bluuebunny/crossref_metadata_2025 huggingface dataset:
A temperature-sensitive mutation in thenodal-related genecyclopsreveals that the floor plate is induced during gastrulation in zebrafish
Authors: Tian Jing , Yam Caleb , Balasundaram Gayathri , Wang Hui , Gore Aniket , Sampath Karuna
Published: June 2003

The floor plate, a specialized group of cells in the ventral midline of the neural tube of vertebrates, plays crucial roles in patterning the central nervous system. Recent work from zebrafish, chick, chick-quail chimeras and mice to investigate the development of the floor plate have led to several models of floor-plate induction. One model suggests that the floor plate is formed by inductive signalling from the notochord to the overlying neural tube. The induction is thought to be mediated by notochord-derived Sonic hedgehog (Shh), a secreted protein, and requires direct cellular contact between the notochord and the neural tube. Another model proposes a role for the organizer in generating midline precursor cells that produce floor plate cells independent of notochord specification, and proposes that floor plate specification occurs early, during gastrulation.

We describe a temperature-sensitive mutation that affects the zebrafish Nodal-related secreted signalling factor, Cyclops, and use it to address the issue of when the floor plate is induced in zebrafish. Zebrafish cyclops regulates the expression of shh in the ventral neural tube. Although null mutations in cyclops result in the lack of the medial floor plate, embryos homozygous for the temperature-sensitive mutation have floor plate cells at the permissive temperature and lack floor plate cells at the restrictive temperature. We use this mutant allele in temperature shift-up and shift-down experiments to answer a central question pertaining to the timing of vertebrate floor plate induction. Abrogation of Cyc/Nodal signalling in the temperature-sensitive mutant embryos at various stages indicates that the floor plate in zebrafish is induced early in development, during gastrulation. In addition, continuous Cyclops signalling is required through gastrulation for a complete ventral neural tube throughout the length of the neuraxis. Finally, by modulation of Nodal signalling levels in mutants and in ectopic overexpression experiments, we show that, similar to the requirements for prechordal plate mesendoderm fates, uninterrupted and high levels of Cyclops signalling are required for induction and specification of a complete ventral neural tube.
Interactions between the secreted protein Amalgam, its transmembrane receptor Neurotactin and the Abelson tyrosine kinase affect axon pathfinding
Authors: Liebl Eric C. , Rowe R. Grant , Forsthoefel David J. , Stammler Amanda L. , Schmidt Erica R. , Turski Michelle , Seeger Mark A.
Published: June 2003

Two novel dosage-sensitive modifiers of the Abelson tyrosine kinase(Abl) mutant phenotype have been identified. Amalgam (Ama) is a secreted protein that interacts with the transmembrane protein Neurotactin(Nrt) to promote cell:cell adhesion. We have identified an unusual missense ama allele, amaM109, which dominantly enhances the Abl mutant phenotype, affecting axon pathfinding. Heterozygous null alleles of ama do not show this dominant enhancement, but animals homozygous mutant for both ama and Abl show abnormal axon outgrowth. Cell culture experiments demonstrate the AmaM109mutant protein binds to Nrt, but is defective in mediating Ama/Nrt cell adhesion. Heterozygous null alleles of nrt dominantly enhance the Abl mutant phenotype, also affecting axon pathfinding. Furthermore,we have found that all five mutations originally attributed to disabled are in fact alleles of nrt. These results suggest Ama/Nrt-mediated adhesion may be part of signaling networks involving the Abl tyrosine kinase in the growth cone.
The Crumbs3-Pals1 complex participates in the establishment of polarity in mammalian epithelial cells
Authors: Roh Michael H. , Fan Shuling , Liu Chia-Jen , Margolis Ben
Published: June 2003

In Drosophila, the Crumbs–Stardust–Discs-lost complex is required during the establishment of polarized epithelia. Embryos that lack a component of this complex or overexpress Crumbs exhibit defects in epithelial morphogenesis. We recently cloned a novel mammalian epithelial Crumbs isoform, Crumbs3 (CRB3). CRB3 exists in a complex at tight junctions(TJs) with Pals1 and PATJ, the mammalian homologues of Stardust and Discs lost, respectively. Here, we observe that overexpression of CRB3 leads to delayed TJ formation in MDCK epithelial cell monolayers and disruption of polarity in MDCK cysts cultured in collagen. Both phenomena require the last four residues of CRB3. Next, we expressed, in MDCK cells, a dominant-negative Myc-Lin-2–Pals1 chimeric protein, where the PDZ domain of Lin-2 was replaced with that of Pals1. TJ and apical polarity defects were also observed in these cells. Collectively, this suggests that the CRB-Pals1 interaction is important for formation of TJs and polarized epithelia. These results provide insight into the function of the mammalian Crumbs complex during TJ formation and epithelial polarization.
A STAT-regulated, stress-induced signalling pathway inDictyostelium
Authors: Araki Tsuyoshi , Tsujioka Masatsune , Abe Tomoaki , Fukuzawa Masashi , Meima Marcel , Schaap Pauline , Morio Takahiro , Urushihara Hideko , Katoh Mariko , Maeda Mineko , Tanaka Yoshimasa , Takeuchi Ikuo , Williams Jeffrey G.
Published: June 2003

