bluuebunny/crossref_metadata_2025 huggingface dataset:
Autoantigens act as tissue-specific chemoattractants
Authors: Oppenheim Joost J , Dong Hui Fang , Plotz Paul , Caspi Rachel R , Dykstra Michelle , Pierce Susan , Martin Roland , Carlos Casey , Finn Olivera , Koul Omanand , Howard O M Zack
Published: May 2005

We have investigated the chemoattractant properties of self-antigens associated with autoimmune diseases and solid tumors. Many autoantigens induced leukocyte migration, especially by immature dendritic cells (iDC) by interacting with various chemoattractant Gi-protein-coupled receptors (GiPCR). Our initial observation that myositis-associated autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)- and CCR3-expressing leukocytes, while other nonautoantigenic aminoacyl-tRNA synthesases were not, suggested that only self-antigens capable of interacting with receptors on antigen-presenting cells were immunogenic. We next determined that self-antigens associated with autoimmune diseases, e.g., multiple sclerosis or experimental autoimmune encephalomyelitis, type I diabetes, scleroderma, systemic lupus erythematosus, autoimmune uveitis, or experimental autoimmune uveitis (EAU), were chemotactic for GiPCR expressed by iDC. The majority of autoantigens were DC chemoattractants at 10–100 ng/ml, but did not induce DC maturation until they reached 1000-fold higher concentrations. Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC. However, although S-antigen does not induce EAU in wild-type mice, it is nevertheless a chemoattractant for murine iDC. These unexpected observations suggested that the chemotactic activity of these tissue-specific self-antigens could be involved in promotion of tissue repair and restoration. Thus, the primary role of autoantigens may be to alert the immune system to danger signals from invaded and damaged tissues to facilitate repair, and autoimmune responses subsequently develop only in subjects with impaired immunoregulatory function.
Effectiveness of whole brain radiotherapy in the treatment of brain metastases: a systematic review
Authors: Pease N J , Edwards A , Moss L J
Published: May 2005

Background: Brain metastases are the most common intracranial tumour in adults, estimated to occur in up to 40% of patients with cancer. Despite being used in clinical practice for 50 years, the effectiveness of whole brain radiotherapy for the treatment of brain metastases remains uncertain.

Objectives: To assess the effectiveness of whole brain radiotherapy (WBRT) on survival and quality of life. To identify whether patient performance status, number of brain metastases, extent of extracranial disease and primary site of cancer are important effect modifiers.

Design: Systematic literature review.

Methods: Electronic searches of four databases, augmented by hand searches of the most frequently encountered journal and assessment of the reference lists of consensus statements and all retrieved papers. Included papers underwent structured data extraction, assessment and qualitative synthesis.

Results: Thirty-two primary studies were included, with a range of study designs, methodological quality, pre-treatment variables, interventions and outcome measures. From the limited evidence available, survival appeared to increase when patients were selected by performance status (survival increasing from approximately three to seven months in high performance status groups, as defined by Karnofsky performance status or Recursive Partitioning Analysis classification). The evidence suggests no survival benefit when patients with poor performance status were treated with whole brain radiotherapy. No studies undertook direct measurement of patients’ quality of life. Surrogate measures of patients’ quality of life, such as improvement in neurological function or improvement/maintenance of KPS] 70, produced response rates ranging from 7 to 90%.

Conclusion: The heterogeneity of study designs, quality and outcomes necessitates caution in interpreting the review findings. WBRT appears to be of benefit in higher performance status patients but not in low performance status patients. This suggests a basis for current practice, however further robust trial evidence is required.
The last days of life of nursing home patients with and without dementia assessed with the Palliative care Outcome Scale
Authors: Brandt Hella E , Deliens Luc , Steen Jenny T van der , Ooms Marcel E , Ribbe Miel W , Wal Gerrit vander
Published: May 2005

The aim of this study was to assess the Palliative care Outcome Scale (POS) for terminally ill nursing home (NH) patients in the Netherlands.

Methods: A prospective observational study of patients with a life-expectancy of six weeks or less in 16 Dutch NHs. NH staff rated the patient characteristics and measured palliative care with the POS, including items on physical, psychosocial, informational, spiritual and practical aspects.

Results: POS nonscores (not applicable; unknown) were mainly found in the psychosocial and spiritual domains, particularly in patients with dementia. Mean scores for non-demented patients and patients with dementia were favourable for the majority of the POS items.

Conclusion: According to the NH staff, fairly good quality care was provided, but the psychosocial and spiritual aspects of care need to be addressed more in the last days of the dying NH patient's life. The results indicate that the POS is an appropriate instrument to assess not only cancer patients, but also non-cancer and (moderately) severely demented patients.
Identifying palliative care patients with symptoms of depression: an algorithm
Authors: Robinson Julie A , Crawford Gregory B
Published: May 2005

Introduction: Even though depression has serious and wide-ranging effects on outcomes in palliative care, errors in the identification of depressed patients are common.

