WE-H-209-00: Carson/Zagzebski Distinguished Lectureship: Image Guided Ultrasound Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives:more » Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments.« less

Intraoperative Functional Ultrasound Imaging of Human Brain Activity.

PubMed

Imbault, Marion; Chauvet, Dorian; Gennisson, Jean-Luc; Capelle, Laurent; Tanter, Mickael

2017-08-04

The functional mapping of brain activity is essential to perform optimal glioma surgery and to minimize the risk of postoperative deficits. We introduce a new, portable neuroimaging modality of the human brain based on functional ultrasound (fUS) for deep functional cortical mapping. Using plane-wave transmissions at an ultrafast frame rate (1 kHz), fUS is performed during surgery to measure transient changes in cerebral blood volume with a high spatiotemporal resolution (250 µm, 1 ms). fUS identifies, maps and differentiates regions of brain activation during task-evoked cortical responses within the depth of a sulcus in both awake and anaesthetized patients.

High-intensity focused ultrasound: advances in technology and experimental trials support enhanced utility of focused ultrasound surgery in oncology

PubMed Central

Malietzis, G; Monzon, L; Hand, J; Wasan, H; Leen, E; Abel, M; Muhammad, A; Abel, P

2013-01-01

High-intensity focused ultrasound (HIFU) is a rapidly maturing technology with diverse clinical applications. In the field of oncology, the use of HIFU to non-invasively cause tissue necrosis in a defined target, a technique known as focused ultrasound surgery (FUS), has considerable potential for tumour ablation. In this article, we outline the development and underlying principles of HIFU, overview the limitations and commercially available equipment for FUS, then summarise some of the recent technological advances and experimental clinical trials that we predict will have a positive impact on extending the role of FUS in cancer therapy. PMID:23403455

Transcranial MRI-guided FUS-induced BBB opening in the rat brain

NASA Astrophysics Data System (ADS)

Treat, Lisa H.; McDannold, Nathan J.; Hynynen, Kullervo

2004-05-01

The blood-brain barrier (BBB) has been a major limitation in treating diseases of the brain because therapeutic agents are either unable to penetrate or have dose-limiting side effects in diffuse opening of the BBB. A previous study demonstrated that focused ultrasound (FUS) can locally open the BBB in a rabbit model when a piece of skull is removed and that magnetic resonance imaging (MRI) can be used to guide and monitor the procedure. This study examined whether the same desired effect of local BBB disruption can be achieved by applying FUS through an intact skull in a rat model. Twenty-eight Sprague-Dawley rats were anesthetized, shaved, and sonicated at four focal locations in the brain, using a 1.5-MHz focused transducer. Contrast-enhanced MR images were obtained before and after sonication. The images indicated contrast agent penetration at the focal coordinates following Optison-enhanced sonication. This study demonstrated that the distortion of the ultrasound beam by the rat skull was not significant enough to inhibit focal BBB opening. Subsequent experiments using MRI-guided FUS to aid in targeted drug delivery to brain tumors in a rodent model could thus be performed more efficiently without cranial surgery. [Research funded by NIH Grant No. CA76550.

Ver-i-Fus: an integrated access control and information monitoring and management system

NASA Astrophysics Data System (ADS)

Thomopoulos, Stelios C.; Reisman, James G.; Papelis, Yiannis E.

1997-01-01

This paper describes the Ver-i-Fus Integrated Access Control and Information Monitoring and Management (IAC-I2M) system that INTELNET Inc. has developed. The Ver-i-Fus IAC-I2M system has been designed to meet the most stringent security and information monitoring requirements while allowing two- way communication between the user and the system. The systems offers a flexible interface that permits to integrate practically any sensing device, or combination of sensing devices, including a live-scan fingerprint reader, thus providing biometrics verification for enhanced security. Different configurations of the system provide solutions to different sets of access control problems. The re-configurable hardware interface, tied together with biometrics verification and a flexible interface that allows to integrate Ver-i-Fus with an MIS, provide an integrated solution to security, time and attendance, labor monitoring, production monitoring, and payroll applications.

Fast Lesion Mapping during HIFU Treatment Using Harmonic Motion Imaging guided Focused Ultrasound (HMIgFUS) In Vitro and In Vivo

PubMed Central

Han, Yang; Wang, Shutao; Payen, Thomas; Konofagou, Elisa

2017-01-01

The successful clinical application of High Intensity Focused Ultrasound (HIFU) ablation depends on reliable monitoring of the lesion formation. Harmonic Motion Imaging guided Focused Ultrasound (HMIgFUS) is an ultrasound-based elasticity imaging technique, which monitors HIFU ablation based on the stiffness change of the tissue instead of the echo intensity change in conventional B-mode monitoring, rendering it potentially more sensitive to lesion development. Our group has shown that predicting the lesion location based on the radiation force-excited region is feasible during HMIgFUS. In this study, the feasibility of a fast lesion mapping method is explored to directly monitor the lesion map during HIFU. The HMI lesion map was generated by subtracting the reference HMI image from the present HMI peak-to-peak displacement map to be streamed on the computer display. The dimensions of the HMIgFUS lesions were compared against gross pathology. Excellent agreement was found between the lesion depth (r2 = 0.81, slope = 0.90), width (r2 = 0.85, slope = 1.12) and area (r2 = 0.58, slope = 0.75). In vivo feasibility was assessed in a mouse with a pancreatic tumor. These findings demonstrate that HMIgFUS can successfully map thermal lesion and monitor lesion development in real time in vitro and in vivo. The HMIgFUS technique may therefore constitute a novel clinical tool for HIFU treatment monitoring. PMID:28323638

Assessment of FUS-Tissue Interactions In Vivo

NASA Astrophysics Data System (ADS)

Haritonova, Alyona V.

Focused ultrasound (FUS) has been proposed for a variety of minimally invasive therapeutic applications, including tumor ablation, neuromodulation, targeted drug delivery and blood brain barrier opening. To date, FUS beams have been primarily monitored through MR and ultrasound diagnostic imaging modalities. The recent introduction of real-time dual-mode ultrasound array (DMUA) systems offers a new paradigm for the guidance of therapeutic focused ultrasound. The DMUA approach allows for inherent registration between the therapeutic and imaging coordinate systems. In this thesis we investigated the use of ultrasound-based thermography to assess FUS-tissue interactions. Specifically, we focused on two aspects of image-guided therapy: 1) monitoring and localization of FUS-tissue interactions, and 2) tissue damage assessment. Towards this end, we presented first experimental results of ultrasound-guided transcranial FUS in a rat brain, both ex vivo and in vivo. DMUA imaging was used to monitor and localize FUS-tissue thermal interactions in real-time. The transcranial echo data allowed for a reliable estimation of temperature change in brain tissue, which had never been done before using ultrasound image guidance. Despite some measurable distortion and loss in focusing gain, transcranial FUS beams at 3.2 MHz were localized axially and laterally. This confirms the results obtained using DMUA-based transcranial ultrasound thermography. A high degree of focusing with the DMUA was then successfully leveraged to perform localized tissue damage assessment in both ex vivo and in vivo. The experimental results presented in this thesis demonstrate some of the unique aspects of image guidance using DMUAs, especially when FUS is subject to significant distortions as in transcranial applications.

Fast lesion mapping during HIFU treatment using harmonic motion imaging guided focused ultrasound (HMIgFUS) in vitro and in vivo

NASA Astrophysics Data System (ADS)

Han, Yang; Wang, Shutao; Payen, Thomas; Konofagou, Elisa

2017-04-01

The successful clinical application of high intensity focused ultrasound (HIFU) ablation depends on reliable monitoring of the lesion formation. Harmonic motion imaging guided focused ultrasound (HMIgFUS) is an ultrasound-based elasticity imaging technique, which monitors HIFU ablation based on the stiffness change of the tissue instead of the echo intensity change in conventional B-mode monitoring, rendering it potentially more sensitive to lesion development. Our group has shown that predicting the lesion location based on the radiation force-excited region is feasible during HMIgFUS. In this study, the feasibility of a fast lesion mapping method is explored to directly monitor the lesion map during HIFU. The harmonic motion imaging (HMI) lesion map was generated by subtracting the reference HMI image from the present HMI peak-to-peak displacement map, as streamed on the computer display. The dimensions of the HMIgFUS lesions were compared against gross pathology. Excellent agreement was found between the lesion depth (r 2  =  0.81, slope  =  0.90), width (r 2  =  0.85, slope  =  1.12) and area (r 2  =  0.58, slope  =  0.75). In vivo feasibility was assessed in a mouse with a pancreatic tumor. These findings demonstrate that HMIgFUS can successfully map thermal lesions and monitor lesion development in real time in vitro and in vivo. The HMIgFUS technique may therefore constitute a novel clinical tool for HIFU treatment monitoring.

Fast lesion mapping during HIFU treatment using harmonic motion imaging guided focused ultrasound (HMIgFUS) in vitro and in vivo.

PubMed

Han, Yang; Wang, Shutao; Payen, Thomas; Konofagou, Elisa

2017-04-21

The successful clinical application of high intensity focused ultrasound (HIFU) ablation depends on reliable monitoring of the lesion formation. Harmonic motion imaging guided focused ultrasound (HMIgFUS) is an ultrasound-based elasticity imaging technique, which monitors HIFU ablation based on the stiffness change of the tissue instead of the echo intensity change in conventional B-mode monitoring, rendering it potentially more sensitive to lesion development. Our group has shown that predicting the lesion location based on the radiation force-excited region is feasible during HMIgFUS. In this study, the feasibility of a fast lesion mapping method is explored to directly monitor the lesion map during HIFU. The harmonic motion imaging (HMI) lesion map was generated by subtracting the reference HMI image from the present HMI peak-to-peak displacement map, as streamed on the computer display. The dimensions of the HMIgFUS lesions were compared against gross pathology. Excellent agreement was found between the lesion depth (r 2   =  0.81, slope  =  0.90), width (r 2   =  0.85, slope  =  1.12) and area (r 2   =  0.58, slope  =  0.75). In vivo feasibility was assessed in a mouse with a pancreatic tumor. These findings demonstrate that HMIgFUS can successfully map thermal lesions and monitor lesion development in real time in vitro and in vivo. The HMIgFUS technique may therefore constitute a novel clinical tool for HIFU treatment monitoring.

Magnetic Resonance-Guided Focused Ultrasound Neurosurgery for Essential Tremor: A Health Technology Assessment

PubMed Central

Schaink, Alexis; Li, Chunmei; Gajic-Veljanoski, Olga; Wells, David; Higgins, Caroline

2018-01-01

Background The standard treatment option for medication-refractory essential tremor is invasive neurosurgery. A new, noninvasive alternative is magnetic resonance-guided focused ultrasound (MRgFUS) neurosurgery. We aimed to determine the effectiveness, safety, and cost-effectiveness of MRgFUS neurosurgery for the treatment of moderate to severe, medication-refractory essential tremor in Ontario. We also spoke with people with essential tremor to gain an understanding of their experiences and thoughts regarding treatment options, including MRgFUS neurosurgery. Methods We performed a systematic review of the clinical literature published up to April 11, 2017, that examined MRgFUS neurosurgery alone or compared with other interventions for the treatment of moderate to severe, medication-refractory essential tremor. We assessed the risk of bias of each study and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic review of the economic literature and created Markov cohort models to assess the cost-effectiveness of MRgFUS neurosurgery compared with other treatment options, including no surgery. We also estimated the budget impact of publicly funding MRgFUS neurosurgery in Ontario for the next 5 years. To contextualize the potential value of MRgFUS neurosurgery as a treatment option for essential tremor, we spoke with people with essential tremor and their families. Results Nine studies met our inclusion criteria for the clinical evidence review. In noncomparative studies, MRgFUS neurosurgery was found to significantly improve tremor severity and quality of life and to significantly reduce functional disability (GRADE: very low). It was also found to be significantly more effective than a sham procedure (GRADE: high). We found no significant difference in improvements in tremor severity, functional disability, or quality of life between MRgFUS neurosurgery and deep brain stimulation (GRADE: very low). We found no significant difference in improvement in tremor severity compared with radiofrequency thalamotomy (GRADE: low). MRgFUS neurosurgery has a favourable safety profile. We estimated that MRgFUS neurosurgery has a mean cost of $23,507 and a mean quality-adjusted survival of 3.69 quality-adjusted life-years (QALYs). We also estimated that the mean costs and QALYs of radiofrequency thalamotomy and deep brain stimulation are $14,978 and 3.61 QALYs, and $57,535 and 3.94 QALYs, respectively. For people ineligible for invasive neurosurgery, we estimated the incremental cost-effectiveness ratio (ICER) of MRgFUS neurosurgery compared with no surgery as $43,075 per QALY gained. In people eligible for invasive neurosurgery, the ICER of MRgFUS neurosurgery compared with radiofrequency thalamotomy is $109,795 per QALY gained; when deep brain stimulation is compared with MRgFUS neurosurgery, the ICER is $134,259 per QALY gained. Of note however, radiofrequency thalamotomy is performed very infrequently in Ontario. We also estimated that the budget impact of publicly funding MRgFUS neurosurgery in Ontario at the current case load (i.e., 48 cases/year) would be about $1 million per year for the next 5 years. People with essential tremor who had undergone MRgFUS neurosurgery reported positive experiences with the procedure. The tremor reduction they experienced improved their ability to perform activities of daily living and improved their quality of life. Conclusions MRgFUS neurosurgery is an effective and generally safe treatment option for moderate to severe, medication-refractory essential tremor. It provides a treatment option for people ineligible for invasive neurosurgery and offers a noninvasive option for all people considering neurosurgery. For people ineligible for invasive neurosurgery, MRgFUS neurosurgery is cost-effective compared with no surgery. In people eligible for invasive neurosurgery, MRgFUS neurosurgery may be one of several reasonable options. Publicly funding MRgFUS neurosurgery for the treatment of moderate to severe, medication-refractory essential tremor in Ontario at the current case load would have a net budget impact of about $1 million per year for the next 5 years. People with essential tremor who had undergone MRgFUS neurosurgery reported positive experiences. They liked that it was a noninvasive procedure and reported a substantial reduction in tremor that resulted in an improvement in their quality of life. PMID:29805721

High intensity focused ultrasound surgery (HIFU) of the brain: A historical perspective, with modern applications

PubMed Central

Jagannathan, Jay; Sanghvi, Narendra K; Crum, Lawrence A; Yen, Chun-Po; Medel, Ricky; Dumont, Aaron S; Sheehan, Jason P; Steiner, Ladislau; Jolesz, Ferenc; Kassell, Neal F

2014-01-01

The field of MRI-guided high intensity focused ultrasound surgery (MRgFUS) is a rapidly evolving one with many potential applications in neurosurgery. This is the first of three articles on MRgFUS, this paper focuses on the historical development of the technology and it's potential applications to modern neurosurgery. The evolution of MRgFUS has occurred in parallel with modern neurological surgery and the two seemingly distinct disciplines share many of the same pioneering figures. Early studies on focused ultrasound treatment in the 1940's and 1950's demonstrated the ability to perform precise lesioning in the human brain, with a favorable risk-benefit profile. However, the need for a craniotomy, as well as lack of sophisticated imaging technology resulted in limited growth of HIFU for neurosurgery. More recently, technological advances, have permitted the combination of HIFU along with MRI guidance to provide an opportunity to effectively treat a variety of CNS disorders. Although challenges remain, HIFU-mediated neurosurgery may offer the ability to target and treat CNS conditions that were previously extremely difficult to perform. The remaining two articles in this series will focus on the physical principles of modern MRgFUS as well as current and future avenues for investigation. PMID:19190451

Detection of FUS induced lesions by MR-elastography

NASA Astrophysics Data System (ADS)

Jenne, Jürgen W.; Divkovic, Gabriela; Siegler, Peter

2005-03-01

MRI (Magnetic Resonance Imaging) has proven to be an exact and safe method to guide FUS (Focused ultrasound surgery) therapy. Besides its excellent soft tissue contrast, important for a precise treatment planning, MRI allows fast and reliable measurement of temperature changes caused by FUS application. In this study we compare standard MR-imaging parameters (relaxation times, spin density) with MR measured tissue elasticity in order to differentiate between FUS induced thermal lesions and normal tissue in vitro. In addition we tried to observe FUS induced shear waves by dynamic MRE. FUS was performed with an MRI compatible 1.7 MHz fixed focus transducer (NA 0.44; f'= 68 mm). With increasing acoustic power (30-70 W) the difference in relaxation times T1, T2 and spin density between normal and lesioned tissue also increased. We measured values in the range 5% to 24%. The difference in tissue strain had a value of 23% at 30 W and was nearly constant (52-61%) at higher FUS power. Compared with standard MRI parameters MRE showed a clearly higher sensitivity to detect FUS induced lesions. With our experimental setup it was possible to image FUS induced shear waves. The measured wave length at 400Hz repetition rate was 7 mm. However, further experiments are necessary to utilize the potential of MRE in practice.

Megasessions for Robotic Hair Restoration.

PubMed

Pereira, Joa O Carlos; Pereira Filho, Joa O Carlos; Cabrera Pereira, Joa O Pedro

2016-11-01

A robotic system can select and remove individual hair follicles from the donor area with great precision and without fatigue. This report describes the use of the robotic system in a megasession for hair restoration. Patients were instructed to cut their hair to 1.0 to 1.2 mm before surgery. The robot selected and removed 600 to 800 grafts per hour so the follicular units (FU)s could be transplanted manually to recipient sites. The robot arm consists of a sharp inner punch and a blunt outer punch which together separate FUs from the sur- rounding tissue. Stereoscopic cameras controlled by image processing software allow the system to identify the angle and direction of hair growth. The physician and one assistant control the harvesting with a hand-held remote control and computer monitor while the patient is positioned in an adjustable chair. When the robot has harvested all the FUs they are removed by technicians with small forceps. Hairline design, creation of recipient sites, and graft placement are performed manually by the physician. Clinical photographs before and after surgery show that patients experience excellent outcomes with the robotic megasession. Phy- sician fatigue during graft extraction is reduced because the robot performs the repetitive movements without fatigue. Variability of graft extraction is minimized because the robot's optical system can be programmed to choose the best FUs. The transection rate is reduced because the robot's graft extraction system uses two needles, a sharp one to piece the skin and a blunt needle to dissect the root without trauma. A robotic megasession for hair restoration is minimally invasive, does not result in linear scars in the donor area, and is associated with minimal fatigue and discomfort for both patient and physician. Healing is rapid and patients experience a high level of satisfaction with the results. J Drugs Dermatol. 2016;15(11):1407-1412..

Magnetic resonance-guided focused ultrasound surgery for treatment of painful osseous metastases

NASA Astrophysics Data System (ADS)

Hurwitz, Mark; Machtinger, Ronit; Fennessy, Fiona

2011-03-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is an emerging technology that can non-invasively heat and ablate targeted tissue utilizing ultrasound energy. Use of MR imaging for treatment guidance provides several key advantages over more widely used ultrasound guidance for focused ultrasound ablation. MR allows for precise targeting, detailed beam path visualization, real time non-invasive temperature measurement, and treatment feedback to ensure therapeutic goals are achieved. In the realm of oncology, management of painful bone metastases is a common and daunting clinical problem. The Insightec ExAblate System has been shown in phase I/II trials for treatment of bone metastases to have an excellent safety profile and high rates of pain response. An international multi-center phase III trial for patients with painful bone metastases or multiple myeloma who are not candidates for radiation therapy is currently open. Patients are randomized 3:1 to MRgFUS or sham treatment with crossover to study treatment allowed for sham failures. The primary study endpoint is assessment of pain control over 3 months following treatment. In addition safety, quality of life, cost effectiveness analysis, and patient perceived clinical benefit are also being assessed. Details of the MRgFUS system, technical and clinical therapeutic parameters, use of real time non-invasive MR thermometry, and examples of patient treatments with use of MRgFUS to treat bone metastases will be discussed. New directions in use of MRgFUS including an update on development of a new mobile applicator and integration of MRgFUS in multimodality oncologic care will also be presented.

Focusing through the rib cage for MR-guided transcostal FUS

NASA Astrophysics Data System (ADS)

Gao, J.; Volovick, A.; Pekelny, Y.; Huang, ZH.; Cochran, S.; Melzer, A.

2012-10-01

The rib cage presents a significant obstacle in transcostal focused ultrasound surgery (FUS). This paper proposes a geometric solution, based on central projection from the focus to identify transducer elements affected by ribs shadowing which should be switched off. Its effectiveness in phantom experiments and simulations is reported, and ways are discussed to further reduce energy deposition on the ribs while enhancing heating at the focus. A tissue-mimicking phantom with phantom of ribs was sonicated using a 208-element 1.15 MHz bowl transducer and a 1000-element 550 kHz planar matrix transducer (both ExAblate, InSightec, Israel). The temperature evolution was monitored with real-time MRI thermometry (GE, USA). Numerical simulations were performed with FEA software (PZFlex, Weidlinger Associates, USA) to investigate different skin-focus and transducer-rib distances. The temperature rise near the ribs was reduced to 16°C and 4°C for the 1.15 MHz and 550 kHz transducers respectively. With the 1.15 MHz transducer, the focal temperature reached the ablation threshold. These measurements are in good agreement with simulations. The proposed method shows promising results for transcostal FUS. Residual temperature rise on the ribs can be further reduced by active cooling, allowing the higher energies essential for efficient ablation.

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles

NASA Astrophysics Data System (ADS)

Burgess, M. T.; Apostolakis, I.; Konofagou, E. E.

2018-03-01

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles.

PubMed

Burgess, M T; Apostolakis, I; Konofagou, E E

2018-03-15

Image-guided monitoring of microbubble-based focused ultrasound (FUS) therapies relies on the accurate localization of FUS-stimulated microbubble activity (i.e. acoustic cavitation). Passive cavitation imaging with ultrasound arrays can achieve this, but with insufficient spatial resolution. In this study, we address this limitation and perform high-resolution monitoring of acoustic cavitation-mediated blood-brain barrier (BBB) opening with a new technique called power cavitation imaging. By synchronizing the FUS transmit and passive receive acquisition, high-resolution passive cavitation imaging was achieved by using delay and sum beamforming with absolute time delays. Since the axial image resolution is now dependent on the duration of the received acoustic cavitation emission, short pulses of FUS were used to limit its duration. Image sets were acquired at high-frame rates for calculation of power cavitation images analogous to power Doppler imaging. Power cavitation imaging displays the mean intensity of acoustic cavitation over time and was correlated with areas of acoustic cavitation-induced BBB opening. Power cavitation-guided BBB opening with FUS could constitute a standalone system that may not require MRI guidance during the procedure. The same technique can be used for other acoustic cavitation-based FUS therapies, for both safety and guidance.

Investigation of temporal vascular effects induced by focused ultrasound treatment with speckle-variance optical coherence tomography

PubMed Central

Tsai, Meng-Tsan; Chang, Feng-Yu; Lee, Cheng-Kuang; Gong, Cihun-Siyong Alex; Lin, Yu-Xiang; Lee, Jiann-Der; Yang, Chih-Hsun; Liu, Hao-Li

2014-01-01

Focused ultrasound (FUS) can be used to locally and temporally enhance vascular permeability, improving the efficiency of drug delivery from the blood vessels into the surrounding tissue. However, it is difficult to evaluate in real time the effect induced by FUS and to noninvasively observe the permeability enhancement. In this study, speckle-variance optical coherence tomography (SVOCT) was implemented for the investigation of temporal effects on vessels induced by FUS treatment. With OCT scanning, the dynamic change in vessels during FUS exposure can be observed and studied. Moreover, the vascular effects induced by FUS treatment with and without the presence of microbubbles were investigated and quantitatively compared. Additionally, 2D and 3D speckle-variance images were used for quantitative observation of blood leakage from vessels due to the permeability enhancement caused by FUS, which could be an indicator that can be used to determine the influence of FUS power exposure. In conclusion, SVOCT can be a useful tool for monitoring FUS treatment in real time, facilitating the dynamic observation of temporal effects and helping to determine the optimal FUS power. PMID:25071945

Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation.

