bluuebunny/crossref_metadata_2025 huggingface dataset:
Reformulating the Determiner Phrase Analysis
Authors: Bernstein Judy B.
Published: October 2008

Developed in the 1980s, the Determiner Phrase (DP) analysis stimulated a lot of interest in the internal structure of nominal phrases and in the study of correspondences between nominal and clausal structure. Research across a range of languages has uncovered correspondences in areas such as agreement morphology, syntactic movement, and argument structure, some of which are reviewed here. Nominal phrases and clauses also match up in terms of their semantic function: both can serve as predicates or arguments. The issue of exactly what distinguishes a nominal argument from a nominal predicate has received a lot of attention, leading in particular to proposals about the underlying role of the definite article (and determiner elements in general). This article reviews some of these issues and proposals and suggests a reformulation that appeals to the feature ‘person’, a feature found in both the nominal and clausal domains.
Monte Carlo Model of Stricture Formation in Photodynamic Therapy of Normal Pig Esophagus
Authors: Jones Linda R. , Preyer Norris W. , Wolfsen Herbert C. , Reynolds Daryl M. , Davis Monica A. , Wallace Michael B.
Published: October 2008

Photodynamic therapy (PDT) is FDA‐approved for use in patients with Barrett’s esophagus using porfimer sodium (2 mg per kg) and a recommended light dose of 130 J cm−1 for high grade dysplasia. Despite uniform drug and light doses, the clinical outcome of PDT is variable. A significant number of PDT cases result in esophageal strictures, a side effect related to excessive energy absorption. The purpose of this project was to model esophageal stricture formation with a Monte Carlo simulation. An original multilayer Monte Carlo computer simulation was developed for esophageal PDT. Optical absorption and scattering coefficients were derived for mucosal and muscle layers of normal porcine esophagus. Porfimer sodium was added to each layer by increasing the absorption coefficient by the appropriate amount. A threshold‐absorbed light dose was assumed to be required for stricture formation and ablation. The simulation predicted irreversible damage to the mucosa with a 160 J cm−1 light dose and damage to the muscle layer with an additional 160 J cm−1 light dose for a tissue porfimer sodium content of 3.5 mg kg−1. The simulation accurately modeled photodynamic stricture formation in normal pig in vivo esophageal tissue. This preliminary work suggests that the absorbed light threshold for stricture formation may be between 2 and 4 J per gram of tissue.
Fluorescence Detection of the Ornamental Fish Cardinal Tetra (Paracheirodon axelrodi)
Authors: Brinn Richard P. , Marcon Jaydione , Tavares‐Dias Marcos , Brinn Ira M.
Published: October 2008

The fluorescence spectra of the tropical fish, Cardinal Tetra (Paracheirodon axelrodi), originating in the Amazon region of Brazil, were determined. These spectra were then treated using factor analysis, generating two contributing spectra and separating out the noise. Time‐resolved fluorescence results indicated that the fluorescent system in the epidermis undergoes excited state reaction. Excited state proton transfer is suggested as being present. Both intentionally stressed and nonstressed individuals were used and some small differences were noted in the contributions of the two calculated contributing spectra to the experimental spectra, presumably as a function of stress. The results are compared with those obtained by the standard determination of cortisol level using the whole body extraction method and it is suggested that the method could be tested as an improved, nondestructive way to determine stress in this species, which is a necessary step in the development of “best management practices” of methods for storage and transport of the fish.
Hydrogen Peroxide‐mediated Inactivation of Two Chloroplastic Peroxidases, Ascorbate Peroxidase and 2‐Cys Peroxiredoxin†
Authors: Kitajima Sakihito
Published: October 2008

Reactive oxygen species (ROS), such as the superoxide anion and hydrogen peroxide, are generated by the photosystems because photoexcited electrons are often generated in excess of requirements for CO2 fixation and used for reducing molecular oxygen, even under normal environmental conditions. Moreover, ROS generation is increased in chloroplasts if plants are subjected to stresses, such as drought, high salinity and chilling. Chloroplast‐localized isoforms of ascorbate peroxidase and possibly peroxiredoxins assume the principal role of scavenging hydrogen peroxide. However, in vitro studies revealed that both types of peroxidases are easily damaged by hydrogen peroxide and lose their catalytic activities. This is one contributing factor for cellular damage that occurs under severe oxidative stress. In this review, I describe mechanisms of hydrogen peroxide‐mediated inactivation of these two enzymes and discuss a reason why they became susceptible to damage by hydrogen peroxide.
Photoprotection in Cyanobacteria: Regulation of Light Harvesting†
Authors: Bailey Shaun , Grossman Arthur
Published: October 2008

