Spreading depolarizations (SDs) are an enigmatic and ubiquitous co-morbidity of neural dysfunction. SDs are propagating waves of local field depolarization and increased extracellular potassium. They increase the metabolic demand on brain tissue, resulting in changes in tissue blood flow, and are associated with adverse neurological consequences including stroke, epilepsy, neurotrauma, and migraine. Their occurrence is associated with poor patient prognosis through mechanisms which are only partially understood. Here we show in vivo that two (structurally dissimilar) drugs, which suppress astroglial gap junctional communication, can acutely suppress SDs. We found that mefloquine hydrochloride (MQH), administered IP, slowed the propagation of the SD potassium waveform and intermittently led to its suppression. The hemodynamic response was similarly delayed and intermittently suppressed. Furthermore, in instances where SD led to transient tissue swelling, MQH reduced observable tissue displacement. Administration of meclofenamic acid (MFA) IP was found to reduce blood flow, both proximal and distal, to the site of SD induction, preceding a large reduction in the amplitude of the SD-associated potassium wave. We introduce a novel image processing scheme for SD wavefront localization under low-contrast imaging conditions permitting full-field wavefront velocity mapping and wavefront parametrization. We found that MQH administration delayed SD wavefront's optical correlates. These two clinically used drugs, both gap junctional blockers found to distinctly suppress SDs, may be of therapeutic benefit in the various brain disorders associated with recurrent SDs.
Cortical Spreading Depression , Epilepsy , Stroke , Humans , Potassium/pharmacology , Multimodal Imaging
Introduction: The purpose of this study was to identify and reveal the different contexts, variables, and factors that may influence adherence to physical activity among veteran, novice, and dropout trainees, such as the frequency of the weekly training units, the trainees preferred type of exercise, the purpose of the physical activity, and the relationship between support and supervision by fitness instructors and professionals. This study also examined the relationships between trainees, seniority and the strength of the habit and adherence to physical activity, the effects of personal variables such as age and gender on adherence to physical activity, and how the seniority and adherence of trainees may affect their quality of life. Methods: A total of 460 participants drawn from the broader Israeli exercise community, which encompasses a diverse range of individuals within the general adult population, were engaged in this study. These participants included seasoned exercisers, individuals who had recently initiated exercise routines, and those who had previously engaged in physical activity. Each participant completed a comprehensive set of questionnaires, including the Self-Report Habit Index, the Exercise Adherence Rating Scale, and the World Health Organization (WHO) Quality of Life Scale. In addition to the questionnaire responses, demographic data and inquiries concerning their physical activity were also collected. Results: The results show that the average frequency of the weekly training units of veteran trainees was significantly higher than that of novice trainees: 3.95 and 2.93, respectively (p < 0.0001). We found no significant differences between novice and veteran trainees regarding their training goal preferences (p = 0.07). Veteran trainees who had been in training for more than a year appeared to have higher self-efficacy since 31.16% reported receiving no supervision compared to 16.67% among novice trainees. In addition, people over 45 appear to have more health-related goals compared to their younger counterparts (p < 0.001). The quality of life scores of the trainees was related to their seniority in physical training, but only by a small magnitude (R2 = 0.06), p < .001). Those who trained in resistance training showed the greatest rate of adherence in relation to flexibility and aerobic training (p < 0.001), and women preferred more body toning and had more weight loss goals than men (p < 0.001). Discussion: The results indicate that there are central and important factors that may affect adherence to physical activity, and that all these aspects must be taken into account when planning a training program or when there is a desire to maintain or increase adherence to physical activity. The research findings indicate that the main factors that can influence adherence to physical activity are identifying and increasing the trainee's self-efficacy, maintaining weekly training units with sufficient frequency to form a habit and incorporating resistance training into the training regime, as resistance training has shown high levels of adherence. Moreover, it seems that people with different degrees of experience in physical training have distinct and varied training goals, and there is no one goal that fits all. In addition, specific factors such as age and gender must also be taken into account, because the age and gender of the trainees may significantly affect the goals of physical training.
