bluuebunny/crossref_metadata_2025 huggingface dataset:
Hybrid magnetohydrodynamic–kinetic model of standing shear Alfvén waves
Authors: DAMIANO PETER A. , SYDORA R. D. , SAMSON J. C.
Published: August 2003

We have developed a hybrid magnetohydrodynamics (MHD) –kinetic box model valid for standing shear Alfvén waves using the cold plasma MHD equations coupled to a system of kinetic electrons. The guiding centre equations are used for the motion of the electrons and the system is closed via an expression for the field-aligned electric field in terms of the perpendicular electric field and moments of the electron distribution function. The perpendicular electric fields are derived from the ideal MHD approximation. We outline the basic model equations and method of solution. Simulations are then presented comparing the hybrid model results with a cold plasma MHD model. Landau damping is shown to heavily damp the standing shear Alfvén wave in the hybrid simulations when $v_{th} \ge V_{A}$. The damping rate is shown to be in good agreement with the theoretical rate calculated for the model parameters.
RAMASD: a semi-automatic method for designing agent organisations
Authors: KARAGEORGOS ANTHONY , MEHANDJIEV NIKOLAY , THOMPSON SIMON
Published: August 2003

Designing realistic multi-agent systems is a complex process, which involves specifying not only the functionality of individual agents, but also the authority relationships and lines of
communication existing among them. In other words, designing a multi-agent system refers to designing an agent organisation. Existing methodologies follow a wide variety of approaches to designing agent organisations, but they do not provide adequate support for the decisions involved in moving from analysis to design. Instead, they require designers to make ad hoc design decisions while working at a low level of abstraction.

We have developed RAMASD (Role Algebraic Multi-Agent System Design), a method for semi-automatic design of agent organisations based on the concept of role models as first-class design
constructs. Role models represent agent behaviour, and the design of the agent system is done by systematically allocating roles to agents. The core of this method is a formal model of basic relations between roles, which we call role algebra. The semantics of this role-relationships model are formally defined using a two-sorted algebra.

In this paper, we review existing agent system
design methodologies to highlight areas where further work is required, describe how our method can address some of the outstanding issues and demonstrate its application to a case study involving
telephone repair service teams.
J. Robert Oppenheimer: Proteus Unbound
Authors: Schweber Silvan S.
Published: August 2003

Argument

J. Robert Oppenheimer was a complex person. His work in physics during the 1930s, at Los Alamos during the 1940s, and as governmental advisor in the immediate postwar period, gave him a deep sense of connection with communities that had distinctive purposes. But he found it difficult to conceive an overall creative vision for himself or to devise a compelling objective for the community he belonged to if one had not been formulated at the time he assumed its leadership. I analyze the reasons for his successes: the vision and demands of physics during the 1930s, the make-up of Los Alamos, and the challenges of the postwar atomic world. In each of these enterprises he assumed a distinctive role and came to represent a distinctive persona – but he could not integrate his activities into a coherent whole that might be a model for the intellectual in the new world he had helped to shape.
Objectivity and the Scientist: Heisenberg Rethinks
Authors: Carson Cathryn
Published: August 2003

Argument

Objectivity has been constitutive of the modern scientific persona. Its significance has depended on its excision of standpoint, which has legitimated the scientist epistemically and sociopolitically at once. But if the nineteenth century reinforced those paired effects, the twentieth century brought questioning of both. The figure of Werner Heisenberg (1901–1976) puts the latter process on display. From the Kaiserreich to the Federal Republic of Germany, between quantum mechanics and interest group politics, his evolution shows an increasing openness to perspectival pluralism, together with an attempt to save some form of objectivity as discursive coherence. Heisenberg’s self-understanding and the reactions of his publics display the transmutation of the persona as objectivity was rethought. By the end of the day, speaking “as a scientist” would mean something different from what it had at the start.
Charles Darwin as a Celebrity
Authors: Browne Janet
Published: August 2003

Argument

Several recent works in sociology examine the manufacture of public identities through the notion of celebrity. This paper explores the imagery of Charles Darwin as a nineteenth-century scientific celebrity by comparing the public character deliberately manufactured by Darwin and his friends with images constructed by the public as represented here by caricatures in humorous magazines of the era. It is argued that Darwin’s outward persona drew on a subtle tension between public and private. The boundaries between public and private were blurred by the ritual of Darwin “showing” himself in the flesh, either at home to visitors or, more rarely, on public occasions. The reputation for privacy and illness that he built up added materially to this public face. By contrast, caricatures tended to depict him as an ape. These apish representations played a significant role in associating Darwin, rather than any other thinker, with the notion of evolution, and in creating an alternative public persona over which he had no direct control.
Skulls, Brains, and Memorial Culture: On Cerebral Biographies of Scientists in the Nineteenth Century
Authors: Hagner Michael
Published: August 2003

