bluuebunny/crossref_metadata_2025 huggingface dataset:
Robotically guided radiosurgery for children
Authors: Giller Cole A. , Berger Brian D. , Pistenmaa David A. , Sklar Frederick , Weprin Bradley , Shapiro Kenneth , Winick Naomi , Mulne Arlynn F. , Delp Janice L. , Gilio Joseph P. , Gall Kenneth P. , Dicke Karel A. , Swift Dale , Sacco David , Harris‐Henderson Kesha , Bowers Daniel
Published: November 2004

Background

A robotically guided linear accelerator has recently been developed which provides frameless radiosurgery with high precision. Potential advantages for the pediatric population include the avoidance of the cognitive decline associated with whole brain radiotherapy, the ability to treat young children with thin skulls unsuitable for frame‐based methods, and the possible avoidance of general anesthesia. We report our experience with this system (the “Cyberknife”) in the treatment of 21 children.

Procedures

Cyberknife radiosurgery was performed on 38 occasions for 21 patients, age ranging from 8 months to 16 years (7.0 ± 5.1 years), with tumors considered unresectable. Three had pilocytic astrocytomas, two had anaplastic astrocytomas, three had ependymomas (two anaplastic), four had medulloblastomas, three had atypical teratoid/rhabdoid tumors, three had craniopharyngiomas, and three had other pathologies. The mean target volume was 10.7 ± 20 cm3, mean marginal dose was 18.8 ± 8.1 Gy, and mean follow‐up is 18 ± 11 months. Twenty‐seven (71%) of the treatments were single‐shot and eight (38%) patients did not require general anesthesia.

Results

Local control was achieved in the patients with pilocytic and anaplastic astrocytoma, three of the patients with medulloblastoma, and the three with craniopharyngioma, but not for those with ependymoma. Two of the patients with rhabdoid tumors are alive 16 and 35 months after this diagnosis. There have been no procedure related deaths or complications.

Conclusion

Cyberknife radiosurgery can be used to achieve local control for some children with CNS tumors without the need for rigid head fixation. © 2004 Wiley‐Liss, Inc.
Ab initio analysis of electron currents in thioalkanes
Authors: Seminario Jorge M. , Yan Liuming
Published: November 2004

A combined density functional theory and Green's function procedure is used to calculate the electrical characteristics of a group of alkanethiols representing possible experimental settings. It is found that the current running through the molecule is the sum of the contributions from all molecular orbitals each presenting a barrier to electron transport equal to their energy difference from the Fermi level of the contacts. For the alkanethiols the location of these intrinsic barriers are at 0.78 eV (highest occupied molecular orbital [HOMO] and HOMO‐1), 1.99 eV (HOMO‐2 and HOMO‐3), 2.07 eV (LUMO and LUMO+1), and 2.67 eV (HOMO‐4). However, barriers obtained through fittings to known models do not bear any physical meaning at the molecular level, as they are sort of exponential average of the intrinsic barriers. We have also found that the exponential dependence of the current with the length of the alkane is practically independent of the contact nature, perhaps due to the large resistance of the alkanes. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005
Comparing the concentration curves directly in a pharmacokinetics, bioavailability/bioequivalence study
Authors: Liao Jason J. Z.
Published: November 2004

In a traditional pharmacokinetics (PK), bioavailability (BA) /bioequivalence (BE) study, the same number of time points and sampling times are used for each subject. Often, an indirect inference is then made on some PK parameters such as area under the plasma concentration curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) or half‐life. However, since these PK parameters are summarized from repeated measurements, a lot of information can be lost. The indirect inferences on some PK parameters are not always accurate. Taking the repeated measurements of the concentration curve into consideration, a functional linear model has been developed to compare concentration curves directly instead of the PK parameters. Considering the nature of repeated measurements, a multiple testing procedure is proposed to assess the equality of two concentration curves. A real data set is used to demonstrate the proposed procedure. Copyright © 2004 John Wiley & Sons, Ltd.
Redefinition of the yellow hypotrichous ciliate, Pseudokeronopsis flava (Hypotrichida: Ciliophora)
Authors: Song Weibo , Sun Ping , Ji Daode
Published: November 2004

The morphology and infraciliature of a population of Pseudokeronopsis flava, a yellow-coloured ciliate collected from the coastal water near Zhanjiang, South China are investigated and described. Based on previous and present studies, an improved diagnosis is supplied: yellow to yellow-brown coloured marine Pseudokeronopsis, in vivo 140–350×30–50 μm with flexible and slender body; bicorona comprising about five pairs of frontal cirri; one buccal, 2–3 frontoterminal and 2–4 transverse cirri; midventral rows consisting of ≈30 pairs of cirri, which terminate subcaudally above the inconspicuous transverse cirri; about 50 adoral membranelles; left and right marginal rows separated at posterior end; 3–4 dorsal kineties; colourless, blood-cell-shaped cortical granules ellipsoid in shape, distributed over whole cell while yellow to yellow-brownish pigments positioned in a P. rubra-pattern; contractile vacuole positioned in posterior 1/4–1/5 of body; numerous macronuclear segments.
Seasonal and developmental variation in the lipids of Acanthostepheia malmgreni (Amphipoda) from the hyperbenthos of a cold-ocean environment (Conception Bay, Newfoundland)
Authors: Richoux Nicole B. , Thompson Raymond J. , Deibel Don , Parrish Christopher C.
Published: November 2004

