incorrectly identified to species and the other not identified at all, were lying together simply because they happened to fit.
Early‐onset autoimmune hemolytic anemia after cladribine therapy for Waldenström's macroglobulinemia
Authors: Aslan Deniz L. , Peterson Bruce A. , Long‐Tsai Michaela , Eastlund Ted
Published: November 2005

BACKGROUND: Purine nucleoside analogs are a class of antineoplastic drugs with potent lymphotoxicity against T and B lymphocytes, causing prolonged lymphopenia and linked to delayed immune complications such as opportunistic infections and more recently autoimmune hemolytic anemia (AIHA), seen mostly in patients with chronic lymphocytic leukemia (CLL). A characteristic temporal relation between fludarabine therapy and the appearance of a warm‐reactive immunoglobulin G (IgG)‐mediated AIHA in patients with CLL has been observed and, in some, the AIHA has been fatal. Whether both fludarabine and cladribine cause AIHA is uncertain because AIHA is commonly seen in patients with CLL without the use of these drugs. In contrast, AIHA is encountered in Waldenström's macroglobulinemia (WM) much less frequently, and the autoantibody is usually cold‐reactive and IgM‐mediated. In a few reported cases of AIHA arising in patients with WM after cladribine therapy, there was a latency of 24 to 60 months between therapy and the onset of AIHA, three of which were warm‐reactive and IgG‐mediated.

CASE REPORT: A warm‐reacting IgG red cell autoantibody and evidence of hemolysis detected 1 month after completing cladribine therapy for WM, with warm antibody AIHA developing 4 months later, are described.

CONCLUSIONS: Cladribine, like fludarabine, is possibly able to produce this complication during or early after therapy. Because the use of purine analogs is becoming increasingly common, it is important to have an awareness of the complications that can arise during and after treatment. Further observations of warm AIHA during cladribine therapy are needed to establish it as a distinct complication.
Relationships between physical activity and physical capacity in adolescent females and bone mass in adulthood
Authors: Barnekow‐Bergkvist M. , Hedberg G. , Pettersson U. , Lorentzon R.
Published: November 2005

This study investigates whether physical activity and physical performance in adolescence are positively related to adult bone mineral density (BMD). In 1974, physical activity, endurance, and muscular strength were measured in 204 randomly selected female students, age 16.1 ± 0.3 year (range 15–17 years). Twenty years later, 36 of the women volunteered to undergo a measurement of their BMD. Women who were members in a sports club in adolescence had significantly higher adult BMD (mean differences of 5% to 17% depending on site) compared with subjects who were not engaged in a sports club. Furthermore, women with persistent weight‐bearing activity in adulthood had significantly higher BMD compared with women who had stopped being active or had never been active. The differences ranged between 5% and 19% with the highest difference found in trochanter BMD. Stepwise regression analyses showed that membership in a sports club at baseline was a significant independent predictor of BMD in the total body, lumbar spine, legs, trochanter, and femoral neck, explaining 17–26% of the variation in BMD. Change in body weight was a strong independent predictor of BMD of the total body and arms, explaining 8% of the variation in both sites. In addition, running performance at baseline was an independent predictor of total body BMD, whereas the two‐hand lift performance significantly predicted BMD of the total body, legs and trochanter. The hanging leg‐lift and handgrip were both significant predictors of arm BMD. In conclusion, membership in a sports club and site‐specific physical performance in adolescence together with the change in body weight were significantly associated with adult BMD in premenopausal women.
Satyriasis: The Antiquity Term for Vulvodynia?
Authors: McElhiney Janice , Kelly Sarah , Rosen Raymond , Bachmann Gloria
Published: November 2005

From ancient times, through the Middle Ages, and well into the 19th century, physicians concentrated on catastrophic medical conditions and illnesses rather than on quality of life issues. Wars, plagues, and pestilence left little time, energy, or concern for “discomfort” problems. Therefore, it is not surprising that women's conditions that caused distressing symptoms but fell short of major morbidity and mortality were not given a prominent position in medicine until relatively recently. This is especially the case with vulvodynia, a condition that has been reported to affect approximately 15% (and in some studies up to 27%) of the female population at some point in their lives. Despite its high prevalence, this condition was not discussed or reported in traditional medical textbooks until the end of the 1800s. Now, we propose another viewpoint on when the first description of vulvodynia appeared; that is, that vulvodynia was described as far back as the 1st century CE. From our review of the ancient medical literature, we believe that the condition described by Soranus as “satyriasis in females” was actually vulvodynia.
From evidence to practice: Audit of adjuvant chemotherapy after complete resection of non‐small cell lung cancer in an Australian lung cancer center
Authors: DANIELS Marissa , NEWNHAM Genni M , WRIGHT Gavin M
Published: November 2005

Objective:  To investigate patterns in the rate of referral and uptake of platinum‐based adjuvant chemotherapy following resection of non‐small cell lung cancer (NSCLC) after recent landmark evidence‐based publications.