Argument

In this paper I will argue that the scientific investigation of skulls and brains of geniuses went hand in hand with hagiographical celebrations of scientists. My analysis starts with late-eighteenth century anatomists and anthropologists who highlighted quantitative parameters such as the size and weight of the brain in order to explain intellectual differences between women and men and Europeans and non-Europeans, geniuses and ordinary persons. After 1800 these parameters were modified by phrenological inspections of the skull and brain. As the phrenological examination of the skulls of Immanuel Kant, Wilhelm Heinse, Arthur Schopenhauer and others shows, the anthropometrical data was interpreted in light of biographical circumstances. The same pattern of interpretation can be found in non-phrenological contexts: Reports about extraordinary brains were part of biographical sketches, mainly delivered in celebratory obituaries. It was only in this context that moral reservations about dissecting the brains of geniuses could be overcome, which led to a more systematic investigation of brains of geniuses after 1860.
Geometric numerical integration illustrated by the Störmer–Verlet method
Authors: Hairer Ernst , Lubich Christian , Wanner Gerhard
Published: August 2003

The subject of geometric numerical integration deals with numerical integrators that preserve geometric properties of the flow of a differential equation, and it explains how structure preservation leads to improved long-time behaviour. This article illustrates concepts and results of geometric numerical integration on the important example of the Störmer–Verlet method. It thus presents a cross-section of the recent monograph by the authors, enriched by some additional material.

After an introduction to the Newton–Störmer–Verlet–leapfrog method and its various interpretations, there follows a discussion of geometric properties: reversibility, symplecticity, volume preservation, and conservation of first integrals. The extension to Hamiltonian systems on manifolds is also described. The theoretical foundation relies on a backward error analysis, which translates the geometric properties of the method into the structure of a modified differential equation, whose flow is nearly identical to the numerical method. Combined with results from perturbation theory, this explains the excellent long-time behaviour of the method: long-time energy conservation, linear error growth and preservation of invariant tori in near-integrable systems, a discrete virial theorem, and preservation of adiabatic invariants.
Ability of a global three‐dimensional model to locate regional events
Authors: Ritzwoller M. H. , Shapiro N. M. , Levshin A. L. , Bergman E. A. , Engdahl E. R.
Published: August 2003

We assess the ability of a global three‐dimensional (3D) seismic model of the crust and upper mantle (CUB2.0) to locate seismic events using regional travel time data alone (epicentral distances <20°). Assessments are based on a “ground truth” (GT) database, comprising nearly 1000 uncommonly well‐located events which occur in 23 event clusters across Eurasia and North Africa, groomed P and Pn arrival time data observed at regional distances from individual events, and ∼1000 empirical phase path anomalies produced from event clusters. Evidence is presented that supports the conversion of the shear velocities (vs) in CUB2.0 to compressional velocities (vp) in the upper mantle using the thermoelastic properties of an assumed mantle composition rather than traditional empirical scaling relationships. Two principal results are presented. First, this 3D vp model fits the empirical P and Pn phase path anomalies very well in both pattern and absolute level. Second, location assessments demonstrate that intrinsic regional location accuracy is ∼5 km using the 3D vp model and ∼10 km using the 1D model AK135. These findings highlight the importance of GT databases in assessing regional travel time models and establish that a global 3D vs model, together with vp inferred from it, provides a solid basis on which to build improvements in regional location capabilities.
Imaging the transition between the region of mantle melt generation and the crustal magma chamber beneath the southern East Pacific Rise with short‐period Love waves
Authors: Dunn Robert A. , Forsyth Donald W.
Published: August 2003

Beneath the southern East Pacific Rise resides a crustal magma chamber confined to the immediate vicinity of the rise axis, yet the mantle melt production region is broad and asymmetric. Short‐period (4–17 s) Love waves propagating along the rise provide a means of probing the transition from the asymmetric melt production region to the rise‐centered crustal magma chamber. Low velocities beneath the rise act as a waveguide for Love wave energy. We model this complex wave propagation with a Gaussian beam representation as part of our nonlinear inversion for velocity structure. Our results show that the asymmetry exists at the crust‐mantle interface, or Moho, and increases downward; the lowest velocities are located beneath the rise at the Moho; beneath the rise there is an asymmetric gap in the high‐velocity “lid” at the top of the mantle; and there are lower asthenospheric velocities beneath the Pacific plate than the Nazca plate. The transition from the broad upwelling region to the narrow crustal magmatic system occurs over a ∼15‐km‐depth interval at the top of the mantle. Our observations indicate higher temperatures and greater melt production beneath the Pacific plate. East of the rise, melting appears to abruptly shut off at shallow levels, perhaps due to a component of downward mantle flow. We suggest that melt percolates upward, increasing in concentration, until reaching a permeability barrier beneath the lithosphere, it then moves up along the lithosphere to accumulate at the Moho beneath the rise. West of the rise, higher temperatures and upward percolation of melt delay growth of the lithosphere.
Space weathering effects on lunar cold trap deposits
Authors: Crider Dana Hurley , Vondrak Richard R.
Published: August 2003

