bluuebunny/crossref_metadata_2025 huggingface dataset:
Parsing of Melody: Quantification and Testing of the Local Grouping Rules of Lerdahl and Jackendoff's A Generative Theory of Tonal Music
Authors: Frankland Bradley W. , Cohen Annabel J.
Published: May 2004

In two experiments, the empirical parsing of melodies was compared with predictions derived from four grouping preference rules of A Generative Theory of Tonal Music (F. Lerdahl & R. Jackendoff, 1983). In Experiment 1 (n = 123), listeners representing a wide range of musical training heard two familiar nursery-rhyme melodies and one unfamiliar tonal melody, each presented three times. During each repetition, listeners indicated the location of boundaries between units by pressing a key. Experiment 2 (n = 33) repeated Experiment 1 with different stimuli: one familiar and one unfamiliar nursery-rhyme melody, and one unfamiliar, tonal melody from the classical repertoire. In all melodies of both experiments, there was good within-subject consistency of boundary placement across the three repetitions (mean r = .54). Consistencies between Repetitions 2 and 3 were even higher (mean r = .63). Hence, Repetitions 2 and 3 were collapsed. After collapsing, there was high between-subjects similarity in boundary placement for each melody (mean r = .62), implying that all participants parsed the melodies in essentially the same (though not identical) manner. A role for musical training in parsing appeared only for the unfamiliar, classical melody of Experiment 2. The empirical parsing profiles were compared with the quantified predictions of Grouping Preference Rules 2a (the Rest aspect of Slur/Rest), 2b (Attack-point), 3a (Register change), and 3d (Length change). Based on correlational analyses, only Attack-point (mean r = .80) and Rest (mean r = .54) were necessary to explain the parsings of participants. Little role was seen for Register change (mean r = .14) or Length change (mean r = –â€“.09). Solutions based on multiple regression further reduced the role for Register and Length change. Generally, results provided some support for aspects of A Generative Theory of Tonal Music, while implying that some alterations might be useful.
Justice Denied: The Waco Civil Trial
Authors: Wright Stuart A.
Published: May 2004

ABSTRACT: A critical analysis is conducted of the wrongful death lawsuit brought against the United States government by Branch Davidian survivors and relatives. It is argued that a flawed verdict, exonerating the government of wrongdoing, was the result of evidentiary and procedural rulings by the trial judge that prevented the jury from hearing key evidence. The substance of this evidence is discussed and evaluated for its implications in producing an engineered verdict.
The Use of the Military at Waco: The Danforth Report in Context
Authors: Rosenfeld Jean E.
Published: May 2004

ABSTRACT: In 1999 former Senator John Danforth was appointed by Attorney General Janet Reno as Special Counsel to investigate alleged illegal or improper behavior by government agencies before and during the Waco critical incident in 1993. His final report to the Deputy Attorney General exculpated the Bureau of Alcohol, Tobacco, and Firearms (BATF), the Federal Bureau of Investigation (FBI) and the armed forces regarding possible violations of posse comitatus law and related statutes. However, examination of the Danforth interim and final reports in context with three other government sources reveals that Danforth engaged in a hermeneutical defense of the government. Comparison of these major documents reveals inconsistencies, errors, omissions, terminology, and interpretations that raise questions about violations of the laws separating the armed forces from civilian police operations against United States citizens on U.S. soil. Danforth called for government openness and candor regarding Waco, but delivered an unequivocal defense of government forces instead.
Immigrant Buddhism in America: A Model of Religious Change
Authors: Machacek David W.
Published: May 2004

ABSTRACT: There have been several attempts to classify the variety of Buddhist religions present in America. This paper compares the two most widely used classification schemes and shows how they can be combined to form a model with both descriptive and predictive power. The resulting model shows how demand-side and supply-side influences propel immigrant religions on a path toward Americanization. The utility of the model is demonstrated by comparing the developmental histories of two major Japanese Buddhist organizations in America: Soka Gakkai International-USA and Buddhist Churches of America.
Alterations in placental 11β-hydroxysteroid dehydrogenase (11βHSD) activities and fetal cortisol:cortisone ratios induced by nutritional restriction prior to conception and at defined stages of gestation in ewes
Authors: McMullen S , Osgerby J C , Thurston L M , Gadd T S , Wood P J , Wathes D C , Michael A E
Published: June 2004

In the placenta, cortisol is inactivated by NADP+- and NAD+-dependent isoforms of 11β-hydroxysteroid dehydrogenase (11βHSD). Decreased placental 11βHSD activities have been implicated in intrauterine growth restriction (IUGR) and fetal programming of adult diseases. The objective of this study was to investigate whether placental 11βHSD activities and fetal plasma cortisol:cortisone ratios could be affected by nutritional restriction of ewes (70% maintenance diet) throughout gestation, for specific stages of gestation, or prior to mating. Chronic nutritional restriction from day 26 of gestation onwards decreased NAD+-dependent 11βHSD activities by 52 ± 4% and 45 ± 6% on days 90 and 135 of gestation respectively. Although the decreases in enzyme activities were associated with fetal IUGR, the cortisol:cortisone ratio in fetal plasma was unaffected by chronic nutritional restriction throughout pregnancy. Nutritional restriction confined to early (days 26–45), mid- (days 46–90) and late gestation (days 91–135), or the 30 days prior to mating, had no significant effect on NAD+-dependent, placental 11βHSD activities, nor was there evidence of IUGR. However, nutritional restriction at each stage of pregnancy and prior to mating was associated with significant decreases in the fetal plasma cortisol:cortisone ratio (3.2 ± 0.7 in control fetuses; 1.0 to 1.6 in fetuses carried by nutritionally restricted ewes). We conclude that nutritional restriction of pregnant ewes for more than 45 consecutive days can significantly decrease NAD+-dependent placental 11βHSD activities in association with IUGR. While the cortisol:cortisone ratio in fetal plasma is sensitive to relatively acute restriction of nutrient intake, even prior to mating, this ratio does not reflect directex vivomeasurements of placental 11βHSD activities.
Effects of parity and body condition at parturition on endocrine and reproductive parameters of the cow
Authors: Meikle A , Kulcsar M , Chilliard Y , Febel H , Delavaud C , Cavestany D , Chilibroste P
Published: June 2004

