bluuebunny/crossref_metadata_2025 huggingface dataset:
Goodness‐of‐fit tests of normality for the innovations in ARMA models
Authors: Ducharme Gilles R. , Lafaye de Micheaux Pierre
Published: May 2004

Abstract.  In this paper, we propose a goodness‐of‐fit test of normality for the innovations of an ARMA(p, q) model with known mean or trend. The test is based on the data driven smooth test approach and is simple to perform. An extensive simulation study is conducted to study the behaviour of the test for moderate sample sizes. It is found that our approach is generally more powerful than existing tests while holding its level throughout most of the parameter space and, thus, can be recommended. This agrees with theoretical results showing the superiority of the data driven smooth test approach in related contexts.
Asymmetric adjustment and smooth transitions: a combination of some unit root tests
Authors: Sollis Robert
Published: May 2004

Abstract.  Conventional Dickey–Fuller unit root tests have been generalized to allow for nonlinearity under the alternative hypothesis by Enders and Granger [Journal of Business Economics and Statistics, 16 (1998) 304] (EG) and Leybourne, Newbold and Vougas [Journal of Time Series Analysis, 19 (1998) 83] (LNV). EG focus on the case of asymmetric adjustment modelled as threshold autoregression, while LNV extend the concept of trend stationarity to that of stationarity around a smooth transition between deterministic linear trends. In this study, the EG and LNV methodologies are combined to develop tests of the null hypothesis of a unit root, that under the alternative hypothesis allow for stationary asymmetric adjustment around a smooth transition between deterministic linear trends. The empirical power of the combined tests is briefly investigated and an empirical application to time series on aggregate industrial production in the UK and the US is considered.
Hypoxia induces adenosine release from the rat carotid body
Authors: Conde Sílvia V. , Monteiro Emília C.
Published: May 2004

The effect of hypoxia on the release of adenosine was studied in vitro in the rat whole carotid body (CB) and compared with the effect of hypoxia (2%, 5% and 10% O2) on adenosine concentrations in superior cervical ganglia (SCG) and carotid arteries. Moderate hypoxia (10% O2) increased adenosine concentrations released from the CBs by 44%, but was not a strong enough stimulus to evoke adenosine release from SCG and arterial tissue. The extracellular pathways of adenosine production in rat CBs in normoxia and hypoxia were also investigated. S‐(p‐nitrobenzyl)‐6‐thioinosine (NBTI) and dipyridamole were used as pharmacological tools to inhibit adenosine equilibrative transporters (ENT) and α,β‐methylene ADP (AOPCP) to inhibit ecto‐5′‐nucleotidase. Approximately 40% of extracellular adenosine in the CB came from the extracellular catabolism of ATP, under both normoxic and hypoxic conditions. Low pO2 triggers adenosine efflux through activation of NBTI‐sensitive ENT. This effect was only apparent in hypoxia and when adenosine extracellular concentrations were reduced by the blockade of ecto‐5′‐nucleotidase. We concluded that CB chemoreceptor sensitivity could be related to its low threshold for the release of adenosine in response to hypoxia here quantified for the first time.
Regulation and function of somatostatin receptors
Authors: Olias Gisela , Viollet Cécile , Kusserow Heike , Epelbaum Jacques , Meyerhof Wolfgang
Published: May 2004

This review summarizes the latest advances that have been made to elucidate the somatostatinergic system in respect to somatostatin receptor evolution, the development of receptor agonists/antagonists, receptor regulation, signal transduction, effects on cell proliferation, receptor–receptor or receptor–protein interactions and receptor function.
Regulation of protein kinase C by the anti‐Parkinson drug, MAO‐B inhibitor, rasagiline and its derivatives, in vivo
Authors: Bar‐Am Orit , Yogev‐Falach Merav , Amit Tamar , Sagi Yotam , Youdim Moussa B. H.
Published: May 2004

We have recently shown that the anti‐Parkinson‐propargyl‐containing monoamine oxidase B (MAO‐B) inhibitor drug, rasagiline [N‐propargyl‐(1R)‐aminoindan], and its cholinesterase inhibitor derivatives TV3326 and TV3279, regulate amyloid precursor protein (APP) processing by a protein kinase C (PKC)‐dependent mechanism in SH‐SY5Y neuroblastoma and PC12 cells. In the present study, we investigated the effect of rasagiline and its derivatives on the regulation of the PKC‐dependent mechanism and APP processing under in vivo conditions. Administration of rasagiline (0.1 mg/kg) to male C57/BL mice for 14 days significantly decreased membrane‐bound holoprotein APP levels in the hippocampus. Additionally, we observed that rasagiline up‐regulated p‐PKC levels and the expression of α and ε PKC isozymes in the hippocampus, indicating that the mechanism by which rasagiline affects APP processing may be related to PKC‐associated signalling. The results also demonstrate that rasagiline treatment significantly elevated the levels of phosphorylated myristoylated alanine‐rich C kinase substrate (p‐MARCKS), a major substrate for PKC, as well as the levels of receptors for activated C kinase 1 (RACK1). Similar effects on APP and PKC levels were also demonstrated for the two cholinesterase inhibitor derivatives of rasagiline, TV3326 and TV3279. These results indicate that rasagiline and its derivatives regulate PKC‐dependent mechanisms and APP processing. The activation and induction of PKC and MARCKS by these drugs may have a crucial role not only in their neuroprotective activity, but also in their ability to affect neuronal plasticity and spatial learning processes.
Acute ammonia intoxication induces an NMDA receptor‐mediated increase in poly(ADP‐ribose) polymerase level and NAD+ metabolism in nuclei of rat brain cells
Authors: Kosenko Elena , Montoliu Carmina , Giordano Gennaro , Kaminsky Yury , Venediktova Natalia , Buryanov Yaroslav , Felipo Vicente
Published: May 2004

