bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetic Analysis and Simulation of the Time‐Concentration Profile of Etanercept in Pediatric Patients With Juvenile Rheumatoid Arthritis
Authors: Yim Dong‐Seok , Zhou Honghui , Buckwalter Mary , Nestorov Ivan , Peck Carl C. , Lee Howard 
Published: February 2005

This study was performed to estimate the population pharmacokinetic (PK) parameters of etanercept in pediatric juvenile rheumatoid arthritis (JRA) patients and to compare the steady‐state time‐concentration profiles between etanercept 0.8‐mg/kg once‐weekly and 0.4‐mg/kg twice‐weekly subcutaneous (SC) regimens by clinical trial simulation. To this end, mixed‐effect analysis (NONMEM, Version 5.1) was performed using the etanercept PK database consisting of 69 JRA patients (4–17 years). Based on the population PK parameters obtained herein, a Monte Carlo clinical trial simulation experiment was conducted to compare the PK profiles in 200 virtual JRA patients who randomly received either etanercept 0.4 mg/kg SC twice weekly or 0.8 mg/kg once weekly for 12 weeks. The following population PK model could adequately describe etanercept PK profiles for twice‐weekly SC dosing of 0.4 mg/kg:
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The means ± standard deviations of simulated trough concentrations for 0.8‐mg/kg once‐weekly and 0.4‐mg/kg twice‐weekly dosing regimens were 1.58 ± 1.07 mg/L and 1.92 ± 1.09 mg/L, respectively. Peaks during 0.8‐mg/kg once‐weekly dosing (2.92 ± 1.41 mg/L) were only 11% higher than during 0.4 mg/kg twice‐weekly dosing (2.62 ± 1.23 mg/L). In conclusion, the clinical trial simulation confirmed that 0.8‐mg/kg once‐weekly and 0.4‐mg/kg twice‐weekly SC regimens of etanercept are expected to yield overlapping steady‐state time‐concentration profiles, leading to equivalent clinical outcomes. This has been the basis of the recent Food and Drug Administration approval of the 0.8‐mg/kg once‐weekly regimen in pediatric patients with JRA.
Topical Ketoprofen Patch (100 mg) for the Treatment of Ankle Sprain: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Mazières Bernard , Rouanet Stéphanie , Velicy Joanne , Scarsi Claudia , Reiner Valentina 
Published: February 2005

Background Topical nonsteroidal anti-inflammatory drugs offer the advantage of enhanced drug delivery to local affected tissues with low plasma levels and an expected reduced incidence of systemic adverse events (mainly peptic ulcer disease and gastrointestinal hemorrhage). Hypothesis To test the efficacy and tolerability of a 100-mg patch of ketoprofen applied once a day. Study Design Randomized controlled clinical trial; Level of evidence, 1. Methods The 2-week trial included patients suffering painful (spontaneous pain ≥50 mm on a 0- to 100-mm visual analog scale), benign (grade I or II), recent (<2 days) ankle sprains as a model of general traumatic soft tissue injuries. The primary efficacy criterion was spontaneous pain change after 7 days of treatment in the intention-to-treat population. One hundred sixty-three patients were randomized (ketoprofen, 81; placebo, 82). Results After 1 week of treatment, the decrease in spontaneous pain was -50 ± 20 mm for ketoprofen and -38 ± 24 mm for the placebo, showing a statistically significant intergroup difference (P =. 0007). The majority of the secondary criteria were also statistically significant in favor of the ketoprofen patch. Tolerance was good in both groups, adverse events being mostly local. Conclusion This trial suggested that a 7-day course of treatment with a ketoprofen patch is useful in benign ankle sprain, without revealing unexpected adverse events.
Risk Factors for Injury in Subelite Rugby League Players
Authors: Gabbett Tim J. , Domrow Nathan 
Published: February 2005

