bluuebunny/crossref_metadata_2025 huggingface dataset:
Zoledronic Acid Significantly Reduces Skeletal Complications Compared With Placebo in Japanese Women With Bone Metastases From Breast Cancer: A Randomized, Placebo-Controlled Trial
Authors: Kohno Norio , Aogi Kenjiro , Minami Hironobu , Nakamura Seigo , Asaga Taro , Iino Yuichi , Watanabe Toru , Goessl Carsten , Ohashi Yasuo , Takashima Shigemitsu
Published: March 2005

Purpose

To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer.

Patients and Methods

Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis.

Results

The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase.

Conclusion

Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.
Protective role of Coptidis Rhizoma alkaloids against peroxynitrite-induced damage to renal tubular epithelial cells
Authors: Yokozawa Takako , Satoh Akiko , Cho Eun Ju , Kashiwada Yoshiki , Ikeshiro Yasumasa
Published: March 2005

A study was conducted to elucidate and compare the protective activity of alkaloids from Coptidis Rhizoma (berberine, coptisine, palmatine, epiberberine, jatrorhizine, groenlandicine and magnoflorine) using an LLC-PK1 cell under peroxynitrite (ONOO−) generation model. Treatment with 3-morpholino-sydnonimine (SIN-1) led to an increase in cellular ONOO− generation in comparison with non-treated cells. However, Coptidis Rhizoma extract and its alkaloids, except for berberine, reduced the cellular ONOO− level. In addition, DNA fragmentation induced by SIN-1 was significantly decreased by the extract, and also by coptisine, epiberberine, jatrorhizine, groenlandicine and magnoflorine. Moreover, treatment with berberine, coptisine, palmatine and epiberberine exerted a protective effect against G0/G1 phase arrest of cell cycle induced by SIN-1. The increase in cellular ONOO− generation, DNA damage and disturbance of the cell cycle by SIN-1 resulted in a decrease in cell viability. However, Coptidis Rhizoma extract, epiberberine, jatrorhizine, groenlandicine and magnoflorine significantly increased cell viability even at a concentration as low as 10μg mL−1. These findings demonstrate that Coptidis Rhizoma extract and its alkaloids can ameliorate the cell damage associated with ONOO− generation in renal tubular LLC-PK1 cells, and that the various alkaloids have distinctive mechanisms of action, such as ONOO− scavenging, protection from DNA damage and control of the cell cycle. Furthermore, the data suggest that among the Coptidis Rhizoma alkaloids, coptisine is the most effective for protection against SIN-1-induced cellular injury in terms of its potency and content.
Altered dose-to-effect of propofol due to pharmacokinetics in rats with experimental diabetes mellitus
Authors: Leal N , Calvo R , Agrad F Z , Lukas J C , de la Fuente L , Suarez E
Published: March 2005

Pathology related alterations in the pharmacokinetics or the pharmacodynamics of propofol could contribute to the observed large variability in the hypnotic dose. We have tested the influence of diabetes mellitus on the induction dose and the pharmacokinetics and pharmacodynamics of propofol in rats. Diabetes was induced in rats by administration of streptozotocin (60 mg kg−1, i.p.) while control rats received vehicle intraperitoneally. All animals had glucose, cholesterol, triglycerides and albumin levels measured. In-vitro protein binding was determined by ultrafiltration. Rats were randomly split into set 1 (dose-concentration-effect study) with control and streptozotocin rats, and set 2 (pharmacokinetic study), with control and streptozotocin rats. Rats in the effect set received either a variable infusion of 6 mg kg−1 min−1 propofol until onset (induction dose) of the hypnotic effect (loss of the righting reflex), or a 15 mg kg−1 bolus to assess offset time (recovery of the righting reflex). Blood (Cblood) and brain (Cbrain) propofol concentrations at onset and offset were assayed by HPLC. In the pharmacokinetic study, propofol was administered intravenously at 6 mg kg−1 min−1 for 2 min. Arterial blood samples were collected between 0.5 and 540 min and assayed for propofol. A mixed effects compartmental pharmacokinetic modelling method (NONMEM) was used to analyse the observations and variabilities. The dose necessary for onset differed between streptozotocin and controls, and so did the pharmacokinetics with two- and three-compartment descriptions, respectively. Cblood and Cbrain at onset and offset were similar, possibly rejecting changes in pharmacodynamics. The total and unbound volume of distribution was significantly lower in the streptozotocin group with no differences in clearance (CL) between streptozotocin and controls, (mean (inter-animal CV%)) CL = 0.026 (17%) and 0.025 (62%) L min−1, respectively. Individual Bayes Vdss (volume of distribution at steady state) were different, (mean (s.d.)) Vdss = 7.7 (2.67) and 1.11 (0.09) L, respectively. The pharmacokinetic model was validated by comparison with the data from set 1. Simulations of total and unbound Cblood, for both groups, at the hypnotic dose for the controls, revealed differences throughout the time course of the pharmacokinetics. The difference observed in the induction dose of propofol to streptozotocin and control rats was due to alterations in the pharmacokinetics, secondary to the pathology.
Myosin light chain kinase and Rho-kinase participate in P2Y receptor-mediated acceleration of permeability through the endothelial cell layer
Authors: Tanaka Naoko , Nejime Namie , Kubota Yoko , Kagota Satomi , Yudo Keiko , Nakamura Kazuki , Kunitomo Masaru , Takahashi Koichi , Hashimoto Michio , Shinozuka Kazumasa
Published: March 2005