Both steady and episodic sources have been proposed as sources of hydrogen observed by Lunar Prospector in association with the regions of permanent shadow at the poles of the Moon. Either source could supply significant quantities of water to the poles. However, space weathering processes affect the retention of water in the cold traps. We investigate those effects by simulating the evolution of a column of regolith in the region of permanent shadow over time. We determine the hydrogen concentration as a function of depth using a Monte Carlo model of discrete impacts and of delivery from the solar wind. We treat the delivery, sublimation, sputtering, and very small scale impacts as continual processes. Comparing the amount of water delivered to the poles to the amount remaining after space weathering, we find a retention efficiency of 5.6%. The retention efficiency of the polar cold traps is adequate for preserving volatile deposits over long periods of time. The average hydrogen concentration in the regolith column is 4100 ppm in the top meter after 1 Gyr. This is a saturation level in the regolith. Increasing the amount of time deepens the enriched layer but does not lead to increased concentrations. In 1 Gyr, about 1.6 m of the regolith is gardened. Therefore the top meter, which is probed by the neutron spectroscopy technique, has reached steady state in the simulations. The 4100 ppm saturation level is about half of the amount of hydrogen inferred from the Lunar Prospector neutron data.
Arctic Ocean during the Last Glacial Maximum: Atlantic and polar domains of surface water mass distribution and ice cover
Authors: Nørgaard‐Pedersen Niels , Spielhagen Robert F. , Erlenkeuser Helmut , Grootes Pieter M. , Heinemeier Jan , Knies Jochen
Published: August 2003

On the basis of 52 sediment cores, analyzed and dated at high resolution, the paleoceanography and climate of the Last Glacial Maximum (LGM) were reconstructed in detail for the Fram Strait and the eastern and central Arctic Ocean. Sediment composition and stable isotope data suggest three distinct paleoenvironments: (1) a productive region in the eastern to central Fram Strait and along the northern Barents Sea continental margin characterized by Atlantic Water advection, frequent open water conditions, and occasional local meltwater supply and iceberg calving from the Barents Sea Ice Sheet; (2) an intermediate region in the southwestern Eurasian Basin (up to 84–85°N) and the western Fram Strait characterized by subsurface Atlantic Water advection and recirculation, a moderately high planktic productivity, and a perennial ice cover that breaks up only occasionally; and (3) a central Arctic region (north of 85°N in the Eurasian Basin) characterized by a low‐salinity surface water layer and a thick ice cover that strongly reduces bioproduction and bulk sedimentation rates. Although the total inflow of Atlantic Water into the Arctic Ocean may have been reduced during the LGM, its impact on ice coverage and halocline structure in the Fram Strait and southwestern Eurasian Basin was strong.
A new model for soil hydraulic properties based on a stochastic conceptualization of porous media
Authors: Chan T. P. , Govindaraju R. S.
Published: August 2003

The nature and distribution of soil particles and pores plays a strong role in determining the soil hydraulic properties (specifically the soil water retention curve and the relative hydraulic conductivity curve) that govern water movement. A new mathematical model for these hydraulic properties was developed by conceptualizing the soil as a random assemblage of soil particles represented by randomly sized overlapping spheres (fully penetrable spheres). The spatial arrangement of the spheres was assumed to follow a homogeneous Poisson process. A stochastic analysis was utilized to obtain analytical expressions for soil water retention curves and relative conductivity at varying water contents. Unlike the existing models of soil hydraulic properties, this new model incorporates soil porosity in estimating model parameters. Furthermore, because of this conceptualization, we are able to determine the types of soils for which the model is appropriate. A quantitative evaluation of the new model was performed by examining data on hydraulic properties for several soils. In addition, quantitative and qualitative comparisons were made with currently used expressions (such as the van Genuchten model, Brooks‐Corey relationship, and Kosugi model) for the same data sets. Results show that the new model provides reasonable fits with the observed water retention curve and good predictions of the hydraulic conductivity, particularly for soils exhibiting a distinct air entry pressure.
Improving climatic signal representation in tropical ice cores: A case study from the Quelccaya Ice Cap, Peru
Authors: Seimon Anton
Published: August 2003

The published ice core records for Quelccaya, Peru are shown to contain numerous errors in annual layer determination, introduced by the subjective methodology of the original analysis. A new methodology is presented that aligns and then merges d18O sample measurement profiles from the two Quelccaya cores. Absolute dating of the stratigraphy is established by comparison of prominent dust anomalies with documented earthquake reference‐marker events. The results demonstrate that the original sample measurements can register a comprehensive millennial climate history at sub‐annual resolution, thus also offering great potential for clearer interpretations of ENSO signals in tropical Andean ice cores.
Three‐dimensional radiative interactions in a polluted broken cloud system
Authors: Podgorny I. A.
Published: August 2003

This paper is a theoretical study of short‐wave radiative interactions in a polluted broken cloud scene encountered during the Indian Ocean Experiment (INDOEX). Towards this goal, the nadir reflectance has been obtained by integrating INDOEX in‐situ observations and a 3D Monte‐Carlo Aerosol‐Cloud radiation model. The comparison of 2D radiative transfer and independent pixel approximation (IPA) results demonstrates that IPA substantially underestimates nadir reflectances between the clouds. The effect can be explained by the radiative smoothing resulting from the horizontal photon transport. For the polluted cloud scene considered, the radiative smoothing is responsible for a 50% bias in aerosol optical depth retrieved between the clouds based on the plane‐parallel theory.
Coupled vegetation‐precipitation variability observed from satellite and climate records
Authors: Lotsch Alexander , Friedl Mark A. , Anderson Bruce T. , Tucker Compton J.
Published: August 2003