The effect of parity (multiparous vs primiparous) and body condition score (BCS; <3.0 or ≥3.0, lean vs fat) at parturition on metabolic and endocrine profiles from 1 month before to 2 months after parturition were studied in 42 Holstein cows grazing on improved pastures. BCS and milk production were determined every 2 weeks. Non-esterified fatty acids (NEFA), β-hydroxy-butyrate (BHB), insulin, IGF-I, leptin, thyroxine (T4) and 3,3′,5-tri-iodothyroinine (T3) were determined in plasma every 10 days. Progesterone was determined three times per week after parturition. Primiparous cows had a lower BCS during the early postpartum period and produced less milk than multiparous animals. Primiparous cows had higher NEFA concentrations and they presented more samples with BHB concentrations of >1 mmol/l than multiparous cows. Multiparous cows had higher T3, T4 and IGF-I concentrations, while fat cows had higher leptin and IGF-I concentrations. All hormone concentrations were diminished in the first week postpartum. Primiparous cows and fat cows presented a steeper decay of IGF-I and leptin around parturition than multiparous cows and lean cows. While thyroid hormones and IGF-I showed increasing concentrations from approximately day 30, leptin concentrations remained low until the end of the experimental period. The initiation of ovarian cyclicity was delayed in primiparous cows and especially in primiparous lean cows, consistent with longer intervals from parturition to first service and to conception. The endocrine signals most likely to inform the reproductive axis regarding a negative energy balance were IGF-I and leptin.
The cultured rodent follicle as a model for investigations of gonadotrophin surge-attenuating factor (GnSAF) production
Authors: Fowler Paul A , Spears Norah
Published: June 2004

Gonadotrophin surge-attenuating factor (GnSAF) bioactivity (the suppression of GnRH-induced but not basal LH and FSH secretion from pituitary gonadotrophs) is produced by granulosa cells in vitro. Previous studies to investigate this bioactivity used dispersed granulosa cells which lack some cell types and the structural components of the follicle in vivo. The aim of this study, therefore, was to investigate whether intact rodent follicle culture was a suitable model for the study of the production of GnSAF bioactivity, allowing GnSAF to be investigated in a more physiologically realistic environment while still retaining culture conditions from which, as with granulosa cell cultures, extraneous factors can be excluded. Follicles from 16-day-old rats and 21-day-old mice were cultured for 3–6 days in the presence or absence of FSH and/or LH. The follicle-conditioned medium, and matching samples of unconditioned culture medium were added to our established rat pituitary monolayer GnSAF bioassay. Both mouse and rat intact follicles produced GnSAF bioactivity, reducing GnRH-induced LH secretion significantly. GnSAF output from the mouse follicles was highest during days 1–3 of culture, when follicles were at an early antral stage of development, and fell on days 4–6 as the follicles grew to the mid antral stage. While the stimulatory effects of FSH on rat follicle GnSAF secretion was dose-dependent, LH alone did not increase GnSAF production. An antibody against human GnSAF blocked GnSAF bioactivity produced by rat follicles, and recognised proteins within the expected pI and molecular weight range for GnSAF in two-dimensional gels of rat follicle-conditioned medium, showing a good homology between rodent and human GnSAF proteins. In conclusion, the release of GnSAF bioactivity is principally from small follicles stimulated by FSH. Therefore, intact rodent follicle culture systems offer an excellent model for the investigation of factors controlling GnSAF production under relatively physiological conditions.
PKC signalling regulates tight junction membrane assembly in the pre-implantation mouse embryo
Authors: Eckert Judith J , McCallum Amanda , Mears Andrew , Rumsby Martin G , Cameron Iain T , Fleming Tom P
Published: June 2004

Epithelial differentiation including tight junction (TJ) formation occurs exclusively within the trophectoderm (TE) lineage of the mouse blastocyst. Here we examine mechanisms by which TJ protein membrane assembly might be regulated by protein kinase C (PKC) in the embryo. To overcome the inherent staging asynchrony of individual blastomeres within intact embryos, we have used isolated inner cell masses (ICMs) from early blastocysts to induce epithelial differentiation in their outer cells responding to their new cell contact pattern. Two TJ proteins examined retain their order of membrane assembly in isolated ICMs in culture as during normal development (early-assembling ZO-2 and late-assembling ZO-1α+), but this process is highly accelerated. Using six chemical modulators of PKC activity, we show here that PKC signalling is involved in the regulation of TJ membrane assembly. While indolactam-mediated PKC activation stimulates membrane assembly of both TJ proteins, TPA-mediated PKC activation stimulates only that of ZO-1α+. The PKC inhibitors Ro-31-8220, Ro-31-8425 and Gö 6983 suppress the stimulatory effect of both PKC activators on membrane assembly to varying extents according to inhibitor and TJ protein examined. Gö 6983 similarly inhibits ZO-2 and ZO-1α+membrane assembly. PKC inhibition by Gö 6976 appeared to stimulate TJ membrane assembly. Despite the broad PKC isotype specificity of the inhibitors used, these data suggest that the two TJ proteins are differently regulated by PKC isotypes or subfamilies. As Gö 6983 uniquely affects aPKC (particularly PKCζ) and we find that both PKCδ and ζ relocate upon activator treatment to colocalise partially with the TJ proteins in isolated ICMs, we suggest that at least PKCδ and ζ may play a central role in regulating TJ membrane assembly.
Possible Effect of Refrigeration of Warfarin on the International Normalized Ratio
Authors: Sharp Randall P. , Havrda Dawn E.
Published: May 2004

