bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement in quality of life of patients with AL amyloidosis treated with high-dose melphalan and autologous stem cell transplantation
Authors: Seldin David C. , Anderson Jennifer J. , Sanchorawala Vaishali , Malek Karim , Wright Daniel G. , Quillen Karen , Finn Kathleen T. , Berk John L. , Dember Laura M. , Falk Rodney H. , Skinner Martha
Published: May 2004

Treatment of AL amyloidosis patients with high-dose melphalan chemotherapy followed by autologous peripheral blood stem cell transplantation (HDM/SCT) can produce hematologic complete responses (CRs) and improvement in organ function. To determine whether these responses are accompanied by improvement in quality of life (QOL), we employed the Medical Outcomes Study (MOS) 36-item Short Form General Health Survey (SF-36) questionnaire for 544 patients evaluated between 1994 and 2002. At baseline, the scores were significantly lower on all 8 SF-36 scales compared with age-matched population norms: the composite physical component summary (PCS) for the AL patients was 34.5 versus the population norm of 46.8, and the mental component summary (MCS) was 45.0 versus the norm of 51.5. All SF-36 scores improved at 1 year, with the MCS reaching the population norm. The PCS, though improved, was still lower than normal but was greater in the subgroup of patients who achieved a hematologic CR; the PCS normalized at 2 years in these patients. Thus, treatment of AL amyloidosis patients with HDM/SCT produces measurable and sustained improvements in quality of life, particularly in those patients who achieve hematologic CR.
Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host
Authors: Rivailler Pierre , Carville Angela , Kaur Amitinder , Rao Pasupuleti , Quink Carol , Kutok Jeffery L. , Westmoreland Susan , Klumpp Sherry , Simon Meredith , Aster Jon C. , Wang Fred
Published: May 2004

To develop a model for Epstein-Barr virus (EBV) pathogenesis in immunosuppressed hosts, we studied experimental infections of immunocompetent versus SHIV 89.6P–infected, immunosuppressed rhesus macaques with the EBV-related rhesus lymphocryptovirus (LCV). Primary LCV infection after oral inoculation of 4 immunocompetent animals was characterized by an acute viremia and seroconversion followed by asymptomatic LCV persistence. Four immunosuppressed macaques infected orally with LCV failed to develop an LCV-specific humoral response and viremia was more pronounced, but there was no evidence of LCV-induced lymphoproliferative disease. A more aggressive primary challenge was administered by intravenous inoculation of 108 autologous, LCV-immortalized B cells in 4 additional immunosuppressed animals. Two animals with modest immunosuppression remained asymptomatic, and 1 of 2 severely immunosuppressed animals developed an aggressive, monoclonal LCV-positive lymphoma. These studies demonstrate the potential for lymphomagenesis in an experimental model system for EBV infection and underscore the strength and depth of immune control in limiting LCV-induced lymphoproliferative disease.
Transduction of NO-bioactivity by the red blood cell in sepsis: novel mechanisms of vasodilation during acute inflammatory disease
Authors: Crawford Jack H. , Chacko Balu K. , Pruitt Heather M. , Piknova Barbora , Hogg Neil , Patel Rakesh P.
Published: May 2004

Sepsis is an acute inflammatory disease characterized by dysfunctional blood flow and hypotension. Nitric oxide (NO) is elevated during sepsis and plays an integral role in the associated vascular pathology. However, precise mechanisms and functions of NO in sepsis remain unclear. In this study, we show that red blood cells (RBCs) are foci for nitrosative reactions during acute inflammation, resulting in the formation of cells that can promote systemic vascular relaxation in an uncontrolled manner. Specifically, using experimental models of endotoxemia and surgical sepsis, NO adducts were found in the RBCs, including S-nitrosohemoglobin (SNOHb). These RBCs, referred to as septic RBCs, spontaneously stimulated vasodilation in a manner consistent with elevated SNOHb concentrations. Moreover, relaxation was cyclic guanosine monophosphate (cGMP) dependent and was inhibited by RBC lysis and glutathione but not by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide (C-PTIO). The potential mechanism of septic RBC–mediated vasorelaxation is discussed and may involve the intermediate, nitroxyl (HNO). Coupled with data showing that NO adducts in septic RBCs were dependent on the inducible nitric oxide synthase and correlated with plasma nitrite, these findings provide a novel framework to understand mechanisms underlying dysfunctional blood flow responses during sepsis. Specifically, the concept that RBCs directly mediate systemic hypotension through NO-dependent mechanisms is discussed.
The Fresnel volume and transmitted waves
Authors: Spetzler Jesper , Snieder Roel
Published: May 2004