Variability in precipitation regimes at seasonal and longer time scales strongly influences ecosystem dynamics in arid and semi‐arid regions. In this paper, we use time series of global precipitation and satellite normalized difference vegetation index (NDVI) data to analyze joint spatial and temporal variability between terrestrial ecosystems and precipitation regimes. Accumulated monthly rainfall anomalies are quantified using a standardized precipitation index (SPI), which provides a better measure of ecologically significant precipitation excess or deficit at growing season time scales relative to monthly precipitation data. Results from canonical correlation analysis reveal geographically extensive patterns of joint NDVI‐SPI variability suggestive of strong climate‐biosphere coupling. Further, leading modes of covariability are shown to be related to large‐scale ocean‐atmosphere circulation anomalies. These results illustrate the global extent and sensitivity of ecosystems susceptible to climate change‐induced perturbations in precipitation regimes.
Scalings for large turbulent flow structures in gravel‐bed rivers
Authors: Paiement‐Paradis Geneviève , Buffin‐Bélanger Thomas , Roy André G.
Published: August 2003

The relations between frequency and duration of large‐scale turbulent flow structures in gravel‐bed rivers and the distributions of the time intervals between turbulent events are investigated using flow visualisation and velocity measurements. The time of occurrence and the duration and amplitude of large bursting motions were estimated independently from a five minute underwater video and from high‐resolution velocity time series sampled at 20 Hz during 38 minutes at three heights above the bed. Results from both experiments show that the frequency‐duration relations of the large‐scale turbulent flow structures follow a power function with exponents ranging between −1.4 and −1.95, values that are typical of bursting systems (e.g., solar flares). The frequency distributions of time intervals between two successive ejections display an exponential tail. These findings provide models for simulating sequences of large‐scale turbulent events in a gravel‐bed river, an important step in linking flow turbulence and sediment transport.
Explanation of discrepancies among satellite observations of the aerosol indirect effects
Authors: Rosenfeld Daniel , Feingold Graham
Published: August 2003

Satellite‐based remote sensing instruments for measuring the aerosol indirect effect (IE = −d ln re/d ln τa where re is the cloud drop effective radius and τa is the aerosol optical depth) show large disparities in the magnitude of the effect for similar regions of the globe. Over the oceans, the Advanced Very High Resolution Radiometer (AVHRR) measures an indirect effect twice that measured by the POLarization and Directionality of the Earth Reflectances (POLDER) (0.17 vs. 0.085). We address possible reasons for these disparities. It is argued that AVHRR misses the optically thin and broken clouds, especially over land, while POLDER misses clouds with variable top heights in its field of view. POLDER is also biased to thinner, less turbulent clouds. The sensitivity of the indirect effect to cloud turbulence therefore biases POLDER to lower values. POLDER measures an indirect effect over the ocean that is about twice that over the land (0.085 vs. 0.04). By considering factors such as dynamics, variability in cloud liquid water path, decoupling of the boundary layer, and the effect of salt particles, we argue that this could be an artifact, and that the indirect effect on cloud microstructure may be stronger over land than over the ocean.
Induction of carbohydrate‐specific antibodies in HLA‐DR transgenic mice by a synthetic glycopeptide: a potential anti cancer vaccine for human use
Authors: Vichier‐Guerre S. , Lo‐Man R. , BenMohamed L. , Dériaud E. , Kovats S. , Leclerc C. , Bay S.
Published: August 2003

Abstract: Over the last few years, anticancer immunotherapy has emerged as a new exciting area for controlling tumors. In particular, vaccination using synthetic tumor‐associated antigens (TAA), such as carbohydrate antigens hold promise for generating a specific antitumor response by targeting the immune system to cancer cells. However, development of synthetic vaccines for human use is hampered by the extreme polymorphism of human leukocyte‐associated antigens (HLA). In order to stimulate a T‐cell dependent anticarbohydrate response, and to bypass the HLA polymorphism of the human population, we designed and synthesized a glycopeptide vaccine containing a cluster of a carbohydrate TAA B‐cell epitope (Tn antigen: α‐GalNAc‐Ser) covalently linked to peptides corresponding to the Pan DR ‘universal’ T‐helper epitope (PADRE) and to a cytotoxic T lymphocyte (CTL) epitope from the carcinoembryonic antigen (CEA). The immunogenicity of the construct was evaluated in outbred mice as well as in HLA transgenic mice (HLA‐DR1, and HLA‐DR4). A strong T‐cell dependent antibody response specific for the Tn antigen was elicited in both outbred and HLA transgenic mice. The antibodies induced by the glycopeptide construct efficiently recognized a human tumor cell line underlying the biological relevance of the response. The rational design and synthesis of the glycopeptide construct presented herein, together with its efficacy to induce antibodies specific for native tumor carbohydrate antigens, demonstrate the potential of a such synthetic molecule as an anticancer vaccine candidate for human use.
Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study
Authors: Benfield Mark R. , McDonald Ruth A. , Bartosh Sharon , Ho P. L. , Harmon William
Published: July 2003