Objectives: To examine the clinical validity of widely publicised one-and two-question screening tools for depression in two palliative care settings. Also, to examine the construct validity and acceptability of a new empirically derived algorithm.

Method: Participants were Australian palliative care patients in an inpatient hospice (n–22) or the community (n –69). Patients completed an unstructured interview about their feelings, questions relevant to three reference standards, two screening questions for depression and questions about the acceptability of the screening questions.

Results: The clinical validity of the one-and two-question screening tools did not generalise across the two care settings. In contrast, the algorithm met stringent criteria for clinical validity for two reference standards in both settings. The algorithm also selectively identified patients whose unstructured interviews referred to themes consistent with depression. The algorithm includes potentially sensitive questions about anhedonia and depressed affect. However, almost all patients and staff reported that asking such questions soon after referral was acceptable.

Conclusions:A four-question algorithm designed to identify patients who warrant follow-up for depression showed clinical validity, generalizability and construct validity, and the content was acceptable to patients and clinicians.
Medroxyprogesterone Acetate and Dihydrotestosterone Induce Coronary Hyperreactivity in Intact Male Rhesus Monkeys
Authors: Mishra Rajesh G. , Hermsmeyer R. Kent , Miyagawa Koichi , Sarrel Philip , Uchida Barry , Stanczyk Frank Z. , Burry Kenneth A. , Illingworth D. Roger , Nordt Frank J.
Published: May 2005

Coronary hyperreactivity (CH), characterized by persistent severe vasoconstrictions in response to vasoconstrictor challenge, is oppositely influenced by progesterone (P) and medroxyprogesterone acetate (MPA) treatment in surgically menopausal primates. In this study we tested whether multiweek MPA or dihydrotestosterone (DHT) exposure induced CH in intact male rhesus monkeys. Coronary angiographic experiments with intracoronary serotonin and the thromboxane A2 analog U46619 stimulated brief vasoconstriction (for 1–3 min) in large epicardial coronaries in untreated male monkeys. In contrast, MPA- and DHT-treated monkeys displayed long-duration constrictions (>5 min), with significantly greater reductions in the minimal diameters of epicardial coronaries. Immunocytochemistry demonstrated androgen receptors (AR) and P receptors in aorta and coronary arteries, and immunocytochemistry and Western blotting showed AR and P receptors in rhesus coronary vascular muscle cells. In vivo, MPA or DHT increased thromboxane prostanoid (TP) receptor expression in the aorta. In vitro, MPA or DHT increased, whereas P did not change, TP receptor expression in primary coronary vascular muscle cell. This MPA- or DHT-mediated increase in TP receptor expression was attenuated by the AR antagonist flutamide. MPA or DHT induction of CH in intact adult male primates, hypothesized to occur via androgenic up-regulation of vascular muscle TP receptor expression, could predispose to CH-mediated myocardial ischemia.
Hypertension and Hypothalamo-Pituitary-Adrenal Axis Hyperactivity Affect Frontal Lobe Integrity
Authors: Gold Stefan M. , Dziobek Isabel , Rogers Kimberley , Bayoumy Abdul , McHugh Pauline F. , Convit Antonio
Published: May 2005

Chronically elevated cortisol levels have been associated with elevated blood pressure, brain atrophy, and cognitive impairments. In this cross-sectional exploratory study, we assessed whether hypertension was related to hypothalamo-pituitary-adrenal axis hyperactivity and whether this may in part explain prefrontal brain atrophy and cognitive impairments in this population. We studied 27 patients with hypertension and 27 normotensive control subjects. Glucocorticoid feedback was assessed using the combined dexamethasone-CRH test. All participants completed a neuropsychological battery and received brain magnetic resonance imaging for volumetric measurement of frontal and medial temporal lobe regions. Hypertension was significantly associated with impaired glucocorticoid feedback control after statistically controlling for age, gender, and body mass index (P = 0.01). Hypertensive patients also showed a trend toward reductions in frontal lobe volume (P = 0.09) and had significantly lower scores in one of two tests of executive function (P = 0.03). Significant correlations were observed between hypothalamo-pituitary-adrenal hyperactivity and frontal lobe atrophy. Our data indicate that impaired glucocorticoid feedback control may partly account for the prefrontal volume reductions present in patients with hypertension. Future studies assessing the impact of hypertension on the brain should include cortisol assessments.
Plasma Adiponectin in Nonalcoholic Fatty Liver Is Related to Hepatic Insulin Resistance and Hepatic Fat Content, Not to Liver Disease Severity
Authors: Bugianesi Elisabetta , Pagotto Uberto , Manini Rita , Vanni Ester , Gastaldelli Amalia , de Iasio Rosaria , Gentilcore Elena , Natale Stefania , Cassader Maurizio , Rizzetto Mario , Pasquali Renato , Marchesini Giulio
Published: May 2005

Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116).

When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R2, 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R2, 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R2, 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011).