We have shown that P2Y receptor stimulation accelerates macromolecular permeation through the endothelial cell layer. To elucidate the mechanism of this acceleration, we examined the effects of ML-9, a myosin light chain kinase inhibitor, and Y-27632, a Rho-kinase inhibitor, on fluorescein isothiocyanate dextran (FD-4) permeation across the human umbilical vein endothelial cell monolayer. FD-4 permeation was analysed by high-performance liquid chromatography fluorescence detection. A P2Y receptor agonist, 2meS-ATP, enhanced the permeability of FD-4, which was inhibited by pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), a P2Y-receptor antagonist. The 2meS-ATP-induced increase in the permeability of FD-4 was significantly inhibited by ML-9. Also, Y-27632 prevented the 2meS-ATP-induced increase in the permeability of FD-4. Neither ML-9 nor Y-27632 influenced the spontaneous permeation of FD-4. These results suggest that phosphorylation of the myosin light chain may play an important role in the purinergic regulation of macromolecular permeation through the vascular endothelium.
Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration
Authors: Alencar V B M , Assreuy A M S , Alencar N M N , Meireles A V P , Mota M R L , Aragão K S , Cajazeiras J B , Nagano C S , Brito G A C , Silva L I M M , Pinto V P T , Sampaio A H , Debray H , Cavada B S , Ribeiro R A
Published: March 2005

PAL is a glucose/mannose-specific lectin isolated from Pisum arvense seeds. Previously, we demonstrated the capacity of other leguminous lectins to induce oedema formation and neutrophil stimulation. To investigate the potential pro-inflammatory activity of PAL, we have studied its ability to induce neutrophil migration into peritoneal cavities of rats and neutrophil chemotaxis in-vitro. The role of resident cells and sugar residues on PAL activity was analysed. PAL or saline (control) were administered intraperitoneally to rats, and total and differential leucocyte (macrophages, neutrophils and mast cells) counts were performed. The role of resident cells on the PAL effect was evaluated using three strategies: reducing the total resident cell population by lavage of rat cavities with saline; increasing macrophage population by treating animals with thioglycolate; and depleting mast cell population by subchronic treatment of rats with compound 48/80. PAL induced in-vitro and in-vivo neutrophil migration. In-vivo, PAL (50, 100, 200 and 300 μg) significantly (P < 0.05) and dose-dependently increased neutrophil migration by 600, 740, 900 and 940%, respectively, showing maximal effect 4 h after injection. PAL induced mononuclear cell migration. The neutrophil stimulatory effect of PAL was potentiated in animals treated with both thioglycolate and compound 48/80. The indirect lectin chemotactic effect was shown in rats injected with supernatant from cultured macrophages stimulated by PAL. In conclusion, PAL was shown to exhibit in-vivo and in-vitro proinflammatory activity. The in-vivo effect seemed to occur by a dual mechanism that was independent, but also dependent, on resident cells.
In-vitro anti-inflammatory activity of Pinus sylvestris and Plantago lanceolata extracts: effect on inducible NOS, COX-1, COX-2 and their products in J774A.1 murine macrophages
Authors: Vigo E , Cepeda A , Gualillo O , Perez-Fernandez R
Published: March 2005

Extracts of the plant species Pinus sylvestris L. and Plantago lanceolata L. have been used in traditional medicine for the treatment of certain respiratory diseases, but little is known about their precise effects and mechanisms of action. In this study, we investigated the effect of these plant extracts on the production of nitric oxide (NO) and prostaglandin E2, NO synthase (NOS) type II, cyclooxygenase-1 (COX-1) and COX-2 mRNA expression in the murine macrophage cell line J774A.1. We found that Pinus sylvestris and Plantago lanceolata extracts inhibited NO production in a concentration-dependent manner in this cell line, without obvious cytotoxic effects as tested by MTT assay. The Plantago lanceolata extract at all doses used, and the Pinus sylvestris extract at high doses, showed significant scavenging of NO radicals released by the NO donor PAPA-NONOate. Our data also show that pre-treatment with these extracts significantly inhibits inducible NOS (iNOS) mRNA production in this cell line, without affecting COX-1 mRNA expression. COX-2 mRNA levels and PGE2 levels induced by lipopolysaccharide/interferon-γ were not modified upon pre-treatment with the extracts. Thus, our results suggest that the anti-inflammatory properties of Pinus sylvestris and Plantago lanceolata extracts may reflect decreased NO production, possibly due to inhibitory effects on iNOS gene expression or to NO-scavenging activity.
Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies
Authors: Gavini Elisabetta , Rassu Giovanna , Sanna Vanna , Cossu Massimo , Giunchedi Paolo
Published: March 2005