Abstract:  The North American Pediatric Renal Transplant Cooperative Study has collected clinical information on children undergoing a renal transplantation since 1987. This cooperative group now includes over 150 participating medical centers in the United States, Canada, Mexico, and Costa Rica. This report covers the years from 1987 through 2001 and includes data on 7545 renal transplants in 6878 patients. This report demonstrates changing trends in many areas of pediatric transplantation including increasing numbers of African American and Hispanic children receiving transplantation, remarkable improvements in the rate of acute rejection, rejection reversal, and short‐ and long‐term allograft survival. In the most recent cohorts of patients, we now see that 1‐yr allograft survival is no different in cadaver donor compared to living donor recipients and in infants compared to all other age groups. However, this analysis also reveals areas of continued challenges including inferior outcomes in African American and adolescent populations, chronic rejection, and the adverse effects of immunosuppression.
Renal function following liver transplantation for unresectable hepatoblastoma
Authors: Lee W. S. , Grundy R. , Milford D. V. , Taylor C. M. , de Ville de Goyet J. , McKiernan P. J. , Beath S. V. , Kelly D. A.
Published: July 2003

Abstract: Combination of cyclosporine (CsA) and tacrolimus immunosuppression post‐liver transplantation (LT) and the chemotherapeutic drugs used to treat hepatoblastoma (HB), are nephrotoxic. We aimed to determine the severity and duration of nephrotoxicity in children following LT for unresectable HB. We reviewed all children undergoing LT for unresectable HB at the Liver Unit, Birmingham Children's Hospital, UK, from 1991 to July 2000. Thirty‐six children undergoing LT for biliary atresia, matched for age and sex, were selected as controls to compare pre‐ and post‐LT renal function. Renal function was determined by estimation of glomerular filtration rate (eGFR) derived from plasma creatinine using Schwartz's formula. Twelve children with HB (mean age of diagnosis 33 months) who underwent LT (mean age 47 months) and 36 controls (mean age of LT 34 months) were studied. CsA was the main immunosuppressive drug used in each group. The median eGFR before, and at 3, 6, 12, 24 and 36 months after LT in HB group was significantly lower than controls (93 vs. 152, 66 vs. 79, 62 vs. 86, 66 vs. 87, 64 vs. 94, 53 vs. 90 mL/min/1.73 m2, respectively; 0.01 < p < 0.03). The reductions in the median eGFR of both the HB group and controls before and at 36 months after LT were 49 and 41%, respectively. At 36 months after LT, there was a trend for partial recovery of the eGFR in the controls but not in the HB group. Children who underwent LT for unresectable HB had renal dysfunction before transplantation that persisted for 36 months after LT.
Anemia in children after transplantation: etiology and the effect of immunosuppressive therapy on erythropoiesis
Authors: Al‐Uzri Amira , Yorgin Peter D. , Kling Pamela J.
Published: July 2003

Abstract:Anemia in children after renal transplantation is more common than previously appreciated. Multiple factors appear to play roles in the development of post‐transplant anemia, the most common of which is absolute and/or functional iron deficiency anemia. Most experts recommend that iron limited anemias in transplant patients should be diagnosed using the same criteria as for chronic renal failure patients. Serum erythropoietin (EPO) levels are expected to normalize after a successful renal transplantation with a normal kidney function, yet both EPO deficiency and resistance have been reported. While no large controlled trials comparing the effect of different immunosuppressive agents on erythropoiesis after transplantation have been performed, generalized bone marrow suppression attributable to azathioprine (AZA), mycophenolate mofetil (MMF), tacrolimus, antithymocyte preparations has been reported. Pure red cell aplasia (PRCA) occurs rarely after transplantation and is characterized by the selective suppression of erythroid cells in the bone marrow. PRCA has been reported with the use of AZA, MMF, tacrolimus, angiotensin converting enzyme inhibitors (ACEI), but not with cyclosporine (CSA) use. Post‐transplant hemolytic uremic syndrome has been reported with orthoclone anti T‐cell antibody (OKT3), CSA and tacrolimus therapy. Viral infections including cytomegalovirus, Epstein–Barr virus and human parvovirus B19 have been reported to cause generalized marrow suppression. Management of severe anemia associated with immunosuppressive drugs generally requires lowering the dose, drug substitution or, when possible, discontinuation of the drug. Because this topic has been incompletely studied, our recommendation as to the best immunosuppressive protocol after renal transplantation remains largely dependent on the clinical response of the individual patient.
Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral®) in pediatric renal transplant recipients and assessment of C2level as a marker for absorption
Authors: Trompeter Richard , Fitzpatrick Margaret , Hutchinson Carol , Johnston Atholl
Published: July 2003

Abstract:Background:There are important differences in CsA pharmacokinetics between adult and pediatric patients, such that pharmacokinetic data can not necessarily be extrapolated from the adult to the pediatric setting. Research in adult renal transplant patients has shown that adequate cyclosporin exposure (AUC0−4) in the first week post‐transplant is important for successful clinical outcome, and that cyclosporin concentration at 2 h post‐dose (C2) provides the optimal single‐time point marker for AUC0−4. Clinically, dose management based on C2level results in a low incidence of acute rejection in the adult renal transplant population. The study reported here undertook pharmacokinetic profiling inde novorenal transplant patients over a period of 6 months and retrospectively assessed alternative monitoring strategies based on pharmacokinetic findings and clinical outcomes.

Methods:This open‐label, observational, prospective study was carried out at four UK transplant centers over a period of 6 months in pediatricde novorenal transplant recipients receiving the microemulsion formulation of cyclosporin (Neoral®) according to local protocol. Twelve‐hour pharmacokinetic profiles (8–16 blood samples each) were performed on days 5 and 14 and at weeks 4, 13 and 26 post‐transplant.