Acute ammonia toxicity is mediated by excessive activation of NMDA receptors. Activation of NMDA receptors leads to activation of poly(ADP‐ribose) polymerase (PARP) which mediates NMDA excitotoxicity. PARP is activated following DNA damage and may lead to cell death via NAD+ and ATP depletion. The aim of the present work was to assess whether acute ammonia intoxication in vivo leads to increased PARP in brain cells nuclei and to altered NAD+ and superoxide metabolism and the contribution of NMDA receptors to these alterations. Acute ammonia intoxication increases PARP content twofold in brain cells nuclei. NAD+ content decreased by 55% in rats injected with ammonia. This was not due to decreased NAD+ synthetase nor increased NAD+ hydrolase activities and would be due to increased NAD+ consumption by PARP. Superoxide radical formation increased by 75% in nuclei of brains of rats injected with ammonia, that also induced protein nitrotyrosylation and DNA damage. Blocking NMDA receptors prevented ammonia‐induced PARP, superoxide and nitrotyrosylation increase, DNA damage and NAD+ decrease. These results show that acute ammonia intoxication in vivo leads to activation of NMDA receptors, leading to increased superoxide formation and PARP content and depletion of NAD+ in brain cells nuclei that contribute to ammonia toxicity.
Different low doses of broad‐band UVA in the treatment of morphea and systemic sclerosis
Authors: El‐Mofty M. , Mostafa W. , El‐Darouty M. , Bosseila M. , Nada H. , Yousef R. , Esmat S. , El‐Lawindy M. , Assaf M. , El‐Enani G.
Published: May 2004

Background: Numerous treatment modalities, some with potentially hazardous side effects, are currently used for morphea (M) and systemic sclerosis (SS) with limited success. Low‐dose ultraviolet A (UVA) phototherapy (20 J/cm2) was found to be highly effective for sclerotic patches, even in patients with advanced and rapidly evolving lesions.

Objective: To determine the effectiveness of different low doses of UVA in treating patients with M and SS.

Methods: Sixty‐three patients complaining of M and 15 patients complaining of SS received 20 sessions of UVA (320–400 nm) each. Patients were divided randomly into three groups that received 5, 10 and 20 J/cm2, with cumulative UVA doses of 100, 200, and 400 J/cm2, respectively. The efficacy of therapy was judged clinically (by sequential inspection and palpation) and histopathologically by morphometry in M cases.

Results: Obvious clinical improvement, with no comparable differences between various low UVA doses, was noted in patients with M and SS, accompanied by histopathological changes towards normalization of collagen.

Conclusions: After 20 sessions, it appears that lower doses of UVA (5, 10 J/cm2) are as beneficial as the relatively higher dose (20 J/cm2) in the treatment of M and SS.
Photoallergic contact dermatitis
Authors: Goossens An
Published: May 2004

Purpose: To determine whether photoallergic contact dermatitis is as uncommon as it is usually considered to be and to review the associated clinical features.

Methods: We reviewed the literature on photoallergic reactions induced by the topical contact of the skin with a chemical in the presence of, or followed by, exposure to UV or visible light. Some of the more recently observed photo‐allergens and those presenting special clinical features are discussed.

Results: The literature cites several topical substances that give rise to photoallergic contact dermatitis, some of them only exceptionally but others quite frequently. The clinical features are not always those of a eczematous eruption, and several parts of the body may be affected.

Conclusions: Many topical photoallergic culprits have been reported in the literature, the most important of which are sunscreen agents and, recently, non‐steroidal anti‐inflammatory agents (NSAIDs). Not at all exceptional is the occurrence of photoaggravation and recurrent transient or even persistent light reactions on previously exposed as well as non‐exposed areas (often sparing the original application site), particularly with the NSAID ketoprofen. Moreover, cross‐reactions with chemically‐related as well as non‐chemically related molecules are common. The potentially misleading clinical features observed in some cases, the diversity of the casual substances identified, and the low frequency with which photopatch testing is carried out in general indicate that the occurrence of photoallergic contact dermatitis might well be underestimated.
Ground‐level solar spectral irradiance in Glasgow: an inter‐comparison oftwosites
Authors: Moseley H. , Clark I. , Pearson A. , Smyth J. , Oliver H. , Mackie R.M.
Published: May 2004

Background: Solar spectral radiometry presents significant challenges to produce accurate and reproducible data. To investigate the reliability of the measurements, several inter‐comparisons have been set up. Although these are useful, their main drawback is that equipment must be dismantled and transported to a common site and re‐calibrated.

Methods: In this study, an inter‐comparison has been performed of two spectroradiometers that are located 3 miles apart some 30 m above sea level. These two systems have operated using different calibration techniques. Data were compared on clear days, to minimise actual differences in ultraviolet irradiation.

Results: There were substantial differences at some individual wavelength points, but overall the mean difference of results at 5 nm intervals on an individual scan from the two systems agreed to within 11%. If the data were used to compute the erythemal irradiance, the differences were reduced to 4%.

