bluuebunny/crossref_metadata_2025 huggingface dataset:
VIRTUAL ACTIVE NETWORK FOR LIVE STREAMING MEDIA DELIVERY
Authors: LI WEN-SYAN , AGRAWAL DIVYAKANT , CANDAN K. SELÇUK , AKCA YUSUF , KANTARCIOGLU MURAT
Published: April 2007

The large amount of bandwidth and other resources required to deliver streaming media limits the number of concurrent users. We propose a virtual active network (VAN) architecture for streaming media data delivery over wide area networks. In the proposed architecture, cooperating proxies support multiplexing and delivery of live streaming media. The hierarchical delivery structure is dynamically adjusted based on user population distribution, usage patterns, and network conditions. The proposed system architecture provides (1) reliable and high quality live streaming media delivery; (2) lower server resource requirements at the content provider sites; (3) reduced inter-ISP traffic; (4) application level routing for rapid deployment; and (5) cost-effective media data delivery. To deal with one characteristics of live broadcasting events, burst traffic at the beginning of the events, our system features a unique function that dynamically clusters multiple proxy servers to form a server farm to handle a large number of user login events when needed. Experimental results show that the proposed VAN architecture consistently delivers reliable live data streams using resources within 10 percent of the theoretically possible lower bound. The experimental results also show the effectiveness of our load balance algorithms to handle various user patterns, server capacity, and network congestion events.
Relative systolic dysfunction in female spontaneously hypertensive rat myocardium
Authors: Renna Brian F. , MacDonnell Scott M. , Reger Patricia O. , Crabbe Deborah L. , Houser Steven R. , Libonati Joseph R.
Published: April 2007

Hypertension and exercise independently induce left ventricular (LV) remodeling and alter LV function. The purpose of this study was to determine systolic and diastolic LV pressure-volume relationships (LV-PV) in spontaneously hypertensive rats (SHR) with and without LV hypertrophy, and to determine whether 6 mo of exercise training modified the LV-PV in SHR. Four-month-old female SHR ( n = 20), were assigned to a sedentary (SHR-SED) or treadmill-trained (SHR-TRD) group (∼60% peak O2 consumption, 5 days/wk, 6 mo), while age-matched female Wistar-Kyoto rats (WKY; n = 13) served as normotensive controls. The LV-PV was determined using a Langendorff isolated heart preparation at 4 (no hypertrophy: WKY, n = 5; SHR, n = 5) and 10 mo of age (hypertrophy: WKY, n = 8; SHR-SED, n = 8; SHR-TRD, n = 7). At 4 mo, the LV-PV in SHR was similar to that observed in WKY controls. However, at 10 mo of age, a rightward shift in the LV-PV occurred in SHR. Exercise training did not alter the extent of the shift in the LV-PV relative to SHR-SED. Relative systolic function, i.e., relative systolic elastance, was ∼50% lower in SHR than WKY at 10 mo of age ( P < 0.05). Doppler-derived LV filling parameters [early wave (E), atrial wave (A), and the E/A ratio] were similar between groups. LV capacitance was increased in SHR at 10 mo ( P < 0.05), whereas LV diastolic chamber stiffness was similar between groups at 10 mo. Hypertrophic remodeling at 10 mo of age in female SHR is manifest with relative systolic decompensation and normal LV diastolic function. Exercise training did not alter the LV-PV in SHR.
Systematics and phylogeny of West African gerbils of the genus Gerbilliscus (Muridae: Gerbillinae) inferred from comparative G- and C-banding chromosomal analyses
Authors: Volobouev V. , Aniskin V.M. , Sicard B. , Dobigny G. , Granjon L.
Published: April 2007

Comparative analysis of the G- and C-banding patterns in six morphologically similar species of the genus Gerbilliscus(G. gambianus, G. guineae, G. kempi, Gerbilliscus sp., G. robustus and G. leucogaster) and one belonging to the genus Gerbillurus (G. tytonis) from 27 West, East and South African localities was carried out. Our study revealed that 17 rearrangements comprising seven fissions, five translocations and five inversions occurred in the evolution of this group, with 1–13 rearrangements differentiating the various species. In addition the unusually large sex chromosomes appear to be species-specific as judged by size and morphology reflecting structural rearrangements as well as the variable presence of a large amount of C-heterochromatin found in each species at a particular chromosomal location. These karyotypic features allow us to recognize five distinct species in West Africa (compared to the two recognized in recent taxonomic lists) and to roughly delimit their geographical distributions. The pattern of phylogenetic relationships inferred from a cladistic analysis of the chromosomal data is in good agreement with recent molecular phylogenetic studies that recognize a West African species group within the genus Gerbilliscus, and the monophyly of both Gerbilliscus and Gerbillurus.
Pseudodicentric 22;Y translocation transmitted through four generations of a large family without phenotypic repercussion
Authors: Morales C. , Soler A. , Bruguera J. , Madrigal I. , Alsius M. , Obon M. , Margarit E. , Sánchez A.
Published: April 2007