Results:Thirty‐two patients were recruited (median age 10 yr, range 3–18 yr). At 6 months, patient survival was 100% and graft survival was 91%. The incidence of clinically determined acute rejection was 41% (13 of 32). Six patients discontinued Neoral before 6 months: three due to graft loss, one due to rejection, one due to renal toxicity and one due to hypertrichosis. At all time points studied, C2correlated more closely with AUC0−4and with AUC0−12than did the pre‐dose cyclosporin concentration (C0, or trough). Patients achieving C2 > 1.5 μg/mL by the fifth postoperative day experienced no acute rejection in the first 6 months, compared with a 50% rejection rate among patients with C2 < 1.5 μg/mL (P < 0.05). Binary logistic regression analysis showed that C2level >1.7 μg/mL was associated with approximately 90% probability of freedom from acute rejection. Analysis of renal function across patients grouped according to cyclosporine exposure (AUC0−4, C2) showed no adverse effects of higher/increased exposure on creatinine or GFR.

Conclusions:C2level provides a more reliable marker for CsA exposure than C0in pediatric renal transplant recipients, and is more closely predictive of acute rejection risk. A C2target of 1.7 μg/mL appears appropriate in this population during the immediate post‐transplant period in order to maximize clinical benefit.
Non‐cardiogenic pulmonary edema during basiliximab induction in three adolescent renal transplant patients
Authors: Bamgbola Fatai O. , Rio Marcela Del , Kaskel Fredrick J. , Flynn Joseph T.
Published: July 2003

Abstract:  Background:  Introduction of the anti‐CD‐25 mAb basiliximab into renal transplant protocols has reduced the incidence of acute rejection. However, its side‐effect profile is still unfolding. We report three adolescents who developed severe non‐cardiogenic PE within 2 days of renal transplantation.

Methods:  Pretransplant cardiorespiratory evaluation was normal in all cases. Transplant immunosuppression consisted of basiliximab induction, corticosteroids, and tacrolimus. Patients received standard fluid management during and after the transplant surgery.

Case reports:  Patients 1 and 2 were 17‐ and 21‐yr‐old females. Pretransplant Hct values were 35 and 25% respectively. Each received 5‐L normal saline during surgery. EBL was 200 and 500 mL in patients 1 and 2, respectively. There was immediate post‐operative diuresis. Both developed non‐cardiogenic PE by POD no. 2. BIPAP and PRVC were administered respectively. In both cases PE resolved within 1 wk. Patient 3 was a 19‐yr‐old male with pretransplant Hct of 43% who received a cadaveric renal transplant after 23.5‐h cold‐ischemia; 3.5 L normal saline was given during surgery. EBL was 100 mL. Non‐cardiogenic PE ensued on POD no. 2 warranting assisted ventilation. The patient died following a sudden cardiopulmonary arrest on POD no. 3.

Conclusions:  Potential mechanisms for the development of PE include cytokine release from basiliximab with increased capillary permeability, volume overload and ischemic‐reperfusion injury. Improved awareness of this potential complication, prudent fluid management, and efforts to minimize graft‐ischemia are recommended to prevent further cases.
Timed Pediatric Risk of Mortality Scores predict outcomes in pediatric liver transplant recipients
Authors: Carroll C. L. , Goodman D. M. , Superina R. A. , Whitington P. F. , Alonso E. M.
Published: July 2003

Abstract: More reliable methods are needed to identify children at risk for poor outcomes following liver transplantation. The Pediatric Risk of Mortality (PRISM) Score is a physiology‐based scoring system used to quantify risk of mortality in pediatric intensive care unit (ICU) populations. We evaluated the PRISM Score as a predictor of outcomes including survival in the pediatric liver transplant (LT) population. We retrospectively reviewed the records of 67 consecutive LTs performed between August 1997 and February 2000 at an urban, tertiary children's hospital in Chicago, IL, USA. Four PRISM Scores were calculated to determine which periods were most meaningful. A Classic PRISM Score was calculated during first 24 h of ICU admission, and three PRISM Scores were timed with the patient's transplant: a pre‐LT PRISM Score (24 h prior to transplant whether in ICU or not), a 24‐h post‐LT PRISM Score and a 48‐h post‐LT PRISM Score. These PRISM Scores and other predictors including transplant number, UNOS status and PELD Score were compared with outcomes including survival using univariate methods. The pre‐LT, the 24‐ and the 48‐h PRISM Score were associated with the post‐LT number of ventilated days (p < 0.05), ICU days (p < 0.05) and with 1‐yr survival (p < 0.04). The PRISM Scores were not related to the post‐LT hospital length of stay (LOS) or to 1‐yr re‐transplantation. The PELD Score correlated with the post‐LT hospital LOS, but was not associated with mortality or with the ICU LOS. A patient's UNOS status and Classic PRISM Score were not associated with any of the outcomes measured. PRISM Scores are valid predictors of outcome including survival in pediatric LT recipients. These findings help to demonstrate the importance in this population of a patient's general physiologic condition and its influence on the overall hospital course and survival.
Quantitative analysis of CMV DNA in children the first year after liver transplantation
Authors: Kullberg‐Lindh Carola , Ascher Henry , Krantz Marie , Lindh Magnus
Published: July 2003