Total lipid (TL) and lipid-class composition in Acanthostepheia malmgreni (Crustacea: Amphipoda) from 240 m depth in Conception Bay were determined from samples collected monthly throughout 1999 and 2000. Variation in lipids among life history stages was studied in relation to the reproductive cycle of A. malmgreni and the timing of the major annual sinking event following the spring phytoplankton bloom in April. Total lipid remained relatively constant in first year juveniles [mean 4·4% dry mass (DM)], after which it gradually increased with the first signs of development of sexual characteristics and the sedimentation of spring bloom material in May. Triacylglycerol (TAG) was the dominant neutral lipid in all stages, with phospholipid (PL) the dominant polar lipid. Highest net accumulation of TL and TAG occurred in a group of large age 2+ individuals from October 1998 to May 1999, and in age 1+ immature males and immature females from July to November 2000 (1·4 mg TL month−1; 0·8 mg TAG month−1). Phospholipid quantities within the population were relatively constant at ≈2% DM. Maximum TL in the population (13% DM) was observed in large adults and some large immature individuals, and significant decreases in both TL and PL were recorded in mature females during the brooding period. This study reveals a dependence of A. malmgreni on seasonal lipid accumulation for reproduction, and a clear trophic link between the amphipod population and the pelagic production cycle.
Studies on spatial distribution of nickel in leaves and stems of the metal hyperaccumulator Stackhousia tryonii Bailey using nuclear microprobe (micro-PIXE) and EDXS techniques
Authors: Bhatia Naveen P. , Walsh Kerry B. , Orlic Ivo , Siegele Rainer , Ashwath Nanjappa , Baker Alan J. M.
Published: November 2004

Stackhousia tryonii Bailey is one of the three nickel hyperaccumulators reported from Australia. It is a rare, herbaceous plant that accumulates (Ni) both in leaf and stem tissues. Localisation of Ni in leaf and stem tissues of S. tryonii was studied using two micro-analytical techniques, energy dispersive X-ray spectrometry (EDXS) and micro-proton-induced X-ray emission spectrometry (micro-PIXE). Dimethylglyoxime complexation of Ni was also visualised by bright- and dark-field microscopy, but this technique was considered to create artefacts in the distribution of Ni. Energy dispersive X-ray spectrometric analysis indicated that guard cells possessed a lower Ni concentration than epidermal cells, and that epidermal cells and vascular tissue contained higher levels of Ni than mesophyll, as reported for other Ni hyperaccumulators. The highest Ni concentration was recorded (PIXE quantitative point analysis) in the epidermal cells and vascular tissue (5400 μg g–1 DW), approximately double that recorded in palisade cells (2500 μg g–1 DW). However, concentrations were variable within these tissues, explaining, in part, the similarity between average Ni concentrations of these tissues (as estimated by region selection mode). Stem tissues showed a similar distribution pattern as leaves, with relatively low Ni concentration in the pith (central) region. The majority of Ni (73–85% for leaves; 80–92% for stem) was extracted from freeze-dried sections by water extraction, suggesting that this metal is present in a highly soluble and mobile form in the leaf and stem tissues of S. tryonii.
Phosphorus deficiency enhances plasma membrane H+-ATPase activity and citrate exudation in greater purple lupin (Lupinus pilosus)
Authors: Ligaba Ayalew , Yamaguchi Mineo , Shen Hong , Sasaki Takayuki , Yamamoto Yoko , Matsumoto Hideaki
Published: November 2004

The response of greater purple lupin (Lupinus pilosus L.) to a combination of phosphorus (P) deficiency and aluminium (Al) toxicity is unknown, and the mechanisms involved in the exudation of organic anions from greater purple lupin have not been reported. Therefore, plants grown with (+P) or without (–P) 250 µm P were exposed to 0 or 50 µm AlCl3 and the amount of organic anions exuded and the activities of plasma membrane H+-ATPase (E.C 3.6.3.6) and H+-pumps were investigated. Twenty days of P deficiency resulted in significantly reduced shoot growth and increased proteoid root formation. Exposure to 50 µm AlCl3 did not induce citrate exudation but did induce some malate exudation in –P plants. In contrast, P deficiency did induce exudation of citrate. Enhanced citrate exudation was attributed to the large increase in the activity of plasma membrane H+-ATPase and associated H+ transport. This was shown by the inhibitory effect of vanadate on plasma membrane H+-ATPase activity in vitro and on citrate exudation in vivo. However, vanadate did not suppress the exudation of malate. During 9 h of Al exposure, exudation of citrate showed a continuing increase for both –P and +P plants, while malate exudation increased only during the first 3 h, after which it rapidly declined. The total amount of organic anion exudation was significantly higher for –P plants. In the presence of 50 µm anion channel blockers [anthracene-9-carboxylic acid (A-9-C), niflumic acid (NIF) and phenylglyoxal (PG)], the exudation of citrate and malate was reduced by 25–40%. It was concluded that P deficiency induces citrate exudation by enhancing the activity of plasma membrane H+-ATPase and H+ export. In L. pilosus, exudation of organic anions occurs primarily in response to P deficiency but not Al toxicity. This contrasts with previous results obtained in Brassica napus L.
A critical overview of model estimates of net primary productivity for the Australian continent
Authors: Roxburgh Stephen H. , Barrett Damian J. , Berry Sandra L. , Carter John O. , Davies Ian D. , Gifford Roger M. , Kirschbaum Miko U. F. , McBeth Bevan P. , Noble Ian R. , Parton William G. , Raupach Michael R. , Roderick Micahel L.
Published: November 2004