The most frequent Y-autosome translocations involve an acrocentric autosome and they are frequently familial with neither phenotypic nor reproductive repercussion. However, different Y-autosome translocations have been related to infertility, due to abnormal pairing of the X and Y chromosomes at meiosis and an abnormal XY-body formation or by the disruption of the AZFs (Azoospermic Factor). Rare forms of Y-autosome translocations are those resulting in an unbalanced 45-chromosome karyotype that includes a dicentric Y+autosome chromosome. We describe a new case of a familial pseudodicentric 22;Y that is carried by 19 male members of a large family without phenotypic repercussion. Cytogenetic analysis, fluorescence in situ hybridisation (FISH) and subtelomeric Multiplex Ligation-dependent Probe Amplification (MLPA) assay have been performed. All male members of the family showed the karyotype 45,X,psu dic(22;Y)(p11.2;qter).ish psu dic(22;Y) (SRY+,DYZ3+,D14/D22Z1+). In conclusion, the presence of the dicentric chromosome in the male members of the family reported does not seem to interfere with the correct progression of spermatogenesis.
Long-Term Benefits of Inhaled Tobramycin in Children with Cystic Fibrosis: First Clinical Observations from Poland
Authors: Stelmach Iwona , Korzeniewska Aleksandra , Stelmach Włodzimierz
Published: April 2007

Background: Respiratory disease is the major cause of mortality in cystic fibrosis (CF) patients and inhaled antibiotic therapy may contribute to the stabilization of lung function. Objectives: This is a small, open, uncontrolled, observational study of clinical experience obtained with 2 years of maintenance treatment with inhaled tobramycin in 12 children and adolescents with CF. Methods: Twelve subjects aged 6–18 years infected by Pseudomonas aeruginosa were qualified for treatment with inhaled tobramycin. Pulmonary function, weight and height, clinical status, and chest X-ray were continually monitored. After an active 2-year treatment period, results of all measured parameters in our patients were compared with their previous results (2-year period before treatment with tobramycin). Results: During 2 years before treatment with tobramycin solution for inhalation (TOBI), pulmonary function decline was observed, the median value of FEV1 change was –7.6% (lower quartile –13.1, upper quartile –5.9). After 2 years of treatment, FEV1 percent predicted value declined by 1.5% (lower quartile –11.1, upper quartile 3.7) from baseline; 2 years of TOBI therapy significantly reduced lung function decline (p = 0.049). There were no significant changes in thoracic gas volume and specific airway resistance before and after treatment. Two years of TOBI therapy significantly improved body mass index (p = 0.02). TOBI treatment significantly delayed progression of pulmonary X-ray changes assessed by Brasfield score (p = 0.02). Conclusions: We found that patients with CF can gain substantial benefits from long-term TOBI treatment, including reduced pulmonary function decline, delayed progression of pulmonary X-ray changes and improved weight gain in growing children and adolescents.
Mechanisms of TGF-β
1
–Induced Intimal Growth
Authors: Otsuka Goro , Stempien-Otero April , Frutkin Andrew D. , Dichek David A.
Published: April 2007

Transforming growth factor (TGF)-β
1
is a potent stimulator of intimal growth. We showed previously that TGF-β
1
stimulates intimal growth through early upregulation of plasminogen activator inhibitor-1 (PAI-1) and, subsequently, PAI-1–dependent increases in cell migration and matrix accumulation. We also showed that PAI-1 negatively regulates TGF-β
1
expression in the artery wall. Here we use plasminogen-deficient mice to test whether TGF-β
1
–stimulated, PAI-1–dependent intimal growth and PAI-1 suppression of TGF-β
1
expression are mediated through inhibition of plasminogen activation by PAI-1. We also use lineage tracing to investigate the origin of cells in TGF-β
1
–induced intimas. Surprisingly, both TGF-β
1
–induced, PAI-1–dependent intimal growth and PAI-1 suppression of TGF-β
1
expression are independent of plasminogen. Moreover, approximately 50% of cells that migrate into the intima of TGF-β
1
–overexpressing arteries carry a smooth muscle lineage marker, <1% carry a bone marrow lineage marker, and the remaining cells carry neither marker. Therefore, PAI-1 stimulates intimal growth and suppresses TGF-β
1
expression through activities other than inhibition of plasminogen activation. In addition, contrary to widely held models, our results do not support a role for plasmin (or thrombospondin) in TGF-β
1
activation in the artery wall. Further identification of the molecular targets through which PAI-1 stimulates intimal formation and suppresses TGF-β
1
expression in the artery wall may reveal new approaches for inhibiting intimal formation. Our studies also discount bone marrow as an important source from which TGF-β
1
recruits intimal cells and suggest instead that TGF-β
1
induces substantial cell migration either from the adventitia or from an extravascular, but nonhematopoietic source.
Elevated Lp-PLA
2
Levels Add Prognostic Information to the Metabolic Syndrome on Incidence of Cardiovascular Events Among Middle-Aged Nondiabetic Subjects
Authors: Persson Margaretha , Hedblad Bo , Nelson Jeanenne J. , Berglund Göran
Published: April 2007

Background—

To explore potential interrelationships between lipoprotein-associated phosholipase A2 (Lp-PLA
2
)
,
the metabolic syndrome (MetS), and incident cardiovascular disease (CVD).

Methods and Results—

MetS was defined by the National Cholesterol Education Program Adult treatment Panel III criteria in 4480 nondiabetic Malmö Diet and Cancer Study subjects without history of CVD. Incidence of first CVD event (stroke [130 cases] or myocardial infarction [131]) was monitored over 10 years of follow-up. Lp-PLA
2
activity and mass were significantly higher in subjects with MetS. Lp-PLA
2
activity compared with Lp-PLA
2
mass was more strongly correlated to individual components and increased more linearly with number of MetS components. Elevated Lp-PLA
2
activity (top compared with bottom tertile), but not elevated Lp-PLA
2
mass, increased risk for incident CVD (relative risk, RR: 1.54, 95% CI 1.07 to 2.24), as did MetS (1.42, 1.06 to 1.90) after taking possible confounders into account. Relative to those without either elevated Lp-PLA
2
activity or MetS, combination of MetS and elevated Lp-PLA
2
activity increased risk for CVD (1.97, 1.34 to 2.90). Elevated Lp-PLA
2
activity without MetS increased risk for CVD (1.40, 1.03 to 1.92) but not MetS without elevated Lp-PLA
2
activity (1.46, 0.94 to 2.27).