To cope with a rapidly fluctuating light environment, vascular plants and algae have evolved a photoprotective mechanism that serves to downregulate the transfer of excitation energy in the light‐harvesting complexes to the photosynthetic reaction centers. This process dissipates excess excitation energy in the chlorophyll pigment bed by a nonradiative pathway. Since this pathway competes with and therefore quenches chlorophyll fluoresence in a nonphotochemical manner, it has been termed Non‐photochemical Quenching (NPQ). For many years, cyanobacteria were not considered capable of performing NPQ as a photoprotective mechanism. Instead, the redistribution of the phycobilisome (PBS) light‐harvesting antenna between reaction centers by a process called state transitions was considered the major means of regulating the utilization of harvested light energy. Recently, it was demonstrated that cyanobacteria are able to use NPQ as one component of their photoprotective strategies. Cyanobacteria exhibit significant NPQ during nutrient‐replete growth, but it becomes a more prominent means of managing absorbed excitation energy when the cells experience iron starvation. Rapid progress in understanding the molecular mechanism of cyanobacterial NPQ has revealed a process that is very distinct from the functionally analogous process in plants and algae. Cyanobacterial NPQ involves the absorption of blue light by a carotenoid binding protein, termed the Orange Carotenoid Protein, and most likely involves quenching in the PBS core. In this study, we summarize work leading to the discovery of NPQ in cyanobacteria and the elucidation of molecular mechanisms associated with this important photoprotective process.
Patterns of Persistent DNA Damage Associated with Sun Exposure and the Glutathione S‐transferase M1 Genotype in Melanoma Patients
Authors: Steinberg Mark L. , Hubbard Karen , Utti Charles , Clas Brian , Hwang Bor‐Jang , Hill Helene Z. , Orlow Irene
Published: October 2008

Solar radiation can lead to changes affecting DNA metabolism resulting in loss of DNA integrity. Skin specimens obtained from melanoma patients treated at the Memorial Sloan‐Kettering Cancer Center were used to study patterns of DNA fragmentation using the comet assay and levels of deletions in mitochondrial DNA (mtDNA) using real‐time PCR. Skin specimens were classified according to the glutathione S‐transferase M1 (GSTM1) genotype (either wild type [WT] or null) and patient sunburn history. GSTM1 null individuals with a sunburn history showed increased levels of both DNA fragmentation by comet assays and mtDNA deletions relative to GSTM1 WT patients with little or no sunburn history. Microarray analyses identified a number of genes whose expression was upregulated ≥5‐fold in cells from GSTM1‐null patients or from those reporting histories of sunburn. These genes encoded small molecule transporters, various growth factor/chemokine receptors, transcription factors and tumor suppressors. Of 17 genes directly involved in DNA repair, three DNA ligases were highly upregulated while the RAD23 UV excision repair gene and the Growth Arrest and DNA Damage gene (GADD45) were downregulated. These findings support the idea that exposure to solar radiation early in life may induce long‐term cellular changes that lead to persistent DNA damage and altered patterns of gene expression.
The Occurrence of the psbS Gene Product in Chlamydomonas reinhardtii and in Other Photosynthetic Organisms and Its Correlation with Energy Quenching†
Authors: Bonente Giulia , Passarini Francesca , Cazzaniga Stefano , Mancone Carmine , Buia Maria Cristina , Tripodi Marco , Bassi Roberto , Caffarri Stefano
Published: October 2008

To avoid photodamage, photosynthetic organisms have developed mechanisms to evade or dissipate excess energy. Lumen overacidification caused by light‐induced electron transport triggers quenching of excited chlorophylls and dissipation of excess energy into heat. In higher plants participation of the PsbS protein as the sensor of low lumenal pH was clearly demonstrated. Although light‐dependent energy quenching is a property of all photosynthetic organisms, large differences in amplitude and kinetics can be observed thus raising the question whether a single common mechanism is in action. We performed a detailed study of PsbS expression/accumulation in Chlamydomonas reinhardtii and investigated its accumulation in other algae and plants. We showed that PsbS cannot be detected in Chlamydomonas under a wide range of growth conditions. Overexpression of the endogenous psbs gene showed that the corresponding protein could not be addressed to the thylakoid membranes. Survey of different unicellular green algae showed no accumulation of anti‐PsbS reactive proteins differently from multicellular species. Nevertheless, some unicellular species exhibit high energy quenching activity, suggesting that a PsbS‐independent mechanism is activated. By correlating growth habitat and PsbS accumulation in different species, we suggest that during the evolution the light environment has been a determinant factor for the conservation/loss of the PsbS function.
Asthma management and asthma control in São Paulo, Brazil and Uppsala, Sweden: a questionnaire‐based comparison
Authors: Skorup Paul , Rizzo Luiz Vicente , Machado‐Boman Lavinia , Janson Christer
Published: October 2008

Background and Aims:  The Global Initiative Against Asthma (GINA) was developed to meet the global challenge of asthma. GINA has been adopted in most countries and comparison of asthma management in different parts of the world may be of help when assessing the global dissemination of the guideline. The overall goals in GINA include that asthma patients should be free of symptoms, acute asthma attacks and activity limitations. The aim of the present study was to compare asthma management and asthma control in São Paulo, Brazil and Uppsala, Sweden.

Materials and Methods:  Information was collected from asthmatics in São Paulo and Uppsala with a questionnaire. The questionnaire dealt with the following issues: symptoms, smoking, self‐management, hospital visits, effect on school/work and medication.

