The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Foam and thin films of hydrophilic silica particles modified by ß-casein.

HYPOTHESIS: Foaming properties of particle dispersions can be modified by addition of amphiphiles. The molar ratio between particles and amphiphiles will influence the wetting properties of the particles as well as the bulk concentration of the amphiphiles. This will have an effect on air/water interfacial composition as well as on the thin film and foam stability of the mixed system. EXPERIMENTS: In this research foams and thin films of hydrophilic silica particles in presence of ß-casein (ß-CN) were investigated with different particle sizes and varying ß-CN/silica weight ratios (between 1:10 and 1:100). Samples were characterized for particles size, morphology as well as contact angle and related to their foaming, interfacial, and thin film properties. FINDINGS: A threshold weight ratio of ß-CN/silica was found to be 1:50 for foam stabilization with mixtures containing silica particles no larger than 1 µm and 1:30 for film stabilization with mixtures containing larger particles. At the interface, the modified silica particles were rather diluted without much interaction for surface compressions up to 30%. Large silica particles (0.0015% ß-CN, Csilica ≤ 0.15%) were dragged to the periphery of the thin liquid films but no decrease of the inner film draining rate by a decrease of capilary pressure gradient across the film was observed. The depletion of ß-casein in the bulk by particles played a major role in foam destabilization.

Harnessing the advantages of hard and soft colloids by the use of core-shell particles as interfacial stabilizers.

The ability of colloidal particles to penetrate fluid interfaces is a crucial factor in the preparation of particle stabilized disperse systems such as foams and emulsions. For hard micron-sized particles the insertion into fluid interfaces requires substantial energy input, but soft particles are known to adsorb spontaneously. Particle hardness, however, may also affect foam and emulsion stability. The high compliance of soft particles may compromise their ability to withstand the lateral compression associated with disproportionation. Hence, particles which can spontaneously adsorb onto fluid interfaces, and yet depict low compliance may be ideal as interfacial stabilizers. In the present work, we prepared core-shell particles comprising a hard, polystyrene core and a soft poly(N-isopropylacrylamide) based shell. We found that such core-shell particles adsorb spontaneously onto various fluid interfaces. The absence of a pronounced energy barrier for interfacial adsorption allowed the facile preparation of particle-stabilized bubbles as well as emulsion droplets. For bubbles, the stability was better than that of bubbles stabilized by entirely soft particles, but disproportionation was not stopped completely. Emulsion droplets, in contrast, showed excellent stability against both coalescence and disproportionation. Lateral compression of core-shell particles due to disproportionation was clearly limited by the presence of the polystyrene core, leading to long-lasting stability. For emulsions, we even observed non-spherical droplets, indicating a negligible Laplace pressure. Our results indicate that core-shell particles comprising a hard core and a soft shell combine the advantageous properties of hard and soft particles, namely spontaneous adsorption and limited compliance, and can therefore be superior materials for the preparation of particle-stabilized dispersions.

Assembly of jammed colloidal shells onto micron-sized bubbles by ultrasound.

Stabilization of gas bubbles in water by applying solid particles is a promising technique to ensure long-term stability of the dispersion against coarsening. However, the production of large quantities of particle stabilized bubbles is challenging. The delivery of particles to the interface must occur rapidly compared to the typical time scale of coarsening during production. Furthermore, the production route must be able to overcome the energy barriers for interfacial adsorption of particles. Here we demonstrate that ultrasound can be applied to agitate a colloidal dispersion and supply sufficient energy to ensure particle adsorption onto the air-water interface. With this technique we are able to produce micron-sized bubbles, solely stabilized by particles. The interface of these bubbles is characterized by a colloidal shell, a monolayer of particles which adopt a hexagonal packing. The particles are anchored to the interface owing to partial wetting and experience lateral compression due to bubble shrinkage. The combination of both effects stops coarsening once the interface is jammed with particles. As a result, stable bubbles are formed. Individual particles can desorb from the interface upon surfactant addition, though. The latter fact confirms that the particle shell is not covalently linked due to thermal sintering, but is solely held together by capillary interaction. In summary, we show that our ultrasound approach allows for the straightforward creation of micron-sized particle stabilized bubbles with high stability towards coarsening.

Mesoscale models of dispersions stabilized by surfactants and colloids.