Conclusion—

Lp-PLA
2
is associated to the MetS. Higher plasma levels of Lp-PLA
2
increased risk for incident CVD regardless of MetS. The simultaneous presence of elevated Lp-PLA
2
activity and MetS may identify an especially high risk individual.
Combining Multiple Approaches for the Secondary Prevention of Vascular Events After Stroke
Authors: Hackam Daniel G. , Spence J. David
Published: April 2007

Background and Purpose—

Numerous effective strategies for the secondary prevention of cardiovascular events in high-risk patients have now been established. We sought to calculate the cumulative benefit of combining multiple strategies for preventing recurrent events in patients with a history of ischemic stroke or transient ischemic attack.

Methods—

A comprehensive literature search was undertaken to identify meta-analyses of randomized controlled trials reporting on the efficacy of secondary prevention strategies. The baseline incidence of vascular events was modeled from the Life Long After Cerebral Ischemia study. Strategies were combined on a multiplicative scale and cumulative risk reductions were computed over a 5-year interval.

Results—

The combination of 5 proven strategies applied to survivors of an initial stroke or transient ischemic attack—dietary modification, exercise, aspirin, a statin, and an antihypertensive agent—could result in a cumulative relative risk reduction of 80%. Given a 5-year major cardiovascular event rate of 24%, this translates to a number needed to treat of about 5. Further gains would result from applying multimodality therapy over longer intervals and enriching the base strategy with dual antiplatelet therapy, high-dose statins, and more intensive blood pressure–lowering. Even more benefit would be present in high-risk subgroups with the addition, where appropriate, of carotid endarterectomy, moderate intensity oral anticoagulants, glycemic control, and smoking cessation.

Conclusions—

At least four-fifths of recurrent vascular events in patients with cerebrovascular disease might be prevented by application of a comprehensive, multifactorial approach.
Inferences and Observations of Turbulent Dissipation and Mixing in the Upper Ocean at the Hawaiian Ridge
Authors: Martin Joseph P. , Rudnick Daniel L.
Published: April 2007

The Hawaiian Ridge is one of the most energetic generators of internal tides in the pelagic ocean. The density and current structure of the upper ocean at the Hawaiian Ridge were observed using SeaSoar and Doppler sonar during a survey extending from Oahu to Brooks Banks and up to 200 km from the ridge peak. Survey observations are used to quantify spatial changes in internal-wave-induced turbulent dissipation and mixing. The turbulent dissipation rate of kinetic energy ɛ and diapycnal eddy diffusivity Kρ are inferred from an established parameterization using internal wave shear as input. At the Kauai Channel (KC) and French Frigate Shoals/Brooks Banks sites, ɛ and Kρ decay away from the ridge with maxima exceeding minima by 5 times. At both sites, average Kρ is everywhere greater than the canonical open-ocean value of 10−5 m2 s−1. Along the ridge, ɛ and Kρ vary by up to 100 times and are largest at sites of largest numerical model internal tide energy density. In the eastern KC, Kρ > 10−3 m2 s−1 is typical in a patch more than 200 m thick located above the path of an M2 internal tide ray. An upper limit on the dissipation rate from M2 internal tides to turbulence within 50 km of the Hawaiian Ridge is roughly estimated to be in the range of 4–9 GW. At KC, the depth-integrated internal wave energy density and dissipation rate are positively correlated. Potential density inversions occur near the main ridge axis at significant topographic features. Average Kρ is larger inside inversions.
Bermuda’s Tale of Two Time Series: Hydrostation S and BATS*
Authors: Phillips Helen E. , Joyce Terrence M.
Published: April 2007

This paper describes the oceanic variability at Bermuda between 1989 and 1999, recorded in two overlapping hydrographic time series. Station S and Bermuda Atlantic Time Series Study (BATS), which are 60 km apart, both show that a multidecadal trend of deep warming has reversed, likely as a result of the increased production of Labrador Sea Water since the early 1980s. In addition to recording similar changes in watermass properties, the two time series show similar mean vertical structure and variance as a function of pressure for temperature, salinity, and density above 1500 dbar. The seasonal cycles of these water properties at the two sites are statistically indistinguishable. The time series differ in the individual eddy events they record and in their variability below 1500 dbar. The two time series are used to investigate the propagation of eddy features. Coherence and phase calculated from the low-mode variability of density show westward propagation at ∼3 cm s−1 of wavelengths around 300–500 km. Satellite altimeter data are used to provide a broader spatial view of the eddy (or wave) field near Bermuda.
Deep-Current Variability near the Sigsbee Escarpment in the Gulf of Mexico
Authors: Hamilton Peter
Published: April 2007