Conclusion: This study demonstrates both the limitations and the level of reliability that might be expected from these systems operating under careful scientific supervision.
Low‐back pain in adolescents is associated with poor hip mobility and high body mass index
Authors: Sjolie Astrid Noreng
Published: May 2004

The objective of this cross‐sectional study was to investigate whether body mass index (BMI) and hip mobility are associated with low‐back pain (LBP) in adolescents. The study population included all adolescents in 8th and 9th grades in a rural and in an urban area in Eastern Norway. Eighty‐eight adolescents participated (mean age 14.7 years), making the response rate 84%. LBP was assessed by a questionnaire answered in the classrooms as pain/discomfort in the low back during the preceding year. Body height and weight were measured, and BMI was calculated. Hip mobility was measured as active movements by a goniometer. The level of significance was set toP≤0.05. In bivariate analysis for the whole group, LBP was associated positively with a higher than mean BMI, while LBP among boys was associated with a less than mean hip flexion, internal rotation, and hamstrings flexibility. In multiple regression analyses, adjusting for gender and well‐being, LBP was associated with a higher than mean BMI, a less than mean hamstrings flexibility, and a less than mean hip flexion. The results suggest further prospective research to investigate whether poor hip mobility and high BMI may predict juvenile LBP.
Muscle temperature and sprint performance during soccer matches – beneficial effect of re‐warm‐up at half‐time
Authors: Mohr M. , Krustrup P. , Nybo L. , Nielsen J. J. , Bangsbo J.
Published: May 2004

The relationship between quadriceps muscle temperature (Tm) and sprint performance was evaluated during soccer matches in 25 competitive players. In one game, Tm was determined frequently (n=9). In another game, eight players performed low‐intensity activities at half‐time (re‐warm‐up, (RW), whereas another eight players recovered passively (CON). Tm was 36.0±0.2 °C at rest and increased (P<0.05) to 39.4±0.2 °C before the game and remained unaltered during the first half. At half‐time, Tm decreased (P<0.05) to 37.4±0.2 °C, but increased (P<0.05) to 39.2±°C during the second half. In CON and RW, Tm and core temperature (Tc) were similar before and after the first half, but 2.1±0.1 and 0.9±0.1 °C higher (P<0.05), respectively, in RW prior to the second half. At the onset of the second half, the sprint performance was reduced (P<0.05) by 2.4% in CON, but unchanged in RW. The decrease in Tm was correlated to the decrease in performance (r=0.60, P<0.05, n=16). This study demonstrates that in soccer, the decline in Tm and Tc during half‐time is associated with a lowered sprint capacity at the onset of the second half, whereas sprint performance is maintained when low‐intensity activities preserve muscle temperature.
Identification of prognostic indicators for patient outcomes in extensor tendinopathy at the elbow
Authors: Paoloni Justin A. , Murrell George A. C.
Published: May 2004

Extensor tendinopathy is a degenerative overuse condition involving the common extensor tendon at the lateral humeral epicondyle. The diagnosis and management of this condition are clinically based. Our aims were to determine if through patient history and clinical examination we could ascertain prognostic factors affecting time to symptom resolution in extensor tendinopathy. Symptomatic patients (N=28) had a thorough history and examination, and rehabilitation monitored regularly for 6 months. Patient outcomes at 6 months were then correlated with specific factors on initial presentation. Factors implicated as having prognostic significance regarding patient outcomes were a current history of manual work (P=0.04, effect size −0.29), and a current history of weekly participation in racquet sports (P=0.01, effect size −0.41). These individual factors had a significantly decreased chance of symptom resolution at the 6‐month stage, and when combined had an effect size of −0.6 (P=0.001). Negative patient outcomes may be related to current high and repetitive levels of tendon stress, and rest from recreational and occupational use of wrist extensor tendons may be necessary to enhance the chances of complete symptom resolution. Enforced rest has monetary and quality‐of‐life implications, but is probably preferable to an incomplete recovery and prolonged tendon pain and dysfunction.
Lincoln: A Weberian Politician Meets the Constitution
Authors: Underwood James E.
Published: May 2004

The central question addressed is how Lincoln as president resolved the potential conflicts among the competing values to which he was committed. Certain of Lincoln's experiences before becoming president are examined, as those experiences shed light on his character and his attitude toward the Constitution and toward slavery. Weber's essay, “Politics as a Vocation,” is employed as a framework for description and analysis. Lincoln's words and actions demonstrate that competing values must almost always give way to what he regarded as transcendent values: the specific duties and limits embodied in the Constitution and what he saw as its implied demand that the Union be preserved. Within the limits of his commitment to the Constitution as embodying transcendent values, Lincoln resembles Weber's “politician with a calling.”
Blue Ribbons, Black Boxes: Toward a Better Understanding of Presidential Commissions
Authors: Zegart Amy B.
Published: May 2004

Presidential commissions usually are thought to tackle domestic policy issues, with little effect. This essay challenges the conventional view by finding greater commission variety and systematic differences in the ways presidents utilize commissions in domestic and foreign affairs. The essay classifies commissions into three ideal types: agenda commissions, which generate support for the president's initiatives and target a mass audience; information commissions, which provide new facts and thinking about policies and target government officials; and political constellation commissions, which seek to foster consensus among competing interests and target commission members themselves. Specific hypotheses comparing how presidents use commissions in foreign versus domestic policy are developed and tested with a data set of all presidential commissions from 1981 to 2001.
The Contemporary Presidency: Unity in the Executive and the Presidential Succession Act
Authors: Crockett David A.
Published: May 2004