The Dictyostelium stalk cell inducer differentiation-inducing factor (DIF) directs tyrosine phosphorylation and nuclear accumulation of the STAT (signal transducer and activator of transcription) protein Dd-STATc. We show that hyperosmotic stress, heat shock and oxidative stress also activate Dd-STATc. Hyperosmotic stress is known to elevate intracellular cGMP and cAMP levels, and the membrane-permeant analogue 8-bromo-cGMP rapidly activates Dd-STATc, whereas 8-bromo-cAMP is a much less effective inducer. Surprisingly,however, Dd-STATc remains stress activatable in null mutants for components of the known cGMP-mediated and cAMP-mediated stress-response pathways and in a double mutant affecting both pathways. Also, Dd-STATc null cells are not abnormally sensitive to hyperosmotic stress. Microarray analysis identified two genes, gapA and rtoA, that are induced by hyperosmotic stress. Osmotic stress induction of gapA and rtoA is entirely dependent on Dd-STATc. Neither gene is inducible by DIF but both are rapidly inducible with 8-bromo-cGMP. Again, 8-bromo-cAMP is a much less potent inducer than 8-bromo-cGMP. These data show that Dd-STATc functions as a transcriptional activator in a stress-response pathway and the pharmacological evidence, at least, is consistent with cGMP acting as a second messenger.
Using a quarter-vehicle multi-body model to estimate the service loads of a suspension arm for durability calculations
Authors: Haiba M , Barton D C , Brooks P C , Levesley M C
Published: June 2003

Predicting the fatigue life of an automotive component requires stress histories that accurately reflect loading conditions. In practice, these loads can only be determined experimentally once a physical prototype exists. If durability is to influence the design process at an early stage, representative loading conditions must be evaluated virtually using tools such as the multi-body system (MBS) technique. This paper investigates the simulation of loading conditions for a suspension arm of a multipurpose vehicle using a quarter-vehicle model (QVM) of varying complexity. Like the physical durability test, the model is driven over a virtual pavé road, which subjects the virtual prototype to inputs likely to cause significant damage, thus placing exacting demands on the model. Though predicted resonant frequencies are close to those measured, comparison between experiment and simulation reveals discrepancies in the amplitudes of acceleration. Possible causes are investigated by studying the sensitivity of the QVM to parameters such as the tyre model and bushing. The paper concludes that, if the virtual prototype is subjected to large amplitude inputs such as those generated by a pavé road, the QVM may not adequately predict representative loading conditions, and a full-vehicle model may be required.
Some characteristic parameters affecting the natural frequency of a rotating shaft supported by defect-free ball bearings
Authors: Akturk N
Published: June 2003

It is now well known that the preload and number of rolling elements of an angular contact ball bearing are two important parameters that affect the bearing-induced vibration of a shaft-bearing assembly. Increasing the preload changes the steady state position of the vibration on the non-linear contact-force relation of the bearing, resulting in the shaft mass being supported on stiffer springs. A larger number of rolling elements causes a similar stiffer equivalent spring. The ball set position is another parameter that affects the vibration of the system. These effects have been investigated by different researchers with simulation programs, and their findings are also supported by the experimental evidence of other researchers. In this paper, therefore, a new analytical investigation into the effects of preload, the number of rolling elements and ball set position is made. Analytical results are found to be in good agreement with simulation results.
Evaluation of Mexiletine Clearance in a Japanese Population
Authors: Ueno Kazuyuki , Tamamura Akira , Matsumoto Kana , Komamura Kazuo , Kamakura Shiro , Miyatake Kunio , Shibakawa Masahiko
Published: June 2003

OBJECTIVE:

To evaluate mexiletine clearance in a Japanese population and to clarify the roles of CYP2D6 and CYP1A2 in mexiletine disposition.

METHODS:

Concentrations of serum and urinary mexiletine and its metabolites were determined and mexiletine clearances were estimated in 334 inpatients receiving mexiletine therapy. Concentrations of mexiletine and its metabolites in serum and urine samples were determined by HPLC.

RESULTS:

Although interindividual variation of mexiletine clearance was small, the effect of age on mexiletine clearance was comparatively large. Mexiletine clearance in patients with dilated cardiomyopathy (DCM) was decreased when compared with other diagnoses (Non-DCM). The fractional contents of p-hydroxymexiletine (POH) and 2-hydroxymexiletine (OHMEX) in urine amounted to approximately 50%. Almost all of the POH was conjugated, whereas less than one-third of the OHMEX was conjugated. Although no significant differences in POH and OHMEX were observed between patients with DCM and those without, a trend toward an increase in conjugation pathway of DCM patients was observed.

CONCLUSIONS:

The interindividual variation of mexiletine clearance was small, while the effect of age on the mexiletine clearance in Non-DCM was comparatively large. A significant difference in mexiletine clearance between patients with DCM and those with Non-DCM was observed. Therefore, when mexiletine is administered to patients with DCM, careful monitoring is needed.
Vitamin B12 Deficiency Associated with Histamine2-Receptor Antagonists and a Proton-Pump Inhibitor
Authors: Ruscin J Mark , Lee Page Robert , Valuck Robert J
Published: June 2003

OBJECTIVE:

To report a case of vitamin B12 deficiency associated with long-term use (∼4½ y) of histamine2 (H2)-receptor antagonists and a proton-pump inhibitor (PPI) in a patient with gastroesophageal reflux.