Background Although player fatigue and playing intensity have been suggested to contribute to injuries in rugby league players, no study has confirmed if the level of physical fitness is a risk factor for injury in rugby league players. The aim of this study was to identify risk factors for injury in subelite rugby league players. Hypothesis Low physical fitness levels are risk factors for injury in subelite rugby league players. Study Design Cohort study; Level of evidence, 2. Methods One hundred fifty-three players from a subelite rugby league club underwent preseason measurements of muscular power (vertical jump), speed (10- and 40-m sprint), and maximal aerobic power (multistage fitness test) over 4 competitive seasons. All injuries sustained by players were prospectively recorded over the 4 competitive seasons. Results The risk of injury was greater in players with low 10- and 40-m speed. Players with a low maximal aerobic power had a greater risk of sustaining a contact injury. In addition, players who completed less than 18 weeks of training before sustaining their initial injuries were at greater risk of sustaining a subsequent injury. Conclusions Subelite rugby league players with low speed and maximal aerobic power are at an increased risk of injury. In addition, players who complete less than 18 weeks of training before sustaining an initial injury are at greater risk of sustaining a subsequent injury. These findings highlight the importance of speed and endurance training to reduce the incidence of injury in subelite rugby league players.
Reliability of Stress Radiography for Evaluation of Posterior Knee Laxity
Authors: Schulz Martin S. , Russe Kai , Lampakis Georgios , Strobel Michael J. 
Published: February 2005

Background Although stress radiography has been recommended for quantifying posterior tibial displacement in knees with posterior cruciate ligament insufficiency, the intratester reliability and intertester reliability of this measurement method have not been evaluated. Hypothesis Stress radiography is a reproducible measurement method in the assessment of posterior knee laxity in patients with posterior cruciate ligament lesions. Study Design Cohort study (diagnosis); Level of evidence, 2. Methods Stress radiographs of 787 patients with suspected posterior cruciate ligament lesions taken using the Telos device were evaluated independently by 3 testers: 2 of the testers were clinically experienced in the evaluation of stress radiographs, and 1 tester was a novice tester. Change in mean, standard error of measurement with calculated confidence intervals, and intraclass correlation coefficients were determined to assess intratester and intertester reliability. Results There was no significant intratester change in mean. Intratester standard error of measurement was 1.03 mm; 95% confidence intervals were ±2.02 mm for a single measurement and ±2.86 mm for a change in measurement. The intratester intraclass correlation coefficient was 0.95. Intertester reliability revealed a significant change in mean between the experienced testers and the novice tester (P <. 001). There was no substantial difference for the standard error of measurement of each tester. The mean intertester standard error of measurement was 1.41 mm; 95% confidence intervals were ±2.77 mm for a single measurement and ±3.91 mm for a change in measurement. The intertester intraclass correlation coefficient was 0.91. Conclusion Stress radiography was found to be a measurement method with a useful reliability for evaluation of posterior laxity in patients with posterior cruciate ligament lesions. The reproducibility of stress radiography may be influenced by multiple variables, and standardized methods are needed to minimize measurement error.
Predicting in vivo Clinical Performance of Anterior Cruciate Ligament Fixation Methods from in Vitro Analysis
Authors: Saweeres Emad S. B. , Kuiper Jan H. , Evans Richard O. , Richardson James B. , White Stephen H. 
Published: February 2005