In this paper we discuss and give an outlook on numerical models describing dispersions, stabilized by surfactants and colloidal particles. Examples of these dispersions are foams and emulsions. In particular, we focus on the potential of the diffuse interface models based on a free energy approach, which describe dispersions with the surface-active agent soluble in one of the bulk phases. The free energy approach renders thermodynamic consistent models with realistic sorption isotherms and adsorption kinetics. The free energy approach is attractive because of its ability to describe highly complex dispersions, such as emulsions stabilized by ionic surfactants, or surfactant mixtures and dispersions with surfactant micelles. We have classified existing numerical methods into classes, using either a Eulerian or a Lagrangian representation for fluid and for the surfactant/colloid. A Eulerian representation gives a more coarse-grained, mean field description of the surface-active agent, while a Lagrangian representation can deal with steric effects and larger complexity concerning geometry and (amphiphilic) wetting properties of colloids and surfactants. However, the similarity between the description of wetting properties of both Eulerian and Lagrangian models allows for the development of hybrid Eulerian/Lagrangian models having advantages of both representations.

Formation, stability, and mechanical properties of bovine serum albumin stabilized air bubbles produced using coaxial electrohydrodynamic atomization.

Bovine serum albumin (BSA) microbubbles were generated using coaxial electrohydrodynamic atomization (CEDHA) using various concentrations of BSA solutions. The bubble characteristics and the long-term stability of the microbubbles were studied through adjustment of processing parameters and the collection media. Bubbles in the range of 40-800 µm were obtained in a controlled fashion, and increasing the flow rate of the BSA solution reduced the polydispersity of the microbubbles. Use of distilled water-glutaraldehyde, glycerol, and glycerol-Tween 80 collection media allowed a remarkable improvement in bubble stability compared to BSA solution collection medium. Possible physical mechanisms were developed to explain the stability of the microbubbles. The collection distance showed a marked influence on stability of the microbubbles. Near-monodisperse particle-reinforced microbubbles were formed with various concentrations of 2,2'-azobis(isobutyramidine) dihydrochloride (AIBA)-polystyrene particle in BSA solution. The bubble size and the size distribution showed negligible change over a period of time irrespective of the concentration of particles at the bubble surface. The compression stiffness of the microbubbles was determined using nanoindentation at ambient temperature and showed that the stiffness of the microbubbles increased from 8 N/m to 20 N/m upon changing the concentration of BSA solution from 5 wt % to 15 wt %.

Moisture diffusivity in food materials.

This paper investigates whether moisture diffusion can be predicted for food materials. We focus especially on mixtures of glucose homopolymers and water. The predictions are based on three theories: (1) the Darken relation, linking the mutual diffusivity to the self diffusivities, (2) the generalised Stokes-Einstein relation for the solute self diffusivity, and (3) the free volume theory for water self diffusivity. Using literature data obtained for the whole class of glucose homopolymer, we show that these theories predict the moisture diffusivity for the whole range of volume fractions, from zero to one, and a broad range of temperatures. Furthermore, we show that the theories equally holds for other hydrophilic biopolymers one finds in food. In the concentrated regime, all experimental data collapse to a single curve. This universal behaviour arises because these biopolymers form a hydrogen bonded network, where water molecules move via rearrangement of the free volume.

Water content or water activity: what rules crispy behavior in bread crust?

A dry crust loses its crispness when water migrates into the crust. It is not clear if it is the amount of water absorbed or the water activity ( a w) that leads to a loss of crispness. The hysteresis effect observed when recording a water sorption isotherm allowed us to study the effects of a w and moisture content separately. All experiments were carried out on model bread crusts made from Soissons bread flour. The effect of water content and water activity on the glass transition of model bread crusts was studied in detail using two complimentary techniques: phase transition analysis (PTA) and nuclear magnetic resonance (NMR). The results were compared with sensory data and results from a puncture test, which provided data on acoustic emission and fracture mechanics during breaking of the crusts. The water content of the crust was found to be decisive for the transition point as measured by PTA and NMR. However, both water content and water activity had an effect on perceived crispness and number of force and sound peaks. From this may be concluded that the distribution of the water in the samples with a history of high water content is more inhomogeneous, which results in crispy and less crispy regions, thus making them overall more crispy than samples with the same water content but higher a w.