Net primary production links the biosphere and the climate system through the global cycling of carbon, water and nutrients. Accurate quantification of net primary productivity (NPP) is therefore critical in understanding the response of the world’s ecosystems to global climate change, and how changes in ecosystems might themselves feed back to the climate system. Twelve model estimates of long-term annual NPP for the Australian continent were reviewed. These models varied considerably in the approaches adopted and the inputs required. The model estimates ranged 5-fold, from 0.67 to 3.31 Gt C y–1. Within-continent variation was similarly large, with most of the discrepancies occurring in the arid zone of Australia, which comprises most of the continent. It is also within this zone that empirical NPP data are most lacking. Comparison with a recent global-scale analysis of six dynamic global vegetation models showed a similar level of variability in continental total NPP, 0.38 to 2.85 Gt C y–1, and similar within-continent spatial variability. As a first tentative step towards model validation the twelve NPP estimates were compared with existing field measurements, although the ability to reach definitive conclusions was limited by insufficient data, and incompatibilities between the field-based observations and the model predictions. It was concluded that the current NPP-modelling capability falls short of the accuracy required for effective application in understanding the terrestrial biospheric implications of global atmospheric / climatic change. Potential methods that could be used in future work for improving modelled estimates of Australian continental NPP and their validation are discussed. These include increasing the spatial coverage of empirical NPP estimates within arid ecosystems, the use of existing high quality site data for more detailed model exploration, and a formal model inter-comparison using uniform driver datasets to investigate more intensively differences in model behaviour and assumptions.
Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele
Authors: Graveel Carrie , Su Yanli , Koeman Julie , Wang Ling-Mei , Tessarollo Lino , Fiscella Michele , Birchmeier Carmen , Swiatek Pamela , Bronson Roderick , Vande Woude George
Published: November 2004

Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas as well as in other cancers. These mutations have been examined in several
in vitro
systems, where they cause constitutive Met activation, focus formation, and cell motility, and are tumorigenic in xenografts. To study the influence of these mutations on tumorigenesis
in vivo
, we generated mice with targeted mutations in the murine
met
locus. The following five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. We observed that mice harboring D1226N, Y1228C
,
and M1248T/L1193V mutations developed a high frequency of sarcomas and some lymphomas, whereas the M1248T mice developed carcinomas and lymphomas. Of considerable interest, we observed trisomy of chromosome 6 and duplication of the mutant
met
allele in a majority of the tumors, similar to what has been reported in patients with hereditary renal papillary carcinomas. These results demonstrate that activating Met mutations and
met
amplification play key roles in promoting tumorigenesis
in vivo
. Moreover, our findings show that different mutations in the Met kinase domain can influence the types of cancers that develop.
Experimental test of the birdsong error-correction model
Authors: Leonardo Anthony
Published: November 2004

Adult zebra finches require auditory feedback to maintain their songs. It has been proposed that the lateral magnocellular nucleus of the anterior nidopallium (LMAN) mediates song plasticity based on auditory feedback. In this model, neurons in LMAN, tuned to the spectral and temporal properties of the bird's own song (BOS), are thought to compute the difference between the auditory feedback from the bird's vocalizations and an internal song template. This error-correction signal is then used to initiate changes in the motor system that make future vocalizations a better match to the song template. This model was tested by recording from single LMAN neurons while manipulating the auditory feedback heard by singing birds. In contrast to the model predictions, LMAN spike patterns are insensitive to manipulations of auditory feedback. These results suggest that BOS tuning in LMAN is not used for error detection and constrain the nature of any error signal from LMAN to the motor system. Finally, LMAN neurons produce spikes locked precisely to the bird's song, independent of the auditory feedback heard by the bird. This finding suggests that a large portion of the input to this nucleus is from the motor control signals that generate the song rather than from auditory feedback.
Effects of a Tropical Cyclone on the Drinking‐Water Quality of a Remote Pacific Island
Authors: Mosley Luke M. , Sharp Donald S. , Singh Sarabjeet
Published: November 2004

The effect of a cyclone (Ami, January 2003) on drinking‐water quality on the island of Vanua Levu, Fiji was investigated. Following the cyclone nearly three‐quarters of the samples analysed did not conform to World Health Organisation (WHO) guideline values for safe drinking‐water in terms of chlorine residual, total and faecal coliforms, and turbidity. Turbidity and total coliform levels significantly increased (up 56 and 62 per cent, respectively) from pre‐cyclone levels, which was likely due to the large amounts of silt and debris entering water‐supply sources during the cyclone. The utility found it difficult to maintain a reliable supply of treated water in the aftermath of the disaster. Communities were unaware they were drinking‐water that had not been adequately treated. Circumstances permitted this cyclone to be used as a case study to assess whether a simple paper‐strip water‐quality test (the hydrogen sulphide, H2S) kit could be distributed and used for community‐based monitoring following such a disaster event to better protect public health. The H2S test results correlated well with faecal and total coliform results as found in previous studies. A small percentage of samples (about 10 per cent) tested positive for faecal and total coliforms but did not test positive in the H2S test. It was concluded that the H2S test would be well suited to wider use, especially in the absence of water‐quality monitoring capabilities for outer island groups as it is inexpensive and easy to use, thus enabling communities and community health workers with minimal training to test their own water supplies without outside assistance. The importance of public education before and after natural disasters is also discussed.
Supplementary winter feeding of wild red deer Cervus elaphus in Europe and North America: justifications, feeding practice and effectiveness
Authors: PUTMAN R. J. , STAINES B. W.
Published: November 2004