Integrated photonic sensors can provide large scale, flexible detection schemes. Photonic crystal slabs (PCSs) offer a miniaturized platform for wideband, sensitive ultrasound detection by exploiting the photoelastic effect in water. However, poor modal overlap with the sensing medium and non-negligible absorption loss of the aqueous medium have previously limited PCS sensor performance. In this study, we detail the development and optimization of a PCS-based acoustic sensor by adding to it a low-loss high-index polymer cladding layer. Exploiting a mode-optimized TM-like optical resonance present in a PCS, with high bulk index sensitivity (>600nm/RIU) and quality factor Q (>8000), we demonstrate real-time ultrasound sensing at a noise equivalent pressure of 170 Pa (1.9Pa/Hz). The PCS sensor is backside-coupled to an optical fiber, which, along with its intensity-based ultrasound-sensing architecture, will allow us to scale up easily to a 2D array. This work paves the way to a sensitive compact ultrasound detector for photoacoustic-based diagnostics and monitoring of tissue.
Additive manufacturing attracts much interest for manufacturing and repair of structural parts for the aerospace industry. This paper presents comparative characterization of aircraft items made of Al 4047 alloy, Ti-6Al-4V alloy, and 17-4 precipitation hardened (PH) (AISI 630) stainless steel, either manufactured or repaired by laser engineered net shaping (LENS). Chemical analysis, density, and surface roughness measurements, X-ray micro-computed tomography (µ-CT) analysis, metallography, and micro-hardness testing were conducted. In all three materials, microstructures typical of rapid solidification were observed, along with high density, chemical composition, and hardness comparable to those of the counterpart wrought alloys (even in hard condition). High standard deviation in hardness values, anisotropic geometrical distortion, and overbuild at top edges were observed. The detected defects included partially melted and unmelted powder particles, porosity, and interlayer lack of fusion, in particular at the interface between the substrate plate and the build. There was a fairly good match between the density values measured by µ-CT and those measured by the Archimedes method; there was also good correlation between the type of defects detected by both techniques. Surface roughness, density of partially melted powder particles, and the content of bulk defects were significantly higher in Al 4047 than in 17-4 PH stainless steel and Ti-6Al-4V alloy. Optical gaging can be used reliably for surface roughness measurements. The implications of these findings are discussed.
We demonstrate ultrasound detection with 500-µm-diameter photonic-crystal slab (PCS) sensors fabricated from CMOS-compatible technology. An ultrasound signal impinging a PCS sensor causes a local modulation of the refractive index (RI) of the medium (water) in which the PCS is immersed, resulting in a periodic spectral shift of the optical resonance of the PCS. The acoustic sensitivity is found to scale with the index sensitivity S and quality factor Q. A noise equivalent pressure (NEP) of 650 Pa with averaging (7.4 Pa/Hz) and relative wavelength shifts of up to 4.3×10-5 MPa-1 are measured. The frequency response of the sensors is observed to be flat from 1 to 20 MHz, with the range limited only by our measurement apparatus.