In seismic imaging experiments, it is common to use a geometric ray theory that is an asymptotic solution of the wave equation in the high‐frequency limit. Consequently, it is assumed that waves propagate along infinitely narrow lines through space, called rays, that join the source and receiver. In reality, recorded waves have a finite‐frequency content. The band limitation of waves implies that the propagation of waves is extended to a finite volume of space around the geometrical ray path. This volume is called the Fresnel volume. In this tutorial, we introduce the physics of the Fresnel volume and we present a solution of the wave equation that accounts for the band limitation of waves. The finite‐frequency wave theory specifies sensitivity kernels that linearly relate the traveltime and amplitude of band‐limited transmitted and reflected waves to slowness variations in the earth. The Fresnel zone and the finite‐frequency sensitivity kernels are closely connected through the concept of constructive interference of waves. The finite‐frequency wave theory leads to the counterintuitive result that a pointlike velocity perturbation placed on the geometric ray in three dimensions does not cause a perturbation of the phase of the wavefield. Also, it turns out that Fermat's theorem in the context of geometric ray theory is a special case of the finite‐frequency wave theory in the limit of infinite frequency. Last, we address the misconception that the width of the Fresnel volume limits the resolution in imaging experiments.
Viscous deformation of unconsolidated reservoir sands—Part 1: Time‐dependent deformation, frequency dispersion, and attenuation
Authors: Hagin Paul N. , Zoback Mark D.
Published: May 2004

Laboratory experiments on dry, unconsolidated reservoir sands from the Wilmington field, California, reveal significant viscous creep strain under a variety of loading conditions. In hydrostatic compression tests, following initial loading to 10 MPa, the creep strain that accompanies 5‐MPa loading steps to 15, 20, 25, and 30 MPa exceeds the magnitude of the instantaneous strain (∼3 × 10−3). We observed a two‐fold increase in bulk modulus with frequency over the range of frequencies tested (10−6to 10−2Hz), which is consistent with a viscoelastic rheology of unconsolidated sand. The data demonstrate that the effective static bulk modulus is approximately one‐third of that at seismic frequencies. By measuring the phase lag between stress and strain during the loading cycles, we were also able to show that inelastic attenuation is nearly constant (Q ≈ 5) over the four‐decade range of frequencies tested at a strain amplitude of 10−3. Interestingly, the viscous effects only appear when loading a sample beyond its preconsolidation. Triaxial tests show that the relationship between differential stress and axial strain is positively dependent on axial strain‐rate, and that unconsolidated sand continues to deform viscously even at large strains (∼7%). All experiments were conducted at room temperature and humidity. A limited number of experiments with unconsolidated reservoir sand from the Gulf of Mexico show similar behavior.
Viscous deformation of unconsolidated reservoir sands—Part 2: Linear viscoelastic models
Authors: Hagin Paul N. , Zoback Mark D.
Published: May 2004

Laboratory creep experiments show that dry unconsolidated reservoir sands follow a power law function of time (at constant stress), and cyclic loading tests (at quasi‐static frequencies of 10−6 to 10−2 Hz) show that the bulk modulus increases by a factor of two with increasing frequency while attenuation remains constant. In this paper, we attempt to model these observations using linear viscoelasticity theory by considering several simple phenomenological models. We investigated two classes of models: spring‐dashpot models, which are represented by exponential functions with a single relaxation time, and power law models. Although almost all of the models considered were capable of fitting the creep data with time, they result in very different predictions of attenuation and bulk modulus dispersion. We used the model parameters derived from fitting the creep strain to predict the bulk modulus dispersion and attenuation as a function of frequency, to find a single phenomenological model (and model parameters) that could explain the material's creep response with time as well as its dispersion and attenuation characteristics. Spring‐dashpot models, such as the Burgers and standard linear solid models, produce reasonable fits to the creep strain and bulk modulus dispersion data, but do not reproduce the attenuation data. We find that a combined power law–Maxwell creep model adequately fits all of the data. Extrapolating the power law–Maxwell creep model out to 30 years (to simulate the lifetime of a reservoir) predicts that the static bulk modulus is only 25% of the dynamic modulus. Including the instantaneous component of deformation into the previous prediction results in 2% total vertical strain at the wellbore, in good agreement with field observations.
Layered and laterally constrained 2D inversion of resistivity data
Authors: Auken Esben , Christiansen Anders Vest
Published: May 2004

In a sedimentary environment, quasi‐layered models often can represent the actual geology more accurately than smooth minimum‐structure models. We present a 2D inversion scheme with lateral constraints and sharp boundaries (LCI) for continuous resistivity data. All data and models are inverted as one system, producing layered solutions with laterally smooth transitions. The models are regularized through lateral constraints that tie interface depths or thicknesses and resistivities of adjacent layers. A priori information, used to resolve ambiguities and to add, for example, geological information, can be added at any point of the profile and migrates through the lateral constraints to parameters at adjacent sites. Similarly, information from areas with well‐resolved parameters migrates through the constraints to help resolve areas with poorly constrained parameters. The estimated model is complemented by a full sensitivity analysis of the model parameters supporting quantitative evaluation of the inversion result.

A simple synthetic model proves the need for a quasi‐layered, 2D inversion when compared with a traditional 2D minimum‐structure inversion. A 2D minimum‐structure inversion produces models with spatially smooth resistivity transitions, making identification of layer boundaries difficult.

