Multiscale photoacoustic tomography using reversibly switchable thermochromics.

Significance: Based on acoustic detection of optical absorption, photoacoustic tomography (PAT) allows functional and molecular imaging beyond the optical diffusion limit with high spatial resolution. However, multispectral functional and molecular PAT is often limited by decreased spectroscopic accuracy and reduced detection sensitivity in deep tissues, mainly due to wavelength-dependent optical attenuation and inaccurate acoustic inversion. Aim: Previous work has demonstrated that reversible color-shifting can drastically improve the detection sensitivity of PAT by suppressing nonswitching background signals. We aim to develop a new color switching-based PAT method using reversibly switchable thermochromics (ReST). Approach: We developed a family of ReST with excellent water dispersion, biostability, and temperature-controlled color changes by surface modification of commercial thermochromic microcapsules with the hydrophilic polysaccharide alginate. Results: The optical absorbance of the ReST was switched on and off repeatedly by modulating the surrounding temperature, allowing differential photoacoustic detection that effectively suppressed the nonswitching background signal and substantially improved image contrast and detection sensitivity. We demonstrate reversible thermal-switching imaging of ReST in vitro and in vivo using three PAT modes at different length scales. Conclusions: ReST-enabled PAT is a promising technology for high-sensitivity deep tissue imaging of molecular activity in temperature-related biomedical applications, such as cancer thermotherapy.

Atom Probe Tomography of Encapsulated Hydroxyapatite Nanoparticles.

Hydroxyapatite nanoparticles (HAP NPs) are important for medicine, bioengineering, catalysis, and water treatment. However, current understanding of the nanoscale phenomena that confer HAP NPs their many useful properties is limited by a lack of information about the distribution of the atoms within the particles. Atom probe tomography (APT) has the spatial resolution and chemical sensitivity for HAP NP characterization, but difficulties in preparing the required needle-shaped samples make the design of these experiments challenging. Herein, two techniques are developed to encapsulate HAP NPs and prepare them into APT tips. By sputter-coating gold or the atomic layer deposition of alumina for encapsulation, partially fluoridated HAP NPs are successfully characterized by voltage- or laser-pulsing APT, respectively. Analyses reveal that significant tradeoffs exist between encapsulant methods/materials for HAP characterization and that selection of a more robust approach will require additional technique development. This work serves as an essential starting point for advancing knowledge about the nanoscale spatiochemistry of HAP NPs.

Application of digital holographic tomography in antitumor effect of cantharides complex on 4T1 breast cancer cells.

The study focuses on a methodology providing noninvasive monitoring and evaluation of the antitumor effect of traditional Chinese medicine, cantharides complex (canth), on 4T1 breast tumor cells. Digital holographic tomography (DHT) and developed data post-processing algorithms were used for quantitative estimation of changes in optical and morphological parameters of cells. We calculated and compared data on the refractive index, thickness, and projected area of 4T1 breast tumor cells in control untreated specimens and those treated with doxorubicin hydrochloride (DOX), canth, and their combinations. Post-treatment changes in cellular morphology recorded by DHT demonstrated that the two drugs led to noticeably different morphological changes in cells that can be presumably associated with different pathways of their death, apoptosis, or necrosis. The effect of combined treatment with these two drugs strongly depended on their relative concentrations and could lead to changes characteristic either for DOX or for canth; however, being more profound than those obtained when using each drug solely. The results obtained by DHT are in a good correspondence with commonly used cell viability analysis and immunofluorescent analysis of changes in cellular cytoskeleton.

Feasibility of Electroacoustic Tomography: A Simulation Study.

The feasibility of electroacoustic tomography (EAT) was investigated for in situ monitoring the electric field distribution in soft tissue. EAT exploits the phenomenon that the amplitude of acoustic emission generated by an electric field is proportional to the electrical energy deposition in tissue. After detecting these acoustic waves with ultrasound transducers, an image of the electric field distribution can be reconstructed in real-time. In our computer simulations, the electric field distribution in soft tissue was generated by solving general partial differential equations (PDEs) using finite element analysis (FEA). The electric field distributions were converted into initial pressure distributions, and the propagation of the induced acoustic waves was simulated using K-Wave simulation. A circular array of 128 ultrasound transducers was placed around the target to detect the acoustic waves, and a time reversal reconstruction algorithm was used to reconstruct the EAT image. A different number of electrodes set at different distances with different voltage inputs on the electrodes were performed to simulate different electric field distributions during electroporation. It was found that the electrical energy deposition in reconstructed EAT imaging is decreased as the distance of the electrodes increases. We also have investigated the sensitivity of the EAT imaging with different voltage inputs. The minimal voltage we can detect with EAT is 970 V at the pulsewidth of 180 ns. The results of this study demonstrated that EAT is a feasible technique for monitoring the electric field distribution and guiding the electrotherapy in future clinical practice.