Design and setting:  An audit of all patients who underwent complete resection of NSCLC by a specialist thoracic surgeon between 1 January 2002 and 31 December 2004. Results of several randomised trials of adjuvant therapy (including the largest ever multicentre trial) were reported during this period and confirmed an overall and disease‐free survival benefit.

Patients:  One hundred and twenty‐six adult patients who underwent complete resection of histologically confirmed NSCLC between 1 January 2002 and 31 December 2004.

Main outcome measure:  Percentage of patients referred, commencing and completing platinum‐based adjuvant chemotherapy between January and June 2002, July and December 2002, January and June 2003, July and December 2003, January and June 2004, and July and December 2004.

Results:  Of patients who underwent complete resection of NSCLC in each of the 6‐month intervals, 0.0%, 3.4%, 30.8%, 52.2%, 58.8% and 68.3% were referred for adjuvant chemotherapy, respectively. Treatment delivery rates were 0.0%, 3.4%, 7.7%, 30.4%, 29.4% and 36.8%, respectively. The most common reason for failing to receive adjuvant chemotherapy after referral was excessive risks compared with benefits of treatment as perceived by the medical oncologist and/or patient.

Conclusion:  Both rate of referral and utilization of platinum‐based adjuvant chemotherapy have increased with successive publications of evidence of survival benefit. Further improvements may be possible by routine referral policy, earlier timing and choice of regimen.
Outpatient 5‐fluorouracil +α‐interferon + interleukin‐2 chemoimmunotherapy in metastatic renal cell cancer patients
Authors: ER Ozlem , OZKAN Metin , ALTINBAS Mustafa , COSKUN Hasan Senol , ESER Bulent , ALTUNTAS Fevzi , CETIN Mustafa , UNAL Ali
Published: November 2005

Background:  Renal cell carcinoma is the most common malignancy of the kidney in adults. The treatment of metastatic disease remains a particularly difficult problem given the resistance of this disease to most treatment options and usually requires hospitalization. This prospective study aimed to determine the efficacy and systemic toxicity of outpatient Chemoimmunotherapy (CIT) in metastatic renal cell cancer (MRCC) patients.

Methods:  The patients with MRCC received a combination of 5‐fluorouracil 400 mg/m2 intravenously on day 1 once a week, interferon‐α 10 MU on days 1,3,5 during weeks 1 and 3, interleukin‐2 18 MU on days 1,3,5 during weeks 2 and 4 subcutaneously.

Results:  Twenty‐three MRCC patients were enrolled into the study. The performance status was ECOG 0–2. The median age was 60 years. Twenty patients were evaluable. Chemoimmunotherapy was administered for a median of 10 weeks (range 2–32). Partial remission was obtained in two patients, stable disease in five and no complete response was detected. Median overall survival (OAS) was 10.0 months (95% CI 5.5–14.5 months), progression‐free survival (PFS) 7.0 months (95% CI 5.1–8.9 months). The 1‐year OAS and PFS rate was 27% and 7%, respectively. Median OAS for patients with and without nephrectomy was 10.0 months (95%CI 7.2–12.8 months) and 6.0 months (95%CI 1.4–10.5 months), median PFS 7.0 months (95% CI 4.1–9.9 months) and 5.0 months (95% CI 3.7–6.2 months), respectively, and there was no statistical significant difference (P = 0.27 and P = 0.20). Most common complaints were fatigue, fever and nausea. Grade 3–4 side‐effects were not observed.

Conclusion:  This CIT scheme showed a low objective response rate, but when combined with stable disease, clinical benefit is favorable. Outpatient administration with mild toxicity is advantageous.
HER‐2 gene polymorphism at codon 655 in familial prostate cancer in a Japanese population
Authors: SEKINE Yoshitaka , HASUMI Masaru , OHTAKE Nobuaki , NAKATA Seiji , NAKAZATO Haruki , KOIKE Hidekazu , SUZUKI Kazuhiro
Published: November 2005

Background:  The Ile to Val polymorphism at codon 655 of HER‐2 was reported to be associated with a risk of sporadic prostate cancer and breast cancer. In this study, we examined the association of the HER‐2 polymorphism with familial prostate cancer in a Japanese population.