A continuous vertical electrical sounding field example from Sweden with a depression in the depth to bedrock supports the conclusions drawn from the synthetic example. A till layer on top of the bedrock, hidden in the traditional inversion result, is identified using the 2D LCI scheme. Furthermore, the depth to the bedrock surface is easily identified for most of the profile with the 2D LCI model, which is not the case with the model from the traditional minimum‐structure inversion.
Linearized least‐squares method for interpretation of potential‐field data from sources of simple geometry
Authors: Salem Ahmed , Ravat Dhananjay , Mushayandebvu Martin F. , Ushijima Keisuke
Published: May 2004

We present a new method for interpreting isolated potential‐field (gravity and magnetic) anomaly data. A linear equation, involving a symmetric anomalous field and its horizontal gradient, is derived to provide both the depth and nature of the buried sources. In many currently available methods, either higher order derivatives or postprocessing is necessary to extract both pieces of information; therefore, data must be of very high quality. In contrast, for gravity work with our method, only a first‐order horizontal derivative is needed and the traditional data quality is sufficient. Our proposed method is similar to the Euler technique; it uses a shape factor instead of a structural index to characterize the buried sources. The method is tested using theoretical anomaly data with and without random noise. In all cases, the method adequately estimates the location and the approximate shape of the source. The practical utility of the method is demonstrated using gravity and magnetic field examples from the United States and Zimbabwe.
Vertical fracture detection by exploiting the polarization properties of ground‐penetrating radar signals
Authors: Tsoflias Georgios P. , Van Gestel Jean‐Paul , Stoffa Paul L. , Blankenship Donald D. , Sen Mrinal
Published: May 2004

Vertically oriented thin fractures are not always detected by conventional single‐polarization reflection profiling ground‐penetrating radar (GPR) techniques. We study the polarization properties of EM wavefields and suggest multipolarization acquisition surveying to detect the location and azimuth of vertically oriented fractures. We employ analytical solutions, 3D finite‐difference time‐domain modeling, and field measurements of multipolarization GPR data to investigate EM wave transmission through fractured geologic formations. For surface‐based multipolarization GPR measurements across vertical fractures, we observe a phase lead when the incident electric‐field component is oriented perpendicular to the plane of the fracture. This observation is consistent for nonmagnetic geologic environments and allows the determination of vertical fracture location and azimuth based on the presence of a phase difference and a phase lead relationship between varying polarization GPR data.
The physics and simulation of wave propagation at the ocean bottom
Authors: Carcione José M. , Helle Hans B.
Published: May 2004

We investigate some aspects of the physics of wave propagation at the ocean bottom (ranging from soft sediments to crustal rocks). Most of the phenomena are associated to the presence of attenuation. The analysis requires the use of an anelastic stress‐strain relation and a highly accurate modeling algorithm. Special attention is given to modeling the boundary conditions at the ocean‐bottom interface and the related physical phenomena. For this purpose, we further develop and test the pseudospectral modeling algorithm for wave propagation at fluid‐anelastic solid interfaces. The method is based on a domain‐decomposition technique (one grid for the fluid part and another grid for the solid part) and the Fourier and Chebyshev differential operators. We consider the reflection, transmission, and propagation of seismic waves at the ocean bottom, modeled as a plane boundary separating an acoustic medium (ocean) and a viscoelastic solid (sediment). The main physical phenomena associated with this interface are illustrated, namely, amplitude variations with offset, the Rayleigh window, and the propagation of Scholte and leaky Rayleigh waves. Modeling anelasticity is essential to describe these effects, in particular, amplitude variations near and beyond the critical angle, the Rayleigh window, and the dissipation of the fundamental interface mode. The physics of wave propagation is investigated by means of a plane‐wave analysis and the novel modeling algorithm. A wavenumber–frequency domain method is used to compute the reflection coefficient and phase angle from the synthetic seismograms. This method serves to verify the algorithm, which is shown to model with high accuracy the Rayleigh‐window phenomenon and the propagation of interface waves. The modeling is further verified by comparisons with the analytical solution for a fluid‐solid interface in lossless media, with source and receivers away from and at the ocean bottom. Using the pseudospectral modeling code, which allows general material variability, a complete and accurate characterization of the seismic response of the ocean bottom can be obtained. An example illustrates the effects of attenuation on the propagation of dispersive Scholte waves at the bottom of the North Sea.
Documenting catchment suspended sediment sources: problems, approaches and prospects
Authors: Collins A. L. , Walling D. E.
Published: May 2004

