Integrated sampling-and-sensing using microdialysis and biosensing by particle motion for continuous cortisol monitoring

Microdialysis catheters are small probes that allow sampling from biological systems and human subjects with minimal perturbation. Traditionally, microdialysis samples are collected in vials, transported to a laboratory, and analysed with typical turnaround times of hours to days. To realize a continuous sampling-and-sensing methodology with minimal time delay, we studied the integration of microdialysis sampling with a sensor for continuous biomolecular monitoring based on Biosensing by Particle Motion (BPM). A microfluidic flow cell was designed with a volume of 12 μl in order to be compatible with flowrates of microdialysis sampling. The analyte recovery and the time characteristics of the sampling-and-sensing system were studied using a food colorant in buffer and using cortisol in buffer and in blood plasma. Concentration step functions were applied, and the system response was measured using optical absorption and a continuous BPM cortisol sensor. The cortisol recovery was around 80% for a 30 mm microdialysis membrane with a 20 kDa molecular weight cut-off and a flowrate of 2 μl min−1. The concentration-time data could be fitted with a transport delay time and single-exponential relaxation curves. The total delay time of the sampling-and-sensing methodology was about 15 minutes. Continuous sampling-and-sensing was demonstrated over a period of 5 hours. These results represent an important step toward integrated sampling-and-sensing for the continuous monitoring of a wide variety of low-concentration biomolecular substances for applications in biological and biomedical research.</p

Integrated sampling-and-sensing using microdialysis and biosensing by particle motion for continuous cortisol monitoring

Microdialysis catheters are small probes that allow sampling from biological systems and human subjects with minimal perturbation. Traditionally, microdialysis samples are collected in vials, transported to a laboratory, and analysed with typical turnaround times of hours to days. To realize a continuous sampling-and-sensing methodology with minimal time delay, we studied the integration of microdialysis sampling with a sensor for continuous biomolecular monitoring based on Biosensing by Particle Motion (BPM). A microfluidic flow cell was designed with a volume of 12 μl in order to be compatible with flowrates of microdialysis sampling. The analyte recovery and the time characteristics of the sampling-and-sensing system were studied using a food colorant in buffer and using cortisol in buffer and in blood plasma. Concentration step functions were applied, and the system response was measured using optical absorption and a continuous BPM cortisol sensor. The cortisol recovery was around 80% for a 30 mm microdialysis membrane with a 20 kDa molecular weight cut-off and a flowrate of 2 μl min−1. The concentration-time data could be fitted with a transport delay time and single-exponential relaxation curves. The total delay time of the sampling-and-sensing methodology was about 15 minutes. Continuous sampling-and-sensing was demonstrated over a period of 5 hours. These results represent an important step toward integrated sampling-and-sensing for the continuous monitoring of a wide variety of low-concentration biomolecular substances for applications in biological and biomedical research.</p

The validity of family size preference measurements in rural Latin America

Includes bibliograph

Price Variations in a Stock Market With Many Agents

Large variations in stock prices happen with sufficient frequency to raise doubts about existing models, which all fail to account for non-Gaussian statistics. We construct simple models of a stock market, and argue that the large variations may be due to a crowd effect, where agents imitate each other's behavior. The variations over different time scales can be related to each other in a systematic way, similar to the Levy stable distribution proposed by Mandelbrot to describe real market indices. In the simplest, least realistic case, exact results for the statistics of the variations are derived by mapping onto a model of diffusing and annihilating particles, which has been solved by quantum field theory methods. When the agents imitate each other and respond to recent market volatility, different scaling behavior is obtained. In this case the statistics of price variations is consistent with empirical observations. The interplay between ``rational'' traders whose behavior is derived from fundamental analysis of the stock, including dividends, and ``noise traders'', whose behavior is governed solely by studying the market dynamics, is investigated. When the relative number of rational traders is small, ``bubbles'' often occur, where the market price moves outside the range justified by fundamental market analysis. When the number of rational traders is larger, the market price is generally locked within the price range they define.Comment: 39 pages (Latex) + 20 Figures and missing Figure 1 (sorry), submitted to J. Math. Eco

Towards continuous monitoring of TNF-α at picomolar concentrations using biosensing by particle motion