CASE SUMMARY:

A 78-year-old nonvegetarian white woman with symptomatic gastroesophageal reflux (GER) was started on cimetidine 300 mg 4 × daily in February 1990 and took various other antisecretory medications over the course of the next 4½ years. She had a normal serum vitamin B12 concentration of 413 pg/mL in August 1992. In June 1994, her serum vitamin B12 concentration was found to be in the low normal range at 256 pg/mL. Biochemical markers of vitamin B12–dependent enzyme activity were measured at that time, and methylmalonic acid (MMA) and homocysteine (HCYS) were elevated at 757 nmol/L and 27.3 μmol/L, respectively. Serum folate was within the normal range at 4.9 ng/mL, and serum creatinine was slightly elevated at 1.4 mg/dL. MMA and HCYS concentrations decreased dramatically with oral replacement of vitamin B12 1000 μg/d, which confirmed vitamin B12 deficiency. Oral replacement also demonstrated that the woman was able to adequately absorb nonprotein—bound vitamin B12 from the gastrointestinal tract, suggesting that her deficiency was a result of food—cobalamin malabsorption. The accumulation of MMA and HCYS was not a consequence of renal dysfunction, since both metabolites dramatically decreased with vitamin B12 replacement.

DISCUSSION:

Malabsorption of dietary protein-bound vitamin B12 has been demonstrated with the use of H2-receptor antagonists and PPIs. One previous case report of vitamin B12 deficiency resulting from long-term use of omeprazole has been published. The malabsorption of dietary vitamin B12 is thought to be a result of its impaired release from food protein, which requires gastric acid and pepsin as the initial step in the absorption process.

CONCLUSIONS:

The use of H2-receptor antagonists and/or PPIs may impair the absorption of protein-bound dietary vitamin B12 and could contribute to the development of vitamin B12 deficiency with prolonged use. Patients taking these medications for extended periods of time, particularly >4 years, should be monitored for vitamin B12 status.
Methodology to Determine Duration of Action for Antihypertensive Drugs
Authors: Lefebvre Jean , Poirier Luc , Lacourcière Yves
Published: June 2003

OBJECTIVE:

To review and comment on methods used to assess the duration of action of antihypertensive drugs.

DATA SOURCES:

A MEDLINE search (1966–June 2000) using key terms such as trough-to-peak ratio and ambulatory blood pressure monitoring was conducted.

STUDY SELECTION:

An article was considered for this review if it pertained to the assessment of the duration of action of antihypertensive drugs. Special attention was given to articles dealing with methodologic aspects.

DATA SYNTHESIS:

Antihypertensive drugs with a long duration of action are thought to provide better therapeutic coverage against hypertensive complications compared with that of short-acting agents. Measuring blood pressure at the end of the dosing interval may be a way to assess the duration of action of a drug. However, the use of high doses of a short-acting agent to obtain sufficient effect when at trough concentrations can potentially cause dose-related adverse effects at the peak time, contributing to nonadherence to therapy and thus to adverse outcomes. To alleviate this problem, the US Food and Drug Administration (FDA) has conceptualized the trough-to-peak (T:P) ratio. Although this arithmetic index has since been widely used to characterize the duration and safety of blood pressure control achieved by antihypertensive agents, several methodologic flaws limit its interpretation in the clinic. Ambulatory blood pressure monitoring (ABPM) is a more reliable approach to assess the duration of action and outcome of antihypertensive therapy.

CONCLUSIONS:

Different methodologic approaches exist to evaluate the duration of action of antihypertensive drugs. Although the T:P ratio has been suggested by the FDA, it is difficult to establish a fair comparison among various antihypertensive agents based solely on this index. Treatment evaluation based on ABPM may be preferable to those guided by T:P because ABPM is more reproducible and is now established as a predictor of cardiovascular risk.
Alteplase Use for Prevention of Central Line Occlusion in a Preterm Infant
Authors: Lee Edith K
Published: June 2003

OBJECTIVE:

To report the use of alteplase for catheter clearance in a neonate of 27 weeks' gestation at day 50 of life.

SETTING:

Neonatal Intensive Care Unit, Naval Medical Center.

CASE SUMMARY:

At day 50 of life, a neonate boy of 27 weeks' gestation had a clotted peripherally inserted central catheter line. He required central access to complete a 28-day course of amphotericin B. An alteplase dose of 0.3 mg/0.3 mL was instilled into the catheter, for an indwelling time of 1 hour. The initial attempt was successful, and the patient was able to finish the course of amphotericin B.

DISCUSSION:

When a catheter becomes occluded, the cause must be determined initially; then an appropriate treatment option can be initiated. Hydrochloric acid and ethanol are some of the pharmacologic agents available, with their use dependent on the precipitating cause of the occlusion. Thrombolytic agents, such as streptokinase and urokinase, have also been used in catheter clearance. The potential risk of anaphylactic reactions with streptokinase and the unavailability of urokinase have clinicians searching for other pharmacologic alternatives. Alteplase, a synthetic tissue plasminogen actitvator, has been shown to be a promising alternative agent. There are various reports of alteplase use in pediatric patients for catheter clearance, with different suggested doses ranging from 0.25 to 2 mg. To minimize the risk of bleeding events, initiation with low doses from the suggested range is recommended.

CONCLUSIONS:

Alteplase was shown to be safe and effective for clearance of an occluded central line in a preterm infant.
Opioid Dependence Treatment, Including Buprenorphine/Naloxone
Authors: Raisch Dennis W , Fye Carol L , Boardman Kathy D , Sather Mike R
Published: June 2003

OBJECTIVE:

To review opioid dependence (OD) and its treatment. Pharmacologic treatments, including the use of buprenorphine/naloxone, are presented. Pharmaceutical care functions for outpatient OD treatment are discussed.

DATA SOURCES:

Primary and review articles were identified by MEDLINE and HEALTHSTAR searches (from 1966 to November 2000) and through secondary sources. Tertiary sources were also reviewed regarding general concepts of OD and its treatment.