Microparticulate delivery systems designed for the nasal administration of an antiemetic drug, metoclopramide hydrochloride, were prepared. Microspheres composed of sodium alginate, chitosan hydrochloride, or both, were obtained using a spray-drying method; some batches of drug-free microparticles were prepared as a comparison. The morphology, in-vitro swelling behaviour, mucoadhesive properties and drug release from microparticles were evaluated. Ex-vivo drug permeation tests were carried out using sheep nasal mucosa; permeation test of the drug solution was peformed as comparison. During ex-vivo permeation tests, transmission electron microscopy (TEM) analyses were carried out on the nasal mucosa to study the morphological changes of epithelial cells and tight junctions, while the change in microsphere morphology was examined using photostereo microscopy (PM). Spray-dried microparticles had a mean diameter (dvs) in the range of about 3–10 μm. They showed good in-vitro mucoadhesive properties. In-vitro release profiles and swelling behaviour depended on their composition: the drug release occurred in 1–3 h. Ex-vivo studies showed that drug permeation through the mucosa from microparticles based on chitosan was higher than from those consisting of alginate alone. This can be related to the penetration enhancing properties of chitosan. Complexation of chitosan with alginate led to a control of the drug release. Microscopy observation of microspheres during the permeation tests revealed that microparticles swelled and gelled, maintaining their shape. TEM analyses of the mucosa after exposure to the microparticles consisting of alginate/chitosan showed opened tight junctions. This preliminary study shows that alginate/chitosan spray-dried microspheres have promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.
Metabolism of pantoprazole involving conjugation with glutathione in rats
Authors: Zhong Dafang , Xie Zhiyong , Chen Xiaoyan
Published: March 2005

We have investigated the metabolism of pantoprazole and have provided an explanation for the formation mechanism of its metabolites. Metabolites found in the urine of rats after oral administration of pantoprazole sodium (25 mg kg−1) were analysed by liquid chromatography/ion trap mass spectrometry (LC/MSn). The N-acetylcysteine derivatives of benzimidazole (M1) and pyridine (M2), four pyridine-related metabolites (M3–M6), and three benzimidazole-related metabolites (M7–M9) were found, none of which had been reported previously. Five of the metabolites (M1, M2, M3, M7, and M8) were isolated from the urine of rats after oral administration of pantoprazole sodium by semi-preparative HPLC. Structures of these metabolites were identified by a combination analysis of LC/MSn and 1H NMR spectra. Structures of the remaining four metabolites (M4, M5, M6, and M9) were tentatively assigned through LC/MSn. The metabolites M2, M3, M4, M5 and M6 and the other metabolites (M1, M7, M8, and M9) reflected the fate of the pyridine moiety and the benzimidazole moiety, respectively. The proposed formation route of M3–M6 was via initial reduction to mercaptopyridine followed by S-methylation, O-demethylation, and S-oxidation to the corresponding sulfoxide or sulfone. Meanwhile, M8 and M9 were formed via initial reduction to the 5-difluoromethoxy-1H-benzoimidazole-2-thiol (M7) followed by hydroxylation and S-methylation. The metabolism of pantoprazole included an attack by glutathione on the benzimidazole-2-carbon and pyridine-7′-carbon. It is an important metabolic pathway of pantoprazole in rats.
The stereoselective biotransformation of the anti-obesity drug sibutramine in rat liver microsomes and in primary cultures of rat hepatocytes
Authors: Link Marek , Novotná Romana , Suchanová Bohumila , Skálová Lenka , Wsól Vladimír , Szotáková Barbora
Published: March 2005

Sibutramine is an anti-obesity drug sold as a racemic mixture under the trademark Meridia or Reductil. With the aim of evaluating the stereoselectivity in phase I of sibutramine biotransformation, the formation of the main metabolites from R-sibutramine, S-sibutramine and rac-sibutramine was studied in rat microsomes and primary cultures of hepatocytes. A novel analytical method for the determination of sibutramine and its phase I metabolites in culture medium and microsomal incubates using isocratic reversed-phase liquid chromatography with UV detection was developed. Only two metabolites, mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2), were found in the rat microsomes incubated with sibutramine and NADPH. The kinetics of M1 and M2 formation slightly differed depending on the enantiomeric form of the sibutramine used. The stereoselectivity in sibutramine biotransformation was much more evident in primary cultures of rat hepatocytes. While R-sibutramine incubation led to the formation of M1 and M2 metabolites only, the incubation of S-sibutramine or rac-sibutramine (to a lesser extent) resulted in four major metabolites (M1, M2, M3 and M4) and 2 or 3 minor metabolites. On the basis of our results, R-sibutramine might represent the more advantageous sibutramine enantiomer from the pharmacokinetic standpoint.
Actin-filament cross-linking protein T-plastin increases Arp2/3-mediated actin-based movement
Authors: Giganti Adeline , Plastino Julie , Janji Bassam , Van Troys Marleen , Lentz Delphine , Ampe Christophe , Sykes Cécile , Friederich Evelyne
Published: March 2005