The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.
Insulin-Like Factor 3 Serum Levels in 135 Normal Men and 85 Men with Testicular Disorders: Relationship to the Luteinizing Hormone-Testosterone Axis
Authors: Bay K. , Hartung S. , Ivell R. , Schumacher M. , Jürgensen D. , Jorgensen N. , Holm M. , Skakkebaek N. E. , Andersson A.-M.
Published: May 2005

Insulin-like factor 3 (INSL3) serum levels were measured in 135 andrologically well-characterized normal men and 85 patients with testicular disorders to investigate how the hormone, which is a major secretory product of human Leydig cells, is related to testosterone (T), LH, and semen quality. INSL3 was measured by using a newly developed fluorescence immunoassay.

Median (2.5–97.5 percentiles) INSL3 serum levels were as follows: normal men (n = 135), 0.99 (0.55–1.73) ng/ml; infertile men (n = 23), 1.11 (0.60–2.07) ng/ml; anorchid men (n = 21), nondetectable (ND); patients with 47, XXY, Klinefelter syndrome (n = 21), 0.12 (ND–0.78) ng/ml; men with hypogonadotropic hypogonadism and T substitution (n = 11), ND; and men with hypogonadotropic hypogonadism and human chorionic gonadotropin (hCG) treatment (n = 5), 0.36 (0.13–0.73) ng/ml. Before testicular biopsy, two infertile men had blood samples drawn directly from vena spermatica. Here, the serum INSL3 levels were 15-fold higher than in serum from peripheral blood samples (13.84 and 14.00 ng/ml, respectively). In two unilaterally orchiectomized former testis cancer patients, who underwent hCG stimulation test, INSL3 serum levels were unchanged 72 and 96 h after hCG stimulation. In conclusion, we provide a normal range for INSL3 serum levels in adult men and show that the majority, if not all, circulating INSL3 derives from the testes. Furthermore, our data strongly indicate that INSL3 secretion is dependent on the differentiating effect of LH on Leydig cells but independent of the steroidogenic LH-mediated action. Thus, even though T and INSL3 are both dependent on LH, these two Leydig cell hormones are regulated differently.
No Evidence for Hepatic Conversion of Dehydroepiandrosterone (DHEA) Sulfate to DHEA: In Vivo and in Vitro Studies
Authors: Hammer Fabian , Subtil Sandra , Lux Philipp , Maser-Gluth Christiane , Stewart Paul M. , Allolio Bruno , Arlt Wiebke
Published: May 2005

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA. It is generally accepted that DHEA and DHEAS interconvert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted downstream to sex steroids. Here we analyzed DHEA/DHEAS interconversion in vivo and in vitro. We administered oral DHEA (100 mg) and iv DHEAS (25 mg) to eight healthy young men, resulting in similar increases in serum DHEAS compared with baseline. However, although DHEA administration significantly increased serum DHEA (P < 0.05), no such increase was observed after DHEAS. Similarly, DHEA but not DHEAS was converted downstream to androstenedione, estrone, and androstanediol glucuronide. The striking absence of conversion of DHEAS to DHEA was mirrored by our in vitro findings in HepG2 cells, revealing dose-dependant conversion of DHEA (0.1–2 μm) to DHEAS but no conversion of DHEAS (0.1–2 μm). These results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS. DHEAS does not seem to represent a circulating storage pool for DHEA regeneration, and therefore serum DHEAS is unlikely to reflect bioavailable DHEA.
Neonatal Detection of Congenital Hypothyroidism of Central Origin
Authors: van Tijn David A. , de Vijlder Jan J. M. , Verbeeten Bernard , Verkerk Paul H. , Vulsma Thomas
Published: May 2005

Due to the high frequency of concurrent pituitary hormone deficiencies, congenital hypothyroidism (CH) of central origin (CH-C) is a life-threatening disorder. Yet only a minority of these patients are detected by neonatal CH screening programs worldwide. We conducted a prospective multicenter study involving a 2-yr cohort of neonatally diagnosed CH-C patients to determine whether a T4-TSH-based neonatal CH screening protocol extended with T4 binding globulin determinations improves early detection of CH-C and to assess the extent of pituitary hormone deficiency among the identified CH-C patients. In all infants with screening results indicative of CH-C, the functional integrity of the hypothalamo-hypophyseal system was investigated by dynamic tests; the anatomical integrity was investigated by magnetic resonance imaging. Initial test results were evaluated after 5 yr of follow-up. Among 385,000 infants screened over the 2-yr period, 19 cases of permanent CH-C were detected (prevalence, 1:20,263; 95% confidence interval, 1:12,976 to 1:33,654), representing 13.5% of all detected cases of permanent CH. The majority (78%) had multiple pituitary hormone deficiency, whereas 53% had pituitary malformations on magnetic resonance imaging. We conclude that infants with CH-C can very well be detected by neonatal screening. The estimated prevalence and the severity of pituitary dysfunction of this treatable disorder call for explicit attention for this entity of CH in neonatal screening programs worldwide.
Alix regulates cortical actin and the spatial distribution of endosomes
Authors: Cabezas Alicia , Bache Kristi G. , Brech Andreas , Stenmark Harald
Published: May 2005

