bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacogenetic Screening of CYP3A and ABCB1 in Relation to Population Pharmacokinetics of Docetaxel
Authors: Bosch Tessa M. , Huitema Alwin D.R. , Doodeman Valerie D. , Jansen Robert , Witteveen Els , Smit Wim M. , Jansen Rob L. , van Herpen Carla M. , Soesan Marcel , Beijnen Jos H. , Schellens Jan H.M.
Published: October 2006

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel.

Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling.

Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (−25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified.

Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.
Extracellular pH and P-31 Magnetic Resonance Spectroscopic Variables are Related to Outcome in Canine Soft Tissue Sarcomas Treated with Thermoradiotherapy
Authors: Lora-Michiels Michaël , Yu Daohai , Sanders Linda , Poulson Jean M. , Azuma Chieko , Case Beth , Vujaskovic Zeljko , Thrall Donald E. , Charles H. Cecil , Dewhirst Mark W.
Published: October 2006

Purpose: The objective was to test whether tumor pH and 31P magnetic resonance spectroscopic end points were related to treatment outcome in pet canine patients with spontaneous soft tissue sarcomas treated with thermoradiotherapy.

Experimental Design: Forty-two dogs with evaluable 31P magnetic resonance spectroscopic end points and pH data were included in this study. Tumor variables (grade and volume), extracellular pH (pHe), T2 relaxation times, intracellular pH, and selected phosphometabolite ratios were examined for correlation with clinical outcome.

Results: From 39 dogs, pHe was a predictor of metastasis-free survival (MFS), with hazard ratio (HR, 0.29; P = 0.005) and overall survival (OS) with (HR, 0.36; P = 0.013). Tumor volume (>19 cm3) was related to MFS (HR, 2.14; P = 0.04), time to local failure (HR, 3.4; P = 0.025), and OS (HR, 2.27; P = 0.03). There was no association between T2 or intracellular pH and clinical outcome. Tumor grade (high versus low/intermediate) and phosphodiester/βATP ratio were identified as significant predictors for MFS, with (HR, 2.66; P = 0.009) and (HR, 0.75; P = 0.027), respectively, and as predictors of OS with (HR, 2.66; P = 0.009) and (HR, 0.76; P = 0.03), respectively. The phosphodiester/phosphocreatinine ratio predicted time to local failure (HR, 1.24; P = 0.017).

Conclusions: pHe was predictive of metastasis and OS in canine spontaneous sarcomas. To our knowledge, this is the first time that pHe has been shown to be predictive of clinical outcome. The results suggest that additional studies should be considered evaluating the prognostic significance of this variable. Phospholipid resonances, related to membrane metabolism, were related to clinical outcome, confirming recent results reported in human patients with soft tissue sarcomas treated with thermoradiotherapy.
YKL-40 and Matrix Metalloproteinase-9 as Potential Serum Biomarkers for Patients with High-Grade Gliomas
Authors: Hormigo Adília , Gu Bin , Karimi Sasan , Riedel Elyn , Panageas Katherine S. , Edgar Mark A. , Tanwar Meena K. , Rao Jasti S. , Fleisher Martin , DeAngelis Lisa M. , Holland Eric C.
Published: October 2006

Purpose: Biomarkers can facilitate diagnosis, monitor treatment response, and assess prognosis in some patients with cancer. YKL-40 and matrix metalloproteinase-9 (MMP-9) are two proteins highly differentially expressed by malignant gliomas. We obtained prospective longitudinal serum samples from patients with gliomas to determine whether YKL-40 or MMP-9 could be used as serum markers.

Experimental Design: Serum samples were obtained concurrently with magnetic resonance imaging scans. YKL-40 and MMP-9 were determined by ELISA and the values correlated with the patient's radiographic status and survival.

Results: High-grade glioma patients who underwent a surgical resection of their tumor had transient increase of both YKL-40 and MMP-9 serum levels in the postoperative period. Glioblastoma multiforme (GBM) patients with no radiographic evidence of disease (n = 10 patients, 50 samples) had a significantly lower level of YKL-40 and MMP-9 than patients with active tumor (n = 66 patients, 209 samples; P = 0.0003 and 0.0002, respectively). Anaplastic glioma patients with no radiographic evidence of disease (n = 32 patients, 107 samples) also had a significantly lower level of YKL-40 compared with those patients with active tumor (n = 48 patients, 199 samples; P = 0.04). There was a significant inverse association between YKL-40 and survival in GBM, hazard ratio (hazard ratio, 1.4; P = 0.02), and anaplastic astrocytoma patients (hazard ratio, 2.2; P = 0.05).