A 43‐year‐old African‐American woman taking warfarin for prevention of ischemic stroke experienced fluctuating international normalized ratio (INR) values over 8.5 months; no cause could be identified. After reading a pharmacy information sheet that accompanied a warfarin refill, she reported that she had been refrigerating her warfarin because her other drugs had been “sticking together.” She then was instructed to store her warfarin at room temperature. During the 8.5 months she had been refrigerating her warfarin, 80% of her INR values had been outside her goal range versus 37.5% during 9 months of storage at room temperature. A MEDLINE search and communication with the drug's manufacturer provided no information regarding storage of warfarin outside the temperature range of 59–86°F and resultant changes in potency of the drug. Because of potential fluctuation in anticoagulation control, patients should be reminded to store their warfarin at room temperature.
Development of Resistance Mutations to Nevirapine as Part of Triple‐Drug Therapy in Children
Authors: Seifert Lynn L.
Published: May 2004

Five children received nevirapine, a nonnucleoside reverse transcriptase inhibitor used as part of a triple‐drug regimen to treat human immunodeficiency virus infection. They all developed resistance mutations to the agent within 4–10 months. They differed in compliance with drug therapy and development of specific mutations. Whether these mutations predict clinical resistance has yet to be determined.
Use of Thrombolytic Therapy to Treat Heparin‐Refractory Pulmonary Embolism in a Menstruating Patient
Authors: Koch Ada Z. , Abubaker Jawed , Barnett V. Theodore , Chan Lingtak‐Neander
Published: May 2004

A 26‐year‐old woman developed an acute pulmonary embolism at the beginning of her menstrual cycle and was admitted to the hospital. When she failed initial standard treatment with heparin, the only other therapeutic option was a thrombolytic agent such as recombinant tissue plasma activator (rt‐PA). Use of these agents, however, carries a large risk of major bleeding complications and brings concern of increased menstrual blood flow and duration. A literature search of the use of thrombolytic agents in menstruating patients found only limited reports. Our patient responded well to rt‐PA therapy. Her hemoglobin levels remained stable, and she experienced no bleeding complications. Careful monitoring and caution are recommended when administering thrombolytic agents to menstruating patients.
Sexual Dysfunction Secondary to Gemfibrozil
Authors: James Christopher W. , Wu Tina S. , McNelis Kelly C.
Published: May 2004

Hypertriglyceridemia is a well‐recognized complication of protease inhibitor therapy, specifically ritonavir. Fibrate derivatives are recommended as first‐line therapy for isolated triglyceride elevations, and gemfibrozil has been successful for managing protease inhibitor‐induced lipid changes. A 35‐year‐old man experienced sexual dysfunction 3 weeks after starting gemfibrozil. The temporal relationship and improvement in sexual function after the drug was discontinued suggest that gemfibrozil may have been responsible for his sexual dysfunction.
Hormonal Emergency Contraception
Authors: Wanner Melissa Sanders , Couchenour Rachel L.
Published: May 2004

In the 1960s, high‐dose estrogen was identified as a highly effective emergency contraceptive but was associated with a high frequency of nausea and vomiting. The combination of low‐dose estrogen and a progestin (the Yuzpe regimen) is highly effective and much better tolerated. Recently, a progestin‐only regimen containing levonorgestrel was found to be more effective than the Yuzpe regimen and caused significantly less nausea and vomiting. Danazol, an antigonadotropin, is well tolerated but has questionable efficacy. Mifepristone has several pharmacologic actions that make it highly effective with an adverse‐effect profile similar to that of the Yuzpe regimen. Progress has been made in the last 3 years toward increasing the number of emergency contraceptives that are accessible to women in the United States, and several highly effective options are available. The most effective and well‐tolerated regimen available is levonorgestrel. However, the barriers to access and low patient and provider awareness limit the impact of emergency contraception on the rate of unintended pregnancies.
An Economic Analysis of Amiodarone versus Placebo for the Prevention of Atrial Fibrillation After Open Heart Surgery
Authors: Reddy Prabashni , Dunn Alisha B. , White C. Michael , Tsikouris James P. , Giri Satyendra , Kluger Jeffrey
Published: May 2004

Study Objective. To determine if the additional costs of oral amiodarone in patients undergoing open heart surgery would be offset by reductions in the frequency of atrial fibrillation.

Design. Piggyback cost analysis of the data from a randomized, double‐blind, placebo‐controlled trial.

Setting. Urban academic hospital.

Patients. Two hundred twenty elderly patients (≥ 60 yrs old) undergoing open heart surgery.

Intervention. Hospital costs of open heart surgery in patients given amiodarone for the prevention of atrial fibrillation and in prespecified subgroups were compared with those for patients given placebo (i.e., standard care with β‐blockers alone).