PubMed

Hersh, David S; Kim, Anthony J; Winkles, Jeffrey A; Eisenberg, Howard M; Woodworth, Graeme F; Frenkel, Victor

2016-11-01

: Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased-array transducers and real-time temperature monitoring with magnetic resonance thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest because FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; to enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier or improving distribution through the brain extracellular space; and to modulate the tumor microenvironment to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for using FUS in neuro-oncology. BBB, blood-brain barrierCED, convection-enhanced delivery5-Ala, 5-aminolevulinic acidFUS, focused ultrasoundGBM, glioblastoma multiformeHSP, heat shock proteinMRgFUS, magnetic resonance-guided focused ultrasoundpFUS, pulsed focused ultrasound.

Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

PubMed Central

Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

2013-01-01

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

An integrated model-based software for FUS in moving abdominal organs.

PubMed

Schwenke, Michael; Strehlow, Jan; Haase, Sabrina; Jenne, Juergen; Tanner, Christine; Langø, Thomas; Loeve, Arjo J; Karakitsios, Ioannis; Xiao, Xu; Levy, Yoav; Sat, Giora; Bezzi, Mario; Braunewell, Stefan; Guenther, Matthias; Melzer, Andreas; Preusser, Tobias

2015-05-01

Focused ultrasound surgery (FUS) is a non-invasive method for tissue ablation that has the potential for complete and controlled local tumour destruction with minimal side effects. The treatment of abdominal organs such as the liver, however, requires particular technological support in order to enable a safe, efficient and effective treatment. As FUS is applied from outside the patient's body, suitable imaging methods, such as magnetic resonance imaging or diagnostic ultrasound, are needed to guide and track the procedure. To facilitate an efficient FUS procedure in the liver, the organ motion during breathing and the partial occlusion by the rib cage need to be taken into account in real time, demanding a continuous patient-specific adaptation of the treatment configuration. Modelling the patient's respiratory motion and combining this with tracking data improves the accuracy of motion predictions. Modelling and simulation of the FUS effects within the body allows the use of treatment planning and has the potential to be used within therapy to increase knowledge about the patient status. This article describes integrated model-based software for patient-specific modelling and prediction for FUS treatments of moving abdominal organs.

Usage of Magnetic Resonance Guided Focused Ultrasound Surgery (mrgfus) in Oncology

NASA Astrophysics Data System (ADS)

Bauer, Yair

2011-09-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is a non-invasive incision-less surgical approach which limits the tissue destruction to the targeted tumor. Acoustic energy penetrates through intact skin and through the tissues surrounding the tumor without causing any significant bio-effects. Energy deposition takes place mainly at the focal spot where heat induced thermal coagulation of the targeted tissue is accomplished. Real time targeting and image guidance is provided by MRI tumor margin definition and real time thermometry provides closed loop feedback control of energy deposition. The patient lies in the MRI scanner throughout the treatment planning and treatment, and the physician conducts the treatment from the MRgFUS workstation in the adjacent MR control room. The ExAblate system for MRgFUS is commercially available in many countries for treatment of uterine fibroids. The system has also received CE and KFDA approval for pain palliation of bone metastases, and research of other oncologic applications is underway.

Optimizing MR imaging-guided navigation for focused ultrasound interventions in the brain

NASA Astrophysics Data System (ADS)

Werner, B.; Martin, E.; Bauer, R.; O'Gorman, R.

2017-03-01

MR imaging during transcranial MR imaging-guided Focused Ultrasound surgery (tcMRIgFUS) is challenging due to the complex ultrasound transducer setup and the water bolus used for acoustic coupling. Achievable image quality in the tcMRIgFUS setup using the standard body coil is significantly inferior to current neuroradiologic standards. As a consequence, MR image guidance for precise navigation in functional neurosurgical interventions using tcMRIgFUS is basically limited to the acquisition of MR coordinates of salient landmarks such as the anterior and posterior commissure for aligning a stereotactic atlas. Here, we show how improved MR image quality provided by a custom built MR coil and optimized MR imaging sequences can support imaging-guided navigation for functional tcMRIgFUS neurosurgery by visualizing anatomical landmarks that can be integrated into the navigation process to accommodate for patient specific anatomy.

Expulsion of Fibroids to the Endometrial Cavity after Magnetic Resonance Imaging-guided High Intensity Focused Ultrasound Surgery (MRgFUS) Treatment of Intramural Uterine Fibroids

PubMed Central

Jeong, Jae-Hyeok; Hong, Gil Pyo; Kim, Yu-Ri; Hong, Da Gyo; Ha, Jae-Eun; Yeom, Jung In; Kim, Eun-Jeong; Kim, Hyung-Il

2016-01-01

Objectives This report seeks to introduce some cases of the patients who received magnetic resonance imaging (MRI)-guided high intensity focused ultrasound (HIFU) surgery (MRgFUS)-based intramural uterine fibroids treatment where the post-MRgFUS intramural uterine fibroids decreased in its volume and protruded towards the endometrial cavity to be expelled by hysteroscopy. Methods Of the 157 patients who had received MRgFUS treatment in the Obstetrics and Gynecology of the Hospital from March, 2015 to February, 2016; this study examined 6 of the cases where, after high intensity focused ultrasound treatment, intramural uterine fibroids protruded towards the endometrial cavity to be removed by hysteroscopic myomectomy. The high intensity focused ultrasound utilized in the cases were Philips Achieva 1.5 Tesla MR (Philips Healthcare, Best, The Netherlands) and Sonalleve HIFU system. Results The volume of fibroids ranged from 26.0 cm3 to 199.5 cm3, averaging 95.6 cm3. The major axis length ranged from 4.0 cm to 8.2 cm, averaging 6.3 cm. Fibroid location in all of the patients was in intramural uterine before treatment but after the high intensity focused ultrasound treatment, the fibroids were observed to protrude towards the endometrial cavity in at least Day 5 or up to Day 73 to allow hysteroscopic myomectomy. Conclusions In some cases, after an intramural uterine fibroid is treated with MRgFUS, fibroid volume is decreased and the fibroid protrudes towards the endometrial cavity. In this case, hysteroscopic myomectomy can be a useful solution. PMID:28119893

Optimized Hyperthermia Treatment of Prostate Cancer Using a Novel Intracavitary Ultrasound Array

DTIC Science & Technology

2005-01-01

many problems Introduction involved with transducer fabrication. Focused ultrasound surgery ( FUS ) has been shown to give promising results in treating...low frequencies are used) (Hutchinson 1997). With focused ultrasound ( FUS ), tissue is noninvasively necrosed by elevating the temperature at the focal...curved 1.5 dimensional (1.5-D) array that could, but had of a 1.75 dimensional (1.75-D) tapered ultrasound phased array restrictions to the focusing

Magnetic Resonance Imaging-Guided Focused Ultrasound Surgery for the Treatment of Symptomatic Uterine Fibroids.

PubMed

Geraci, Laura; Napoli, Alessandro; Catalano, Carlo; Midiri, Massimo; Gagliardo, Cesare

2017-01-01

Uterine fibroids, the most common benign tumor in women of childbearing age, may cause symptoms including pelvic pain, menorrhagia, dysmenorrhea, pressure, urinary symptoms, and infertility. Various approaches are available to treat symptomatic uterine fibroids. Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) represents a recently introduced noninvasive safe and effective technique that can be performed without general anesthesia, in an outpatient setting. We review the principles of MRgFUS, describing patient selection criteria for the treatments performed at our center and we present a series of five selected patients with symptomatic uterine fibroids treated with this not yet widely known technique, showing its efficacy in symptom improvement and fibroid volume reduction.

An in vivo study of the effects on serum glucose, amylase and histopathology of the feline pancreatic tissue treated by focused ultrasound.

PubMed

Mao, Ying; Fang, Liaoqiong; Ai, Liang; Li, Chongyan; Wang, Zhibiao; Wu, Junru; Bai, Jin; Li, Faqi

2014-01-01

Pancreatic cancer is one of the most malignant neoplasms originating in the digestive system. Focused ultrasound (FUS) treatment instead of the surgery operation has been used to treat Pancreatic cancer noninvasively in clinical trials. The endocrine and exocrine glands in pancreas provide the two unique functions for a person to be healthy. It is critically important to find out if the FUS treatment can still keep the normal functions of the two glands. The goal of this study is to examine and analyze changes in histopathology and serum glucose and amylase levels of the targeted in-vivo felines after the FUS treatment. Various percentage volumes of pancreas of felines were insonified. The FUS treatment (7.5 MHz of central frequency; 5 W of acoustical power; transducer f-number = 0.33; 6 s insonification time per point) effectively generated coagulative necrosis at the insonified site while leaving tissue outside the insonified site intact. It was also observed that all felines endured well with the FUS treatment; changes introduced to pancreatic tissue after up to 50% of a pancreas by volume was insonified by the FUS procedure did not affect its normal endocrine and exocrine functions.

Emerging Applications of Therapeutic Ultrasound in Neuro-Oncology: Moving Beyond Tumor Ablation

PubMed Central

Hersh, David S.; Kim, Anthony J.; Winkles, Jeffrey A.; Eisenberg, Howard M.; Woodworth, Graeme F.; Frenkel, Victor

2016-01-01

Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased array transducers and real-time temperature monitoring with magnetic resonance (MR) thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest, as FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to (1) generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; (2) enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier and/or improving distribution through the brain extracellular space; and (3) modulate the tumor microenvironment in order to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for utilizing FUS in neuro-oncology. PMID:27552589

Focused Ultrasound Steering for Harmonic Motion Imaging.

PubMed

Han, Yang; Payen, Thomas; Wang, Shutao; Konofagou, Elisa

2018-02-01

Harmonic motion imaging (HMI) is a radiation-force-based ultrasound elasticity imaging technique, which is designed for both tissue relative stiffness imaging and reliable high-intensity focused ultrasound treatment monitoring. The objective of this letter is to develop and demonstrate the feasibility of 2-D focused ultrasound (FUS) beam steering for HMI using a 93-element, FUS phased array. HMI with steered FUS beam was acquired in tissue-mimicking phantoms. The HMI displacement was imaged within the steering range of ±1.7 mm laterally and ±2 mm axially. Using the steered FUS beam, HMI can be used to image a larger tissue volume with higher efficiency and without requiring mechanical movement of the transducer.

Robotically assisted MRgFUS system

NASA Astrophysics Data System (ADS)

Jenne, Jürgen W.; Krafft, Axel J.; Maier, Florian; Rauschenberg, Jaane; Semmler, Wolfhard; Huber, Peter E.; Bock, Michael

2010-03-01

Magnetic resonance imaging guided focus ultrasound surgery (MRgFUS) is a highly precise method to ablate tissue non-invasively. The objective of this ongoing work is to establish an MRgFUS therapy unit consisting of a specially designed FUS applicator as an add-on to a commercial robotic assistance system originally designed for percutaneous needle interventions in whole-body MRI systems. The fully MR compatible robotic assistance system InnoMotion™ (Synthes Inc., West Chester, USA; formerly InnoMedic GmbH, Herxheim, Germany) offers six degrees of freedom. The developed add-on FUS treatment applicator features a fixed focus ultrasound transducer (f = 1.7 MHz; f' = 68 mm, NA = 0.44, elliptical shaped -6-dB-focus: 8.1 mm length; O/ = 1.1 mm) embedded in a water-filled flexible bellow. A Mylar® foil is used as acoustic window encompassed by a dedicated MRI loop coil. For FUS application, the therapy unit is directly connected to the head of the robotic system, and the treatment region is targeted from above. A newly in-house developed software tool allowed for complete remote control of the MRgFUS-robot system and online analysis of MRI thermometry data. The system's ability for therapeutic relevant focal spot scanning was tested in a closed-bore clinical 1.5 T MR scanner (Magnetom Symphony, Siemens AG, Erlangen, Germany) in animal experiments with pigs. The FUS therapy procedure was performed entirely under MRI guidance including initial therapy planning, online MR-thermometry, and final contrast enhanced imaging for lesion detection. In vivo trials proved the MRgFUS-robot system as highly MR compatible. MR-guided focal spot scanning experiments were performed and a well-defined pattern of thermal tissue lesions was created. A total in vivo positioning accuracy of the US focus better than 2 mm was estimated which is comparable to existing MRgFUS systems. The newly developed FUS-robotic system offers an accurate, highly flexible focus positioning. With its access to the patient from above, it provides a wide range of flexibility for acoustic target access. In the next step, motion correction unit should be integrated.

Oxidative stress in follicular units during hair transplantation surgery.

PubMed

Crisóstomo, Márcio Rocha; Guimarães, Sérgio Botelho; de Vasconcelos, Paulo Roberto Leitão; Crisóstomo, Marília Gabriela Rocha; Benevides, André Nunes

2011-02-01

Hair transplantation surgery currently is a well-established procedure in plastic surgery. It consists of harvesting a strip of scalp from the back of the head, then obtaining grafts called follicular units (FUs) from this strip and implanting them in the bald area. The FUs undergo oxidative stress during cold ischemia and after their implantation. Surgery was performed for 18 patients between April and July 2008. Follicular units were preserved in solutions containing different growth-stimulating hormone (GSH) concentrations (5, 10, and 20 mmol). Saline solution was used as a control condition. Spectrophotometry was used to measure the thiobarbituric acid-reactive substance (TBARS) and GSH concentrations before ischemia (control group) in the FUs preserved in the four proposed solutions, then after 30 min of cold ischemia and 30 min after grafting. The data obtained were submitted to analysis of variance, t test, and linear regression analysis. The TBARS (μmol of malondialdehyde [MDA]/g) and GSH (μmol/g) concentrations were not significantly different between the four solutions in either the ischemia or grafting group. The GSH concentration did not differ significantly between the control (59.801 ± 30.639 μmol/g) and ischemia (56.284 ± 28.404 μmol/g) groups. The GSH concentrations were significantly greater (p < 0.05) in the postgrafting group (63.815 ± 28.404 μmol/g) than in the group subjected to ischemia. Increasing the GSH concentrations used in FU preservation solutions does not reduce the oxidative effects of cold ischemia and reperfusion injury during hair transplantation surgery.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) of uterine fibroids in Singapore.

PubMed

Han, Nian-Lin R; Ong, Chiou Li

2014-11-01

Uterine fibroids are the most common type of gynaecologic benign tumours, occurring in 25% to 50% of women during their reproductive lives. About half of the affected women have clinically significant symptoms, including abnormal bleeding, menstrual pain, frequent urination, constipation and abdominal distension. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) has been used to treat patients with benign lesions and a variety of malignancies. The objective of this study is to evaluate symptom relief before and after MR-guided ultrasound ablation of fibroids. A total of 37 patients with symptomatic uterine fibroids were treated in this study. MRgFUS treatment led to a significant, time-dependent decrease in not only Symptom Severity Scores (SSS), but also the mean fibroid volume. The average reductions in volume were 41.6% and 52.6% at 6 months and 12 months respectively (P <0.05). The mean SSS of the 37 patients was 41.7 ± 2.8 before treatment whereas the average SSS was 26.9 ± 3.6, 20.7 ± 3.4, 18.5 ± 3.6, 16.5 ± 7.1, 9.8 ± 3.6 at 3 months, 6 months, 1 year, 2 years, and 3 to 4 years respectively. The decrease in scores was significant at all time points up to 3 to 4 years (P <0.05 and P <0.001). MRgFUS is a safe and effective non-invasive treatment for patients with symptomatic fibroids.

[MR-guided focused ultrasound. Current and future applications].

PubMed

Trumm, C G; Napoli, A; Peller, M; Clevert, D-A; Stahl, R; Reiser, M; Matzko, M

2013-03-01

High-intensity focused ultrasound (synonyms FUS and HIFU) under magnetic resonance imaging (MRI) guidance (synonyms MRgFUS and MR-HIFU) is a completely non-invasive technology for accurate thermal ablation of a target tissue while neighboring tissues and organs are preserved. The combination of FUS with MRI for planning, (near) real-time monitoring and outcome assessment of treatment markedly enhances the safety of the procedure. The MRgFUS procedure is clinically established in particular for the treatment of symptomatic uterine fibroids, followed by palliative ablation of painful bone metastases. Furthermore, promising results have been shown for the treatment of adenomyosis, malignant tumors of the prostate, breast and liver and for various intracranial applications, such as thermal ablation of brain tumors, functional neurosurgery and transient disruption of the blood-brain barrier.

Localized Harmonic Motion Imaging for Focused Ultrasound Surgery Targeting

PubMed Central

Curiel, Laura; Hynynen, Kullervo

2011-01-01

Recently, an in vivo real-time ultrasound-based monitoring technique that uses localized harmonic motion (LHM) to detect changes in tissues during focused ultrasound surgery (FUS) has been proposed to control the exposure. This technique can potentially be used as well for targeting imaging. In the present study we evaluated the potential of using LHM to detect changes in stiffness and the feasibility of using it for imaging purposes in phantoms and in vivo tumor detection. A single-element FUS transducer (80 mm focal length, 100 mm diameter, 1.485 MHz) was used for inducing a localized harmonic motion and a separate ultrasound diagnostic transducer excited by a pulser/receiver (5 kHz PRF, 5 MHz) was used to track motion. The motion was estimated using cross-correlation techniques on the acquired RF signal. Silicon phantom studies were performed in order to determine the size of inclusion that was possible to detect using this technique. Inclusions were discerned from the surroundings as a reduction on LHM amplitude and it was possible to depict inclusions as small as 4 mm. The amplitude of the induced LHM was always lower at the inclusions as compared with the one obtained at the surroundings. Ten New Zealand rabbits had VX2 tumors implanted on their thighs and LHM was induced and measured at the tumor region. Tumors (as small as 10 mm in length and 4 mm in width) were discerned from the surroundings as a reduction on LHM amplitude. PMID:21683514

MRI-Guided Focused Ultrasound Surgery for Uterine Fibroid Treatment: A Cost-Effectiveness Analysis

PubMed Central

Kong, Chung Y.; Omer, Zehra B.; Pandharipande, Pari V.; Swan, J. Shannon; Srouji, Serene; Gazelle, G. Scott; Fennessy, Fiona M.

2015-01-01

Objective To evaluate the cost-effectiveness of a treatment strategy for symptomatic uterine fibroids that employs Magnetic Resonance guided Focused Ultrasound (MRgFUS) as a first-line therapy relative to uterine artery embolization (UAE) or abdominal hysterectomy (HYST). Materials and Methods We developed a decision-analytic model to compare the cost-effectiveness of three treatment strategies: MRgFUS, UAE and HYST. Short and long-term utilities specific to each treatment were incorporated, allowing us to account for differences in quality of life across the strategies considered. Lifetime costs and quality-adjusted life-years (QALYs) were calculated for each strategy. An incremental cost-effectiveness analysis was performed, using a societal willingness-to-pay (WTP) threshold of $50,000 per QALY to designate a strategy as cost-effective. Sensitivity analysis was performed on all key model parameters. Results In the base-case analysis, in which treatment for symptomatic fibroids started at age 40, UAE was the most effective and expensive strategy (22.81 QALYs, $22,164), followed by MRgFUS (22.80 QALYs, $19,796) and HYST (22.60 QALYs, $13,291). MRgFUS was cost-effective relative to HYST, with an associated incremental cost-effectiveness ratio (ICER) of $33,110/QALY. MRgFUS was also cost-effective relative to UAE – the ICER of UAE relative to MRgFUS ($270,057) far exceeded the WTP threshold of $50,000/QALY. In sensitivity analysis, results were robust to changes in most parameters, but were sensitive to changes in probabilities of recurrence and symptom relief following certain procedures, and quality of life associated with symptomatic fibroids. Conclusions MRgFUS is cost-effective relative to both UAE and hysterectomy for the treatment of women with symptomatic fibroids. PMID:25055272

Clinical Application of High-intensity Focused Ultrasound in Cancer Therapy

PubMed Central

Hsiao, Yi-Hsuan; Kuo, Shou-Jen; Tsai, Horng-Der; Chou, Ming-Chih; Yeh, Guang-Perng

2016-01-01

The treatment of cancer is an important issue in both developing and developed countries. Clinical use of ultrasound in cancer is not only for the diagnosis but also for the treatment. Focused ultrasound surgery (FUS) is a noninvasive technique. By using the combination of high-intensity focused ultrasound (HIFU) and imaging method, FUS has the potential to ablate tumor lesions precisely. The main mechanisms of HIFU ablation involve mechanical and thermal effects. Recent advances in HIFU have increased its popularity. Some promising results were achieved in managing various malignancies, including pancreas, prostate, liver, kidney, breast and bone. Other applications include brain tumor ablation and disruption of the blood-brain barrier. We aim at briefly outlining the clinical utility of FUS as a noninvasive technique for a variety of types of cancer treatment. PMID:26918034

Scaled signal intensity of uterine fibroids based on T2-weighted MR images: a potential objective method to determine the suitability for magnetic resonance-guided focused ultrasound surgery of uterine fibroids.

PubMed

Park, Hyun; Yoon, Sang-Wook; Sokolov, Amit

2015-12-01

Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) is a non-invasive method to treat uterine fibroids. To help determine the patient suitability for MRgFUS, we propose a new objective measure: the scaled signal intensity (SSI) of uterine fibroids in T2 weighted MR images (T2WI). Forty three uterine fibroids in 40 premenopausal women were included in this retrospective study. SSI of each fibroid was measured from the screening T2WI by standardizing its mean signal intensity to a 0-100 scale, using reference intensities of rectus abdominis muscle (0) and subcutaneous fat (100). Correlation between the SSI and the non-perfused volume (NPV) ratio (a measure for treatment success) was calculated. Pre-treatment SSI showed a significant inverse-correlation with post treatment NPV ratio (p < 0.05). When dichotomizing NPV ratio at 45 %, the optimal cut off value of the SSI was found to be 16.0. A fibroid with SSI value 16.0 or less can be expected to have optimal responses. The SSI of uterine fibroids in T2WI can be suggested as an objective parameter to help in patient selection for MRgFUS. • Signal intensity of fibroid in MR images predicts treatment response to MRgFUS. • Signal intensity is standardized into scaled form using adjacent tissues as references. • Fibroids with SSI less than 16.0 are expected to have optimal responses.

Workflow and intervention times of MR-guided focused ultrasound - Predicting the impact of new techniques.

PubMed

Loeve, Arjo J; Al-Issawi, Jumana; Fernandez-Gutiérrez, Fabiola; Langø, Thomas; Strehlow, Jan; Haase, Sabrina; Matzko, Matthias; Napoli, Alessandro; Melzer, Andreas; Dankelman, Jenny

2016-04-01

Magnetic resonance guided focused ultrasound surgery (MRgFUS) has become an attractive, non-invasive treatment for benign and malignant tumours, and offers specific benefits for poorly accessible locations in the liver. However, the presence of the ribcage and the occurrence of liver motion due to respiration limit the applicability MRgFUS. Several techniques are being developed to address these issues or to decrease treatment times in other ways. However, the potential benefit of such improvements has not been quantified. In this research, the detailed workflow of current MRgFUS procedures was determined qualitatively and quantitatively by using observation studies on uterine MRgFUS interventions, and the bottlenecks in MRgFUS were identified. A validated simulation model based on discrete events simulation was developed to quantitatively predict the effect of new technological developments on the intervention duration of MRgFUS on the liver. During the observation studies, the duration and occurrence frequencies of all actions and decisions in the MRgFUS workflow were registered, as were the occurrence frequencies of motion detections and intervention halts. The observation results show that current MRgFUS uterine interventions take on average 213min. Organ motion was detected on average 2.9 times per intervention, of which on average 1.0 actually caused a need for rework. Nevertheless, these motion occurrences and the actions required to continue after their detection consumed on average 11% and up to 29% of the total intervention duration. The simulation results suggest that, depending on the motion occurrence frequency, the addition of new technology to automate currently manual MRgFUS tasks and motion compensation could potentially reduce the intervention durations by 98.4% (from 256h 5min to 4h 4min) in the case of 90% motion occurrence, and with 24% (from 5h 19min to 4h 2min) in the case of no motion. In conclusion, new tools were developed to predict how intervention durations will be affected by future workflow changes and by the introduction of new technology. Copyright © 2016 Elsevier Inc. All rights reserved.