Background Anterior cruciate ligament graft fixations experience cyclic loads in vivo. Present cyclic loading studies testing fixation use “incremental cycling,”“residual strength” protocols, or a combination. Industrial standards, however, rely on fatigue life testing and use tolerance limits to determine guaranteed minimum levels of cycles to failure. Hypothesis Industrial standards of fatigue life and lower tolerance limits provide a more conservative assessment of cycles to failure than do currently used cyclic loading models, and they facilitate interpretation of data toward clinical performance. Study Design Descriptive laboratory study. Methods Fatigue life curves and lower tolerance limits were calculated for porcine patellar tendon graft fixations that were tested to failure in single pulls or cycled to failure at 2 different load levels. A log curve was constructed so that the expected values at other load levels could be calculated. Comparison of a metal and a composite resorbable interference screw design was used as an example. Results Cycles to failure of both screw designs varied widely at each load level. The guaranteed minimum number of cycles calculated by tolerance limits was therefore much lower than the mean cycles to failure at any given load level. For example, at a load of 250 N, the predicted mean life for the composite screw and the metal screw was 2513 and 1490 cycles, respectively, whereas the 80/80 tolerance limits (the value that 80% could be expected to achieve with 80% confidence) were only 63 and 68 cycles, respectively. Small reductions in load level gave very large increases in minimally expected life. Conclusions Fatigue testing of anterior cruciate ligament reconstructions better shows the wide variation between specimens and the large effect of load levels on expected life. Wide scatter makes mean levels overoptimistic and difficult to interpret. Tolerance limits give estimates that are more conservative and facilitate data interpretation. Clinical Relevance A method for testing and analyzing fatigue properties was presented, results of which are more readily interpreted to clinical practice.
Rapid ubiquitination of Syk following GPVI activation in platelets
Authors: Dangelmaier Carol A. , Quinter Patricia G. , Jin Jianguo , Tsygankov Alexander Y. , Kunapuli Satya P. , Daniel James L. 
Published: February 2005

AbstractSpleen tyrosine kinase (Syk) activation is a key intermediate step in the activation of platelets by the physiologic agonist collagen. We have found that Syk is rapidly ubiquitinated upon activation of platelets by collagen, collagen-related peptide (CRP), and convulxin. The Src family kinase inhibitors prevented Syk phosphorylation and its ubiquitination, indicating that the process is downstream of Src kinases. The ubiquitination of Syk did not cause degradation of the protein as evidenced by the lack of effect of proteasomal and lysosomal inhibitors. We separated ubiquitinated Syk from its nonubiquitinated counterpart and used an in vitro kinase assay to compare their activities. We found that the ubiquitinated Syk appeared to be about 5-fold more active. Using a phosphospecific antibody to Syk (Tyr525/Tyr526) that measures activated Syk, we found that most (60%-75%) of the active Syk is in the ubiquitinated fraction. This result explains the apparent high specific activity of ubiquitinated Syk. In c-Cbl–deficient mice, Syk is not ubiquitinated, implicating c-Cbl as the E3 ligase involved in Syk ubiquitination. Furthermore, Syk is not dephosphorylated in these mice. We propose that c-Cbl plays a regulatory role in glycoprotein VI (GPVI)/Fc receptor γ (FcRγ)-chain–dependent platelet activation through its interaction with Syk.
An Experimental Study of LP-Based Approximation Algorithms for Scheduling Problems
Authors: Savelsbergh Martin W. P. , Uma R. N. , Wein Joel 
Published: February 2005

Recently there has been much progress on the design of approximation algorithms for a variety of scheduling problems in which the goal is to minimize the average weighted completion time of the jobs scheduled. Many of these approximation algorithms have been inspired by polyhedral formulations of the scheduling problems and their use in computing optimal solutions to small instances. In this paper we demonstrate that the progress in the design and analysis of approximation algorithms for these problems also yields techniques with improved computational efficacy. Specifically, we give a comprehensive experimental study of a number of these approximation algorithms for 1|rj∑wjCj, the problem of scheduling jobs with release dates on one machine so as to minimize the average weighted completion time of the jobs scheduled. We study both the quality of lower bounds given for this problem by different linear-programming relaxations and combinatorial relaxations, and the quality of upper bounds delivered by a number of approximation algorithms based on them. The best algorithms, on almost all instances, come within a few percent of the optimal average weighted completion time. Furthermore, we show that this can usually be achieved with O(n log n) computation. In addition we observe that on most kinds of synthetic data used in experimental studies a simple greedy heuristic, used in successful combinatorial branch-and-bound algorithms for the problem, outperforms (on average) all of the LP-based heuristics. We identify, however, other classes of problems on which the LP-based heuristics are superior and report on experiments that give a qualitative sense of the range of dominance of each. We consider the impact of local improvement on the solutions as well. We also consider the performance of the algorithms for the average weighted flow-time criterion, which, although equivalent to average weighted completion time at optimality, is provably much harder to approximate. Nonetheless, we demonstrate that for most instances we consider that the algorithms give very good results for this criterion as well. Finally, we extend the techniques to a rather different and more complex problem that arises from an actual manufacturing application: resource-constrained project scheduling. In this setting as well, the techniques yield algorithms with improved performance; we give the best-known solutions for a set of instances provided by BASF AG, Germany.
Suspected β-Antagonist—Induced Thrombocytopenia
Authors: Stamm Pamela L , Jenkins J Kimble , Vigrass Howard G 
Published: February 2005