Materials and methods:  We performed a case‐control study consisting of 144 familial prostate cancer cases and 119 normal control subjects. The genetic polymorphism was analyzed by the restriction fragment length polymorphism method.

Results:  There was no significant difference between the case group and the control group for the allele or genotype distribution.

Conclusion:  In the present study, we could not confirm any significant association between the HER‐2 polymorphism with familial prostate cancer risk in a Japanese population. Further large‐scale studies are warranted to confirm the association of the HER‐2 polymorphism with the risk of development of prostate cancer.
Importance of a dental approach in head and neck cancer therapy
Authors: GÜNERI Pelin , ÇANKAYA Hülya
Published: November 2005

Recent developments in molecular and genetic science have led to the early diagnosis of malignant cellular alterations of oral tissues, and escalated the number of new oral cancer cases detected each year. However, the treatment methods of cancer have not changed too much over the years, and the complications of surgery, chemotherapy and radiotherapy have continued to cause severe oral problems. Due to the increased frequency of this type of cancer in the population, dental practitioners have more opportunity to treat these patients. Therefore, dental health‐care providers should continuously up‐date their knowledge, not only about the oral cancer therapy and its oral complications, but also about its prevention and management options.
Prevalence of abnormal Papanicolaou smears and cytohistological correlation: A study from Aga Khan University Hospital, Pakistan
Authors: HAQ NAWAZ Fauzia , AZIZ Aliya B , PERVEZ Shahid , RIZVI Javed H
Published: November 2005

Objectives: To determine the prevalence of abnormal Papanicolaou (Pap) smears in patients visiting the gynecologic outpatient department at Aga Khan University Hospital, Karachi (AKUH) and their cytohistologic correlation. This data was also compared with other international institutions.

Methods: A database search of all abnormal cervical cytological cases diagnosed in the gynecologic outpatient department at Aga Khan University Hospital in the last 10 years (i.e. from 1994 to 2004), as well as their follow‐up biopsies, was carried out. The data was then analyzed.

Results: Of the 66 617 Pap smears reviewed, 95% of cases had a diagnosis of ‘negative’, 2% of smears were labeled as ‘inadequate’, 0.54% Pap smears showed dysplastic changes, and 0.14% were labeled as ‘malignant’. These numbers are less than figures in Western countires, but are comparable with Asian figures. The pick‐up rate for abnormal Pap smears was 8/1000, while the overall concordance rate was 74%; positive predictive values for high‐grade cervical lesions and for carcinomas was high 92–100%, respectively; while for ASCUS and low‐grade cervical lesion was 35% and 67%, respectively. A total number of 8 cases were identified where there was a discrepancy between cytological and histological diagnosis, they were reviewed critically.

Conclusion: In most of the developing countries effective Pap screening faces certain barriers. This includes limited or poor quality of cytology services. In a low‐resource country like Pakistan there is a subset of patients (those with atypical cellular abnormalities) who may benefit from repeat smears instead of early cervical biopsies. In order to improve the efficacy of our cytology services, we need to develop specific clinical protocols for subsequent management of abnormal smears.
Cancer curriculum in the Asia–Pacific: Opportunities and challenges in the age of globalization
Authors: KOCZWARA Bogda , BARTON Michael , COVENTRY Brendon , MILLAR Jeremy , OLVER Ian , SABESAN Sabe , SCHWARZ Max
Published: November 2005

With the rising incidence and prevalence of cancer in Asia–Pacific, the need for adequate cancer education of medical graduates in the region has become particularly urgent. There are 769 medical schools across the Asia–Pacific region in 33 countries serving over 60% of the world population in very diverse socioeconomic environments. This paper discusses some of the challenges for medical education in the Asia–Pacific in light of increasing globalization of health care, including the need to develop global standards in the area of diverse resources and health care priorities. It also points out emerging opportunities including online learning, telemedicine and collaborative educational initiatives across the region.
Internet access, awareness and utilization of web‐based evidence: A survey of Australian, New Zealand and Singaporean radiation oncology registrars*
Authors: WONG Karen , VENESS Michael J
Published: November 2005

Background:  Awareness of up‐to‐date published evidence is important in order to optimize patient care and outcome. We report on the utilization and awareness of pre‐appraised web‐based evidence amongst accredited radiation oncology registrars in Australia, New Zealand (ANZ) and Singapore.

Methods:  In 2003, a postal survey was sent to all accredited radiation oncology registrars in ANZ and Singapore. The aims of this study were to ascertain: the extent of previous training in literature searching and critical appraisal, the extent of Internet access, and the current awareness and utilization of medical databases, including pre‐appraised web‐based evidence available at the Cochrane Library and the related Cancer Library.

