Reticulocyte dynamic and hemoglobin variability in hemodialysis patients treated with Darbepoetin alfa and C.E.R.A.: a randomized controlled trial.

BACKGROUND: In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients. METHODS: The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference. RESULTS: No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa. CONCLUSIONS: The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.Trial registrationClinicalTrials.gov NCT01666301.

Dynamic models of viral replication and latency.

PURPOSE OF REVIEW: HIV targets primary CD4(+) T cells. The virus depends on the physiological state of its target cells for efficient replication, and, in turn, viral infection perturbs the cellular state significantly. Identifying the virus-host interactions that drive these dynamic changes is important for a better understanding of viral pathogenesis and persistence. The present review focuses on experimental and computational approaches to study the dynamics of viral replication and latency. RECENT FINDINGS: It was recently shown that only a fraction of the inducible latently infected reservoirs are successfully induced upon stimulation in ex-vivo models while additional rounds of stimulation make allowance for reactivation of more latently infected cells. This highlights the potential role of treatment duration and timing as important factors for successful reactivation of latently infected cells. The dynamics of HIV productive infection and latency have been investigated using transcriptome and proteome data. The cellular activation state has shown to be a major determinant of viral reactivation success. Mathematical models of latency have been used to explore the dynamics of the latent viral reservoir decay. SUMMARY: Timing is an important component of biological interactions. Temporal analyses covering aspects of viral life cycle are essential for gathering a comprehensive picture of HIV interaction with the host cell and untangling the complexity of latency. Understanding the dynamic changes tipping the balance between success and failure of HIV particle production might be key to eradicate the viral reservoir.

Thin Bonded Overlay Evaluation, Construction Report, HR-559, 1999

In recent years, ultra-thin whitetopping (UTW) has evolved as a viable rehabilitation technique for deteriorated asphalt cement concrete (ACC) pavement. Numerous UTW projects have been constructed and tested, enabling researchers to identify key elements contributing to their successful performance. These elements include foundation support, the interface bonding condition, portland cement concrete (PCC) overlay thickness, synthetic fiber reinforcement usage, joint spacing, and joint sealing. The interface bonding condition is the most important of these elements. It enables the pavement to act as a composite structure, thus reducing tensile stresses and allowing an ultra-thin PCC overlay to perform as intended. Although the main factors affecting UTW performance have been identified in previous research, neither the impact that external variables have on the elements nor the element interaction have been thoroughly investigated. The objective of this research was to investigate the interface bonding condition between an ultra-thin PCC overlay and an ACC base over time, considering the previously mentioned variables. Laboratory testing and full scale field testing were planned to accomplish the research objective. Laboratory testing involved monitoring interface strains in fabricated PCC/ACC composite test beams subjected to either static or dynamic flexural loading. Variables investigated included ACC surface preparation, PCC thickness, and synthetic fiber reinforcement usage. Field testing involved monitoring PCC/ACC interface stains and temperatures, falling weight deflectometer (FWD) deflection responses, direct shear strengths, and distresses on a 7.2 mile Iowa Department of Transportation (Iowa DOT) UTW project (HR-559). The project was located on Iowa Highway 21 between Iowa Highway 212 and U.S. Highway 6 in Iowa County, near Belle Plaine, Iowa. Variables investigated included ACC surface preparation, PCC thickness, synthetic fiber reinforcement usage, joint spacing, and joint sealing. This report documents the planning, equipment selection, and construction of the project built in 1994.

Dynamic impacts of the inhibition of the molecular chaperone hsp90 on the T-cell proteome have implications for anti-cancer therapy.

The molecular chaperone Hsp90-dependent proteome represents a complex protein network of critical biological and medical relevance. Known to associate with proteins with a broad variety of functions termed clients, Hsp90 maintains key essential and oncogenic signalling pathways. Consequently, Hsp90 inhibitors are being tested as anti-cancer drugs. Using an integrated systematic approach to analyse the effects of Hsp90 inhibition in T-cells, we quantified differential changes in the Hsp90-dependent proteome, Hsp90 interactome, and a selection of the transcriptome. Kinetic behaviours in the Hsp90-dependent proteome were assessed using a novel pulse-chase strategy (Fierro-Monti et al., accompanying article), detecting effects on both protein stability and synthesis. Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects. As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients. Most likely, consequences of the role of Hsp90 in gene expression determined a global reduction in net de novo protein synthesis. This decrease appeared to be greater in magnitude than a concomitantly observed global increase in protein decay rates. Several novel putative Hsp90 clients were validated, and interestingly, protein families with critical functions, particularly the Hsp90 family and cofactors themselves as well as protein kinases, displayed strongly increased decay rates due to Hsp90 inhibitor treatment. Remarkably, an upsurge in survival pathways, involving molecular chaperones and several oncoproteins, and decreased levels of some tumour suppressors, have implications for anti-cancer therapy with Hsp90 inhibitors. The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions. Data are available via ProteomeXchange with identifier PXD000537.