OBJECTIVE: To report a case of possible β-antagonist—induced thrombocytopenia. CASE SUMMARY: A 44-year-old African American woman with systemic lupus erythematosus developed thrombocytopenia. Splenic sequestration was suspected, but the rise in platelets after splenectomy was temporary. Bacterial and viral etiologies were ruled out, since thrombocytopenia continued 6 months after splenectomy. Her medications acetaminophen, amitriptyline, amlodipine, β-antagonists, and diphenhydramine were suspected. Nadolol and labetalol were started immediately prior to splenectomy. Six months after splenectomy, the woman was hospitalized for pneumonia; the platelet count was 50 times 103/mm3. Nadolol was discontinued on day 2. Within 24 hours, the platelet count rose to 128 times 103/mm3 and exceeded 200 times 103/mm3 by day 7. Labetalol was discontinued on day 8, but no additional significant rise occurred. The patient developed thrombocytopenia one year later when placed on nadolol and famotidine during admission for a gastrointestinal bleed. The platelet count decreased during the admission. Both drugs were discontinued after the last platelet count (100 times 103/mm3). The platelet count had normalized by the follow-up visit 16 days later and remained normal until the patient's death almost a year later. DISCUSSION: Thrombocytopenia is not a common adverse effect of β-antagonist therapy. As of February 1, 2005, only 4 case reports of suspected β-antagonist—associated thrombocytopenia have been published in English, and the medications cited are unavailable within the US. After splenectomy, the thrombocytopenia might have resolved if the β-antagonists had not been present. Since thrombocytopenia resolved within 24 hours of discontinuation of nadolol, it is likely that the continued thrombocytopenia was β-antagonist induced. The likelihood that the β-antagonist caused the adverse event is possible according to the Naranjo probability scale. CONCLUSIONS: The temporal association between the discontinuation of nadolol and the rise in platelets suggests that the thrombocytopenia resulted from nadolol.
Treatment of Type 2 Diabetes in Primary Health Care: A Drug Utilization Study
Authors: Mino-León Dolores , Figueras Albert , Amato Dante , Laporte Joan-Ramon 
Published: February 2005

BACKGROUND: Metabolic control in type 2 diabetes depends on patient adherence to therapy. Quantitative consumption data do not supply information regarding the appropriate use of medicine. Drug utilization studies are useful to identify treatment adherence problems and, thus, design interventions to improve drug use. OBJECTIVE: To describe the treatment and outcome in terms of degree of metabolic control in these patients, assess the agreement between the doses of antidiabetic drugs reported by the patient and those written in the medical record, and describe the drug utilization characteristics in relation to the standards of care. METHODS: This drug utilization study was conducted in primary care centers in Barcelona, Spain. Consecutive patients with type 2 diabetes attending a follow-up visit were interviewed regarding lifestyle, diet, glycosylated hemoglobin level, and treatment. Concordance between the information obtained through medical records and patient interviews was analyzed. RESULTS: Metabolic control was deficient in 73 (40%), acceptable in 50 (28%), and good in 58 (32%) of the 181 patients with available information. For 38 (19%) patients, there was disagreement between the dose of the antidiabetic drug reported by the patient and that written in the medical record. For 83 (41%) patients, the treatment in the medical history was in agreement with published standards. CONCLUSIONS: Identification of disagreement between standards of care and clinical practice in type 2 diabetes management is the basis to improve drug utilization and achieve better metabolic control in these patients.
Pharmacokinetics and Pharmacodynamics of Linezolid in Obese Patients with Cellulitis
Authors: Stein Gary E , Schooley Sharon L , Peloquin Charles A , Kak Vivek , Havlichek Daniel H , Citron Diane M , Tyrrell Kerin L , Goldstein Ellie JC 
Published: February 2005