Establishing catchment suspended sediment sources is fraught with difficulty. Data collection comprises indirect and direct approaches and an overview is provided. The indirect approach uses a range of techniques to measure or evaluate sediment mobilization. Yet, although recent technological advances in surveying, remote sensing and photogrammetry provide improved resolution of temporal and spatial patterns of catchment erosion, these procedures take no account of source-river connectivity and the uncertainties associated with sediment routing. It is therefore only possible to infer the provenance of suspended sediment loads on the exclusive basis of on-site erosion data for different portions of the upstream catchment unless supportive information on sediment delivery is readily available. In contrast, the direct approach attempts to link sediment sources and flux using alternative means and therefore avoids the need for complementary information. Sediment fingerprinting best represents the direct approach to sediment sourcing and there remains substantial scope for exploiting the potential of this technique. The spatial complexity of sediment mobilization and transfer at the catchment scale necessitates a distributed approach to modelling. Recent developments in computer power and programming techniques are proving useful in this respect, but assembling the input and validation data required by distributed models continues to pose problems and it is frequently difficult to apportion the relative contributions from individual sediment sources. General prospects for future developments are discussed.
Plantation forestry impacts on sediment yields and downstream channel dynamics in the UK: a review
Authors: Stott Tim , Mount Nick
Published: May 2004

The impact of coniferous plantation forest on erosion and sediment yields in the UK uplands over the past three decades is reviewed by examining background or natural suspended sediment yields (SSY), bed load yields (BLY) and bank erosion and comparing with studies of‘disturbed’catchments. This paper collates all the UK studies that have monitored changes in erosion and sediment yields at the forest establishment, mature forest and timber harvesting phases of the forest cycle. A simple model based on this comprehensive examination of studies to date suggests that mean sediment yields increase at the initial ground disturbance phase, recover as the forest matures and increase again more significantly at the timber harvesting phase. The likely downstream impacts of these changes in sediment yields on channel dynamics and management is discussed, introducing sediment wave theory with particular reference to the generation of bed load waves downstream of forested catchments. Modelling of downstream changes in unit stream power has implications for the accumulation of nonpoint source sediment in sediment waves. Published studies in which channel changes have resulted from the passage of sediment waves are collated and it is concluded that the translating wave model is best supported. The paper concludes with a discussion of the broader implications for river management and presents advice for river managers.
Ecosystem process models at multiple scales for mapping tropical forest productivity
Authors: Nightingale J. M. , Phinn S. R. , Held A. A.
Published: May 2004

Quantifying mass and energy exchanges within tropical forests is essential for understanding their role in the global carbon budget and how they will respond to perturbations in climate. This study reviews ecosystem process models designed to predict the growth and productivity of temperate and tropical forest ecosystems. Temperate forest models were included because of the minimal number of tropical forest models. The review provides a multiscale assessment enabling potential users to select a model suited to the scale and type of information they require in tropical forests. Process models are reviewed in relation to their input and output parameters, minimum spatial and temporal units of operation, maximum spatial extent and time period of application for each organization level of modelling. Organizational levels included leaf-tree, plot-stand, regional and ecosystem levels, with model complexity decreasing as the time-step and spatial extent of model operation increases. All ecosystem models are simplified versions of reality and are typically aspatial. Remotely sensed data sets and derived products may be used to initialize, drive and validate ecosystem process models. At the simplest level, remotely sensed data are used to delimit location, extent and changes over time of vegetation communities. At a more advanced level, remotely sensed data products have been used to estimate key structural and biophysical properties associated with ecosystem processes in tropical and temperate forests. Combining ecological models and image data enables the development of carbon accounting systems that will contribute to understanding greenhouse gas budgets at biome and global scales.
New insights into complement: a mediator of injury and marker of disease activity in systemic lupus erythematosus
Authors: Manzi S , Ahearn J M , Salmon J
Published: May 2004

Studies performed during the past several decades have demonstrated a role for the complement system in both the etiology and pathogenesis of systemic lupus erythematosus (SLE). However the specifically defective molecular and cellular pathways responsible for the disease and its complications have generally not been identified. In this report, we describe two recent advances in complement pathobiology that highlight future directions for promising investigation toward enhancing our capacity to diagnose SLE, to monitor activity of the disease, and to identify molecular and cellular defects in SLE that can be targeted by therapeuticinhibitors of complement activation.In the first example, we describe recently developed assays to detect erythrocyte C4d and complement receptor1 for diagnosis and monitoring of disease activity in SLE. In the second example, we describe a recently discovered role for complement in mediating fetal loss in antiphospholipid syndrome and discuss the potential for this observation to facilitate identification and development of complement based biomarkers to predict poor fetal outcome in pregnant patients with SLE. These two examples are meant to underscore the importance of complement in the etiology and pathogenesis of SLE and its complications, and to stress the need for further investigation focused on the link between the complement system and SLE.
Multiplexed assays for identification of biomarkers and surrogate markers in systemic lupus erythematosus
Authors: Utz P J
Published: May 2004

Validated biomarkers and surrogate markers are badly needed for monitoring patients with systemic lupus erythematosus (SLE), both for routine clinical care and for clinical trials research. SLE is difficult to study in clinical trials, in part because the disease is so heterogeneous. Very few useful markers have been identified, and even those that historicallyhave been thought to be valid have been recently questioned. This report will focus on the use of emerging multiplexed assay formats that enable analysis of hundreds or even thousands of analytes simultaneously. Their potential and pitfalls for monitoring patients with SLE, particularly those enrolled in clinical trials testing novel therapeutics, will be discussed.
Randomized controlled trials in systemic lupus erythematosus: what has been done and what do we need to do?
Authors: Schiffenbauer J , Simon L S
Published: May 2004