Conclusions: YKL-40 and MMP-9 can be monitored in patients' serum and help confirm the absence of active disease in GBM and YKL-40 in anaplastic glioma patients. YKL-40 can be used as predictor of survival in patients with high-grade glioma. Longitudinal studies with a larger patient population are needed to confirm these findings.
Isodeoxyelephantopin, a Novel Sesquiterpene Lactone, Potentiates Apoptosis, Inhibits Invasion, and Abolishes Osteoclastogenesis through Suppression of Nuclear Factor-κB (NF-κB) Activation and NF-κB-Regulated Gene Expression
Authors: Ichikawa Haruyo , Nair Mangalam S. , Takada Yasunari , Sheeja D.B. Alan , Kumar M.A. Suresh , Oommen Oommen V. , Aggarwal Bharat B.
Published: October 2006

Purpose: Deoxyelephantopin (ESD) and isodeoxyelephantopin (ESI) are two sesquiterpene lactones derived from the medicinal plant Elephantopus scaber Linn. (Asteraceae). Although they are used for the treatment of a wide variety of proinflammatory diseases, very little is known about their mechanism of action. Because most genes that control inflammation are regulated by activation of the transcription factor nuclear factor-κB (NF-κB), we postulated that ESD and ESI mediate their activities through modulation of the NF-κB activation pathway.

Experimental Design: We investigated the effect of ESI and ESD on NF-κB activation by electrophoretic mobility shift assay and NF-κB-regulated gene expression by Western blot analysis.

Results: We found that ESI suppressed NF-κB activation induced by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific, and both inducible and constitutive NF-κB activation was blocked. ESI did not interfere with the binding of NF-κB to DNA but rather inhibited IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. ESI also suppressed the expression of TNF-induced NF-κB-regulated, proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of apoptosis induced by TNF and suppression of TNF-induced invasion and receptor activator of NF-κB ligand-induced osteoclastogenesis.

Conclusion: Our results indicate that ESI inhibits NF-κB activation and NF-κB-regulated gene expression, which may explain the ability of ESI to enhance apoptosis and inhibit invasion and osteoclastogenesis.
Cisplatin Preferentially Binds Mitochondrial DNA and Voltage-Dependent Anion Channel Protein in the Mitochondrial Membrane of Head and Neck Squamous Cell Carcinoma: Possible Role in Apoptosis
Authors: Yang Zejia , Schumaker Lisa M. , Egorin Merrill J. , Zuhowski Eleanor G. , Guo Zhongmin , Cullen Kevin J.
Published: October 2006

Purpose: Cisplatin adducts to nuclear DNA (nDNA) are felt to be the molecular lesions that trigger apoptosis, but the mechanism linking nDNA adduct formation and cell death is unclear. Some literature in the last decade has suggested a possible direct effect of cisplatin on mitochondria independent of nDNA interaction. In this study, we define separately the sequelae of cisplatin interactions with nDNA and with mitochondria in head and neck squamous cell carcinoma (HNSCC) cell lines.

Experimental Design: Cisplatin binding to mitochondrial DNA (mtDNA) and proteins was analyzed by atomic absorption spectroscopy and other methods.

Results: Following 1 hour of exposure to cisplatin, platinum adducts to mtDNA were 300- to 500-fold more abundant than adducts to nDNA; these differences were not due to differences in rates of adduct repair. Whereas HNSCC cell cytoplasts free of nDNA retained the same dose-dependent cisplatin sensitivity as parental cells, HNSCC ρ0 cells free of mtDNA were 4- to 5-fold more resistant to cisplatin than parental cells. Isolated mitochondria released cytochrome c within minutes of exposure to cisplatin, and ultrastructural analysis of intact HNSCC cells by electron microscopy showed marked mitochondrial disruption after 4 hours of cisplatin treatment, whereas the nucleus and other cellular structures remain intact. The very prompt release of cytochrome c from isolated mitochondria implies that apoptosis does not require alteration in mitochondrial gene transcription. Further, cisplatin binds preferentially to mitochondrial membrane proteins, particularly the voltage-dependent anion channel.

Conclusions: Cisplatin binding to nDNA is not necessary for induction of apoptosis in HNSCC, which can result from direct action of cisplatin on mitochondria.
Improvement in Determination of Ice Water Content from Two-Dimensional Particle Imagery. Part I: Image-to-Mass Relationships
Authors: Baker Brad , Lawson R. Paul
Published: October 2006

Ice water content in natural clouds is an important but difficult quantity to measure. The goal of a number of past studies was to find average relationships between the masses and lengths of ice particles to determine ice water content from in situ data, such as those routinely recorded with two-dimensional imaging probes. The general approach in these past studies was to measure maximum length L and mass M of a dataset of ice crystals collected at a ground site. Linear regression analysis was performed on the logarithms of the data to estimate an average mass-to-length relationship of the form M = αLβ. Relationships were determined for subsets of the dataset based on crystal habit (shape) as well as for the full dataset. In this study, alternative relationships for determining mass using the additional parameters of width W, area A, and perimeter P are explored. A 50% reduction in rms error in the determination of mass relative to using L alone is achieved using a single parameter that is a combination of L, W, A, and P. The new parameter is designed to take into account the shape of the ice particle without the need to classify the crystals first. An interesting result is that, when applied to the test dataset, the same reduction in rms error is also shown to be achievable using A alone. Using A alone facilitates the reanalysis and improvement of the determination of ice water content from large existing datasets of two-dimensional images, because A is simply the number of occulted pixels in the digital images. Possible sources of error in this study are investigated, as is the usefulness of first segregating the particles into crystal habits.
Numerical Simulations of the Wake of Kauai
Authors: Lane Todd P. , Sharman Robert D. , Frehlich Rod G. , Brown John M.
Published: October 2006