Measurements and Main Results. Total hospital costs incurred were $15,565 ± $9832 and $16,126 ± $8043 in the amiodarone and placebo groups, respectively (p=0.12). General ward, intensive care unit, operating room, pharmacy, and costs in all other departments were similar between the groups (p>0.05 for all comparisons). Because costs were similar but amiodarone was more effective than placebo, amiodarone was cost‐effective compared with placebo. Amiodarone remained cost‐effective compared with placebo regardless of the following subgroup characteristics: rapid or slow loading strategy, no history of atrial fibrillation or heart failure, age older than 70 years, and no tolerance to preoperative β‐blockers. Moreover, in the one‐way sensitivity analysis, the findings remained robust to changes in effectiveness and cost of amiodarone.
Use of Potentially Inappropriate Drugs in Nursing Homes
Authors: Dhall Jyotsna , Larrat E. Paul , Lapane Kate L.
Published: May 2004

Study Objectives. To examine patterns and determine predictors of inappropriate drug use in nursing homes.

Design. Retrospective study.

Setting. One thousand four hundred ninety‐two nursing homes in five states.

Patients. A total of 44,562 residents admitted to nursing homes over 1 year.

Methods. Frequency of discontinuation and initiation of potentially inappropriate drugs over the first 90 days after admission to a nursing home was calculated. Data were collected using the minimum data set.

Results. On admission, 33% of residents were receiving at least one potentially inappropriate drug. After 90 days, the drug was discontinued in 16% of these residents. Of those not receiving a potentially inappropriate drug on admission, one was begun in 18%. Demographic factors and number of drugs taken by patients were associated with the use of potentially inappropriate drugs.

Conclusions. Use of potentially inappropriate drugs was prevalent on admission and at 90 days after admission. Discontinuation was highest among patients with conditions for which potentially safer therapeutic alternatives existed.
Major Bleeding Caused by Warfarin in a Genetically Susceptible Patient
Authors: Bloch Aharon , Ben‐Chetrit Eldad , Muszkat Mordechai , Caraco Yoseph
Published: May 2004

A 90‐year‐old woman was hospitalized for gastrointestinal bleeding. Although she had been receiving only warfarin 5 mg/day, her international normalized ratio (INR) was 66. Warfarin was discontinued, and her INR fell to 3.7 after transfusion of fresh‐frozen plasma. However, it rose again spontaneously to 7.5. Eleven days after the last dose of warfarin had been administered, it was still detectable in the patient's plasma, indicating that impaired warfarin clearance may have caused an enhanced anticoagulation effect. Genetic analysis of the cytochrome P450 (CYP) isoenzyme 2C9, which mediates the major deactivating pathway of S‐warfarin, revealed that the patient was a compound heterozygote carrying two variant alleles: CYP2C9*2 and CYP2C9*3. The patients enhanced sensitivity to warfarin 5 mg/day can be ascribed to decreased clearance of S‐warfarin secondary to genetic alteration of the gene encoding CYP2C9, resulting in a life‐threatening complication.
Evaluation of Four Once‐Daily Aminoglycoside Dosing Nomograms
Authors: Wallace Allison Wood , Jones Matthew , Bertino Joseph S.
Published: May 2004

Study Objective. To evaluate the accuracy of four once‐daily aminoglycoside dosing nomograms in producing the desired gentamicin peak concentration (Cmax) target of 20 μg/ml in patients with varying degrees of renal function.

Design. Retrospective analysis using prospectively collected pharmacokinetic data.

Setting. Rural teaching hospital.

Patients. Ninety patients receiving intravenous gentamicin divided into three groups (30 patients each) determined by estimated renal function: group 1, creatinine clearance (Clcr) 60 ml/minute or greater; group 2, Clcr 40–59 ml/minute; group 3, Clcr) 20–39 ml/minute.

Intervention. Serum gentamicin concentrations were collected for a 2–point (two consecutive infusions and one predose and one postdose concentration sampled during steady state) or 3–point (single infusion and one predose and two postdose concentrations at least 1.5 estimated half‐lives apart) pharmacokinetic study for determination of patient‐specific pharmacokinetic parameters (elimination rate constant, volume of distribution at steady state, and clearance) after 30–minute infusions of gentamicin 2.8 ± 1.6 mg/kg.

Measurements and Results. The four nomograms evaluated were from Hartford Hospital, Barnes‐Jewish Hospital, University of Rochester, and the Sanford Guide. With a pharmacokinetic analysis program and the patient‐specific pharmacokinetic parameters, CMmax and minimum concentration (Cmin) were determined with use of the recommended doses and dosing intervals of the four nomograms. Also, the gentamicin dose and interval needed to achieve a Cmax) and Cmin) of 20 μg/ml and 0.2 μg/ml, respectively, were determined. Dosing was based on total body weight unless that weight was more than 25% of ideal body weight, in which case, an adjusted body weight was used. In general, the recommended dosages and resultant Cmax) produced by the nomograms were significantly less (p<0.05) than the dosage and Cmax) actually needed to achieve a Cmax): minimum inhibitory concentration (MIC) ratio of 10 or greater for bacteria with an MIC of 2 μg/ml.

Conclusion. Once‐daily aminoglycoside dosing using the four nomograms resulted in inaccurate dosing, and because of the large variability in human pharmacokinetics, dosing nomograms such as these should be abandoned in favor of individualizing dosages with therapeutic drug monitoring.
Risk of Acute Liver Injury in Patients with Diabetes
Authors: Huerta Consuelo , Zhao Sean Z. , Rodríguez Luis Alberto García
Published: May 2004

Study Objectives. To estimate the incidence of acute liver injury in patients with diabetes and compare it with the corresponding incidence in the general population, and to examine the association between occurrence of acute liver injury and administration of antidiabetic drugs in patients with diabetes.