The ability to continuously monitor cytokines is desirable for fundamental research studies and healthcare applications. Cytokine release is characterized by picomolar circulating concentrations, short half-lives, and rapid peak times. Here, we describe the characteristics and feasibility of a particle-based biosensing technique for continuous monitoring of TNF-α at picomolar concentrations. The technique is based on the optical tracking of particle motion and uses an antibody sandwich configuration. Experimental results show how the analyte concentration influences the particle diffusivity and characteristic response time of the sensor, and how the sensitivity range depends on the antibody functionalization density. Furthermore, the data clarifies how antibodies supplemented in solution can shorten the characteristic response time. Finally, we demonstrate association rate-based sensing as a first step towards continuous monitoring of picomolar TNF-α concentrations, over a period of 2 h with delay times under 15 min. The insights from this research will enable the development of continuous monitoring sensors using high-affinity binders, providing the sensitivity and speed needed in applications like cytokine monitoring.</p

Sandwich Immunosensor Based on Particle Motion:How Do Reactant Concentrations and Reaction Pathways Determine the Time-Dependent Response of the Sensor?

To control and optimize the speed of a molecular biosensor, it is crucial to quantify and understand the mechanisms that underlie the time-dependent response of the sensor. Here, we study how the kinetic properties of a particle-based sandwich immunosensor depend on underlying parameters, such as reactant concentrations and the size of the reaction chamber. The data of the measured sensor responses could be fitted with single-exponential curves, with characteristic response times that depend on the analyte concentration and the binder concentrations on the particle and substrate. By comparing characteristic response times at different incubation configurations, the data clarifies how two distinct reaction pathways play a role in the sandwich immunosensor, namely, analyte binding first to particles and thereafter to the substrate, and analyte binding first to the substrate and thereafter to a particle. For a concrete biosensor design, we found that the biosensor is dominated by the reaction pathway where analyte molecules bind first to the substrate and thereafter to a particle. Within this pathway, the binding of a particle to the substrate-bound analyte dominates the sensor response time. Thus, the probability of a particle interacting with the substrate was identified as the main direction to improve the speed of the biosensor while maintaining good sensitivity. We expect that the developed immunosensor and research methodology can be generally applied to understand the reaction mechanisms and optimize the kinetic properties of sandwich immunosensors with particle labels.</p

Mass Models for Spiral Galaxies from 2-D Velocity Maps

We model the mass distributions of 40 high surface brightness spiral galaxies inside their optical radii, deriving parameters of mass models by matching the predicted velocities to observed velocity maps. We use constant mass-to-light disk and bulge models, and we have tried fits with no halo and with three different halo density profiles. The data require a halo in most, but not all, cases, while in others the best fit occurs with negligible mass in the luminous component, which we regard as unphysical. All three adopted halo profiles lead to fits of about the same quality, and our data therefore do not constrain the functional form of the halo profile. The halo parameters display large degeneracies for two of the three adopted halo functions, but the separate luminous and dark masses are better constrained. However, the fitted disk and halo masses vary substantially between the adopted halo models, indicating that even high quality 2-D optical velocity maps do not provide significant constraints on the dark matter content of a galaxy. We demonstrate that data from longslit observations are likely to provide still weaker constraints. We conclude that additional information is needed in order to constrain the separate disk and halo masses in a galaxy.Comment: 41 pages, 13 figures, accepted for publication in A

Holmium-166 Radioembolization: Current Status and Future Prospective

Since its first suggestion as possible option for liver radioembolization treatment, the therapeutic isotope holmium-166 (166Ho) caught the experts’ attention due to its imaging possibilities. Being not only a beta, but also a gamma emitter and a lanthanide, 166Ho can be imaged using single-photon emission computed tomography and magnetic resonance imaging, respectively. Another advantage of 166Ho is the possibility to perform the scout and treatment procedure with the same particle. This prospect paves the way to an individualized treatment procedure, gaining more control over dosimetry-based patient selection and treatment planning. In this review, an overview on 166Ho liver radioembolization will be presented. The current clinical workflow, together with the most relevant clinical findings and the future prospective will be provided

Quantitative 166Ho-microspheres SPECT derived from a dual-isotope acquisition with 99mTc-colloid is clinically feasible