Influence of flavour absorption on oxygen permeation through LDPE, PP, PC and PET plastics food packaging.

The effect of flavour absorption on the oxygen permeability of low-density polyethylene (LDPE), polypropylene (PP), polycarbonate (PC) and polyethylene terephthalate (PET) was studied using an isostatic continuous flow system. Polymer samples were exposed to a model solution containing limonene, hexyl acetate, nonanone and decanal at 40 degrees C. After exposure, one part of each sample was analysed for absorbed flavour compounds using a Large Volume Injection GC Ultrasonic 'in vial' extraction method, and from the other part, oxygen permeability was measured in a permeation cell at 25 degrees C. After 8 h of exposure, LDPE and PP samples showed a significant linear (R2 = 0.82 and 0.99) increase in oxygen permeability of 21 and 130%, respectively. Owing to swelling of the polymer samples resulting from flavour absorption, the structure of the polymeric network changed (i.e. opened) and consequently increased oxygen permeability. The oxygen permeability of exposed PC showed a significant linear (R2 = 0.78) decrease of 11% after 21 days. PC obviously did not swell like LDPE or PP. Therefore, it was suggested that absorbed flavour compounds occupied or blocked 'microcavities' through which normally oxygen is transported. Absorption of flavour compounds by PET did not affect the oxygen permeability of PET significantly.

Adsorption properties of proteins at and near the air/water interface from IRRAS spectra of protein solutions.

A detailed study is performed using infrared reflection absorption spectroscopy (IRRAS) to characterize the molecular behaviour of proteins at and near the air/water interface of protein solutions. IRRAS spectra of beta-casein solutions in H2O and D2O show spectral shifts and derivative-like features not commonly observed in monomolecular layer systems. They can be fully understood using optical theory. Fair agreement between experimental and simulated IRRAS spectra over a broad spectral range (4000-1000 cm(-1)) is obtained using a stratified layer model. An attenuated total reflection and transmission spectrum is used to represent the protein extinction coefficient in H2O and D2O, respectively. It is shown that the derivative-like features observed result from the reflective properties of the proteins themselves. Furthermore, both concentration and film thickness could be fitted. At high protein concentrations (100 mg/mL) the spectrum is that of a single homogeneous protein solution. At 0.1 mg/mL, beta-casein is accumulated at the surface in a thin layer of approximately 10 nm thickness, with a concentration about 2500 times higher than in the sub-phase. At an initial concentration of 10 mg/mL, the concentration in the surface layer is about 15 times higher than in the subphase, while the thickness is about 30 nm.

The role of ankle plantar flexor muscle work during walking.

Impaired ankle plantar flexor (APF) function is a frequent cause of gait limitations, but the role of the APF in the forward propulsion of the body remains controversial. To better understand both the direct and indirect effects of the APF during push-off and through advancement of the leg, mechanical work and inverse dynamic analyses were performed on 8 normal subjects during level walking. During push-off, 23.1 joules (J) of energy were generated, primarily by the APF, but only 4.2 J of this energy is transferred into the trunk. Ankle plantar flexor work is primarily used to accelerate the leg into swing. Most of the energy, 18.6 J, is recovered by transfer into the trunk at the end of swing. The timing of the energy transfers relative to the trunk motion imply that the APF contributes to the forward kinetic energy of the trunk but that other mechanisms likely account for the work used to raise the trunk against gravity.

Effect of prosthetic mass on swing phase work during above-knee amputee ambulation.

Recent advances in prosthetic technology have resulted in prosthetic limbs that weigh substantially less than those previously used by amputees. Although one of the clinical expectations associated with lighter limbs was that they would reduce the abnormally high metabolic cost of amputee ambulation, this has not be shown in oxygen consumption studies. This expectation was based on previous studies of normal walking, which showed that the greatest changes in mechanical work occurs in the leg during swing phase acceleration and deceleration. To better understand the relationship between limb mass and mechanical work, this study assessed the effect of varying prosthetic limb masses on the sources and magnitude of the mechanical work required for limb movement during swing. Eight above-knee amputees were studied during over ground walking at their self-selected speeds while wearing identical prosthetic limbs under three weight conditions: unweighted; 0.68 kg of added mass; 1.34 kg of added mass. Using inverse dynamics, the mechanical work from muscle sources and joint transfer sources that was used to accelerate the limb forward during late stance and early swing was determined and compared with the recovery of energy from the limb by hip joint transfer to the trunk during terminal swing deceleration. With the addition of 1.34 kg of mass, there was a combined increase in hip flexor muscle concentric work and mechanical energy transfer across the hip joint of 5.4 J, which was needed to accelerate the heavier prosthetic limb into the swing phase. The increase in acceleration work was balanced by a comparable increase (5.6 J) in the recovery of leg energy during terminal swing deceleration. By effectively conserving the additional mechanical work needed to propel a heavier limb, amputees appear to minimize any adverse effect of prosthetic mass on the mechanical work of walking. This may explain the absence of differences in metabolic cost between limbs of different masses.