Alix/AIP1 is a proline-rich protein that has been implicated in apoptosis, endocytic membrane trafficking and viral budding. To further elucidate the functions of Alix, we used RNA interference to specifically suppress its expression. Depletion of Alix caused a striking redistribution of early endosomes from a peripheral to a perinuclear location. The redistribution of endosomes did not affect transferrin recycling or degradation of endocytosed epidermal growth factor receptors, although the uptake of transferrin was mildly reduced when Alix was downregulated. Quantitative immunoelectron microscopy showed that multivesicular endosomes of Alix-depleted cells contained normal amounts of CD63, whereas their levels of lysobisphosphatidic acid were reduced. Alix depletion also caused an accumulation of unusual actin structures that contained clathrin and cortactin, a protein that couples membrane dynamics to the cortical actin cytoskeleton. Our results suggest that Alix functions in the actin-dependent intracellular positioning of endosomes, but that it is not essential for endocytic recycling or for trafficking of membrane proteins between early and late endosomes in non-polarised cells.
Transition Metal-complexed Catenanes and Rotaxanes as Light-driven Molecular Machines Prototypes
Authors: Collin Jean-Paul , Sauvage Jean-Pierre
Published: May 2005

In the course of the last decade, many dynamic molecular systems, for which the movements are controlled from the outside, have been elaborated. These compounds are generally referred to as “molecular machines.” Our group has made and studied catenanes and rotaxanes since the early 80s. An important class of molecular machines is based on these interlocking or threaded ring compounds. Although a “molecular muscle” is briefly discussed in the present review article, we mostly focus on light-driven machines, consisting of ruthenium(II)-complexed rotaxanes or catenanes. The synthetic approach is based on the template effect of an octahedral ruthenium(II) centres. Two 1,10-phenanthroline ligands are incorporated in an axis or in a ring, affording the precursor to the rotaxane or the catenane, respectively. Ru(diimine)32+ complexes display the universally used 3MLCT (metal-to-ligand charge transfer) excited state and, another interesting excited state, the 3LF (ligand field) state, which is strongly dissociative. In the past, the 3LF state has mostly been considered as detrimental and thus, its reactivity has not been frequently utilised. By taking advantage of this latter state, it has been possible to propose a new family of molecular machines, which are set in motion by populating the dissociative 3LF state, thus leading to ligand exchange in the coordination sphere of the ruthenium(II) centre.
Systematics of Stability Constants of Fulvate Complexes with Rare Earth Ions
Authors: Yamamoto Yuhei , Takahashi Yoshio , Shimizu Hiroshi
Published: May 2005

Stability constants of all rare earth ions (REE) with fulvic acid were determined using solvent extraction coupled with ICP-MS detection. REE pattern of the stability constant of REE fulvates shows a similar pattern to REE–carboxylate complex, suggesting that carboxylic group is the main binding site of REE in humic substances. The stability constants for all REE are indispensable for the understanding of REE patterns in natural aquifer.
Low-temperature Benzene-thermal Synthesis of Photoluminescent Turbostratic Boron Nitride Powders
Authors: Guo Qixun , Xie Yi , Zhu Lei , Yi Chengqi , Hou Hongwei
Published: May 2005

Photoluminescent turbostratic boron nitride (t-BN) powders can be easily synthesized from NaBF4 and NaNH2 via a facile benzene-thermal process at 260 °C. The prepared samples were characterized by XRD, XPS, FTIR, PL, TEM, and HRTEM. The possible active intermediates (BF3 and Na3N) are believed to be responsible for the growth of t-BN under mild conditions.
Beyond the Endogeneity Bias: The Effect of Unmeasured Brand Characteristics on Household-Level Brand Choice Models
Authors: Chintagunta Pradeep , Dubé Jean-Pierre , Goh Khim Yong
Published: May 2005

We investigate the role of potential weekly brand-specific characteristics that influence consumer choices, but are unobserved or unmeasurable by the researcher. We use an empirical approach, based on the estimation methods used for standard random coefficients logit models, to account for the presence of such unobserved attributes. Using household scanner panel data, we find evidence that ignoring such time-varying latent (to the researcher) characteristics can lead to two types of problems. First, consistent with previous literature, we find that these unobserved characteristics may lead to biased estimates of the mean price response parameters. This argument is based on a form of price endogeneity. If marketing managers set prices based on consumer willingness to pay, then the observed prices will likely be correlated with the latent (to the researcher) brand characteristics. We resolve this problem by using an instrumental variables procedure. Our findings suggest that simply ignoring these attributes may also lead to larger estimates of the variance in the heterogeneity distribution of preferences and price sensitivities across households. This could overstate the benefits from marketing activities such as household-level targeting. We resolve the problem by using weekly brand intercepts, embedded in a random coefficients brand choice model, to control for weekly brand-specific characteristics, while accounting for household heterogeneity. Overall, our results extend the finding on the endogeneity bias from the mean of the heterogeneity distribution (i.e., the price effect) to include the variance of that distribution.
A Longitudinal Model of Continued IS Use: An Integrative View of Four Mechanisms Underlying Postadoption Phenomena
Authors: Kim Sung S. , Malhotra Naresh K.
Published: May 2005

