bluuebunny/crossref_metadata_2025_split huggingface dataset:
Giant cell arteritis: an updated review
Authors: Kawasaki Aki , Purvin Valerie 
Published: October 2008

Abstract.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

Abstract.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

Abstract.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

Abstract.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

ABSTRACT

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

ABSTRACT

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

ABSTRACTEtravirine, 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

ABSTRACT
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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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.