Results:  Sixty‐nine of 90 registrars responded (77% response rate). Fifty‐four percent of respondents had previously undertaken some form of training related to literature searching or critical appraisal. The majority (67%) felt confident in performing a literature search, although 81% indicated interest in obtaining further training. Most (68%) reported accessing web‐based evidence for literature searching in the previous week and 91% did so in the previous month. Nearly all respondents (90%) accessed web‐based evidence at work. Almost all (94%) were aware of the Cochrane Library with 49% of respondents having used it. Sixty‐seven percent were aware of the Cancer Library. In 2000, a survey of radiation oncologists and registrars on evidence‐based medicine revealed only 68% of registrars were aware of, and only 30% had used, the Cochrane Library.

Conclusion:  The findings from this survey reveal almost universal access to the Internet and use of web‐based evidence amongst radiation oncology registrars in ANZ and Singapore. Since 2000, there has been a marked increase in awareness and utilization of the Cochrane Library with a majority also aware of the Cancer Library.
A Continuum Damage Mechanics Model on Creep Rupture Life Assessment of a Steam Turbine Rotor
Authors: JianPing Jing , Guang Meng , Yi Sun , SongBo Xia
Published: November 2005

A nonlinear continuum damage mechanics model is proposed to assess the high temperature creep life of a steam turbine rotor, in which the effect of mean stress is taken into account and the damage is accumulated nonlinearly. The model is applied to a 300 MW steam turbine under hot start operation. The results are compared with those from the linear accumulation theory that is dominant in the creep life assessment of steam turbine rotors at present. The comparison results show that the nonlinear continuum damage mechanics model describes the accumulation and development of damage better than the linear accumulation theory.
Heat Transfer in Reciprocating Planar Curved Tube With Piston Cooling Application
Authors: Chang Shyy Woei , Zheng Yao
Published: November 2005

This paper describes an experimental study of heat transfer in a reciprocating planar curved tube that simulates a cooling passage in piston. The coupled inertial, centrifugal, and reciprocating forces in the reciprocating curved tube interact with buoyancy to exhibit a synergistic effect on heat transfer. For the present experimental conditions, the local Nusselt numbers in the reciprocating curved tube are in the range of 0.6–1.15 times of static tube levels. Without buoyancy interaction, the coupled reciprocating and centrifugal force effect causes the heat transfer to be initially reduced from the static level but recovered when the reciprocating force is further increased. Heat transfer improvement and impediment could be superimposed by the location-dependent buoyancy effect. The empirical heat transfer correlation has been developed to permit the evaluation of the individual and interactive effects of inertial, centrifugal, and reciprocating forces with and without buoyancy interaction on local heat transfer in a reciprocating planar curved tube.
A Generic Approach for Gas Turbine Adaptive Modeling
Authors: Visser W. P. J. , Kogenhop O. , Oostveen M.
Published: November 2005

For gas turbine engine performance analysis, a variety of simulation tools is available. In order to minimize model development and software maintenance costs, generic gas turbine system simulation tools are required for new modeling tasks. Many modeling aspects remain engine specific however and still require large implementation efforts. One of those aspects is adaptive modeling. Therefore, an adaptive modeling functionality has been developed that can be implemented in a generic component-based gas turbine environment. A single component in a system modeling environment is able to turn any new or existing model into an adaptive model without extra coding. The concept has been demonstrated in the GSP gas turbine modeling environment. An object-oriented architecture allows automatic addition of the necessary equations for the adaptation to measurement values. Using the adaptive modeling component, the user can preconfigure the adaptive model and quickly optimize gas path diagnostics capability using experimentation with field data. The resulting adaptive model can be used by maintenance engineers for diagnostics. In this paper the integration of the adaptive modeling function into a system modeling environment is described. Results of a case study on a large turbofan engine application are presented.
Proposal and Analysis of a Novel Zero CO2 Emission Cycle With Liquid Natural Gas Cryogenic Exergy Utilization
Authors: Zhang Na , Lior Noam
Published: November 2005

A novel liquefied natural gas (LNG) fueled power plant is proposed, which has virtually zero CO2 and other emissions and a high efficiency. Natural gas is fired in highly enriched oxygen and recycled CO2 flue gas. The plant operates in a quasi-combined cycle mode with a supercritical CO2 Rankine type cycle and a CO2 Brayton cycle, interconnected by the heat transfer process in the recuperation system. By coupling with the LNG evaporation system as the cycle cold sink, the cycle condensation process can be achieved at a temperature much lower than ambient, and high-pressure liquid CO2 ready for disposal can be withdrawn from the cycle without consuming additional power. Good use of the coldness exergy and internal exergy recovery produced a net energy and exergy efficiencies of a base-case cycle over 65% and 50%, respectively, which can be increased up to 68% and 54% when reheat is used. Cycle variants incorporating reheat, intercooling, and reheat+intercooling, as well as no use of LNG coldness, are also defined and analyzed for comparison. The approximate heat transfer area needed for the different cycle variants is also computed. Besides electricity and condensed CO2, the byproducts of the plant are H2O, liquid N2 and Ar.
Buoyancy-Induced Flow in a Heated Rotating Cavity
Authors: Owen J. Michael , Powell Jonathan
Published: November 2005