The study of systemic lupus erythematosus (SLE) is a challenging undertaking. It is difficult to assess outcomes in SLE randomized controlled trials (RCTs), and this is illustrated by the lack of new therapies approved for use in lupus. In a disease that is waxing and waning, and requires constantly changing medications, identifying treatment effects of new therapies may be difficult, and the use of potentially toxic therapies requires a rigorous understandingof the benefit to risk ratio. Some issues that need to be consideredby the investigatorin designingthese studies include:1) should the trial focus on patientswith active or inactive disease; 2) which of the measures of disease activity should be used or should preventionof flares be examined; 3) should the study focus on defined organ specific endpoints or utilize one of the available disease activity indices to identify changes in disease activity; 4) should the trial be a superioritytrial or an equivalencetrial. This review summarizes the critical issues involving the design of studies in lupus and provides the reader with suggestionsand recommendations for considerationbefore embarking on trials in this area.
LJP 394 (abetimus sodium, Riquent) in the management of systemic lupus erythematosus
Authors: Wallace D J , Tumlin J A
Published: May 2004

LJP 394 (abetimus, Riquent, La Jolla Pharmaceuticals)is four oligonucleotideB cell toleragen which acts as an ‘anti-anti DNA’. Given as a weekly infusion, Phase 1, 2, and 3 studies with this biologic on close to 1,000 patients have demonstrated no toxicity of any note. In patients with lupus nephritis and an elevated anti-DNA (Farr assay) who have a high affinity to LJP 394, the drug significantly decreases anti-DNA, improves quality of life, and trends towards reducing renal flares. LJP 394 is a promising inductionand/or maintenancetherapy for lupus patients with elevated anti-DNA and active disease.
Rationale for interleukin-6 blockade in systemic lupus erythematosus
Authors: Tackey E , Lipsky P E , Illei G G
Published: May 2004

Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biological activities that plays an important role in immune regulation and inflammation. Among other actions, it induces terminal differentiation of B lymphocytes into antibody-forming cells and the differentiation of T cells into effector cells. IL-6 also has multiple potent proinflammatory effects. An associationbetween IL-6 and lupus was demonstrated in murine models of SLE and blocking IL-6 improved lupus in all models tested. Data from several studies suggest that IL-6 plays a critical role in the B cell hyperactivity and immunopathology of human SLE, and may have a direct role in mediating tissue damage. Based on these data, we propose that blocking the effect of IL-6 in humans may improve lupus by interacting with the autoinflammatory process both systemically and locally.
Gene therapy in systemic lupus erythematosus
Authors: Kyttaris V C , Juang Y-T , Tsokos G C
Published: May 2004

Preclinical studies have provided proof of concept for the feasibility and efficacy of gene therapy in human systemic lupus erythematosus (SLE). Successful efforts include gene constructs that alter the expression of cytokines or limit the cognate interaction of immune cells. Other efforts may include gene modified cell transfersuch as autologousB cells transfectedwith tolerogenicconstructsor T cells in which specific molecular aberrations have been corrected.
Predicting daylight illuminance by computer simulation techniques
Authors: Li DHW , Lau CCS , Lam JC
Published: May 2004

,!The first step in evaluating the visual performance and energy efficiency provided by daylight requires an accurate estimation of the amount of daylight entering a building. Traditionally, the daylight performance of a building is often evaluated in terms of daylight factors with the calculations being based on the CIE overcast sky. In general, the daylight factor approach is quite simple to use but it cannot predict the dynamic variations in interior illuminance as sky conditions and the sun’s position change. The recently introduced concept of the daylight coefficient, which needs sky luminance data, provides an alternative approach. With the advances in computer technology, the computation of daylight illuminance using the two prediction methods can be conducted by a simulation program. This paper presents a study of the daylight factor and daylight coefficient approaches. The interior daylight illuminance data measured in a scale model and a classroom were compared with the simulated results using RADIANCE computer simulation software. It was found that, in general, the daylight coefficient approach performs better than daylight factor approach. Both methods tend to estimate the daylight illuminance less accurately when the measurement points in the classroom are far away from the window facade. It seems that the parameters for inter-reflection calculations including the furniture layout and external obstructions cannot be input into the RADIANCE program with sufficient detail for accurate simulation.
A study of opinion in offices with and without user controlled lighting
Authors: Moore T , Carter DJ , Slater AI
Published: May 2004