1. Supplementary winter feeding of game animals, and particularly deer, is a common practice throughout northern (continental) Europe and parts of North America. Feeding is normally associated with maintaining high densities of animals for hunting, in terms of: (i) maintaining or increasing body weights and condition overwinter; (ii) improving reproductive performance and fertility; (iii) increasing overwinter survival; and (iv) reducing levels of damage caused to agriculture and forestry or the natural heritage. We consider the balance of evidence on the effectiveness of winter feeding of red deer Cervus elaphus in achieving these objectives. Where that evidence is equivocal, we attempt to reconcile apparent contradictions to evaluate the circumstances under which winter feeding may or may not be effective.

2. In general, feeding of red deer on open range appears to have relatively little effect on body weights or fecundity. Effects on increasing antler size and quality are variable and seem to depend on the degree to which animals may be mineral limited on native range. Effects on survival are similarly ambiguous. It is apparent, however, that to be effective in reducing mortality, any supplementation is required early in the season and not simply when heavy mortalities are already being experienced. If provision of supplementary foods is delayed until animals are perceived already to be in poor condition, such feeding may have little effect.

3. One of the primary goals of winter feeding in both Europe and the USA has become the prevention of environmental damage, particularly damage to commercial and native forests, while maintaining deer populations at densities suitable for hunting. Again, empirical evidence for effectiveness in this regard is inconclusive, with some studies showing a decrease in damage caused, some showing no effect and others showing a significant increase in local impact.

4. There are equally a number of problems associated with the provision of supplementary feeds overwinter. Those animals which come to the feeding stations may develop a reliance on the food supplement provided, reducing intake of natural forages to near zero; where feed provided is less than 100% of daily requirement, such animals may regularly lose, rather than gain condition. Feed provision is also extremely uneven at such feeding stations; dominant stags displace younger stags and hinds from the feed provided until they have themselves finished feeding. Concentrations of high densities of animals around small feed‐areas may also increase the risk of infection and lead to development of high parasite burdens.

5. In an attempt to assess the current status and distribution of supplementary winter feeding in Scotland, a questionnaire was circulated to a number of individual across the country. Results of this survey are summarized and conclusions presented on the likely effectiveness of current feeding practices in achieving their aims.
Does the presence of a human tracker affect the behaviour of radio‐tagged wood miceApodemus sylvaticus?
Authors: PROSSER PHIL , BROWN SARA , BROOKES KATE
Published: November 2004

1. While the effect on animals of handling them and fitting them with radio tags has been investigated, little work has been reported testing the effect of the presence of a human observer tracking an animal.

2. The activity of wood mice fitted with radio collars and confined to a semifield pen was measured in the presence and the absence of a human observer. Free‐ranging wood mice were radio tracked by using two protocols: ‘fixes’ taken periodically, and periods of continuous tracking.

3. There was no significant difference in any quantified aspect of the animals’ behaviour. This suggests that the presence of a human tracker has a negligible effect on the behaviour of wood mice.
Michael Howard: The First Jewish Prime Minister?
Authors: ROTH ANDREW
Published: November 2004

Initially, Michael Howard seemed the saviour of the divided and disheartened Conservative party, reuniting it in the hope of victory at the next general election. Initially, also, he seemed a match for his fellow barrister, Tony Blair. Though successful at winning over Tory MPs, he was much less effective in relation to all those ex‐Tory voters who deserted the party in 1997 and 2001. This failure was confirmed after less than nine months of his leadership, when his party polled poorly at the European elections of June 2004 (where a large slice of the anti‐European vote went to UKIP) and came an ignominious third in the Parliamentary by‐elections of July 2004. These results, combined with Howard's lacklustre response to the Butler Report, sapped Howard's personal ratings and reopened civil war within the Conservative party.
Moral Hazard and Optimal Subsidiary Structure for Financial Institutions
Authors: KAHN CHARLES , WINTON ANDREW
Published: November 2004

Banks and related financial institutions often have two separate subsidiaries that make loans of similar type but differing risk, for example, a bank and a finance company, or a “good bank/bad bank” structure. Such “bipartite” structures may prevent risk shifting, in which banks misuse their flexibility in choosing and monitoring loans to exploit their debt holders. By “insulating” safer loans from riskier loans, a bipartite structure reduces risk‐shifting incentives in the safer subsidiary. Bipartite structures are more likely to dominate unitary structures as the downside from riskier loans is higher or as expected profits from the efficient loan mix are lower.
How to Discount Cashflows with Time‐Varying Expected Returns
Authors: ANG ANDREW , LIU JUN
Published: November 2004