Symptomatic improvement in uterine myomas after MRgFUS: 4 year follow up

NASA Astrophysics Data System (ADS)

Funaki, Kaoru; Fukunishi, Hidenobu

2011-09-01

Objective: To assess the long-term improvement in symptoms after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for uterine myomas. Methods: Japanese women with symptomatic myomas underwent MRgFUS using the ExAblate 2000 system. The symptom severity score (SSS) was examined before and after the treatment at 3, 6, 12, 24, and 48 months. Simultaneously, we asked the patients' satisfaction level regarding the overall change of subjective symptoms: symptom free, improved a great deal, improved to some extent, no change, or worsened. The myoma volumes were measured at 6, 12, 24, 36 and 48 months after MRgFUS. Results: No severe adverse event occurred with any of the patients. The mean SSS value before treatment was 38.3±21.5 (n = 106), which diminished significantly during follow-up for 3-48 months after treatment. Patients' satisfaction level was favorable, although the response rate was low. Over 80% of the patients replied that their symptoms were improved to at least some extent, and over 50% of the patients replied that their symptoms were improved a great deal. This trend continued throughout this follow up period. The mean myoma volume was also decreased from the pretreatment volume in this follow up period. Conclusion: MRgFUS is an effective and safe method for treating symptomatic uterine myomas. Long-term symptomatic improvement is promising.

Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers

NASA Astrophysics Data System (ADS)

Tsai, Chih-Hung; Zhang, Jia-Wei; Liao, Yi-Yi; Liu, Hao-Li

2016-04-01

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r 2  =  0.81). The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery.

Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers.

PubMed

Tsai, Chih-Hung; Zhang, Jia-Wei; Liao, Yi-Yi; Liu, Hao-Li

2016-04-07

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r (2)  =  0.81). The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery.

Restoring Neurological Physiology: The Innovative Role of High-Energy MR-Guided Focused Ultrasound (HIMRgFUS). Preliminary Data from a New Method of Lesioning Surgery.

PubMed

Giugno, Antonella; Maugeri, Rosario; Graziano, Francesca; Gagliardo, Cesare; Franzini, Angelo; Catalano, Carlo; Midiri, Massimo; Iacopino, Domenico Gerardo

2017-01-01

Tremor is a disabling condition, common to several neurodegenerative diseases. Lesioning procedures and deep brain stimulation, respectively, of the ventralis intermedius nucleus for intentional tremor, and of the subthalamic nucleus for parkinsonian resting tremor, have been introduced in clinical practice for patients refractory to medical treatment. The combination of high-energy focused ultrasound (HIFUS) with sophisticated magnetic resonance (MR) instrumentation, together with accurate knowledge of the stereotactic brain coordinates, represents a revolution in neuromodulation. At the Neurosurgical Clinic and the Radiology Department of the University of Palermo,, two patients affected by severe and refractory forms of intentional tremor were treated by MRI-guided FUS (MRgFUS) with a unique 1.5 T MR scanner prototype that uses FUS. This apparatus is the only one of its type in the world." This is the first Italian experience, and the second in Europe, of treatment with MRI-gFUS for intentional tremor. But this is the very first experience in which a 1.5 T MRI apparatus was used. In both patients, the treatment completely abolished the tremor on the treated side, with results being excellent and stable after 7 and 5 months, respectively; no side effects were encountered. MRgFUS, recently introduced in clinical practice, and widely used at several clinical centers, has been shown to be a valid therapeutic alternative in the treatment of tremor in several neurodegenerative diseases. It is virtually safe, noninvasive, and very efficacious. We report this technique in which a 1.5 T MR scanner was used. Further investigations with long-term follow up and larger clinical series are needed.

Drug delivery across the blood-brain barrier using focused ultrasound

PubMed Central

Burgess, Alison; Hynynen, Kullervo H.

2015-01-01

Introduction The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a non-invasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. Areas Covered The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. Expert Opinion The introduction of MRI guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient, and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development. PMID:24650132

Drug delivery across the blood-brain barrier using focused ultrasound.

PubMed

Burgess, Alison; Hynynen, Kullervo

2014-05-01

The presence of the blood-brain barrier (BBB) is a significant impediment to the delivery of therapeutic agents to the brain for treatment of brain diseases. Focused ultrasound (FUS) has been developed as a noninvasive method for transiently increasing the permeability of the BBB to promote drug delivery to targeted regions of the brain. The present review briefly compares the methods used to promote drug delivery to the brain and describes the benefits and limitations of FUS technology. We summarize the experimental data which shows that FUS, combined with intravascular microbubbles, increases therapeutic agent delivery into the brain leading to significant reductions in pathology in preclinical models of disease. The potential for translation of this technology to the clinic is also discussed. The introduction of magnetic resonance imaging guidance and intravascular administration of microbubbles to FUS treatments permits the consistent, transient and targeted opening of the BBB. The development of feedback systems and real-time monitoring techniques improve the safety of BBB opening. Successful clinical translation of FUS has the potential to revolutionize the treatment of brain disease resulting in effective, less-invasive treatments without the need for expensive drug development.

MR-guided focused ultrasound: a potentially disruptive technology.

PubMed

Bradley, William G

2009-07-01

A disruptive technology is a technological innovation that overturns the existing dominant technologies in a market. Magnetic resonance (MR)-guided focused ultrasound (MRgFUS) is a noninvasive procedure based on the combination of real-time MR anatomic guidance, MR thermometry, and high-intensity focused ultrasound. Several hundred transducer elements become convergent at a point under MR guidance, leading to heating and coagulation necrosis. Outside the focal point, there is no significant heating. There is no need to break the skin for procedures in the body or to perform a craniotomy for procedures in the brain. This lack of invasiveness is what makes MRgFUS so disruptive compared with surgery. At present, MRgFUS has been used for the ablation of uterine fibroids, breast tumors, painful bony metastases, and liver tumors. In the brain, it has been used for the ablation of glioblastomas and for functional neurosurgery. Phantom and animal studies suggest future applications for prostate cancer and acute stroke treatment.

First noninvasive thermal ablation of a brain tumor with MR-guided focused ultrasound

PubMed Central

2014-01-01

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) allows for precise thermal ablation of target tissues. While this emerging modality is increasingly used for the treatment of various types of extracranial soft tissue tumors, it has only recently been acknowledged as a modality for noninvasive neurosurgery. MRgFUS has been particularly successful for functional neurosurgery, whereas its clinical application for tumor neurosurgery has been delayed for various technical and procedural reasons. Here, we report the case of a 63-year-old patient presenting with a centrally located recurrent glioblastoma who was included in our ongoing clinical phase I study aimed at evaluating the feasibility and safety of transcranial MRgFUS for brain tumor ablation. Applying 25 high-power sonications under MR imaging guidance, partial tumor ablation could be achieved without provoking neurological deficits or other adverse effects in the patient. This proves, for the first time, the feasibility of using transcranial MR-guided focused ultrasound to safely ablate substantial volumes of brain tumor tissue. PMID:25671132

Review of MRI positioning devices for guiding focused ultrasound systems.

PubMed

Yiallouras, C; Damianou, C

2015-06-01

This article contains a review of positioning devices that are currently used in the area of magnetic resonance imaging (MRI) guided focused ultrasound surgery (MRgFUS). The paper includes an extensive review of literature published since the first prototype system was invented in 1991. The technology has grown into a fast developing area with application to any organ accessible to ultrasound. The initial design operated using hydraulic principles, while the latest technology incorporates piezoelectric motors. Although, in the beginning there were fears regarding MRI safety, during recent years, the deployment of MR-safe positioning devices in FUS has become routine. Many of these positioning devices are now undergoing testing in clinical trials. Existing MRgFUS systems have been utilized mostly in oncology (fibroids, brain, liver, kidney, bone, pancreas, eye, thyroid, and prostate). It is anticipated that, in the near future, there will be a positioning device for every organ that is accessible by focused ultrasound. Copyright © 2014 John Wiley & Sons, Ltd.

Two-photon microscopy for real-time monitoring of focused ultrasound-mediated drug delivery to the brain in a mouse model of Alzheimer's disease

NASA Astrophysics Data System (ADS)

Burgess, Alison; Eterman, Naomi; Aubert, Isabelle; Hynynen, Kullervo

2013-02-01

There is substantial evidence that focused ultrasound (FUS) in combination with microbubble contrast agent can cause disruption of the blood-brain barrier (BBB) to aid in drug delivery to the brain. We have previously demonstrated that FUS efficiently delivers antibodies against amyloid-β peptides (Aβ) through the BBB, leading to a reduction in amyloid pathology at 4 days in a mouse model of Alzheimer's disease. In the current study, we used two-photon microscopy to characterize the effect of FUS in real time on amyloid pathology in the mouse brain. Mice were anesthetized and a cranial window was made in the skull. A custom-built ultrasound transducer was fixed to a coverslip and attached to the skull, covering the cranial window. Methoxy-X04 [2-5mg/kg] delivered intravenously 1 hr prior to the experiment clearly labelled the Aβ surrounding the vessels and the amyloid plaques in the cortex. Dextran conjugated Texas Red (70kDa) administered intravenously, confirmed BBB disruption. BBB disruption occurred in transgenic and non-transgenic animals at similar ultrasound pressures tested. However, the time required for BBB closure following FUS was longer in the Tg mice. We have conjugated Aβ antibodies to the fluorescent molecule FITC for real time monitoring of the antibody distribution in the brain. Our current experiments are aimed at optimizing the parameters to achieve maximal fluorescent intensity of the BAM10 antibody at the plaque surface. Two-photon microscopy has proven to be a valuable tool for evaluating the efficacy of FUS mediated drug delivery, including antibodies, to the Alzheimer brain.

Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model.

PubMed

Arvanitis, Costas D; Vykhodtseva, Natalia; Jolesz, Ferenc; Livingstone, Margaret; McDannold, Nathan

2016-05-01

OBJECT Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an emerging noninvasive alternative to surgery and radiosurgery that is undergoing testing for tumor ablation and functional neurosurgery. The method is currently limited to central brain targets due to skull heating and other factors. An alternative ablative approach combines very low intensity ultrasound bursts and an intravenously administered microbubble agent to locally destroy the vasculature. The objective of this work was to investigate whether it is feasible to use this approach at deep brain targets near the skull base in nonhuman primates. METHODS In 4 rhesus macaques, targets near the skull base were ablated using a clinical TcMRgFUS system operating at 220 kHz. Low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes in conjunction with the ultrasound contrast agent Definity, which was administered as a bolus injection or continuous infusion. The acoustic power level was set to be near the inertial cavitation threshold, which was measured using passive monitoring of the acoustic emissions. The resulting tissue effects were investigated with MRI and with histological analysis performed 3 hours to 1 week after sonication. RESULTS Thirteen targets were sonicated in regions next to the optic tract in the 4 animals. Inertial cavitation, indicated by broadband acoustic emissions, occurred at acoustic pressure amplitudes ranging from 340 to 540 kPa. MRI analysis suggested that the lesions had a central region containing red blood cell extravasations that was surrounded by edema. Blood-brain barrier disruption was observed on contrast-enhanced MRI in the lesions and in a surrounding region corresponding to the prefocal area of the FUS system. In histology, lesions consisting of tissue undergoing ischemic necrosis were found in all regions that were sonicated above the inertial cavitation threshold. Tissue damage in prefocal areas was found in several cases, suggesting that in those cases the sonication exceeded the inertial cavitation threshold in the beam path. CONCLUSIONS It is feasible to use a clinical TcMRgFUS system to ablate skull base targets in nonhuman primates at time-averaged acoustic power levels at least 2 orders of magnitude below what is needed for thermal ablation with this device. The results point to the risks associated with the method if the exposure levels are not carefully controlled to avoid inertial cavitation in the acoustic beam path. If methods can be developed to provide this control, this nonthermal approach could greatly expand the use of TcMRgFUS for precisely targeted ablation to locations across the entire brain.

Low-intensity focused ultrasound alters the latency and spatial patterns of sensory-evoked cortical responses in vivo

NASA Astrophysics Data System (ADS)

Fisher, Jonathan A. N.; Gumenchuk, Iryna

2018-06-01

Objective. The use of transcranial, low intensity focused ultrasound (FUS) is an emerging neuromodulation technology that shows promise for both therapeutic and research applications. Among many, one of the most exciting applications is the use of FUS to rehabilitate or augment human sensory capabilities. While there is compelling empirical evidence demonstrating this capability, basic questions regarding the spatiotemporal extent of the modulatory effects remain. Our objective was to assess the basic, yet often overlooked hypothesis that FUS in fact alters sensory-evoked neural activity within the region of the cerebral cortex at the beam’s focus. Approach. To address this knowledge gap, we developed an approach to optically interrogate patterns of neural activity in the cortex directly at the acoustic focus, in vivo. Implementing simultaneous wide-field optical imaging and FUS stimulation in mice, our experiments probed somatosensory-evoked electrical activity through the use of voltage sensitive dyes (VSDs) and, in transgenic mice expressing GCaMP6f, monitored associated Ca2+ responses. Main results. Our results demonstrate that low-intensity FUS alters both the kinetics and spatial patterns of neural activity in primary somatosensory cortex at the acoustic focus. When preceded by 1 s of pulsed ultrasound at intensities below 1 W cm‑2 (I sppa), the onset of sensory-evoked cortical responses occurred 3.0  ±  0.7 ms earlier and altered the surface spatial morphology of Ca2+ responses. Significance. These findings support the heretofore unconfirmed assumption that FUS-induced sensory modulation reflects, at least in part, altered reactivity in primary sensory cortex at the site of sonication. The findings are significant given the interest in using FUS to target and alter spatial aspects of sensory receptive fields on the cerebral cortex.

Low-intensity focused ultrasound alters the latency and spatial patterns of sensory-evoked cortical responses in vivo.

PubMed

Fisher, Jonathan A N; Gumenchuk, Iryna

2018-06-01

The use of transcranial, low intensity focused ultrasound (FUS) is an emerging neuromodulation technology that shows promise for both therapeutic and research applications. Among many, one of the most exciting applications is the use of FUS to rehabilitate or augment human sensory capabilities. While there is compelling empirical evidence demonstrating this capability, basic questions regarding the spatiotemporal extent of the modulatory effects remain. Our objective was to assess the basic, yet often overlooked hypothesis that FUS in fact alters sensory-evoked neural activity within the region of the cerebral cortex at the beam's focus. To address this knowledge gap, we developed an approach to optically interrogate patterns of neural activity in the cortex directly at the acoustic focus, in vivo. Implementing simultaneous wide-field optical imaging and FUS stimulation in mice, our experiments probed somatosensory-evoked electrical activity through the use of voltage sensitive dyes (VSDs) and, in transgenic mice expressing GCaMP6f, monitored associated Ca 2+ responses. Our results demonstrate that low-intensity FUS alters both the kinetics and spatial patterns of neural activity in primary somatosensory cortex at the acoustic focus. When preceded by 1 s of pulsed ultrasound at intensities below 1 W cm -2 (I sppa ), the onset of sensory-evoked cortical responses occurred 3.0  ±  0.7 ms earlier and altered the surface spatial morphology of Ca 2+ responses. These findings support the heretofore unconfirmed assumption that FUS-induced sensory modulation reflects, at least in part, altered reactivity in primary sensory cortex at the site of sonication. The findings are significant given the interest in using FUS to target and alter spatial aspects of sensory receptive fields on the cerebral cortex.

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping.

PubMed

Wu, Shih-Ying; Aurup, Christian; Sanchez, Carlos Sierra; Grondin, Julien; Zheng, Wenlan; Kamimura, Hermes; Ferrera, Vincent P; Konofagou, Elisa E

2018-05-22

Brain diseases including neurological disorders and tumors remain under treated due to the challenge to access the brain, and blood-brain barrier (BBB) restricting drug delivery which, also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with microbubbles is the sole method to open the BBB noninvasively, locally, and transiently and facilitate drug delivery, while translation to the clinic is challenging due to long procedure, targeting limitations, or invasiveness of current systems. In order to provide rapid, flexible yet precise applications, we have designed a noninvasive FUS and monitoring system with the protocol tested in monkeys (from in silico preplanning and simulation, real-time targeting and acoustic mapping, to post-treatment assessment). With a short procedure (30 min) similar to current clinical imaging duration or radiation therapy, the achieved targeting (both cerebral cortex and subcortical structures) and monitoring accuracy was close to the predicted 2-mm lower limit. This system would enable rapid clinical transcranial FUS applications outside of the MRI system without a stereotactic frame, thereby benefiting patients especially in the elderly population.

A focused ultrasound treatment system for moving targets (part I): generic system design and in-silico first-stage evaluation.

PubMed

Schwenke, Michael; Strehlow, Jan; Demedts, Daniel; Haase, Sabrina; Barrios Romero, Diego; Rothlübbers, Sven; von Dresky, Caroline; Zidowitz, Stephan; Georgii, Joachim; Mihcin, Senay; Bezzi, Mario; Tanner, Christine; Sat, Giora; Levy, Yoav; Jenne, Jürgen; Günther, Matthias; Melzer, Andreas; Preusser, Tobias

2017-01-01

Focused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging. A novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives. With a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator. The estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice.

Initial evaluation of acoustic reflectors for the preservation of sensitive abdominal skin areas during MRgFUS treatment.

PubMed

Gorny, Krzysztof R; Chen, Shigao; Hangiandreou, Nicholas J; Hesley, Gina K; Woodrum, David A; Brown, Douglas L; Felmlee, Joel P

2009-04-21

During MR-guided focused ultrasound (MRgFUS) treatments of uterine fibroids using ExAblate(R)2000 (InSightec, Haifa, Israel), individual tissue ablations are performed extracorporeally through the patient's abdomen using an annular array FUS transducer embedded within the MR table. Ultrasound intensities in the near field are below therapeutic levels and, under normal conditions, heating of the patient skin is minimal. However, increased absorption of ultrasound energy within sensitive skin areas or areas with differing acoustic properties, such as scars, may lead to skin burns and therefore these areas must be kept outside the near field of the FUS beam. Depending on their location and size the sensitive areas may either obstruct parts of the fibroid from being treated or prevent the entire MRgFUS treatment altogether. The purpose of this work is to evaluate acoustic reflector materials that can be applied to protect skin and the underlying sensitive areas. Reflection coefficients of cork (0.88) and foam (0.91) based materials were evaluated with a hydrophone. An ExAblate 2000 MRgFUS system was used to simulate clinical treatment with discs of reflector materials placed in a near field underneath a gel phantom. MR thermometry was used to monitor temperature elevations as well as the integrity of the focal spot. The phantom measurements showed acoustic shadow zones behind the reflectors with zone depths changing between 7 and 27 mm, for reflector disc diameters increasing from 10 to 30 mm (40 mm diameter discs completely blocked the FUS beam at the depth evaluated). The effects on thermal lesions due to the presence of the reflectors in the FUS beam were found to diminish with decreasing disc diameter and increasing sonication depth. For a 20 mm diameter disc and beyond 50 mm sonication depth, thermal lesions were minimally affected by the presence of the disc. No heating was observed on the skin side of the foam reflectors, as confirmed by measurements performed with adhesive temperature labels. We present these data and discuss possible applications to clinical MRgFUS treatments.

Controlled Drug Release and Chemotherapy Response in a Novel Acoustofluidic 3D Tumor Platform.

PubMed

Zervantonakis, Ioannis K; Arvanitis, Costas D

2016-05-01

Overcoming transport barriers to delivery of therapeutic agents in tumors remains a major challenge. Focused ultrasound (FUS), in combination with modern nanomedicine drug formulations, offers the ability to maximize drug transport to tumor tissue while minimizing toxicity to normal tissue. This potential remains unfulfilled due to the limitations of current approaches in accurately assessing and quantifying how FUS modulates drug transport in solid tumors. A novel acoustofluidic platform is developed by integrating a physiologically relevant 3D microfluidic device and a FUS system with a closed-loop controller to study drug transport and assess the response of cancer cells to chemotherapy in real time using live cell microscopy. FUS-induced heating triggers local release of the chemotherapeutic agent doxorubicin from a liposomal carrier and results in higher cellular drug uptake in the FUS focal region. This differential drug uptake induces locally confined DNA damage and glioblastoma cell death in the 3D environment. The capabilities of acoustofluidics for accurate control of drug release and monitoring of localized cell response are demonstrated in a 3D in vitro tumor mode. This has important implications for developing novel strategies to deliver therapeutic agents directly to the tumor tissue while sparing healthy tissue. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of the pain and local tenderness in bone metastasis treated with magnetic resonance-guided focused ultrasound surgery (MRgFUS)

NASA Astrophysics Data System (ADS)

Namba, Hirofumi; Kawasaki, Motohiro; Kato, Tomonari; Tani, Toshikazu; Ushida, Takahiro; Koizumi, Norihiro

2017-03-01

It has been reported that MRgFUS has pain palliative effects on the local pain in patients with bone metastasis. In general, a severity of pain has been evaluated using only subjective method with numerical rating scale (NRS) or visual analogue scale (VAS). It is important to evaluate local pain-palliative effects of MRgFUS treatment with objective and quantitative method. The aim of this study is to investigate changes in the severity of local pain of bone metastasis before and after MRgFUS treatments, measuring pressure pain threshold (PPT) using pressure algometer, and pain intensity using electrical stimulation device (the Pain Vision system) at most painful site of bone metastasis. We have conducted MRgFUS for pain palliation of bone metastasis for 8 patients, and evaluated the local tenderness quantitatively for 8 patients, and evaluated local pain intensity for 7 patients. Before the treatments, PPTs were 106.3kPa [40.0-431.5] at metastatic site and 344.8 kPa [206.0-667.0] at normal control site, which showed a significant difference. The PPTs at metastatic site shows a significant increase from 106.3 kPa [40.0-431.5] at the baseline to 270.5 kPa [93.5-533.5] at 3 months after the treatment. The NRS score shows a significant decrease from 6.0 [4-8] at baseline to 1 [0-3] at 3 months after the treatment. Similarly, the pain intensity shows a significant decrease 245 [96.3-888.7] at baseline to 55.9 [2.8-292] at 3 months after the treatment. The results of our study illustrate the pain-relieving effects of MRgFUS for the treatment of painful bone metastasis. PPT might be a useful parameter not only for assessing a treatment's effect, but also for the decision of the painful area to treat with MRgFUS. Pain Vision seems to be useful for quantitative and objective evaluation of local pain of painful bone metastasis.

The intensity dependence of lesion position shift during focused ultrasound surgery.

PubMed

Meaney, P M; Cahill, M D; ter Haar, G R

2000-03-01

Knowledge of the spatial distribution of intensity loss from an ultrasonic beam is critical for predicting lesion formation in focused ultrasound (US) surgery (FUS). To date, most models have used linear propagation models to predict intensity profiles required to compute the temporally varying temperature distributions used to compute thermal dose contours. These are used to predict the extent of thermal damage. However, these simulations fail to describe adequately the abnormal lesion formation behaviour observed during ex vivo experiments in cases for which the transducer drive levels are varied over a wide range. In such experiments, the extent of thermal damage has been observed to move significantly closer to the transducer with increased transducer drive levels than would be predicted using linear-propagation models. The first set of simulations described herein use the KZK (Khokhlov-Zabolotskaya-Kuznetsov) nonlinear propagation model with the parabolic approximation for highly focused US waves to demonstrate that both the peak intensity and the lesion positions do, indeed, move closer to the transducer. This illustrates that, for accurate modelling of heating during FUS, nonlinear effects should be considered. Additionally, a first order approximation has been employed that attempts to account for the abnormal heat deposition distributions that accompany high transducer drive level FUS exposures where cavitation and boiling may be present. The results of these simulations are presented. It is suggested that this type of approach may be a useful tool in understanding thermal damage mechanisms.

Magnetic resonance guided focused ultrasound surgery (MRgFUS) of bone metastases: From primary pain palliation to local tumor control

NASA Astrophysics Data System (ADS)

Napoli, A.; Leonardi, A.; Andrani, F.; Boni, F.; Anzidei, M.; Catalano, C.