Experimental measurements were made in a rotating-cavity rig with an axial throughflow of cooling air at the center of the cavity, simulating the conditions that occur between corotating compressor disks of a gas-turbine engine. One of the disks in the rig was heated, and the other rotating surfaces were quasi-adiabatic; the temperature difference between the heated disk and the cooling air was between 40 and 100°C. Tests were conducted for axial Reynolds numbers, Rez, of the cooling air between 1.4×103 and 5×104, and for rotational Reynolds numbers, Reϕ, between 4×105 and 3.2×106. Velocity measurements inside the rotating cavity were made using laser Doppler anemometry, and temperatures and heat flux measurements on the heated disk were made using thermocouples and fluxmeters. The velocity measurements were consistent with a three-dimensional, unsteady, buoyancy-induced flow in which there was a multicell structure comprising one, two, or three pairs of cyclonic and anticyclonic vortices. The core of fluid between the boundary layers on the disks rotated at a slower speed than the disks, as found by other experimenters. At the smaller values of Rez, the radial distribution and magnitude of the local Nusselt numbers, Nu, were consistent with buoyancy-induced flow. At the larger values of Rez, the distribution of Nu changed, and its magnitude increased, suggesting the dominance of the axial throughflow.
Hydrogen Fueled Spark-Ignition Engines Predictive and Experimental Performance
Authors: Li Hailin , Karim Ghazi A.
Published: November 2005

Hydrogen is well recognized as a suitable fuel for spark-ignition engine applications that has many unique attractive features and limitations. It is a fuel that can continue potentially to meet the ever-increasingly stringent regulations for exhaust and greenhouse gas emissions. The application of hydrogen as an engine fuel has been tried over many decades by numerous investigators with varying degrees of success. However, the performance data reported often tend not to display consistent agreement between the various investigators, mainly because of the wide differences in engine type, size, operating conditions used, and the differing criteria employed to judge whether knock is taking place or not. With the ever-increasing interest in hydrogen as an engine fuel, there is a need to be able to model extensively various features of the performance of spark ignition (S.I.) hydrogen engines so as to investigate and compare reliably the performance of widely different engines under a wide variety of operating conditions. In the paper we employ a quasidimensional two-zone model for the operation of S.I. engines when fueled with hydrogen. In this approach, the engine combustion chamber at any instant of time during combustion is considered to be divided into two temporally varying zones: a burned zone and an unburned zone. The model incorporates a detailed chemical kinetic model scheme of 30 reaction steps and 12 species, to simulate the oxidation reactions of hydrogen in air. A knock prediction model, developed previously for S.I. methane-hydrogen fueled engine applications was extended to consider operation on hydrogen. The effects of changes in operating conditions, including a very wide range of variations in the equivalence ratio on the onset of knock and its intensity, combustion duration, power, efficiency, and operational limits were investigated. The results of this predictive approach were shown to validate well against the corresponding experimental results, obtained mostly in a variable compression ratio CFR engine. On this basis, the effects of changes in some of the key operational engine variables, such as compression ratio, intake temperature, and spark timing are presented and discussed. Some guidelines for superior knock-free operation of engines on hydrogen are also made.
Visualization of Steam Addition Effect on OH Distribution in a Flame by Isotope Shift/Planar Laser-Induced Fluorescence (IS/PLIF) Spectroscopy
Authors: Katoh Atsushi , Shinoda Masahisa , Kitagawa Kuniyuki , Gupta Ashwani K.
Published: November 2005