This study uses a series of numerical simulations to examine the structure of the wake of the Hawaiian island of Kauai. The primary focus is on the conditions on 26 June 2003, which was the day of the demise of the Helios aircraft within Kauai’s wake. The simulations show that, in an east-northeasterly trade wind flow, Kauai produces a well-defined wake that can extend 40 km downstream of the island. The wake is bounded to the north and south by regions of strong vertical and horizontal shear—that is, shear lines. These shear lines mark the edge of the wake in the horizontal plane and are aligned approximately parallel to the upstream flow direction at each respective height. The highest-resolution simulations show that these shear lines can become unstable and break down through Kelvin–Helmholtz instability. The breakdown generates turbulent eddies that are advected both downstream and into the recirculating wake flow. Turbulence statistics are estimated from the simulation using a technique that analyzes model-derived structure functions. A number of sensitivity studies are also completed to determine the influence of the upstream conditions on the structure of the wake. These simulations show that directional shear controls the tilt of the wake in the north–south plane with height. These simulations also show that at lower incident wind speeds the wake has a qualitatively similar structure but is less turbulent. At higher wind speeds, the flow regime changes, strong gravity waves are generated, and the wake is poorly defined. These results are consistent with previous idealized studies of stratified flow over isolated obstacles.
Development and Testing of Tropical Cyclone Parametric Wind Models Tailored for Midlatitude Application—Preliminary Results
Authors: MacAfee Allan W. , Pearson Garry M.
Published: October 2006

Over the years, researchers have developed parametric wind models to depict the surface winds within a tropical cyclone (TC). Most models were developed using data from aircraft flights into low-latitude (south of 30°N) TCs in the Atlantic Ocean, Gulf of Mexico, and Caribbean Sea. Such models may not adequately reproduce the midlatitude TC wind field where synoptic interaction and acceleration are more pronounced. To tailor these models for midlatitude application, latitude-dependent angular size and shape details were added by using new techniques to set values for model input parameters and by incorporating additional field-shaping procedures. A method to assess the different techniques and field-shaping procedures was developed in which qualitative and quantitative assessment was performed using five parametric models and samples of buoy and 2D surface wind data. Contingency tables and statistical scores such as mean absolute error and bias were used to select the techniques and procedures that create the most realistic depiction of low- and midlatitude TC surface wind fields.
‘Who’s Still Standing?’ A Comment on Antony Duff’s Preconditions of Criminal Liability
Authors: Matravers Matt
Published: October 2006

Antony Duff has argued that an important precondition of criminal liability is that the state has the moral standing to call the offender to account. Conditions of severe social injustice, if allowed or perpetuated by the state, can undermine this standing. Duff’s argument appeals to the ordinary idea that a person’s own behaviour can sometimes negate his standing to call others to account. It is argued that this is an important issue, but that the analogy with individual standing is problematic. Moreover, Duff’s account of standing needs to address two interconnected issues: first, when and in what way the state can lose its standing to call offenders to account, and second, over what range of offences.
Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1
Authors: Yoshida Chikashi , Yoshida Fumiko , Sears Daniel E. , Hart Stephen M. , Ikebe Dai , Muto Akihiko , Basu Subham , Igarashi Kazuhiko , Melo Junia V.
Published: October 2006

The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the Bcr-Abl oncoprotein. We have previously reported that expression of the Bach2 transcription factor, which induces apoptosis in response to oxidative stress, is greatly reduced in CML cells. Because these cells are resistant to apoptosis, we tested whether Bach2 could also be regulated through posttranslational mechanisms that promote inhibition of the apoptotic response to mutagenic stimuli in CML. We found that Bach2 is phosphorylated on S521 via the phosphatidylinositol-3/S6 kinase pathway, and substitution of this site to alanine leads to nuclear accumulation of the protein, indicating that this phosphorylation is important for its subcellular localization. Ectopic expression of the S521 mutant imparts greater impairment to CML cell growth than the wild-type factor. Furthermore, we showed that Bach2 transcriptionally represses heme oxygenase-1, an antiapoptotic factor up-regulated in CML. Because CML cells are known to produce high levels of intracellular reactive oxygen species, overexpression of heme oxygenase-1 resulting from inhibition of Bach2 activity may contribute to their genomic instability and leukemic phenotype.
The crystal structure of superoxide dismutase from Plasmodium falciparum
Authors: Boucher Ian W , Brzozowski Andrzej M , Brannigan James A , Schnick Claudia , Smith Derek J , Kyes Sue A , Wilkinson Anthony J
Published: October 2006

Background

Superoxide dismutases (SODs) are important enzymes in defence against oxidative stress. In Plasmodium falciparum, they may be expected to have special significance since part of the parasite life cycle is spent in red blood cells where the formation of reactive oxygen species is likely to be promoted by the products of haemoglobin breakdown. Thus, inhibitors of P. falciparum SODs have potential as anti-malarial compounds. As a step towards their development we have determined the crystal structure of the parasite's cytosolic iron superoxide dismutase.