While many studies document that the market risk premium is predictable and that betas are not constant, the dividend discount model ignores time‐varying risk premiums and betas. We develop a model to consistently value cashflows with changing risk‐free rates, predictable risk premiums, and conditional betas in the context of a conditional CAPM. Practical valuation is accomplished with an analytic term structure of discount rates, with different discount rates applied to expected cashflows at different horizons. Using constant discount rates can produce large misvaluations, which, in portfolio data, are mostly driven at short horizons by market risk premiums and at long horizons by time variation in risk‐free rates and factor loadings.
The Choice of Private Versus Public Capital Markets: Evidence from Privatizations
Authors: MEGGINSON WILLIAM L. , NASH ROBERT C. , NETTER JEFFRY M. , POULSEN ANNETTE B.
Published: November 2004

We examine the impact of political, institutional, and economic factors on the choice between selling a state‐owned enterprise in the public capital market through a share issue privatization (SIP) and selling it in the private capital market in an asset sale. SIPs are more likely in less developed capital markets, for more profitable state‐owned enterprises, and where there are more protections of minority shareholders. Asset sales are more likely when there is less state control of the economy and when the firm is smaller. Our results suggest the importance of privatization activities in developing the equity markets of privatizing countries.
Two-equation Turbulence Modeling of Pulsatile Flow in a Stenosed Tube
Authors: Ryval J. , Straatman A. G. , Steinman D. A.
Published: November 2004

The study of pulsatile flow in stenosed vessels is of particular importance because of its significance in relation to blood flow in human pathophysiology. To date, however, there have been few comprehensive publications detailing systematic numerical simulations of turbulent pulsatile flow through stenotic tubes evaluated against comparable experiments. In this paper, two-equation turbulence modeling has been explored for sinusoidally pulsatile flow in 75% and 90% area reduction stenosed vessels, which undergoes a transition from laminar to turbulent flow as well as relaminarization. Wilcox’s standard k-ω model and a transitional variant of the same model are employed for the numerical simulations. Steady flow through the stenosed tubes was considered first to establish the grid resolution and the correct inlet conditions on the basis of comprehensive comparisons of the detailed velocity and turbulence fields to experimental data. Inlet conditions based on Womersley flow were imposed at the inlet for all pulsatile cases and the results were compared to experimental data from the literature. In general, the transitional version of the k-ω model is shown to give a better overall representation of both steady and pulsatile flow. The standard model consistently over predicts turbulence at and downstream of the stenosis, which leads to premature recovery of the flow. While the transitional model often under-predicts the magnitude of the turbulence, the trends are well-described and the velocity field is superior to that predicted using the standard model. On the basis of this study, there appears to be some promise for simulating physiological pulsatile flows using a relatively simple two-equation turbulence model.
Fluid Dynamic Analysis of the 50 cc Penn State Artificial Heart Under Physiological Operating Conditions Using Particle Image Velocimetry
Authors: Hochareon Pramote , Manning Keefe B. , Fontaine Arnold A. , Tarbell John M. , Deutsch Steven
Published: November 2004

In order to bridge the gap of existing artificial heart technology to the diverse needs of the patient population, we have been investigating the viability of a scaled-down design of the current 70 cc Penn State artificial heart. The issues of clot formation and hemolysis may become magnified within a 50 cc chamber compared to the existing 70 cc one. Particle image velocimetry (PIV) was employed to map the entire 50 cc Penn State artificial heart chamber. Flow fields constructed from PIV data indicate a rotational flow pattern that provides washout during diastole. In addition, shear rate maps were constructed for the inner walls of the heart chamber. The lateral walls of the mitral and aortic ports experience high shear rates while the upper and bottom walls undergo low shear rates, with sufficiently long exposure times to potentially induce platelet activation or thrombus formation. In this study, we have demonstrated that PIV may adequately map the flow fields accurately in a reasonable amount of time. Therefore, the potential exists of employing PIV as a design tool.
Computational Simulations of Airflow in an In Vitro Model of the Pediatric Upper Airways
Authors: Allen G. M. , Shortall B. P. , Gemci T. , Corcoran T. E. , Chigier N. A.
Published: November 2004

In order to understand mechanisms of gas and aerosol transport in the human respiratory system airflow in the upper airways of a pediatric subject (male aged 5) was calculated using Computational Fluid Dynamic techniques. An in vitro reconstruction of the subject’s anatomy was produced from MRI images. Flow fields were solved for steady inhalation at 6.4 and 8 LPM. For validation of the numerical solution, airflow in an adult cadaver based trachea was solved using identical numerical methods. Comparisons were made between experimental results and computational data of the adult model to determine solution validity. It was found that numerical simulations can provide an accurate representation of axial velocities and turbulence intensity. Data on flow resistance, axial velocities, secondary velocity vectors, and turbulent kinetic energy are presented for the pediatric case. Turbulent kinetic energy and axial velocities were heavily dependant on flow rate, whereas turbulence intensity varied less over the flow rates studied. The laryngeal jet from an adult model was compared to the laryngeal jet in the pediatric model based on Tracheal Reynolds number. The pediatric case indicated that children show axial velocities in the laryngeal jet comparable to adults, who have much higher tracheal Reynolds numbers than children due to larger characteristic dimensions. The intensity of turbulence follows a similar trend, with higher turbulent kinetic energy levels in the pediatric model than would be expected from measurements in adults at similar tracheal Reynolds numbers. There was reasonable agreement between the location of flow structures between adults and children, suggesting that an unknown length scale correlation factor could exist that would produce acceptable predictions of pediatric velocimetry based off of adult data sets. A combined scale for turbulent intensity as well may not exist due to the complex nature of turbulence production and dissipation.
A Novel Application of the Principles of Linear Elastic Fracture Mechanics (LEFM) to the Fatigue Behavior of Tendon Tissue
Authors: Adeeb Samer M. , Zec Michelle L. , Thornton Gail M. , Frank Cyril B. , Shrive Nigel G.
Published: November 2004