Addition of steam to a flame has important implications in the combustion process. The dissociation of the added steam (e.g., H2O↔H+OH, etc.) is one of the effects that contribute to the production of radical species, such as OH, H, and O, in the flame. In order to distinctly visualize two types of OH radicals produced from the fuel-air combustion reaction and that from the dissociation reaction with the added steam, we have developed a new method for planar laser-induced fluorescence spectroscopy in combination with isotope shift (herein called IS/PLIF spectroscopy). This technique has been applied to examine a methane-oxygen-nitrogen premixed flame. Two-dimensional fluorescence intensity distributions of OH radicals in the flames were monitored under three different conditions. They include without steam addition, with H2O steam addition, and with D2O steam addition. From the experimental data obtained under the three conditions, the distinction between the two types of OH radicals could be obtained. The results showed that steam addition reduced the total concentration of OH produced from the combustion and dissociation reactions and that the dissociation reaction of the added steam contributed to the production of OH. Furthermore, the results indicated that the percentage decrease in OH from fuel-air combustion reactions due to the temperature decrease effect with steam addition was almost independent of the equivalence ratio during combustion. In contrast, the percentage increase in OH produced from dissociation reaction with the steam depended on the equivalence ratio.
Biphenylsulfonacetic Acid Inhibitors of the Human Papillomavirus Type 6 E1 Helicase Inhibit ATP Hydrolysis by an Allosteric Mechanism Involving Tyrosine 486
Authors: White Peter W. , Faucher Anne-Marie , Massariol Marie-Josée , Welchner Ewald , Rancourt Jean , Cartier Mireille , Archambault Jacques
Published: November 2005

Human papillomaviruses (HPVs) are the causative agents of benign and malignant lesions of the epithelium. Despite their high prevalence, there is currently no antiviral drug for the treatment of HPV-induced lesions. The ATPase and helicase activities of the highly conserved E1 protein of HPV are essential for viral DNA replication and pathogenesis and hence are considered valid antiviral targets. We recently described novel biphenylsulfonacetic acid inhibitors of the ATPase activity of E1 from HPV type 6 (HPV6). Based on kinetics and mutagenesis studies, we now report that these compounds act by an allosteric mechanism. They are hyperbolic competitive inhibitors of the ATPase activity of HPV6 E1 and also inhibit its helicase activity. Compounds in this series can also inhibit the ATPase activity of the closely related enzyme from HPV11; however, the most potent inhibitors of HPV6 E1 are significantly less active against the type 11 protein. We identified a single critical residue in HPV6 E1, Tyr-486, substituted by a cysteine in HPV11, which is primarily responsible for this difference in inhibitor potency. Interestingly, HPV18 E1, which also has a tyrosine at this position, could be inhibited by biphenylsulfonacetic acid derivatives, thereby raising the possibility that this class of inhibitors could be optimized as antiviral agents against multiple HPV types. These studies implicate Tyr-486 as a key residue for inhibitor binding and define an allosteric pocket on HPV E1 that can be exploited for future drug discovery efforts.
Activities of Acyclic Nucleoside Phosphonates against Orf Virus in Human and Ovine Cell Monolayers and Organotypic Ovine Raft Cultures
Authors: Dal Pozzo F. , Andrei G. , Holý A. , Van Den Oord J. , Scagliarini A. , De Clercq E. , Snoeck R.
Published: November 2005

Orf virus, a member of theParapoxvirusgenus, causes a contagious pustular dermatitis in sheep, goats, and humans. Previous studies have demonstrated the activity of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC; cidofovir; Vistide) against orf virus in cell culture and humans. We have evaluated a broad range of acyclic nucleoside phosphonates (ANPs) against several orf virus strains in primary lamb keratinocytes (PLKs) and human embryonic lung (HEL) monolayers. HPMPC, (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6- diaminopurine (HPMPDAP), and (R)-9-[3-hydroxy-2-(phosphonomethoxy)propoxy]-2,4-diaminopyrimidine (HPMPO-DAPy) were three of the most active compounds that were subsequently tested in a virus yield assay with PLK and HEL cells by virus titration and DNA quantification. HPMPC, HPMPDAP, and HPMPO-DAPy were evaluated for their activities against orf virus replication in organotypic epithelial raft cultures from differentiated PLK cells. At the highest concentrations (50 and 20 μg/ml), full protection was provided by the three drugs, while at 5 μg/ml, only HPMPDAP and HPMPC offered partial protection. The activities of the three compounds in the raft culture system were confirmed by quantification of infectious virus and viral DNA. These findings provide a rationale for the use of HPMPC and other ANPs in the treatment of orf (contagious ecthyma) in humans and animals.
Comparative Efficacies of Conventional Amphotericin B, Liposomal Amphotericin B (AmBisome), Caspofungin, Micafungin, and Voriconazole Alone and in Combination against Experimental Murine Central Nervous System Aspergillosis
Authors: Clemons Karl V. , Espiritu Marife , Parmar Rachana , Stevens David A.
Published: November 2005