Although initial use is an important indicator of information system (IS) success, it does not necessarily lead to the desired managerial outcome unless the use continues. However, compared with the great amount of work done on IS adoption, little systematic effort has gone into providing insight into continued IS use over time. The objective of this study is to develop a longitudinal model of how users’ evaluations and behavior evolve as they gain experience with the information technology application. The proposed model is a unified framework that sheds light on four different mechanisms underlying postadoption phenomena: (1) the processes suggested by the technology acceptance model; (2) sequential updating mechanisms; (3) feedback mechanisms; and (4) repeated behavioral patterns. The proposed model was empirically tested in the context of Web-based IS use in a nonexperimental setting. Our findings suggest that, as hypothesized, each of the four theoretical viewpoints is essential for a deeper understanding of continued IS use. We discuss important findings that emerged from this longitudinal study and suggest directions for additional research.
Analyzing Bioterror Response Logistics: The Case of Anthrax
Authors: Craft David L. , Wein Lawrence M. , Wilkins Alexander H.
Published: May 2005

To aid in understanding how best to respond to a bioterror anthrax attack, we analyze a system of differential equations that includes an atmospheric release model, a spatial array of biosensors, a dose-response model, a disease progression model, and a set of spatially distributed tandem queues for distributing antibiotics and providing hospital care. We derive approximate closed-form expressions for the number of deaths as a function of key parameters and management levers, including the size of the attack, the time at which the attack is detected via symptomatic patients, the number of days to distribute antibiotics, the efficacy (both for treatment and prevention) of antibiotics, the prophylactic antibiotic distribution strategy, the prioritization of the antibiotics queue, and the detection limit, deployment density, and delay time of biosensors.
Collaborative Networks as Determinants of Knowledge Diffusion Patterns
Authors: Singh Jasjit
Published: May 2005

This paper examines whether interpersonal networks help explain two widely documented patterns of knowledge diffusion: (1) geographic localization of knowledge flows, and (2) concentration of knowledge flows within firm boundaries. I measure knowledge flows using patent citation data, and employ a novel regression framework based on choice-based sampling to estimate the probability of knowledge flow between inventors of any two patents. As expected, intraregional and intrafirm knowledge flows are found to be stronger than those across regional or firm boundaries. I explore whether these patterns can be explained by direct and indirect network ties among inventors, as inferred from past collaborations among them. The existence of a tie is found to be associated with a greater probability of knowledge flow, with the probability decreasing as the path length (geodesic) increases. Furthermore, the effect of regional or firm boundaries on knowledge flow decreases once interpersonal ties have been accounted for. In fact, being in the same region or firm is found to have little additional effect on the probability of knowledge flow among inventors who already have close network ties. The overall evidence is consistent with a view that interpersonal networks are important in determining observed patterns of knowledge diffusion.
Association Between Supply Chain Glitches and Operating Performance
Authors: Hendricks Kevin B. , Singhal Vinod R.
Published: May 2005

This paper empirically documents the association between supply chain glitches and operating performance. The results are based on a sample of 885 glitches announced by publicly traded firms. Changes in various operating performance metrics for the sample firms are compared against a sample of control firms of similar size and from similar industries. In the year leading up to the announcement, the control-adjusted mean percent changes in operating income, return on sales, and return on assets for the sample firms are −107%, −114%, and −92%, respectively. During this same period, the control-adjusted changes in the level of return on sales and return on assets are −13.78% and −2.32%, respectively. Relative to controls, firms that experience glitches report on average 6.92% lower sales growth, 10.66% higher growth in cost, and 13.88% higher growth in inventories. More importantly, firms do not quickly recover from the negative economic consequences of glitches. During the two-year time period after the glitch announcement, operating income, sales, total costs, and inventories do not improve. We also find that it does not matter who caused the glitch, what the reason was for the glitch, or what industry a firm belongs to—glitches are associated with negative operating performance across the board.
Generating Volatility Forecasts from Value at Risk Estimates
Authors: Taylor James W.
Published: May 2005

Statistical volatility models rely on the assumption that the shape of the conditional distribution is fixed over time and that it is only the volatility that varies. The recently proposed conditional autoregressive value at risk (CAViaR) models require no such assumption, and allow quantiles to be modeled directly in an autoregressive framework. Although useful for risk management, CAViaR models do not provide volatility forecasts. Such forecasts are needed for several other important applications, such as option pricing and portfolio management. It has been found that, for a variety of probability distributions, there is a surprising constancy of the ratio of the standard deviation to the interval between symmetric quantiles in the tails of the distribution, such as the 0.025 and 0.975 quantiles. This result has been used in decision and risk analysis to provide an approximation of the standard deviation in terms of quantile estimates provided by experts. Drawing on the same result, we construct financial volatility forecasts as simple functions of the interval between CAViaR forecasts of symmetric quantiles. Forecast comparison, using five stock indices and 20 individual stocks, shows that the method is able to outperform generalized autoregressive conditional heteroskedasticity (GARCH) models and moving average methods.
Revenue Management Games: Horizontal and Vertical Competition
Authors: Netessine Serguei , Shumsky Robert A.
Published: May 2005