,!This paper describes a survey of user attitudes toward control systems and the luminous conditions they produce in 14 similar UK office buildings—seven sites with user controlled general lighting and seven sites without. The installations without user control had better conditions when judged in terms of conventional recommendations for task illuminance, and luminance ratios and levels. User opinion in installations with user control were more satisfied with planar illuminance and had more positive attitudes toward control, whilst other aspects relating to lighting quality were assessed similarly in the two types of installation. Given that the controllable systems were typically operated at 50% of maximum output it appears these systems offer considerable scope for energy saving without compromising occupants’ perceived lighting quality.
A demonstration of energy-efficient lighting in residential new construction
Authors: Banwell P , Brons J , Freyssinier-Nova JP , Rizzo P , Figueiro M
Published: May 2004

,!This field study uses a new model home demonstrating good lighting-design principles with energy-efficient solutions. Surveys showed that builders and the general public accepted and even preferred the appearance and the lighting effects of energy-efficient lighting technologies. Key to the success was integration with architectural features, colour schemes, and user lifestyle. Detailed survey results, energy savings, and illuminance comparisons are presented, as well as a discussion of ongoing barriers to the use of energy-efficient technology. Designers share ‘lessons learned’ from this design case study.
A proposed unified system of photometry
Authors: Rea MS , Bullough JD , Freyssinier-Nova JP , Bierman A
Published: May 2004

,!A unified system of photometry is proposed that is based on human vision and allows the specification of visual stimuli at all light levels. To be useful, however, photometry can never be entirely synonymous with vision. Additivity is an essential characteristic of photometry, yet many visual responses, such as brightness matching, incorporate visual channels that are inherently non-additive in responding to light. Following a review of models of mesopic photometry based on a number of experimental techniques, a system of photometry based on reaction times is proposed to bridge conventional photopic and scotopic luminous efficiency functions through the mesopic region. The basis for the unified system is a parameter, X, which describes the proportion of photopic luminous efficacy at any luminance, and luminance can be calculated from a simple closed-form equation. The utility of the system is described, including instrumentation for the measurement of unified luminance.
Multiple-stage screening and mortality in the Multiple Risk Factor Intervention Trial
Authors: Eberly Lynn E , Neaton James D , Thomas Avis J , Dai Yu ,   Multiple Risk Factor Intervention Trial Research Group
Published: May 2004

Background During the design phase of a clinical trial, sample size estimates should take into account medical screening criteria, the ‘healthy volunteer’ effect, consequences of run-in phases, and secular trends in the event rate of interest. All of these have been shown to relate to subsequent event rates, and hence trial power to detect intervention effects. The Multiple Risk Factor Intervention Trial (MRFIT) used three successive screenings of 361 662 men to enroll 12 866; observed coronary heart disease (CHD) mortality after a mean of 6.9 years was substantially lower than projected during design. We explore factors which may have contributed to these mortality differences and whether they persisted throughout follow-up.

Methods Proportional hazards models were used to compare 25-year mortality according to trial eligibility, self-exclusions, medical exclusions, and participation.

Results After adjustment for baseline risk factors and age, there was higher mortality among men excluded for presence of disease [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.43–1.61, for total; HR 1.92, CI 1.75–2.11, for CHD] compared to those not excluded which persisted throughout follow-up. Volunteers had lower total (HR 0.82, CI 0.76–0.87) and CHD (HR 0.79, CI 0.70–0.88) mortality than those discontinuing participation. Men excluded with characteristics deemed likely to interfere with adherence had higher total (HR 1.19, CI 1.07–1.33) and noncardiovascular disease (CVD) (HR 1.32, CI 1.14–1.53) mortality but no higher CVD (HR 1.04, CI 0.88–1.23) or CHD (HR 0.98, CI 0.80–1.20) mortality compared to those not excluded. Differences in mortality were stronger during the first five years, but declined only slightly over 25 years.

Conclusions 25-year mortality was significantly higher for non-volunteers and exclusions. Differences between observed and predicted six-year total mortality for trial participants were largely attributable to volunteers and exclusions, but there were additional differences for CHD mortality, which were likely due to downward secular trends. These results emphasize the importance of anticipating these factors during clinical trial design, even for trials of short duration.
Issues in regulatory guidelines for data monitoring committees
Authors: DeMets David , Califf Robert , Dixon Dennis , Ellenberg Susan , Fleming Thomas , Held Peter , Julian Desmond , Kaplan Richard , Levine Robert , Neaton James , Packer Milton , Pocock Stuart , Rockhold Frank , Seto Belinda , Siegel Jay , Snapinn Steve , Stump David , Temple Robert , Whitley Richard
Published: May 2004

As clinical trials have emerged as the major research method for evaluating new interventions, the process for monitoring intervention safety and benefit has also evolved. The Data Monitoring Committee (DMC) has become the standard approach to implement this responsibility for many Phase III trials. Recent draft guidelines on the operation of DMCs by the Food and Drug Administration (FDA) have raised issues that need further clarification or discussion, especially for industry sponsored trials. These include, the time when DMCs are needed, the role of the independent statistician to support the DMC, and sponsor participation at DMC meetings. This paper provides an overview of these issues, based on the discussions at the January, 2003 workshop sponsored by Duke Clinical Research Institute.
Cell cycle-dependent Ca2+ oscillations in mouse embryos are regulated by nuclear targeting of PLCζ
Authors: Larman Mark G. , Saunders Christopher M. , Carroll John , Lai F. Anthony , Swann Karl
Published: May 2004