CMV infection is a major problem after solid organ transplantation especially in children where primary infection is more common than in adults. Early diagnosis is critical and might be facilitated by quantitative analysis of CMV DNA in blood. In this retrospective study of 18 children who had a liver transplantation 1995–2000, serum samples were analysed by Cobas Amplicor Monitor (Roche). Four patients developed symptomatic CMV infection at a mean time of 4 wk after transplantation. They showed maximum CMV DNA levels in serum of 26 400, 1900, 1300 and 970 copies/mL, respectively. In comparison, CA Monitor was positive, at a low level (415 copies/mL), in one of 11 patients with asymptomatic (4) or latent (7) infection. CMV IgM was detected at significant levels (≥1/80) in all four patients with symptomatic, and in one with asymptomatic CMV infection. Eight patients were given one or several courses of ganciclovir. Five of these lacked symptoms of CMV disease, and had low (415 copies/mL) or undetectable CMV DNA in serum. The data suggest that quantitative analysis of CMV DNA may be of value in early identification of CMV disease and for avoiding unnecessary antiviral treatment.
Alterations of cyclosporin A metabolism induced by mycophenolate mofetil
Authors: Pape L. , Froede K. , Strehlau J. , Ehrich Jochen H. H. , Offner G.
Published: July 2003

Unexpectedly lower CsA 2‐h levels were found in patients who received additional immunosuppression by MMF in our center. The aim of this study is to prove whether there are differences in CsA metabolization when MMF is added to treatment. In 33 children who received an immunosuppression of prednisolone and CsA as well as in 15 children who were treated with additional MMF, C2 and C0 were taken. In 11 children, full AUC of CsA were obtained. C2 levelsdiffered significantly (p < 0.05) between patients treated with (617 ± 230 ng/mL) and without MMF (750 ± 271 ng/mL) but with similar CsA dosages. C2 correlated better with the AUC than CsA levels at other time points with r = 0.95. The equation AUC = 139 + 6.17 × C2 was calculated to match best in a C2‐limited sampling strategy. This formula proved to be safer than equations that had been published before. According to our findings, we suspect that MMF alters the CsA metabolism. When MMF is used in pediatric transplant recipients, either target values of CsA have to be changed or patients may require higher doses of CsA.
Monitoring and modulation of Epstein–Barr virus loads in pediatric transplant patients
Authors: Orentas Rimas J. , Schauer Dennis W. , Ellis Frederick W. , Walczak Joanna , Casper James T. , Margolis David A.
Published: July 2003

Abstract: A major risk faced by bone‐marrow and solid organ transplant patients is the development of post‐transplant lymphoproliferative disease or post‐transplant lymphoma (PTLD). In pediatric transplantation, PTLD onset is often associated with a rapid rise in Epstein–Barr virus (EBV) load in peripheral blood mononuclear cells (PBMC). We have analyzed EBV viral loads in PBMC over time using real‐time quantitative PCR in 56 patients, 19 of which have been followed for more than 1 year. In nine patients; eight bone marrow (BMT) and one kidney transplant, PTLD was associated with a rapid rise in viral load, exceeding 1 × 105 EBV genomes/μg of PBMC‐derived DNA. Four of these patients exceeded 1 × 106 EBV genomes/μg PBMC DNA. All patients with viral loads exceeding 1 × 105 EBV genomes/μg PBMC DNA were clearly at high risk for transplant‐associated mortality, with only six of nine surviving. Importantly, only one of these deaths was directly attributable to EBV. A second elevated state of EBV load, defined as exceeding 2 × 104 EBV genomes/μg PBMC, was seen in a total of 12 BMT, kidney, heart, and liver transplant patients. These patients did not appear to be at immediate lethal risk for PTLD and one EBV‐attributable death was found in this group as well. Thirty‐four transplant patients whose EBV viral load oscillated from undetectable to 10 000 EBV genomes/μg PBMC DNA are reported as well. The threshold for normal EBV viral load based on our combined experience with viral load analysis is defined as 1 × 104 EBV genomes/μg PBMC DNA. The ability to rapidly analyze EBV load allows rapid changes in viral load, such as those that occur with PTLD onset, and the impact of anti‐CD20 antibody therapy to be rapidly detected.
Lymphocyte data in Epstein–Barr‐virus induced post‐transplant lymphoproliferative disorder treated by rituximab
Authors: Entz‐Werle Natacha , Cojean Nadine , Barats Audrey , Eyer Didier , Munzer Martine , Uring‐Lambert Béatrice , Falkenrodt Annie , Babin Annie , Lutz Patrick
Published: July 2003

Abstract:  Viral infection is an important cause of morbidity and mortality in the post‐allograft period. Recently, a new therapeutic approach was developed in post‐tranplant lymphoproliferative disorder (PTLD) induced by Epstein–Barr virus (EBV): the anti‐CD20 monoclonal antibody or rituximab®. We performed a single‐center study on the treatment effectiveness of rituximab in three EBV‐induced PTLD and evaluated biologic data, such as T and B lymphocytes count, during PTLD development and treatment. Before PTLD treatment, blood cell profile showed a severe T lymphopenia with a progressive increase of CD8+ cells and B lymphopenia. Secondly, during treatment, there appeared a T response, as in primary EBV, and a regressive B lymphopenia.
Risk of hearing impairment in pediatric liver transplant recipients: A single center study
Authors: Bucuvalas John C. , O'Connor Amy , Buschle Kristen , Krug Susan , Ryckman Frederick C. , Atherton Harry , Alonso Maria P. , Balistreri William F.
Published: July 2003