Central nervous system (CNS) aspergillosis is a severe disease that responds poorly to current therapies. The current studies examined the efficacies of several antifungal agents alone or in combination with a murine model of CNS aspergillosis. Immunosuppressed mice were infected intracerebrally withAspergillus fumigatusand treated with an amphotericin B preparation, an echinocandin, or voriconazole (VCZ) given alone or in combination. Monotherapy studies showed that micafungin (MICA), caspofungin (CAS), VCZ, conventional amphotericin B (AMB), Abelcet (ABLC) (a lipid-carried AMB formulation; Enzon Pharmaceuticals, Inc.), and AmBisome (AmBi) (liposomal AMB; Gilead Sciences, Inc.) were efficacious. However, doses of AmBi above 15 mg/kg of body weight showed reduced efficacy. Neither MICA nor CAS showed dose responsiveness at the doses tested (1, 5, or 10 mg/kg). Only the 40-mg/kg dose of VCZ was effective. AmBi and ABLC showed dose responsiveness, with 10-mg/kg doses causing a significant reduction in fungal burden; they had equivalent activities at the 10-mg/kg dose. Suboptimal dosages of AmBi in combination with MICA, CAS, or VCZ were effective in prolonging survival. However, significantly enhanced activity was demonstrated only with AmBi and VCZ in combination. AmBi in combination with MICA or CAS showed a trend toward enhanced activity, but the combination was not significantly superior to monotherapy. The use of AmBi with CAS or VCZ at optimal doses did not improve efficacy. Cure was not attained with any dosage combinations. These results indicate that AmBi in combination with VCZ may be superior for treatment of CNS aspergillosis; combinations of AmBi and MICA or CAS were not antagonistic and may have a slight benefit.
Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1
Authors: Strizki Julie M. , Tremblay Cecile , Xu Serena , Wojcik Lisa , Wagner Nicole , Gonsiorek Waldemar , Hipkin R. William , Chou Chuan-Chu , Pugliese-Sivo Catherine , Xiao Yushi , Tagat Jayaram R. , Cox Kathleen , Priestley Tony , Sorota Steve , Huang Wei , Hirsch Martin , Reyes Gregory R. , Baroudy Bahige M.
Published: November 2005

Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5′-[
35
S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.
Potent Antiviral Activity of North-Methanocarbathymidine against Kaposi's Sarcoma-Associated Herpesvirus
Authors: Zhu Weimin , Burnette Angela , Dorjsuren Dorjbal , Roberts Paula E. , Huleihel Mahmoud , Shoemaker Robert H. , Marquez Victor E. , Agbaria Riad , Sei Shizuko
Published: November 2005

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is a prerequisite for the development of Kaposi's sarcoma (KS). Blocking lytic KSHV replication may hinder KS tumorigenesis. Here, we report potent in vitro anti-KSHV activity of 2′-
exo
-methanocarbathymidine [North-methanocarbathymidine (N-MCT)], a thymidine analog with a pseudosugar ring locked in the northern conformation, which has previously been shown to block the replication of herpes simplex virus types 1 and 2. N-MCT inhibited KSHV virion production in lytically induced KSHV-infected BCBL-1 cells with a substantially lower 50% inhibitory concentration (IC
50
) than those of cidofovir (CDV) and ganciclovir (GCV) (IC
50
, mean ± standard deviation: 0.08 ± 0.03, 0.42 ± 0.07, and 0.96 ± 0.49 μM for N-MCT, CDV, and GCV, respectively). The reduction in KSHV virion production was accompanied by a corresponding decrease in KSHV DNA levels in the N-MCT-treated BCBL-1 cells, indicating that the compound blocked lytic KSHV DNA replication. A time- and dose-dependent accumulation of N-MCT-triphosphate (TP) was demonstrated in lytically induced BCBL-1 cells, while uninfected cells showed virtually no accumulation. The levels of N-MCT-TP were significantly decreased in the presence of 5′-ethynylthymidine, a potent inhibitor of herpesvirus thymidine kinase, resulting in the abrogation of anti-KSHV activity of N-MCT. N-MCT-TP more effectively blocked in vitro DNA synthesis by KSHV DNA polymerase with an IC
50
of 6.24 ± 0.08 μM (mean ± standard deviation) compared to CDV-diphosphate (14.70 ±2.47 μM) or GCV-TP (24.59 ± 5.60 μM). Taken together, N-MCT is a highly potent and target-specific anti-KSHV agent which inhibits lytic KSHV DNA synthesis through its triphosphate metabolite produced in KSHV-infected cells expressing a virally encoded thymidine kinase.
Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis
Authors: Marchand Sandrine , Dahyot Claire , Lamarche Isabelle , Plan Elodie , Mimoz Olivier , Couet William
Published: November 2005