During the first cell cycle Ca2+ oscillations are regulated in a cell cycle-dependent manner, such that the oscillations are unique to M phase. How the Ca2+ oscillations are regulated with such cell cycle stage-dependency is unknown, despite their importance for egg activation and embryo development. We recently identified a novel, sperm-specific phospholipase C (PLCzeta; PLCζ) that triggers Ca2+ oscillations similar to those caused by sperm. We show that PLCζ-induced Ca2+ oscillations also occur exclusively during M phase. The cell cycle-dependency can be explained by PLCζ's localisation to the pronuclei, which depends specifically upon a nuclear localisation signal sequence. Preventing pronuclear localisation of PLCζ by mutation of the nuclear localisation signal, or by inhibiting pronuclear formation/import, can prolong Ca2+ oscillations or allow them to occur during interphase. These data suggest a novel mechanism for regulating a PLC through nuclear sequestration and may explain the cell cycle-dependent regulation of Ca2+ oscillations following fertilisation.
The sequences appended to the amyloid core region of the HET-s prion protein determine higher-order aggregate organization in vivo
Authors: Balguerie Axelle , Dos Reis Suzana , Coulary-Salin Bénédicte , Chaignepain Stéphane , Sabourin Martine , Schmitter Jean-Marie , Saupe Sven J.
Published: May 2004

The [Het-s] prion of the fungus Podospora anserina propagates as a self-perpetuating amyloid form of the HET-s protein. This protein triggers a cell death reaction termed heterokaryon incompatibility when interacting with the HET-S protein, an allelic variant of HET-s. HET-s displays two distinct domains, a N-terminal globular domain and a C-terminal unstructured prion-forming domain (residues 218-289). Here, we describe the characterization of HET-s(157-289), a truncated form of HET-s bearing an extensive deletion in the globular domain but retaining full activity in incompatibility and prion propagation. In vitro, HET-s(157-289) polymerizes into amyloid fibers displaying the same core region as full-length HET-s fibers. We have shown previously that fusions of green fluorescent protein (GFP) with HET-s or HET-s(218-289) form dot-like aggregates in vivo upon transition to the prion state. By contrast, a HET-s(157-289)/GFP fusion protein forms elongated fibrillar aggregates in vivo. Such elongated aggregates can reach up to 150 μm in length. The in vivo dynamics of these organized structures is analysed by time lapse microscopy. We find that the large elongate structures grow by lateral association of shorter fibrillar aggregates. When co-expressed with HET-s(157-289), full-length HET-s and HET-s(218-289) can be incorporated into such elongated aggregates. Together, our data indicate that HET-s(157-289) aggregates can adopt an organized higher-order structure in vivo and that the ability to adopt this supramolecular organization is conferred by the sequences appended to the amyloid core region.
Inhibition of basement membrane formation by a nidogen-binding laminin γ1-chain fragment in human skin-organotypic cocultures
Authors: Breitkreutz Dirk , Mirancea Nicolae , Schmidt Cathrine , Beck Regina , Werner Ulrich , Stark Hans-Jürgen , Gerl Martin , Fusenig Norbert E.
Published: May 2004

Basement membranes generally determine different tissue compartments in complex organs, such as skin, playing not only an important structural but also a regulatory role. We have previously demonstrated the formation of a regular basement membrane in organotypic three-dimensional (3D)-cocultures of human skin keratinocytes and fibroblasts by indirect immunofluorescence and transmission electron microscopy. In this assembly process, cross-linking of type IV collagen and the laminin γ1 chain by nidogen is considered a crucial step. For a functional proof, we have now competitively inhibited nidogen binding to laminin in 3D-cocultures with a recombinant laminin γ1 fragment (γ1III3-5 module) spanning this binding site. Repeated treatment abolished the deposition of nidogen at the epithelial-matrix interface but also greatly perturbed the presence of other matrix constituents such as laminin and perlecan. This effect persisted over the entire observation period of 10 to 21 days. In contrast, some components of the basement membrane zone were only moderately affected, with the laminin-5 isoform (γ2 chain), type IV collagen and integrin α6ß4 still showing a distinct staining at their regular position, when seen by light microscopy. Furthermore, epidermal morphology and differentiation remained largely normal as indicated by the regular location of keratins K1/K10 and also of late differentiation markers. Ultrastructural examination demonstrated that the γ1 fragment completely suppressed any formation of basement membrane structures (lamina densa) and also of hemidesmosomal adhesion complexes. As a consequence of hemidesmosome deficiency, keratin filament bundles were not attached to the ventral basal cell aspect. These findings were further substantiated by immuno-electron microscopy, revealing either loss or drastic reduction and dislocation of basement membrane and hemidesmosomal components. Taken together, in this simplified human skin model (representing a `closed system') a functional link has been demonstrated between compound structures of the extra- and intracellular space at the junctional zone providing a basis to interfere at distinct points and in a controlled fashion.
Temperature-dependent oxygen limitation in insect eggs
Authors: Woods H. Arthur , Hill Ryan I.
Published: May 2004