Background: Experiments on the fatigue of tendons have shown that cyclic loading induces failure at stresses lower than the ultimate tensile strength (UTS) of the tendons. The number of cycles to failure Nf has been shown to be dependent upon the magnitude of the applied cyclic stress. Method of approach: Utilizing data collected by Schechtman (1995), we demonstrate that the principles of Linear Elastic Fracture Mechanics (LEFM) can be used to predict the fatigue behavior of tendons under cyclic loading for maximum stress levels that are higher than 10% of the ultimate tensile strength (UTS) of the tendon (the experimental results at 10% UTS did not fit with our equations). Conclusions: LEFM and other FM approaches may prove to be very valuable in advancing our understanding of damage accumulation in soft connective tissues.
Anisotropic Mechanical Properties of Tissue Components in Human Atherosclerotic Plaques
Authors: Holzapfel Gerhard A. , Sommer Gerhard , Regitnig Peter
Published: November 2004

Knowledge of the biomechanical properties of human atherosclerotic plaques is of essential importance for developing more insights in the pathophysiology of the cardiovascular system and for better predicting the outcome of interventional treatments such as balloon angioplasty. Available data are mainly based on uniaxial tests, and most of the studies investigate the mechanical response of fibrous plaque caps only. However, stress distributions during, for example, balloon angioplasty are strongly influenced by all components of atherosclerotic lesions. A total number of 107 samples from nine human high-grade stenotic iliac arteries were tested; associated anamnesis of donors reported. Magnetic resonance imaging was employed to test the usability of the harvested arteries. Histological analyses has served to characterize the different tissue types. Prepared strips of 7 different tissue types underwent cyclic quasistatic uniaxial tension tests in axial and circumferential directions; ultimate tensile stresses and stretches were documented. Experimental data of individual samples indicated anisotropic and highly nonlinear tissue properties as well as considerable interspecimen differences. The calcification showed, however, a linear property, with about the same stiffness as observed for the adventitia in high stress regions. The stress and stretch values at calcification fracture are smaller (179±56 kPa and 1.02±0.005) than for each of the other tissue components. Of all intimal tissues investigated, the lowest fracture stress occurred in the circumferential direction of the fibrous cap (254.8±79.8 kPa at stretch 1.182±0.1). The adventitia demonstrated the highest and the nondiseased media the lowest mechanical strength on average.
Enteropathogenic
Escherichia coli
Infection Triggers Host Phospholipid Metabolism Perturbations
Authors: Wu Y. , Lau B. , Smith S. , Troyan K. , Barnett Foster D. E.
Published: November 2004

Enteropathogenic
Escherichia coli
(EPEC) specifically recognizes phosphatidylethanolamine (PE) on the outer leaflet of host epithelial cells. EPEC also induces apoptosis in epithelial cells, which results in increased levels of outer leaflet PE and increased bacterial binding. Consequently, it is of interest to investigate whether EPEC infection perturbs host cell phospholipid metabolism and whether the changes play a role in the apoptotic signaling. Our findings indicate that EPEC infection results in a significant increase in the epithelial cell PE level and a corresponding decrease in the phosphatidylcholine (PC) level. PE synthesis via both the de novo pathway and the serine decarboxylation pathway was enhanced, and de novo synthesis of phosphatidylcholine via CDP-choline was reduced. The changes were transitory, and the maximum change was noted after 4 to 5 h of infection. Addition of exogenous PC or CDP-choline to epithelial cells prior to infection abrogated EPEC-induced apoptosis, suggesting that EPEC infection inhibits the CTP-phosphocholine cytidylyltransferase step in PC synthesis, which is reportedly inhibited during nonmicrobially induced apoptosis. On the other hand, incorporation of exogenous PE by the host cells enhanced EPEC-induced apoptosis and necrosis without increasing bacterial adhesion. This is the first report that pathogen-induced apoptosis is associated with significant changes in PE and PC metabolism, and the results suggest that EPEC adhesion to a host membrane phospholipid plays a role in disruption of host phospholipid metabolism.
Downregulation of CXCR1 and CXCR2 Expression on Human Neutrophils byHelicobacter pylori: a New Pathomechanism inH. pyloriInfection?
Authors: Schmausser Bernd , Josenhans Christine , Endrich Simon , Suerbaum Sebastian , Sitaru Cassian , Andrulis Mindaugas , Brändlein Stephanie , Rieckmann Peter , Müller-Hermelink Hans Konrad , Eck Matthias
Published: November 2004