2017-03-01

Purpose: To evaluate the clinical performance of MRgFUS in primary pain palliation of painful bone metastases and in local tumor control. Materials and Methods: We enrolled 26 consecutive patients (female/male 12/14; age: 64.7±7.5yrs) with painful bone metastases. Before and 3 months after MRgFUS treatment pain severity and pain interference scores were assessed according to Brief Pain Inventory-Quality of Life (BPI-QoL) criteria and patients underwent both CT and MRI. Local tumor control was evaluated according to lesion size, density and perfusion at CT, dynamic contrast enhancement at MRI (Discovery 750HD, GE; Gd-Bopta, Bracco) and metabolic activity at PET or scintigraphy. Patients were classified as responders or non-responders. Results: No treatment-related adverse events were recorded during the study. As statistically significant difference between baseline and follow-up values for both pain severity and pain interference scores was observed (p<0.05). Increased bone density was observed in 9/26 (34.6%) patients. Non-Perfused Volume values ranged between 20% and 92%. There was no difference in NPV values between responders and non-responders (46.7±24.2% [25 - 90 %] vs. 45±24.9% [20 - 93 %]; p=0.7). In 6 patients (5 prostate and 1 breast primary cancer) there was nearly absence of metabolic activity after treatment (mean SUV=1.2). Conclusion: MRgFUS can be safely and effectively used as the primary treatment for pain palliation in patients with painful bone metastases; moreover our experience demonstrated also a potential role for the MRgFUS in local tumor control.

Open-source, small-animal magnetic resonance-guided focused ultrasound system.

PubMed

Poorman, Megan E; Chaplin, Vandiver L; Wilkens, Ken; Dockery, Mary D; Giorgio, Todd D; Grissom, William A; Caskey, Charles F

2016-01-01

MR-guided focused ultrasound or high-intensity focused ultrasound (MRgFUS/MRgHIFU) is a non-invasive therapeutic modality with many potential applications in areas such as cancer therapy, drug delivery, and blood-brain barrier opening. However, the large financial costs involved in developing preclinical MRgFUS systems represent a barrier to research groups interested in developing new techniques and applications. We aim to mitigate these challenges by detailing a validated, open-source preclinical MRgFUS system capable of delivering thermal and mechanical FUS in a quantifiable and repeatable manner under real-time MRI guidance. A hardware and software package was developed that includes closed-loop feedback controlled thermometry code and CAD drawings for a therapy table designed for a preclinical MRI scanner. For thermal treatments, the modular software uses a proportional integral derivative controller to maintain a precise focal temperature rise in the target given input from MR phase images obtained concurrently. The software computes the required voltage output and transmits it to a FUS transducer that is embedded in the delivery table within the magnet bore. The delivery table holds the FUS transducer, a small animal and its monitoring equipment, and a transmit/receive RF coil. The transducer is coupled to the animal via a water bath and is translatable in two dimensions from outside the magnet. The transducer is driven by a waveform generator and amplifier controlled by real-time software in Matlab. MR acoustic radiation force imaging is also implemented to confirm the position of the focus for mechanical and thermal treatments. The system was validated in tissue-mimicking phantoms and in vivo during murine tumor hyperthermia treatments. Sonications were successfully controlled over a range of temperatures and thermal doses for up to 20 min with minimal temperature overshoot. MR thermometry was validated with an optical temperature probe, and focus visualization was achieved with acoustic radiation force imaging. We developed an MRgFUS platform for small-animal treatments that robustly delivers accurate, precise, and controllable sonications over extended time periods. This system is an open source and could increase the availability of low-cost small-animal systems to interdisciplinary researchers seeking to develop new MRgFUS applications and technology.

Proteomic analysis of FUS interacting proteins provides insights into FUS function and its role in ALS.

PubMed

Kamelgarn, Marisa; Chen, Jing; Kuang, Lisha; Arenas, Alexandra; Zhai, Jianjun; Zhu, Haining; Gal, Jozsef

2016-10-01

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Mutations in the Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) gene cause a subset of familial ALS cases and are also implicated in sporadic ALS. FUS is typically localized to the nucleus. The ALS-related FUS mutations cause cytoplasmic mis-localization and the formation of stress granule-like structures. Abnormal cytoplasmic FUS localization was also found in a subset of frontotemporal dementia (FTLD) cases without FUS mutations. To better understand the function of FUS, we performed wild-type and mutant FUS pull-downs followed by proteomic identification of the interacting proteins. The FUS interacting partners we identified are involved in multiple pathways, including chromosomal organization, transcription, RNA splicing, RNA transport, localized translation, and stress response. FUS interacted with hnRNPA1 and Matrin-3, RNA binding proteins whose mutations were also reported to cause familial ALS, suggesting that hnRNPA1 and Matrin-3 may play common pathogenic roles with FUS. The FUS interactions displayed varied RNA dependence. Numerous FUS interacting partners that we identified are components of exosomes. We found that FUS itself was present in exosomes, suggesting that the secretion of FUS might contribute to the cell-to-cell spreading of FUS pathology. FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. Our results provide insights into the physiological functions of FUS as well as important pathways where mutant FUS can interfere with cellular processes and potentially contribute to the pathogenesis of ALS. Copyright © 2016 Elsevier B.V. All rights reserved.

Design and validation of an MR-conditional robot for transcranial focused ultrasound surgery in infants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Price, Karl D., E-mail: karl.price@sickkids.ca

Purpose: Current treatment of intraventricular hemorrhage (IVH) involves cerebral shunt placement or an invasive brain surgery. Magnetic resonance-guided focused ultrasound (MRgFUS) applied to the brains of pediatric patients presents an opportunity to treat IVH in a noninvasive manner, termed “incision-less surgery.” Current clinical and research focused ultrasound systems lack the capability to perform neonatal transcranial surgeries due to either range of motion or dexterity requirements. A novel robotic system is proposed to position a focused ultrasound transducer accurately above the head of a neonatal patient inside an MRI machine to deliver the therapy. Methods: A clinical Philips Sonalleve MRgFUS systemmore » was expanded to perform transcranial treatment. A five degree-of-freedom MR-conditional robot was designed and manufactured using MR compatible materials. The robot electronics and control were integrated into existing Philips electronics and software interfaces. The user commands the position of the robot with a graphical user interface, and is presented with real-time MR imaging of the patient throughout the surgery. The robot is validated through a series of experiments that characterize accuracy, signal-to-noise ratio degeneration of an MR image as a result of the robot, MR imaging artifacts generated by the robot, and the robot’s ability to operate in a representative surgical environment inside an MR machine. Results: Experimental results show the robot responds reliably within an MR environment, has achieved 0.59 ± 0.25 mm accuracy, does not produce severe MR-imaging artifacts, has a workspace providing sufficient coverage of a neonatal brain, and can manipulate a 5 kg payload. A full system demonstration shows these characteristics apply in an application environment. Conclusions: This paper presents a comprehensive look at the process of designing and validating a new robot from concept to implementation for use in an MR environment. An MR conditional robot has been designed and manufactured to design specifications. The system has demonstrated its feasibility as a platform for MRgFUS interventions for neonatal patients. The success of the system in experimental trials suggests that it is ready to be used for validation of the transcranial intervention in animal studies.« less

FUS immunogold labelling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy

PubMed Central

Page, Tristan; Gitcho, Michael A.; Mosaheb, Sabrina; Carter, Deborah; Chakraverty, Sumi; Perry, Robert H.; Bigio, Eileen H.; Gearing, Marla; Ferrer, Isidre; Goate, Alison M.; Cairns, Nigel J.; Thorpe, Julian R.

2012-01-01

Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three FTLD entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of α-internexin and neurofilament proteins. Herein, we have: (1) shown that FUS becomes relatively insoluble in NIFID and there are no post-translational modifications; (2) shown there are no pathogenic abnormalities in the FUS gene in NIFID; (3) performed an immunoelectron microscopy analysis of the precise localizations of FUS in NIFID, as this has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the ‘loosely aggregated cytoplasmic inclusions’ (LACI), 81% of which had moderate or high levels of FUS-immunoreactivity. Much rarer ‘compact cytoplasmic inclusions’ (CCI) and ‘Tangled twine ball inclusions’ (TTBI) were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations. PMID:21603978

Casualty Evacuation in the Contemporary Operating Environment

DTIC Science & Technology

2002-05-20

HIFU ), or Focused Ultrasound ( FUS ), can be used to rapidly kill tissue (directly applicable to cancer treatment, for example) and to stop internal...132 Peter Kaczkowski, Development of a High-Intensity Focused Ultrasound System for Image-guided Ultrasound Surgery...spatial dimension, with acquisition and display occurring nearly in real time.135 Recent research has shown that High Intensity Focused Ultrasound

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.

PubMed

Alli, Saira; Figueiredo, Carlyn A; Golbourn, Brian; Sabha, Nesrin; Wu, Megan Yijun; Bondoc, Andrew; Luck, Amanda; Coluccia, Daniel; Maslink, Colin; Smith, Christian; Wurdak, Heiko; Hynynen, Kullervo; O'Reilly, Meaghan; Rutka, James T

2018-05-15

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H&E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions. Copyright © 2018 Elsevier B.V. All rights reserved.

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function

PubMed Central

Sharma, Aarti; Lyashchenko, Alexander K.; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z.; Shneider, Neil A.

2016-01-01

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations. PMID:26842965

ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.

PubMed

Sharma, Aarti; Lyashchenko, Alexander K; Lu, Lei; Nasrabady, Sara Ebrahimi; Elmaleh, Margot; Mendelsohn, Monica; Nemes, Adriana; Tapia, Juan Carlos; Mentis, George Z; Shneider, Neil A

2016-02-04

Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.

[Magnetic resonance guided focused ultrasound surgery for pain palliation of bone metastases: early experience of clinical application in China].

PubMed

Gu, Jianjun; Wang, Han; Tang, Na; Hua, Yingqi; Yang, Haiyan; Qiu, Yimin; Ge, Renbin; Zhou, Ying; Wang, Wenwen; Zhang, Guixiang

2015-11-03

To evaluate the safety and efficacy of magnetic resonance guided focused ultrasound surgery (MRgFUS) in treatment for pain palliation of bone metastases. Eighty-one patients of painful bone metastases were volunteered to screen for this study in Shanghai General Hospital from June 2014 to February 2015. Twenty-three patients among them were treated by MRgFUS, who was more than 18-years old, having the ability to fully understand the informed consent of the research, suffering with pain of numeric rating scale (NRS) ≥ 4, non-received radiotherapy or chemotherapy for pain palliation of bone metastases in the past two weeks. The NRS, the standard question of Brief Pain Inventory (BPI-QoL), and the standard question of Europe Organization for Research and Treatment of Cancer Quality of Life Questionnaire- Bone Metastases 22 (EORTC QLQ-BM22) were respectively recorded before and 1-week, 1-month, 3-month after the treatment. The related adverse events of MRgFUS were observed and recorded in 3 months after the treatment as well. (1)Twenty-three metastatic bone tumor lesions of 23 patients were treated by MRgFUS, the treatment data was as follows: the mean treatment time was (88 ± 33) minutes, the mean sonication number was 13 ± 8. (2) Adverse events included: pain in therapy area 3/23, which spontaneous relieving within one week; numbness in lower limb (1/23), which relieved after physiotherapy. (3) The NRS of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 6.0 ± 1.5, 3.7 ± 1.7,3.1 ± 2.0, and 2.2 ± 1.0,which significantly decreased after the treatment (P<0.01). (4) The BPI-QoL score of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 39 ± 16, 27 ± 18, 26 ± 18, and 21 ± 18, which significantly decreased after the treatment (P<0.01). (5) The EORTC QLQ-BM22 score of before treatment and at 1-week, 1-month, and 3-month after treatment respectively was 52 ± 13, 44 ± 12, 42 ± 12, and 39 ± 12, which also significantly decreased after the treatment (P<0.01). MRgFUS can be used as a non-invasive, safe, and effective method for treating painful bone metastases. Its clinical benefits of pain palliation and patient's quality of life improving are sustained after the treatment at least to 3 months.

The dynamic of FUS-induced BBB Opening in Mouse Brain assessed by contrast enhanced MRI

NASA Astrophysics Data System (ADS)

Jenne, Jürgen W.; Krafft, Axel J.; Maier, Florian; Krause, Marie N.; Kleber, Susanne; Huber, Peter E.; Martin-Villalba, Ana; Bock, Michael

2010-03-01

Focused ultrasound (FUS) in combination with the administration of gas-filled microbubbles, can induce a localized and reversible opening of the blood brain barrier (BBB). Contrast enhanced magnetic resonance imaging (MRI) has been demonstrated as a precise tool to monitor such a local BBB disruption. However, the opening/closing mechanisms of the BBB with FUS are still largely unknown. In this ongoing project, we study the BBB opening dynamics in mouse brain comparing an interstitial and an intravascular MR contrast agent (CA). FUS in mouse brain was performed with an MRI compatible treatment setup (1.7 MHz fix-focus US transducer, f' = 68 mm, NA = 0.44; focus: 8.1 mm length; O/ = 1.1 mm) in a 1.5 T whole body MRI system. For BBB opening, forty 10 ms-long FUS-pulses were applied at a repetition rate of 1 Hz at 1 MPa. The i.v. administration of the micro bubbles (50 μl SonoVue®) was started simultaneously with FUS exposure. To analyze the BBB opening process, short-term and long-term MRI signal dynamics of the interstitial MR contrast agent Magnevist® and the intravascular CA Vasovist® (Bayer-Schering) were studied. To assess short-term signal dynamics, T1-weighted inversion recovery turbo FLASH images (1s) were repeatedly acquired. Repeated 3D FLASH acquisitions (90 s) were used to assess long-term MRI signal dynamics. The short-term MRI signal enhancements showed comparable time constants for both types of MR contrast agents: 1.1 s (interstitial) vs. 0.8 s (intravascular). This time constant may serve as a time constant of the BBB opening process with the given FUS exposure parameters. For the long-term signal dynamics the intravascular CA (62±10 min) showed a fife times greater time constant as the interstitial contrast agent (12±10 min). This might be explained by the high molecular weight (˜60 kDa) of the intravascular Vasovist due to its reversible binding to blood serum albumin resulting in a prolonged half-life in the blood stream compared to the interstitial CA. As the intravascular CA offers a much longer time window for therapy assessment, FUS-BBB therapy control with an intravascular CA might be favorable.

Investigation of Cellular and Molecular Responses to Pulsed Focused Ultrasound in a Mouse Model

PubMed Central

Burks, Scott R.; Ziadloo, Ali; Hancock, Hilary A.; Chaudhry, Aneeka; Dean, Dana D.; Lewis, Bobbi K.; Frenkel, Victor; Frank, Joseph A.

2011-01-01

Continuous focused ultrasound (cFUS) has been widely used for thermal ablation of tissues, relying on continuous exposures to generate temperatures necessary to induce coagulative necrosis. Pulsed FUS (pFUS) employs non-continuous exposures that lower the rate of energy deposition and allow cooling to occur between pulses, thereby minimizing thermal effects and emphasizing effects created by non-thermal mechanisms of FUS (i.e., acoustic radiation forces and acoustic cavitation). pFUS has shown promise for a variety of applications including drug and nanoparticle delivery; however, little is understood about the effects these exposures have on tissue, especially with regard to cellular pro-homing factors (growth factors, cytokines, and cell adhesion molecules). We examined changes in murine hamstring muscle following pFUS or cFUS and demonstrate that pFUS, unlike cFUS, has little effect on the histological integrity of muscle and does not induce cell death. Infiltration of macrophages was observed 3 and 8 days following pFUS or cFUS exposures. pFUS increased expression of several cytokines (e.g., IL-1α, IL-1β, TNFα, INFγ, MIP-1α, MCP-1, and GMCSF) creating a local cytokine gradient on days 0 and 1 post-pFUS that returns to baseline levels by day 3 post-pFUS. pFUS exposures induced upregulation of other signaling molecules (e.g., VEGF, FGF, PlGF, HGF, and SDF-1α) and cell adhesion molecules (e.g., ICAM-1 and VCAM-1) on muscle vasculature. The observed molecular changes in muscle following pFUS may be utilized to target cellular therapies by increasing homing to areas of pathology. PMID:21931834

Factors associated with successful magnetic resonance-guided focused ultrasound treatment: efficiency of acoustic energy delivery through the skull.

PubMed

Chang, Won Seok; Jung, Hyun Ho; Zadicario, Eyal; Rachmilevitch, Itay; Tlusty, Tal; Vitek, Shuki; Chang, Jin Woo

2016-02-01

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) was recently introduced as treatment for movement disorders such as essential tremor and advanced Parkinson's disease (PD). Although deep brain target lesions are successfully generated in most patients, the target area temperature fails to increase in some cases. The skull is one of the greatest barriers to ultrasonic energy transmission. The authors analyzed the skull-related factors that may have prevented an increase in target area temperatures in patients who underwent MRgFUS. The authors retrospectively reviewed data from clinical trials that involved MRgFUS for essential tremor, idiopathic PD, and obsessive-compulsive disorder. Data from 25 patients were included. The relationships between the maximal temperature during treatment and other factors, including sex, age, skull area of the sonication field, number of elements used, skull volume of the sonication field, and skull density ratio (SDR), were determined. Among the various factors, skull volume and SDR exhibited relationships with the maximum temperature. Skull volume was negatively correlated with maximal temperature (p = 0.023, r(2) = 0.206, y = 64.156 - 0.028x, whereas SDR was positively correlated with maximal temperature (p = 0.009, r(2) = 0.263, y = 49.643 + 11.832x). The other factors correlate with the maximal temperature, although some factors showed a tendency to correlate. Some skull-related factors correlated with the maximal target area temperature. Although the number of patients in the present study was relatively small, the results offer information that could guide the selection of MRgFUS candidates.

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

PubMed

Scekic-Zahirovic, Jelena; Sendscheid, Oliver; El Oussini, Hajer; Jambeau, Mélanie; Sun, Ying; Mersmann, Sina; Wagner, Marina; Dieterlé, Stéphane; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Drenner, Kevin; Birling, Marie-Christine; Qiu, Jinsong; Zhou, Yu; Li, Hairi; Fu, Xiang-Dong; Rouaux, Caroline; Shelkovnikova, Tatyana; Witting, Anke; Ludolph, Albert C; Kiefer, Friedemann; Storkebaum, Erik; Lagier-Tourenne, Clotilde; Dupuis, Luc

2016-05-17

FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

FUS and TARDBP but Not SOD1 Interact in Genetic Models of Amyotrophic Lateral Sclerosis

PubMed Central

Kabashi, Edor; Bercier, Valérie; Lissouba, Alexandra; Liao, Meijiang; Brustein, Edna; Rouleau, Guy A.; Drapeau, Pierre

2011-01-01

Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS–related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS–related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1. PMID:21829392

FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis.

PubMed

Kabashi, Edor; Bercier, Valérie; Lissouba, Alexandra; Liao, Meijiang; Brustein, Edna; Rouleau, Guy A; Drapeau, Pierre

2011-08-01

Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS-related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS-related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1.

FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice.

PubMed

Kino, Yoshihiro; Washizu, Chika; Kurosawa, Masaru; Yamada, Mizuki; Doi, Hiroshi; Takumi, Toru; Adachi, Hiroaki; Katsuno, Masahisa; Sobue, Gen; Hicks, Geoffrey G; Hattori, Nobutaka; Shimogori, Tomomi; Nukina, Nobuyuki

2016-10-14

FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS +/- double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration.

FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress.

PubMed

Sama, Reddy Ranjith K; Ward, Catherine L; Kaushansky, Laura J; Lemay, Nathan; Ishigaki, Shinsuke; Urano, Fumihiko; Bosco, Daryl A

2013-11-01

FUsed in Sarcoma/Translocated in LipoSarcoma (FUS/TLS or FUS) has been linked to several biological processes involving DNA and RNA processing, and has been associated with multiple diseases, including myxoid liposarcoma and amyotrophic lateral sclerosis (ALS). ALS-associated mutations cause FUS to associate with stalled translational complexes called stress granules under conditions of stress. However, little is known regarding the normal role of endogenous (non-disease linked) FUS in cellular stress response. Here, we demonstrate that endogenous FUS exerts a robust response to hyperosmolar stress induced by sorbitol. Hyperosmolar stress causes an immediate re-distribution of nuclear FUS to the cytoplasm, where it incorporates into stress granules. The redistribution of FUS to the cytoplasm is modulated by methyltransferase activity, whereas the inhibition of methyltransferase activity does not affect the incorporation of FUS into stress granules. The response to hyperosmolar stress is specific, since endogenous FUS does not redistribute to the cytoplasm in response to sodium arsenite, hydrogen peroxide, thapsigargin, or heat shock, all of which induce stress granule assembly. Intriguingly, cells with reduced expression of FUS exhibit a loss of cell viability in response to sorbitol, indicating a prosurvival role for endogenous FUS in the cellular response to hyperosmolar stress. Copyright © 2013 Wiley Periodicals, Inc.

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

NASA Astrophysics Data System (ADS)

Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

2016-06-01

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress

PubMed Central

Sama, Reddy Ranjith K; Ward, Catherine L.; Kaushansky, Laura J.; Lemay, Nathan; Ishigaki, Shinsuke; Urano, Fumihiko; Bosco, Daryl A.

2014-01-01

FUsed in Sarcoma/Translocated in LipoSarcoma (FUS/TLS or FUS) has been linked to several biological processes involving DNA and RNA processing, and has been associated with multiple diseases, including myxoid liposarcoma and amyotrophic lateral sclerosis (ALS). ALS-associated mutations cause FUS to associate with stalled translational complexes called stress granules under conditions of stress. However, little is known regarding the normal role of endogenous (non-disease linked) FUS in cellular stress response. Here, we demonstrate that endogenous FUS exerts a robust response to hyperosmolar stress induced by sorbitol. Hyperosmolar stress causes an immediate re-distribution of nuclear FUS to the cytoplasm, where it incorporates into stress granules. The redistribution of FUS to the cytoplasm is modulated by methyltransferase activity, whereas the inhibition of methyltransferase activity does not affect the incorporation of FUS into stress granules. The response to hyperosmolar stress is specific, since endogenous FUS does not redistribute to the cytoplasm in response to sodium arsenite, hydrogen peroxide, thapsigargin, or heat shock, all of which induce stress granule assembly. Intriguingly, cells with reduced expression of FUS exhibit a loss of cell viability in response to sorbitol, indicating a prosurvival role for endogenous FUS in the cellular response to hyperosmolar stress. PMID:23625794

ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism

PubMed Central

Murakami, Tetsuro; Yang, Seung-Pil; Xie, Lin; Kawano, Taizo; Fu, Donald; Mukai, Asuka; Bohm, Christopher; Chen, Fusheng; Robertson, Janice; Suzuki, Hiroshi; Tartaglia, Gian Gaetano; Vendruscolo, Michele; Kaminski Schierle, Gabriele S.; Chan, Fiona T.S.; Moloney, Aileen; Crowther, Damian; Kaminski, Clemens F.; Zhen, Mei; St George-Hyslop, Peter

2012-01-01

It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions. PMID:21949354

ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism.

PubMed

Murakami, Tetsuro; Yang, Seung-Pil; Xie, Lin; Kawano, Taizo; Fu, Donald; Mukai, Asuka; Bohm, Christopher; Chen, Fusheng; Robertson, Janice; Suzuki, Hiroshi; Tartaglia, Gian Gaetano; Vendruscolo, Michele; Kaminski Schierle, Gabriele S; Chan, Fiona T S; Moloney, Aileen; Crowther, Damian; Kaminski, Clemens F; Zhen, Mei; St George-Hyslop, Peter

2012-01-01

It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions.

High-intensity focused ultrasound in obstetrics and gynecology: the birth of a new era of noninvasive surgery?

PubMed

Griffiths, A; terHaar, G; Rivens, I; Giussani, D; Lees, C

2012-12-01

Although ultrasound is an essential investigative modality in obstetrics and gynecology, the potential for therapeutic high-intensity focused ultrasound (HIFU) (also referred to as focused ultrasound surgery, FUS) to offer an alternative to invasive surgery is less well known. The ability of HIFU to create discrete regions of tissue necrosis only in precisely targeted positions by careful placement of the focus, without the need for any surgical intervention, has made HIFU of interest to those seeking noninvasive alternatives to conventional abdominal surgery. This article reviews the current experimental and clinical experience with HIFU in obstetrics and gynecology, and outlines potential future applications in fetal medicine and the challenges faced in their development. © Georg Thieme Verlag KG Stuttgart · New York.

Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets.

PubMed

Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying; Olumolade, Oluyemi O; Dayton, Paul A; Konofagou, Elisa E

2013-12-28

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature. © 2013.

Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs RNA granules formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takanashi, Keisuke; Yamaguchi, Atsushi, E-mail: atsyama@restaff.chiba-u.jp

Highlights: • Aggregation of ALS-linked FUS mutant sequesters ALS-associated RNA-binding proteins (FUS wt, hnRNP A1, and hnRNP A2). • Aggregation of ALS-linked FUS mutant sequesters SMN1 in the detergent-insoluble fraction. • Aggregation of ALS-linked FUS mutant reduced the number of speckles in the nucleus. • Overproduced ALS-linked FUS mutant reduced the number of processing-bodies (PBs). - Abstract: Protein aggregate/inclusion is one of hallmarks for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). FUS/TLS, one of causative genes for familial ALS, encodes a multifunctional DNA/RNA binding protein predominantly localized in the nucleus. C-terminal mutations in FUS/TLS cause the retention and the inclusionmore » of FUS/TLS mutants in the cytoplasm. In the present study, we examined the effects of ALS-linked FUS mutants on ALS-associated RNA binding proteins and RNA granules. FUS C-terminal mutants were diffusely mislocalized in the cytoplasm as small granules in transiently transfected SH-SY5Y cells, whereas large aggregates were spontaneously formed in ∼10% of those cells. hnRNP A1, hnRNP A2, and SMN1 as well as FUS wild type were assembled into stress granules under stress conditions, and these were also recruited to FUS mutant-derived spontaneous aggregates in the cytoplasm. These aggregates stalled poly(A) mRNAs and sequestered SMN1 in the detergent insoluble fraction, which also reduced the number of nuclear oligo(dT)-positive foci (speckles) in FISH (fluorescence in situ hybridization) assay. In addition, the number of P-bodies was decreased in cells harboring cytoplasmic granules of FUS P525L. These findings raise the possibility that ALS-linked C-terminal FUS mutants could sequester a variety of RNA binding proteins and mRNAs in the cytoplasmic aggregates, which could disrupt various aspects of RNA equilibrium and biogenesis.« less

EWS and FUS bind a subset of transcribed genes encoding proteins enriched in RNA regulatory functions.

PubMed

Luo, Yonglun; Blechingberg, Jenny; Fernandes, Ana Miguel; Li, Shengting; Fryland, Tue; Børglum, Anders D; Bolund, Lars; Nielsen, Anders Lade

2015-11-14

FUS (TLS) and EWS (EWSR1) belong to the FET-protein family of RNA and DNA binding proteins. FUS and EWS are structurally and functionally related and participate in transcriptional regulation and RNA processing. FUS and EWS are identified in translocation generated cancer fusion proteins and involved in the human neurological diseases amyotrophic lateral sclerosis and fronto-temporal lobar degeneration. To determine the gene regulatory functions of FUS and EWS at the level of chromatin, we have performed chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Our results show that FUS and EWS bind to a subset of actively transcribed genes, that binding often is downstream the poly(A)-signal, and that binding overlaps with RNA polymerase II. Functional examinations of selected target genes identified that FUS and EWS can regulate gene expression at different levels. Gene Ontology analyses showed that FUS and EWS target genes preferentially encode proteins involved in regulatory processes at the RNA level. The presented results yield new insights into gene interactions of EWS and FUS and have identified a set of FUS and EWS target genes involved in pathways at the RNA regulatory level with potential to mediate normal and disease-associated functions of the FUS and EWS proteins.

R521C and R521H mutations in FUS result in weak binding with Karyopherinβ2 leading to Amyotrophic lateral sclerosis: a molecular docking and dynamics study.

PubMed

Swetha, Rayapadi G; Ramaiah, Sudha; Anbarasu, Anand

2017-08-01

Fused in sarcoma (FUS) gene encodes the RNA binding protein FUS. This gene is mapped to chromosome 16p11.2. The FUS protein binds with karyopherineβ2 (Kapβ2) through its proline/tyrosine nuclear localization signal (PY-NLS) that helps in the localization of FUS protein within the nucleus. Arginine residue in 521 position (R521) of PY-NLS plays a vital role in the binding of FUS protein with Kapβ2. Mutations in this position (R521C and R521H) are the most predominant mutations associated with amyotrophic lateral sclerosis (ALS). However, the mechanism by which these mutations lead to ALS is poorly understood. We examined the binding behaviour of the mutants FUS (R521C) and FUS (R521H) with Kapβ2 through protein-protein docking and molecular dynamics simulation. The binding patterns of mutants were compared with the binding behaviour of wild FUS-Kapβ2. Our results suggest that these mutants have relatively weak binding affinity with Kapβ2 when compared with wild FUS-Kapβ2 as indicated by the lesser number of interactions found between the mutant FUS and Kapβ2. Hence, these mutations weakens the binding and this results in the cytoplasmic mislocalization of mutant FUS; and thereby it increases the severity of ALS.

Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1.

PubMed

Lin, J; Sun, T; Ji, L; Deng, W; Roth, J; Minna, J; Arlinghaus, R

2007-10-25

In lung cancer, frequent loss of one allele of chromosome 3p is seen in both small cell lung cancer and non-small cell lung cancer (NSCLC), providing evidence of tumor suppressor genes (TSGs) in this chromosomal region. The mechanism of Fus1 tumor suppressor activity is unknown. We have found that a Fus1 peptide inhibits the Abl tyrosine kinase in vitro (IC(50) 35 microM). The inhibitory Fus1 sequence was derived from a region that was deleted in a mutant FUS1 gene (FUS1 (1-80)) detected in some lung cancer cell lines. Importantly, a stearic acid-modified form of this peptide was required for the inhibition, but stearic acid alone was not inhibitory. Two NSCLC cell lines, which lack expression of wild-type Fus1, contain activated c-Abl. Forced expression of an inducible FUS1 cDNA in H1299 NSCLC cells decreased levels of activated c-Abl and inhibited its tyrosine kinase activity. Similarly, treatment of c-Abl immune complexes with the inhibitory Fus1 peptide also reduced the level of c-Abl in these immune complexes. The size and number of colonies of the NSCLC cell line, H1,299, in soft agar was strongly inhibited by the Abl kinase inhibitor imatinib mesylate. Co-expression of FUS1 and c-ABL in COS1 cells blocked activation of c-Abl tyrosine kinase. In contrast, co-expression of mutant FUS1 (1-80) with c-ABL had little inhibitory activity against c-Abl. These findings provide strong evidence that c-Abl is a possible target in NSCLC patients that have reduced expression of Fus1 in their tumor cells.

WE-AB-BRA-03: Non-Invasive Controlled Release from Implantable Hydrogel Scaffolds Using Ultrasound

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moncion, A; Kripfgans, O.D; Putnam, A.J

Purpose: To control release of a model payload in acoustically responsive scaffolds (ARSs) using focused ultrasound (FUS). Methods: Fluorescently-labeled dextran (10 kDa) was encapsulated in sonosensitive perfluorocarbon (C{sub 6}F{sub 14} or C{sub 5}F{sub 12}) double emulsions (mean diameter: 2.9±0.1 µm). For in vitro release studies, 0.5 mL ARSs (10 mg/mL fibrin, 1% (v/v) emulsion) were polymerized in 24 well plates and covered with 0.5 mL medium. Starting one day after polymerization, ARSs were exposed to FUS (2.5 MHz, Pr = 8 MPa, 13 cycles, 100 Hz PRF) for 2 min daily. The amount of dextran released into the media wasmore » quantified. For in vivo studies, 0.25 mL ARSs were prepared as described previously and injected subcutaneously in the lower back of BALB/c mice. After polymerization, a subset of the implanted ARSs were exposed to FUS (as previously described). Animals were imaged longitudinally using a fluorescence imaging system to quantify the amount of dextran released from the ARSs. Results: In vitro: Over 6 days, +FUS displayed an 8.2-fold increase in dextran release compared to −FUS (−FUS: 2.7±0.6%; +FUS: 22.2±3.0%) for C{sub 6}F{sub 14} ARSs, and a 6.7-fold increase (−FUS: 5.0±0.8%; +FUS: 38.5±1.6%) for C{sub 5}F{sub 12}:C{sub 6}F{sub 14} ARSs. In vivo: +FUS displayed statistically greater dextran release compared to −FUS one day after implantation for C{sub 5}F{sub 12}:C{sub 6}F{sub 14} ARSs (−FUS: 55.1±1.5%; +FUS: 74.1±2.2%) and three days after implantation for C{sub 6}F{sub 14} ARSs (−FUS: 1.4±6.5%; +FUS: 30.4±5.4%). Conclusion: FUS enables non-invasive control of payload release from an ARS, which could benefit growth factor delivery for tissue regeneration. ARS are versatile due to their tunability (i.e. stiffness, emulsion composition, FUS pressure, FUS frequency, etc.) and can be modified to for optimal payload release. Future work will optimize ARS formulations for in vivo use to minimize payload release in the absence of FUS. This work was supported by NIH Grant R21 AR065010 (M.L. Fabiilli) and the Basic Radiologic Sciences Innovative Research Award (M.L. Fabiilli). A. Moncion is supported by the National Science Foundation Graduate Student Research Fellowship (Grant DGE 1256260).« less

Non-invasive transcranial stimulation of rat abducens nerve by focused ultrasound

PubMed Central

Kim, Hyungmin; Taghados, Seyed Javid; Fischer, Krisztina; Maeng, Lee-So; Park, Shinsuk; Yoo, Seung-Schik

2012-01-01

Non-pharmacological and non-surgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36 msec tone burst duration (TBD), 1.5 kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histological and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB) as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential in diagnostic and therapeutic applications in diseases of the peripheral nervous system. PMID:22763009

Analytical estimation of ultrasound properties, thermal diffusivity, and perfusion using magnetic resonance-guided focused ultrasound temperature data

PubMed Central

Dillon, C R; Borasi, G; Payne, A

2016-01-01

For thermal modeling to play a significant role in treatment planning, monitoring, and control of magnetic resonance-guided focused ultrasound (MRgFUS) thermal therapies, accurate knowledge of ultrasound and thermal properties is essential. This study develops a new analytical solution for the temperature change observed in MRgFUS which can be used with experimental MR temperature data to provide estimates of the ultrasound initial heating rate, Gaussian beam variance, tissue thermal diffusivity, and Pennes perfusion parameter. Simulations demonstrate that this technique provides accurate and robust property estimates that are independent of the beam size, thermal diffusivity, and perfusion levels in the presence of realistic MR noise. The technique is also demonstrated in vivo using MRgFUS heating data in rabbit back muscle. Errors in property estimates are kept less than 5% by applying a third order Taylor series approximation of the perfusion term and ensuring the ratio of the fitting time (the duration of experimental data utilized for optimization) to the perfusion time constant remains less than one. PMID:26741344

The ALS gene FUS regulates synaptic transmission at the Drosophila neuromuscular junction

PubMed Central

Machamer, James B.; Collins, Sarah E.; Lloyd, Thomas E.

2014-01-01

Mutations in the RNA binding protein Fused in sarcoma (FUS) are estimated to account for 5–10% of all inherited cases of amyotrophic lateral sclerosis (ALS), but the function of FUS in motor neurons is poorly understood. Here, we investigate the early functional consequences of overexpressing wild-type or ALS-associated mutant FUS proteins in Drosophila motor neurons, and compare them to phenotypes arising from loss of the Drosophila homolog of FUS, Cabeza (Caz). We find that lethality and locomotor phenotypes correlate with levels of FUS transgene expression, indicating that toxicity in developing motor neurons is largely independent of ALS-linked mutations. At the neuromuscular junction (NMJ), overexpression of either wild-type or mutant FUS results in decreased number of presynaptic active zones and altered postsynaptic glutamate receptor subunit composition, coinciding with a reduction in synaptic transmission as a result of both reduced quantal size and quantal content. Interestingly, expression of human FUS downregulates endogenous Caz levels, demonstrating that FUS autoregulation occurs in motor neurons in vivo. However, loss of Caz from motor neurons increases synaptic transmission as a result of increased quantal size, suggesting that the loss of Caz in animals expressing FUS does not contribute to motor deficits. These data demonstrate that FUS/Caz regulates NMJ development and plays an evolutionarily conserved role in modulating the strength of synaptic transmission in motor neurons. PMID:24569165

FUS/TLS-immunoreactive neuronal and glial cell inclusions increase with disease duration in familial amyotrophic lateral sclerosis with an R521C FUS/TLS mutation.

PubMed

Suzuki, Naoki; Kato, Shinsuke; Kato, Masako; Warita, Hitoshi; Mizuno, Hideki; Kato, Masaaki; Shimakura, Naoko; Akiyama, Haruhiko; Kobayashi, Zen; Konno, Hidehiko; Aoki, Masashi

2012-09-01

Basophilic inclusions (BIs) are pathological features of a subset of frontotemporal lobar degeneration disorders, including sporadic amyotrophic lateral sclerosis (ALS) and familial ALS (FALS). Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have recently been identified as a cause of FALS. The FUS/TLS-immunoreactive inclusions are consistently found in cases of frontotemporal lobar degeneration with BIs; however, the association between ALS cases with BIs and FUS/TLS accumulation is not well understood. We used immunohistochemistry to analyze 3 autopsy cases of FALS with the FUS/TLS mutation and with BIs using anti-FUS/TLS antibodies. The disease durations were 1, 3, and 9 years. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions. As early as 1 year after the onset, BIs, neuronal cytoplasmic inclusions and glial cytoplasmic inclusions were found in the substantia nigra in addition to the anterior horn of the spinal cord. Glial cytoplasmic inclusions are found earlier and in a wider distribution than neuronal cytoplasmic inclusions. The distribution of FUS/TLS-immunoreactive inclusions in FUS/TLS-mutated FALS with BIs was broader than that of BIs alone, suggesting that the pathogenetic mechanism may have originated from the FUS/TLS proteinopathy.

Treatment envelope evaluation in transcranial magnetic resonance-guided focused ultrasound utilizing 3D MR thermometry

PubMed Central

2014-01-01

Background Current clinical targets for transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) are all located close to the geometric center of the skull convexity, which minimizes challenges related to focusing the ultrasound through the skull bone. Non-central targets will have to be reached to treat a wider variety of neurological disorders and solid tumors. Treatment envelope studies utilizing two-dimensional (2D) magnetic resonance (MR) thermometry have previously been performed to determine the regions in which therapeutic levels of FUS can currently be delivered. Since 2D MR thermometry was used, very limited information about unintended heating in near-field tissue/bone interfaces could be deduced. Methods In this paper, we present a proof-of-concept treatment envelope study with three-dimensional (3D) MR thermometry monitoring of FUS heatings performed in a phantom and a lamb model. While the moderate-sized transducer used was not designed for transcranial geometries, the 3D temperature maps enable monitoring of the entire sonication field of view, including both the focal spot and near-field tissue/bone interfaces, for full characterization of all heating that may occur. 3D MR thermometry is achieved by a combination of k-space subsampling and a previously described temporally constrained reconstruction method. Results We present two different types of treatment envelopes. The first is based only on the focal spot heating—the type that can be derived from 2D MR thermometry. The second type is based on the relative near-field heating and is calculated as the ratio between the focal spot heating and the near-field heating. This utilizes the full 3D MR thermometry data achieved in this study. Conclusions It is shown that 3D MR thermometry can be used to improve the safety assessment in treatment envelope evaluations. Using a non-optimal transducer, it is shown that some regions where therapeutic levels of FUS can be delivered, as suggested by the first type of envelope, are not necessarily safely treated due to the amount of unintended near-field heating occurring. The results presented in this study highlight the need for 3D MR thermometry in tcMRgFUS. PMID:25343028

FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis

PubMed Central

Deng, Han-Xiang; Zhai, Hong; Bigio, Eileen H.; Yan, Jianhua; Fecto, Faisal; Ajroud, Kaouther; Mishra, Manjari; Ajroud-Driss, Senda; Heller, Scott; Sufit, Robert; Siddique, Nailah; Mugnaini, Enrico; Siddique, Teepu

2014-01-01

Objective Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration. Most cases of ALS are sporadic (SALS), but about 5-10% of ALS cases are familial (FALS). Recent studies have shown that mutations in FUS are causal in approximately 4-5% of FALS and some apparent SALS cases. The pathogenic mechanism of the mutant FUS-mediated ALS and potential roles of FUS in non-FUS ALS remain to be investigated. Methods Immunostaining was performed on postmortem spinal cords from 78 ALS cases, including SALS (n=52), ALS with dementia (ALS/dementia, n=10) and FALS (n=16). In addition, postmortem brains or spinal cords from 22 cases with or without frontotemporal lobar degeneration (FTLD) were also studied. In total, 100 cases were studied. Results FUS-immunoreactive inclusions were observed in spinal anterior horn neurons in all sporadic and familial ALS cases, except for those with SOD1 mutations. The FUS-containing inclusions were also immunoreactive with antibodies to TDP43, p62 and ubiquitin. A fraction of tested FUS antibodies recognized FUS inclusions and an unusual antigen retrieval appeared to be important for detection of the skein-like FUS inclusions. Interpretation Although mutations in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be a common component of the cellular inclusions in non-SOD1 ALS and some other neurodegenerative conditions, implying a shared pathogenic pathway underlying SALS, non-SOD1 FALS, ALS/dementia and related disorders. Our data also indicate that SOD1-linked ALS may have a distinct pathogenic pathway from SALS and other types of FALS. PMID:20517935

Fast Numerical Simulation of Focused Ultrasound Treatments During Respiratory Motion With Discontinuous Motion Boundaries.

PubMed

Schwenke, Michael; Georgii, Joachim; Preusser, Tobias

2017-07-01

Focused ultrasound (FUS) is rapidly gaining clinical acceptance for several target tissues in the human body. Yet, treating liver targets is not clinically applied due to a high complexity of the procedure (noninvasiveness, target motion, complex anatomy, blood cooling effects, shielding by ribs, and limited image-based monitoring). To reduce the complexity, numerical FUS simulations can be utilized for both treatment planning and execution. These use-cases demand highly accurate and computationally efficient simulations. We propose a numerical method for the simulation of abdominal FUS treatments during respiratory motion of the organs and target. Especially, a novel approach is proposed to simulate the heating during motion by solving Pennes' bioheat equation in a computational reference space, i.e., the equation is mathematically transformed to the reference. The approach allows for motion discontinuities, e.g., the sliding of the liver along the abdominal wall. Implementing the solver completely on the graphics processing unit and combining it with an atlas-based ultrasound simulation approach yields a simulation performance faster than real time (less than 50-s computing time for 100 s of treatment time) on a modern off-the-shelf laptop. The simulation method is incorporated into a treatment planning demonstration application that allows to simulate real patient cases including respiratory motion. The high performance of the presented simulation method opens the door to clinical applications. The methods bear the potential to enable the application of FUS for moving organs.

Numerical study on microbubble-enhanced heating for various parameters in EUS-FUS

NASA Astrophysics Data System (ADS)

Okita, Kohei; Maezawa, Miyuki; Takagi, Shu; Matsumoto, Yoichiro

2012-11-01

Endoscopic ultrasonography guided focused ultrasound surgery (EUS-FUS) have been developed as a less-invasive treatment for pancreatic cancer. In the present study, microbubble-enhanced heating for various parameters in EUS-FUS is investigated numerically. Mass and momentum equations for bubbly mixture are solved to reproduce the propagation of ultrasound of 4.8MHz through the gel containing microbubbles as Sonazoid®. The dynamics of bubble is governed by the equation which considers the elasticity of both shell and surrounding media. Additionally, the heat equation with the time averaged heat source is solved to obtain a temperature distribution. The basic equations are discretized by the 6th-order finite difference method and developed based on FDTD method. The mixture and bubbles are coupled by Euler-Lagrange method. As the results, the temperature around the target increased due to the microbubble oscillation with increasing the initial void fraction fG0 from 10-5 to 10-4%. However, at fG0=10-3%, ultrasounds were too attenuated to heat the target. The heating region moved from the target to the transducer side. By comparing the results with and without shell, the shell of bubble induced the heating around focus. This is because the decrease of the attenuation due to the elasticity of the shell and the increase of the viscous dissipation rate due to the viscosity of the shell.

Position-specific binding of FUS to nascent RNA regulates mRNA length

PubMed Central

Masuda, Akio; Takeda, Jun-ichi; Okuno, Tatsuya; Okamoto, Takaaki; Ohkawara, Bisei; Ito, Mikako; Ishigaki, Shinsuke; Sobue, Gen

2015-01-01

More than half of all human genes produce prematurely terminated polyadenylated short mRNAs. However, the underlying mechanisms remain largely elusive. CLIP-seq (cross-linking immunoprecipitation [CLIP] combined with deep sequencing) of FUS (fused in sarcoma) in neuronal cells showed that FUS is frequently clustered around an alternative polyadenylation (APA) site of nascent RNA. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) of RNA polymerase II (RNAP II) demonstrated that FUS stalls RNAP II and prematurely terminates transcription. When an APA site is located upstream of an FUS cluster, FUS enhances polyadenylation by recruiting CPSF160 and up-regulates the alternative short transcript. In contrast, when an APA site is located downstream from an FUS cluster, polyadenylation is not activated, and the RNAP II-suppressing effect of FUS leads to down-regulation of the alternative short transcript. CAGE-seq (cap analysis of gene expression [CAGE] combined with deep sequencing) and PolyA-seq (a strand-specific and quantitative method for high-throughput sequencing of 3' ends of polyadenylated transcripts) revealed that position-specific regulation of mRNA lengths by FUS is operational in two-thirds of transcripts in neuronal cells, with enrichment in genes involved in synaptic activities. PMID:25995189

Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy.

PubMed

Santos, Marc A; Goertz, David E; Hynynen, Kullervo

2017-01-01

The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo . A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.

Real-time control of focused ultrasound heating based on rapid MR thermometry.

PubMed

Vimeux, F C; De Zwart, J A; Palussiére, J; Fawaz, R; Delalande, C; Canioni, P; Grenier, N; Moonen, C T

1999-03-01

Real-time control of the heating procedure is essential for hyperthermia applications of focused ultrasound (FUS). The objective of this study is to demonstrate the feasibility of MRI-controlled FUS. An automatic control system was developed using a dedicated interface between the MR system control computer and the FUS wave generator. Two algorithms were used to regulate FUS power to maintain the focal point temperature at a desired level. Automatic control of FUS power level was demonstrated ex vivo at three target temperature levels (increase of 5 degrees C, 10 degrees C, and 30 degrees C above room temperature) during 30-minute hyperthermic periods. Preliminary in vivo results on rat leg muscle confirm that necrosis estimate, calculated on-line during FUS sonication, allows prediction of tissue damage. CONCLUSIONS. The feasibility of fully automatic FUS control based on MRI thermometry has been demonstrated.