Observations of deep currents, from a closely spaced array deployed at the base of the Sigsbee Escarpment, south of the Mississippi Delta, are dominated by energetic, short-period (∼10 days) topographic Rossby waves. Over a 2-yr interval, distinct trains of waves occurred, with differing characteristic periods, wavelengths, and horizontal energy distribution, usually initiated with a burst of large-amplitude current fluctuations that slowly decay over the next 2–3 months. Two of the wave trains were associated with the shedding and westward passage of major Loop Current anticyclones; however, one event occurred when upper-layer currents were quiescent. This latter wave train showed that bottom-trapped topographic wave motions can be traced to within 300 m of the surface in a 2000-m water column. Ray tracing showed that a likely source region of the short-period waves was the west side of an extended Loop Current. The data and ray paths suggest that, through refraction and reflection, the steep escarpment keeps the energetic waves confined to the deep water. These mechanisms help to explain why short-period fluctuations are not observed farther west in the central and western gulf basin.
A Model Analysis of the Behavior of the Mediterranean Water in the North Atlantic
Authors: Jia Yanli , Coward Andrew C. , de Cuevas Beverly A. , Webb David J. , Drijfhout Sybren S.
Published: April 2007

The behavior of the Mediterranean Water in the North Atlantic Ocean sector of a global ocean general circulation model is explored, starting from its entry point at the Strait of Gibraltar. The analysis focuses primarily on one experiment in which explicit watermass exchange between the Mediterranean Sea and the Atlantic at the Strait of Gibraltar is permitted. The model produces an exchange rate of approximately 1 Sv (Sv ≡ 106 m3 s−1). This is comparable to estimates derived from field measurements. The density of the Mediterranean outflow, however, is lower than observed, mainly because of its high temperature (more than 2°C higher than in reality). The lower density of the outflow and the model’s inadequate representation of the entrainment mixing in the outflow region cause the Mediterranean Water to settle in a depth range ∼800–1000 m in the North Atlantic, about 200 m shallower than observed. Here an interesting current system forms in response to the intrusion of the Mediterranean Water, involving three main pathways. In the first, the Mediterranean Water heads roughly westward across the basin and joins the deep western boundary current. In the second, the water travels northward along the eastern boundary reaching as far as Iceland, where it turns westward to participate in the deep circulation of the subpolar gyre. In the third, the water initially moves westward to the central Atlantic just north of 30°N before turning northwestward to reach an upwelling region at the Grand Banks off Newfoundland. At this location, the saline Mediterranean Water is drawn upward to the ocean upper layer and entrained into the North Atlantic Current system flowing to the northeastern basin; part of the current system enters the Nordic seas.
Three-Dimensional Structure of Frontal Waves and Associated Salinity Minimum Formation along the Kuroshio Extension
Authors: Kouketsu Shinya , Yasuda Ichiro , Hiroe Yutaka
Published: April 2007

High-resolution hydrographic observations were conducted in September 2002 to describe the detailed structure of frontal waves along the Kuroshio Extension. Frontal waves were observed both in the upper and intermediate layers, which corresponded to the depths of North Pacific Subtropical Mode Water and North Pacific Intermediate Water, respectively. The frontal wave in the upper layer preceded the intermediate-depth frontal wave by about 1/4 wavelength. The vertical phase lag created situations in which the low-salinity Oyashio water in the intermediate layer was superimposed below the upper-layer high-salinity Kuroshio water, thus forming a vertical salinity minimum. The frontal waves with a wavelength of about 200 km and a phase speed of 0.2–0.3 m s−1 propagating in the downstream direction were consistent with those from satellite images. Vertical velocity fields were estimated with the quasigeostrophic omega equation. Downwelling around the trough (from the crest to trough) of the intermediate-depth (upper layer) frontal wave and upwelling around the crest (from the trough to the crest) were similar to the features observed in the Gulf Stream meanders. The phase difference between the upper and intermediate layers suggested that the frontal waves were baroclinically unstable waves.
Spectral Energy Fluxes in Geostrophic Turbulence: Implications for Ocean Energetics
Authors: Scott Robert B. , Arbic Brian K.
Published: April 2007

The energy pathways in geostrophic turbulence are explored using a two-layer, flat-bottom, f-plane, quasigeostrophic model forced by an imposed, horizontally homogenous, baroclinically unstable mean flow and damped by bottom Ekman friction. A systematic presentation of the spectral energy fluxes, the mean flow forcing, and dissipation terms allows for a comprehensive understanding of the sources and sinks for baroclinic and barotropic energy as a function of length scale. The key new result is a robust inverse cascade of kinetic energy for both the baroclinic mode and the upper layer. This is consistent with recent observations of satellite altimeter data over the South Pacific Ocean. The well-known forward cascade of baroclinic potential and total energy was found to be very robust. Decomposing the spectral fluxes into contributions from different terms provided further insight. The inverse baroclinic kinetic energy cascade is driven mostly by an efficient interaction between the baroclinic velocity and the barotropic vorticity, the latter playing a crucial catalytic role. This cascade can be further enhanced by the baroclinic mode self-interaction, which is only present with nonuniform stratification (unequal layer depths). When model parameters are set such that modeled eddies compare favorably with observations, the inverse baroclinic kinetic energy cascade is actually much stronger than the well-known inverse cascade in the barotropic mode. The upper-layer kinetic energy cascade was found to dominate the lower-layer cascade over a wide range of parameters, suggesting that the surface cascade and time mean density stratification may be sufficient for estimating the depth-integrated cascade from ocean observations. This may find useful application in inferring the kinetic to gravitational potential energy conversion rate from satellite measurements.
Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells
Authors: Rink Lori , Slupianek Artur , Stoklosa Tomasz , Nieborowska-Skorska Margaret , Urbanska Katarzyna , Seferynska Ilona , Reiss Krzysztof , Skorski Tomasz
Published: April 2007