Results

The cytosolic iron superoxide dismutase from P. falciparum (Pf FeSOD) has been overexpressed in E. coli in a catalytically active form. Its crystal structure has been solved by molecular replacement and refined against data extending to 2.5 Å resolution. The structure reveals a two-domain organisation and an iron centre in which the metal is coordinated by three histidines, an aspartate and a solvent molecule. Consistent with ultracentrifugation analysis the enzyme is a dimer in which a hydrogen bonding lattice links the two active centres.

Conclusion

The tertiary structure of Pf FeSOD is very similar to those of a number of other iron-and manganese-dependent superoxide dismutases, moreover the active site residues are conserved suggesting a common mechanism of action. Comparison of the dimer interfaces of Pf FeSOD with the human manganese-dependent superoxide dismutase reveals a number of differences, which may underpin the design of parasite-selective superoxide dismutase inhibitors.
The PedsQL™ Present Functioning Visual Analogue Scales: preliminary reliability and validity
Authors: Sherman Sandra A , Eisen Sarajane , Burwinkle Tasha M , Varni James W
Published: October 2006

Background

The PedsQL™ Present Functioning Visual Analogue Scales (PedsQL™ VAS) were designed as an ecological momentary assessment (EMA) instrument to rapidly measure present or at-the-moment functioning in children and adolescents. The PedsQL™ VAS assess child self-report and parent-proxy report of anxiety, sadness, anger, worry, fatigue, and pain utilizing six developmentally appropriate visual analogue scales based on the well-established Varni/Thompson Pediatric Pain Questionnaire (PPQ) Pain Intensity VAS format.

Methods

The six-item PedsQL™ VAS was administered to 70 pediatric patients ages 5–17 and their parents upon admittance to the hospital environment (Time 1: T1) and again two hours later (Time 2: T2). It was hypothesized that the PedsQL™ VAS Emotional Distress Summary Score (anxiety, sadness, anger, worry) and the fatigue VAS would demonstrate moderate to large effect size correlations with the PPQ Pain Intensity VAS, and that patient" parent concordance would increase over time.

Results

Test-retest reliability was demonstrated from T1 to T2 in the large effect size range. Internal consistency reliability was demonstrated for the PedsQL™ VAS Total Symptom Score (patient self-report: T1 alpha = .72, T2 alpha = .80; parent proxy-report: T1 alpha = .80, T2 alpha = .84) and Emotional Distress Summary Score (patient self-report: T1 alpha = .74, T2 alpha = .73; parent proxy-report: T1 alpha = .76, T2 alpha = .81). As hypothesized, the Emotional Distress Summary Score and Fatigue VAS were significantly correlated with the PPQ Pain VAS in the medium to large effect size range, and patient and parent concordance increased from T1 to T2.

Conclusion

The results demonstrate preliminary test-retest and internal consistency reliability and construct validity of the PedsQL™ Present Functioning VAS instrument for both pediatric patient self-report and parent proxy-report. Further field testing is required to extend these initial findings to other ecologically relevant pediatric environments.
Adiponectin Concentration in Umbilical Cord Serum Is Positively Associated with the Weight Ratio of Fetus to Placenta
Authors: Kadowaki Kozo , Waguri Masako , Nakanishi Isao , Miyashita Yoshihiro , Nakayama Masahiro , Suehara Noriyuki , Funahashi Tohru , Shimomura Iichiro , Fujita Tomio
Published: October 2006

Context: Adiponectin (APN) concentration in umbilical cord serum is higher than that in adult serum. Except for the positive association between birth weight and cord APN concentration, little is known about the pathophysiological function of APN in fetal development.

Objective: The objective of this study was to evaluate the relationship of cord serum APN and IGF-I concentrations with the development of the fetoplacental unit.

Design and Methods: Umbilical cord serum APN and IGF-I concentrations were measured in term singleton deliveries (n = 94). The association of cord APN and IGF-I concentrations was evaluated in relation to fetal weight, placental weight, and fetoplacental (F/P) weight ratio.

Results: Mean concentrations and sd of APN and IGF-I were 36.1 ± 14.0 μg/ml and 58.6 ± 27.0 ng/ml, respectively. Cord APN concentration was positively associated with F/P weight ratio (r = 0.375, P < 0.001) as well as fetal weight (r = 0.389, P < 0.001) but not placental weight. Cord IGF-I concentration was positively associated with fetal weight (r = 0.405, P < 0.001) and placental weight (r = 0.400, P < 0.001) but not F/P weight ratio. In multiregression analysis, only APN concentration resulted in a significant determinant of F/P weight ratio among variables (β = 0.376, P < 0.001).