STUDY SELECTION/DATA EXTRACTION:

Relevant articles were reviewed after identification from published abstracts. Articles were selected based on the objectives for this article. Studies of the treatment of OD with buprenorphine were selected based on the topic (pharmacology, pharmacokinetics, adverse reactions) and study design (randomized, controlled clinical trials in patients with OD with active/placebo comparisons and/or comparisons of active OD treatments). Articles regarding pharmacists' activities in the treatment and prevention of OD were reviewed for the pharmaceutical care section.

DATA SYNTHESIS:

OD is considered a medical disorder with costly adverse health outcomes. Although methadone maintenance treatment (MMT) is cost-effective for OD, only about 12% of individuals with OD receive this treatment. Psychological and pharmacologic modalities are used to treat OD, but patients often relapse. Drug therapy includes α2-agonists for withdrawal symptoms, detoxification regimens with or without opioids, opioid antagonists, and opioid replacement including methadone, levomethadyl acetate, and buprenorphine. The Drug Addiction Treatment Act of 1999 allows for office-based opioid replacement therapies. Sublingual buprenorphine with naloxone can be used in this milieu. Buprenorphine with naloxone is currently under new drug application review with the Food and Drug Administration. Clinical research shows buprenorphine to be equal in effectiveness to methadone, but safer in overdose due to its ceiling effect on respiratory depression. It has lower abuse potential and fewer withdrawal symptoms when discontinued. Naloxone is included to decrease diversion and injection of the tablets. Pharmacists in outpatient settings who are familiar with OD have opportunities to provide pharmaceutical care to patients receiving this treatment. Pharmaceutical care functions for OD include ensuring appropriate drug administration, monitoring adverse effects, alleviating withdrawal symptoms, treating intercurrent illnesses, minimizing diversion, and preventing relapse.

CONCLUSIONS:

OD is a critical unmet health problem in the US. Buprenorphine combined with naloxone represents an innovative treatment for OD in outpatient settings. This new treatment has advantages over MMT.
Acute Cholestatic Hepatitis after Exposure to Isoflurane
Authors: Malnick Stephen DH , Mahlab Keren , Borchardt Jakob , Sokolowski Nadia , Attali Malka
Published: June 2003

OBJECTIVE:

To report a case of acute cholestatic hepatitis following exposure to the inhalational anesthetic isoflurane.

CASE SUMMARY:

A 70-year-old healthy woman from Iraq developed acute cholestatic hepatitis 3 weeks following repair of the right rotator cuff under general anesthesia. There was no evidence for viral, autoimmune, or metabolic causes of hepatitis. No other medications were involved except for dipyrone for analgesia. The alanine aminotransferase was elevated to a peak concentration of 1533 U/L and the serum bilirubin reached a peak of 17.0 mg/dL. There was slow improvement over 4 months. Accidental reexposure by the patient to dipyrone was uneventful.

DISCUSSION:

The clinical and histologic picture of this case resembles halothane hepatitis, which has a significant mortality rate.

CONCLUSIONS:

Isoflurane, a common anesthetic agent, can cause severe cholestatic hepatitis.
Celecoxib-Induced Nonoliguric Acute Renal Failure
Authors: Alkhuja Samer , Menkel Robert A , Alwarshetty Mamata , Ibrahimbacha Ahmad M
Published: June 2003

OBJECTIVE:

To report a case of nonoliguric acute renal failure secondary to use of celecoxib in a patient with rheumatoid arthritis.

CASE SUMMARY:

A 43-year-old Hispanic woman started receiving celecoxib 200 mg/d for treatment of rheumatoid arthritis. Fourteen days after initiating therapy, she developed nonoliguric acute renal failure. Celecoxib was discontinued. Renal function improved, but had not returned to normal 30 days after presentation.

DISCUSSION:

Only 2 cases of reversible oliguric acute renal failure and volume overload have been reported 13 and 14 days after initiating therapy with celecoxib. Renal function in the 2 patients returned to baseline after treatment with diuretics. To our knowledge, the development of nonoliguric acute renal failure secondary to treatment with celecoxib has not previously been reported.

CONCLUSIONS:

Celecoxib can probably result in reversible, or nonoliguric, acute renal failure. Although renal function improves after discontinuation of celecoxib, it may not return to baseline. Celecoxib should be used cautiously in individuals at risk of developing acute renal failure.
Telithromycin: The First of the Ketolides
Authors: Shain Christopher S , Amsden Guy W
Published: June 2003

OBJECTIVE:

To review the chemistry, spectrum of activity, pharmacology, clinical efficacy, and safety of telithromycin.

DATA SOURCES:

A MEDLINE search from 1966 to December 2000 was performed via OVID and PubMed using the following search terms: HMR 3647, HMR3647, Ketek, RU 66647, and telithromycin. An extensive review of retrieved literature, abstracts from international scientific conferences, and minutes from regulatory authority meetings was also performed.

DATA EXTRACTION:

Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the antimicrobial activity, clinical efficacy, pharmacology, and safety of telithromycin.