The Presidential Succession Act of 1947 was passed to make the solution to the problem of a double vacancy in the presidency and vice presidency more democratic. The current law, however, privileges “democracy” at the expense of “energy” in the executive, especially as that energy is reflected in the unitary nature of the presidency. Hamilton explains in Federalist no. 70 why unity in the executive is important, both for the purposes of energetic leadership and accountability. The possibility that a successor under the 1947 statute could be from a party other than that elected by the people diminishes the energy that is key to this branch of government. This article explores the central constitutional question surrounding the issue of double vacancy: whether the current law meets the two goals of providing for the possibility of a double vacancy while still retaining the energy that typifies the office of the presidency.
The Polls: Presidential Traits and Job Approval: Some Aggregate‐Level Evidence
Authors: Newman Brian
Published: May 2004

In a previous article in this journal, Cohen (2001) introduced time series measures of public perceptions of Bill Clinton's personal characteristics. Here, I explore the political impact of these perceptions, asking whether they affect the public's evaluations of presidential job performance. I find that they do, adding aggregate‐level support to existing individual‐level evidence of the importance of character assessments. Finding a connection between character perceptions and job approval in the aggregate time series context helps answer questions previous studies leave unresolved, with significant implications for our understanding of presidential approval and presidential politics more generally.
SCALAR FIELD IN A MINIMALLY COUPLED BRANE WORLD: NO-HAIR AND OTHER NO-GO THEOREMS
Authors: BRONNIKOV K. A. , FADEEV S. B. , MICHTCHENKO A. V.
Published: May 2004

In the brane-world framework, we consider static, spherically symmetric configurations of a scalar field with the Lagrangian (∂ϕ)2/2-V(ϕ), confined on the brane. We use the 4D Einstein equations on the brane obtained by Shiromizu et al., containing the conventional stress tensor [Formula: see text], the tensor [Formula: see text] which is quadratic in [Formula: see text], and [Formula: see text] describing interaction with the bulk. For models under study, the tensor [Formula: see text] has zero divergence, allowing one to consider [Formula: see text]. Such a brane, whose 4D gravity is decoupled from the bulk geometry, may be called minimally coupled. Assuming [Formula: see text], we try to extend to brane worlds some theorems valid for scalar fields in general relativity (GR). Thus, the list of possible global causal structures in all models under consideration is shown to be the same as is known for vacuum with a cosmological constant in GR: Minkowski, Schwarzschild, (anti-) de Sitter and Schwarzschild–(anti-)de Sitter. A no-hair theorem, saying that, given a potential V≥0, asymptotically flat black holes cannot have nontrivial external scalar fields, is proved under certain restrictions. Some objects, forbidden in GR, are allowed on the brane, e.g, traversable wormholes supported by a scalar field, but only at the expense of enormous matter densities in the strong field region.
VACUUM POLARIZATION OF A CHARGED MASSLESS FERMIONIC FIELD BY A MAGNETIC FLUX IN THE COSMIC STRING SPACETIME
Authors: SPINELLY J. , BEZERRA DE MELLO E. R.
Published: May 2004

We calculate the vacuum averages of the energy–momentum tensor associated with a massless left-handed spinor fields due to magnetic fluxes on idealized cosmic string spacetime. In this analysis three distinct configurations of magnetic fields are considered: (i) a homogeneous field inside the tube, (ii) a magnetic field proportional to 1/r, and (iii) a cylindrical shell with δ-function. In these three cases the axis of the infinitely long tubes of radius R coincides with the cosmic string. In order to proceed with these calculations we explicitly obtain the Euclidean Feynman propagators associated with these physical systems. As we shall see, these propagators possess two distinct parts. The first are the standard ones, i.e. corresponding to the spinor Green's functions associated with the massless fermionic fields on the idealized cosmic string spacetime with a magnetic flux running through the line singularity. The second parts are new, they are due to the finite thickness of the radius of the tubes. As we shall see these extra parts provide relevant contributions to the vacuum averages of the energy–momentum tensor.
OPERATIONAL INDISTINGUISHABLY OF VARYING SPEED OF LIGHT THEORIES
Authors: JAFARI NOSRATOLLAH , SHARIATI AHMAD
Published: May 2004

The varying speed of light theories have been recently proposed to solve the standard model problems and anomalies in the ultra high energy cosmic rays. These theories try to formulate a new relativity with no assumptions about the constancy of the light speed. In this regard, we study two theories and want to show that these theories are not the new theories of relativity, but only re-descriptions of Einstein's special relativity.
BLACK HOLES AND THE THIRD LAW OF THERMODYNAMICS
Authors: BELGIORNO F. , MARTELLINI M.
Published: May 2004

We discuss in the framework of black hole thermodynamics some aspects relative to the third law in the case of black holes of the Kerr–Newman family. In the light of the standard proof of the equivalence between the unattainability of the zero temperature and the entropic version of the third law it is remarked that the unattainability has a special character in black hole thermodynamics. Also the zero temperature limit which obtained in the case of very massive black holes is discussed and it is shown that a violation of the entropic version in the charged case occurs. The violation of the Bekenstein–Hawking law in favour of zero entropy SE=0 in the case of extremal black holes is suggested as a natural solution for a possible violation of the second law of thermodynamics. Thermostatic arguments in support of the unattainability are explored, and SE=0 for extremal black holes is shown to be again a viable solution. The third law of black hole dynamics by W. Israel is then interpreted as a further strong corroboration to the picture of a discontinuity between extremal states and non-extremal ones.
Activity-Dependent Synaptic Competition at Mammalian Neuromuscular Junctions
Authors: Buffelli Mario , Busetto Giuseppe , Bidoia Carlo , Favero Morgana , Cangiano Alberto
Published: May 2004