Nbs1, a member of the Mre11-RAD50-Nbs1 complex, is phosphorylated by ATM, the product of the ataxia-telangiectasia mutated gene and a member of the phosphatidylinositol 3-kinase–related family of serine-threonine kinases, in response to DNA double-strand breaks (DSBs) to regulate DNA damage checkpoints. Here we show that BCR/ABL stimulated Nbs1 expression by induction of c-Myc–dependent transactivation and protection from caspase-dependent degradation. BCR/ABL-related fusion tyrosine kinases (FTKs) such as TEL/JAK2, TEL/PDGFβR, TEL/ABL, TEL/TRKC, BCR/FGFR1, and NPM/ALK as well as interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) also stimulated Nbs1 expression. Enhanced ATM kinase–dependent phosphorylation of Nbs1 on serine 343 (S343) in response to genotoxic treatment was detected in leukemia cells expressing BCR/ABL and other FTKs in comparison to normal counterparts stimulated with IL-3, GM-CSF, and SCF. Expression of Nbs1-S343A mutant disrupted the intra–S-phase checkpoint, decreased homologous recombinational repair (HRR) activity, down-regulated XIAP expression, and sensitized BCR/ABL-positive cells to cytotoxic drugs. Interestingly, inhibition of Nbs1 phosphorylation by S343A mutant enhanced the antileukemia effect of the combination of imatinib and genotoxic agent.
Disruption of palladin leads to defects in definitive erythropoiesis by interfering with erythroblastic island formation in mouse fetal liver
Authors: Liu Xue-Song , Li Xi-Hua , Wang Yi , Shu Run-Zhe , Wang Long , Lu Shun-Yuan , Kong Hui , Jin Yue-E , Zhang Li-Jun , Fei Jian , Chen Sai-Juan , Chen Zhu , Gu Ming-Min , Lu Zhen-Yu , Wang Zhu-Gang
Published: April 2007

Palladin was originally found up-regulated with NB4 cell differentiation induced by all-trans retinoic acid. Disruption of palladin results in neural tube closure defects, liver herniation, and embryonic lethality. Here we further report that Palld−/− embryos exhibit a significant defect in erythropoiesis characterized by a dramatic reduction in definitive erythrocytes derived from fetal liver but not primitive erythrocytes from yolk sac. The reduction of erythrocytes is accompanied by increased apoptosis of erythroblasts and partial blockage of erythroid differentiation. However, colony-forming assay shows no differences between wild-type (wt) and mutant fetal liver or yolk sac in the number and size of colonies tested. In addition, Palld−/− fetal liver cells can reconstitute hematopoiesis in lethally irradiated mice. These data strongly suggest that deficient erythropoiesis in Palld−/− fetal liver is mainly due to a compromised erythropoietic microenvironment. As expected, erythroblastic island in Palld−/− fetal liver was found disorganized. Palld−/− fetal liver cells fail to form erythroblastic island in vitro. Interestingly, wt macrophages can form such units with either wt or mutant erythroblasts, while mutant macrophages lose their ability to bind wt or mutant erythroblasts. These data demonstrate that palladin is crucial for definitive erythropoiesis and erythroblastic island formation and, especially, required for normal function of macrophages in fetal liver.
The Use of Oral Fluid for Therapeutic Drug Management
Authors: LANGMAN LORALIE J.
Published: April 2007

Abstract:  One of the underlying tenets of clinical pharmacology is that only free drugs are pharmacologically active. It is thought that only free drugs can cross biological membranes to interact with a given receptor to alter its function, and that drug responses, both efficacious and toxic, are a function of unbound concentrations. The rationale for measuring drugs in oral fluid is that the free fraction of a drug in plasma reaches equilibrium with the drug in saliva. Although reports concerning the appearance of organic solutes in saliva have been in the literature for over 70 years, it has only been in the past 30 years that there has been emphasis on the appearance of drugs. Although many assumptions for drug level monitoring in saliva are made, the primary requisite for salivary monitoring to be useful is a constant or predictable relationship between the drug concentration in saliva and the drug concentration in plasma. Measurement of oral fluid drug levels for the purpose of managing patients and making dosage adjustments may be useful for select drugs or drug classes. However, it does not appear to be useful for the majority of drugs therapeutically monitored. Some work with antipsychotic medications has indicated that although the measurement of drug concentrations themselves may not be useful for dosage adjustment, the ratio of parent drug to metabolite may reflect altered metabolic status due to either pharmacogenetic variation or other clinical conditions. Furthermore, analysis of saliva may provide a cost‐effective approach for the screening of large populations.
Human Breath Odors and Their Use in Diagnosis
Authors: WHITTLE CHRIS L. , FAKHARZADEH STEVEN , EADES JASON , PRETI GEORGE
Published: April 2007