Results:  The São Paulo patients were more likely to have uncontrolled asthma (36% vs 13%, P < 0.001), having made emergency room visits (57% vs 29%, P < 0.001) and having lost days at school or work because of their asthma (46% vs 28%, P = 0.03) than the asthmatics from Uppsala. There were no difference in the use of inhaled corticosteroids, but the Brazilian patients were more likely to be using theophylline (18% vs 1%, P = 0.001) and less likely to be using long‐acting beta‐2 agonists (18% vs 37%, P < 0.001).

Conclusion:  We conclude that the level of asthma control was lower among the patients from São Paulo than Uppsala. Few of the patients in either city reached the goals set up by GINA. Improved asthma management may therefore lead to health–economic benefits in both locations.

Please cite this paper as: Skorup P, Rizzo LV, Machado‐Boman L and Janson C. Asthma management and asthma control in São Paulo, Brazil and Uppsala, Sweden: a questionnaire‐based comparison. The Clinical Respiratory Journal 2009; 3: 22–28.
Repeated peribulbar injections of triamcinolone acetonide: a successful and safe treatment for moderate to severe Graves’ ophthalmopathy
Authors: Bordaberry Marcela , Marques Daniela L. , Pereira‐Lima Julio C. , Marcon Italo M. , Schmid Helena
Published: October 2008

Purpose:  In this study, we aimed to evaluate the efficacy of peribulbar triamcinolone injections to treat inflammatory signs of Graves’ ophthalmopathy (GO) in patients with moderate to severe GO and associated optic neuropathy (ON).

Methods:  Twenty‐one patients with active GO [clinical activity score (CAS) ≥ 4] and systemic thyroid disease under control were enrolled in this prospective pilot study. Peribulbar triamcinolone acetonide was injected in each orbit (42 eyes), in four doses of 20 mg at 2‐week intervals. Ophthalmological examination including CAS evaluation, visual field, computerized tomography (CT) scan and digital photography were performed before and after treatment.

Results:  Twenty‐one patients (11 with moderate disease, 10 with ON) were enrolled in this study and followed for at least 14 months. Initial mean CAS was 6.38 ± 1.49, which dropped to 1.8 ± 1.12 after 6 months of treatment (P = 0.01; mean difference of 4.57 ± 1.56; range 1–8 score points). ON was diagnosed in 10 patients. Of these, 66% improved with peribulbar triamcinolone exclusively. A transitory increase in intraocular pressure in two patients was controlled with topic medication.

Conclusion:  Peribulbar triamcinolone injections reduce the inflammatory signs of moderate GO, as measured by the CAS, and could also be used as an alternative treatment for ON. Randomized clinical trials are needed to compare the results of triamcinolone peribulbar injections to those of other treatment modalities.
Giant cell arteritis: an updated review
Authors: Kawasaki Aki , Purvin Valerie
Published: October 2008

Giant cell arteritis (GCA) is the most common primary vasculitis of adults. The incidence of this disease is practically nil in the population under the age of 50 years, then rises dramatically with each passing decade. The median age of onset of the disease is about 75 years. As the ageing population expands, it is increasingly important for ophthalmologists to be familiar with GCA and its various manifestations, ophthalmic and non‐ophthalmic. A heightened awareness of this condition can avoid delays in diagnosis and treatment. It is well known that prompt initiation of steroids remains the most effective means for preventing potentially devastating ischaemic complications. This review summarizes the current concepts regarding the immunopathogenetic pathways that lead to arteritis and the major phenotypic subtypes of GCA with emphasis on large vessel vasculitis, novel modalities for disease detection and investigative trials using alternative, non‐steroid therapies.
Minor surgery for the repair of retinal detachment emanating from retinoschisis
Authors: Lincoff Harvey , Kreissig Ingrid , Uram Dominik
Published: October 2008

Purpose:  To propose a mechanism for the development of the outer layer retinal tears that occur with retinoschisis and the detachment emanating from it that is consistent with the limited extent of the detachment and the response to binocular occlusion and local buckles.

Methods:  A consecutive series of 24 patients with retinoschisis, collected over 15 years, was analysed. Seven patients developed a symptomatic retinal detachment emanating from breaks in the outer layers of retinoschisis. The detachments responded to binocular occlusion, a sponge buckle, or a temporary balloon buckle and laser coagulation to the edges of the breaks.

Results:  Two retinas attached completely after 48 hr of binocular occlusion, four responded to local sponge buckles and one to a temporary balloon buckle. All attached without drainage of subretinal fluid. Final visual acuity was 20/20 in six eyes and 20/25 in one eye.

Conclusion:  The detachment emanating from retinoschisis responds to ocular rest or a local buckle to breaks in the outer layers. It is proposed that the mechanism for the detachment that emanates from retinoschisis is intraretinal traction by residual transretinal fibres at the edge of the schisis cavity.
Repeatability in and interchangeability between the macular and the fast macular thickness map protocols: a study on normal eyes with Stratus optical coherence tomography
Authors: Eriksson Urban , Alm Albert
Published: October 2008

Purpose:  To collect a normal material and to compare the macular and the fast macular thickness map protocols regarding normal values and repeatability.