Synapse elimination is a widespread developmental process in the peripheral and central nervous system that brings about refinement of neural connections through epigenetic mechanisms. Here we describe recent advances concerning the role of the pattern of motoneuronal firing, synchronous or asynchronous, in neuromuscular synapse elimination.
Role of Superoxide as a Signaling Molecule
Authors: Buetler Timo M. , Krauskopf Alexandra , Ruegg Urs T.
Published: May 2004

Superoxide is known to affect vascular physiology in several ways and has also been recognized to contribute significantly to vascular physiopathology. Here we discuss the emerging role of superoxide as an essential signaling molecule in normal physiology.
The Sarcoplasmic Reticulum, Ca2+Trapping, and Wave Mechanisms in Smooth Muscle
Authors: McCarron John G. , Bradley Karen N. , MacMillan Debbi , Chalmers Susan , Muir Thomas C.
Published: May 2004

The sarcoplasmic reticulum (SR) and apposed regions of the sarcolemma passively trap Ca2+entering the cell to limit the rise in cytoplasmic Ca2+concentration without SR pump involvement. When “leaky” the SR facilitates Ca2+entry to the cytoplasm. SR Ca2+release via inositol 1,4,5-trisphosphate receptors (IP3Rs) propagates as calcium waves; IP3Rs alone account for wave propagation.
Aldosterone: Refreshing a Slow Hormone by Swift Action
Authors: Boldyreff Brigitte , Wehling Martin
Published: May 2004

Aldosterone elicits not only genomic effects with physiological consequences within hours or days but also elicits rapid nongenomic effects, such as activation of sodium transport in target cells, within seconds or minutes. Rapid aldosterone effects, which have also been shown in several in vivo studies in humans (e.g., increase in peripheral vascular resistance and blood pressure), are of potential clinical importance.
Limited Sampling Strategy of S‐Warfarin Concentrations, but Not Warfarin S/R Ratios, Accurately Predicts S‐Warfarin AUC during Baseline and Inhibition in CYP2C9 Extensive Metabolizers
Authors: Ma Joseph D. , Nafziger Anne N. , Kashuba Angela D. M. , Kim Myong‐Jin , Gaedigk Andrea , Rowland Elizabeth , Kim Jooran S. , Bertino Joseph S.
Published: May 2004

S‐warfarin area under the concentration‐time curve (AUC0–∞) and clearance are used as measures of cytochrome P450 (CYP) 2C9 activity. In addition, warfarin S/R ratios are used to assess CYP2C9 activity. The determination of S‐warfarin AUC0–∞ requires multiple blood samples. Limited sampling strategy (LSS) is a validated technique that estimates AUC0–∞ using limited blood samples. The objective of this study was to evaluate LSS of S‐warfarin concentrations and warfarin S/R ratios to predict S‐warfarin AUC0–∞ during CYP2C9 baseline activity and inhibition with fluvastatin. Fifty‐one healthy subjects, genotyped as CYP2C9 extensive metabolizers, were administered oral warfarin 10 mg. Blood samples were collected over 96 hours. S‐warfarin AUC0–∞ equations were derived from a training set of 20 subjects using multiple linear regression. Validation of the equations used data from the remaining 31 subjects. All derived equations were within acceptable limits for measures of bias and precision. Single‐point and two‐point S‐warfarin concentrations, but not warfarin S/R ratios, were predictive of S‐warfarin AUC0–∞ during CYP2C9 baseline activity and inhibition. No correlation was observed between CYP2C9*1/*1 and *1/*2 genotypes and either S‐warfarin concentrations or warfarin S/R ratios. The equation using two‐point S‐warfarin concentrations at 24 and 48 hours was the most accurate predictor of S‐warfarin AUC0–∞. LSS using S‐warfarin concentrations is an efficient and accurate technique to evaluate S‐warfarin AUC0–∞ when using warfarin as a CYP2C9 probe drug
Drug‐Drug, Drug—Dietary Supplement, and Drug—Citrus Fruit and Other Food Interactions: What Have We Learned?
Authors: Huang Shiew‐Mei , Lesko Lawrence J.
Published: May 2004

Serious drug‐drug interactions have contributed to recent U.S. market withdrawals and also recent nonapprovals of a few new molecular entities. Many of these interactions involved the inhibition or induction of metabolizing enzymes and efflux transporters, resulting in altered systemic exposure and adverse drug reactions or loss of efficacy. In addition to drug‐drug interactions, drug—dietary supplement and drug—citrus fruit interactions, among others, could also cause adverse drug reactions or loss of efficacy and are important issues to consider in the evaluation of new drug candidates. This commentary reviews (1) the current understanding of the mechanistic basis of these interactions, (2) issues to consider in the interpretation of study results, and (3) recent labeling examples to illustrate the translation of study results to information useful for patients and health care providers.
The Influence of St. John's Wort on CYP2C19 Activity with Respect to Genotype
Authors: Wang Lian‐Sheng , Zhu Bing , El‐Aty A. M. Abd , Zhou Gan , Li Zhi , Wu Jun , Chen Guo‐Lin , Liu Jie , Tang Zhi Rong , An Wang , Li Qing , Wang Dan , Zhou Hong‐Hao
Published: May 2004