Conclusions: In cord hyperadiponectinemia, fetuses tend to be disproportionately larger for their placental weight and vice versa in cord hypoadiponectinemia. APN is shown to be the first biomarker positively associated with F/P weight ratio.
Temporalis pericranial muscle flap for reconstruction of the lateral face and head
Authors: Renner Gregory , Davis William E. , Templer Jerry
Published: October 2006

Large ablative surgical tissue defects of the lateral face and head can pose a difficult task for the reconstructive surgeon who must choose from among a large variety of possible reparativce techniques. In many situations the temporalis pericranial muscle flap offers the outstanding feature of providing a large amount of soft tissue at no direct expense of donor site skin cover. It is easily obtained and results in negligible functional loss. With care taken to preserve the neurovascular pedicle, this flap may be rotated in multiple directions and even overturned as either surface can receive surface skin closure. The amount of operative time and effort required is much less than for many of the more elaborate reconstructive flaps. Five representative cases are presented.
Diagnostic value of vestibular function tests: An analysis of 200 consecutive cases
Authors: Kumar Arvind , Sutton Dale L.
Published: October 2006

The contribution that vestibular function tests can make in achieving a topographic and etiologic diagnosis is being increasingly questioned. A greater reliance is therefore being placed on audiometeric tests including auditory brain stem tests. Our experience with vestibular testing has been most favorable, using photoelectric nystagmography and the Torok monothermal differential caloric test. This analysis of 200 consecutive cases shows that patients with normal vestibular function can be differentiated with certainty from those with organic disorders. In the latter group the site of lesion could be confirmed with greater than 90% accuracy. The reasons why vestibular tests in general are non‐productive are discussed.
Primary melanoma of the middle ear
Authors: Mckenna Ernest L. , Holmes William F. , Harwick Robert
Published: October 2006

We present a case of a 52‐year‐old white female with what we believe is the first documented example of a primary melanoma of the middle ear. Multiple myringotomies and two tube insertions over a 14‐month period were curried out until frank hemorrhage was encountered on the last one. Middle ear exploration found the lesion to be a primary melanoma. The supposed course of her diseased ear is discussed as regards the lag between effusion and frank blood when tumor was finally hit on the last myringotomy.
Bell's palsy: The steroid controversy revisited
Authors: Burgess Lawrence P. A. , Yim Donald W. S. , Lepore Michael L.
Published: October 2006

The treatment of Bell's palsy with steroids is controversial. Several series of patients have shown steroids to be beneficial to a statistically significant degree; however, their experimental design was of poor quality and made this data less clinically valuable. The negative trials showing no benefit with steroids did not examine enough patients to have a chance to show a clinically important difference. These series must be considered as partially completed studies and not as conclusive negative trials. A Type I error analysis is the accepted method of statistically analyzing the data of these trials. After reviewing the evidence, it becomes clear that further scientific research is needed.
Relationship of optic neuritis to disease of the paranasal sinuses
Authors: Rothstein Jack , Maisel Robert H. , Berlinger Norman T. , Wirtschafter Jonathan D.
Published: October 2006

The relationship of paranasal sinusitis to optic neuritis remains an intriguing curiosity to both the otolaryngologist and the ophthalmologist. The literature is replete with anecdotal case reports of patients whose sinusitis appears to have caused optic neuritis. There is much speculation about the pathophysiological mechanisms which relate these two distinct disease entities. Five new cases are described which highlight distinct pathophysiologic routes through which paranasal sinus disease has caused optic neuritis. These include compressive optic neuropathy secondary to mucoceles and/or pyoceles; direct extension of sinus infection to the optic nerve from suppurative paranasal sinusitis; and, in one case, from osteomyelitis of the ethmoid and sphenoid sinuses. The usefulness of computerized axial tomography of the orbits and paranasal sinuses to evaluate optic neuritis and to elucidate in detail the pathophysiology of its relationship to disease of the paranasal sinuses is emphasized.

Currently, optic neuritis is felt to be a rare complication of paranasal sinusitis. Paranasal sinus surgery is advocated in those cases where sinus suppuration is suspected, or when a compressive optic neuropathy is caused by a sinus mucocele or pyoeele. Since in most cases, however, optic neuritis is self‐limited, it is difficult to evaluate the results of surgery in circumstances other than those mentioned already. Continued careful evaluation, management, and documentation of this group of patients is necessary to help better define the relationship between these two disease entities.
Neuronal Activity of Histaminergic Tuberomammillary Neurons During Wake–Sleep States in the Mouse
Authors: Takahashi Kazumi , Lin Jian-Sheng , Sakai Kazuya
Published: October 2006

Using extracellular single-unit recordings alone and in combination with neurobiotin juxtacellular labeling and histamine immunohistochemistry, we have identified, for the first time in nonanesthetized, head-restrained mice, histamine neurons in the tuberomammillary nuclei of the posterior hypothalamus. They are all characterized by triphasic broad action potentials. They are active only during wakefulness, and their activity is related to a high level of vigilance. During waking states, they display a slow (<10 Hz) tonic, repetitive, irregular firing pattern. Their activity varies in the different waking states, being lowest during quiet waking, moderate during active waking, and highest during attentive waking. They cease firing during quiet waking before the onset of EEG synchronization, the EEG sign of sleep (drowsy state), and remain silent during slow-wave sleep and paradoxical (or rapid eye movement) sleep. They exhibit a pronounced delay in firing during transitions from sleep to wakefulness or remain quiescent during the same transitions if the animals are not fully alert. They either respond with a long delay, or do not respond, to an arousing stimulus if the stimulus does not elicit an overt alert state. These data support the view that the activity of histaminergic tuberomammillary neurons plays an important role, not in the induction of wakefulness per se, but in the maintenance of the high level of vigilance necessary for cognitive processes. Conversely, cessation of their activity may play an important role in both the initiation and maintenance of sleep.
A New Compartment at Stereocilia Tips Defined by Spatial and Temporal Patterns of Myosin IIIa Expression
Authors: Schneider Mark E. , Dosé Andréa C. , Salles Felipe T. , Chang Weise , Erickson Floyd L. , Burnside Beth , Kachar Bechara
Published: October 2006