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

PubMed

Qamar, Seema; Wang, GuoZhen; Randle, Suzanne J; Ruggeri, Francesco Simone; Varela, Juan A; Lin, Julie Qiaojin; Phillips, Emma C; Miyashita, Akinori; Williams, Declan; Ströhl, Florian; Meadows, William; Ferry, Rodylyn; Dardov, Victoria J; Tartaglia, Gian G; Farrer, Lindsay A; Kaminski Schierle, Gabriele S; Kaminski, Clemens F; Holt, Christine E; Fraser, Paul E; Schmitt-Ulms, Gerold; Klenerman, David; Knowles, Tuomas; Vendruscolo, Michele; St George-Hyslop, Peter

2018-04-19

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

MR-guided pulsed high intensity focused ultrasound enhancement of docetaxel combined with radiotherapy for prostate cancer treatment

NASA Astrophysics Data System (ADS)

Mu, Zhaomei; Ma, C.-M.; Chen, Xiaoming; Cvetkovic, Dusica; Pollack, Alan; Chen, Lili

2012-01-01

The purpose of this study is to evaluate the efficacy of the enhancement of docetaxel by pulsed focused ultrasound (pFUS) in combination with radiotherapy (RT) for treatment of prostate cancer in vivo. LNCaP cells were grown in the prostates of male nude mice. When the tumors reached a designated volume by MRI, tumor bearing mice were randomly divided into seven groups (n = 5): (1) pFUS alone; (2) RT alone; (3) docetaxel alone; (4) docetaxel + pFUS (5) docetaxel + RT (6) docetaxel + pFUS + RT, and (7) control. MR-guided pFUS treatment was performed using a focused ultrasound treatment system (InSightec ExAblate 2000) with a 1.5T GE MR scanner. Animals were treated once with pFUS, docetaxel, RT or their combinations. Docetaxel was given by i.v. injection at 5 mg kg-1 before pFUS. RT was given 2 Gy after pFUS. Animals were euthanized 4 weeks after treatment. Tumor volumes were measured on MRI at 1 and 4 weeks post-treatment. Results showed that triple combination therapies of docetaxel, pFUS and RT provided the most significant tumor growth inhibition among all groups, which may have potential for the treatment of prostate cancer due to an improved therapeutic ratio.

The prion-like domain of FUS is multiphosphorylated following DNA damage without altering nuclear localization.

PubMed

Rhoads, Shannon N; Monahan, Zachary T; Yee, Debra S; Leung, Andrew Y; Newcombe, Cameron G; O'Meally, Robert N; Cole, Robert N; Shewmaker, Frank P

2018-06-13

FUS is an abundant, predominantly nuclear protein involved in RNA processing. Under various conditions, FUS functionally associates with RNA and other macromolecules to form distinct, reversible phase-separated liquid structures. Persistence of the phase-separated state and increased cytoplasmic localization are both hypothesized to predispose FUS to irreversible aggregation, which is a pathological hallmark of subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. We previously showed that phosphorylation of FUS's prion-like domain suppressed phase separation and toxic aggregation, proportionally to the number of added phosphates. However, phosphorylation of FUS's prion-like domain was previously reported to promote its cytoplasmic localization, potentially favoring pathological behavior. Here, we used mass spectrometry and human cell models to further identify phosphorylation sites within FUS's prion-like domain, specifically following DNA-damaging stress. In total, 28 putative sites have been identified, about half of which are DNA-dependent protein kinase (DNA-PK) consensus sites. Custom antibodies were developed to confirm the phosphorylation of two of these sites (Ser26 and Ser30). Both sites were usually phosphorylated in a sub-population of cellular FUS following a variety of DNA-damaging stresses, but not necessarily equally or simultaneously. Importantly, we found DNA-PK-dependent multi-phosphorylation of FUS's prion-like domain does not cause cytoplasmic localization.

Mutational analysis of FUS gene and its structural and functional role in amyotrophic lateral sclerosis 6.

PubMed

Kamaraj, Balu; Rajendran, Vidya; Sethumadhavan, Rao; Kumar, Chundi Vinay; Purohit, Rituraj

2015-01-01

Amyotrophic lateral sclerosis 6 (ALS6) is an autosomal recessive disorder caused by heterozygous mutation in the Fused in Sarcoma (FUS) gene. ALS6 is a neurodegenerative disorder, which affects the upper and lower motor neurons in the brain and spinal cord, resulting in fatal paralysis. ALS6 is caused by the genetic mutation in the proline/tyrosine-nuclear localization signals of the Fused in sarcoma Protein (FUS). FUS gene also known as TLS (Translocated in liposarcoma), which encodes a protein called RNA-binding protein-Fus (FUS), has a molecular weight of 75 kDa. In this analysis, we applied computational approach to filter the most deleterious and neurodegenerative disease of ALS6-associated mutation on FUS protein. We found H517Q as most deleterious and disease associated using PolyPhen 2.0, I-Mutant 3.0, SIFT, SNPs&GO, PhD-SNP, Pmut, and Mutpred tools. Molecular dynamics simulation (MDS) approach was conducted to investigate conformational changes in the mutant protein structure with respect to its native conformation. MDS results showed the flexibility loss in mutant (H517Q) FUS protein. Due to mutation, FUS protein became more rigid in nature and might alter the structural and functional behavior of protein and play a major role in inducing ALS6. The results obtained from this investigation would help in the field of pharmacogenomics to develop a potent drug target against FUS-associated neurodegenerative diseases.

A Yeast Model of FUS/TLS-Dependent Cytotoxicity

PubMed Central

Ju, Shulin; Tardiff, Daniel F.; Han, Haesun; Divya, Kanneganti; Zhong, Quan; Maquat, Lynne E.; Bosco, Daryl A.; Hayward, Lawrence J.; Brown, Robert H.; Lindquist, Susan; Ringe, Dagmar; Petsko, Gregory A.

2011-01-01

FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression. PMID:21541368

TDP-43/FUS in Motor Neuron Disease: Complexity and Challenges

PubMed Central

Mitra, Joy; Hegde, Pavana M.; Stowell, Sara E.; Liachko, Nicole F; Kraemer, Brian C.; Garruto, Ralph M.; Rao, K. S.; Hegde, Muralidhar L.

2016-01-01

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases. PMID:27693252

Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

PubMed

Kim, Hyungmin; Taghados, Seyed Javid; Fischer, Krisztina; Maeng, Lee-So; Park, Shinsuk; Yoo, Seung-Schik

2012-09-01

Nonpharmacologic and nonsurgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36-msec tone burst duration (TBD), 1.5-kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histologic and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB), as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential for diagnostic and therapeutic applications in diseases of the peripheral nervous system. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

HIFU Monitoring and Control with Dual-Mode Ultrasound Arrays

NASA Astrophysics Data System (ADS)

Casper, Andrew Jacob

The biological effects of high-intensity focused ultrasound (HIFU) have been known and studied for decades. HIFU has been shown capable of treating a wide variety of diseases and disorders. However, despite its demonstrated potential, HIFU has been slow to gain clinical acceptance. This is due, in part, to the difficulty associated with robustly monitoring and controlling the delivery of the HIFU energy. The non-invasive nature of the surgery makes the assessment of treatment progression difficult, leading to long treatment times and a significant risk of under treatment. This thesis research develops new techniques and systems for robustly monitoring HIFU therapies for the safe and efficacious delivery of the intended treatment. Systems and algorithms were developed for the two most common modes of HIFU delivery systems: single-element and phased array applicators. Delivering HIFU with a single element transducer is a widely used technique in HIFU therapies. The simplicity of a single element offers many benefits in terms of cost and overall system complexity. Typical monitoring schemes rely on an external device (e.g. diagnostic ultrasound or MRI) to assess the progression of therapy. The research presented in this thesis explores using the same element to both deliver and monitor the HIFU therapy. The use of a dual-mode ultrasound transducer (DMUT) required the development of an FPGA based single-channel arbitrary waveform generator and high-speed data acquisition unit. Data collected from initial uncontrolled ablations led to the development of monitoring and control algorithms which were implemented directly on the FPGA. Close integration between the data acquisition and arbitrary waveform units allowed for fast, low latency control over the ablation process. Results are presented that demonstrate control of HIFU therapies over a broad range of intensities and in multiple in vitro tissues. The second area of investigation expands the DMUT research to an ultrasound phased-array. The phased-array allows for electronic steering of the HIFU focus and imaging of the acoustic medium. Investigating the dual-mode ultrasound array (DMUA) required the design and construction of a novel ultrasound-guided focused ultrasound (USgFUS) platform. The platform consisted of custom hardware designed for the unique requirements of operating a phased-array in both therapeutic and imaging modes. The platform also required the development of FPGA based signal processing and GPU based beamforming algorithms for online monitoring of the therapy process. The results presented in this thesis represent the first demonstration of a real-time USgFUS platform based around a DMUA. Experimental imaging and therapy results from series of animal experiments, including a 12 animal GLP study, are presented. In addition, in vitro control results, which build upon the DMUT work, are presented.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Meng; Cao, Xia; Jia, Qingli

Triacylglycerol (TAG) is the main storage lipid in plant seeds and the major form of plant oil used for food and, increasingly, for industrial and biofuel applications. Several transcription factors, including FUSCA3 (At3 g26790, FUS3), are associated with embryo maturation and oil biosynthesis in seeds. However, the ability of FUS3 to increase TAG biosynthesis in other tissues has not been quantitatively examined. Here, we evaluated the ability of FUS3 to activate TAG accumulation in non-seed tissues. Overexpression of FUS3 driven by an estradiol-inducible promoter increased oil contents in Arabidopsis seedlings up to 6% of dry weight; more than 50-fold overmore » controls. Eicosenoic acid, a characteristic fatty acid of Arabidopsis seed oil, accumulated to over 20% of fatty acids in cotyledons and leaves. These large increases depended on added sucrose, although without sucrose TAG increased three- to four-fold. Inducing the expression of FUS3 in tobacco BY2 cells also increased TAG accumulation, and co-expression of FUS3 and diacylglycerol acyltransferase 1 (DGAT1) further increased TAG levels to 4% of dry weight. BY2 cell growth was not altered by FUS3 expression, although Arabidopsis seedling development was impaired, consistent with the ability of FUS3 to induce embryo characteristics in non-seed tissues. Microarrays of Arabidopsis seedlings revealed that FUS3 overexpression increased the expression of a higher proportion of genes involved in TAG biosynthesis than genes involved in fatty acid biosynthesis or other lipid pathways. Together these results provide additional insights into FUS3 functions in TAG metabolism and suggest complementary strategies for engineering vegetative oil accumulation.« less

Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Zi Chao; Chook, Yuh Min

Mutations in the proline/tyrosine–nuclear localization signal (PY-NLS) of the Fused in Sarcoma protein (FUS) cause amyotrophic lateral sclerosis (ALS). Here we report the crystal structure of the FUS PY-NLS bound to its nuclear import receptor Karyopherinβ2 (Kapβ2; also known as Transportin). The FUS PY-NLS occupies the structurally invariant C-terminal arch of Kapβ2, tracing a path similar to that of other characterized PY-NLSs. Unlike other PY-NLSs, which generally bind Kapβ2 in fully extended conformations, the FUS peptide is atypical as its central portion forms a 2.5-turn α-helix. The Kapβ2-binding epitopes of the FUS PY-NLS consist of an N-terminal PGKM hydrophobic motif,more » a central arginine-rich α-helix, and a C-terminal PY motif. ALS mutations are found almost exclusively within these epitopes. Each ALS mutation site makes multiple contacts with Kapβ2 and mutations of these residues decrease binding affinities for Kapβ2 (K D for wild-type FUS PY-NLS is 9.5 nM) up to ninefold. Thermodynamic analyses of ALS mutations in the FUS PY-NLS show that the weakening of FUS-Kapβ2 binding affinity, the degree of cytoplasmic mislocalization, and ALS disease severity are correlated.« less

PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

PubMed Central

Rulten, Stuart L.; Rotheray, Amy; Green, Ryan L.; Grundy, Gabrielle J.; Moore, Duncan A. Q.; Gómez-Herreros, Fernando; Hafezparast, Majid; Caldecott, Keith W

2014-01-01

Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUSR521G, harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS. PMID:24049082

Autophagy meets fused in sarcoma-positive stress granules.

PubMed

Matus, Soledad; Bosco, Daryl A; Hetz, Claudio

2014-12-01

Mutations in fused in sarcoma and/or translocated in liposarcoma (FUS, TLS or FUS) are linked to familial cases of amyotrophic lateral sclerosis (ALS). Mutant FUS selectively accumulates into discrete cytosolic structures known as stress granules under various stress conditions. In addition, mutant FUS expression can alter the dynamics and morphology of stress granules. Although the link between mutant FUS and stress granules is well established, the mechanisms modulating stress granule formation and disassembly in the context of ALS are poorly understood. In this issue of Neurobiology of Aging, Ryu et al. uncover the impact of autophagy on the potential toxicity of mutant FUS-positive stress granules. The authors provide evidence indicating that enhanced autophagy activity reduces the number of stress granules, which in the case of cells containing mutant FUS-positive stress granules, is neuroprotective. Overall, this study identifies an intersection between the proteostasis network and alterations in RNA metabolism in ALS through the dynamic assembly and disassembly of stress granules. Copyright © 2014 Elsevier Inc. All rights reserved.

FET Proteins TAF15 and EWS Are Selective Markers that Distinguish FTLD with FUS Pathology from Amyotrophic Lateral Sclerosis with "FUS" Mutations

ERIC Educational Resources Information Center

Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A.; Munoz, David G.; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R. A.

2011-01-01

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in "FUS" as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with "FUS" mutations. The mechanisms…

Overlapping and distinct roles of AKIN10 and FUSCA3 in ABA and sugar signaling during seed germination.

PubMed

Tsai, Allen Yi-Lun; Gazzarrini, Sonia

2012-10-01

The Arabidopsis B3-domain transcription factor FUSCA3 (FUS3) is a master regulator of seed maturation and also a central modulator of hormonal responses during late embryogenesis and germination. Recently, we have identified AKIN10, the Arabidopsis ortholog of Snf1 (Sucrose Non-Fermenting-1)-Related Kinase1 (SnRK1), as a FUS3-interacting protein. We demonstrated that AKIN10 physically interacts with and phosphorylates FUS3 at its N-terminal region, and genetically interacts with FUS3 to regulate developmental phase transition and lateral organ growth. Snf1/AMPK/SnRK1 kinases are important sensors of the cellular energy level, and they are activated in response to starvation and cellular stress. Here we present findings that indicate FUS3 and AKIN10 functionally overlap in ABA signaling, but play different roles in sugar responses during germination. Seeds overexpressing FUS3 and AKIN10 both display ABA-hypersensitivity and delayed germination. The latter is partly dependent on de novo ABA synthesis in both genotypes, as delayed germination can be partially rescued by the ABA biosynthesis inhibitor, fluridone. However, seeds and seedlings overexpressing FUS3 and AKIN10 show different sugar responses. AKIN10-overexpressing seeds and seedlings are hypersensitive to glucose, while those overexpressing FUS3 display overall defects in osmotic stress, primarily during seedling growth, as they show increased sensitivity toward sorbitol and glucose. Hypersensitivity to sugar and/or osmotic stress during germination are partly dependent on de novo ABA synthesis for both genotypes, although are likely to act through distinct pathways. This data suggests that AKIN10 and FUS3 both act as positive regulators of seed responses to ABA, and that AKIN10 regulates sugar signaling while FUS3 mediates osmotic stress responses.

FUSCA3 activates triacylglycerol accumulation in Arabidopsis seedlings and tobacco BY2 cells

DOE PAGES

Zhang, Meng; Cao, Xia; Jia, Qingli; ...

2016-06-11

Triacylglycerol (TAG) is the main storage lipid in plant seeds and the major form of plant oil used for food and, increasingly, for industrial and biofuel applications. Several transcription factors, including FUSCA3 (At3 g26790, FUS3), are associated with embryo maturation and oil biosynthesis in seeds. However, the ability of FUS3 to increase TAG biosynthesis in other tissues has not been quantitatively examined. Here, we evaluated the ability of FUS3 to activate TAG accumulation in non-seed tissues. Overexpression of FUS3 driven by an estradiol-inducible promoter increased oil contents in Arabidopsis seedlings up to 6% of dry weight; more than 50-fold overmore » controls. Eicosenoic acid, a characteristic fatty acid of Arabidopsis seed oil, accumulated to over 20% of fatty acids in cotyledons and leaves. These large increases depended on added sucrose, although without sucrose TAG increased three- to four-fold. Inducing the expression of FUS3 in tobacco BY2 cells also increased TAG accumulation, and co-expression of FUS3 and diacylglycerol acyltransferase 1 (DGAT1) further increased TAG levels to 4% of dry weight. BY2 cell growth was not altered by FUS3 expression, although Arabidopsis seedling development was impaired, consistent with the ability of FUS3 to induce embryo characteristics in non-seed tissues. Microarrays of Arabidopsis seedlings revealed that FUS3 overexpression increased the expression of a higher proportion of genes involved in TAG biosynthesis than genes involved in fatty acid biosynthesis or other lipid pathways. Together these results provide additional insights into FUS3 functions in TAG metabolism and suggest complementary strategies for engineering vegetative oil accumulation.« less

FUSCA3 activates triacylglycerol accumulation in Arabidopsis seedlings and tobacco BY2 cells.

PubMed

Zhang, Meng; Cao, Xia; Jia, Qingli; Ohlrogge, John

2016-10-01

Triacylglycerol (TAG) is the main storage lipid in plant seeds and the major form of plant oil used for food and, increasingly, for industrial and biofuel applications. Several transcription factors, including FUSCA3 (At3 g26790, FUS3), are associated with embryo maturation and oil biosynthesis in seeds. However, the ability of FUS3 to increase TAG biosynthesis in other tissues has not been quantitatively examined. Here, we evaluated the ability of FUS3 to activate TAG accumulation in non-seed tissues. Overexpression of FUS3 driven by an estradiol-inducible promoter increased oil contents in Arabidopsis seedlings up to 6% of dry weight; more than 50-fold over controls. Eicosenoic acid, a characteristic fatty acid of Arabidopsis seed oil, accumulated to over 20% of fatty acids in cotyledons and leaves. These large increases depended on added sucrose, although without sucrose TAG increased three- to four-fold. Inducing the expression of FUS3 in tobacco BY2 cells also increased TAG accumulation, and co-expression of FUS3 and diacylglycerol acyltransferase 1 (DGAT1) further increased TAG levels to 4% of dry weight. BY2 cell growth was not altered by FUS3 expression, although Arabidopsis seedling development was impaired, consistent with the ability of FUS3 to induce embryo characteristics in non-seed tissues. Microarrays of Arabidopsis seedlings revealed that FUS3 overexpression increased the expression of a higher proportion of genes involved in TAG biosynthesis than genes involved in fatty acid biosynthesis or other lipid pathways. Together these results provide additional insights into FUS3 functions in TAG metabolism and suggest complementary strategies for engineering vegetative oil accumulation. © 2016 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.

Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUS(P525L) mutation.

PubMed

Aizawa, Hitoshi; Hideyama, Takuto; Yamashita, Takenari; Kimura, Takashi; Suzuki, Naoki; Aoki, Masashi; Kwak, Shin

2016-10-01

Mutations in the fused in sarcoma (FUS) gene can cause amyotrophic lateral sclerosis (ALS), and FUS gene mutations have been reported in sporadic ALS patients with basophilic cytoplasmic inclusions. Deficiency of adenosine deaminase acting on RNA 2 (ADAR2), an enzyme that specifically catalyzes GluA2 Q/R site-editing, has been reported in considerable proportions of spinal motor neurons of the majority of sporadic ALS patients. We describe the relationship between GluA2 Q/R site-editing efficiency and FUS-positive inclusions in a patient with FUS(P525L). A 24-year-old woman with ALS presented with basophilic cytoplasmic inclusions, significantly reduced GluA2 Q/R site-editing efficiency in the spinal motor neurons, and markedly decreased ADAR2 mRNA levels. Neuropathologic examination showed that not all spinal motor neurons expressed ADAR2 and revealed FUS-positive cytoplasmic inclusions in motor neurons irrespective of ADAR2 immunoreactivity. There were no phosphorylated transactive response (TAR) DNA-binding protein 43 kDa (TDP-43)-positive inclusions, indicating that there was no tight correlation between ADAR2 deficiency and TDP-43 deposition. ADAR2 deficiency can occur in ALS patients with a FUS(P525L) mutation and is unrelated to the presence of FUS-positive inclusions. FUS-associated ALS may share neurodegenerative characteristics with classical sporadic ALS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification and regulation of fusA, the polyketide synthase gene responsible for fusarin production in Fusarium fujikuroi.

PubMed

Díaz-Sánchez, Violeta; Avalos, Javier; Limón, M Carmen

2012-10-01

Fusarins are a class of mycotoxins of the polyketide family produced by different Fusarium species, including the gibberellin-producing fungus Fusarium fujikuroi. Based on sequence comparisons between polyketide synthase (PKS) enzymes for fusarin production in other Fusarium strains, we have identified the F. fujikuroi orthologue, called fusA. The participation of fusA in fusarin biosynthesis was demonstrated by targeted mutagenesis. Fusarin production is transiently stimulated by nitrogen availability in this fungus, a regulation paralleled by the fusA mRNA levels in the cell. Illumination of the cultures results in a reduction of the fusarin content, an effect partially explained by a high sensitivity of these compounds to light. Mutants of the fusA gene exhibit no external phenotypic alterations, including morphology and conidiation, except for a lack of the characteristic yellow and/or orange pigmentation of fusarins. Moreover, the fusA mutants are less efficient than the wild type at degrading cellophane on agar cultures, a trait associated with pathogenesis functions in Fusarium oxysporum. The fusA mutants, however, are not affected in their capacities to grow on plant tissues.

Acoustic Cavitation-Based Monitoring of the Reversibility and Permeability of Ultrasound-Induced Blood-Brain Barrier Opening

PubMed Central

Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C.; Konofagou, Elisa E.

2015-01-01

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n = 60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 days thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: 1) the duration of the BBB opening (r2 = 0.77); 2) the permeability of the opened BBB (r2 = 0.82); 3) the likelihood of safe opening (P < 0.05, safe opening compared to cases of damage; P < 0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r2 = 0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug circulation time. In addition, avoiding adverse effects in the brain and assessing the pharmacokinetics of the compounds delivered can also be achieved by monitoring and controlling the stable cavitation emissions. PMID:26562661

Phenotypic variability within the inclusion body spectrum of basophilic inclusion body disease and neuronal intermediate filament inclusion disease in frontotemporal lobar degenerations with FUS-positive inclusions.

PubMed

Gelpi, Ellen; Lladó, Albert; Clarimón, Jordi; Rey, Maria Jesús; Rivera, Rosa Maria; Ezquerra, Mario; Antonell, Anna; Navarro-Otano, Judith; Ribalta, Teresa; Piñol-Ripoll, Gerard; Pérez, Anna; Valldeoriola, Francesc; Ferrer, Isidre

2012-09-01

Basophilic inclusion body disease and neuronal intermediate filament inclusion disease (NIFID) are rare diseases included among frontotemporal lobar degenerations with FUS-positive inclusions (FTLD-FUS). We report clinical and pathologic features of 2 new patients and reevaluate neuropathologic characteristics of 2 previously described cases, including an early-onset case of basophilic inclusion body disease (aged 38 years) with a 5-year disease course and abundant FUS-positive inclusion bodies and 3 NIFID cases. One NIFID case (aged 37 years) presented with early-onset psychiatric disturbances and rapidly progressive cognitive decline. Two NIFID cases had later onset (aged 64 years and 70 years) and complex neurologic deficits. Postmortem neuropathologic studies in late-onset NIFID cases disclosed α-internexin-positive "hyaline conglomerate"-type inclusions that were positive with 1 commercial anti-FUS antibody directed to residues 200 and 250, but these were negative to amino acids 90 and 220 of human FUS. Early-onset NIFID had similar inclusions that were positive with both commercial anti-FUS antibodies. Genetic testing performed on all cases revealed no FUS gene mutations. These findings indicate that phenotypic variability in NIFID, including clinical manifestations and particular neuropathologic findings, may be related to the age at onset and individual differences in the evolution of lesions.

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.

PubMed

Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid; Zhu, Yueming; Goodwin, J Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston J T; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V

2017-03-26

Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.

FUS and TDP43 genetic variability in FTD and CBS

PubMed Central

Huey, Edward D.; Ferrari, Raffaele; Moreno, Jorge H.; Jensen, Christopher; Morris, Christopher M.; Potocnik, Felix; Kalaria, Rajesh N.; Tierney, Michael; Wassermann, Eric M.; Hardy, John; Grafman, Jordan; Momeni, Parastoo

2015-01-01

This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180–4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185–4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls. PMID:21943958

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

PubMed Central

Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid; Zhu, Yueming; Goodwin, J. Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston J.T.; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V.