Increasing evidence suggests that actin cross-linking or bundling proteins might not only structure the cortical actin cytoskeleton but also control actin dynamics. Here, we analyse the effects of T-plastin/T-fimbrin, a representative member of an important actin-filament cross-linking protein by combining a quantitative biomimetic motility assay with biochemical and cell-based approaches. Beads coated with the VCA domain of the Wiskott/Aldrich-syndrome protein (WASP) recruit the actin-nucleating Arp2/3 complex, polymerize actin at their surface and undergo movement when placed in cell-free extracts. T-Plastin increased the velocity of VCA beads 1.5 times, stabilized actin comets and concomitantly displaced cofilin, an actin-depolymerizing protein. T-Plastin also decreased the F-actin disassembly rate and inhibited cofilin-mediated depolymerization of actin filaments in vitro. Importantly, a bundling-incompetent variant comprising the first actin-binding domain (ABD1) had similar effects. In cells, this domain induced the formation of long actin cables to which other actin-regulating proteins were recruited. Altogether, these results favor a mechanism in which binding of ABD1 controls actin turnover independently of cross-link formation. In vivo, this activity might contribute to the assembly and maintenance of the actin cytoskeleton of plasma-membrane protrusions.
An Integrated Model and Solution Approach for Fleet Sizing with Heterogeneous Assets
Authors: Wu Peiling , Hartman Joseph C. , Wilson George R.
Published: March 2005

This paper addresses a fleet-sizing problem in the context of the truck-rental industry. Specifically, trucks that vary in capacity and age are utilized over space and time to meet customer demand. Operational decisions (including demand allocation and empty truck repositioning) and tactical decisions (including asset procurements and sales) are explicitly examined in a linear programming model to determine the optimal fleet size and mix. The method uses a time-space network, common to fleet-management problems, but also includes capital cost decisions, wherein assets of different ages carry different costs, as is common to replacement analysis problems. A two-phase solution approach is developed to solve large-scale instances of the problem. Phase I allocates customer demand among assets through Benders decomposition with a demand-shifting algorithm assuring feasibility in each subproblem. Phase II uses the initial bounds and dual variables from Phase I and further improves the solution convergence without increasing computer memory requirements through the use of Lagrangian relaxation. Computational studies are presented to show the effectiveness of the approach for solving large problems within reasonable solution gaps.
Medium-Term Pricing and Operations Planning in Intermodal Transportation
Authors: Li Li , Tayur Sridhar
Published: March 2005

Motivated by a real application that requires effective medium-term planning in intermodal transportation, we develop a mathematical programming model that jointly considers pricing and operations planning. Building on available work from marketing and transportation literature, we develop a new method for considering pricing, as well as develop distinctly different operations submodels that are appropriate for this context. We solve the resulting nonlinear optimization problem (with continuous and 0-1 variables) to optimality through a decomposition that exploits the structure of subproblems. Computational testing on industrial-sized problems shows that our algorithm is very quick, allowing for effective scenario testing and “what-if” analysis.
Discordance Analysis Characteristics as a New Method to Compare the Diagnostic Accuracy of Tests: Example of Complexed Versus Total Prostate-Specific Antigen
Authors: Keller Thomas , Butz Hermann , Lein Michael , Kwiatkowski Maciej , Semjonow Axel , Luboldt Hans-Joachim , Hammerer Peter , Stephan Carsten , Jung Klaus
Published: March 2005

Background: ROC curve analysis is used to compare the overall diagnostic accuracy of tests, but its application to subgroups selected by a concentration range of only one marker may show severe biases. We developed a new approach, which we have named discordance analysis characteristics (DAC).

Methods: The DAC method is based on a generalization of the McNemar test so that for a given pair of cutoff values only those patients are analyzed who are categorized differently by the two tests compared. The analyses are performed for all cutoff pairs that deliver identical sensitivities for both tests. We used data for total (tPSA) and complexed prostate-specific antigen (cPSA) from a recently published multicenter study to demonstrate the DAC method.

Results: The example shows that ROC analyses of subgroups can give contradictory results about the diagnostic accuracy of two markers, depending on the marker used for the selection of subgroups. The DAC method avoids artifacts attributable to questionable selection of subgroups and facilitates overall and local comparisons of the diagnostic accuracy of tests. The DAC results of the analyzed data set suggest that cPSA has higher diagnostic accuracy than does tPSA.