Class III myosins are motor proteins that contain an N-terminal kinase domain and a C-terminal actin-binding domain. We show that myosin IIIa, which has been implicated in nonsyndromic progressive hearing loss, is localized at stereocilia tips. Myosin IIIa progressively accumulates during stereocilia maturation in a thimble-like pattern around the stereocilia tip, distinct from the cap-like localization of myosin XVa and the shaft localization of myosin Ic. Overexpression of deletion mutants for functional domains of green fluorescent protein (GFP)–myosin IIIa shows that the motor domain, but not the actin-binding tail domain, is required for stereocilia tip localization. Deletion of the kinase domain produces stereocilia elongation and bulging of the stereocilia tips. The thimble-like localization and the influence myosin IIIa has on stereocilia shape reveal a previously unrecognized molecular compartment at the distal end of stereocilia, the site of actin polymerization as well as operation of the mechanoelectrical transduction apparatus.
Optimal Taxation of Bequests
Authors: Beckmann Klaus B.
Published: October 2006

A critique of Kaplow's (2001) optimal taxation (OT) framework for assessing inheritance taxation is outlined in this paper. Several points are raised, the most important one being that Kaplow's central result cannot be extrapolated to the important case of altruism very easily. Several formal problems of modelling altruism are discussed. Finally, I propose a simple OT model which can justify a marginal subsidy of bequests, and point out the limits of this approach.
Book Reviews
Authors: Genchev Vassil , Kelen András , Berenson Dekel
Published: October 2006

Damien Kingsbury et al.: Key Issues in Development. (Houndmills: Palgrave Macmillan, 2004, 336 pp.) Rev. by Vassil Genchev. (2) Ádám Török - Balázs Borsi - András Telcs: Competitiveness in Research and Development; Comparisons and Performanc. (Cheltenham: Edward Elgar Publishing Ltd, 2005, 251 pp.) Rev. by András Kelen. (3) Bernardo Bortolotti - Domenico Siniscalco. The Challenges of Privatisation: An International Analysis (London: Oxford University Press, 2004, 160 pp.) Rev. by Dekel Berenson.
Shaping different carbon nano- and submicro-structures by alcohol chemical vapor deposition
Authors: Zhao Z.G. , Bai S. , Ying Z. , Bai Jin-Bo , Cheng H.M.
Published: October 2006

A variety of carbon nano- and submicro-structures with spectacular morphologies such as spaghetti-like, dendritic, and segmented carbon fibers; carbon pillars; and single-walled carbon nanotubes (SWNTs) was selectively synthesized by the alcohol chemical vapor deposition (CVD) method. The phase structure and morphologies were investigated by scanning electron microscopy (SEM), transmission electron microscopy (TEM), selected-area electron diffraction (SAED), and Raman spectroscopy. The carbon structures could be controlled by adjusting the deposition position and the growth temperature. The formation mechanism of these carbon structures was discussed on the basis of the experimental results. The various CVD products obviously imply that the growth mechanism for our alcohol CVD process evolves from catalytic growth mode to pyrolytic carbon deposition mode. The obtained various carbon nano- and submicro-structures may be promising for applications in functional nanodevices.
In situ transmission electron microscope study of interface sliding and migration in an ultrafine lamellar structure
Authors: Hsiung L.M. , Zhou J. , Nieh T.G.
Published: October 2006

The instability of interfaces in an ultrafine TiAl-(γ)/Ti3Al-(α2) lamellar structure by straining at room temperature has been investigated using in situ straining techniques performed in a transmission electron microscope. The purpose of this study was to obtain experimental evidence to support the creep mechanisms based upon the interface sliding in association with a cooperative movement of interfacial dislocations, which was proposed previously to rationalize a nearly linear creep behavior of ultrafine lamellar TiAl alloys. The results reveal that the sliding and migration of lamellar interfaces can take place simultaneously as a result of the cooperative movement of interfacial dislocations, which can lead to an adverse effect in the performance of ultrafine lamellar TiAl alloy.
Oxidation of silicon carbide and the formation of silica polymorphs
Authors: Guinel Maxime J-F. , Norton M. Grant
Published: October 2006