Feasibility Study of Dynamic Overload and Ultimate Load Tests of Full-Scale Highway Bridges, HR-160, 1973

As a result of the construction of the Saylorville Dam and Reservoir on the Des Moines River, six highway bridges are scheduled for removal. Five of these are old high-truss single-lane bridges, each bridge having several simple spans. The other bridge is a fairly modern (1955) double 4-span continuous beam-and-slab composite highway bridge. The availability of these bridges affords an unusual opportunity for study of the behavior of full-scale bridges. Because of the magnitude of the potential testing program, a feasibility study was initiated and the results are presented in this two-part final report. Part I summarizes the findings and Part II presents the supporting detailed information.

Problems of Bridge Supporting and Expansion Devices and an Experimental Comparison of the Dynamic Behavior of Rigid and Elastomeric Bearings, HR-105, 1965

The design of satisfactory supporting and expansion devices for highway bridges is a problem which has concerned bridge design engineers for many years. The problems associated with these devices have been emphasized by the large number of short span bridges required by the current expanded highway program of expressways and interstate highways. The initial objectives of this investigation were: (1) To review and make a field study of devices used for the support of bridge superstructures and for provision of floor expansion; (2) To analyze the forces or factors which influence the design and behavior of supporting devices and floor expansion systems; and (3) To ascertain the need for future research particularly on the problems of obtaining more economical and efficient supporting and expansion devices, and determining maximum allowable distance between such devices. The experimental portion was conducted to evaluate one of the possible simple and economical solutions to the problems observed in the initial portion. The investigation reported herein is divided into four major parts or phases as follows: (1) A review of literature; (2) A survey by questionnaire of design practice of a number of state highway departments and consulting firms; (3) Field observation of existing bridges; and, (4) An experimental comparison of the dynamic behavior of rigid and elastomeric bearings.

Use of a dynamic foot pressure index to monitor the effects of treatment for equinus gait in children with cerebral palsy.

The purpose of this study is to introduce and describe a newly developed index using foot pressure analysis to quantify the degree of equinus gait in children with cerebral palsy before and after injection with botulinum toxin. Data were captured preinjection and 12 weeks postinjection. Ten children aged 2(1/2) to 6(1/2) years took part (5 boys and 5 girls). Three of them had a diagnosis of spastic diplegia and 7 of congenital hemiplegia. In total, 13 limbs were analyzed. After orientation and segmentation of raw pedobarographic data, we determined a dynamic foot pressure index graded 0 to 100 that quantified the relative degree of heel and forefoot contact during stance. These data were correlated (Pearson correlation) with clinical measurements of dorsiflexion at the ankle (on a slow and fast stretch) and video observation (using the Observational Gait Scale). Pedobarograph data were strongly correlated with both the Observational Gait Scale scores (R = 0.79, P < 0.005) and clinical measurements of dorsiflexion on a fast stretch, which is reflective of spasticity (R = 0.70, P < 0.005). We demonstrated the index's sensitivity in detecting changes in spasticity and good correlation with video observations seems to indicate this technique's potential validity. When manipulated and segmented appropriately, and with the development of a simple ordinal index, we found that foot pressure data provided a useful tool in tracking changes in patients with spastic equinus.