2017-01-01

Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response. Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies. PMID:28351997

Overlapping and distinct roles of AKIN10 and FUSCA3 in ABA and sugar signaling during seed germination

PubMed Central

Tsai, Allen Yi-Lun; Gazzarrini, Sonia

2012-01-01

The Arabidopsis B3-domain transcription factor FUSCA3 (FUS3) is a master regulator of seed maturation and also a central modulator of hormonal responses during late embryogenesis and germination. Recently, we have identified AKIN10, the Arabidopsis ortholog of Snf1 (Sucrose Non-Fermenting-1)–Related Kinase1 (SnRK1), as a FUS3-interacting protein. We demonstrated that AKIN10 physically interacts with and phosphorylates FUS3 at its N-terminal region, and genetically interacts with FUS3 to regulate developmental phase transition and lateral organ growth. Snf1/AMPK/SnRK1 kinases are important sensors of the cellular energy level, and they are activated in response to starvation and cellular stress. Here we present findings that indicate FUS3 and AKIN10 functionally overlap in ABA signaling, but play different roles in sugar responses during germination. Seeds overexpressing FUS3 and AKIN10 both display ABA-hypersensitivity and delayed germination. The latter is partly dependent on de novo ABA synthesis in both genotypes, as delayed germination can be partially rescued by the ABA biosynthesis inhibitor, fluridone. However, seeds and seedlings overexpressing FUS3 and AKIN10 show different sugar responses. AKIN10-overexpressing seeds and seedlings are hypersensitive to glucose, while those overexpressing FUS3 display overall defects in osmotic stress, primarily during seedling growth, as they show increased sensitivity toward sorbitol and glucose. Hypersensitivity to sugar and/or osmotic stress during germination are partly dependent on de novo ABA synthesis for both genotypes, although are likely to act through distinct pathways. This data suggests that AKIN10 and FUS3 both act as positive regulators of seed responses to ABA, and that AKIN10 regulates sugar signaling while FUS3 mediates osmotic stress responses. PMID:22902692

Quantification of transient increase of the blood–brain barrier permeability to macromolecules by optimized focused ultrasound combined with microbubbles

PubMed Central

Shi, Lingyan; Palacio-Mancheno, Paolo; Badami, Joseph; Shin, Da Wi; Zeng, Min; Cardoso, Luis; Tu, Raymond; Fu, Bingmei M

2014-01-01

Radioimmunotherapy using a radiolabeled monoclonal antibody that targets tumor cells has been shown to be efficient for the treatment of many malignant cancers, with reduced side effects. However, the blood–brain barrier (BBB) inhibits the transport of intravenous antibodies to tumors in the brain. Recent studies have demonstrated that focused ultrasound (FUS) combined with microbubbles (MBs) is a promising method to transiently disrupt the BBB for the drug delivery to the central nervous system. To find the optimal FUS and MBs that can induce reversible increase in the BBB permeability, we employed minimally invasive multiphoton microscopy to quantify the BBB permeability to dextran-155 kDa with similar molecular weight to an antibody by applying different doses of FUS in the presence of MBs with an optimal size and concentration. The cerebral microcirculation was observed through a section of frontoparietal bone thinned with a micro-grinder. About 5 minutes after applying the FUS on the thinned skull in the presence of MBs for 1 minute, TRITC (tetramethylrhodamine isothiocyanate)-dextran-155 kDa in 1% bovine serum albumin in mammalian Ringer’s solution was injected into the cerebral circulation via the ipsilateral carotid artery by a syringe pump. Simultaneously, the temporal images were collected from the brain parenchyma ~100–200 μm below the pia mater. Permeability was determined from the rate of tissue solute accumulation around individual microvessels. After several trials, we found the optimal dose of FUS. At the optimal dose, permeability increased by ~14-fold after 5 minutes post-FUS, and permeability returned to the control level after 25 minutes. FUS without MBs or MBs injected without FUS did not change the permeability. Our method provides an accurate in vivo assessment for the transient BBB permeability change under the treatment of FUS. The optimal FUS dose found for the reversible BBB permeability increase without BBB disruption is reliable and can be applied to future clinical trials. PMID:25258533

Inhibition of FUSCA3 degradation at high temperature is dependent on ABA signaling and is regulated by the ABA/GA ratio.

PubMed

Chiu, Rex Shun; Saleh, Yazan; Gazzarrini, Sonia

2016-11-01

During seed imbibition at supra-optimal temperature, an increase in the abscisic acid (ABA)/gibberellin (GA) ratio imposes secondary dormancy to prevent germination (thermoinhibition). FUSCA3 (FUS3), a positive regulator of seed dormancy, accumulates in seeds imbibed at high temperature and increases ABA levels to inhibit germination. Recently, we showed that ABA inhibits FUS3 degradation at high temperature, and that ABA and high temperature also inhibit the ubiquitin-proteasome system, by dampening both proteasome activity and protein polyubiquitination. Here, we investigated the role of ABA signaling components and the ABA antagonizing hormone, GA, in the regulation of FUS3 levels. We show that the ABA receptor mutant, pyl1-1, is less sensitive to ABA and thermoinhibition. In this mutant background, FUS3 degradation in vitro is faster. Similarly, GA alleviates thermoinhibition and also increases FUS3 degradation. These results indicate that inhibition of FUS3 degradation at high temperature is dependent on a high ABA/GA ratio and a functional ABA signaling pathway. Thus, FUS3 constitutes an important node in ABA-GA crosstalk during germination at supra-optimal temperature.

MRI-Guided Focused Ultrasound as a New Method of Drug Delivery

PubMed Central

Thanou, M.; Gedroyc, W.

2013-01-01

Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. PMID:23738076

Targeted delivery of erythropoietin by transcranial focused ultrasound for neuroprotection against ischemia/reperfusion-induced neuronal injury: a long-term and short-term study.

PubMed

Wu, Sheng-Kai; Yang, Ming-Tao; Kang, Kai-Hsiang; Liou, Houng-Chi; Lu, Dai-Hua; Fu, Wen-Mei; Lin, Win-Li

2014-01-01

Erythropoietin (EPO) is a neuroprotective agent against cerebral ischemia/reperfusion (I/R)-induced brain injury. However, its crossing of blood-brain barrier is limited. Focused ultrasound (FUS) sonication with microbubbles (MBs) can effectively open blood-brain barrier to boost the vascular permeability. In this study, we investigated the effects of MBs/FUS on extending the therapeutic time window of EPO and its neuroprotective effects in both acute and chronic phases. Male Wistar rats were firstly subjected to two common carotid arteries and right middle cerebral artery occlusion (three vessels occlusion, 3VO) for 50 min, and then the rats were treated with hEPO (human recombinant EPO, 5000 IU/kg) with or without MBs/FUS at 5 h after occlusion/reperfusion. Acute phase investigation (I/R, I/R+MBs/FUS, I/R+hEPO, and I/R+hEPO+MBs/FUS) was performed 24 h after I/R; chronic tests including cylinder test and gait analysis were performed one month after I/R. The experimental results showed that MBs/FUS significantly increased the cerebral content of EPO by bettering vascular permeability. In acute phase, both significant improvement of neurological score and reduction of infarct volume were found in the I/R+hEPO+MBs/FUS group, as compared with I/R and I/R+hEPO groups. In chronic phase, long-term behavioral recovery and neuronal loss in brain cortex after I/R injury was significantly improved in the I/R+hEPO+MBs/FUS group. This study indicates that hEPO administration with MBs/FUS sonication even at 5 h after occlusion/reperfusion can produce a significant neuroprotection.

FUS GENE MUTATIONS IN FAMILIAL AND SPORADIC AMYOTROPHIC LATERAL SCLEROSIS

PubMed Central

Rademakers, Rosa; Stewart, Heather; DeJesus-Hernandez, Mariely; Krieger, Charles; Graff-Radford, Neill; Fabros, Marife; Briemberg, Hannah; Cashman, Neil; Eisen, Andrew; Mackenzie, Ian R. A.

2010-01-01

Introduction Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). Methods We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. Results In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. Discussion This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS. It suggests there are specific clinicogenetic correlations and provides the first detailed neuropathological description. PMID:20544928

Methylene blue protects against TDP-43 and FUS neuronal toxicity in C. elegans and D. rerio.

PubMed

Vaccaro, Alexandra; Patten, Shunmoogum A; Ciura, Sorana; Maios, Claudia; Therrien, Martine; Drapeau, Pierre; Kabashi, Edor; Parker, J Alex

2012-01-01

The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans and zebrafish animal models expressing mutant human TDP-43 (A315T or G348C) or FUS (S57Δ or R521H) that reflect certain aspects of ALS including motor neuron degeneration, axonal deficits, and progressive paralysis. To explore the potential of our humanized transgenic C. elegans and zebrafish in identifying chemical suppressors of mutant TDP-43 and FUS neuronal toxicity, we tested three compounds with potential neuroprotective properties: lithium chloride, methylene blue and riluzole. We identified methylene blue as a potent suppressor of TDP-43 and FUS toxicity in both our models. Our results indicate that methylene blue can rescue toxic phenotypes associated with mutant TDP-43 and FUS including neuronal dysfunction and oxidative stress.

Methylene Blue Protects against TDP-43 and FUS Neuronal Toxicity in C. elegans and D. rerio

PubMed Central

Vaccaro, Alexandra; Patten, Shunmoogum A.; Ciura, Sorana; Maios, Claudia; Therrien, Martine; Drapeau, Pierre; Kabashi, Edor; Parker, J. Alex

2012-01-01

The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans and zebrafish animal models expressing mutant human TDP-43 (A315T or G348C) or FUS (S57Δ or R521H) that reflect certain aspects of ALS including motor neuron degeneration, axonal deficits, and progressive paralysis. To explore the potential of our humanized transgenic C. elegans and zebrafish in identifying chemical suppressors of mutant TDP-43 and FUS neuronal toxicity, we tested three compounds with potential neuroprotective properties: lithium chloride, methylene blue and riluzole. We identified methylene blue as a potent suppressor of TDP-43 and FUS toxicity in both our models. Our results indicate that methylene blue can rescue toxic phenotypes associated with mutant TDP-43 and FUS including neuronal dysfunction and oxidative stress. PMID:22848727

Clinical Consideration of Treatment to Ablate Uterine Fibroids with Magnetic Resonance Imaging-guided High Intensity Focused Ultrasound (MRgFUS): Sonalleve

PubMed Central

Jeong, Jae-Hyeok; Hong, Gil Pyo; Kim, Yu-Ri; Ha, Jae-Eun

2016-01-01

Objectives Magnetic resonance imaging (MRI)-guided high intensity focused ultrasound surgery (MRgFUS) is a newly emerging non-invasive technique for the treatment of uterine fibroids. The purpose of this study is to review the clinical impact of MRgFUS. Methods This study examined 157 patients. The high intensity focused ultrasound (HIFU) utilized in this study was Philips Achieva 1.5 Tesla MR (Philips Healthcare, Best, the Netherlands) and Sonalleve HIFU system. The patients were followed in post-operative Month 1, Month 3, and Month 6 to investigate any change. Then, these were further classified according to the use of uterine stimulant (oxytocin) in parallel, Funaki Type of uterine fibroid, HIFU intensity, and non-perfused volume (NPV) ratio. Results When the uterine stimulant was utilized, the HIFU intensity was measured at significantly lower levels, compared with the group not using uterine stimulant, and treatment duration was significantly. The NPV ratio was found significantly higher in the group using uterine stimulant. Concerning the correlation between Funaki Type of uterine fibroid and average sonication power, it was found that the closer to Type I, the lower the sonication power, the shorter the treatment duration, and the higher the NPV ratio significantly. Conclusions In this study, it was found that the lower the Funaki Types of uterine fibroids, and the higher the NPV ratio immediately after the operation, the larger the uterine fibroid volume decrease and SSS change were. Also, if uterine stimulant was used in parallel in treatment, treatment duration and HIFU intensity could become shorter and lower. PMID:27617244

Safety and Efficacy of Focused Ultrasound Thalamotomy for Patients With Medication-Refractory, Tremor-Dominant Parkinson Disease: A Randomized Clinical Trial.

PubMed

Bond, Aaron E; Shah, Binit B; Huss, Diane S; Dallapiazza, Robert F; Warren, Amy; Harrison, Madaline B; Sperling, Scott A; Wang, Xin-Qun; Gwinn, Ryder; Witt, Jennie; Ro, Susie; Elias, W Jeffrey

2017-12-01

Clinical trials have confirmed the efficacy of focused ultrasound (FUS) thalamotomy in essential tremor, but its effectiveness and safety for managing tremor-dominant Parkinson disease (TDPD) is unknown. To assess safety and efficacy at 12-month follow-up, accounting for placebo response, of unilateral FUS thalamotomy for patients with TDPD. Of the 326 patients identified from an in-house database, 53 patients consented to be screened. Twenty-six were ineligible, and 27 were randomized (2:1) to FUS thalamotomy or a sham procedure at 2 centers from October18, 2012, to January 8, 2015. The most common reasons for disqualification were withdrawal (8 persons [31%]), and not being medication refractory (8 persons [31%]). Data were analyzed using intention-to-treat analysis, and assessments were double-blinded through the primary outcome. Twenty patients were randomized to unilateral FUS thalamotomy, and 7 to sham procedure. The sham group was offered open-label treatment after unblinding. The predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor (CRST). Secondary outcomes included descriptive results of Unified Parkinson's Disease Rating Scale (UPDRS) scores and quality of life measures. Of the 27 patients, 26 (96%) were male and the median age was 67.8 years (interquartile range [IQR], 62.1-73.8 years). On-medication median tremor scores improved 62% (IQR, 22%-79%) from a baseline of 17 points (IQR, 10.5-27.5) following FUS thalamotomy and 22% (IQR, -11% to 29%) from a baseline of 23 points (IQR, 14.0-27.0) after sham procedures; the between-group difference was significant (Wilcoxon P = .04). On-medication median UPDRS motor scores improved 8 points (IQR, 0.5-11.0) from a baseline of 23 points (IQR, 15.5-34.0) following FUS thalamotomy and 1 point (IQR, -5.0 to 9.0) from a baseline of 25 points (IQR, 15.0-33.0) after sham procedures. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (4 events [20%]), finger paresthesia (1 event [5%]), and ataxia (1 event [5%]). Focused ultrasound thalamotomy for patients with TDPD demonstrated improvements in medication-refractory tremor by CRST assessments, even in the setting of a placebo response. ClinicalTrials.gov identifier NCT01772693.

Low-Pressure Burst-Mode Focused Ultrasound Wave Reconstruction and Mapping for Blood-Brain Barrier Opening: A Preclinical Examination

PubMed Central

Xia, Jingjing; Tsui, Po-Hsiang; Liu, Hao-Li

2016-01-01

Burst-mode focused ultrasound (FUS) exposure has been shown to induce transient blood-brain barrier (BBB) opening for potential CNS drug delivery. FUS-BBB opening requires imaging guidance during the intervention, yet current imaging technology only enables postoperative outcome confirmation. In this study, we propose an approach to visualize short-burst low-pressure focal beam distribution that allows to be applied in FUS-BBB opening intervention on small animals. A backscattered acoustic-wave reconstruction method based on synchronization among focused ultrasound emission, diagnostic ultrasound receiving and passively beamformed processing were developed. We observed that focal beam could be successfully visualized for in vitro FUS exposure with 0.5–2 MHz without involvement of microbubbles. The detectable level of FUS exposure was 0.467 MPa in pressure and 0.05 ms in burst length. The signal intensity (SI) of the reconstructions was linearly correlated with the FUS exposure level both in-vitro (r2 = 0.9878) and in-vivo (r2 = 0.9943), and SI level of the reconstructed focal beam also correlated with the success and level of BBB-opening. The proposed approach provides a feasible way to perform real-time and closed-loop control of FUS-based brain drug delivery. PMID:27295608

Low-Pressure Burst-Mode Focused Ultrasound Wave Reconstruction and Mapping for Blood-Brain Barrier Opening: A Preclinical Examination

NASA Astrophysics Data System (ADS)

Xia, Jingjing; Tsui, Po-Hsiang; Liu, Hao-Li

2016-06-01

Burst-mode focused ultrasound (FUS) exposure has been shown to induce transient blood-brain barrier (BBB) opening for potential CNS drug delivery. FUS-BBB opening requires imaging guidance during the intervention, yet current imaging technology only enables postoperative outcome confirmation. In this study, we propose an approach to visualize short-burst low-pressure focal beam distribution that allows to be applied in FUS-BBB opening intervention on small animals. A backscattered acoustic-wave reconstruction method based on synchronization among focused ultrasound emission, diagnostic ultrasound receiving and passively beamformed processing were developed. We observed that focal beam could be successfully visualized for in vitro FUS exposure with 0.5-2 MHz without involvement of microbubbles. The detectable level of FUS exposure was 0.467 MPa in pressure and 0.05 ms in burst length. The signal intensity (SI) of the reconstructions was linearly correlated with the FUS exposure level both in-vitro (r2 = 0.9878) and in-vivo (r2 = 0.9943), and SI level of the reconstructed focal beam also correlated with the success and level of BBB-opening. The proposed approach provides a feasible way to perform real-time and closed-loop control of FUS-based brain drug delivery.

The role of the Arabidopsis FUSCA3 transcription factor during inhibition of seed germination at high temperature.

PubMed

Chiu, Rex S; Nahal, Hardeep; Provart, Nicholas J; Gazzarrini, Sonia

2012-01-27

Imbibed seeds integrate environmental and endogenous signals to break dormancy and initiate growth under optimal conditions. Seed maturation plays an important role in determining the survival of germinating seeds, for example one of the roles of dormancy is to stagger germination to prevent mass growth under suboptimal conditions. The B3-domain transcription factor FUSCA3 (FUS3) is a master regulator of seed development and an important node in hormonal interaction networks in Arabidopsis thaliana. Its function has been mainly characterized during embryonic development, where FUS3 is highly expressed to promote seed maturation and dormancy by regulating ABA/GA levels. In this study, we present evidence for a role of FUS3 in delaying seed germination at supraoptimal temperatures that would be lethal for the developing seedlings. During seed imbibition at supraoptimal temperature, the FUS3 promoter is reactivated and induces de novo synthesis of FUS3 mRNA, followed by FUS3 protein accumulation. Genetic analysis shows that FUS3 contributes to the delay of seed germination at high temperature. Unlike WT, seeds overexpressing FUS3 (ML1:FUS3-GFP) during imbibition are hypersensitive to high temperature and do not germinate, however, they can fully germinate after recovery at control temperature reaching 90% seedling survival. ML1:FUS3-GFP hypersensitivity to high temperature can be partly recovered in the presence of fluridone, an inhibitor of ABA biosynthesis, suggesting this hypersensitivity is due in part to higher ABA level in this mutant. Transcriptomic analysis shows that WT seeds imbibed at supraoptimal temperature activate seed-specific genes and ABA biosynthetic and signaling genes, while inhibiting genes that promote germination and growth, such as GA biosynthetic and signaling genes. In this study, we have uncovered a novel function for the master regulator of seed maturation, FUS3, in delaying germination at supraoptimal temperature. Physiologically, this is important since delaying germination has a protective role at high temperature. Transcriptomic analysis of seeds imbibed at supraoptimal temperature reveal that a complex program is in place, which involves not only the regulation of heat and dehydration response genes to adjust cellular functions, but also the activation of seed-specific programs and the inhibition of germination-promoting programs to delay germination. © 2011 Chiu et al; licensee BioMed Central Ltd.

The role of the Arabidopsis FUSCA3 transcription factor during inhibition of seed germination at high temperature

PubMed Central

2012-01-01

Background Imbibed seeds integrate environmental and endogenous signals to break dormancy and initiate growth under optimal conditions. Seed maturation plays an important role in determining the survival of germinating seeds, for example one of the roles of dormancy is to stagger germination to prevent mass growth under suboptimal conditions. The B3-domain transcription factor FUSCA3 (FUS3) is a master regulator of seed development and an important node in hormonal interaction networks in Arabidopsis thaliana. Its function has been mainly characterized during embryonic development, where FUS3 is highly expressed to promote seed maturation and dormancy by regulating ABA/GA levels. Results In this study, we present evidence for a role of FUS3 in delaying seed germination at supraoptimal temperatures that would be lethal for the developing seedlings. During seed imbibition at supraoptimal temperature, the FUS3 promoter is reactivated and induces de novo synthesis of FUS3 mRNA, followed by FUS3 protein accumulation. Genetic analysis shows that FUS3 contributes to the delay of seed germination at high temperature. Unlike WT, seeds overexpressing FUS3 (ML1:FUS3-GFP) during imbibition are hypersensitive to high temperature and do not germinate, however, they can fully germinate after recovery at control temperature reaching 90% seedling survival. ML1:FUS3-GFP hypersensitivity to high temperature can be partly recovered in the presence of fluridone, an inhibitor of ABA biosynthesis, suggesting this hypersensitivity is due in part to higher ABA level in this mutant. Transcriptomic analysis shows that WT seeds imbibed at supraoptimal temperature activate seed-specific genes and ABA biosynthetic and signaling genes, while inhibiting genes that promote germination and growth, such as GA biosynthetic and signaling genes. Conclusion In this study, we have uncovered a novel function for the master regulator of seed maturation, FUS3, in delaying germination at supraoptimal temperature. Physiologically, this is important since delaying germination has a protective role at high temperature. Transcriptomic analysis of seeds imbibed at supraoptimal temperature reveal that a complex program is in place, which involves not only the regulation of heat and dehydration response genes to adjust cellular functions, but also the activation of seed-specific programs and the inhibition of germination-promoting programs to delay germination. PMID:22279962

Clinical characterization of bvFTD due to FUS neuropathology

PubMed Central

Lee, Suzee E.; Seeley, William W.; Poorzand, Pardis; Rademakers, Rosa; Karydas, Anna; Stanley, Christine M.; Miller, Bruce L.; Rankin, Katherine P.

2011-01-01

In 2009, inclusions containing the fused in sarcoma (FUS) protein were identified as a third major molecular class of pathology underlying the behavioral variant frontotemporal dementia (bvFTD) syndrome. Due to the low prevalence of FUS pathology, few clinical descriptions have been published and none provides information about specific social-emotional deficits despite evidence for severe behavioral manifestations in this disorder. We evaluated a patient with bvFTD due to FUS pathology using a comprehensive battery of cognitive and social-emotional tests. A structural MRI scan and genetic tests for tau, progranulin, and FUS mutations were also performed. The patient showed preserved general cognitive functioning and superior working memory, but severe deficits in emotion attribution, sensitivity to punishment, and the capacity for interpersonal warmth and empathy. The gray matter atrophy pattern corresponded to this focal deficit profile, with preservation of dorsolateral fronto-parietal regions associated with executive functioning but severe damage to right worse than left frontoinsula, temporal pole, subgenual anterior cingulate, medial orbitofrontal cortex, amygdala, and caudate. This patient demonstrates the striking focality associated with FUS neuropathology in patients with bvFTD. PMID:22060063

Evaluation of Mechanical Properties and Marginal Fit of Crowns Fabricated Using Commercially Pure Titanium and FUS-Invest

PubMed Central

Wu, Jinshuang; Wang, Xianli; Xing, Helin; Guo, Tianwen; Dong, Chaofang

2017-01-01

This study investigated the mechanical properties and single crown accuracy of the tailor-made Fourth University Stomatology investment (FUS-invest) for casting titanium. Background. Current investment for casting titanium is not optimal for obtaining high-quality castings, and the commercially available titanium investment is costly. Methods. Titanium specimens were cast using the tailor-made FUS-invest. The mechanical properties were tested using a universal testing machine. Fractured castings were characterized by energy-dispersive spectroscopy. 19 titanium crowns were produced using FUS-invest and another 19 by Symbion. The accuracy of crowns was evaluated. Results. The mechanical properties of the titanium cast by FUS-invest were elastic modulus 125.6 ± 8.8 GPa, yield strength 567.5 ± 11.1 MPa, tensile strength 671.2 ± 15.6 MPa, and elongation 4.6 ± 0.2%. For marginal fit, no significant difference (P > 0.05) was found at four marker points of each group. For internal fit, no significant difference (P > 0.05) was found between two groups, whereas significant difference (P < 0.01) was found at different mark point of each group. Conclusions. The mechanical properties of titanium casted using FUS-invest fulfilled the ISO 9693 criteria. The marginal and internal fit of the titanium crowns using either the FUS-invest or Symbion were similar. PMID:28913355

Update on Clinical MR-guided Focused Ultrasound Applications

PubMed Central

McDannold, Nathan

2015-01-01

SYNOPSIS Focused ultrasound (FUS) can be used to thermally ablate tissue. The performance of FUS under magnetic resonance (MR) guidance enables aiming the focus at the target, accurate treatment planning, real-time temperature mapping, and evaluation of the treatment. This review updates several clinical applications of MR-guided FUS. MR-guided FUS has a CE mark and FDA approval for thermal ablation for uterine fibroids and bone metastases related pain management. Thousands of uterine fibroid patients have successfully been treated with minor side effects. Technical improvements, increased experience, and the use of a screening MRI examination should further improve treatment outcome. When used for bone metastases and other bone diseases, thermal ablation leads to pain relief due to denervation, and debulking of the tumor. The use of a hemi-spherical multi-element transducer and phase corrections have enabled application of FUS through the skull. Transcranial MR-guided FUS has received CE certification for ablation of deep, central locations in the brain such as the thalamus. Thermal ablation of specific parts of the thalamus can result in relief of the symptoms in neurological disorders such as essential tremor, Parkinson’s, and neuropathic pain. No CE mark or FDA approval has been obtained as yet for treatment of prostate cancer or breast cancer, but several approaches have been proposed and clinical trials should show the potential of MR-guided FUS for these and other applications. PMID:26499282

Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis.