The oxidation of both single crystal and relatively pure polycrystalline silicon carbide, between 973 and 2053 K, resulted in the formation of cristobalite, quartz, or tridymite, which are the stable crystalline polymorphs of silica (SiO2) at ambient pressure. The oxide scales were found to be pure SiO2 with no contamination resulting from the oxidizing environment. The only variable affecting the occurrence of a specific polymorph was the oxidation temperature. Cristobalite was formed at temperatures ≥1673 K, tridymite between 1073 and 1573 K, and quartz formed at 973 K. The polymorphs were determined using electron diffraction in a transmission electron microscope. These results were further confirmed using infrared and Raman spectroscopies. Cristobalite was observed to grow in a spherulitic fashion from amorphous silica. This was not the case for tridymite and quartz, which appeared to grow as oriented crystalline films. The presence of a thin silicon oxycarbide interlayer was detected at the interface between the SiC substrate and the crystalline silica using x-ray photoelectron spectroscopy.
Agent-Based Modeling of Drinking Behavior: A Preliminary Model and Potential Applications to Theory and Practice
Authors: Gorman Dennis M. , Mezic Jadranka , Mezic Igor , Gruenewald Paul J.
Published: October 2006

Objectives. We developed a preliminary agent-based simulation model designed to examine agent–environment interactions that support the development and maintenance of drinking behavior at the population level.

Methods. The model was defined on a 1-dimensional lattice along which agents might move left or right in single steps at each iteration. Agents could exchange information about their drinking with each other. In the second generation of the model, a “bar” was added to the lattice to attract drinkers.

Results. The model showed that changes in drinking status propagated through the agent population as a function of probabilities of conversion, rates of contact, and contact time. There was a critical speed of population mixing beyond which the conversion rate of susceptible nondrinkers was saturated, and the bar both enhanced and buffered the rate of propagation, changing the model dynamics.

Conclusions. The models demonstrate that the basic dynamics underlying social influences on drinking behavior are shaped by contacts between drinkers and focused by characteristics of drinking environments.
Population-Level Changes in Folate Intake by Age, Gender, and Race/Ethnicity after Folic Acid Fortification
Authors: Bentley Tanya G.K. , Willett Walter C. , Weinstein Milton C. , Kuntz Karen M.
Published: October 2006

Objectives. We sought to quantify the impact of the 1998 US Food and Drug Administration (FDA) folic acid fortification policy by estimating folate intake at the population level.

Methods. We analyzed total folate intake levels (from food and supplements) according to gender, age, and race/ethnicity, using data from 2 National Health and Nutrition Examination Surveys. We measured pre- and postfortification folate intake distributions, adjusted for measurement error, and examined proportions of the population who reached certain thresholds of daily total folate intake.

Results. Mean daily food and total folate intake increased by approximately 100 μg/day after fortification. The proportion of women aged 15–44 years who consume more than 400 μg/day of folate has increased since fortification, but has not yet reached the FDA’s 50% target and varies by race/ethnicity from 23% to 33%. Among persons aged 65 years and older who may be at risk for masking a vita-μg/day (the min B12 deficiency, the percentage who consume more than 1000 “tolerable upper intake level”) has at least doubled among Whites and Black men, but has remained less than 5% for all groups.

Conclusions. Since fortification, folic acid intake among the US population has increased, and there are substantial variations by age, gender, and race/ethnicity.
Genes, Race, and Population: Avoiding a Collision of Categories
Authors: Kahn Jonathan
Published: October 2006

A wide array of federal mandates have a profound impact on the use of racial and ethnic categories in biomedical research, clinical practice, product development, and health policy. Current discussions over the appropriate use of racial and ethnic categories in biomedical contexts have largely focused on the practices of individual researchers.

By contrast, our discussion focuses on relations between the daily practices of biomedical professionals and federal regulatory mandates. It draws upon the legal doctrine of equal protection to move beyond such debates and to propose guidelines to address the structural forces imposed by federal regulations that mandate how data about race and ethnicity are used in biomedical research. It offers a framework to manage the tension involved in using existing federally mandated categories of race and ethnicity alongside new scientific findings about human genetic variation.
Public Willingness to Participate in and Public Opinions About Genetic Variation Research: A Review of the Literature
Authors: Sterling Rene , Henderson Gail E. , Corbie-Smith Giselle
Published: October 2006

Scientists are turning to genetic variation research in hopes of addressing persistent racial/ethnic disparities in health. Despite ongoing controversy, the advancement of genetic variation research is likely to produce new knowledge and technologies that will substantially change the ways in which we understand and value health. They also may affect the ways in which individuals and groups organize socially, politically, and economically.

Addressing concerns that may exist in different communities is vital to the scientific and ethical advancement of genetic variation research. We review empirical studies of public willingness to participate in and opinions about genetic research with particular attention to differences in consent and opinion by racial/ethnic group membership.
Voluntary Participation and Informed Consent to International Genetic Research
Authors: Marshall Patricia A. , Adebamowo Clement A. , Adeyemo Adebowale A. , Ogundiran Temidayo O. , Vekich Mirjana , Strenski Teri , Zhou Jie , Prewitt T. Elaine , Cooper Richard S. , Rotimi Charles N.
Published: October 2006

Objectives. We compared voluntary participation and comprehension of informed consent among individuals of African ancestry enrolled in similarly designed genetic studies of hypertension in the United States and Nigeria.