DATA SYNTHESIS:

Several chemical modifications to the macrolide structure have led to the development of telithromycin, the first ketolide antimicrobial that demonstrates improved activity against penicillin- and macrolide/azalide-resistant Streptococcus pneumoniae due to its unique binding to the ribosomal target site. Although telithromycin may be useful in the treatment of community-acquired respiratory tract infections due to its activity against common typical and atypical pathogens, questions concerning its reliable activity against Haemophilus influenzae need to be addressed. Telithromycin's pharmacokinetics permit once-daily dosing for abbreviated periods and good distribution into lung tissue and phagocytic cells. Clinical and bacteriologic cure rates have been similar to those of comparator agents in human efficacy trials; however, the incidence of adverse gastrointestinal events were generally higher with telithromycin patients. Like other macrolides and many newer fluoroquinolones, telithromycin's ability to prolong the QTc interval is a potential safety issue, especially in elderly patients with predisposing conditions or those who are concurrently receiving drugs that are substrates for CYP2D6 and 3A4. Liver function test elevations demonstrated during clinical trials, although not overtly severe, may warrant monitoring in some patients taking multiple hepatically metabolized/cleared agents.

CONCLUSIONS:

Telithromycin offers potential advantages over traditional macrolides/azalides for community-acquired respiratory tract infections caused by macrolide-resistant pathogens. Further studies are needed to elucidate its clinical efficacy against H. influenzae, potential drug interactions, and safety in various subpopulations.
Factors Affecting Medication Adherence in Hypertensive Patients
Authors: Patel Rosalie P , Taylor Stephanie D
Published: June 2003

BACKGROUND:

Adherence to medication is a critical factor in the continued health and well-being of patients with hypertension. Patients' acceptance of medical advice and information may be influenced by their subjective beliefs about their health condition; therefore, it is essential that their beliefs be taken into account when giving health advice or medical treatment.

OBJECTIVE:

To determine whether a relationship exists between illness attribution, perceived control, and adherence to antihypertensive medications.

METHODS:

A prospective, cross-sectional survey of hypertensive patients was conducted at the University of Michigan Medical Centers, Hypertension Clinic, Ann Arbor, MI. One hundred two patients with a goal to reduce their blood pressure were included in the study. Written and follow-up telephone survey questions assessing patients' illness attributions, perceived control, and medication adherence were administered. Associations between these variables were analyzed using correlation analyses.

RESULTS:

The majority of patients (67.7%) were adherent with their hypertensive medications. Patients indicated that modifiable variables were the most common attribution believed to cause hypertension; however, there was no significant relationship to medication adherence. A significant inverse relationship was found between perceived control over hypertension and medication adherence (p < 0.01).

CONCLUSIONS:

The findings suggest that patients' greater perception of control over trying to reduce blood pressure may result in decreased reliance on medications and subsequent nonadherence to drug therapy. Implications of these findings on pharmacy practice are discussed.
Potential Use of HMG-CoA Reductase Inhibitors for Osteoporosis
Authors: Cushenberry Lolita M , de Bittner Magaly Rodriguez
Published: June 2003

OBJECTIVE:

To review the current clinical data describing the effects of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in bone formation and reduction of fracture incidence and their potential use for osteoporosis.

DATA SOURCES:

English-language articles and abstracts were identified from a MEDLINE database search (1966–May 2001) that used the key words osteoporosis, HMG-CoA reductase inhibitors, and treatment.

STUDY SELECTION AND DATA EXTRACTION:

All the articles identified from the data sources were evaluated, and all information deemed relevant was included in this review.

DATA SYNTHESIS:

In the past, there has been considerable emphasis placed in the detection, prevention, and treatment of osteoporosis. New drug therapies have been introduced in the market aimed at decreasing bone loss and increasing bone formation, with the ultimate goal of decreasing fractures. Currently, there are a variety of agents available for the treatment of osteoporosis. A limited number of case—control studies have suggested that HMG-CoA reductase inhibitors (statins) may have the potential to reduce the risk of fractures by increasing bone formation, although other studies have failed to show a benefit in fracture reduction. The potential benefit of this therapy is still undetermined because of a lack of randomized, controlled, clinical trials and conflicting data.

CONCLUSIONS:

At this time, there are limited data on the role of statins in the treatment of osteoporosis. Practitioners must be cautious when using these agents over other proven conventional therapies. Randomized, controlled, clinical trials are needed to accurately determine the role of these agents in the treatment of osteoporosis.
In Vitro Assessment of Urinary Isolates of Ampicillin-Resistant Enterococci
Authors: Williamson John C , Craft David W , Butts John D , Raasch Ralph H
Published: June 2003

OBJECTIVE:

Susceptibility and minimum inhibitory concentration (MIC) studies of ampicillin-resistant enterococci (ARE) were performed with vancomycin, ciprofloxacin, and trovafloxacin. Ampicillin MICs were determined to make comparisons with achievable urinary concentrations of ampicillin.

DESIGN:

From July 1998 to April 1999, all enterococci isolated from urinary specimens were tested for susceptibility to ampicillin by disk diffusion. For all ARE, vancomycin, ciprofloxacin, and trovafloxacin susceptibilities were determined by use of either disk diffusion or the E-test. Ampicillin MICs were determined for these isolates by liquid agar microdilution testing. ARE were identified to the species level on the basis of biochemical reactions.

SETTING:

The study was performed at a university-affiliated tertiary care hospital.

OUTCOME MEASURES:

In vitro susceptibility studies and MIC determinations were performed in accordance with the National Committee for Clinical Laboratory Standards.