Conclusions: The DAC method is a suitable tool for comparing the clinical usefulness of laboratory markers. The DAC method could be considered as an additional tool to ROC analysis and could replace comparative ROC analyses of diagnostic tests, especially within subgroups defined by only one of the markers.
Evaluation and Management of Pain in Patients with Klippel-Trenaunay Syndrome: A Review
Authors: Lee Adriana , Driscoll David , Gloviczki Peter , Clay Ricky , Shaughnessy William , Stans Anthony
Published: March 2005

Klippel-Trenaunay syndrome (KTS) is a rare disorder that consists of a triad of capillary vascular malformation, venous malformations and/or varicose veins, and soft tissue and/or bony hypertrophy. Pain is a real and debilitating problem in these patients. We have observed 9 common causes of pain in KTS: (1) chronic venous insufficiency, (2) cellulitis, (3) superficial thrombophlebitis, (4) deep vein thrombosis, (5) calcification of vascular malformations, (6) growing pains, (7) intraosseous vascular malformation, (8) arthritis, and (9) neuropathic pain. The management of pain in patients with KTS depends on its cause. These patients are best evaluated initially in a center with an experienced multidisciplinary team that includes a primary health care provider, surgeons, and ancillary staff. The ongoing care of a patient with KTS often depends on a local provider who is more readily accessible to the patient but may not have the expertise of a large center to manage the complications of KTS. The purpose of this communication is to review the common causes of pain in these patients to provide local health care providers and patients and their families with appropriate management strategies.
Does Melanoma Behave Differently in Younger Children Than in Adults? A Retrospective Study of 33 Cases of Childhood Melanoma From a Single Institution
Authors: Ferrari Andrea , Bono Aldo , Baldi Marzia , Collini Paola , Casanova Michela , Pennacchioli Elisabetta , Terenziani Monica , Marcon Ilaria , Santinami Mario , Bartoli Cesare
Published: March 2005

Objective.To ascertain whether childhood melanoma presents any peculiar clinical features or differences in prognosis with respect to adults, we retrospectively analyzed the data from 33 patients who were up to 14 years of age and treated for cutaneous melanoma at the Istituto Nazionale Tumori, Milan, over a 25-year period.

Methods.Primary lesions were amelanotic in half of the cases and raised in 73%. Lower extremities were the most common primary sites. Histologically, 9 cases were classified as nodular type, and median thickness was 2.5 mm. Nine children had nodal involvement at diagnosis, 2 in-transit metastases, and 1 distant spread. Surgery was the mainstay of treatment; 9 patients underwent lymph node dissection, 3 received chemotherapy, and 2 received radiotherapy.

Results.With a median follow-up of 122 months, 5-year event-free survival and overall survival were 60% and 70%, respectively. Age seemed to correlate with survival, event-free survival being 90% in children under 10 and 47% in older patients, although the initial microstaging seemed worse in the former.

Conclusion.By comparison with adult cases, childhood melanoma can have a higher percentage of atypical clinical features (amelanotic and raised lesions), nodular histotype, and thick lesions. Although we have no data to support any suggestion of biological differences between young children and adolescents or adults, our findings give the impression that melanoma behaves differently in the younger age group.
Asthma Phenotypes, Risk Factors, and Measures of Severity in a National Sample of US Children
Authors: Kelley Colleen F. , Mannino David M. , Homa David M. , Savage-Brown Amanda , Holguin Fernando
Published: March 2005

Objective. To examine a nationally representative sample of US children aged 6 to 16 years old and determine whether there are differences in risk factors and measures of severity between children with different asthma phenotypes.

Methods. We analyzed data from the Third National Health and Nutrition Examination Survey. We used questionnaire and skin-prick testing data to separate children into the following mutually exclusive categories: atopic asthma, nonatopic asthma, resolved asthma, frequent respiratory symptoms with no asthma diagnosis, and normal. We used multivariate regression to determine whether demographic or potential risk factors varied between phenotypes and whether measures of severity varied by phenotype.

Results. We found that 4.8% of children had atopic asthma, 1.9% had nonatopic asthma, 3.4% had resolved asthma, and 4.3% had frequent respiratory symptoms. Risk factors varied by phenotype, for example, the mean BMI was higher among children with nonatopic asthma, prenatal maternal smoking was a risk factor for resolved asthma, and child care attendance was a risk factor for frequent respiratory symptoms with no asthma diagnosis. Patients with atopic and nonatopic asthma were similar for most measures of asthma severity (medication use, health status, and lung function impairment). In contrast, patients with resolved asthma had fewer symptoms but a similar level of lung function impairment to that seen in patients with current asthma, whereas children with frequent respiratory symptoms but no asthma diagnosis had normal lung function.

Conclusions. Asthma risk factors and measures of severity vary between children with different asthma phenotypes.
Provider and Practice Characteristics Associated With Antibiotic Use in Children With Presumed Viral Respiratory Tract Infections
Authors: Gaur Aditya H. , Hare Marion E. , Shorr Ronald I.
Published: March 2005

Objective. Although overuse of antibiotics in children has been well documented, relatively little information is known about provider and facility characteristics associated with this prescribing practice. This study was done to evaluate the differences in overuse of antibiotics among staff physicians and resident/interns (housestaff [HS]) who work in hospital-based outpatient clinics.

Methods. This cross-sectional study involved patient encounters in outpatient departments that were included in the US National Hospital Ambulatory Medical Care Survey database from 1995 to 2000. Encounters with patients who were aged <18 years and had a primary diagnosis suggestive of viral respiratory tract infection were evaluated. Patients with comorbid conditions that might justify antibiotic use were excluded.