Methods. Survey questionnaires were used to evaluate factors associated with voluntariness (the number of people volunteering) and understanding of the study’s genetic purpose. A total of 655 individuals (United States: 348; Nigeria: 307) were interviewed after participation in the genetic studies.

Results. Most US respondents (99%), compared with 72% of Nigerian respondents, reported being told the study purpose. Fewer than half of the respondents at both sites reported that the study purpose was to learn about genetic inheritance of hypertension. Most respondents indicated that their participation was voluntary. In the United States, 97% reported that they could withdraw, compared with 67% in Nigeria. In Nigeria, nearly half the married women reported asking permission from husbands to enroll in the hypertension study; no respondents sought permission from local elders to participate in the study.

Conclusions. Our findings highlight the need for more effective approaches and interventions to improve comprehension of consent for genetic research among ethnically and linguistically diverse populations in all settings.
Addressing the scheduling of chemical supply chains under demand uncertainty
Authors: Guillén Gonzalo , Espuña Antonio , Puigjaner Luis
Published: October 2006

A multistage stochastic optimization model is presented to address the scheduling of supply chains with embedded multipurpose batch chemical plants under demand uncertainty. In order to overcome the numerical difficulties associated with the resulting large‐scale stochastic mixed‐integer‐linear‐programming (MILP) problem, an approximation strategy comprising two steps, and based on the resolution of a set of deterministic and two‐stage stochastic models is presented. The performance of the proposed strategy regarding computation time and optimality gap is studied through comparison with other traditional approaches that address optimization under uncertainty. Results indicate that the proposed strategy provides better solutions than stand‐alone two‐stage stochastic programming and two‐stage shrinking‐horizon algorithms for similar computational efforts and incurs much lower computation times than the rigorous multistage stochastic model. © 2006 American Institute of Chemical Engineers AIChE J, 2006
Biochemical markers of bone turnover in diagnosis of myeloma bone disease
Authors: Dizdar Omer , Barista Ibrahim , Kalyoncu Umut , Karadag Omer , Hascelik Gulsen , Cila Aysenur , Pinar Asli , Celik Ismail , Kars Ayse , Tekuzman Gulten
Published: October 2006

This study was designed to explore the value of markers of bone turnover, macrophage inflammatory protein‐1α (MIP‐1α), and osteopontin (OPN) in the diagnosis of myeloma bone disease. Twenty‐five patients with newly diagnosed and untreated multiple myeloma (MM), and 22 age‐, sex‐, and bone mineral density‐matched control subjects were enrolled. Levels of MIP‐1α, OPN, carboxy‐terminal telopeptide of Type‐1 collagen (C‐telopeptide or Ctx), deoxypyridinoline (DPD), Type‐1 collagen propeptide (T1Pro), and bone‐specific alkaline phosphatase (BALP) were assessed in both groups. Twenty‐two of the patients had bone involvement documented by skeletal surveys and lumbar spinal magnetic resonance imaging. Levels of serum Ctx, OPN, MIP‐1α, and urine DPD were significantly higher in MM patients with bone disease than in controls (P < 0.01). Serum Ctx levels were elevated in 90.9% of patients with MM and 40.9% of controls (P < 0.001). Urine DPD levels were elevated in 90.4% of the patients and 31.8% of the controls (P < 0.001). The serum OPN and MIP‐1α levels of the patients were significantly correlated with β2‐microglobulin and lactate dehydrogenase levels (P < 0.05). Our study indicates that Ctx and DPD are sensitive markers of bone disease in MM, and higher than normal values suggest presence of bone disease rather than benign osteoporosis in MM. The utility of OPN and MIP‐1α needs to be further investigated. Am. J. Hematol., 2007. © 2006 Wiley‐Liss, Inc.
Diagnostic yield of chromosome analysis in patients with developmental delay or mental retardation who are otherwise nondysmorphic
Authors: Macayran Joanne F. , Cederbaum Stephen D. , Fox Michelle A.
Published: October 2006

There is a standard recommendation that chromosomes be obtained in any patient who presents with developmental delay (DD) or mental retardation (MR) regardless of whether or not they have dysmorphic features. Increasingly, if patients are physically well‐formed, the option to perform a karyotype is questioned because of the presumed low yield of a chromosomal abnormality. We hypothesize that patients with DD/MR who are non‐dysmorphic do not have abnormal chromosomes at a rate high enough to warrant obtaining a karyotype on all patients in this population. A retrospective analysis of patients with DD/MR who were non‐dysmorphic was performed. The total number of subjects was 134. Of these, 120 patients were recommended to have high‐resolution chromosomes performed, among whom seven were lost to follow‐up. In the remaining 113 patients, all had normal karyotypes. Three subjects were found to have fragile X syndrome, accounting for 3% of the males. One subject had a pathological mutation in MECP2. Our yield of chromosome analysis in non‐dysmorphic patients with DD/MR is less than that previously described. The role of array‐comparative genomic hybridization (array‐CGH) as an auxiliary or alternative procedure in this patient population will be discussed. © 2006 Wiley‐Liss, Inc.