RESULTS:

A total of 310 urine samples were culture positive for enterococcus. Thirty (9.7%) unduplicated isolates were resistant to ampicillin. Of these, nine ARE isolates (30%) were also vancomycin resistant, whereas only 2 ampicillin-susceptible isolates were vancomycin resistant (p < 0.05). All ARE were resistant to ciprofloxacin, and 29 (96.7%) were resistant to trovafloxacin. Nine (30%), 18 (60%), and 3 (10%) isolates had an ampicillin MIC of 128, 256, and 512 μg/mL, respectively. Ampicillin MICs did not differ significantly between vancomycin-susceptible and -resistant isolates (p = 0.963). Twenty-seven isolates (90%) were identified as Enterococcus faecium; the other 3 were either Enterococcus avium or Enterococcus raffinosus.

CONCLUSIONS:

Ampicillin resistance is associated with resistance to vancomycin. Most ARE are resistant to fluoroquinolone antibiotics such as ciprofloxacin and trovafloxacin. Ampicillin MICs for ARE found in these urinary specimens were all within 1 dilution of 256 μg/mL, a concentration achievable in the urine with higher doses of oral amoxicillin or intravenous ampicillin. Additional studies are needed to assess the clinical implications of these data.
Thalidomide Use in Pediatric Patients
Authors: Bessmertny Olga , Pham Trinh
Published: June 2003

OBJECTIVE:

To provide a detailed overview of thalidomide use in pediatric patients.

DATA SOURCES:

English-language articles were identified through a MEDLINE search (1966–February 2001); key terms included thalidomide, child, graft-versus-host disease, cancer, HIV, Crohn's disease, Behcet's disease, and lupus erythematosus. References cited in those articles were also evaluated.

DATA SYNTHESIS:

Thalidomide appears to be effective in patients with chronic, not acute, graft-versus-host disease (GVHD) and in healing aphthous ulcers in patients with HIV infection. Limited case reports suggest efficacy of thalidomide in the treatment of cutaneous manifestations of Behçet's disease, Crohn's disease, and lupus in children; however, the recurrence of disease is almost universal on drug discontinuation.

CONCLUSIONS:

Thalidomide should be used as a last resort when all other therapies fail, preferably in male or prepubescent female patients.
Lamotrigine Update and its Use in Mood Disorders
Authors: Hurley Stephen C
Published: June 2003

OBJECTIVE:

To provide a qualitative, systematic update and review of the pharmacology, pharmacokinetics, efficacy in mood disorders, adverse effects, and costs of lamotrigine.

DATA SOURCES:

Citations obtained from MEDLINE searches (1985–September 2001) using lamotrigine as a text word, articles identified in reference lists of pertinent articles, abstracts presented at conferences, and research data from GlaxoSmithKline.

DATA EXTRACTION:

English-language articles were considered for possible inclusion. Each title and abstract was examined to determine whether the publication contained up-to-date information relevant to the objective. Twenty clinical trials that provided data on response rates in mood disorders were tabulated.

DATA SYNTHESIS:

Lamotrigine's primary action is to modulate voltage-gated sodium channels. Evidence suggests that it decreases glutamate transmission, directly reduces calcium influx, mildly blocks transmitter reuptake, and alters intracellular mechanisms of resting transmitter release. The average half-life of lamotrigine is approximately 24 hours, but decreases to approximately 7.4 hours when used concurrently with phenytoin, and increases to approximately 59 hours with valproic acid. Seven of the 20 clinical trials were randomized, double-blind, and controlled. Existing data are inadequate to evaluate lamotrigine use in major depression. The pooled response rates for patients with depressed, manic, mixed, and rapid cycling bipolar disorder were similar, ranging from 52% to 63%. Adverse effects are infrequent when the drug is used alone, but become more frequent when lamotrigine is combined with other anticonvulsants. While most rashes are mild, approximately 1 in 500 patients develops exfoliative dermatitis. A slow upward dose titration is recommended to reduce the incidence of serious rash, but this may delay the attainment of adequate dosage for 6 weeks. Lamotrigine has positive effects on cognitive function, but occasionally produces insomnia. Lamotrigine costs 2–4 × more than lithium, carbamazepine, and generic valproic acid.

CONCLUSIONS:

When efficacy, adverse effects, and cost are considered, lamotrigine should probably be reserved as a second-line agent for bipolar depression.
Intravenous versus Oral Corticosteroids for Treatment of Acute Asthma Exacerbations
Authors: Fulco Patricia Pecora , Lone Amista A , Pugh Carol B
Published: June 2003

OBJECTIVE:

To compare the duration of hospitalization of patients treated with either oral or intravenous corticosteroids for an acute asthma exacerbation.

METHODS:

A retrospective chart review was performed on a random sample of inpatients. Patients were included with the following: a discharge diagnosis of an acute asthma exacerbation, a past medical history significant for asthma, age between 16 and 60 years, and treatment with either oral or intravenous corticosteroids at the time of admission. Exclusion criteria included: patients receiving chronic prednisone therapy, a past medical history significant for chronic obstructive pulmonary disease, an admission to the intensive care unit, or a consistent smoking habit of at least 1 pack daily. Length of hospitalization was the primary outcome measured. Secondary outcomes included 24-hour peak expiratory flow rate, 24-hour pulse oximetry (pO2), and amount of β-agonist and ipratropium used.

RESULTS:

Fifty-three patients were included in the final data analysis. Patients were grouped by route of corticosteroid administration (intravenous or oral). No significant differences were noted between the 2 groups for race, gender, age, height, weight, admission peak expiratory flow rate, admission pO2, or types of asthma medications used prior to admission. No significant differences were demonstrated in any of the outcome measures.