Design. Retrospective cohort study.

Setting. United Kingdom General Practice Research Database.

Patients. A total of 34,328 patients with adult‐onset (type 2) diabetes and a random sample of 50,000 patients with no recorded diagnosis of diabetes; all were aged 20–79 years from 1994–1998 and free of risk factors for hepatic disease.

Intervention. Using the United Kingdom General Practice Research Database as our resource, we followed the two cohorts to identify patients with a recorded diagnosis compatible with acute liver injury. Medical records of all patients identified as potentially having liver injury were requested from the general practitioners to validate the diagnosis.

Measurement and Main Results. After validation, 27 patients met our definition for having acute liver injury: 14 in the diabetes cohort and 13 in the general population cohort. Overall annual incidence was 14.2 and 8.8/100,000 patient‐years in the diabetes and general population cohorts, respectively. The adjusted relative risk of acute liver injury in the diabetes cohort compared with that of the general population cohort was 1.0 (95% confidence interval [CI] 0.2–3.7). Patients with diabetes taking antidiabetic drugs had a relative risk of 2.8 (95% CI 0.6–12.5) compared with those not taking these drugs.

Conclusion. Our findings suggest that diabetes itself does not constitute a major risk for acute liver injury and that a small increased risk could be associated with use of antidiabetic drugs. However, due to the low number of cases detected, the estimates of risk with individual drugs are not conclusive.
Differences in Antimicrobial Drug Exposure in Patients with Various Degrees of Renal Function Based on Recommendations from Dosing References
Authors: Bonapace Charles R. , White Roger L. , Friedrich Lawrence V. , Bosso John A.
Published: May 2004

Study Objective. To calculate and compare 24–hour area under the unbound drug concentration‐time curves (AUC0.24) of antimicrobials with dosing recommendations from six commonly used dosing references.

Intervention. Unbound plasma concentration‐time profiles of 13 antimicrobial agents (4 penicillins, 3 cephalosporins, 2 carbapenems, aztreonam, 3 fluoroquinolones) were simulated at steady state using a one‐compartment open model for a 70–kg adult based on pharmacokinetic parameters obtained from peer‐reviewed literature. Simulations were performed at five levels of creatinine clearance (Clcr).

Measurements and Main Results. Differences in AUC0–24 for each antimicrobial agent were noted among the six references at each level of Clcr as well as within references across the range of Clcr. In addition, up to 16–fold and 3–fold ranges in AUC0–24 values were observed for β‐lactams and fluoroquinolones, respectively, in one reference based on dosing recommendations at a single level of Clcr (due to more than one dose and/or dosing interval).

Conclusion. Clinicians should be aware of differences among common references when selecting dosages of antimicrobial agents, especially for patients with moderate‐to‐severe renal impairment. (Pharmacotherapy 2002;22(9):1097–1104)
Valganciclovir: A New Oral Alternative for Cytomegalovirus Retinitis in Human Immunodeficiency Virus‐Seropositive Individuals
Authors: Segarra‐Newnham Marisel , Salazar Martha I.
Published: May 2004

Oral valganciclovir recently was approved by the Food and Drug Administration for treatment of cytomegalovirus (CMV) retinitis. We performed MEDLINE (June 1998–May 2002) and AIDSLINE (June 1998–December 2000) searches of available information on valganciclovir, and the drug's prescribing information was used to identify relevant articles. Additional studies, case reports, reviews, and abstracts were identified from references in the reviewed literature. Most of the information was obtained from abstracts or product labeling, since few trials have been published in the medical literature. Valganciclovir is a prodrug of ganciclovir and has been shown to have significantly higher oral absorption than ganciclovir capsules. One short‐term study found valganciclovir to be as effective as intravenous ganciclovir in treating CMV retinitis. Recommended dosages for patients with normal renal function are valganciclovir 900 mg twice/day for induction and 900 mg once/day for maintenance. Side effects are similar to those of intravenous ganciclovir and require periodic monitoring of complete blood count and renal function. Given the need for lifelong therapy for CMV retinitis in some human immunodeficiency virus‐positive patients, valganciclovir is a welcome alternative to long‐term administration of intravenous antivirals.
A Review of Methotrexate‐Induced Accelerated Nodulosis
Authors: Patatanian Edna , Thompson Dennis F.
Published: May 2004

Objective. To review the English‐language literature on methotrexate‐induced accelerated nodulosis, compile case reports of its occurrences, and make recommendations on the clinical management of patients.

Methods. A comprehensive search of MEDLINE, TOXLINE, and EMBASE databases was performed, along with a bibliographic search of key articles. Case reports were compiled separately. The Naranjo adverse drug reaction probability scale was used to assess causality.

Results. Twenty‐seven case reports of patients with methotrexate‐induced accelerated nodulosis were identified along with one series of 10 patients and one series of 21 patients. Probability assessment for most of the case reports was weak and left room for doubt regarding causality. Most patients were older than 50 years, were positive for rheumatoid factor, and had nodules on their fingers but did not have concurrent vasculitis. Some unusual sites of nodulosis were the larynx, lungs, Achilles tendon, and heart. Of 19 patients given hydroxychloroquine, colchicine, sulfasalazine, azathioprine, or D‐penicillamine, all except two showed regression of the nodules; the response was unknown for one patient.

