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Functionalized monodisperse microbubbles have the potential to boost the sensitivity and efficacy of molecular ultrasound imaging and targeted drug delivery using bubbles and ultrasound. Monodisperse bubbles can be produced in a microfluidic flow focusing device. However, their functionalization and sequential use require removal of the excess lipids from the bubble suspension to minimize the use of expensive ligands and to avoid competitive binding and blocking of the receptor molecules. To date, excess lipid removal is performed by centrifugation, which is labor intensive and challenging to automate. More importantly, as we show, the increased hydrostatic pressure during centrifugation can reduce bubble monodispersity. Here, we introduce a novel automated microfluidic 'washing' method. First, bubbles are injected in a microfluidic chamber 1 mm in height where they are left to float against the top wall. Second, lipid-free medium is pumped through the chamber to remove excess lipids while the bubbles remain located at the top wall. Third, the washed bubbles are resuspended and removed from the device into a collection vial. We demonstrate that the present method can (i) reduce the excess lipid concentration by 4 orders of magnitude, (ii) be fully automated, and (iii) be performed in minutes while the size distribution, functionality, and acoustic response of the bubbles remain unaffected. Thus, the presented method is a gateway to the fully automated production of functionalized monodisperse microbubbles. [ABSTRACT FROM AUTHOR]

Purpose: In arterial disease, the presence of two or more serial stenotic lesions is common. For mild lesions, it is difficult to predict whether their combined effect is hemodynamically significant. This study assessed the hemodynamic significance of idealized serial stenotic lesions by simulating their hemodynamic interaction in a computational flow model. Materials and Methods: Flow was simulated with SimVascular software in 34 serial lesions, using moderate (15 mL/s) and high (30 mL/s) flow rates. Combinations of one concentric and two eccentric lesions, all 50% area reduction, were designed with variations in interstenotic distance and in relative direction of eccentricity. Fluid and fluid–structure simulations were performed to quantify the combined pressure gradient. Results: At a moderate flow rate, the combined pressure gradient of two lesions ranged from 3.8 to 7.7 mmHg, which increased to a range of 12.5–24.3 mmHg for a high flow rate. Eccentricity caused an up to two-fold increase in pressure gradient relative to concentric lesions. At a high flow rate, the combined pressure gradient for serial eccentric lesions often exceeded the sum of the individual lesions. The relative direction of eccentricity altered the pressure gradient by 15–25%. The impact of flow pulsatility and wall deformability was minor. Conclusion: This flow simulation study revealed that lesion eccentricity is an adverse factor in the hemodynamic significance of isolated stenotic lesions and in serial stenotic lesions. Two 50% lesions that are individually non-significant can combine more often than thought to hemodynamic significance in hyperemic conditions. [ABSTRACT FROM AUTHOR]

Purpose: The feasibility of using a compressed interwoven Supera stent as a flow diverting device for popliteal aneurysms was recently demonstrated in patients. It is unclear, however, what the optimal flow diverting strategy is, because of the fusiform shape of popliteal aneurysms and their exposure to triphasic flow. To assess this flow diverting strategy for popliteal aneurysms, flow profiles and thrombus formation likelihood were investigated in popliteal aneurysm models. Materials and Methods: Six popliteal aneurysm models were created and integrated into a pulsatile flow set-up. These models covered a bent and a straight anatomy in three configurations: control, single-lined and dual-lined Supera stents. Two-dimensional flow velocities were visualized by laser particle image velocimetry. In addition, the efficacy of the stent configurations for promoting aneurysm thrombosis was assessed by simulations of residence time and platelet activation. Results: On average for the two anatomies, the Supera stent led to a twofold reduction of velocities in the aneurysm for single-lined stents, and a fourfold reduction for dual-lined stents. Forward flow was optimally diverted, whereas backward flow was generally deflected into the aneurysm. The dual-lined configuration led to residence times of 15–20 s, compared to 5–15 s for the single stent configurations. Platelet activation potential was not increased by the flow diverting stents. Conclusion: A compressed Supera stent was successfully able to divert flow in a popliteal aneurysm phantom. A dual-lined configuration demonstrated superior hemodynamic characteristics compared to its single-lined counterpart. [ABSTRACT FROM AUTHOR]