Most terrestrial insect embryos support metabolism with oxygen from the environment by diffusion across the eggshell. Because metabolism is more temperature sensitive than diffusion, embryos should be relatively oxygen-limited at high temperatures. We tested whether survival, development time and metabolism of eggs of a moth, Manduca sexta, were sensitive to experimentally imposed variation in atmospheric oxygen availability(5–50 kPa; normoxia at sea level is 21 kPa) across a range of biologically realistic temperatures. Temperature–oxygen interactions were apparent in most experiments. Hypoxia affected survival more strongly at warmer temperatures. Metabolic rates, measured as rates of CO2emission, were virtually insensitive to hypo- and hyperoxia at 22°C but were strongly influenced at 37°C. Radial profiles of PO2 inside eggs, measured using an oxygen microelectrode, demonstrated that 3-day-old eggs had broad central volumes with PO2 less than 2 kPa, and that higher temperature led to lower PO2. These data indicate that at realistically high temperatures (32–37°C) eggs of M. sexta were oxygen limited, even in normoxia. This result has important implications for insect population ecology and the evolution of eggshell structures, and it suggests a novel hypothesis about insect gigantism during Paleozoic hyperoxia.
Dietary influences over proliferating cell nuclear antigen expression in the locust midgut
Authors: Zudaire E. , Simpson S. J. , Illa I. , Montuenga L. M.
Published: May 2004

We have studied the influence of variations in dietary protein (P) and digestible carbohydrate (C), the quantity of food eaten, and insect age during the fifth instar on the expression of the proliferating cell nuclear antigen(PCNA) in the epithelial cells of the midgut (with special reference to the midgut caeca) in the African migratory locust, Locusta migratoria. Densitometric analysis of PCNA-immunostained cells was used as an indirect measure of the levels of expression of PCNA, and a PCNA cellular index(PCNA-I) was obtained. Measurements of the DNA content of the cells have also been carried out by means of microdensitometry of Feulgen-stained, thick sections of midgut. A comparison between the PCNA nuclear level and the DNA content was performed. The PCNA levels were significantly different among the cells of the five regions studied: caeca, anterior ventricle, medial ventricle, posterior ventricle and ampullae of the Malpighian tubules. We have studied in more detail the region with highest PCNA-I, i.e. the caeca. The quality and the quantity of food eaten under ad libitum conditions were highly correlated with both the PCNA and DNA levels in the caeca cells. Locusts fed a diet with a close to optimal P:C content (P 21%, C 21%) showed the highest PCNA and DNA content. In locusts fed a food that also contained a 1:1 ratio of P to C but was diluted three-fold by addition of indigestible cellulose (P 7%, C 7%), a compensatory increase in consumption was critical to maintaining PCNA levels. Our measurements also showed that the nuclear DNA content of the mature and differentiated epithelial cells was several-fold higher than the levels in the undifferentiated stem cells of the regenerative nests. These results, combined with the low number of mitotic figures found in the regenerative nests of the caeca and the marked variation in PCNA levels among groups, suggest that some type of DNA endoreduplication process may be taking place. Our data also indicate that the DNA synthetic activity in the midgut is related to feeding in locusts. The possible dietary and nutritional regulatory mechanisms and the significance of the differences found are discussed.
Respiration rate of hepatocytes varies with body mass in birds
Authors: Else Paul L. , Brand M. D. , Turner N. , Hulbert A. J.
Published: May 2004

Hepatocytes were isolated from eight species of birds ranging from 13 g zebra finches to 35 kg emus. This represents a 2800-fold range of body mass(Mb). Liver mass (g) was allometrically related to species body mass by the equation: liver mass=19.6×Mb0.91. There was a significant allometric decline in hepatocyte respiration rate (HRR; nmol O2mg–1 dry mass min–1) with species body mass(kg) described by the relationship:HRR=5.27×Mb–0.10. The proportions of hepatocyte oxygen consumption devoted to (i) mitochondrial ATP production,(ii) mitochondrial proton leak and (iii) non-mitochondrial processes were estimated by using excess amounts of appropriate inhibitors. It was found that although hepatocyte respiration rate varied with body mass in birds, these processes constitute a relatively constant proportion of hepatocyte metabolic rate irrespective of the size of the bird species. The respective percentages were 54%, 21% and 25%. The portion of hepatocyte respiration devoted to ATP production for use by the sodium pump was estimated and found to be a relatively constant 24% of hepatocyte respiration and 45% of mitochondrial ATP production in different-sized bird species. These results are discussed in the context of competing theories to explain the metabolism–body size allometry, and are found to support the `allometric cascade' model.