Detecting the presence of circulating tumor cells (CTCs) in peripheral blood can be useful for monitoring treatment in patients, metastasis prognosis, and even early detection. The epidermal growth factor receptor (EGFR) is overexpressed in carcinoma, e.g. in colorectal cancer. Here, we use atomic force microscopy (AFM) force spectroscopy to study the mechanical properties of A431 cells, which simulate EGFR-overexpressing epithelial CTCs and were magnetically isolated by Bio-Ferrography (BF). BF is found useful in isolating individual cancerous cells for mechanical testing, thus avoiding cell-cell interactions. Different stages in the pre-isolation sample preparation steps (namely, cell fixation, PLL coating of the glass substrate, and immunomagnetic labeling) are found to affect the estimated Young's modulus. The BF magnetic isolation step itself does not change the elasticity of the captured cells in comparison to the pre-isolated microbeads-bound cells. The reported increase in the estimated Young's modulus between BF-isolated target cells and fixed cells that are not bound to magnetic microbeads can be used as a quantitative mechanical indicator for objective detection of CTCs. Furthermore, we report a 2.8-fold increase in the adhesion force between the AFM tip and the BF-isolated cells compared to the pre-isolated magnetic microbead-bound A431 fixed cells. This adhesion force correlation could potentially serve as an additional quantitative mechanical indicator for distinguishing between the target and background cells, without the use of cell staining assay and subjective analysis by an expert pathologist. This study demonstrates the powerful combination of the highly sensitive cell isolation by BF and the subsequent analysis of mechanical properties of individual captured cancerous cells by AFM. This combination has potential use in cancer research.
Mechanical Phenomena , Microscopy, Atomic Force , Biomechanical Phenomena , Cell Line, Tumor , Elastic Modulus , Humans , Neoplasm Metastasis
Single-frame blood flow maps from laser speckle contrast imaging (LSCI) contain high spatiotemporal variation that obscures high spatial-frequency vascular features, making precise image registration for signal amplification challenging. In this work, novel bivariate standardized moment filters (BSMFs) were used to provide stable measures of vessel edge location, permitting more robust LSCI registration. Relatedly, BSMFs enabled the stable reconstruction of vessel edges from sparsely distributed blood flow map outliers, which were found to retain most of the temporal dynamics. Consequently, data discarding and BSMF-based reconstruction enable efficient real-time quantitative LSCI data compression. Smaller LSCI-kernels produced log-normal blood flow distributions, enhancing sparse-to-dense inference.
We developed a multi-modal brain imaging system to investigate the relationship between blood flow, blood oxygenation/volume, intracellular calcium and electrographic activity during acute seizure-like events (SLEs), both before and after pharmacological intervention. Rising blood volume was highly specific to SLE-onset whereas blood flow was more correlated with all eletrographic activity. Intracellular calcium spiked between SLEs and at SLE-onset with oscillation during SLEs. Modified neurovascular and ionic SLE responses were observed after intervention and the interval between SLEs became shorter and more inconsistent. Comparison of artery and vein pulsatile flow suggest proximal interference and greater vascular leakage prior to intervention.
We report on a miniature label-free imaging system for monitoring brain blood flow and blood oxygenation changes in awake, freely behaving rats. The device, weighing 15 grams, enables imaging in a â¼ 2 × 2 mm field of view with 4.4 µm lateral resolution and 1 - 8 Hz temporal sampling rate. The imaging is performed through a chronically-implanted cranial window that remains optically clear between 2 to > 6 weeks after the craniotomy. This imaging method is well suited for longitudinal studies of chronic models of brain diseases and disorders. In this work, it is applied to monitoring neurovascular coupling during drug-induced absence-like seizures 6 weeks following the craniotomy.
Objective pain assessment methods pose an advantage over the currently used subjective pain rating tools. Advanced signal processing methodologies, including the wavelet transform (WT) and the orthogonal matching pursuit algorithm (OMP), were developed in the past two decades. The aim of this study was to apply and compare these time-specific methods to heart rate samples of healthy subjects for acute pain detection. Fifteen adult volunteers participated in a study conducted in the pain clinic at a single center. Each subject's heart rate was sampled for 5-min baseline, followed by a cold pressor test (CPT). Analysis was done by the WT and the OMP algorithm with a Fourier/Wavelet dictionary separately. Data from 11 subjects were analyzed. Compared to baseline, The WT analysis showed a significant coefficients' density increase during the pain incline period (p < 0.01) and the entire CPT (p < 0.01), with significantly higher coefficient amplitudes. The OMP analysis showed a significant wavelet coefficients' density increase during pain incline and decline periods (p < 0.01, p < 0.05) and the entire CPT (p < 0.001), with suggestive higher amplitudes. Comparison of both methods showed that during the baseline there was a significant reduction in wavelet coefficient density using the OMP algorithm (p < 0.001). Analysis by the two-way ANOVA with repeated measures showed a significant proportional increase in wavelet coefficients during the incline period and the entire CPT using the OMP algorithm (p < 0.01). Both methods provided accurate and non-delayed detection of pain events. Statistical analysis proved the OMP to be by far more specific allowing the Fourier coefficients to represent the signal's basic harmonics and the wavelet coefficients to focus on the time-specific painful event. This is an initial study using OMP for pain detection; further studies need to prove the efficiency of this system in different settings.