The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg · kg−1over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n= 8) and control (n= 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P< 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.
Antibiotic Susceptibility Testing of
Mycoplasma genitalium
by TaqMan 5′ Nuclease Real-Time PCR
Authors: Hamasuna Ryoichi , Osada Yukio , Jensen Jørgen Skov
Published: November 2005

Mycoplasma genitalium
is an important pathogen in male nongonococcal urethritis (NGU). Isolation of
M. genitalium
from clinical specimens by axenic culture is very difficult and time-consuming, and very few strains are available for antibiotic susceptibility testing. Primary isolation of
M. genitalium
by coculture with Vero cells improves the isolation rate significantly. However, some strains cannot be adapted to axenic culture. In this study, we determined the antibiotic susceptibility of
M. genitalium
strains grown in Vero cell culture with dilutions of antibiotics. Growth of
M. genitalium
was monitored by a quantitative PCR assay detecting a single-copy region of the
mgpB
adhesin gene. Growth inhibition in the presence of antibiotics was expressed as a percentage of the DNA load of controls grown in the absence of antibiotics. Eighteen strains were examined, including 6 new strains isolated from urethral swab specimens and 4 new strains isolated from urine specimens collected from Japanese men. Eight strains adapted to axenic culture were also tested by the conventional broth dilution method. The two methods had an acceptable correlation. Azithromycin was the most active drug against
M. genitalium
. Among the fluoroquinolones, moxifloxacin had the highest activity, with MICs ranging from 0.03 to 0.5 mg/liter, whereas ciprofloxacin and levofloxacin were considerably less active, with MICs ranging from 0.5 to 16 mg/liter and 0.25 to 4 mg/liter, respectively. MICs for tetracycline ranged from 0.125 to 4 mg/liter. This new method could increase the number of
M. genitalium
strains available for antibiotic susceptibility testing and significantly shorten the time from sampling to MIC results.
Absolute Bioavailability and Intracellular Pharmacokinetics of Azithromycin in Patients with Cystic Fibrosis
Authors: Beringer Paul , Huynh Kitty My Tu , Kriengkauykiat Jane , Bi Luke , Hoem Nils , Louie Stan , Han Emily , Nguyen Thao , Hsu Donald , Rao Purush A. , Shapiro Bertrand , Gill Mark
Published: November 2005

Chronic pulmonary infections with
Pseudomonas aeruginosa
are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg;
P
< 0.01) and body mass index (19.7 versus 23.2;
P
< 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h;
P
= 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%;
P
= 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h
−1
;
P
= 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h
−1
;
P
< 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 ± 6.0 mg/liter) far exceeded the maximum serum drug concentration (∼50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.
In Vitro Activity of Linezolid against Key Gram-Positive Organisms Isolated in the United States: Results of the LEADER 2004 Surveillance Program
Authors: Draghi Deborah C. , Sheehan Daniel J. , Hogan Patricia , Sahm Daniel F.
Published: November 2005

Since the approval of linezolid in 2000, sporadic reports of resistance have been given and a greater understanding of the underlying mechanisms of resistance has been gained. However, since these developments, an updated status of the in vitro activity of linezolid against gram-positive organisms from the United States has not been reported. The LEADER 2004 surveillance initiative was undertaken to obtain current and representative data on the activity of linezolid against key species, including isolates with significant resistance phenotypes. Organisms were isolated during 2004 and included 2,872
Staphylococcus aureus
, 496 coagulase-negative staphylococcus (CNS), 428
Enterococcus faecalis
, 196
Enterococcus faecium
, and 422
Streptococcus pneumoniae
isolates. All
S. aureus
isolates (54.2% oxacillin resistant) were susceptible to linezolid (MIC
90
= 2 μg/ml); MIC distributions were consistent, regardless of oxacillin or multidrug resistance status. For CNS, one nonsusceptible isolate was encountered (
Staphylococcus epidermidis
; MIC = 32 μg/ml), but overall, the MIC
90
(1 μg/ml) was lower than that obtained with
S. aureus
. For
E. faecalis
and
E. faecium
, 99.5% and 96.4% of isolates, respectively, were linezolid susceptible. Both species had an MIC
90
of 2 μg/ml, and MIC distributions did not vary with the vancomycin susceptibility status of the populations analyzed. Linezolid nonsusceptibility was not encountered among the
S. pneumoniae
isolates. These findings indicate that linezolid nonsusceptibility has remained rare among staphylococci and uncommon and sporadic among enterococci. Nonetheless, careful and ongoing monitoring of the in vitro effectiveness of linezolid will be needed so that any changes to the current status may be detected as soon as possible.