Microelectrode array electrical impedance tomography for fast functional imaging in the thalamus.

Electrical Impedance Tomography (EIT) has the potential to be able to observe functional tomographic images of neural activity in the brain at millisecond time-scales. Prior modelling and experimental work has shown that EIT is capable of imaging impedance changes from neural depolarisation in rat somatosensory cortex. Here, we investigate the feasibility of EIT for imaging impedance changes using a stereotaxically implanted microelectrode array in the thalamus. Microelectrode array EIT was simulated using an anatomically accurate marmoset brain model. Impedance imaging was validated and detectability estimated using physiological noise recorded from the marmoset visual thalamus. The results suggest that visual-input-driven impedance changes in visual subcortical bodies within 300 µm of the implanted array could be reliably reconstructed and localised, comparable to local field potential measurements. Furthermore, we demonstrated that microelectrode array EIT could reconstruct concurrent activity in multiple subcortical bodies simultaneously.

Closed-loop mechanical ventilation for lung injury: a novel physiological-feedback mode following the principles of the open lung concept.

Adherence to low tidal volume (VT) ventilation and selected positive end-expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the "open lung" concept. Lung injury was induced by surfactant washout in pigs (n = 8). Animals were ventilated following the principles of the "open lung approach" (OLA) using a fully closed-loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low VT-ventilation for 6 h in severely lung injured pigs. Using the "open lung" approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the "open lung approach"-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions.

Neuralgia del pudendo: a propósito de 2 casos / Pudendal neuralgia. A report of 2 cases

La neuralgia del pudendo es una causa infradiagnosticada de dolor neuropático en la zona perineal. Se produce a raíz del atrapamiento del nervio pudendo en algún punto de su trayecto. Su diagnóstico de sospecha es fundamentalmente clínico y se confirma mediante electromiografía y/o la mejoría tras infiltraciones perineurales. El tratamiento recomendado es inicialmente conservador y, si fracasa, quirúrgico. La rehabilitacio¿n tanto precirugía como después de la intervención quirúrgica tiene un papel importante en esta patología, aunque la pauta a seguir no está bien establecida. Como médicos rehabilitadores debemos tener en cuenta el atrapamiento del nervio pudendo como posible causa de dolor crónico en la región genital. Presentamos los casos de 2 pacientes diagnosticadas de neuralgia del pudendo que fueron derivadas a nuestra consulta de rehabilitación ambulatoria para valoración de tratamiento (AU)

Pudendal neuralgia is an underdiagnosed cause of neuropathic pain in the perineal area. It is caused by pudendal nerve entrapment at some point. Diagnosis is mainly clinical, and confirmation is by electromyography and/or improvement after perineural infiltration. The recommended treatment is initially conservative and, if unsuccessful, surgery can be performed. Pre- and post-surgical rehabilitation plays an important role in this disease, although there is still no well-established protocol. Specialists in physical medicine and rehabilitation should consider pudendal nerve entrapment as a cause of chronic pain in the genital region. We present the cases of two patients diagnosed with pudendal neuralgia who were referred to our clinic for treatment evaluation (AU)

A New Method for Treatment of Lymphedema of Limbs: Standardized Manual Massage with a New Device Linforoll in Conservative and Surgical Therapy Protocols.

OBJECTIVES: Edema fluid in lymphedematous limbs should be evacuated to sites where it can be absorbed. It should be moved either to the hypogastrium or arm/scapular regions along tissue channels or implanted silicon channels or through lymphovenous anastomoses. For that purpose, the manual lymphatic drainage of limb is an effective method. Standardization of manual massage applied force and timing becomes necessary. AIM: A device with known pressing area and continuously showing the applied force while moving it toward the root of the limb is needed. Moreover, force could be adjusted to the stiffness of the massaged tissues that varies at different levels of the limb. Results from such a device would be repeatable and reproducible by others. METHODS: In this study we present data on tissue fluid hydromechanics obtained from 20 patients with obstructive limb lymphedema during massage with a massaging roller called Linforoll. Linforoll is composed of a hand piece with roller and pressure sensor connected wireless to the computer displaying the pressure curve of the applied force. Electron microscopy studies for checking eventual tissue changes were done. RESULTS AND CONCLUSIONS: Linforoll provides the possibilities of: 1) regulating the applied force according to the hydromechanic conditions of the massaged tissues; 2) standardization of massage repeatable in the same patient; 3) decrease of limb volume; 4) evident increase in tissue elasticity; 5) application as a driving force for fluid flow along the surgically implanted tubing and vessels running to the lymphovenous shunts.