Acute Pain/diagnosis , Acute Pain/physiopathology , Algorithms , Heart Rate/physiology , Adult , Female , Humans , Male , Signal Processing, Computer-Assisted , Wavelet Analysis , Young Adult
We report a new physical mechanism for simultaneous tuning of quality factors, spectral responses, and field distributions in photonic crystal slabs through removal of polarization mode degeneracy using a lattice of elliptical nano-holes. The quality factors in these structures can become higher than those obtained with much smaller circular nano-holes. Furthermore, the modes can be superimposed by either rotating or morphing the elliptical nano-holes into a corrugated grating. These findings will enable improved radiation-matter interaction in optical, microwave, and THZ frequencies along with enhanced opto-acoustic coupling.
Optical Devices , Photons , Silicon Dioxide , Spectrum Analysis
BACKGROUND: Circulating tumor cells (CTCs) in blood circulation may play a role in monitoring and even in early detection of metastasis patients. Due to the limited presence of CTCs in blood circulation, viable CTCs isolation technology must supply a very high recovery rate. METHODS: Here, we implement design of experiments (DOE) methodology in order to optimize the Bio-Ferrography (BF) immunomagnetic isolation (IMI) procedure for the EGFR high positive CTCs application. All consequent DOE phases such as screening design, optimization experiments and validation experiments were used. RESULTS: A significant recovery rate of more than 95% was achieved while isolating 100 EGFR high positive CTCs from 1 mL human whole blood. CONCLUSIONS: The recovery achievement in this research positions BF technology as one of the most efficient IMI technologies, which is ready to be challenged with patients' blood samples.
Biomarkers, Tumor/analysis , ErbB Receptors/analysis , Flow Cytometry/methods , Immunomagnetic Separation/methods , Neoplastic Cells, Circulating/chemistry , Cell Line, Tumor , Equipment Design , Flow Cytometry/instrumentation , Humans , Immunomagnetic Separation/instrumentation
Laser Speckle Contrast Imaging (LSCI) is a flexible, easy-to-implement technique for measuring blood flow speeds in-vivo. In order to obtain reliable quantitative data from LSCI the object must remain in the focal plane of the imaging system for the duration of the measurement session. However, since LSCI suffers from inherent frame-to-frame noise, it often requires a moving average filter to produce quantitative results. This frame-to-frame noise also makes the implementation of rapid autofocus system challenging. In this work, we demonstrate an autofocus method and system based on a novel measure of misfocus which serves as an accurate and noise-robust feedback mechanism. This measure of misfocus is shown to enable the localization of best focus with sub-depth-of-field sensitivity, yielding more accurate estimates of blood flow speeds and blood vessel diameters.