Microcirculation in the footsole as a function of mechanical pressure.

OBJECTIVE: In this study an experimental set-up for measuring skin microvascular responses of the footsole to changes in externally applied pressure was analysed. DESIGN: A clinical study. Skin microvascular blood flow was measured in healthy volunteers, during and after external mechanical pressure of different magnitudes. BACKGROUND: During standing and walking the footsole is commonly exposed to high static and dynamic mechanical pressure, resulting in changes in the microcirculation of the footsole. In diabetic patients a disturbed interaction between externally applied pressure and skin microvascular response seems to be involved in the development of a foot ulcer. METHODS: Eleven volunteers participated in the study. Static loads were applied to the heel part of the footsole with the person in a supine position. Contact pressure and skin blood flux, based on the laser Doppler technique, were simultaneously monitored. The pressure used was varied in five discrete steps between 10 and 160 kPa and applied during a period of 5 min each. The microcirculation was measured during as well as after pressure loading. RESULTS: Pressures of 40 kPa and higher do stop the blood flow in the skin microcirculation. Releasing the applied pressure resulted in a hyperaemic response. This response appears to increase in amplitude at increasing pressures up to 800% of the baseline laser Doppler fluxmetry level. Beyond a pressure level of 80 kPa the hyperaemic response seems not to be influenced by the pressure level. The time needed to achieve the maximal laser Doppler fluxmetry level decreased when the pressure was raised from 10 to 80 kPa, but increased again when higher pressures were applied (P = 0.051). An intraindividual variation of 11-50% was observed for the parameters describing the blood flux before, during, and after pressure application. CONCLUSION: Simultaneously measuring changes in contact pressure and laser Doppler flux of the footsole is a useful method to study the interaction of external mechanical pressure and skin microvascular reactions. Pressures above 40 kPa stop skin microvascular blood flow. Releasing the applied pressure results in a hyperaemic response, which increases when the applied pressure increases from 40 to 80 kPa. Higher pressures do not influence the amplitude in skin microvascular response, but result in a longer delay to maximal hyperaemia.

The stretch reflex response in the normal and spastic ankle: effect of ankle position.

OBJECTIVE: The influence of stretch of the gastrocnemiussoleus muscle on the stretch reflex activity was studied, by varying the ankle angle in steps from 10 degrees of plantarflexion (PF) to 5 degrees of dorsiflexion (DF). DESIGN: Nonrandomized control trial. SETTING: Department of Rehabilitation Medicine of a university medical center. PATIENTS: Sixteen subjects with and 16 subjects without spasticity. MAIN OUTCOME MEASURES: The passive elastic stiffness and active reflex response, expressed by the total and elastic path lengths, were determined at each ankle angle as a sinusoidal displacement of 5 degrees was applied to the joint at frequencies from 3 to 12 Hz. RESULTS: The elastic stiffness showed no difference between the spastic and normal subjects for all ankle angles (p > .05). The elastic stiffness increased linearly similarly in both groups when the ankle was dorsiflexed. The reflex response was significantly greater in the spastic group for all positions (p < or = .01). The total and elastic path lengths showed a linear increase in both groups when the ankle angle was varied from PF to DF. The spastic group, however, had a significantly faster increase (p < or = .005). Between-group comparison showed a significant quadratic trend in the elastic path length for the spastic group (p < or = .05), with a maximum at 2.5 degrees of DF. CONCLUSIONS: This study showed that the stretch reflex activity varies with the ankle position. This must be considered when performing spasticity tests subsequent to an intervention that has changed the available range of motion and when comparing subjects measured at different ankle positions.