Abstract:  Humans emit a complex array of volatile and nonvolatile molecules that are influenced by an individual's genetics, health, diet, and stress. Olfaction is the most ancient of our distal senses and may be used to evaluate food and environmental toxins as well as recognize kin and potential predators. Many body odors evolved to be olfactory messengers, which convey information between individuals. Consequently, those practicing the healing arts have used olfaction to aid in their diagnosis of disease since the dawn of medical practice. Studies using modern instrumental analyses have focused upon analysis of breath volatiles for biomarkers of internal diseases. In these studies, a subject's oral health status appears to seldom be considered. However, saliva and properly collected alveolar air samples must pass over or come in contact with the posterior dorsal surface of the tongue, a site of bacterial plaque development and source of halitosis‐related volatiles. Because of our basic research into the nature of human body odors, our lab has received referrals of people with idiopathic malodor production, from either the oral cavity or body. We developed a protocol to help differentiate individuals with chronic halitosis from those with the genetic, odor‐producing metabolic disorder trimethylaminuria (TMAU). In our referred population, TMAU is the largest cause of undiagnosed body odor. Many TMAU‐positive individuals present with oral symptoms of dysguesia and halitosis as well as body odor. We present data regarding the presentation of our referred subjects as well as the analytical results from a small number of these subjects regarding their oral levels of halitosis‐related malodorants and trimethylamine.
Evaluation of Immunoassay‐Based MMP‐8 Detection in Gingival Crevicular Fluid on a Point‐of‐Care Platform
Authors: MUNJAL S. K. , PRESCHER N. , STRUCK F. , SORSA T. , MAIER K. , NETUSCHIL L.
Published: April 2007

Abstract:  A novel immunology‐based point‐of‐care test has been designed to assess the activated form of matrix metalloproteinase‐8 (aMMP‐8) for diagnosis and monitoring of periodontal diseases. The test has been automated using an analyzer, which quantitatively measures aMMP‐8 in 18 min in gingival crevicular fluid (GCF). Fluid samples were collected from healthy, gingivitis‐, and periodontitis‐affected teeth. The test results from the analyzer were compared with quantitative aMMP‐8 immunofluorometric assay (IFMA) and in‐house enzyme‐linked immunosorbent assay (ELISA) as well as with the periodontal state. Preliminary results of analyzer measurements of these 34 clinical samples showed a good agreement with the results from IFMA and in‐house ELISA and with the clinical picture.
Evaluation of UPlink–RSV
Authors: MOKKAPATI VIJAYA K. , SAM NIEDBALA R. , KARDOS KEITH , PEREZ RONELITO J. , GUO MING , TANKE HANS J. , CORSTJENS PAUL L. A. M.
Published: April 2007

Abstract:  A prototype rapid antigen test for the on‐site detection of respiratory syncytial virus (RSV) infection was developed and evaluated. The platform uses instrumented assay analysis, eliminating potential operator bias in the interpretation of the test result that may occur with visually interpreted rapid antigen assays. The device was tested as the first point‐of‐care (POC) infectious disease application of novel reporter up‐converting phosphor technology (UPT) using a specifically designed portable UPT reader (UPlink™)®. Assays were performed by mixing nasopharyngeal specimen with RSV‐specific UPT reporter particles and addition of the mixture to a disposable cassette containing a lateral flow (LF) strip with RSV capture antibodies. UPT reporters bound on the specific capture zone were analyzed with the UP

link

reader. Reproducibility testing of the UP

link

–RSV (UPR) test by naïve users confirmed the potential of UP

link

for POC applications where testing is not always performed by highly trained medical staff. The performance of UPR was further evaluated with clinical nasopharyngeal specimens. A prospective study at an independent test site demonstrated clinical parameters of 90% sensitivity and 98.3% specificity with an overall correlation of 96.2% as compared to viral culture with RT‐PCR verification. These results are in agreement with in‐house retrospective studies and results obtained with other available commercial rapid antigen assays.
Patterns of Salivary Estradiol and Progesterone across the Menstrual Cycle
Authors: GANDARA BEATRICE K. , LERESCHE LINDA , MANCL LLOYD
Published: April 2007

Abstract:  The aim of this study was to characterize the normality of menstrual cycles on the basis of progesterone and estradiol levels in self‐collected saliva samples. Twenty‐two women, ages 19–40 years, self‐collected whole unstimulated saliva specimens each morning for two consecutive menstrual cycles. On the basis of presence/timing of hormone peaks, two investigators classified 24 cycles as normal, 10 as likely normal, and 10 as clearly not normal with respect to expected profiles. Our results show that whole saliva samples collected at home on a daily basis provide a noninvasive, feasible method of determining menstrual cycle profiles.
Lab‐on‐a‐Chip Technologies for Oral‐Based Cancer Screening and Diagnostics
Authors: MAUK MICHAEL G. , ZIOBER BARRY L. , CHEN ZONGYUAN , THOMPSON JASON A. , BAU HAIM H.
Published: April 2007

Abstract:  The design of a microfluidic lab‐on‐a‐chip system for point‐of‐care cancer screening and diagnosis of oral squamous cell carcinoma (OSCC) is presented. The chip is based on determining a ∼30‐gene transcription profile in cancer cells isolated from oral fluid samples. Microfluidic cell sorting using magnetic beads functionalized with an antibody against cancer‐specific cell‐surface antigens (e.g., epithelial cell adhesion molecule [EpCAM]) is described. A comprehensive cancer diagnostics chip will integrate microfluidic components for cell lysis, nucleic acid extraction, and amplification and detection of a panel of mRNA isolated from a subpopulation of cancer cells contained in a clinical specimen.
Oral Fluid–Based Biomarkers of Alveolar Bone Loss in Periodontitis
Authors: KINNEY JANET S. , RAMSEIER CHRISTOPH A. , GIANNOBILE WILLIAM V.
Published: April 2007