BACKGROUND: (1)H low field nuclear magnetic resonance (LF-NMR) relaxometry has been suggested as a tool to distinguish between different molecular ensembles in complex systems with differential segmental or whole molecular motion and/or different morphologies. In biodiesel applications the molecular structure versus liquid-phase packing morphologies of fatty acid methyl esters (FAMEs) influences physico-chemical characteristics of the fuel, including flow properties, operability during cold weather, blending, and more. Still, their liquid morphological structures have scarcely been studied. It was therefore the objective of this work to explore the potential of this technology for characterizing the molecular organization of FAMEs in the liquid phase. This was accomplished by using a combination of supporting advanced technologies. RESULTS: We show that pure oleic acid (OA) and methyl oleate (MO) standards exhibited both similarities and differences in the (1)H LF-NMR relaxation times (T2s) and peak areas, for a range of temperatures. Based on X-ray measurements, both molecules were found to possess a liquid crystal-like order, although a larger fluidity was found for MO, because as the temperature is increased, MO molecules separate both longitudinally and transversely from one another. In addition, both molecules exhibited a preferred direction of diffusion based on the apparent hydrodynamic radius. The close molecular packing arrangement and interactions were found to affect the translational and segmental motions of the molecules, as a result of dimerization of the head group in OA as opposed to weaker polar interactions in MO. CONCLUSIONS: A comprehensive model for the liquid crystal-like arrangement of FAMEs in the liquid phase is suggested. The differences in translational and segmental motions of the molecules were rationalized by the differences in the (1)H LF-NMR T2 distributions of OA and MO, which was further supported by (13)C high field (HF)-NMR spectra and (1)H HF-NMR relaxation. The proposed assignment allows for material characterization based on parameters that contribute to properties in applications such as biodiesel fuels.
BACKGROUND: The epidermal growth factor receptor (EGFR) is overexpressed in carcinoma. In some cases, including in colorectal cancer, it is used as a therapeutic target. Bio-Ferrography is a nondestructive method for isolating magnetized cells and tissues from a fluid onto a glass slide based on their interaction with an external, strong, and focused magnetic field. METHODS: Here, we implement Bio-Ferrography to separate EGFR-positive cancer cells from EGFR-negative noncancer cells, mixed at a ratio of 1 to 1 × 10(6) , from either phosphate-buffered saline or human whole blood. Incubation of the cells with an anti-EGFR antibody and magnetic microbeads coupled to a secondary antibody was used to magnetize the target cells prior to the ferrographic analysis. RESULTS: A procedure was developed for "a proof of concept" isolation. Recovery values as high as 78% for 1 mL phosphate-buffered saline, and 53% for 1 mL human whole blood, with a limit-of-detection of 30 and 100 target cells, respectively, were achieved. CONCLUSIONS: These capture efficiency values are considered significant and, therefore, warrant further study on isolation of real circulating tumor cells from blood samples of patients, aiming at early diagnosis of EGFR-overexpressing tumor types.
ErbB Receptors/analysis , ErbB Receptors/biosynthesis , Flow Cytometry/methods , Magnets/analysis , Neoplastic Cells, Circulating/chemistry , Neoplastic Cells, Circulating/metabolism , Animals , Humans , Magnetic Phenomena , Mice , NIH 3T3 Cells
Background: The epidermal growth factor receptor (EGFR) is overexpressed in carcinoma. In some cases, including in colorectal cancer, it is used as a therapeutic target. Bio-Ferrography is a non-destructive method for isolating magnetized cells and tissues from a fluid onto a glass slide based on their interaction with an external, strong and focused magnetic field. Methods: Here, we implement Bio-Ferrography to separate EGFR positive cancer cells from EGFR negative non-cancer cells, mixed at a ratio of 1 to 1 × 106 , from either PBS or human whole blood (HWB). Incubation of the cells with an anti-EGFR antibody and magnetic microbeads coupled to a secondary antibody was used to magnetize the target cells prior to the ferrographic analysis. Results: A procedure was developed for "a proof of concept" isolation. Recovery values as high as 78% for 1 mL PBS, and 53% for 1 mL HWB, with a limit of detection (LOD) of 30 and 100 target cells, respectively, were achieved. Conclusions: These capture efficiency values are considered significant and therefore warrant further study on isolation of real circulating tumor cells (CTCs) from blood samples of patients, aiming at early diagnosis of EGFR overexpressing tumor types. This article is protected by copyright. All rights reserved.