Methods:  Sixty‐seven individuals underwent three repeated scans with the macular thickness protocol; 45 of them also had three scans with the fast thickness protocol in Stratus optical coherence tomography (OCT). The maps were divided into nine ETDRS fields, where thickness values were presented. The repeatability was calculated as intraclass correlation coefficient (ICC), coefficient of variance (CV) and coefficient of repeatability (CR). For comparison between the two protocols, limits of agreement were determined according to Bland–Altman.

Results:  Normal values for the two protocols were very close. Repeatability was high. ICC for all areas was 0.92–0.98. CV was less than 1% and CR was 6–8 μm for both protocols, with the exception of the fovea in the fast protocol (where CV was 1.44% and CR 12.4 μm). Limits of agreement between the two protocols were less than 10 μm as a rule.

Conclusion:  Normal values for the protocols are equal and they both have excellent repeatability. The fast macular map is a good alternative with the possible exception of the fovea, where variation is twice that of the macular thickness map.
Association between corneal hysteresis and central corneal thickness in glaucomatous and non‐glaucomatous eyes
Authors: Mangouritsas George , Morphis George , Mourtzoukos Spyridon , Feretis Elias
Published: October 2008

Purpose:  We aimed to determine corneal hysteresis values (CH) using the ocular response analyser (ORA) in non‐glaucomatous and glaucomatous eyes and their relationship with central corneal thickness (CCT).

Methods:  Corneal hysteresis, intraocular pressure (IOP) as measured by Goldmann applanation tonometry (GAT) and CCT were prospectively evaluated in 74 non‐glaucoma subjects with IOP < 21 mmHg and in 108 patients with treated primary open‐angle glaucoma (POAG). One eye in each subject was randomly selected for inclusion in the analysis.

Results:  Mean (± standard deviation [SD]) age was 59.2 ± 14.2 years in the non‐glaucoma group and 62.4 ± 9.8 years in the glaucoma group. Mean (± SD) GAT IOP was 15.7 ± 2.65 mmHg and 16.38 ± 2.73 mmHg in the non‐glaucoma and glaucoma groups, respectively. There was no statistically significant difference between the two groups in mean age (p = 0.396) or mean GAT IOP (p = 0.098). Mean (± SD) CH was 10.97 ± 1.59 mmHg in the non‐glaucoma and 8.95 ± 1.27 mmHg in the glaucoma groups, respectively. The difference in mean CH between the two groups was statistically significant (p < 0.0001). There was a strong positive correlation between CH and CCT in the non‐glaucoma group (r = 0.743) and a significantly (p = 0.001) weaker correlation (r = 0.426) in the glaucoma group.

Conclusions:  Corneal hysteresis was significantly lower in eyes with treated POAG than in non‐glaucomatous eyes. The corneal biomechanical response was strongly associated with CCT in non‐glaucoma subjects, but only moderately so in glaucoma patients. It can be assumed that diverse structural factors, in addition to thickness, determine the differences in the corneal biomechanical profile between non‐glaucomatous and glaucomatous eyes. Corneal hysteresis could be a useful tool in the diagnosis of glaucoma.
Pharmacokinetics of
l
-Arginine in Adults with Moderately Severe Malaria
Authors: Yeo Tsin W. , Rooslamiati Indri , Gitawati Retno , Tjitra Emiliana , Lampah Daniel A. , Kenangalem Enny , McNeil Yvette R. , Price Richard N. , Anstey Nicholas M. , Duffull Stephen B.
Published: October 2008

Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of
l
-arginine, the substrate for NO synthase. Supplementation with
l
-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for
l
-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g,
l
-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received
l
-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of
l
-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous
l
-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the

K
m

of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.
Selected Replicon Variants with Low-Level In Vitro Resistance to the Hepatitis C Virus NS5B Polymerase Inhibitor PSI-6130 Lack Cross-Resistance with R1479
Authors: Ali Samir , Leveque Vincent , Le Pogam Sophie , Ma Han , Philipp Friederike , Inocencio Nicole , Smith Mark , Alker Andre , Kang Hyunsoon , Najera Isabel , Klumpp Klaus , Symons Julian , Cammack Nick , Jiang Wen-Rong
Published: October 2008

PSI-6130 (β-
d
-2′-deoxy-2′-fluoro-2′-
C
-methylcytidine) is a selective inhibitor of hepatitis C virus (HCV) replication that targets the NS5B polymerase. R7128, the prodrug of PSI-6130, has shown antiviral efficacy in patients chronically infected with HCV genotype 1a (GT-1a) and GT-1b. We observed that the compound exhibited potent in vitro activity against laboratory-optimized HCV replicons as well as against a panel of replicons containing NS5B HCV polymerases derived from GT-1a and GT-1b clinical isolates. We used the HCV replicon cell system to examine the emergence of variants with reduced sensitivity to PSI-6130. Short-term treatment of cells harboring the HCV subgenomic replicon with PSI-6130 cleared the replicon without generating resistant variants. Long-term culture of the cells under the compound selection generated the S282T substitution in a complex pattern with other amino acid substitutions in the NS5B polymerase. The presence of the coselected substitutions did not increase the moderate three- to sixfold loss of sensitivity to PSI-6130 mediated by the S282T substitution; however, their presence enhanced the replication capacity compared to the replication levels seen with the S282T substitution alone. We also observed a lack of cross-resistance between PSI-6130 and R1479 and demonstrated that long-term culture selection with PSI-6130 in replicon cells harboring preexisting mutations resistant to R1479 (S96T/N142T) results in the emergence of the S282T substitution and the reversion of S96T to wild-type serine. In conclusion, PSI-6130 presents a high barrier to resistance selection in vitro, selects for variants exhibiting only low-level resistance, and lacks cross-resistance with R1479, supporting the continued development of the prodrug R7128 as a therapeutic agent for the treatment of HCV infection.
Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects
Authors: Anderson Matt S. , Kakuda Thomas N. , Hanley William , Miller Jutta , Kost James T. , Stoltz Randall , Wenning Larissa A. , Stone Julie A. , Hoetelmans Richard M. W. , Wagner John A. , Iwamoto Marian
Published: October 2008

Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC0-12), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (Cmax), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C12); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC0-12, 1.04 (0.97, 1.12) forCmax, and 1.17 (1.10, 1.26) forC12. All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.
Bacteriophage Therapy and the Mutant Selection Window
Authors: Cairns Benjamin J. , Payne Robert J. H.
Published: October 2008

We use kinetic models to investigate how to design antimicrobial phage therapies to minimize emergence of resistant bacteria. We do this by modifying the “mutant selection window” hypothesis in a way that accounts for the ongoing self-replication of the phage. We show that components of combination phage therapies need to be appropriately matched if treatment is to avoid the emergence of resistant bacteria. Matching of components is more easily achieved when phage dosages are high enough that ongoing phage replication is not needed for the clearance of the bacteria. Theoretical predictions such as ours need to be tested experimentally if applications of phage therapy are to avoid the problems of widespread resistance that have beset chemical antibiotics.
Mechanisms Accounting for Fluoroquinolone Resistance in
Escherichia coli
Clinical Isolates
Authors: Morgan-Linnell Sonia K. , Becnel Boyd Lauren , Steffen David , Zechiedrich Lynn
Published: October 2008

Fluoroquinolone MICs are increased through the acquisition of chromosomal mutations in the genes encoding gyrase (
gyrA
and
gyrB
) and topoisomerase IV (
parC
and
parE
), increased levels of the multidrug efflux pump AcrAB, and the plasmid-borne genes
aac
(
6
′)-
Ib
-cr and the
qnr
variants in
Escherichia coli
. In the accompanying report, we found that ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs for fluoroquinolone-resistant
E. coli
clinical isolates were very high and widely varied (L. Becnel Boyd, M. J. Maynard, S. K. Morgan-Linnell, L. B. Horton, R. Sucgang, R. J. Hamill, J. Rojo Jimenez, J. Versalovic, D. Steffen, and L. Zechiedrich, Antimicrob. Agents Chemother.
53:
229-234, 2009). Here, we sequenced
gyrA
,
gyrB
,
parC
, and
parE
; screened for
aac
(
6
′)-
Ib
-cr and
qnrA
; and quantified AcrA levels in
E. coli
isolates for which patient sex, age, location, and site of infection were known. We found that (i) all fluoroquinolone-resistant isolates had
gyrA
mutations; (ii) ∼85% of
gyrA
mutants also had
parC
mutations; (iii) the ciprofloxacin and norfloxacin MICs for isolates harboring
aac
(
6
′)-
Ib
-cr (∼23%) were significantly higher, but the gatifloxacin and levofloxacin MICs were not; (iv) no isolate had
qnrA
; and (v) ∼33% of the fluoroquinolone-resistant isolates had increased AcrA levels. Increased AcrA correlated with nonsusceptibility to the fluoroquinolones but did not correlate with nonsusceptibility to any other antimicrobial agents reported from hospital antibiograms. Known mechanisms accounted for the fluoroquinolone MICs of 50 to 70% of the isolates; the remaining included isolates for which the MICs were up to 1,500-fold higher than expected. Thus, additional, unknown fluoroquinolone resistance mechanisms must be present in some clinical isolates.
In Vitro Activities of Doripenem, a New Broad-Spectrum Carbapenem, against Recently Collected Clinical Anaerobic Isolates, with Emphasis on the
Bacteroides fragilis
Group
Authors: Snydman David R. , Jacobus Nilda V. , McDermott Laura A.
Published: October 2008

Doripenem was evaluated against 527 recent clinical isolates, i.e., 404
Bacteroides fragilis
isolates and 123 gram-positive anaerobe isolates. Against
B. fragilis
, doripenem was as active as imipenem, meropenem, and piperacillin-tazobactam and more active than ertapenem or ampicillin-sulbactam. Doripenem was active against isolates resistant to ertapenem, ampicillin-sulbactam, cefoxitin, clindamycin, and moxifloxacin. All of the gram-positive isolates tested were susceptible to doripenem.
Relationships among Ciprofloxacin, Gatifloxacin, Levofloxacin, and Norfloxacin MICs for Fluoroquinolone-Resistant
Escherichia coli
Clinical Isolates
Authors: Becnel Boyd Lauren , Maynard Merry J. , Morgan-Linnell Sonia K. , Horton Lori Banks , Sucgang Richard , Hamill Richard J. , Jimenez Javier Rojo , Versalovic James , Steffen David , Zechiedrich Lynn
Published: October 2008