Results. This study included 1952 patient encounters with a primary diagnosis suggestive of a viral infection and 33.2% of these patients receiving antibiotics. Overall, antibiotic use was significantly less among HS (19.5%) than staff physicians (36.4%; odds ratio [OR]: 0.44; 95% confidence interval [CI]: 0.33–0.59). This difference between HS (19.5%) and staff physicians (32.5%) persisted even within teaching hospitals (OR: 0.5; 95% CI: 0.4-0.7). Among staff physicians, antibiotic use was greater among those who work in nonteaching (39.6%) compared with teaching hospitals (32.5%; OR: 1.51; 95%: CI 1.15-1.98). Controlling for other patient and provider variables, antibiotic use occurred less among HS than among staff physicians in teaching hospitals (OR: 0.53; 95% CI: 0.38-0.75).

Conclusions. Antibiotic prescribing in the context of an outpatient visit for a diagnosis suggestive of a viral respiratory tract illness occurs more commonly among staff physicians than trainees and among staff physicians more commonly in nonteaching compared with teaching institutions.
Home Use of the GlucoWatch G2 Biographer in Children With Diabetes
Authors: Hathout Eba , Patel Nina , Southern Christina , Hill Julie , Anderson Reginald , Sharkey Jeannine , Hadley-Scofield Merrilee , Tran Long , Leptien Amy , Lopatin Margarita , Wang Betty , Mace John , Eastman Richard
Published: March 2005

Objective. To evaluate usability, accuracy, and hypoglycemia detection of the GlucoWatch G2 Biographer (GW2B) in children aged 1 to 17 years.

Methods. After a 15-hour study of device accuracy, 46 children (15 <7 years, 31 ≥7 years) with type 1 diabetes were enrolled for an extended-wear outcome study: 2 daytime and 2 nighttime 15-hr wear periods each week and blood glucose monitoring 4 times daily for 3 months.

Results. A total of 531 paired GW2B/meter readings were available for accuracy assessment. The correlation coefficients were 0.58 and 0.74 (ages <7 and ≥7 years, respectively). There was no significant change in hemoglobin A1C or weight-adjusted insulin dose at 3 months after biographer use. Forty-two episodes of hypoglycemia were detected by the GW2B, 33 of which were confirmed by blood glucose meters. Sensitivity and specificity of audible low-glucose alerts were ∼79% and 83%, respectively. No significant side effects were reported.

Conclusion. The GW2B is usable and safe in children who are <7 years or older in the home setting. The GW2B can detect asymptomatic nocturnal hypoglycemia in younger children.
Physician and Dentist Tobacco Use Counseling and Adolescent Smoking Behavior: Results From the 2000 National Youth Tobacco Survey
Authors: Shelley Donna , Cantrell Jennifer , Faulkner Dorothy , Haviland Lyndon , Healton Cheryl , Messeri Peter
Published: March 2005

Objective. The present study describes patterns of tobacco use counseling among physicians and dentists as reported by adolescents and determines the association between provider advice to quit and cessation activities among current smokers.

Methods. Data were analyzed from the 2000 National Youth Tobacco Survey, an anonymous, self-administered, school-based survey. The National Youth Tobacco Survey was administered to a nationally representative sample of 35828 students in grades 6 to 12 in 324 schools.

Results. Thirty-three percent of adolescents who visited a physician or a dentist in the past year reported that a physician counseled them about the dangers of tobacco use, and 20% reported that a dentist provided a similar message. Among students who smoked in the past year, 16.4% received advice to quit from a physician and 11.6% received advice to quit from a dentist. Physician or dentist advice to quit was correlated with 1 or more quit attempts in the past 12 months.

Conclusion. On the basis of adolescent reports, physician and dentist practice patterns remain well below recommended guidelines. Results suggest that provider advice to quit is associated with cessation activity. Additional studies are needed to confirm whether the low prevalence of brief provider tobacco use counseling is a missed opportunity to affect adolescent smoking behavior.
Complementary Therapies in Pediatrics: A Legal Perspective
Authors: Cohen Michael H. , Kemper Kathi J.
Published: March 2005

Increasing use of complementary and alternative medicine (CAM) therapies such as chiropractic, massage therapy, and herbal medicine, raises questions about the clinically appropriate use of CAM in pediatrics. Nonjudicious use of CAM therapies may cause either direct harm or, by creating an unwarranted financial and emotional burden, indirect harm. When advising patients concerning CAM therapies, pediatricians face 2 major legal risks: medical malpractice and professional discipline. Pediatricians can incorporate these considerations into advising and clinical decision-making about CAM therapies to address the best interest of the pediatric patient while helping to manage potential liability risk. This article provides a suggested framework, including asking the following questions: (1) Do parents elect to abandon effective care when the child's condition is serious or life-threatening? (2) Will use of the CAM therapy otherwise divert the child from imminently necessary conventional treatment? (3) Are the CAM therapies selected known to be unsafe and/or ineffective? (4) Have the proper parties consented to the use of the CAM therapy? (5) Is the risk-benefit ratio of the proposed CAM therapy acceptable to a reasonable, similarly situated clinician, and does the therapy have at least minority acceptance or support in the medical literature? Such an approach ideally can help guide the pediatrician toward clinical conduct that is clinically responsible, ethically appropriate, and legally defensible.
Retrospective Review of Serious Bacterial Infections in Infants Who Are 0 to 36 Months of Age and Have Influenza A Infection
Authors: Smitherman Hannah F. , Caviness A. Chantal , Macias Charles G.
Published: March 2005