Background: Two-dimensional (2D) ultrasound is well established for thyroid nodule assessment and treatment guidance. However, it is hampered by a limited field of view and observer variability that may lead to inaccurate nodule classification and treatment. To cope with these limitations, we investigated the use of real-time three-dimensional (3D) ultrasound to improve the accuracy of volume estimation and needle placement during radiofrequency ablation. We assess a new 3D matrix transducer for nodule volume estimation and image-guided radiofrequency ablation. Methods: Thirty thyroid nodule phantoms with thermochromic dye underwent volume estimation and ablation guided by a 2D linear and 3D mechanically-swept array and a 3D matrix transducer. Results: The 3D matrix nodule volume estimations had a lower median difference with the ground truth (0.4 mL) compared to the standard 2D approach (2.2 mL, p < 0.001) and mechanically swept 3D transducer (2.0 mL, p = 0.016). The 3D matrix-guided ablation resulted in a similar nodule ablation coverage when compared to 2D-guidance (76.7% versus 80.8%, p = 0.542). The 3D mechanically swept transducer performed worse (60.1%, p = 0.015). However, 3D matrix and 2D guidance ablations lead to a larger ablated volume outside the nodule than 3D mechanically swept (5.1 mL, 4.2 mL (p = 0.274), 0.5 mL (p < 0.001), respectively). The 3D matrix and mechanically swept approaches were faster with 80 and 72.5 s/mL ablated than 2D with 105.5 s/mL ablated. Conclusions: The 3D matrix transducer estimates volumes more accurately and can facilitate accurate needle placement while reducing procedure time. [ABSTRACT FROM AUTHOR]

Background: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations.Methods: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation.Results: For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi.Conclusions: Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells. [ABSTRACT FROM AUTHOR]

Background:Adjuvant therapy increases disease-free survival in endometrial cancer (EC), but has no impact on overall survival and negatively influences the quality of life. We investigated the discriminatory power of classical and immunological predictors of recurrence in a cohort of EC patients and confirmed the findings in an independent validation cohort.Methods:We reanalysed the data from 355 EC patients and tested our findings in an independent validation cohort of 72 patients with EC. Predictors were selected and Harrell's C-index for concordance was used to determine discriminatory power for disease-free survival in the total group and stratified for histological subtype.Results:Predictors for recurrence were FIGO stage, lymphovascular space invasion and numbers of cytotoxic and memory T-cells. For high risk cancer, cytotoxic or memory T-cells predicted recurrence as well as a combination of FIGO stage and lymphovascular space invasion (C-index 0.67 and 0.71 vs 0.70). Recurrence was best predicted when FIGO stage, lymphovascular space invasion and numbers of cytotoxic cells were used in combination (C-index 0.82). Findings were confirmed in the validation cohort.Conclusions:In high-risk EC, clinicopathological or immunological variables can predict regional or distant recurrence with equal accuracy, but the use of these variables in combination is more powerful. [ABSTRACT FROM AUTHOR]

The root canal system of a tooth is a complex geometrical entity, consisting not only of the main root canal, but also of accessory and lateral canals. Bacteria can reside up to hundreds of micrometers inside those channels and may be difficult to reach for the antimicrobial agents with which root canals are irrigated during a root canal treatment. A combined numerical and experimental study was performed to assess the penetration rate of a root canal irrigant into the lateral canals and tubules, considering both diffusion and convection. The numerical model was validated experimentally using a fluorescent dye. Convection was studied separately using a Computational Fluid Dynamics model, validated with Particle Imaging Velocimetry experiments. Both diffusion and convection were found to be slow on the timescale of an irrigation procedure. The contribution of convection was limited to two canal diameters from the canal entrance, making diffusion the main irrigant transport mechanism. More than 10 min of fresh irrigant delivery was required to obtain an 86 % concentration of the irrigant at the far end of a tubule, in the ideal case of a straight tubule without reaction taking place. Diffusion was even slower when the concentration at the lateral canal entrance was not kept constant, as in the case of a single delivery, which suggests that frequent irrigant replenishment and/or irrigant activation during a root canal treatment are beneficial. Alternative methods should be considered to improve irrigant penetration into lateral canals and tubules. [ABSTRACT FROM AUTHOR]

During a root canal treatment the root canal is irrigated with an antimicrobial fluid, commonly performed with a needle and a syringe. Irrigation of a root canal with two different types of needles can be modeled as an impinging axisymmetric or non-axisymmetric jet. These jets are investigated experimentally with high-speed Particle Imaging Velocimetry, inside and outside the confinement (concave surface) of a root canal, and compared to theoretical predictions for these jets. The efficacy of irrigation fluid refreshment with respect to the typical reaction time of the antimicrobial fluid with a biofilm is characterized with a non-dimensional Damköhler number. The pressure that these jets induce on a wall or at the apex of the root canal is also measured. The axisymmetric jet is found to be stable and its velocity agrees with the theoretical prediction for this type of jet, however, a confinement causes instabilities to the jet. The confinement of the root canal has a pronounced influence on the flow, for both the axisymmetric and non-axisymmetric jet, by reducing the velocities by one order of magnitude and increasing the pressure at the apex. The non-axisymmetric jet inside the confinement shows a cascade of eddies with decreasing velocities, which at the apex does not provide adequate irrigation fluid refreshment. [ABSTRACT FROM AUTHOR]