Abstract:  As survival rates following liver transplantation have increased, health care providers must assess the impact of transplantation on dimensions other than traditional medical measures. Hearing impairment may adversely impact social, emotional, cognitive, academic, and speech and language development. We hypothesized that children who undergo liver transplantation are at risk for hearing impairment due to exposure to ototoxic drugs. We conducted a review of 74 children who had undergone liver transplantation between December 1996 and September 2000 at Cincinnati Children's Hospital Medical Center. Hearing was assessed at discharge by an audiologist using age and developmentally appropriate techniques. The principal outcome measure was sensorineural hearing impairment. Independent variables were age at transplantation, United Network for Organ Sharing (UNOS) status at transplantation, primary diagnosis, post‐transplant length of hospital stay, days of treatment with aminoglycosides, and days of treatment with loop diuretics. Eleven of 74 children (15%) had sensorineural hearing loss, of whom four had severe to profound hearing loss. Multivariate analyses showed that the adjusted relative risk for hearing loss in patients with hepatoblastoma was 66 and that there was a 5% increase risk for hearing loss for each additional day of hospitalization. Age at transplantation, UNOS status, and days of treatment with loop diuretics or aminoglycosides did not achieve significance in the model. Sensorineural hearing impairment occurs in a subset of pediatric patients following liver transplantation. Patients with hepatoblastoma or those who experience prolonged hospitalization after transplantation are at increased risk. Our observations are of particular importance for pediatric liver transplant recipients since the median age at transplantation is 12–18 months, a critical period for language acquisition.
β‐Glucuronidase inhibitor tectorigenin isolated from the flower of Pueraria thunbergiana protects carbon tetrachloride‐induced liver injury
Authors: Lee Hae‐Woong , Choo Min‐Kyung , Bae Eun‐Ah , Kim Dong‐Hyun
Published: July 2003

Background/Aim: To understand the relationship between the fluctuation in serum β‐glucuronidase and hepatotoxicity, an inhibitor of β‐glucuronidase was isolated from the flowers of Pueraria thunbergiana and its hepatoprotective activity was measured.

Method: Tectorigenin was isolated from the flowers of pueria thunbergiana as an inhibitor of β‐glucuronidase, and serum ALT, AST and biological parameters as markers for its hepatoprotective activity were measured on CCl4‐induced liver injury in mice. The relationship between serum β‐glucuronidase and hepatoprotective activities in mice was measured.

Results: When tectorigenin at a dose of 100 mg/kg was intraperitoneally administered on CCl4‐induced liver injury in mice, it significantly inhibited the increase of plasma ALT, AST and LDH activities. The inhibitory effect of tectorigenin is much more potent than that of dimethyl diphenyl bicarboxylate (DDB), which has been used as a commercial hepatoprotective agent. When tectoridin transformed to tectorigenin by intestinal bacteria was orally administered to mice, it showed hepatoprotective activity. However, when tectoridin was intraperitoneally administrated to mice, it did not exhibit hepatoprotective activity. Moreover, orally administered tectoridin not only inhibited β‐glucuronidase but also increased GSH content and GST activity on CCl4‐induced hepatotoxicity of mice.

Conclusion: We insist that an inhibitor of β‐glucuronidase tectorigenin may be hepatoprotective and tectoridin should be a prodrug transformed to tectorigenin.
Clinical significance of antibody against hepatitis B virus core antigen in patients with hepatitis C virus‐related hepatocellular carcinoma
Authors: Yano Yoichi , Yamashita Fumihiko , Sumie Shuji , Kuwaki Kotaro , Yamamoto Hiroshi , Toyoda Naoko , Ando Eiji , Tanaka Masatoshi , Sata Michio
Published: July 2003

Purpose: We investigated the unsettled issue of whether seropositivity for antibody to hepatitis B core antigen (anti‐HBc) affects characteristics of hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC).

Methods: Antibody status was determined by enzyme immunoassay in 243 patients with this cancer, and associations with clinicopathologic characteristics and outcome were analysed. Serum hepatitis B virus (HBV) DNA was determined by real‐time polymerase chain reaction.

Results: Of 235 patients with unequivocal serologic status, 142 were seropositive and 93 were seronegative. Clinicopathologic characteristics and overall cumulative survival rates were comparable between the two groups. However, seropositivity tended to predict poor outcome for patients in Child class B or C (P=0.068), those in tumour‐nodes‐metastasis‐based stage 3 or 4 (P=0.081), those with tumours exceeding 25 mm (P=0.068), and those with a past history of clinical liver disease (P=0.088). Multivariate analysis identified serum albumin, portal vein tumour thrombosis, and tumour size as independent determinants of survival. Serum HBV DNA was below 1.7 log copies/ml in all 40 patients tested.

Conclusions: Overall, the clinical features of HCV‐HCC were unaffected by seropositivity for anti‐HBc. Seropositivity tended to worsen prognosis for subgroup with poor hepatic reserve or advanced tumours.