Atom Probe Tomographic Mapping Directly Reveals the Atomic Distribution of Phosphorus in Resin Embedded Ferritin.

Here we report the atomic-scale analysis of biological interfaces within the ferritin protein using atom probe tomography that is facilitated by an advanced specimen preparation approach. Embedding ferritin in an organic polymer resin lacking nitrogen provided chemical contrast to visualise atomic distributions and distinguish the inorganic-organic interface of the ferrihydrite mineral core and protein shell, as well as the organic-organic interface between the ferritin protein shell and embedding resin. In addition, we definitively show the atomic-scale distribution of phosphorus as being at the surface of the ferrihydrite mineral with the distribution of sodium mapped within the protein shell environment with an enhanced distribution at the mineral/protein interface. The sample preparation method is robust and can be directly extended to further enhance the study of biological, organic and inorganic nanomaterials relevant to health, energy or the environment.

Hyperthermia treatment planning for cervical cancer patients based on electrical conductivity tissue properties acquired in vivo with EPT at 3 T MRI.

Introduction The reliability of hyperthermia treatment planning (HTP) is strongly dependent on the accuracy of the electric properties of each tissue. The values currently used are mostly based on ex vivo measurements. In this study, in vivo conductivity of human muscle, bladder content and cervical tumours, acquired with magnetic resonance-based electric properties tomography (MR-EPT), are exploited to investigate the effect on HTP for cervical cancer patients. Methods Temperature-based optimisation of five different patients was performed using literature-based conductivity values yielding certain antenna settings, which are then used to compute the temperature distribution of the patient models with EPT-based conductivity values. Furthermore, the effects of altered bladder and muscle conductivity were studied separately. Finally, the temperature-based optimisation was performed with patient models based on EPT conductivity values. Results The tumour temperatures for all EPT-based dielectric patient models were lower compared to the optimal tumour temperatures based on literature values. The largest deviation was observed for patient 1 with ΔT90 = -1.37 °C. A negative impact was also observed when the treatment was optimised based on the EPT values. For four patients ΔT90 was less than 0.6 °C; for one patient it was 1.5 °C. Conclusions Electric conductivity values acquired by EPT are higher than commonly used from literature. This difference has a substantial impact on cervical tumour temperatures achieved during hyperthermia. A higher conductivity in the bladder and in the muscle tissue surrounding the tumour leads to higher power dissipation in the bladder and muscle, and therefore to lower tumour temperatures.

The effects of noise vocoding on gap detection thresholds.

Gap detection threshold (GDT), the shortest silent interval a person can perceive, is a commonly used measure of temporal processing resolution. The purposes of this study were: (1) to examine the effects of noise vocoding, which has been used to simulate what signals sound like through a cochlear implant, on GDTs in normal-hearing subjects, and (2) to further the understanding of neural mechanisms underlying gap detection using the Auditory Late Response (ALR). Thirteen normal listeners participated. In behavioral tests, the GDTs were determined for the original and vocoded stimuli. In ALR recordings, the subjects were presented with auditory stimuli with and without containing gaps and stimuli with and without being vocoded. Results showed that GDTs were significantly elevated for vocoded stimuli with spectral resolutions of 4 and 20 channels compared to those for the original stimuli. A gap effect was observed in the post-gap ALR. Current densities for N1 peaks evoked by stimuli with zero- vs. non-zero ms gaps, pre- vs. post-gap markers, and original vs. vocoded stimuli were obtained using the standardized low-resolution brain electromagnetic tomography (sLORETA) method. Paired comparisons of pre- and post-gap current density values were made. Results showed a statistical difference between the N1s evoked by pre- vs. post-gap markers, with the activation in the middle frontal gyrus and precentral gyrus. The results suggest that: (1) noise vocoding does affect temporal processing resolution assessed with GDTs, (2) gap detection may involve the recruitment of cognitive neural resources, and (3) the ALR has a potential value of objectively estimating temporal processing resolution.