A well-studied problem in the literature on airline revenue (or yield) management is the optimal allocation of seat inventory among fare classes, given a demand distribution for each class. In practice, the seat allocation decisions of one airline affect the passenger demands for seats on other airlines. In this paper, we examine the seat inventory control problem under both horizontal competition (two airlines compete for passengers on the same flight leg) and vertical competition (different airlines fly different legs on a multileg itinerary). Such vertical competition can be the outcome of a code-sharing agreement between airlines, because each airline sells seats on the partner airlines’ flights but the airlines are unwilling, or unable, to coordinate yield management decisions. We provide a general sufficient condition under which a pure-strategy Nash equilibrium exists in these revenue management games, and we also compare the total number of seats available in each fare class with, and without, competition. Analytical results as well as numerical examples demonstrate that more seats are protected for higher-fare passengers under horizontal competition than when a single airline acts as a monopoly. Under vertical competition the booking limit may be higher or lower, however, than the monopoly level, depending on the demand for connecting flights in each fare class. Finally, we discuss revenue-sharing contracts that coordinate the actions of both airlines.
On the Timing of CEO Stock Option Awards
Authors: Lie Erik
Published: May 2005

This study documents that the abnormal stock returns are negative before unscheduled executive option awards and positive afterward. The return pattern has intensified over time, suggesting that executives have gradually become more effective at timing awards to their advantage, and possibly explaining why the results in this study differ from those in past studies. Moreover, I document that the predicted returns are abnormally low before the awards and abnormally high afterward. Unless executives possess an extraordinary ability to forecast the future marketwide movements that drive these predicted returns, the results suggest that at least some of the awards are timed retroactively.
Using Bucket Brigades to Migrate from Craft Manufacturing to Assembly Lines
Authors: Bartholdi John J. , Eisenstein Donald D.
Published: May 2005

One way to organize workers that lies between traditional assembly lines, where workers are specialists, and craft assembly, where workers are generalists, are “bucket brigades.” We describe how one firm used bucket brigades as an intermediate strategy to migrate from craft assembly to assembly lines. The adoption of bucket brigades led to a narrowing of tasks for each worker and thus accelerated learning. The increased production more than compensated for the time lost when workers walk back to get more work, which was significant in this implementation.

To understand the trade-offs in migrating from craft to assembly lines, we extend the standard model of bucket brigades to capture hand-off and walk-back times.
Hedging Inventory Risk Through Market Instruments
Authors: Gaur Vishal , Seshadri Sridhar
Published: May 2005

We address the problem of hedging inventory risk for a short life cycle or seasonal item when its demand is correlated with the price of a financial asset. We show how to construct optimal hedging transactions that minimize the variance of profit and increase the expected utility for a risk-averse decision maker. We show that for a wide range of hedging strategies and utility functions, a risk-averse decision maker orders more inventory when he or she hedges the inventory risk. Our results are useful to both risk-neutral and risk-averse decision makers because (1) the price information of the financial asset is used to determine both the optimal inventory level and the hedge, (2) this enables the decision maker to update the demand forecast and the financial hedge as more information becomes available, and (3) hedging leads to lower risk and higher return on inventory investment. We illustrate these benefits using data from a retailing firm.
In This Issue
Authors: van Ryzin Garrett J.
Published: May 2005

A regular feature of Manufacturing & Service Operations Management, “In This Issue” briefly describes each issue’s articles and highlights their contributions.
Thrombocytosis During Antifungal Therapy of Candidemia
Authors: Saathoff Angela D , Elkins Stephanie L , Chapman Stanley W , McAllister Susan Fleming , Cleary John D
Published: May 2005

BACKGROUND

Secondary, “reactive,” thrombocytosis has been attributed to bacterial infection and treatment with multiple pharmaceuticals and may be associated with an increase in the incidence of gastrointestinal tract bleeding and thrombotic events (eg, stroke).

OBJECTIVE

To characterize the dynamics of thrombocytosis in patients with candidemia receiving antifungal therapy.

METHODS

We initiated a retrospective observational description of patients with candidemia who were treated with antifungal agents. A total of 108 patients diagnosed with candidemia between August 1995 and September 2003 at our teaching hospital were enrolled. Three groups (candidemia with antifungal therapy, candidemia without antifungal therapy, antifungal therapy without candidemia) of patients >18 years of age were evaluated for the resence of thrombocytosis. Platelet administration, pharmacologic or pathologic contributors to thrombocytosis, and other pertinent details related to an elevation of platelet counts were scrutinized.