Conclusion. Controversy surrounds the management of patients who develop accelerated nodulosis while receiving methotrexate therapy for rheumatoid arthritis. Our review of these data does not allow definitive conclusions because the available case reports and clinical trials are fragmented and incomplete.
Development and Validation of a Survey to Assess Barriers to Drug Use in Patients with Chronic Heart Failure
Authors: Simpson Scot H. , Johnson Jeffrey A. , Farris Karen B. , Tsuyuki Ross T.
Published: May 2004

Objective. To report the development of and initial experience with a survey designed to assess patient‐perceived barriers to drug use in ambulatory patients with heart failure.

Methods. The Barriers to Medication Use (BMU) survey, developed from previous qualitative work by our group, was administered to 128 consecutive patients attending an outpatient heart failure clinic. The first 42 patients to return the survey were mailed a second survey to evaluate response stability over time. The survey contained 31 questions in five barrier domains (knowledge, previous drug therapy experiences, social support, communication, and relationship with health care professionals). Patients also completed the Minnesota Living with Heart Failure (MLHF) questionnaire and a self‐reported drug use scale. Frequency of drug refills was used to estimate adherence. Reliability and construct validity of the BMU survey were assessed using correlation coefficients.

Results. Response rates were 89% and 93% for the first and retest surveys, respectively. The BMU survey showed modest internal consistency in the overall survey and in two of the five barrier domains. Responses to the first and retest surveys showed good stability over time in the overall survey and in four of the five barrier domains. Patients with good adherence reported few barriers; however, the association was not strong (Pearson correlation coefficient r = −0.14, p=0.14). Patients who reported few barriers also reported better MLHF scores (r = 0.42, p<0.001), with the strongest association in the social support domain (r = 0.53; p<0.001). All respondents reported having a good relationship with health care professionals. The most common barriers to drug use were poor support networks and previous adverse reactions.

Conclusion. The BMU survey demonstrated reasonable reliability and validity characteristics in this first clinical experience. Despite high adherence, patients still reported barriers that may hinder optimal drug use.
Lactobacillus Species as a Cause of Ventilator‐Associated Pneumonia in a Critically Ill Trauma Patient
Authors: Wood G. Christopher , Boucher Bradley A. , Croce Martin A. , Fabian Timothy C.
Published: May 2004

Lactobacillus species are ubiquitous inhabitants of the human gastrointestinal and genitourinary tracts and rarely cause infections. Pneumonia caused by Lactobacillus has been reported only in immunocompromised patients and in one patient with structural lung disease. A 39–year‐old, immunocompetent, critically ill woman developed ventilator‐associated pneumonia, which was found to be caused by Lactobacillus. To our knowledge, this is the first such report. The infection was treated successfully with 14 days of intravenous vancomycin. Based on this case, Lactobacillus should be considered a possible cause of ventilator‐associated pneumonia in immunocompetent, critically ill patients.
Toxic Epidermal Necrolysis After Celecoxib Therapy
Authors: Berger Peter , Dwyer Daniel , Corallo Carmela E.
Published: May 2004

Toxic epidermal necrolysis (TEN) is a rare disease that is defined by extensive detachment of full‐thickness epidermis. It most often is related to an adverse drug reaction. The drugs implicated in most cases of TEN have been sulfonamides, anticonvulsants, allopurinol, and some of the conventional nonsteroidal anti‐inflammatory agents. We describe a patient who developed a generalized desquamating rash after therapy with celecoxib.
Bradycardia Associated with Intravenous Methadone Administered for Sedation in a Patient with Acute Respiratory Distress Syndrome
Authors: Karir Veena
Published: May 2004

The use of low tidal volumes with permissive hypercapnia in patients with acute respiratory distress syndrome may require heavy sedation to allow them to tolerate mechanical ventilation. Administration of methadone for sedation is an alternative to using other opioids, given its longer elimination half‐life and incomplete cross‐tolerance with other μ‐receptor‐active opioids. Methadone appears to have a molecular structure similar to that of verapamil, a calcium channel blocker, and may exhibit similar cardiac properties as well. A 43–year‐old man with acute respiratory distress syndrome experienced bradycardia while receiving a continuous infusion of methadone for sedation and mechanical ventilation management. This case report demonstrates that caution is warranted when high dosages of methadone are administered because of its potential cardiac effects.
Recurrent Peripheral Arterial Thrombosis Induced by Cisplatin and Etoposide
Authors: Cool Rita M. , Herrington Jon D. , Wong Lucas
Published: May 2004

A 64–year‐old woman receiving intravenous chemotherapy for stage IIIB non‐small cell lung cancer experienced acute arterial thrombosis of the distal radial and entire ulnar arteries with subsequent arterial occlusion of the right popliteal artery. Two separate arterial occlusions occurred after administration of cisplatin and etoposide chemotherapy; the second occlusion occurred after rechallenge with the second cycle of chemotherapy. Although venous thrombosis is more common in patients with cancer than in the general population, chemotherapy‐induced arterial thrombosis rarely has been reported. To our knowledge, peripheral arterial occlusion after the first and second cycles of platinum‐based chemotherapy has not been reported in the literature.
Combination Antiplatelet Therapy: Implications for Pharmacists
Authors: Talbert Robert L. , Spinier Sarah A. , Nappi Jean M. , Bottorff Michael B.
Published: May 2004

Objectives. To present two case reports of patients who received suboptimal oral antiplatelet therapy and to review recent changes in national guidelines for management of acute coronary syndromes.