InHelicobacter pylorigastritis, neutrophil activation and migration, which play central roles in the pathogenesis of the disease, are regulated by the neutrophil attractant chemokines interleukin 8 (IL-8) and Groα, whose secretion is induced byH. pylori. However, the modulation of the corresponding chemokine receptors CXCR1 and CXCR2 on human neutrophils under the influence ofH. pylorihas not been investigated. Incubation of neutrophils withcag+andcagdeletionH. pyloristrains resulted in a complete downregulation of the CXCR1 and the CXCR2 receptors after 0.5 h, as tested by fluorescence-activated cell sorter analysis, independent of thecagstatus. Downregulation of CXCR1 and CXCR2 seems to occur via receptor internalization and rapid degradation, as shown by confocal microscopy and immunoblotting. Neither the proinflammatory cytokines IL-8 and tumor necrosis factor alpha produced by the neutrophils themselves norH. pylorilipopolysaccharide, which are the known regulators of these two chemokine receptors, was responsible for the downregulation. Reverse transcription-PCR analysis showed that CXCR1 and CXCR2 mRNAs of neutrophils were reduced at a later time than the CXCR1 and CXCR2 proteins. Moreover,cag+H. pyloristrains induced significantly stronger downregulation of CXCR1 and CXCR2 mRNAs than thecagdeletion mutant. Therefore, receptor protein and mRNA downregulation seem to be mediated by two independent mechanisms. Data obtained by immunohistochemistry suggested that downmodulation of CXCR1 and CXCR2 on neutrophils may also occur in vivo in the human stomach duringH. pyloriinfection. Downregulation of CXCR1 and CXCR2 expression on neutrophils inH. pyloriinfection byH. pyloriitself may represent a new mechanism of modulating neutrophil migration and activation in the gastric mucosa.
Rapid Sequential Changeover of Expressed
p44
Genes during the Acute Phase of
Anaplasma phagocytophilum
Infection in Horses
Authors: Wang Xueqi , Rikihisa Yasuko , Lai Tzung-Hui , Kumagai Yumi , Zhi Ning , Reed Stephen M.
Published: November 2004

Anaplasma phagocytophilum
immunodominant polymorphic major surface protein P44s have been hypothesized to go through antigenic variation, but the within-host dynamics of
p44
expression has not been demonstrated. In the present study we investigated the composition and changes of
p44
transcripts in the blood during the acute phase of well-defined laboratory
A. phagocytophilum
infections in naïve equine hosts. Three traveling waves of sequential population changeovers of the
p44
transcript species were observed within a single peak of rickettsemia of less than 1 month. During the logarithmic increase, the rapid switch-off of the initial dominant transcript
p44-18
occurred regardless of whether the bacterium was transmitted by ticks or by intravenous inoculation. Each of the subsequently dominant
p44
transcript species was phylogenetically dissimilar from
p44-18
. Development of antibody to the hypervariable region of P44-18 during the rickettsemia suggests the suppression of dominance of immuno-cross-reactive
p44
populations. When
A. phagocytophilum
was preincubated with plasma from the infected horse and then coincubated with HL-60 cells, the dominance of the
p44-18
transcript was rapidly suppressed in vitro and most of the newly emerged
p44
transcript species were previously undetected in this horse. This work provides experimental evidence of within-host
p44
antigenic variation. Results suggest that the rapid and synchronized switch of expression is an intrinsic property of
p44
s reinitiated after transmission to naïve mammalian hosts and shaped upon exposure to immune plasma.
Identification of TwoMycobacterium marinumLoci That Affect Interactions with Macrophages
Authors: El-Etr Sahar H. , Subbian Selvakumar , Cirillo Suat L. G. , Cirillo Jeffrey D.
Published: November 2004

Mycobacterium marinumis closely related toMycobacterium tuberculosis, the cause of tuberculosis in humans.M. marinumhas become an important model system for the study of the molecular mechanisms involved in causing tuberculosis in humans. Through molecular genetic analysis of the differences between pathogenic and nonpathogenic mycobacteria, we identified two loci that affect the ability ofM. marinumto infect macrophages, designatedmel1andmel2. In silico analyses of the 11 putative genes in these loci suggest thatmel1encodes secreted proteins that include a putative membrane protein and two putative transglutaminases, whereasmel2is involved in secondary metabolism or biosynthesis of fatty acids. Interestingly,mel2is unique toM. marinumand theM. tuberculosiscomplex and not present in any other sequenced mycobacterial species.M. marinummutants with mutations inmel1andmel2, constructed by allelic exchange, are defective in the ability to infect both murine and fish macrophage cell lines. These data suggest that the genes inmel1andmel2are important for the ability ofM. marinumto infect host cells.
Nitric Oxide Production and Nitric Oxide Synthase Activity in Malaria-Exposed Papua New Guinean Children and Adults Show Longitudinal Stability and No Association with Parasitemia
Authors: Boutlis Craig S. , Weinberg J. Brice , Baker Joanne , Bockarie Moses J. , Mgone Charles S. , Cheng Qin , Anstey Nicholas M.
Published: November 2004