Abstract. We report a series of Raman-Rayleigh-LIF measurements in two turbulent natural-gas jet diffusion flames produced by the Delft piloted jet diffusion flame burner. The main objective of the Raman-Rayleigh-LIF measurements was to obtain detailed information on the major species concentrations in the flames. The measurements provide simultaneous data on temperature, the concentrations of the major species and the radicals OH and NO and mixture fraction. The application of the Raman technique in the undiluted naturalgas flames proves to be very challenging because of the high fluorescence interference levels. The interference contributions to the recorded Raman signals are identified and subtracted using empirical correlations between the Raman signals and the signals on fluorescence interference monitor channels. The calibration and data reduction of the RamanRayleigh and LIF signals are discussed in detail. The resulting dataset compares excellently with data from previous experiments. Because the Raman-Rayleigh-LIF data provide quantitative concentrations and accordingly quantitative mixture fractions, they form a valuable and useful extension of the existing database tot the Delft piloted jet diffusion flame burner. [ABSTRACT FROM AUTHOR]

A technique has been developed to measure the absolute OH concentration at atmospheric pressures by using a combination of direct absorption and laser-induced fluorescence (LIF) detection. The technique is independent of collisions, because it uses laser beams in a bi-directional configuration, thereby eliminating collisional quenching. The absolute OH concentration is measured spatially resolved in two dimensions by using absorption on the Q[sub 1] (6) rotational line in the A[sup 2] Σ[sup +] (v[sup ′] =0)←X[sup 2] Π(v[sup ′′] =0) band of OH at 309 nm. The requirements for obtaining a good signal-to-noise ratio for the technique are discussed and the possibilities of single-shot measurements are investigated. [ABSTRACT FROM AUTHOR]

A tunable excimer laser at 248 nm (KrF) and 193 nm (ArF) has been used to monitor two-dimensional OH and NO distributions in the turbulent flame of a 100 kW natural gas burner. Spatially resolved fluorescence (spatial resolution better than 1.0 mm) from a 20 cm×20 cm area is collected under single shot conditions. We describe the problems encountered when laser-induced fluorescence imaging techniques are applied to large scale flames. Special experimental arrangements, imposed by the turbulent behavior of the flame we used, are also described. [ABSTRACT FROM AUTHOR]

Liver from 14 day-old fetuses, bone marrow, spleen, and blood from normal adult mice, and bone marrow, spleen, blood, and liver from adult endotoxin (ET)-treated mice were used for isogeneic hemopoietic restoration in lethally whole-body irradiated mice. The number of CFU-S required to prevent 50% mortality of irradiated mice was about 3 for fetal liver, 7-10 for bone marrow, 20 for normal blood and for blood, liver, and spleen of ET-treated mice, and 80 for spleen of normal mice. CFU-S growth curves in femoral bone marrow and spleen showed some variations but the differences in survival of irradiated and protected mice could not easily be explained by differences in CFU-S growth curves. It can be concluded that the CFU-S from peripheral blood, although somewhat less effective than CFU-S from bone marrow, can be a valuable source of CFU-S for bone marrow transplantation. [ABSTRACT FROM AUTHOR]

Dopamine causes a dose-dependent contraction of the rat rectum in vitro followed by a relaxation. This contraction can be inhibited by apomorphine and phenylephrine. This inhibition can be attenuated by the β-endorphin (βE) fragments 2-17 (des-Tyr-γ-endorphin, DTγE) and 6-17 (des-enkephalin-γ-endorphin, DEγE). βE 6-17 seems to be the shortest sequence with full activity in this respect since a shorter fragment (βE 10-17) was less effective. The atypical neuroleptics oxypertine, sulpiride, and clozapine, the classic neuroleptic haloperidol and metoclopramide have a similar action to DEγE. The peptides and atypical neuroleptics do not affect the dopamine response per se while the classic neuroleptics haloperidol and metoclopramide enhance the dopamine response. The effects of the α-type endorphins are opposite to those of the γ-type endorphins, since des-Tyr-α-endorphin (DTαE, βE 2-16) and des-enkephalin-α-endorphin (DEαE, βE 6-16) enhance the phenylephrine-induced decreased responsiveness to dopamine. Structure-activity studies revealed that the active moiety of the α-endorphin fragments probably resides in the 6-9 region. In addition the α-type endorphins directly inhibit the dopamine response. It is concluded that the rat rectum may be used to analyse neuroleptic-like action. In this model α- and γ-endorphin fragments may directly or indirectly influence the interaction of dopamine with the rectum. Because of the strong similarities between the effects of γ-type endorphins and that of neuroleptics the results support the purported neurolepticlike action of γ-type endorphins. The influence of α-type endorphins and γ-type endorphins on the apomorphine or phenylephrine induced decreased responsiveness to dopamine, although opposite, seems to be mediated by an influence on different dopamine sensitive systems. [ABSTRACT FROM AUTHOR]