Fluoroquinolones are some of the most prescribed antibiotics in the United States. Previously, we and others showed that the fluoroquinolones exhibit a class effect with regard to the CLSI-established breakpoints for resistance, such that decreased susceptibility (i.e., an increased MIC) to one fluoroquinolone means a simultaneously decreased susceptibility to all. For defined strains, however, clear differences exist in the pharmacodynamic properties of each fluoroquinolone and the extent to which resistance-associated genotypes affect the MICs of each fluoroquinolone. In a pilot study of 920 clinical
Escherichia coli
isolates, we uncovered tremendous variation in norfloxacin MICs. The MICs for all of the fluoroquinolone-resistant isolates exceeded the resistance breakpoint, reaching 1,000 μg/ml. Approximately 25% of the isolates (
n
= 214), representing the full range of resistant norfloxacin MICs, were selected for the simultaneous determinations of ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs. We found that (i) great MIC variation existed for all four fluoroquinolones, (ii) the ciprofloxacin and levofloxacin MICs of >90% of the fluoroquinolone-resistant isolates were higher than the resistance breakpoints, (iii) ciprofloxacin and levofloxacin MICs were distributed into two distinct groups, (iv) the MICs of two drug pairs (ciprofloxacin and norfloxacin by Kendall's Tau-b test and gatifloxacin and levofloxacin by paired
t
test) were similar with statistical significance but were different from each other, and (v) ∼2% of isolates had unprecedented fluoroquinolone MIC relationships. Thus, although the fluoroquinolones can be considered equivalent with regard to clinical susceptibility or resistance, fluoroquinolone MICs differ dramatically for fluoroquinolone-resistant clinical isolates, likely because of differences in drug structure.
Genetic Characterization of Vga ABC Proteins Conferring Reduced Susceptibility to Pleuromutilins in
Staphylococcus aureus
Authors: Gentry Daniel R. , McCloskey Lynn , Gwynn Michael N. , Rittenhouse Stephen F. , Scangarella Nicole , Shawar Ribhi , Holmes David J.
Published: October 2008

Retapamulin MICs of ≥2 μg/ml were noted for 6 of 5,676
S. aureus
recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.
Glycerol Monolaurate Does Not Alter Rhesus Macaque (
Macaca mulatta
) Vaginal Lactobacilli and Is Safe for Chronic Use
Authors: Schlievert Patrick M. , Strandberg Kristi L. , Brosnahan Amanda J. , Peterson Marnie L. , Pambuccian Stefan E. , Nephew Karla R. , Brunner Kevin G. , Schultz-Darken Nancy J. , Haase Ashley T.
Published: October 2008

Glycerol monolaurate (GML) is a fatty acid monoester that inhibits growth and exotoxin production of vaginal pathogens and cytokine production by vaginal epithelial cells. Because of these activities, and because of the importance of cytokine-mediated immune activation in human immunodeficiency virus type 1 (HIV-1) transmission to women, our laboratories are performing studies on the potential efficacy of GML as a topical microbicide to interfere with HIV-1 transmission in the simian immunodeficiency virus-rhesus macaque model. While GML is generally recognized as safe by the FDA for topical use, its safety for chronic use and effects on normal vaginal microflora in this animal model have not been evaluated. GML was therefore tested both in vitro for its effects on vaginal flora lactobacilli and in vivo as a 5% gel administered vaginally to monkeys. In vitro studies demonstrated that lactobacilli are not killed by GML; GML blocks the loss of their viability in stationary phase and does not interfere with lactic acid production. GML (5% gel) does not quantitatively alter monkey aerobic vaginal microflora compared to vehicle control gel. Lactobacilli and coagulase-negative staphylococci are the dominant vaginal aerobic microflora, with beta-hemolytic streptococci,
Staphylococcus aureus
, and yeasts sporadically present; gram-negative rods are not part of their vaginal flora. Colposcopy and biopsy studies indicate that GML does not alter normal mucosal integrity and does not induce inflammation; instead, GML reduces epithelial cell production of interleukin 8. The studies suggest that GML is safe for chronic use in monkeys when applied vaginally; it does not alter either mucosal microflora or integrity.
MexCD-OprJ Multidrug Efflux System of
Pseudomonas aeruginosa
: Involvement in Chlorhexidine Resistance and Induction by Membrane-Damaging Agents Dependent upon the AlgU Stress Response Sigma Factor
Authors: Fraud Sebastien , Campigotto Aaron J. , Chen Zhilin , Poole Keith
Published: October 2008