RESULTS

Reactive thrombocytosis was observed in approximately 10% of treated patients with candidemia. Within the subgroup developing reactive thrombocytosis, life-threatening thrombotic complications were uncommon. Mean baseline platelet counts were 393 × 103/mm3, with a mean peak (695 × 103/mm3) occurring an average of 13 days after initiation of therapy. All patients had resolution within 7 days after therapy. The maximum peak (1056 × 103/mm3) was observed in a patient after 14 days of antifungal therapy. The onset of thrombocytosis in this patient was 4 days and lasted 4 days after therapy.

CONCLUSIONS

Reactive thrombocytosis occurs during treatment of candidemia. The causative agent (drug vs disease), the risk associated with this reaction, and evaluation of treatment need to be elucidated by a larger epidemiologic study or controlled, prospective clinical trial.
Breakthrough Candida Infections in Patients Receiving Voriconazole
Authors: Gerzenshtein Lana , Patel Shilpa M , Scarsi Kimberly K , Postelnick Michael J , Flaherty John P
Published: May 2005

OBJECTIVE

To describe 2 instances of breakthrough Candida infection in 2 patients on treatment doses of voriconazole.

CASE SUMMARIES

A 27-year-old woman with systemic lupus erythematosus was receiving high-dose voriconazole (400 mg twice daily) for central nervous system lesions of unknown origin and developed oral thrush. The patient was receiving concomitant therapy with phenytoin 400 mg/day. The voriconazole dose was increased to 400 mg 3 times daily, and the thrush resolved. A 50-year-old man with HIV infection was receiving enfuvirtide, lamivudine, tenofovir, and efavirenz 600 mg/day, as well as prophylactic trimethoprim/sulfamethoxazole and azithromycin. He was started on voriconazole 200 mg twice daily for pulmonary aspergillosis and developed esophageal candidiasis. The voriconazole dose was increased to 350 mg twice daily, and the thrush eventually resolved.

DISCUSSION

Both reactions were probable according to the Naranjo probability scale. Significant drug interactions may have played a role in the development of breakthrough infections in these patients, specifically with phenytoin and efavirenz. Voriconazole is metabolized primarily by CYP2C19, as well as CYP2C9 and CYP3A4. Voriconazole is also known to inhibit these enzymes, and the manufacturer reports an extensive list of drugs that interact with voriconazole.

CONCLUSIONS

Although requiring systematic evaluation, there may be a role for voriconazole serum concentration monitoring to ensure therapeutic efficacy when significant drug interactions are suspected.
Use of Methylphenidate in Traumatic Brain Injury
Authors: Siddall O'Rita M
Published: May 2005

OBJECTIVE

To review literature regarding the effectiveness of methylphenidate in the management of the cognitive and behavioral changes observed following traumatic brain injury (TBI).

DATA SOURCES

A literature search was conducted using the following databases: MEDLINE (1966–June 2004); Cochrane Central Register of Controlled Trials, fourth quarter 2004 (1988–June 2004); and International Pharmaceutical Abstracts (1970–June 2004). Methylphenidate and brain injury were the key search terms used. Limits were set to include clinical trial publications, human subjects, and English language.

DATA SYNTHESIS

Ten clinical trials evaluating the efficacy and safety of methylphenidate in pediatric and adult patients with TBI are reviewed. Improvements in different aspects of cognition and behavior were evaluated before, during, and after treatment with methylphenidate. The results demonstrated that methylphenidate is likely to improve memory, attention, concentration, and mental processing, but its effects on behavior have not been determined.

CONCLUSIONS

Larger, double-blind, placebo-controlled studies are needed to determine optimal doses, during which phase of recovery to begin treatment, length of treatment, and long-term effects for patients with mild, moderate, and severe TBI.
Acute Myocardial Infarction After Sildenafil Citrate Ingestion
Authors: Kekilli Murat , Beyazit Yavuz , Purnak Tugrul , Dogan Serkan , Atalar Enver
Published: May 2005

OBJECTIVE

To report a case of acute myocardial infarction (MI) associated with the use of oral sildenafil in a nitrate-free patient.

CASE SUMMARY

A 45-year-old man was admitted to the hospital with acute left-sided chest pain, nausea, and vomiting that started approximately 30 minutes after taking sildenafil 100 mg before a sexual contact. The patient was diagnosed with an acute anterior MI, and therapy with aspirin, metoprolol, and unfractionated heparin was initiated. Early coronary reperfusion treatment with primary percutaneous transluminal coronary angioplasty was performed after initial evaluation. Balloon angioplasty followed by coronary stenting was performed successfully in the 80%-occluded left anterior descending artery. The patient was discharged one week after the coronary intervention without complication.

DISCUSSION

Sildenafil-associated MI is rarely seen in patients without documented coronary artery disease. By inhibiting phosphodiesterase type 5, sildenafil can cause an increase in cyclic guanosine monophosphate levels, which mediates the relaxation of vascular smooth muscle in the corpus cavernosum. Although sildenafil can cause a major decline in systemic arterial pressure in the existence of organic nitrates, physicians should be aware of its adverse cardiovascular effects even in nitrate-free patients. The Naranjo probability scale indicates that sildenafil was the possible cause of the MI.