Induction of cytochrome P450 isozymes is the major cause for clinical drug interactions of St. John's wort. The relationships of St. John's wort to cytochrome P450 isoforms have been fully investigated, but its effect on CYP2C19 is lacking. Thus, the aim of the present study was to observe the effect of St. John's wort on CYP2C19 activity using CYP1A2 as a control. Twelve healthy adult men—6 extensive metabolizers of CYP2C19 (2C19*1/2C19*1) and 6 poor metabolizers (4 2C19*2/ 2C19*2 and 2 2C19*2/2C19*3)—were enrolled in a two‐phase, randomized, crossover manner. All subjects took a 300‐mg St. John's wort tablet or placebo three times daily for 14 days, and then the activities of CYP2C19 and CYP1A2 were measured using mephenytoin and caffeine. It was found that St. John's wort treatment significantly increased CYP2C19 activity in CYP2C19 wild‐genotype subjects, with urinary 4′‐hydroxymephenytoin excretion raised by 151.5% ± 91.9% (p = 0.0156), whereas no significant alteration was observed for CYP2C19 poor metabolizers. Repeated St. John's wort administration did not affect the CYP1A2 phenotypic ratio for both CYP2C19 genotype subjects. In conclusion, St. John's wort is an inducer to the human CYP2C19, and clinicians should pay great attention when St. John's wort is added to or withdrawn from an existing drug regimen containing substrates for such enzymes.
Population Pharmacokinetic Analysis of Anidulafungin, an Echinocandin Antifungal
Authors: Dowell James A. , Knebel William , Ludden Tom , Stogniew Marty , Krause David , Henkel Tim
Published: May 2004

The objective of this analysis was to describe the pharmacokinetic characteristics of anidulafungin in patients with serious fungal disease based on pharmacokinetic data collected during four recently completed or ongoing Phase II/III clinical studies. A total of 600 anidulafungin plasma samples from 225 patients across the four studies were available for analysis. Patients received daily intravenous infusions of 50, 75, or 100 mg anidulafungin, preceded by a loading dose that was twice the daily dose. The analysis population consisted of 129 patients with esophageal candidiasis, 87 with invasive candidiasis, 7 with invasive aspergillosis, and 2 with azole refractory mucosal candidiasis. A population analysis approach was used to develop a steady‐state pharmacokinetic model for anidulafungin, assess the significance of possible covariates, and determine the amount of intersubject and random residual variability. A two‐compartment model with first‐order elimination provided the best fit to the data. The clearance of anidulafungin was influenced by weight and gender, and subjects in the invasive candidiasis study had a typical clearance that was approximately 30% higher than subjects from other studies. Weight was determined to be a predictor of the central volume of distribution. The covariates on clearance accounted for less than 20% of the intersubject variability and therefore are deemed to be of little clinical relevance. There was no evidence that the presence of rifampin or metabolic substrates, inhibitors, or inducers of cytochrome P450 influenced the clearance of anidulafungin. This indicates that dosing adjustments are not necessary when anidulafungin is administered in the presence of medications falling into these classifications.
Single‐Dose Pharmacokinetics of Daptomycin in Young and Geriatric Volunteers
Authors: Dvorchik Barry , Damphousse David
Published: May 2004

Daptomycin is a novel lipoprotein antibiotic that was recently approved for the treatment of complicated skin and skin structure infections caused by aerobic gram‐positive bacteria. The pharmacokinetics of daptomycin was evaluated after a single 0.5‐hour intravenous infusion of 4 mg/kg to groups of young adult (18–30 years) and geriatric (≥ 75 years) volunteers. Daptomycin was safe and well tolerated. No adverse events related to the infusion were reported. With increased age, there were increases in the area under the plasma concentration‐time curve extrapolated to infinity (AUC∞) and the terminal elimination half‐life. Systemic (CL) and renal clearance (CLR) both decreased with increasing age. The observed changes seen in CL between the two cohorts were most likely a result of changes in renal function, as estimated by creatinine clearance. No statistically significant differences were observed between the two groups in the maximum plasma concentration (Cmax) and volume of distribution at steady state (Vdss). The confidence intervals for the arithmetic mean ratios of the fraction of the dose excreted in the urine as daptomycin (%Fe) (geriatric subjects over younger subjects) were 60% to 101%, indicating that %Fedose was lower in geriatric subjects. These results demonstrate that changes in the pharmacokinetics of daptomycin in the elderly are attributable to changes in renal function, whereas age per se is not a significant factor.
Sequence motifs that distinguish ATP(CTP):tRNA nucleotidyl transferases from eubacterial poly(A) polymerases
Authors: MARTIN GEORGES , KELLER WALTER
Published: May 2004

ATP(CTP):tRNA nucleotidyl transferases, tRNA maturing enzymes found in all organisms, and eubacterial poly(A) polymerases, enzymes involved in mRNA degradation, are so similar that until now their biochemical functions could not be distinguished by their amino acid sequence. BLAST searches and analysis with the program “Sequence Space” for the prediction of functional residues revealed sequence motifs which define these two protein families. One of the poly(A) polymerase defining motifs specifies a structure that we propose to function in binding the 3′ terminus of the RNA substrate. Similar motifs are found in other homopolyribonucleotidyl transferases. Phylogenetic classification of nucleotidyl tranferases from sequenced genomes reveals that eubacterial poly(A) polymerases have evolved relatively recently and are found only in a small group of bacteria and surprisingly also in plants, where they may function in organelles.
Reevaluation of the conclusion that IRES-activity reported within the 5′ leader of the TIF4631 gene is due to promoter activity
Authors: MAURO VINCENT P. , EDELMAN GERALD M. , ZHOU WEI
Published: May 2004