Abstract:  Periodontal disease is a bacteria‐induced chronic inflammatory disease affecting the soft and hard supporting structures encompassing the teeth. When left untreated, the ultimate outcome is alveolar bone loss and exfoliation of the involved teeth. Traditional periodontal diagnostic methods include assessment of clinical parameters and radiographs. Though efficient, these conventional techniques are inherently limited in that only a historical perspective, not current appraisal, of disease status can be determined. Advances in the use of oral fluids as possible biological samples for objective measures of current disease state, treatment monitoring, and prognostic indicators have boosted saliva and other oral‐based fluids to the forefront of technology. Oral fluids contain locally and systemically derived mediators of periodontal disease, including microbial, host‐response, and bone‐specific resorptive markers. Although most biomarkers in oral fluids represent inflammatory mediators, several specific collagen degradation and bone turnover‐related molecules have emerged as possible measures of periodontal disease activity. Pyridinoline cross‐linked carboxyterminal telopeptide (ICTP), for example, has been highly correlated with clinical features of the disease and decreases in response to intervention therapies, and has been shown to possess predictive properties for possible future disease activity. One foreseeable benefit of an oral fluid–based periodontal diagnostic would be identification of highly susceptible individuals prior to overt disease. Timely detection and diagnosis of disease may significantly affect the clinical management of periodontal patients by offering earlier, less invasive, and more cost‐effective treatment therapies.
Salivary Proteome and Its Genetic Polymorphisms
Authors: OPPENHEIM FRANK G. , SALIH ERDJAN , SIQUEIRA WALTER L. , ZHANG WEIMIN , HELMERHORST EVA J.
Published: April 2007

Abstract:  Salivary diagnostics for oral as well as systemic diseases is dependent on the identification of biomolecules reflecting a characteristic change in presence, absence, composition, or structure of saliva components found under healthy conditions. Most of the biomarkers suitable for diagnostics comprise proteins and peptides. The usefulness of salivary proteins for diagnostics requires the recognition of typical features, which make saliva as a body fluid unique. Salivary secretions reflect a degree of redundancy displayed by extensive polymorphisms forming families for each of the major salivary proteins. The structural differences among these polymorphic isoforms range from distinct to subtle, which may in some cases not even affect the mass of different family members. To facilitate the use of modern state‐of‐the‐art proteomics and the development of nanotechnology‐based analytical approaches in the field of diagnostics, the salient features of the major salivary protein families are reviewed at the molecular level. Knowledge of the structure and function of salivary gland–derived proteins/peptides has a critical impact on the rapid and correct identification of biomarkers, whether they originate from exocrine or non‐exocrine sources.
Salivary Biomarkers Associated with Alveolar Bone Loss
Authors: SCANNAPIECO F.A. , NG PBY , HOVEY K. , HAUSMANN E. , HUTSON A. , WACTAWSKI‐WENDE J
Published: April 2007

Abstract:  A longitudinal case–control study was performed to measure the association of salivary biomarkers with alveolar bone loss from a sub‐sample of 1,256 post‐menopausal women enrolled in the Buffalo Women's Health Initiative. From this cohort, 40 subjects with significant alveolar bone loss over a 5‐year period were compared to 40 age‐matched control subjects having no alveolar bone loss. Several biomarkers were quantitated in saliva collected at baseline by immunoassay. A positive association was noted between alveolar bone loss and salivary concentrations of hepatocyte growth factor, and interleukin‐1 beta, while a negative association was noted for alveolar bone loss and salivary osteonectin. This study provides preliminary evidence that several salivary biomarkers measured at baseline may serve to predict future alveolar bone loss.
Visualization and Other Emerging Technologies as Change Makers for Oral Cancer Prevention
Authors: ROSIN MIRIAM P. , POH CATHERINE F. , GUILLARD MARTIAL , MICHELE WILLIAMS P. , ZHANG LEWEI , MacAULAY CALUM
Published: April 2007

Abstract:  The genomic era has fueled a rapid emergence of new information at the molecular level with a great potential for developing innovative approaches to detection, risk assessment, and management of oral cancers and premalignant disease. As yet, however, little research has been done on complementary approaches that would use different technology in conjunction with molecular approaches to create a rapid and cost‐effective strategy for patient assessment and management. In our ongoing 8‐year longitudinal study, a set of innovative technologies is being validated alone and in combination to best correlate with patient outcome. The plan is to use these devices in a step‐by‐step sequence to guide key clinicopathological decisions on patient risk and treatment. The devices include a hand‐held visualization device that makes use of tissue autofluorescence to detect and delineate abnormal lesions and fields requiring follow‐up, to be used in conjunction with optical contrast agents such as toluidine blue. In addition, two semi‐automated high‐resolution computer microscopy systems will be used to quantitate the protein expression phenotype of cell nuclei in tissue sections and exfoliated cell brushings. Previously identified risk‐associated molecular changes are being used to validate these systems as well as to establish their place in a population‐based triage program that will filter out high‐risk cases in the community and funnel them to dysplasia clinics where higher‐cost molecular tools will guide intervention. A critical development for the translation of this technology into community settings is the establishment of an effective methodology for education and training of health practitioners on the front lines.
Layered Peptide Arrays
Authors: GANNOT GALLYA , TANGREA MICHAEL A. , CHUAQUI RODRIGO F. , GILLESPIE JOHN W. , EMMERT‐BUCK MICHAEL R.
Published: April 2007