The integrity of the blood brain barrier (BBB) can contribute to the development of many brain disorders. We evaluate laser speckle contrast imaging (LSCI) as an intrinsic modality for monitoring BBB disruptions through simultaneous fluorescence and LSCI with vertical cavity surface emitting lasers (VCSELs). We demonstrated that drug-induced BBB opening was associated with a relative change of the arterial and venous blood velocities. Cross-sectional flow velocity ratio (veins/arteries) decreased significantly in rats treated with BBB-opening drugs, ≤0.81 of initial values.
Performance improvements in instrumentation for optical imaging have contributed greatly to molecular imaging in living subjects. In order to advance molecular imaging in freely moving, untethered subjects, we designed a miniature vertical-cavity surface-emitting laser (VCSEL)-based biosensor measuring 1cm(3) and weighing 0.7g that accurately detects both fluorophore and tumor-targeted molecular probes in small animals. We integrated a critical enabling component, a complementary metal-oxide semiconductor (CMOS) read-out integrated circuit, which digitized the fluorescence signal to achieve autofluorescence-limited sensitivity. After surgical implantation of the lightweight sensor for two weeks, we obtained continuous and dynamic fluorophore measurements while the subject was un-anesthetized and mobile. The technology demonstrated here represents a critical step in the path toward untethered optical sensing using an integrated optoelectronic implant.
Low-resolution nuclear magnetic resonance (LR-NMR) relaxometry is a powerful tool that can be harnessed for characterizing constituents in complex materials. Conversion of the relaxation signal into a continuous distribution of relaxation components is an ill-posed inverse Laplace transform problem. The most common numerical method implemented today for dealing with this kind of problem is based on L2-norm regularization. However, sparse representation methods via L1 regularization and convex optimization are a relatively new approach for effective analysis and processing of digital images and signals. In this article, a numerical optimization method for analyzing LR-NMR data by including non-negativity constraints and L1 regularization and by applying a convex optimization solver PDCO, a primal-dual interior method for convex objectives, that allows general linear constraints to be treated as linear operators is presented. The integrated approach includes validation of analyses by simulations, testing repeatability of experiments, and validation of the model and its statistical assumptions. The proposed method provides better resolved and more accurate solutions when compared with those suggested by existing tools. © 2013 Wiley Periodicals, Inc. Concepts Magn Reson Part A 42A: 72-88, 2013.
BACKGROUND: Biodiesel production has increased dramatically over the last decade, raising the need for new rapid and non-destructive analytical tools and technologies. 1H Low Field Nuclear Magnetic Resonance (LF-NMR) applications, which offer great potential to the field of biodiesel, have been developed by the Phyto Lipid Biotechnology Lab research team in the last few years. RESULTS: Supervised and un-supervised chemometric tools are suggested for screening new alternative biodiesel feedstocks according to oil content and viscosity. The tools allowed assignment into viscosity groups of biodiesel-petrodiesel samples whose viscosity is unknown, and uncovered biodiesel samples that have residues of unreacted acylglycerol and/or methanol, and poorly separated and cleaned glycerol and water. In the case of composite materials, relaxation time distribution, and cross-correlation methods were successfully applied to differentiate components. Continuous distributed methods were also applied to calculate the yield of the transesterification reaction, and thus monitor the progress of the common and in-situ transesterification reactions, offering a tool for optimization of reaction parameters. CONCLUSIONS: Comprehensive applied tools are detailed for the characterization of new alternative biodiesel resources in their whole conformation, monitoring of the biodiesel transesterification reaction, and quality evaluation of the final product, using a non-invasive and non-destructive technology that is new to the biodiesel research area. A new integrated computational-experimental approach for analysis of 1H LF-NMR relaxometry data is also presented, suggesting improved solution stability and peak resolution.