Tumoración pétrea paracervical en paciente con esclerosis sistémica forma limitada / Hard paracervical tumor in a patient with limited systemic sclerosis

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In vivo tomographic imaging with fluorescence and MRI using tumor-targeted dual-labeled nanoparticles.

Dual-modality imaging combines the complementary advantages of different modalities, and offers the prospect of improved preclinical research. The combination of fluorescence imaging and magnetic resonance imaging (MRI) provides cross-validated information and direct comparison between these modalities. Here, we report on the application of a novel tumor-targeted, dual-labeled nanoparticle (NP), utilizing iron oxide as the MRI contrast agent and near infrared (NIR) dye Cy5.5 as the fluorescent agent. Results of in vitro experiments verified the specificity of the NP to tumor cells. In vivo tumor targeting and uptake of the NPs in a mouse model were visualized by fluorescence and MR imaging collected at different time points. Quantitative analysis was carried out to evaluate the efficacy of MRI contrast enhancement. Furthermore, tomographic images were also acquired using both imaging modalities and cross-validated information of tumor location and size between these two modalities was revealed. The results demonstrate that the use of dual-labeled NPs can facilitate the dual-modal detection of tumors, information cross-validation, and direct comparison by combing fluorescence molecular tomography (FMT) and MRI.

Thalamocortical input onto layer 5 pyramidal neurons measured using quantitative large-scale array tomography.

The subcellular locations of synapses on pyramidal neurons strongly influences dendritic integration and synaptic plasticity. Despite this, there is little quantitative data on spatial distributions of specific types of synaptic input. Here we use array tomography (AT), a high-resolution optical microscopy method, to examine thalamocortical (TC) input onto layer 5 pyramidal neurons. We first verified the ability of AT to identify synapses using parallel electron microscopic analysis of TC synapses in layer 4. We then use large-scale array tomography (LSAT) to measure TC synapse distribution on L5 pyramidal neurons in a 1.00 × 0.83 × 0.21 mm(3) volume of mouse somatosensory cortex. We found that TC synapses primarily target basal dendrites in layer 5, but also make a considerable input to proximal apical dendrites in L4, consistent with previous work. Our analysis further suggests that TC inputs are biased toward certain branches and, within branches, synapses show significant clustering with an excess of TC synapse nearest neighbors within 5-15 µm compared to a random distribution. Thus, we show that AT is a sensitive and quantitative method to map specific types of synaptic input on the dendrites of entire neurons. We anticipate that this technique will be of wide utility for mapping functionally-relevant anatomical connectivity in neural circuits.

Relaxation versus fractionation as hypnotic deepening: do they differ in physiological changes?

After rapid hypnotic induction, 12 healthy volunteers underwent hypnotic deepening with relaxation or with fractionation (without relaxation) in a random latin-square protocol. Electroencephalographic occipital alpha activity was measured, low-resolution brain electromagnetic tomography was performed, and hemodynamics (stroke volume, heart rate, cardiac output, mean arterial blood pressure, forearm arterial flow and resistance) were monitored in basal conditions and after deepening. After relaxation, both forearm flow (-18%) and blood pressure (-4%) decreased; forearm resistance remained unchanged. After fractionation, a forearm flow decrease comparable to that recorded after relaxation was observed, but blood pressure remained unchanged, leading to an increase of forearm resistance (+51%). Central hemodynamics did not change. Alpha activity increased in the precuneus after fractionation only. In conclusion, both relaxation and fractionation have vasoconstrictor effects, but fractionation is also associated with an increase in peripheral resistance.

Differential effects of nicotine on P50 amplitude, its gating, and their neural sources in low and high suppressors.

Sensory gating impairment in schizophrenia has been documented in the form of aberrant middle latency P50 event-related brain potential responses to S(1) and/or S(2) stimuli in a paired (S(1)-S(2)) auditory stimulus paradigm. Evidenced by a failure to suppress S(2) P50 or by attenuated S(1) P50s, these sensory deficits have been associated with increased smoking behaviour in this disorder, and may be related to the putative ameliorating effects of smoke-inhaled nicotine on neural mechanisms regulating gating. Comparison of healthy controls with low versus high gating efficiency has been forwarded as a model for investigating the actions of antipsychotic agents on aberrant gating functions. In the current study, the effect of a single dose (6 mg) of nicotine gum on P50, gating indices, and their cortical sources indexed with sLORETA (standardized low resolution electromagnetic tomography), was examined in healthy non-smokers (n=24) stratified for low and high gating levels. Scalp surface recordings revealed nicotine modulation of P50 and its gating to be differentially exhibited in high (decreasing gating) and low (increasing gating) suppressors while the underlying cortical sources influenced by nicotine (middle frontal gyrus, inferior/superior parietal lobules, pre- and post-central gyri) were seen only in low suppressors. These findings suggest that nicotine impacts sensory gating in healthy volunteers and as the gating enhancing effects were dependent on low baseline gating efficiency, nicotinic receptor agonists may be associated with unique P50 modulating actions in schizophrenia.