Purpose: Accurate dosimetry is essential in radioembolization. To this purpose, an automatic protocol for healthy liver dosimetry based on dual isotope (DI) SPECT imaging, combining holmium-166 ( 166Ho)-microspheres, and technetium-99 m ( 99mTc)-colloid was developed: 166Ho-microspheres used as scout and therapeutic particles, and 99mTc-colloid to identify the healthy liver. DI SPECT allows for an automatic and accurate estimation of absorbed doses, introducing true personalized dosimetry. However, photon crosstalk between isotopes can compromise image quality. This study investigates the effect of 99mTc downscatter on 166Ho dosimetry, by comparing 166Ho-SPECT reconstructions of patient scans acquired before ( 166Ho-only) and after additional administration of 99mTc-colloid ( 166Ho-DI). Methods: The 166Ho-only and 166Ho-DI scans were performed in short succession by injecting 99mTc-colloid on the scanner table. To compensate for 99mTc downscatter, its influence was accounted for in the DI image reconstruction using energy window-based scatter correction methods. The qualitative assessment was performed by independent blinded comparison by two nuclear medicine physicians assessing 65 pairs of SPECT/CT. Inter-observer agreement was tested by Cohen’s kappa coefficient. For the quantitative analysis, two volumes of interest within the liver, VOI TUMOR, and VOI HEALTHY were manually delineated on the 166Ho-only reconstruction and transferred to the co-registered 166Ho-DI reconstruction. Absorbed dose within the resulting VOIs, and in the lungs (VOI LUNGS), was calculated based on the administered therapeutic activity. Results: The qualitative assessment showed no distinct clinical preference for either 166Ho-only or 166Ho-DI SPECT (kappa = 0.093). Quantitative analysis indicated that the mean absorbed dose difference between 166Ho-DI and 166Ho-only was − 2.00 ± 2.84 Gy (median 27 Gy; p value < 0.00001), − 5.27 ± 8.99 Gy (median 116 Gy; p value = 0.00035), and 0.80 ± 1.08 Gy (median 3 Gy; p value < 0.00001) for VOI HEALTHY, VOI TUMOR, and VOI LUNGS, respectively. The corresponding Pearson’s correlation coefficient between 166Ho-only and 166Ho-DI for absorbed dose was 0.97, 0.99, and 0.82, respectively. Conclusion: The DI protocol enables automatic dosimetry with undiminished image quality and accuracy. Clinical trials: The clinical study mentioned is registered with Clinicaltrials.gov (NCT02067988) on 20 February 2014

166Holmium–99mTechnetium dual‑isotope imaging: scatter compensation and automatic healthy‑liver segmentation for 166Holmium radioembolization dosimetry

Background Partition modeling allows personalized activity calculation for holmium-166 (166Ho) radioembolization. However, it requires the definition of tumor and non-tumorous liver, by segmentation and registration of a separately acquired CT, which is time-consuming and prone to error. A protocol including 166Ho-scout, for treatment simulation, and technetium-99m (99mTc) stannous phytate for healthy-liver delineation was proposed. This study assessed the accuracy of automatic healthy-liver segmentation using 99mTc images derived from a phantom experiment. In addition, together with data from a patient study, the effect of different 99mTc activities on the 166Ho-scout images was investigated. To reproduce a typical scout procedure, the liver compartment, including two tumors, of an anthropomorphic phantom was filled with 250 MBq of 166Ho-chloride, with a tumor to non-tumorous liver activity concentration ratio of 10. Eight SPECT/CT scans were acquired, with varying levels of 99mTc added to the non-tumorous liver compartment (ranging from 25 to 126 MBq). For comparison, forty-two scans were performed in presence of only 99mTc from 8 to 240 MBq. 99mTc image quality was assessed by cold-sphere (tumor) contrast recovery coefficients. Automatic healthy-liver segmentation, obtained by thresholding 99mTc images, was evaluated by recovered volume and Sørensen–Dice index. The impact of 99mTc on 166Ho images and the role of the downscatter correction were evaluated on phantom scans and twenty-six patients’ scans by considering the reconstructed 166Ho count density in the healthy-liver. Results All 99mTc image reconstructions were found to be independent of the 166Ho activity present during the acquisition. In addition, cold-sphere contrast recovery coefficients were independent of 99mTc activity. The segmented healthy-liver volume was recovered fully, independent of 99mTc activity as well. The reconstructed 166Ho count density was not influenced by 99mTc activity, as long as an adequate downscatter correction was applied. Conclusion The 99mTc image reconstructions of the phantom scans all performed equally well for the purpose of automatic healthy-liver segmentation, for activities down to 8 MBq. Furthermore, 99mTc could be injected up to at least 126 MBq without compromising 166Ho image quality. Clinical trials The clinical study mentioned is registered with Clinicaltrials.gov (NCT02067988) on February 20, 2014