Abstract:  The layered peptide array (LPA) is a recently developed technique designed to measure antibody levels in a multiplex, high‐throughput manner. LPAs can assess antibody presence either in fluid samples or from tissues while maintaining the two‐dimensional orientation of the life science platform. In this manuscript, we evaluated and assessed the performance of the LPA platform, focusing on throughput capability, sensitivity, and specificity of the assay in several different systems.
Different Induction of GRP78 and CHOP as a Predictor of Sensitivity to Proteasome Inhibitors in Thyroid Cancer Cells
Authors: Wang Hua-Qin , Du Zhen-Xian , Zhang Hai-Yan , Gao Da-Xin
Published: April 2007

Proteasome inhibitors represent a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. Emerging lines of evidence suggest that the unfolded protein response is implicated in proteasome inhibitors-induced apoptosis. Glucose-regulated protein 78 kDa (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) as part of the unfolded protein response play critical roles in cell survival or death. Here we demonstrate that induction of GRP78 and CHOP are differently regulated upon proteasome inhibition in different thyroid cancer cell lines, and GRP78 levels as well as preferential induction of GRP78 or CHOP appears to be involved in the responsiveness. Insensitive ARO, 8305C, and 8505C cell lines inherently express relatively high levels of GRP78 compared with sensitive cell lines, and its levels are further up-regulated upon treatment with proteasome inhibitors. CHOP levels are dramatically induced in sensitive cell lines until 24 h after proteasome inhibition. On the other hand, only a slight increase is observed at 4 h in insensitive cell lines, and this increase is unable to be detected after 8 h. Insensitive cells are sensitized to proteasome inhibition by suppression of GRP78. Furthermore, suppression of CHOP induction or overexpression of GRP78 partially prevents proteasome inhibition-mediated cell death. Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors. Our experiments therefore suggest a novel approach toward sensitization of thyroid cancer cells to proteasome inhibitors.
Atomic and Electronic Structures and Properties of Nanomaterials on Metal Substrates
Authors: Kiguchi Manabu
Published: April 2007

We have fabricated well-defined nanostructures and investigate their chemical and physical properties. First, we studied atomic and electronic structures of alkali halide films grown on metal substrates. Alkali halides were found to grow heteroepitaxially on fcc metal (001) surfaces, that is, a well-defined insulator/metal interface could be prepared. We could obtain clear experimental evidence for the formation of metal-induced gap states at the interface using near edge X-ray absorption fine structure. Second, we fabricated a polar MgO(111) thin film by alternate adsorption of Mg and O2 on Ag(111). The polar MgO(111) surface was not an insulating surface, but a semiconducting or metallic surface. Third, we studied the chemical and physical properties of these well-defined nanostructures. In case of monoatomic Au wires, we succeeded in controlling the switching behavior of conductance by the external perturbation, electrochemical potential.
Reversible O2-Binding and Activation with Dicopper and Diiron Complexes Stabilized by Various Hexapyridine Ligands. Stability, Modulation, and Flexibility of the Dinuclear Structure as Key Aspects for the Dimetal/O2 Chemistry
Authors: Kodera Masahito , Kano Koji
Published: April 2007

Reversible O2-binding and activation have been studied using dicopper and diiron complexes of various hexapyridine ligands as functional models of hemocyanin (Hc) and soluble methane monooxygenase (sMMO), respectively. Dicopper(I) complexes of sterically hindered hexapyridine ligands react with O2 to form μ-η2:η2-peroxo–dicopper(II) complexes stable at room temperature, which release O2 to attain reversible O2-binding. When a sterically hindered hexapyridine ligand methylated at the bridgehead positions is used, the O2-release becomes easier, and reversibility is greatly improved. Detailed structural studies of CuI and CuII complexes of sterically hindered tripyridine ligands showed that the bridgehead alkyl group causes a pyridine shift leading to structural modulation of the copper complexes. A hexapyridine ligand can be used to form a thermally stable peroxo–diiron(III) complex, which can oxygenate hydrocarbons upon addition of acid chloride/DMF. Diiron(III) complexes of a bis-tpa type hexapyridine ligand catalyze epoxidation of various alkenes with H2O2. A peroxo–diiron(III) complex is detected as an intermediate. Detailed isotope-labeling experiments showed that the peroxo intermediate is converted to dioxo–μ-oxo–diiron(IV) complex, and that three oxygen atoms of the active species scramble with each other. Stable dinuclear structure, structural modulation, and structural flexibility, which may be from the hexapyridine ligands, play key roles in reversible O2-binding and activation by the dicopper and diiron complexes.
Theoretical Study of Geometries and Electronic Transition of Color-Switching Molecules: Tetra-Aza Macrocycle and Its Zinc Complexes
Authors: Zhu Zhenxia , Takano Keiko , Furuhama Ayako , Ogawa Shojiro , Tsuchiya Shinji
Published: April 2007

Tetra-aza macrocycles containing 2,2′-bipyridine moieties fascinatingly undergo color-switching. Here, a tetra-aza macrocycle was analyzed as well as its zinc complexes from the viewpoint of ab initio molecular orbital (MO) and density functional theory (DFT) calculations. As a result of systematic geometry searches, obtained geometries of stable conformers were consistent with the structural formula developed from the experimental results. Transition energies and oscillator strengths of the stable conformers were calculated based on time-dependent DFT (TDDFT) and compared with the experimental data. The effect of the solvent was considered by using a polarization continuum model (PCM). The calculated transition energies qualitatively agreed with the experimental UV spectra. Structural changes upon complexation and the features of the molecular orbitals related to the transition from the ground state to the excited states are discussed.