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 μg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 μg/mL), Bacteroides fragilis (MIC 2.0 μg/mL), and Peptostreptococcus magnus (MIC 1.0 μg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 μg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 μg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (⩾6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 μg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC ⩾4.0 μg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.
Propranolol-Exacerbated Mesenteric Ischemia in a Patient with Hyperthyroidism
Authors: Köksal Aydin Şeref , Üsküdar Oğuz , Köklü Seyfettin , Yüksel Osman , Beyazit Yavuz , Şahin Burhan 
Published: February 2005

OBJECTIVE: To report a case of acute mesenteric ischemia associated with the use of oral propranolol. CASE SUMMARY: A 59-year-old white man was admitted to the hospital with chronic diarrhea and weight loss. The patient was diagnosed as having hyperthyroidism. Therapy with propylthiouracil 100 mg 3 times daily and propranolol 20 mg twice daily was initiated on an outpatient basis. The following day, the patient was readmitted to our hospital with increased abdominal pain and bloody diarrhea. Angiography revealed superior mesenteric artery occlusion. Antegrade aorta-mesenteric bypass surgery was performed for revascularization, and the patient was discharged 10 days after the surgery. The patient was well both clinically and endoscopically at a follow-up visit 8 months later. DISCUSSION: Although mesenteric ischemia is a devastating illness of varied causes, drug-associated mesenteric ischemia is rarely seen. By decreasing cardiac output and selective vasodilatory receptor inhibition in the splanchnic circulation, propranolol can cause a decline in splanchnic blood flow. An objective causality assessment indicated that propranolol was the possible cause of the arterial occlusion. CONCLUSIONS: Propranolol may rarely be associated with mesenteric ischemia. In cases of newly developed acute abdomen undergoing propranolol therapy, physicians should be aware of this rare and serious adverse reaction to this drug.
Peri-Infarct Depolarizations Reveal Penumbra-Like Conditions in Striatum
Authors: Umegaki Masao , Sanada Yasuhiro , Waerzeggers Yannic , Rosner Gerhard , Yoshimine Toshiki , Heiss Wolf-Dieter , Graf Rudolf 
Published: February 2005

Spreading depression-like peri-infarct depolarizations not only characterize but also worsen penumbra conditions in cortical border zones of experimental focal ischemia. We intended to investigate the relevance of ischemic depolarization in subcortical regions of ischemic territories.Calomel electrodes measured DC potentials simultaneously in the lateral and medial portions of the caudate nucleus (CN) of 11 anesthetized cats after permanent occlusion of the middle cerebral artery. Additionally, platinum electrodes measured cerebral blood flow (CBF) in the CN, and laser Doppler probes CBF in the cortex.Depolarizations (negative DC shifts >10 mV) were obtained in 10 of 11 cats. Further differentiation revealed that short-lasting spreading depression-like depolarizations (SDs; 5 of 10 cats: 5.24 ± 1.22 min total duration; 23.3 ± 4.2 mV amplitude) were predominantly found in medial and longer depolarizations (LDs; 4 of 10 cats: 64.7 ± 47.5 min; 25.0 ± 11.3 mV) in the lateral CN. Terminal depolarizations (TDs; 6 of 10 cats; without repolarization) occurred immediately after occlusion or at later stages, being then accompanied by elevations of intracranial pressure presumably inducing secondary CBF reduction. CBF tended to be lower in regions with TDs (33.3 ± 29.9% of control) and LDs (37.3 ± 22.8%) than in regions with SDs (51.5 ± 48.0%).We conclude that in focal ischemia, transient peri-infarct depolarizations emerge not only in cortical but also in striatal gray matter, thereby demonstrating the existence of subcortical zones of ischemic penumbra. The generation of these ischemic depolarizations is a multifocal process possibly linked to brain swelling and intracranial pressure rise in the later course of focal ischemia, and therefore a relevant correlate of progressively worsening conditions.