Experimental investigation of rotational tomography in reconstructed middle ears with clinical implications.

A large air-bone-gap after ossiculoplasty may be due to a malpositioned or displaced prosthesis. Rotational tomography (RT) has the potential to provide high-resolution images of implants without artifacts and with less radiation dosage than CT scan. Twenty-seven temporal bone specimens underwent measurements of middle ear transfer function using Laser-Doppler-Vibrometry (LDV) before and after placement of ossicular replacement prostheses (PORPs, TORPs) made of titanium. RT was performed on all specimens. RT allowed 3-dimensional viewing of the temporal bone, accurate localization of implants within the reconstructed middle ear and determination of angles between the inserted prostheses and the tympanic membrane (TM) and/or the malleus handle (MH). Presence or absence of contact between the implant and the TM, malleus or stapes could be clearly visualized. Displaced prostheses were readily identified. The functional LDV-measurements for TORPs showed a trend favoring coupling to the malleus handle, while for PORPs, coupling to the TM was favored. For PORPs, sound transmission was worse with increasing angles between the PORP and stapes superstructure (p<0.05). Following our experimental results RT is an innovative, relevant and useful imaging technique to obtain immediate postoperative feedback after ossicular reconstruction and to precisely determine the position of middle ear implants.

Pre-clinical whole-body fluorescence imaging: Review of instruments, methods and applications.

Fluorescence sampling of cellular function is widely used in all aspects of biology, allowing the visualization of cellular and sub-cellular biological processes with spatial resolutions in the range from nanometers up to centimeters. Imaging of fluorescence in vivo has become the most commonly used radiological tool in all pre-clinical work. In the last decade, full-body pre-clinical imaging systems have emerged with a wide range of utilities and niche application areas. The range of fluorescent probes that can be excited in the visible to near-infrared part of the electromagnetic spectrum continues to expand, with the most value for in vivo use being beyond the 630 nm wavelength, because the absorption of light sharply decreases. Whole-body in vivo fluorescence imaging has not yet reached a state of maturity that allows its routine use in the scope of large-scale pre-clinical studies. This is in part due to an incomplete understanding of what the actual fundamental capabilities and limitations of this imaging modality are. However, progress is continuously being made in research laboratories pushing the limits of the approach to consistently improve its performance in terms of spatial resolution, sensitivity and quantification. This paper reviews this imaging technology with a particular emphasis on its potential uses and limitations, the required instrumentation, and the possible imaging geometries and applications. A detailed account of the main commercially available systems is provided as well as some perspective relating to the future of the technology development. Although the vast majority of applications of in vivo small animal imaging are based on epi-illumination planar imaging, the future success of the method relies heavily on the design of novel imaging systems based on state-of-the-art optical technology used in conjunction with high spatial resolution structural modalities such as MRI, CT or ultrasound.

Development of non-uniform breast phantom and its microwave imaging for tumor detection by CP-MCT.

Phantom model of the breast which has actual shape and size has been developed for evaluation of microwave imaging by Chirp Pulse Microwave Computed Tomography (CP-MCT). This phantom model will also be successfully used for hyperthermia experiments using microwaves. This phantom model is consisted of four kinds of tissue mimicking materials, that is, the skin-, breast fat-, muscle-, and tumor-simulators. The principal ingredients of the phantom are water, liquid paraffin, super stuff (TX-150), sugar, and salt. It is easy to simulate permittivity of the real breasts in addition to the shape and size. This is the advantage of this non-homogeneous phantom. CP-MCT is a modality for microwave imaging of a human body using chirp pulse microwaves to extract the component which transmits the straight path between two antennas. Possibility of tumor detection by CP-MCT has been demonstrated by using the higher frequency model of CP-MCT and the non-homogeneous breast phantom.