Individuals in areas of intense malaria transmission exhibit resistance (or tolerance) to levels of parasitemia in their blood that would normally be associated with febrile illness in malaria-naïve subjects. The resulting level of parasitemia associated with illness (the pyrogenic threshold) is highest in childhood and lowest in adulthood. Clinical parallels between malarial and bacterial endotoxin tolerance have led to the supposition that both share common physiological processes, with nitric oxide (NO) proposed as a candidate mediator. The hypotheses that NO mediates tolerance and blood stage parasite killing in vivo were tested by determining its relationship to age and parasitemia cross-sectionally and longitudinally in a population of 195 children and adults from Papua New Guinea encountering intense malaria exposure. Despite pharmacological clearance of asymptomatic parasitemia, NO production and mononuclear cell NO synthase (NOS) activity were remarkably stable within individuals over time, were not influenced by parasitemia, and varied little with age. These results contrast with previous smaller cross-sectional studies. Baseline NO production and NOS activity did not protect against recurrent parasitemia, consistent with previous data suggesting that NO does not have antiparasitic effects against blood stage infection in vivo. The NO indices studied were markedly higher in specimens from study subjects than in samples from Australian controls, and NOS activity was significantly associated with plasma immunoglobulin E levels, consistent with induction of NO by chronic exposure to other infections and/or host genetic factors. These results suggest that NO is unlikely to mediate killing of blood stage parasites in this setting and is unlikely to be the primary mediator in the acquisition or maintenance of malarial tolerance.
A Heterologous DNA Priming-
Mycobacterium bovis
BCG Boosting Immunization Strategy Using Mycobacterial Hsp70, Hsp65, and Apa Antigens Improves Protection against Tuberculosis in Mice
Authors: Ferraz Jose C. , Stavropoulos Evangelos , Yang Min , Coade Steve , Espitia Clara , Lowrie Douglas B. , Colston M. Joseph , Tascon Ricardo E.
Published: November 2004

Tuberculosis is responsible for >2 million deaths a year, and the number of new cases is rising worldwide. DNA vaccination combined with
Mycobacterium bovis
bacillus Calmette Guérin (BCG) represents a potential strategy for prevention of this disease. Here, we used a heterologous prime-boost immunization approach using a combination of DNA plasmids and BCG in order to improve the efficacy of vaccination against
Mycobacterium tuberculosis
infection in mice. As model antigens, we selected the
M. tuberculosis
Apa (for alanine-proline-rich antigen) and the immunodominant Hsp65 and Hsp70 mycobacterial antigens combined with BCG. We demonstrated that animals injected with a combination of DNA vectors expressing these antigens, when boosted with BCG, showed increased specific antimycobacterial immune responses compared to animals vaccinated with BCG alone. More importantly, the protection achieved with this regimen was also significantly better than with BCG alone.
The C-Terminal Fragment of the Internal 110-Kilodalton Passenger Domain of the Hap Protein of NontypeableHaemophilus influenzaeIs a Potential Vaccine Candidate
Authors: Liu Dai-Fang , Mason Kathryn W. , Mastri Maria , Pazirandeh Mehran , Cutter David , Fink Doran L. , St. Geme Joseph W. , Zhu Duzhang , Green Bruce A.
Published: November 2004

NontypeableHaemophilus influenzaeis a major causative agent of bacterial otitis media in children.H. influenzaeHap autotransporter protein is an adhesin composed of an outer membrane Hapβ region and a moiety of an extracellular internal 110-kDa passenger domain called HapS. The HapSmoiety promotes adherence to human epithelial cells and extracellular matrix proteins, and it also mediates bacterial aggregation and microcolony formation. A recent work (D. L. Fink, A. Z. Buscher, B. A. Green, P. Fernsten, and J. W. St. Geme, Cell. Microbiol.5:175-186, 2003) demonstrated that HapSadhesive activity resides within the C-terminal 311 amino acids (the cell binding domain) of the protein. In this study, we immunized mice subcutaneously with recombinant proteins corresponding to the C-terminal region of HapSfromH. influenzaestrains N187, P860295, and TN106 and examined the resulting immune response. Antisera against the recombinant proteins from all three strains not only recognized native HapSpurified from strain P860295 but also inhibitedH. influenzaeHap-mediated adherence to Chang epithelial cells. Furthermore, when mice immunized intranasally with recombinant protein plus mutant cholera toxin CT-E29H were challenged with strain TN106, they were protected against nasopharyngeal colonization. These observations demonstrate that the C-terminal region of HapSis capable of eliciting cross-reacting antibodies that reduce nasopharyngeal colonization, suggesting utility as a vaccine antigen for the prevention of nontypeableH. influenzaediseases.
Relative Contributions of
Pseudomonas aeruginosa
ExoU, ExoS, and ExoT to Virulence in the Lung
Authors: Shaver Ciara M. , Hauser Alan R.
Published: November 2004

Pseudomonas aeruginosa
uses a type III secretion system to promote development of severe disease, particularly in patients with impaired immune defenses. While the biochemical and enzymatic functions of ExoU, ExoS, and ExoT, three effector proteins secreted by this system, are well defined, the relative roles of each protein in the pathogenesis of acute infections is not clearly understood. Since ExoU and ExoS are usually not secreted by the same strain, it has been difficult to directly compare the effects of these proteins during infection. In the work described here, several isogenic mutants of a bacterial strain that naturally secretes ExoU, ExoS, and ExoT were generated to carefully evaluate the relative contribution of each effector protein to pathogenesis in a mouse model of acute pneumonia. Measurements of mortality, bacterial persistence in the lung, and dissemination indicated that secretion of ExoU had the greatest impact on virulence while secretion of ExoS had an intermediate effect and ExoT had a minor effect. It is of note that these results conclusively show for the first time that ExoS is a virulence factor. Infection with isogenic mutants secreting wild-type ExoS, ExoS defective in GTPase-activating protein (GAP) activity, or ExoS defective in ADP-ribosyltransferase activity demonstrated that the virulence of ExoS was largely dependent on its ADP-ribosyltransferase activity. The GAP activity of this protein had only a minor effect in vivo. The relative virulence associated with each of these type III effector proteins may have important prognostic implications for patients infected with
P. aeruginosa
.