Data Sources. Personal observation by the authors, and clinical practice guidelines and related clinical trials of the American Heart Association and the American College of Cardiology.

Summary. The American College of Cardiology and the American Heart Association revised the guidelines for administration of antiplatelet and anticoagulant therapy in patients with unstable angina and non‐ST‐segment elevation myocardial infarction in March 2002. Two cases observed by the authors illustrate the consequences of suboptimal antiplatelet therapy when a combination of two antiplatelet drugs should have been administered.

Conclusion. Evidence from recent randomized controlled trials led to changes in the national guidelines for administration of oral antiplatelet therapy in patients with acute coronary syndromes. Pharmacists should be aware of these changes and counsel patients about appropriate administration of antiplatelet drugs.
Pharmacokinetics of Intravenous and Oral Levofloxacin in Critically Ill Adults in a Medical Intensive Care Unit
Authors: Rebuck Jill A. , Fish Douglas N. , Abraham Edward
Published: May 2004

Study Objective. To characterize the pharmacokinetic disposition of intravenous and oral levofloxacin in critically ill adults.

Design. Prospective, open‐label study.

Setting. University teaching hospital.

Patients. Thirty critically ill patients in a medical intensive care unit (ICU).

Interventions. All patients received levofloxacin as part of their routine medical care. Pharmacokinetic evaluations were performed in 28 patients receiving intravenous levofloxacin. Ten of these patients subsequently were switched to oral levofloxacin and underwent a second pharmacokinetic evaluation during oral therapy.

Measurements and Main Results. Mean ± SD levofloxacin half‐life, clearance at steady state, and volume of distribution in all 28 patients were 8.0 ± 1.7 hours, 134 ± 35 ml/minute, and 1.2 ± 0.3 L/kg, respectively. Maximum and minimum serum concentrations (Cmax and Cmin) and area under the serum concentration‐time curve from 0–24 hours (AUC0‐24) in patients receiving levofloxacin 500 mg intravenously were 7.5 ± 0.8 mg/L, 1.0 ± 0.5 mg/L, and 66.1 ± 15.7 mg · hour/L, respectively. Observed Cmax, Cmin, and time at which maximum concentration was achieved after oral doses of levofloxacin 500 mg were 5.5 ± 1.1 mg/L, 0.8 ± 0.4 mg/L, and 1.3 ± 0.4 hours, respectively These values were significantly different (p<0.05) from those observed after intravenous dosing in the same patients; other pharmacokinetic parameters were similar. Statistically significant increases (p<0.05) in Cmax, Cmin, half‐life, and AUC0–24 were found in critically ill patients administered multiple doses of intravenous levofloxacin compared with historical data from healthy volunteers.

Conclusions. The dosage regimen of intravenous levofloxacin 500 mg once/day appears adequate for most pathogens found in critically ill patients with normal renal function. Less susceptible pathogens may require an increased daily dose for more optimal therapy. Orally administered levofloxacin appears to be well absorbed in selected ICU patients and has pharmacokinetics similar to those of intravenously administered levofloxacin.
Imatinib Mesylate, the First Molecularly Targeted Gene Suppressor
Authors: Pindolia Vanita K. , Zarowitz Barbara J.
Published: May 2004

Objective. To review the pharmacology, pharmacokinetics, efficacy, safety and drug‐drug and drug‐food interactions of imatinib and the economic considerations of imatinib in the treatment of chronic myeloid leukemia (CML).

Data Sources. Literature accessed through MEDLINE (January 1970‐January 2002), abstracts from the 2001 annual meetings of the American Society of Clinical Oncology and the American Society of Hematology, imatinib product labeling, and additional studies or abstracts identified from the bibliographies of the reviewed literature were used to compile data. Key search terms were allogeneic bone marrow transplant and stem cell transplant, chronic myeloid leukemia, imatinib, interferon, Gleevec, leukemia, gastrointestinal stromal tumors, STI‐571, and tyrosine kinase inhibitors.

Findings. Imatinib is a distinctively characteristic drug targeted toward inhibition of tyrosine kinase activity. Imatinib is indicated for the treatment of patients with CML who failed interferon (IFN)‐a therapy and for the treatment of patients with gastrointestinal stromal tumors (GISTs) expressing the tyrosine kinase receptor c‐kit. Imatinib produces positive short‐term hematologic and cytogenetic responses in patients with CML; short‐term positive objective responses have been shown for patients with GISTs. To our knowledge, there are no controlled trials demonstrating long‐term safety, improvement in disease‐related symptoms, or increased survival with imatinib. Serious adverse effects requiring dosage decreases and/or therapy termination are edema, hepatotoxicity, and hematologic toxicity. Imatinib also has been found to inhibit tyrosine kinases involved in the growth of other malignancies. The role of imatinib in tumors that express a tyrosine kinase is constantly evolving with new research results.