We previously reported that the 5′ leader of the mRNA-encoding initiation factor eIF4G in Saccharomyces cerevisiae can function as a translational enhancer and as an internal ribosome entry site (IRES) when tested in cells. However, Verge and colleagues recently suggested that this sequence does not facilitate translation initiation, but inhibits translation in vitro and has promoter activity when tested in cells. We disagree with these conclusions and respond by showing that the data are most consistent with an internal initiation mechanism.
Curbing Foreign Distributor Opportunism: An Examination of Trust, Contracts, and the Legal Environment in International Channel Relationships
Authors: Cavusgil S. Tamer , Deligonul Seyda , Zhang Chun
Published: May 2004

Many tenets of cross-border governance arrangements are broad-brush projections of domestic findings. To explore such generalizations, this study uses data from a large set of U.S.-based manufacturers to formulate and test propositions about limiting the potential opportunistic behavior of foreign distributors. The findings challenge two generalizations about governance arrangements in the cross-border context. The first is that a manufacturer is often handicapped disproportionately by its level of brand and scale prominence. Formal contracts as prescribed by transaction cost analysis, though negatively related to opportunism, do not have a significant effect on the alleviation of foreign distributor opportunism. The second generalization is that the joint use of trust and formal contracts is not significantly associated with opportunism. Trust and formal contracts serve different purposes. Trust makes the relationship function, and contracts institute and legitimize it. Furthermore, previous studies investigate opportunism in isolation, whereas this study points to the influence of legal hostility on the management of opportunism in the export market.
Minor Self‐Harm and Psychiatric Disorder: A Population‐Based Study
Authors: Skegg Keren , Nada‐Raja Shyamala , Moffitt Terrie E.
Published: May 2004

Little is known about the extent to which minor self‐harm in the general population is associated with psychiatric disorder. A population‐based sample of 980 young adults was interviewed independently about past‐year suicidal and self‐harm behavior and thoughts, and psychiatric disorders. Self‐harm included self‐harmful behaviors such as self‐battery as well as traditional methods of suicide (ICD [International Classification of Diseases] self‐harm). All with ICD self‐harm and most with other self‐harmful behavior met the criteria for DSM‐IV disorder. Suicidal/self‐harmful thoughts increased the odds for self‐harm, even in men without psychiatric disorder (odds ratio 4.9, 95% confidence interval 1.3 – 17.9). Young adults engaging in even minor self‐harm warrant screening for psychiatric disorder.
A Call for Research on Planned vs. Unplanned Suicidal Behavior
Authors: Conner Kenneth R.
Published: May 2004

Unplanned acts of suicidal behavior involve little preparation or forethought whereas planned acts may be carefully conceived and implemented. Planned acts are associated with greater depression, hopelessness, and lethality, but there are meager data on other factors associated with planning. The prevention of planned and unplanned acts may require different strategies, but in either case improved knowledge is required to tailor prevention efforts. Improved knowledge can be facilitated by the acceleration of validation studies on assessments of planning, taking steps to avoid the conflation of assessments of planning with measurements of psychopathology such as impulsivity, and the use of controlled research designs.
Synthesis and crystal structure of two dimeric cadmium(II) complexes bonded with pseudohalides, 1.1 and 1.3 bonding
Authors: Ercan Filiz , Arıcı Cengiz , Ülkü Dinçer , Kurtaran Raif , Aksu Mecit , Atakol Orhan
Published: May 2004

Two different complexes were obtained from (dmpp) and Cd(II) ions with the aid of pseudohalide ions in non-aqueous solvents. The dinuclear complex formed with thiocyanate ions show, using XRD, to posses two 1.3 bond μ bridges [CdL(SCN)2]2. The other dinuclear complex was also seen to form with cyanate ions but with the μ-bridge in a 1.1 position [CdL(OCN)2]. All Cd atoms are located in a distorted octahedral environment in 1 and 2 complexes. The Cd…Cda distances are 6.032(4) Å in 1 and 3.704(3) Å in 2, respectively. The N—C—S and O—C—N angles are approximately linear as 178.1(3) and 178.6(3)° in 1 and 177.2(5) and 176.9(7)° in 2, respectively. The Cd—(μ
N,S-NCS)2—Cda bonds form a zig-zag structure in 1 and the Cd—(μ
O,N-OCN)2—Cda bonds form a distorted square planar in 2.
Impact of Atypical Coverage for Patients with Community‐Acquired Pneumonia Managed on the Medical Ward: Results from the United States Community‐Acquired Pneumonia Project
Authors: Frei Christopher R. , Koeller Jim M. , Burgess David S. , Talbert Robert L. , Johnsrud Michael T.
Published: May 2004

Study Objective. As current guidelines for treatment of community‐acquired pneumonia (CAP) recommend empiric antimicrobial coverage for atypical pathogens, we evaluated the need for atypical coverage by examining length of hospital stay (LOS) and mortality in patients with CAP who were managed on the medical ward.