CONCLUSIONS

Sildenafil may rarely be associated with MI in patients with no known cardiac history. Physicians should be aware of this rare and serious adverse reaction to sildenafil and counsel patients not to take sildenafil before undergoing a complete physical evaluation and further testing if warranted.
Are Brand-Name and Generic Warfarin Interchangeable? Multiple N-of-1 Randomized, Crossover Trials
Authors: Pereira Jennifer A , Holbrook Anne M , Dolovich Lisa , Goldsmith Charles , Thabane Lehana , Douketis James D , Crowther Mark A , Bates Shannon M , Ginsberg Jeffrey S
Published: May 2005

BACKGROUND

Warfarin is a commonly used anticoagulant in North America. Several generic formulations have been approved, raising concern over the safety and efficacy of these products compared with brand-name Coumadin.

OBJECTIVE

To ensure that generic warfarin products can be safely interchanged with Coumadin.

METHODS

Multiple n-of-1 randomized, double-blind, crossover trials switched outpatients (N = 7) between a generic warfarin formulation (Apo-warfarin) and Coumadin over 30 weeks. Study patients took each drug for five 3-week periods, with international normalized ratio (INR) measurements taken twice per period. Inter- and intrapatient differences between generic warfarin and Coumadin were compared, and overall study patient results were compared with those of a Coumadin control group.

RESULTS

There were no differences between warfarin products in terms of mean INR results or number of dosage adjustments required. There also was no difference in INR variation based on warfarin formulation (p > 0.69), nor was a patient and warfarin interaction found (p > 0.81). The INR results were not influenced by whether patients were maintained on Coumadin only (control group) or interchanged between Coumadin and generic warfarin (p = 0.98).

CONCLUSIONS

It appears that patients can safely and effectively switch between generic warfarin and Coumadin.
Thrombotic Thrombocytopenic Purpura Associated with Quetiapine
Authors: Huynh Minh , Chee Karen , Lau Derick HM
Published: May 2005

OBJECTIVE

To report a case of thrombotic thrombocytopenic purpura (TTP) caused by the antipsychotic quetiapine on 2 occasions in the same patient and review the hematologic adverse events associated with quetiapine.

CASE SUMMARY

A 25-year-old African American male with a history of bipolar disorder was treated with quetiapine and developed thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure consistent with a diagnosis of TTP on 2 occasions 2 years apart. On each occasion, TTP was successfully treated with plasmapheresis.

DISCUSSION

Many medications, including antibiotics, immunosuppressants, and antineoplastics, have been implicated as causative agents of TTP. Although, as of this writing, a review of the medical literature reveals no previous report of TTP associated with quetiapine, the Food and Drug Administration database of the Adverse Event Reporting System has compiled, as of this writing, 3 cases of TTP occurring in patients on quetiapine as their sole medication. In addition, this database has recorded other common hematologic adverse effects, including neutropenia and thrombocytopenia, that are possibly associated with quetiapine. In our patient, quetiapine-associated TTP presented within a few days after exposure to the drug, with early thrombocytopenia followed by delayed appearance (2–3 days) of microangiopathic hemolysis.

CONCLUSIONS

An objective causality assessment suggests that quetiapine was the highly probable cause of TTP in this patient. Early recognition, discontinuation of the drug, and institution of plasmapheresis are paramount for prompt resolution of this life-threatening hematologic disorder.
Polyadenylate polymerase modulations in human epithelioid cervix and breast cancer cell lines, treated with etoposide or cordycepin, follow cell cycle rather than apoptosis induction
Authors: Thomadaki Hellinida , Tsiapalis Chris M. , Scorilas Andreas
Published: May 2005

Cancer results from an imbalance between cell cycle progression and apoptosis. Therefore, most anticancer drugs exert their antiproliferative and cytotoxic activity via cell cycle arrest and induction of apoptosis, a controlled form of cell death that is dysregulated in cancer. Many polyadenylationtrans-acting factors, including polyadenylate polymerase (PAP), are increasingly found to be involved in cell cycle, apoptosis and cancer prognosis. The objective of the present study was to identify PAP modulations in the response of two epithelial cancer cell lines (HeLa and MCF-7) to apoptosis induction by the anticancer drugs etoposide and cordycepin. Cells were assessed for PAP activity and isoforms by the highly sensitive PAP activity assay and Western blotting, respectively. Induction of apoptosis was determined by endonucleosomal DNA cleavage, 4′6-diamidino-2-phenylindol (DAPI) staining and caspase-6 activity assay, whereas cytotoxicity and cell cycle status were assessed by trypan blue staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Our results indicate that PAP changes very early in response to either etoposide or cordycepin treatment, even prior to the hallmarks of apoptosis (chromatin condensation and cleavage), in both cell lines tested, but in a different mode. Our results suggest, for the first time, that in the epithelial cancer cell lines used, PAP modulations follow cell cycle progression rather than the course of apoptosis.