The biocide chlorhexidine (CHX) as well as additional membrane-active agents were shown to induce expression of the
mexCD-oprJ
multidrug efflux operon, dependent upon the AlgU stress response sigma factor. Hyperexpression of this efflux system in
nfxB
mutants was also substantially AlgU dependent. CHX resistance correlated with efflux gene expression in various mutants, consistent with MexCD-OprJ being a determinant of CHX resistance.
Minimal Effects of Ritonavir and Efavirenz on the Pharmacokinetics of Raltegravir
Authors: Iwamoto Marian , Wenning Larissa A. , Petry Amelia S. , Laethem Martine , De Smet Marina , Kost James T. , Breidinger Sheila A. , Mangin Eric C. , Azrolan Neal , Greenberg Howard E. , Haazen Wouter , Stone Julie A. , Gottesdiener Keith M. , Wagner John A.
Published: October 2008

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (
C
12 h
) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC
0
-
∞
) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (
C
max
) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced:
C
12 h
GMR (90% CI) was 0.79 (0.49, 1.28); AUC
0-
∞
was 0.64 (0.52, 0.80); and
C
max
was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.
Binding of Excreted and/or Secreted Products of Adult Hookworms to Human NK Cells inNecator americanus-Infected Individuals from Brazil
Authors: Teixeira-Carvalho Andréa , Fujiwara Ricardo T. , Stemmy Erik J. , Olive Denise , Damsker Jesse M. , Loukas Alex , Corrêa-Oliveira Rodrigo , Constant Stephanie L. , Bethony Jeffrey M.
Published: October 2008

The impact of the interaction between excreted and/or secreted (ES)Necator americanusproducts and NK cells fromNecator-infected individuals was analyzed. We investigated the binding of ES products to NK cells, the expression of NK cell receptors (CD56, CD159a/NKG2A, CD314/NKG2D, CD335/NKp46, and KLRF1/NKp80), the frequency of gamma interferon (IFN-γ)-producing NK cells after whole-blood in vitro stimulation, and the capacity ofN. americanusES products to induce NK cell chemotaxis. In contrast to those from noninfected individuals, NK cells fromNecator-infected individuals demonstrated no binding withN. americanusES products. This phenomenon was not due to alterations in NK cell receptor expression in infected subjects and could not be reproduced with NK cells from uninfected individuals by incubation with immunoregulatory cytokines (interleukin-10/transforming growth factor β). Further, we found that a significantly greater percentage of NK cells from infected subjects than NK cells from uninfected individuals spontaneously produced IFN-γ upon ex vivo culture. Our findings support a model whereby NK cells fromNecator-infected individuals may interact with ES products, making these cells refractory to binding with exogenous ES products. DuringN. americanusinfection, human NK cells are attracted to the site of infection by chemotactic ES products produced by adultNecatorworms in the gut mucosa. Binding of ES products causes the NK cells to become activated and secrete IFN-γ locally, thereby contributing to the adult hookworm's ability to evade host immune responses.
Uropathogenic
Escherichia coli
CFT073 Is Adapted to Acetatogenic Growth but Does Not Require Acetate during Murine Urinary Tract Infection
Authors: Anfora Andrew T. , Halladin David K. , Haugen Brian J. , Welch Rodney A.
Published: October 2008

In vivo accumulation of
d
-serine by
Escherichia coli
CFT073 leads to elevated expression of PAP fimbriae and hemolysin by an unknown mechanism. Loss of
d
-serine catabolism by CFT073 leads to a competitive advantage during murine urinary tract infection (UTI), but loss of both
d
- and
l
-serine catabolism results in attenuation. Serine is the first amino acid to be consumed in closed tryptone broth cultures and precedes the production of acetyl phosphate, a high-energy molecule involved in intracellular signaling, and the eventual secretion of acetate. We propose that the colonization defect associated with the loss of serine catabolism is due to perturbations of acetate metabolism. CFT073 grows more rapidly on acetogenic substrates than does
E. coli
K-12 isolate MG1655. As shown by transcription microarray results,
d
-serine is catabolized into acetate via the phosphotransacetylase (
pta
) and acetate kinase (
ackA
) genes while downregulating expression of acetyl coenzyme A synthase (
acs
). CFT073
acs
, which is unable to reclaim secreted acetate, colonized mouse bladders and kidneys in the murine model of UTI indistinguishably from the wild type. Both
pta
and
ackA
are involved in the maintenance of intracellular acetyl phosphate. CFT073
pta
and
ackA
mutants were screened to investigate the role of acetyl phosphate in UTI pathogenesis. Both single mutants are at a competitive disadvantage relative to the wild type in the kidneys but normally colonize the bladder. CFT073
ackA pta
was attenuated in both the bladder and the kidneys. Thus, we demonstrate that CFT073 is adapted to acetate metabolism as a result of requiring a proper cycling of the acetyl phosphate pathway for colonization of the upper urinary tract.
Implications of bevacizumab on vascular endothelial growth factor and endostatin in human choroidal neovascularisation
Authors: Tatar O , Shinoda K , Kaiserling E , Claes C , Eckardt C , Eckert T , Pertile G , Boeyden V , Scharioth G B , Yoeruek E , Szurman P , Bartz-Schmidt K U , Group Tuebingen Bevacizumab Study , Grisanti S
Published: October 2008

Aim:

To evaluate the implications of intravitreal bevacizumab on proangiogenic vascular endothelial growth factor (VEGF) with regard to the endogenous angiogenesis inhibitor endostatin in human choroidal neovascularisation (CNV) secondary to age-related macular degeneration.