Objective. Previous studies of febrile children who were 3 to 36 months of age and had clinically recognizable viral syndromes have shown low rates of concurrent bacteremia. We sought to determine the prevalence of serious bacterial infections (SBIs) among children with influenza A, a viral syndrome that can be established definitively by specific tests.

Methods. We performed a retrospective cross-sectional study of patients who were 0 to 36 months of age and presented with fever to the emergency department (ED) over 4 consecutive influenza seasons. Chest radiographs and urine and cerebrospinal fluid cultures also were reviewed.

Results. Of 705 included patients, 163 (23%) were influenza positive (IP) and 542 (77%) were influenza negative (IN). Only 1 IP patient was bacteremic (0.6%) versus 23 of the 542 IN control subjects (4.2%). Two (1.8%) of 110 IP cases had urinary tract infections versus 38 (9.9%) of the 382 IN control subjects. Thirteen (25.4%) of 51 IP patients had radiographic evidence of pneumonia versus 99 (41.9%) of 236 IN control subjects. There were no cases of meningitis in 41 cerebrospinal fluid samples obtained from IP patients versus 4 (2.2%) cases of culture-positive meningitis in 179 IN control subjects. A total of 16 (9.8%) SBIs were identified in the IP cases versus 153 (28.2%) in the IN control subjects.

Conclusions. Febrile children with influenza A had a lower prevalence of bacteremia, urinary tract infections, consolidative pneumonia, or any SBI compared with those without influenza A infection in this study.
Late Gestation Cerebellar Growth Is Rapid and Impeded by Premature Birth
Authors: Limperopoulos Catherine , Soul Janet S. , Gauvreau Kimberlee , Huppi Petra S. , Warfield Simon K. , Bassan Haim , Robertson Richard L. , Volpe Joseph J. , du Plessis Adré J.
Published: March 2005

Objective. Cognitive impairments and academic failure are commonly reported in survivors of preterm birth. Recent studies suggest an important role for the cerebellum in the development of cognitive and social functions. The objective of this study was to examine the impact of prematurity itself, as well as prematurity-related brain injuries, on early postnatal cerebellar growth with quantitative MRI.

Methods. Advanced 3-dimensional volumetric MRI was performed and cerebellar volumes were obtained by manual outlining in preterm (<37 weeks) and healthy term-born infants. Intracranial and total brain volumes were also calculated.

Results. A total of 169 preterm and 20 healthy full-term infants were studied; 145 had preterm MRI (pMRI), 75 had term MRI (tMRI), and 51 underwent both pMRI and tMRI. From 28 weeks’ postconceptional age to term, mean cerebellar volume (177%) in preterm infants increased at a much faster rate than did mean intracranial (110%) or mean brain (107%) volumes. Smaller cerebellar volume was significantly related to lower gestational age at birth and to intracranial and total brain volumes. Mean cerebellar volume of preterm infants at tMRI was significantly smaller than the volumes of term-born infants. Cerebellar growth impairment was correlated strongly with associated brain injuries, even in the absence of direct cerebellar injury.

Conclusions. Our data suggest that the growth of the immature cerebellum is particularly rapid during late gestation. However, this accelerated growth seems to be impeded by premature birth and associated brain injury. The long-term neurodevelopmental disabilities seen in survivors of premature birth may be attributable in part to impaired cerebellar development.
Training Young Pediatricians as Leaders for the 21st Century
Authors: Leslie Laurel K. , Miotto Mary Beth , Liu Gilbert C. , Ziemnik Suzanne , Cabrera Antonio G. , Calma Shellane , Huang Christina , Slaw Kenneth
Published: March 2005

Objective. To conduct a needs assessment with young pediatricians who participate in a leadership training program and to evaluate the effectiveness of that program.

Methods. In concert with the Johnson & Johnson Pediatric Institute, LLC, the American Academy of Pediatrics developed a 1-year strategy to train pediatricians who are <40 years old or <5 years in practice in leadership skills. Participants were nominated by American Academy of Pediatrics chapters and/or sections and were required to complete a detailed needs assessment, attend a 3-day training program, and commit to 1 leadership-related behavior change to be implemented within 6 months. A preanalytic/postanalytic design strategy was used.

Results. A total of 56 applicants representing 33 US states participated; 44.6% were male, and more than half (51.8%) were employed at a medical school/hospital. The needs assessment indicated that participants were confident in many of their leadership qualities but desired increased training, particularly in areas of time and priority management and leading “from the middle.” Postsurvey instruments (n = 54, 96% response rate) determined that participants positively evaluated the training program and improved in self-reported basic competencies; 87% also reported fully or partially achieving a leadership-related goal identified in a behavior change contract.