Conclusions. Imatinib therapy should be limited to patients whose tumor growth is related to a genetically defective tyrosine kinase. In cases of CML, imatinib should be further limited to patients who have tried and failed IFN‐a therapy or who are not candidates for an allogeneic stem cell transplant.
Symptomatic Orthostasis with Extended‐Release Nifedipine and Protease Inhibitors
Authors: Rossi Deanna R. , Rathbun R. Chris , Slater Leonard N.
Published: May 2004

Human immunodeficiency virus (HIV) protease inhibitors are prone to drug interactions with other agents. As individuals with HIV infection live longer, the clinical significance of many interactions is becoming recognized. A 51‐year‐old man with HIV infection who was receiving extended‐release nifedipine developed symptomatic orthostasis and heart block after starting antiretroviral therapy that included nelfinavir. He experienced dizziness, fatigue, and hypotension and developed complete heart block with a junctional escape rhythm. Electrocardiogram abnormalities abated within 24 hours of discontinuing antiretroviral therapy. The patient developed orthostatic symptoms after restarting nelfinavir. He was switched successfully to an efavirenz‐based regimen. Subsequent administration of antiretroviral therapy containing ritonavir and indinavir with extended‐release nifedipine resulted in recurrence of his orthostatic symptoms. Discontinuation of atenolol, and nifedipine dosage reduction by 50% were effective in managing his orthostatic changes. Careful monitoring by clinicians is necessary when concomitant administration of HIV protease inhibitors are prescribed with other agents that are metabolized through the cytochrome P450 system.
Cyclooxygenase‐2 Inhibitor—Associated Acute Renal Failure: Case Report with Rofecoxib and Review of the Literature
Authors: Morales Enid , Mucksavage Jeffrey J.
Published: May 2004

Cyclooxygenase (COX)‐2 inhibitors are widely prescribed for their antiinflammatory and analgesic effects. The potential for COX‐2 inhibitors to exert deleterious effects on renal function similar to those of traditional nonsteroidal antiinflammatory drugs is not well defined. Until recently, COX‐1 was considered responsible for the synthesis of renal prostaglandins. However, COX‐2 is also constitutively expressed in the human kidney Clinical studies have reported a significant decrease in glomerular filtration rate in young and elderly sodium‐depleted volunteers given COX‐2 inhibitors. We describe the case of a 71‐year‐old woman who developed acute renal failure after receiving a 50‐mg dose of the selective COX‐2 inhibitor rofecoxib.
Clinical Pharmacy Services, Hospital Pharmacy Staffing, and Medication Errors in United States Hospitals
Authors: Bond C. A. , Raehl Cynthia L. , Franke Todd
Published: May 2004

The direct relationships and associations among clinical pharmacy services, pharmacist staffing, and medication errors in United States hospitals were evaluated. A database was constructed from the 1992 National Clinical Pharmacy Services database. Both simple and multiple regression analyses were employed to determine relationships and associations. A total of 429,827 medication errors were evaluated from 1081 hospitals (study population). Medication errors occurred in 5.22% of patients admitted to these hospitals each year. Hospitals experienced a medication error every 22.04 hours (every 19.13 admissions). These findings suggest that at minimum, 90,895 patients annually were harmed by medication errors in our nation's general medical‐surgical hospitals. Factors associated with increased medication errors/occupied bed/year were drug‐use evaluation (slope = 0.0023476, p=0.006), increased staffing of hospital pharmacy administrators/occupied bed (slope = 29.1972932, p<0.001), and increased staffing of dispensing pharmacists/occupied bed (slope = 19.3784148, p<0.001). Factors associated with decreased medication errors/occupied bed/year were presence of a drug information service (slope = −0.1279301, p<0.001), pharmacist‐provided adverse drug reaction management (slope = −0.3409332, p<0.001), pharmacist‐provided drug protocol management (slope = −0.3981472, p=0.013), pharmacist participation on medical rounds (slope = −0.6974303, p<0.001), pharmacist‐provided admission histories (slope = −1.6021493, p<0.001), and increased staffing of clinical pharmacists/occupied bed (slope = −9.5483813, p<0.001). As staffing increased for clinical pharmacists/occupied bed from the 10th percentile to the 90th percentile, medication errors decreased from 700.98 ± 601.42 to 245.09 ± 197.38/hospital/year, a decrease of 286%. Specific increases or decreases in yearly medication errors associated with these clinical pharmacy services in the 1081 study hospitals were drug‐use evaluation (21,372 more medication errors), drug information services (26,738 fewer medication errors), adverse drug reaction management (44,803 fewer medication errors), drug protocol management (90,019 fewer medication errors), medical round participation (42,859 fewer medication errors), and medication admission histories (17,638 fewer medication errors). Overall, clinical pharmacy services and hospital pharmacy staffing variables were associated with medication error rates. The results of this study should help hospitals reduce the number of medication errors that occur each year.
Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Tibolone 2.5 mg in Early Postmenopausal Women
Authors: Timmer Cees J. , Doorstam Dennis P.
Published: May 2004

Study Objective. To determine the influence of renal function on the pharmacokinetics of tibolone and its primary metabolites, Δ4‐tibolone, 3α‐hydroxytibolone, and 3β‐hydroxytibolone.

Design. Open‐label, single‐center, single‐dose study.

Setting. Drug research center, Balatonfüred, Hungary.

Subjects. Twenty‐four postmenopausal women aged 45–65 years.

Intervention. Subjects were assigned to one of four groups based on their renal function, as assessed by glomerular filtration rate (normal to severely impaired), and received a single dose of tibolone 2.5 mg. Pharmacokinetic parameters of tibolone and its primary metabolites were derived from blood samples taken at predefined intervals for up to 48 hours after tibolone administration. Pharmacokinetic parameters were calculated using standard noncompartmental methods and compared by analysis of covariance.

Measurements and Main Results. Pharmacokinetic parameters of tibolone and its primary metabolites were similar in subjects with normal to severely impaired renal function. Pharmacokinetic profiles of tibolone and its metabolites were independent of the degree of renal impairment.

Conclusion. Pharmacokinetic parameters of tibolone were not affected by varying degrees of renal function