CONCLUSIONS:

Both the intravenous and oral corticosteroid groups demonstrated similar clinical outcomes and lengths of hospitalization in the treatment of acute asthma exacerbations. These results support the initial use of oral corticosteroids for the treatment of acute asthma exacerbations in adult patients admitted to a general medical service.
Gender- and Age-Related Prescription Drug Use Patterns
Authors: Roe Catherine M , McNamara Ann M , Motheral Brenda R
Published: June 2003

OBJECTIVE:

To report the top 15 prescription drug categories used by males and females of all ages and to compare this information with national prevalence data.

METHODS:

Data used were pharmacy claim and eligibility information over the period January 1, 1999, through December 31, 1999, for 1 294 295 members of a large pharmacy benefit manager. Participant ages ranged from 1 to more than 100 years. Each participant was assigned to 1 of 9 age categories. Use of a drug category was defined as filling at least 1 prescription for a medication in that category during the study year. The percentage of males and females that used each drug group was established, and the 15 drug groups used most frequently were reported for each age category.

RESULTS:

Most gender differences in medication use appear after or around the puberty years. Women are more likely to use several classes of medications, including antidepressants and antianxiety and pain medications. Except for diuretics, men use cardiovascular medications at an earlier age than do women. The use of medications for chronic conditions increases with older age categories for both genders. The use of female hormones represents only a small proportion of the difference in medication use between genders.

CONCLUSIONS:

Analysis of data from the epidemiologic literature suggests that the gender differences in medication use shown in this study generally are to be expected.
Cutaneous and Systemic Manifestations of Drug-Induced Vasculitis
Authors: Holder Sandra M ten , Joy Melanie S , Falk Ronald J
Published: June 2003

OBJECTIVE:

To evaluate the literature for published cases of drug-induced vasculitis with cutaneous and/or systemic manifestations.

DATA SOURCES:

The MEDLINE database was searched from 1965 to December 1999 for articles focusing on drugs and vasculitis, using various search terminologies (e.g., Churg-Strauss syndrome, Goodpasture's syndrome, Henoch-Schönlein purpura, various drugs suspected to induce vasculitis). Cases were included when they met the established criteria as described in the methodology.

DATA SYNTHESIS:

Drugs found to be most frequently associated with vasculitis were propylthiouracil, hydralazine, colony-stimulating factors, allopurinol, cefaclor, minocycline, D-penicillamine, phenytoin, isotretinoin, and methotrexate. The interval between the first exposure and appearance of symptoms was reported to be extremely variable (hours to years). Vasculitis has occurred after drug dosage increases and after rechallenge with the suspected drug. In the majority of cases, vasculitis has resolved after discontinuing the drug. Patients with more severe, often life-threatening, manifestations have required treatment with corticosteroids, plasmapheresis, hemodialysis, or cyclophosphamide. Death was the result in 10% of all published cases, with a predominance in patients in whom multiple organ systems were involved.

CONCLUSIONS:

Clinicians need to be suspect of drug-induced vasculitis to enable prompt diagnosis and treatment. This should improve patient outcomes based on the data referenced for this article.
Delayed Wound Healing with Sirolimus after Liver Transplant
Authors: Guilbeau Jane M
Published: June 2003

OBJECTIVE:

To report 3 separate cases of wound dehiscence in liver transplant recipients receiving sirolimus for immunosuppressive therapy.

CASE SUMMARIES:

Three patients who had received liver transplants experienced a delay in wound granulation and healing after being placed on an immunosuppressive regimen containing sirolimus and steroids. Each patient was admitted and treated for wound dehiscence, at which time sirolimus was discontinued. When other immunosuppressive agents were substituted for sirolimus, each incisional wound granulated and closed without complication.

DISCUSSION:

Sirolimus is an important adjunctive immunosuppressant used to prevent acute rejection episodes in patients who have undergone transplant, particularly when nephrotoxic effects from first-line calcineurin inhibitors become problematic. The unique ability of sirolimus to inhibit smooth muscle cell proliferation and intimal thickening by blocking important growth factors may subsequently become a significant feature to prevent the development of chronic rejection. Theoretically, by this same mechanism, sirolimus may play a role in forestalling wound healing and may even promote dehiscence.

CONCLUSIONS:

These case reports describe patients who underwent liver transplant who developed wound dehiscence possibly secondary to sirolimus therapy. Although the cases were complicated by acute rejection, wound infections, and comorbidities, wound granulation and healing began after discontinuation of sirolimus. Substitution with another immunosuppressant may be necessary for patients who experience wound dehiscence after transplant.
Influence of Standardized Orders on Postoperative Nausea and Vomiting after Gynecologic Surgery
Authors: St. Pierre Edith , Frighetto Luciana , Marra Carlo A
Published: June 2003

OBJECTIVE:

The risk of postoperative nausea and vomiting (PONV) after gynecologic surgery remains high, despite effective prophylactic medications. Thus, the objectives of this study were to determine whether standardized orders for the prophylaxis and treatment of PONV in gynecologic surgery patients (1) reduce PONV occurrence, (2) reduce total costs, and (3) influence the choice of medications used for PONV prophylaxis and treatment.

METHODS:

A retrospective design was employed in which a random sample of 200 patients was selected from each of the two 6-month phases before (pre) and after (post) the implementation of standardized orders for PONV prophylaxis and treatment. The primary outcome was the occurrence of any PONV episode. Logistic regression was used to adjust for potential confounding factors. All costs were in 1999 Canadian dollars (Canadian dollar = US$0.673 in 1999).