Methods:

Retrospective review of an interventional case series of 48 patients who underwent full macular translocation surgery with removal of CNV. Twenty-five patients were treated with intravitreal bevacizumab injection 1 to 154 days prior to surgery (bevacizumab CNV). Twenty-three CNV without any kind of previous treatment were used as controls (control CNV). CNV were stained for CD34, cytokeratin18, VEGF, endostatin and E-selectin. A “predominance score of VEGF over endostatin” (PS) was defined by the difference between VEGF and endostatin staining scores.

Results:

Bevacizumab CNV revealed a weaker VEGF expression in endothelial cells (p = 0.0245) but significantly more intense endostatin in retina pigment epithelium (RPE) (p = 0.0001) and stroma (p<0.0001). Consequently, PS was significantly lower in RPE (p = 0.02), vessels (p = 0.03) and stroma (p = 0.0004) in bevacizumab CNV. The intensity of E-selectin expression in bevacizumab CNV was comparable with that in control CNV.

Conclusions:

A shift within the angiogenic balance in terms of decreased VEGF predominance over endostatin is detected in human CNV treated with bevacizumab.
One-year follow-up of a randomised controlled trial on added splinting to eccentric exercises in chronic midportion Achilles tendinopathy
Authors: de Jonge S , de Vos R J , Van Schie H T M , Verhaar J A N , Weir A , Tol J L
Published: October 2008

Objective

The study examined whether the addition of a night splint to eccentric exercises is beneficial for functional outcome in chronic midportion Achilles tendinopathy.

Design

One-year follow-up of a randomised controlled single blinded clinical trial.

Setting

Sports medicine department in a general hospital.

Patients

58 patients (70 tendons) were included.

Interventions

All patients completed a 12-week heavy load eccentric training programme. One group received a night splint in addition to eccentric exercises.

Main outcome measurements

Outcome scores were: Victorian Institute of Sport Assessment—Achilles (VISAA) score, subjective patient satisfaction and neovascularisation score measured with power Doppler ultrasonography (PDU).

Results

For both groups the VISA-A score increased significantly (from 50 to 76 (p<0.01) in the eccentric group and from 49 to 78 (p<0.01) in the night splint group). No significant differences in the VISA-A score were found between the groups from baseline to one year (p = 0.32). The presence of neovessels at baseline did not predict a change in the VISA-A score after one year in the whole group (p = 0.71).

Conclusion

Eccentric exercises with or without a night splint improved functional outcome at one year follow-up. At follow-up there was no significant difference in clinical outcome when a night splint was used in addition to an eccentric exercise programme. Between 3 months and one year follow-up, a continuing increase in the VISA-A score was found. Assessment of the neovascularisation score with PDU at baseline has no prognostic value on long-term clinical outcome.
Linking performance and chronic disease risk: indices of physical performance are surrogates for health
Authors: Booth F W , Roberts C K
Published: October 2008

Recent studies have identified a remarkable association between indices of athletic performance and optimal health of the general public. Both high aerobic capacity and high skeletal muscle strength are associated with lower mortality. Furthermore, higher aerobic capacity and often higher skeletal muscle strength are associated with a lower prevalence of most chronic diseases. Also, maintenance of aerobic capacity and skeletal muscle strength by lifelong physical activity delays the biological ageing in most organ systems, therefore delaying premature death. These facts raise the question whether associations between high aerobic capacity and muscle strength are causally or associatively related to either metabolic health or elite performance. If a causal relationship was noted at the molecular level, it would have major public health implications. In this review, evidence is presented for the assertion that research on elite athletes and chronic disease prevention by exercise is actually addressing the same biochemical, physiological and genomic phenomena.
Altered hip and trunk muscle function in individuals with patellofemoral pain
Authors: Cowan S M , Crossley K M , Bennell K L
Published: October 2008

Objective:

The purpose of this study was to investigate the role of hip muscles in patellofemoral pain (PFP), specifically by investigating neuromotor control, strength and range of motion of the hip muscles.

Design:

Cross-sectional.

Setting:

University laboratory.

Patients:

Ten participants diagnosed with PFP and 27 asymptomatic controls were recruited, using standard inclusion and exclusion criteria.

Main outcome measures:

Electromyographic activity of the vasti and anterior gluteus medius (GM) were recorded using surface electrodes and posterior GM using fine wire electrodes while the participant completed a stair-stepping task. Hip strength and trunk side flexion strength was assessed using a hand-held dynamometer and hip range of motion with an inclinometer. Pain and disability measures were recorded for the PFP participants.

Results:

When individuals with PFP completed the stair-stepping task there was a delay in activation of both anterior and posterior GM (p<0.02) and an alteration in vasti control (p = 0.001). In addition, trunk side flexion strength was significantly less (29%) in individuals with PFP (p = 0.03).

Conclusion:

This study provides evidence that trunk side flexion strength and neuromotor control of the GM are affected in people with PFP. This study also confirms the presence of a delayed vastus medialis obliquus relative to vastus lateralis, providing further evidence underpinning the importance of retraining the vasti function in patients with PFP.