Methods. Medical records of patients with CAP admitted from January 1, 1997‐December 31, 2001, from 176 United States nonteaching community hospitals were reviewed. Patients were divided into one of three mutually exclusive groups on the basis of intravenous antimicrobials received on days 1 or 2 of hospital stay: ceftriaxone monotherapy, ceftriaxone plus a macrolide, or levofloxacin. Variables evaluated for their ability to predict outcome were patient age, year of hospital admission, geographic region, preadmission setting, preadmission antimicrobial treatment, timing of antimicrobial administration, comorbid disease, and duration of intravenous antimicrobial treatment. The impact of initial antimicrobial regimen on LOS and mortality was evaluated in regression models while controlling for significant predictors of outcome.

Results. Of 8975 patients evaluated, 2453 met the inclusion criteria. Significant differences were noted among patients who received ceftriaxone (932 patients), ceftriaxone plus a macrolide (872), and levofloxacin (649) with respect to mean ± SD age (72 ± 16, 67 ± 18, and 70 ± 17 yrs, respectively; p<0.0001), admission from a nursing home (21%, 11%, and 15%, respectively; p<0.0001), and duration of intravenous antimicrobial treatment (4.4 ± 2.7, 4.0 ± 2.6, and 3.6 ± 2.5 days, respectively; p<0.0001). The LOS predictors were age, geographic region, coexisting heart failure, and duration of intravenous antimicrobial therapy. Mortality predictors were age, admission from a nursing home, coexisting heart failure, and coexisting cancer. After controlling for these predictors of outcome, no significant differences were noted among the three groups for LOS (5.5 ± 3.5, 4.8 ± 2.9, and 4.8 ± 2.9 days, respectively; p=0.2791) or mortality (3.1%, 2.0%, and 2.6%, respectively; p=0.8461).

Conclusion. Initial coverage for atypical pathogens does not affect LOS or mortality among patients with CAP managed on the medical ward.
Acute Tubular Necrosis Associated with Propylene Glycol from Concomitant Administration of Intravenous Lorazepam and Trimethoprim‐Sulfamethoxazole
Authors: Hayman Marybeth , Seidl Edward C. , Ali Median , Malik Khalid
Published: May 2004

A 46‐year‐old morbidly obese man was admitted to the medical intensive care unit with respiratory failure. He required pressure‐control ventilation and high levels of sedation with continuous‐infusion lorazepam. He developed Stenotrophomonas maltophilia pneumonia; treatment included scheduled intravenous trimethoprim‐sulfamethoxazole. Each of these drugs contain several hundred milligrams/milliliter of propylene glycol. On day 17 of his hospital course, 3 days after starting the trimethoprim‐sulfamethoxazole, the patient developed acute renal failure consistent with acute tubular necrosis. Propylene glycol toxicity was suspected; therefore, all drugs containing propylene glycol were discontinued, and laboratory data were collected. A marked osmol gap, metabolic acidosis, and renal toxicity were attributed to both continuous and large intermittent doses of intravenous propylene glycol. Particular attention should be paid to the total amount of propylene glycol provided to patients from administered drugs. Patients in the intensive care setting who require high doses of intravenous lorazepam for sedation, as well as antimicrobial therapy with trimethoprim‐sulfamethoxazole for treatment of either Stenotrophomonas maltophilia or Pneumocystis carinii pneumonia, may be at increased risk for propylene glycol toxicity and should be monitored closely.
Management of Nephrotic Syndrome in Children
Authors: Robinson Renee F. , Nahata Milap C. , Mahan John D. , Batisky Donald L.
Published: May 2004

Idiopathic childhood nephrotic syndrome generally has a favorable long‐term prognosis. Prompt administration of and improved guidelines for monitoring therapy have decreased morbidity and mortality. The treatment goal is to induce prompt remission while minimizing complications and adverse events. Aggressive therapy induces remission and decreases the frequency of relapse in most patient populations; however, such treatment often results in unnecessary toxicity. We critically assessed the current clinical evidence that supports each pharmacologic therapy. For each drug regimen, the risks and monitoring parameters required to reduce complications and optimize therapy are discussed. Some of the treatments are the common corticosteroid approaches, cytotoxic therapies (chlorambucil, cyclophosphamide), cyclosporine, less frequently used drugs (e.g., levamisole), and experimental therapies. Further studies are needed to identify the most effective and least toxic therapeutic regimens for inducing and maintaining remission in children with nephrotic syndrome.
Acetaminophen Intoxication and Length of Treatment: How Long Is Long Enough?
Authors: Kociancic Todd , Reed Michael D.
Published: May 2004

The currently recommended dosing scheme for treating acetaminophen overdose in the United States consists of a loading dose of oral N‐acetylcysteine 140 mg/kg, followed by 70 mg/kg every 4 hours for 17 doses, for a total of 72 hours of oral N‐acetylcysteine therapy. This protocol has been both effective and safe. We critically evaluated the evidence that supports reducing the course of N‐acetylcysteine therapy from 72 hours to 24 or 36 hours. This shorter regimen offers important benefits for both the patient and the patient's family, such as increased drug tolerability and reduced hospital stay. Patients who intentionally ingested acetaminophen with harmful intent could receive appropriate psychosocial treatment more quickly. In addition, shorter courses of N‐acetylcysteine therapy have positive financial ramifications by reducing the hospital stay by 1 or 2 days. Clearly, a shorter treatment regimen would not be appropriate for all patients, particularly those who seek treatment late (> 24 hrs after ingestion) and those with evidence of organ toxicity. In order to provide the necessary evidence to support a change in accepted clinical practice, further investigation on the safety and efficacy of a shorter N‐acetylcysteine regimen should be conducted by clinical researchers in a controlled manner.