RESULTS:

Characteristics were similar except for surgical and anesthesia length between phases. The proportion of patients who received PONV prophylaxis increased from 31% (pre) to 47% (post; p = 0.002). There was a reduction in the risk of a PONV event in the post-phase (odds ratio [OR] 0.67, 95% CI 0.67 to 0.97; p = 0.04). The risk of PONV was significantly reduced with the administration of prophylactic medications (OR 0.46, 95% CI 0.46 to 0.67; p = 0.001). There was a reduction in the mean number of PONV episodes in the post-phase (1.47 events) versus the pre-phase (1.81 events; p = 0.02). A reduction in mean PONV management costs was observed in the post-phase ($8.31, SD ± 8.50) compared with the pre-phase ($10.23, SD ± 8.25; p = 0.02). For mean prophylactic costs, these were significantly higher in the postimplementation phase compared with the preimplementation phase ($1.64, SD ± 3.36 vs. $0.91, SD ± 2.43; p = 0.013). For mean total PONV costs (prophylaxis plus management costs), there was a nonsignificant reduction in the postimplementation phase compared with the preimplementation phase ($9.95, SD ± 9.20 vs. $11.15, SD ± 8.51, respectively; p = 0.18). Univariate sensitivity analyses revealed that the economic results were sensitive to several parameters.

CONCLUSIONS:

The implementation of preprinted order forms for PONV prophylaxis and treatment appears to be an effective and economically attractive strategy.
Gabapentin for Hot Flashes in Prostate Cancer
Authors: Jeffery Sean M , Pepe Jeffrey J , Popovich Lisa M , Vitagliano Gail
Published: June 2003

OBJECTIVE:

To report a case of successful treatment of refractory hot flashes with gabapentin in a patient with prostate cancer who was receiving combination antiandrogen and gonadotropin hormone—releasing hormone (GnRH) analog therapy.

CASE SUMMARY:

A 70-year-old white man with a history of advancing prostate cancer experienced disabling hot flashes from combination therapy with the antiandrogen bicalutamide and the GnRH analog goserelin acetate. He failed to respond to clonidine 0.1 mg twice daily, megestrol acetate 40 mg/d, diethylstilbestrol 1 mg/d, and venlafaxine 25 mg twice daily. The patient was then treated with gabapentin 600 mg once daily, at which time he experienced near-complete resolution of his symptoms.

DISCUSSION:

This case supports a previous report of the marked improvement in severity and duration of hot flashes associated with antiandrogen or GnRH analog therapy in prostate cancer. The mechanism by which gabapentin reduces hot flashes is unknown.

CONCLUSIONS:

Hot flashes resulting from antiandrogen or GnRH analog therapy are often difficult to treat and leave many patients disabled. Gabapentin has been shown to markedly reduce the severity, frequency, and duration of these hot flashes. Controlled trials are necessary to evaluate gabapentin against other therapeutic modalities.
Bupropion-Induced Acute Dystonia
Authors: Detweiler Mark B , Harpold Gary J
Published: June 2003

OBJECTIVE:

To report a case of acute dystonia consisting of neck stiffness, trismus, and unilateral temporomandibular joint (TMJ) pain and subluxation secondary to an increase in sustained-release (SR) bupropion.

CASE SUMMARY:

A 44-year-old white man with a history of chronic low-back pain and tension headaches, taking no other medications, was started on bupropion SR 150 mg once a day for depression. The dosage was increased to 150 mg SR twice a day and eventually augmented with buspirone 15 mg 3 × a day. He developed bilateral trismus, inability to rotate his head laterally, and spontaneous left TMJ subluxation. Symptoms recessed with discontinuation of both medications and failed to reappear with a trial of buspirone 15 mg 3 × a day alone. A retrial of bupropion alone evidenced no adverse effects at a dosage of 150 mg SR once a day. However, when the dosage was increased to 150 mg SR twice a day, the patient reexperienced initial signs of neck stiffness, jaw muscle tightness, and left TMJ subluxation within 24–48 hours. Reduction of the bupropion dosage to 150 mg SR once daily stopped the symptoms; the patient has continued at this dosage without adverse effects for >1 year.

DISCUSSION:

Medication-induced focal dystonias usually present with dramatic head (most frequently oral—buccal) and neck muscle spasm with occasional jaw clenching, bruxism, and TMJ syndrome. In this case, the rapid onset of neck and jaw symptoms within 24–48 hours of an increase of bupropion SR from 150 mg once a day to 150 mg twice a day suggest that the patient may have been sensitized by an initial trial of bupropion and buspirone, or by the increased dose of bupropion alone. Both agents are reported to interact with both the dopaminergic and serotonergic systems. Although buspirone has been implicated in inducing acute dystonia, it did not do so in this case when used alone at a dose of 45 mg a day. During a second trial of bupropion SR 150 mg a day, neck and jaw symptoms recurred within 24–48 hours of increasing the dose to 150 mg SR twice a day. The symptoms receded when the bupropion dose was returned to 150 mg SR once a day, suggesting a dose—response relationship. The Naranjo probability scale indicated that this untoward reaction was probable.

CONCLUSIONS:

This case suggests that selected patients may experience dose-related acute dystonic adverse reactions to bupropion with or without buspirone augmentation. Dystonias, which usually follow administration of antipsychotics, have been linked to acute dopamine depletion and basal ganglion—derived γ synchronization dysfunction. Acute dystonia symptoms may begin within hours of starting or changing antipsychotic drug dosage; however, 90% of symptoms are observed during the first 3–5 days of starting or increasing dosage. To the best of our knowledge, there have been no reports of bupropion-induced dystonia.