Conclusions. Results demonstrate that young physicians are eager for leadership training and that continuing medical education in this area can be provided with positive results. Core competencies, curriculum, and evaluative tools need to be developed further and training opportunities need to be expanded to other subpopulations of pediatricians and pediatric health care providers.
Impact of Postnatal Systemic Corticosteroids on Mortality and Cerebral Palsy in Preterm Infants: Effect Modification by Risk for Chronic Lung Disease
Authors: Doyle Lex W. , Halliday Henry L. , Ehrenkranz Richard A. , Davis Peter G. , Sinclair John C.
Published: March 2005

Objective. In preterm infants, chronic lung disease (CLD) is associated with an increased risk for cerebral palsy (CP). However, systemic postnatal corticosteroid therapy to prevent or treat CLD, although effective in improving lung function, may cause CP. The objective of this study was to determine the effect of systemic postnatal corticosteroid treatment on death and CP and to assess any modification of effect arising from risk for CLD.

Methods. Randomized, controlled trials of postnatal corticosteroid therapy for prevention or treatment of CLD in preterm infants that reported rates of both mortality and CP were reviewed and their data were synthesized. Twenty studies with data on 1721 randomized infants met eligibility criteria. The relationship between the corticosteroid effect on the combined outcome, death or CP, and the risk for CLD in control groups was analyzed by weighted meta-regression.

Results. Among all infants who were randomized, a significantly higher rate of CP after corticosteroid treatment (typical risk difference [RD]: 0.05; 95% confidence interval [CI]: 0.02, 0.08) was partly offset by a nonsignificant reduction in mortality (typical RD: −0.02; 95% CI: −0.06 to 0.02). Consequently, there was no significant effect of corticosteroid treatment on the combined rate of mortality or CP (typical RD: 0.03; 95% CI: −0.01 to 0.08). However, on meta-regression, there was a significant negative relationship between the treatment effect on death or CP and the risk for CLD in control groups. With risks for CLD below 35%, corticosteroid treatment significantly increased the chance of death or CP, whereas with risks for CLD exceeding 65%, it reduced this chance.

Conclusions. The effect of postnatal corticosteroids on the combined outcome of death or CP varies with the level of risk for CLD.
“Binkie Flutter,” an Apparently Voluntary Behavior of Infants, Possibly Related to Vibratory Jaw Movements in Dogs: Report of 4 Cases
Authors: Gall John
Published: March 2005

Four cases of apparently voluntary rapid vibratory pacifier movements occurring in normal, unstressed infants up to 1 year of age and captured on video are presented. I speculate on the possible relationship of the movements to similar vibratory jaw movements in dogs, in which species they may represent a neuromuscular mechanism for rapid feedback control.
Chronic Abdominal Pain in Children
Authors:   Subcommittee on Chronic Abdominal Pain
Published: March 2005

Children and adolescents with chronic abdominal pain pose unique challenges to their caregivers. Affected children and their families experience distress and anxiety that can interfere with their ability to perform regular daily activities. Although chronic abdominal pain in children is usually attributable to a functional disorder rather than organic disease, numerous misconceptions, insufficient knowledge among health care professionals, and inadequate application of knowledge may contribute to a lack of effective management. This clinical report accompanies a technical report (see page e370 in this issue) on childhood chronic abdominal pain and provides guidance for the clinician in the evaluation and treatment of children with chronic abdominal pain. The recommendations are based on the evidence reviewed in the technical report and on consensus achieved among subcommittee members.
Chronic Abdominal Pain in Children
Authors:   Subcommittee on Chronic Abdominal Pain
Published: March 2005

Chronic abdominal pain, defined as long-lasting intermittent or constant abdominal pain, is a common pediatric problem encountered by primary care physicians, medical subspecialists, and surgical specialists. Chronic abdominal pain in children is usually functional, that is, without objective evidence of an underlying organic disorder. The Subcommittee on Chronic Abdominal Pain of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition has prepared this report based on a comprehensive, systematic review and rating of the medical literature. This report accompanies a clinical report based on the literature review and expert opinion.

The subcommittee examined the diagnostic and therapeutic value of a medical and psychological history, diagnostic tests, and pharmacologic and behavioral therapy. The presence of alarm symptoms or signs (such as weight loss, gastrointestinal bleeding, persistent fever, chronic severe diarrhea, and significant vomiting) is associated with a higher prevalence of organic disease. There was insufficient evidence to state that the nature of the abdominal pain or the presence of associated symptoms (such as anorexia, nausea, headache, and joint pain) can discriminate between functional and organic disorders. Although children with chronic abdominal pain and their parents are more often anxious or depressed, the presence of anxiety, depression, behavior problems, or recent negative life events does not distinguish between functional and organic abdominal pain. Most children who are brought to the primary care physician's office for chronic abdominal pain are unlikely to require diagnostic testing. Pediatric studies of therapeutic interventions were examined and found to be limited or inconclusive.