Development of Asphalt Dynamic Modulus Master Curve Using Falling Weight Deflectometer Measurements, TR-659

The asphalt concrete (AC) dynamic modulus (|E*|) is a key design parameter in mechanistic-based pavement design methodologies such as the American Association of State Highway and Transportation Officials (AASHTO) MEPDG/Pavement-ME Design. The objective of this feasibility study was to develop frameworks for predicting the AC |E*| master curve from falling weight deflectometer (FWD) deflection-time history data collected by the Iowa Department of Transportation (Iowa DOT). A neural networks (NN) methodology was developed based on a synthetically generated viscoelastic forward solutions database to predict AC relaxation modulus (E(t)) master curve coefficients from FWD deflection-time history data. According to the theory of viscoelasticity, if AC relaxation modulus, E(t), is known, |E*| can be calculated (and vice versa) through numerical inter-conversion procedures. Several case studies focusing on full-depth AC pavements were conducted to isolate potential backcalculation issues that are only related to the modulus master curve of the AC layer. For the proof-of-concept demonstration, a comprehensive full-depth AC analysis was carried out through 10,000 batch simulations using a viscoelastic forward analysis program. Anomalies were detected in the comprehensive raw synthetic database and were eliminated through imposition of certain constraints involving the sigmoid master curve coefficients. The surrogate forward modeling results showed that NNs are able to predict deflection-time histories from E(t) master curve coefficients and other layer properties very well. The NN inverse modeling results demonstrated the potential of NNs to backcalculate the E(t) master curve coefficients from single-drop FWD deflection-time history data, although the current prediction accuracies are not sufficient to recommend these models for practical implementation. Considering the complex nature of the problem investigated with many uncertainties involved, including the possible presence of dynamics during FWD testing (related to the presence and depth of stiff layer, inertial and wave propagation effects, etc.), the limitations of current FWD technology (integration errors, truncation issues, etc.), and the need for a rapid and simplified approach for routine implementation, future research recommendations have been provided making a strong case for an expanded research study.

A dynamic model of keratinocyte stem cell renewal and differentiation: role of the p21WAF1/Cip1 and Notch1 signaling pathways.

We present here a dynamic model of functional equilibrium between keratinocyte stem cells, transit amplifying populations and cells that are reversibly versus irreversibly committed to differentiation. According to this model, the size of keratinocyte stem cell populations can be controlled at multiple levels, including relative late steps in the sequence of events leading to terminal differentiation and by the influences of a heterogeneous extra-cellular environment. We discuss how work in our laboratory, on the interconnection between the cyclin/CDK inhibitor p21WAF1/Cip1 and the Notch1 signaling pathways, provides strong support to this dynamic model of stem cell versus committed and/or differentiated keratinocyte populations.

Polychlorinated trityl radicals for dynamic nuclear polarization: the role of chlorine nuclei

Polychlorinated trityl radicals bearing carboxylate substituents are water soluble persistent radicals that can be used for dynamic nuclear polarization. In contrast to other trityl radicals, the polarization mechanism differs from the classical solid effect. DFT calculations performed to rationalize this behaviour support the hypothesis that polarization is transferred from the unpaired electron to chlorine nuclei and from these to carbon by spin diffusion. The marked differences observed between neutral and anionic forms of the radical will be discussed.

Proton NMR of (15)N-choline metabolites enhanced by dynamic nuclear polarization.

Chemical shifts of protons can report on metabolic transformations such as the conversion of choline to phosphocholine. To follow such processes in vivo, magnetization can be enhanced by dynamic nuclear polarization (DNP). We have hyperpolarized in this manner nitrogen-15 spins in (15)N-labeled choline up to 3.3% by irradiating the 94 GHz electron spin resonance of admixed TEMPO nitroxide radicals in a magnetic field of 3.35 T during ca. 3 h at 1.2 K. The sample was subsequently transferred to a high-resolution magnet, and the enhanced polarization was converted from (15)N to methyl- and methylene protons, using the small (2,3)J((1)H,(15)N) couplings in choline. The room-temperature lifetime of nitrogen polarization in choline, T(1)((15)N) approximately 200 s, could be considerably increased by partial deuteration of the molecule. This procedure enables studies of choline metabolites in vitro and in vivo using DNP-enhanced proton NMR.

Dynamic Speed Feedback Signs, 2014

Dynamic speed feedback sign (DSFS) systems are traffic control devices that are programmed to provide a message to drivers exceeding a certain speed thresh¬old. A DSFS system typically consists of a speed-measuring device, which may be loop detectors or radar, and a message sign that displays feedback to drivers who exceed a predetermined speed threshold. The feedback may be the driver’s actual speed, a message like “SLOW DOWN,” or activation of a warning device such as beacons or a curve warning sign. For more on this topic by these authors, see also "Evaluation of Dynamic Speed Feedback Signs on Curves: A National Demonstration Project": http://www.trb.org/main/blurbs/172092.aspx