PubMed

Shang, Yulei; Huang, Eric J

2016-09-15

Recent advances in the genetics of amyotrophic lateral sclerosis (ALS) have provided key mechanistic insights to the pathogenesis of this devastating neurodegenerative disease. Among many etiologies for ALS, the identification of mutations and proteinopathies in two RNA binding proteins, TDP-43 (TARDBP or TAR DNA binding protein 43) and its closely related RNA/DNA binding protein FUS (fused in sarcoma), raises the intriguing possibility that perturbations to the RNA homeostasis and metabolism in neurons may contribute to the pathogenesis of these diseases. Although the similarities between TDP-43 and FUS suggest that mutations and proteinopathy involving these two proteins may converge on the same mechanisms leading to neurodegeneration, there is increasing evidence that FUS mutations target distinct mechanisms to cause early disease onset and aggressive progression of disease. This review focuses on the recent advances on the molecular, cellular and genetic approaches to uncover the mechanisms of wild type and mutant FUS proteins during development and in neurodegeneration. These findings provide important insights to understand how FUS mutations may perturb the maintenance of dendrites through fundamental processes in RNA splicing, RNA transport and DNA damage response/repair. These results contribute to the understanding of phenotypic manifestations in neurodegeneration related to FUS mutations, and to identify important directions for future investigations. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Neuronavigation-guided focused ultrasound-induced blood-brain barrier opening: A preliminary study in swine

NASA Astrophysics Data System (ADS)

Liu, Hao-Li; Tsai, Hong-Chieh; Lu, Yu-Jen; Wei, Kuo-Chen

2012-11-01

FUS-induced BBB opening is a promising technique for noninvasive and local delivery of drugs into the brain. Here we propose the novel use of a neuronavigation system to guide the FUS-induced BBB opening procedure, and investigate its feasibility in vivo in large animals. We developed an interface between the neuronavigator and FUS to allow guidance of the focal energy produced by the FUS transducer. The system was tested in 29 pigs by more than 40 sonication procedures and evaluated by MRI. Gd-DTPA concentration was quantitated in vivo by MRI R1 relaxometry and compared by ICP-OES assay. Brain histology after FUS exposure was investigated by HE and TUNEL staining. Neuronavigation could successfully guide the focal beam with comparable precision to neurosurgical stereotactic procedures (2.3 ± 0.9 mm). FUS pressure of 0.43 MPa resulted in consistent BBB-opening. Neuronavigation-guided BBB-opening increased Gd-DTPA deposition by up to 1.83 mM (140% increase). MR relaxometry demonstrated high correlation to ICP-OES measurements (r2 = 0.822), suggesting that Gd-DTPA deposition can be directly measured by imaging. Neuronavigation could provide sufficient precision for guiding FUS to temporally and locally open the BBB. Gd-DTPA deposition in the brain could be quantified by MR relaxometry, providing a potential tool for the in vivo quantification of therapeutic agents in CNS disease treatment.

Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening

NASA Astrophysics Data System (ADS)

Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C.; Konofagou, Elisa E.

2015-12-01

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r2  =  0.77) (2) the permeability of the opened BBB (r2  =  0.82) (3) the likelihood of safe opening (P  <  0.05, safe opening compared to cases of damage; P  <  0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r2  =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug circulation time. In addition, avoiding adverse effects in the brain and assessing the pharmacokinetics of the compounds delivered can also be achieved by monitoring and controlling the stable cavitation emissions.

Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening.

PubMed

Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C; Konofagou, Elisa E

2015-12-07

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r(2)  =  0.77); (2) the permeability of the opened BBB (r(2)  =  0.82); (3) the likelihood of safe opening (P  <  0.05, safe opening compared to cases of damage; P  <  0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r(2)  =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug circulation time. In addition, avoiding adverse effects in the brain and assessing the pharmacokinetics of the compounds delivered can also be achieved by monitoring and controlling the stable cavitation emissions.

Focused ultrasound-mediated drug delivery through the blood-brain barrier

PubMed Central

Burgess, Alison; Shah, Kairavi; Hough, Olivia; Hynynen, Kullervo

2015-01-01

Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods which can be used to circumvent the BBB to promote drug delivery is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents. PMID:25936845

Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin.

PubMed

Zou, Zhang-Yu; Liu, Ming-Sheng; Li, Xiao-Guang; Cui, Li-Ying

2016-01-01

Juvenile onset ALS is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age. Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) genes have been associated with familial ALS with juvenile onset and slow progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear. We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients. Four cases (25%) carrying FUS mutations and one individual (6%) harbouring a SOD1 mutation were identified. All cases had an aggressive disease course. Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin. Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course.

Quantification of intraventricular blood clot in MR-guided focused ultrasound surgery

NASA Astrophysics Data System (ADS)

Hess, Maggie; Looi, Thomas; Lasso, Andras; Fichtinger, Gabor; Drake, James

2015-03-01

Intraventricular hemorrhage (IVH) affects nearly 15% of preterm infants. It can lead to ventricular dilation and cognitive impairment. To ablate IVH clots, MR-guided focused ultrasound surgery (MRgFUS) is investigated. This procedure requires accurate, fast and consistent quantification of ventricle and clot volumes. We developed a semi-autonomous segmentation (SAS) algorithm for measuring changes in the ventricle and clot volumes. Images are normalized, and then ventricle and clot masks are registered to the images. Voxels of the registered masks and voxels obtained by thresholding the normalized images are used as seed points for competitive region growing, which provides the final segmentation. The user selects the areas of interest for correspondence after thresholding and these selections are the final seeds for region growing. SAS was evaluated on an IVH porcine model. SAS was compared to ground truth manual segmentation (MS) for accuracy, efficiency, and consistency. Accuracy was determined by comparing clot and ventricle volumes produced by SAS and MS, and comparing contours by calculating 95% Hausdorff distances between the two labels. In Two-One-Sided Test, SAS and MS were found to be significantly equivalent (p < 0.01). SAS on average was found to be 15 times faster than MS (p < 0.01). Consistency was determined by repeated segmentation of the same image by both SAS and manual methods, SAS being significantly more consistent than MS (p < 0.05). SAS is a viable method to quantify the IVH clot and the lateral brain ventricles and it is serving in a large-scale porcine study of MRgFUS treatment of IVH clot lysis.

Detoxification of Fusarium-contaminated maize with sodium sulphite - in vivo efficacy with special emphasis on mycotoxin residues and piglet health.

PubMed

Tran, Anh Tuan; Kluess, Jeannette; Berk, Andreas; Paulick, Marleen; Frahm, Jana; Schatzmayr, Dian; Winkler, Janine; Kersten, Susanne; Dänicke, Sven

2018-02-01

A feeding experiment with piglets was performed to examine the efficacy of a wet preservation of Fusarium (FUS)-contaminated maize with sodium sulphite (SoS) based on deoxynivalenol (DON) and zearalenone (ZEN) residue levels in urine, bile and liquor and health traits of piglets. For this purpose, 80 castrated male piglets (7.57 ± 0.92 kg BW) were assigned to four treatment groups: CON- (control diet, with 0.09 mg DON and <0.01 mg ZEN/kg diet), CON+ (diet CON-, wet-preserved with 5 g SoS/kg maize; containing 0.05 mg DON and <0.01 mg ZEN/kg diet), FUS- (diet with mycotoxin-contaminated maize; containing 5.36 mg DON and 0.29 mg ZEN/kg diet), and FUS+ (diet FUS-, wet-preserved with 5 g SoS/kg maize; resulting in 0.83 mg DON and 0.27 mg ZEN/kg diet). After 42 d, 40 piglets (n = 10 per group) were sampled. A clear reduction of DON levels by approximately 75% was detected in all specimens of pigs fed diet FUS+. ZEN was detected in all urine, bile and liquor samples, while their metabolites were only detectable in urine and bile. Additionally, their concentrations were not influenced by SoS treatment. Among the health-related traits, feeding of FUS diets increased the total counts of leukocytes and segmented neutrophil granulocytes irrespective of SoS treatment. SoS treatment increased the total blood protein content slightly with a similar numerical trend in albumin concentration. These effects occurred at an obviously lower level in FUS-fed groups. Moreover, SoS treatment recovered the reduction of NO production induced by feeding diet FUS- indicating an effect on the redox level. As this effect only occurred in group FUS+, it is obviously related to the adverse effects of the Fusarium toxins. In conclusion, treatment of FUS-contaminated maize with SoS decreased the inner exposure with DON as indicated by the lower DON levels in various piglet specimens. However, health-related traits did not consistently reflect this decreased exposure.

Determination of the Fusarium mycotoxins, fusaproliferin and beauvericin by high-performance liquid chromatography-electrospray ionization mass spectrometry.

PubMed

Sewram, V; Nieuwoudt, T W; Marasas, W F; Shephard, G S; Ritieni, A

1999-10-15

A method is described using LC-MS for the detection of the mycotoxins fusaproliferin (FUS) and beauvericin (BEA) in cultures of Fusarium subglutinans and in naturally contaminated maize. Protonated molecular ion signals for FUS and BEA were observed at m/z 445 and m/z 784, respectively. Collision induced dissociation of the readily dehydrated protonated molecular ion of the sesterterpene FUS (m/z 427) led to the loss of another water molecule (m/z 409) and acetic acid (m/z 385), while the cyclic lactone trimer BEA fragmented to yield the protonated dimer (m/z 523) and monomer (m/z 262), respectively. Detection of FUS was best performed in the MS-MS mode while BEA displayed a stronger signal in the MS mode. The on-column instrumental detection limits for pure FUS and BEA were found to be 2 ng and 20 pg (S/N=2) while those in naturally contaminated maize were 1 microg/kg and 0.5 microg/kg, respectively. Five South African strains of F. subglutinans were analyzed following methanol extraction of which four produced FUS at levels between 330 mg/kg and 2630 mg/kg while only three produced BEA at levels between 140 mg/kg and 700 mg/kg. Application of this method to naturally contaminated maize samples from the Transkei region of South Africa showed FUS at levels of 8.8-39.6 microg/kg and BEA at 7.6-238.8 microg/kg.

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

PubMed Central

Kia, Azadeh; McAvoy, Kevin; Krishnamurthy, Karthik; Trotti, Davide

2018-01-01

Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS. PMID:29380416

Neurotrophic effects of progranulin in vivo in reversing motor neuron defects caused by over or under expression of TDP-43 or FUS

PubMed Central

Chitramuthu, Babykumari P.; Kay, Denis G.; Bateman, Andrew; Bennett, Hugh P. J.

2017-01-01

Progranulin (PGRN) is a glycoprotein with multiple roles in normal and disease states. Mutations within the GRN gene cause frontotemporal lobar degeneration (FTLD). The affected neurons display distinctive TAR DNA binding protein 43 (TDP-43) inclusions. How partial loss of PGRN causes TDP-43 neuropathology is poorly understood. TDP-43 inclusions are also found in affected neurons of patients with other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, TDP-43 inclusions are typically also immunoreactive for fused in sarcoma (FUS). Mutations within TDP-43 or FUS are themselves neuropathogenic in ALS and some cases of FTLD. We used the outgrowth of caudal primary motor neurons (MNs) in zebrafish embryos to investigate the interaction of PGRN with TDP-43 and FUS in vivo. As reported previously, depletion of zebrafish PGRN-A (zfPGRN-A) is associated with truncated primary MNs and impaired motor function. Here we found that depletion of zfPGRN-A results in primary MNs outgrowth stalling at the horizontal myoseptum, a line of demarcation separating the myotome into dorsal and ventral compartments that is where the final destination of primary motor is assigned. Successful axonal outgrowth beyond the horizontal myoseptum depends in part upon formation of acetylcholine receptor clusters and this was found to be disorganized upon depletion of zfPGRN-A. PGRN reversed the effects of zfPGRN-A knockdown, but a related gene, zfPGRN-1, was without effect. Both knockdown of TDP-43 or FUS, as well as expression of humanTDP-43 and FUS mutants results in MN abnormalities that are reversed by co-expression of hPGRN mRNA. Neither TDP-43 nor FUS reversed MN phenotypes caused by the depletion of PGRN. Thus TDP-43 and FUS lie upstream of PGRN in a gene complementation pathway. The ability of PGRN to override TDP-43 and FUS neurotoxicity due to partial loss of function or mutation in the corresponding genes may have therapeutic relevance. PMID:28358904

Feasibility of MRI-guided Focused Ultrasound as Organ-Sparing Treatment for Testicular Cancer

NASA Astrophysics Data System (ADS)

Staruch, Robert; Curiel, Laura; Chopra, Rajiv; Hynynen, Kullervo

2009-04-01

High cure rates for testicular cancer have prompted interest in organ-sparing surgery for patients with bilateral disease or single testis. Focused ultrasound (FUS) ablation could offer a noninvasive approach to organ-sparing surgery. The objective of this study was to determine the feasibility of using MR thermometry to guide organ-sparing focused ultrasound surgery in the testis. The testes of anesthetized rabbits were sonicated in several discrete locations using a single-element focused transducer operating at 2.787MHz. Focal heating was visualized with MR thermometry, using a measured PRF thermal coefficient of -0.0089±0.0003 ppm/° C. Sonications at 3.5-14 acoustic watts applied for 30 seconds produced maximum temperature elevations of 10-80° C, with coagulation verified by histology. Coagulation of precise volumes in the testicle is feasible with MRI-guided focused ultrasound. Variability in peak temperature for given sonication parameters suggests the need for online temperature feedback control.

Physiological Motion and Registration of Abnormalities in Liver During Focused Ultrasound Surgery

NASA Astrophysics Data System (ADS)

Chauhan, Sunita; Rh, Abhilash

Continuous deformation and dislocation of soft tissues in the abdominal and thoracic region presents a major issue for effective targeting of all non-invasive ablative modalities such as radiotherapy/surgery and Focused Ultrasound Surgery. Most significant among these is the movement of the target organs due to physiological processes such as respiration. The movement is found to be most significant for liver and kidneys. We studied movement and compensation strategies with the aim to implement them during ultrasound ablation using our robotic system for targeted FUS dose delivery. The motion pattern of the liver can be assumed to be in a single plane as it closely follows the movement of the diaphragm. However, the movement of kidneys is three dimensional and follows complicated patterns. Kidney motion is highly subject specific and has poor repeatability. In our research, we quantify the relation of liver movement and the breathing pattern so as to achieve real-time movement compensation using a prediction-correlation approach.

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

PubMed Central

2013-01-01

Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer’s disease. The requirements for clinical translation of FUS will be discussed. PMID:23379618

RNA Seeds Higher Order Assembly of FUS Protein

PubMed Central

Schwartz, Jacob C.; Wang, Xueyin; Podell, Elaine R.; Cech, Thomas R.

2014-01-01

SUMMARY The abundant nuclear RNA-binding protein FUS binds the CTD of RNA polymerase II in an RNA-dependent manner, affecting Ser2 phosphorylation and transcription. Here we examine the mechanism of this process and find that RNA binding nucleates the formation of higher order FUS RNP assemblies that bind the CTD. Both the low-complexity domain and the RGG domain of FUS contribute to assembly. The assemblies appear fibrous by electron microscopy and have characteristics of beta-zipper structures. These results support the emerging view that the pathologic protein aggregation seen in neurodegenerative diseases such as ALS may occur by exaggeration of functionally important assemblies of RNA-binding proteins. PMID:24268778

Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model

NASA Astrophysics Data System (ADS)

Wang, Po-Hsun; Liu, Hao-Li; Hsu, Po-Hung; Lin, Chia-Yu; Chris Wang, Churng-Ren; Chen, Pin-Yuan; Wei, Kuo-Chen; Yen, Tzu-Chen; Li, Meng-Lin

2012-06-01

In this study, we develop a novel photoacoustic imaging technique based on gold nanorods (AuNRs) for quantitatively monitoring focused-ultrasound (FUS) induced blood-brain barrier (BBB) opening in a rat model in vivo. This study takes advantage of the strong near-infrared absorption (peak at ~800 nm) of AuNRs and the extravasation tendency from BBB opening foci due to their nano-scale size to passively label the BBB disruption area. Experimental results show that AuNR contrast-enhanced photoacoustic microscopy (PAM) successfully reveals the spatial distribution and temporal response of BBB disruption area in the rat brains. The quantitative measurement of contrast enhancement has potential to estimate the local concentration of AuNRs and even the dosage of therapeutic molecules when AuNRs are further used as nano-carrier for drug delivery or photothermal therapy. The photoacoustic results also provide complementary information to MRI, being helpful to discover more details about FUS induced BBB opening in small animal models.

Intracranial inertial cavitation threshold and thermal ablation lesion creation using MRI-guided 220-kHz focused ultrasound surgery: preclinical investigation.

PubMed

Xu, Zhiyuan; Carlson, Carissa; Snell, John; Eames, Matt; Hananel, Arik; Lopes, M Beatriz; Raghavan, Prashant; Lee, Cheng-Chia; Yen, Chun-Po; Schlesinger, David; Kassell, Neal F; Aubry, Jean-Francois; Sheehan, Jason

2015-01-01

In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology. Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions. Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as follows: no cavitation, stable cavitation, and inertial cavitation. Low-power and longer sonications induced only thermal lesions, with a peak temperature threshold for lesioning of 53°C. Hemorrhagic lesions occurred only with high-power and shorter sonications. The sizes of the hemorrhages measured on macroscopic histological examinations correlated with the intensity of the cavitation activity (R2 = 0.74). The acoustic cavitation activity detected by the passive cavitation detectors exhibited a threshold of 0.09 V·Hz for the occurrence of hemorrhages. This work demonstrates that 220-kHz ultrasound is capable of inducing a thermal lesion in the brain of living swines without hemorrhage. Although the same acoustic energy can induce either a hemorrhage or a thermal lesion, it seems that low-power, long-duration sonication is less likely to cause hemorrhage and may be safer. Although further study is needed to decrease the likelihood of ischemic infarction associated with the 220-kHz ultrasound, the threshold established in this work may allow for the detection and prevention of deleterious cavitations.

A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma Identifies Driver Functions in Addition to NF-κB.

PubMed

Ozawa, Tatsuya; Arora, Sonali; Szulzewsky, Frank; Juric-Sekhar, Gordana; Miyajima, Yoshiteru; Bolouri, Hamid; Yasui, Yoshie; Barber, Jason; Kupp, Robert; Dalton, James; Jones, Terreia S; Nakada, Mitsutoshi; Kumabe, Toshihiro; Ellison, David W; Gilbertson, Richard J; Holland, Eric C

2018-06-26

The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA (RELA FUS ). Neural stem cells transduced with RELA FUS ex vivo form ependymomas when implanted in the brain. These tumors display enhanced NF-κB signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELA FUS is sufficient to drive de novo ependymoma tumorigenesis in the brain and, if so, whether these tumors also arise from neural stem cells. We show that RELA FUS drives ST-ependymoma formation from periventricular neural stem cells in mice and that RELA FUS -induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-κB. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

NASA Astrophysics Data System (ADS)

Downs, Matthew E.; Buch, Amanda; Karakatsani, Maria Eleni; Konofagou, Elisa E.; Ferrera, Vincent P.

2015-10-01

Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

Systematic review of frequent users of emergency departments in non-US hospitals: state of the art.

PubMed

van Tiel, Sofie; Rood, Pleunie P M; Bertoli-Avella, Aida M; Erasmus, Vicky; Haagsma, Juanita; van Beeck, Ed; Patka, Peter; Polinder, Suzanne

2015-10-01

This review focuses on frequent users (FUs) of the emergency department (ED). Elucidation of the characteristics of frequent ED users will help to improve healthcare services. A systematic review of the literature (from 1999 onwards) on frequent ED users in non-US hospitals was performed. Twenty-two studies were included. FUs are responsible for a wide variety of 1-31% of ED visits depending on the FU definition used. They have a mean age between 40 and 50 years and are older than nonfrequent users. Chronic physical and mental diseases seem to be the main reasons for frequent ED visits. In terms of social characteristics, lacking a partner is more frequently reported among FUs in some studies. The absence of a universal definition for FUs complicates the determination of the burden on emergency healthcare services. FUs are a heterogeneous group of patients with genuine medical needs and high consumption of other healthcare services.

Focused ultrasound-mediated sonochemical internalization: an alternative to light-based therapies

NASA Astrophysics Data System (ADS)

Gonzales, Jonathan; Nair, Rohit Kumar; Madsen, Steen J.; Krasieva, Tatiana; Hirschberg, Henry

2016-07-01

Activation of sonosensitizers via focused ultrasound (FUS), i.e., sonodynamic therapy has been proposed as an extension to light-activated photodynamic therapy for the treatment of brain as well as other tumors. The use of FUS, as opposed to light, allows treatment to tumor sites buried deep within tissues as well as through the intact skull. We have examined ultrasonic activation of sonosensitizers together with the anticancer agent bleomycin (BLM), i.e., sonochemical internalization (SCI). SCI is a technique that utilizes FUS for the enhanced delivery of endo-lysosomal trapped macromolecules into the cell cytoplasm in a similar manner to light-based photochemical internalization. The released agent can, therefore, exert its full biological activity, in contrast to being degraded by lysosomal hydrolases. Our results indicate that, compared to drug or FUS treatment alone, FUS activation of the sonosensitizer AlPcS2a together with BLM significantly inhibits the ability of treated glioma cells to grow as three-dimensional tumor spheroids in vitro.

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

PubMed Central

Murakami, Tetsuro; Qamar, Seema; Lin, Julie Qiaojin; Schierle, Gabriele S. Kaminski; Rees, Eric; Miyashita, Akinori; Costa, Ana R.; Dodd, Roger B.; Chan, Fiona T.S.; Michel, Claire H.; Kronenberg-Versteeg, Deborah; Li, Yi; Yang, Seung-Pil; Wakutani, Yosuke; Meadows, William; Ferry, Rodylyn Rose; Dong, Liang; Tartaglia, Gian Gaetano; Favrin, Giorgio; Lin, Wen-Lang; Dickson, Dennis W.; Zhen, Mei; Ron, David; Schmitt-Ulms, Gerold; Fraser, Paul E.; Shneider, Neil A.; Holt, Christine; Vendruscolo, Michele; Kaminski, Clemens F.; St George-Hyslop, Peter

2015-01-01

Summary The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins. PMID:26526393

Active MRI tracking for robotic assisted FUS

NASA Astrophysics Data System (ADS)

Xiao, Xu; Huang, Zhihong; Melzer, Andreas

2017-03-01

MR guided FUS is a noninvasive method producing thermal necrosis at the position of tumors with high accuracy and temperature control. Because the typical size of the ultrasound focus is smaller than the area of interested treatment tissues, focus repositioning become necessary to achieve multiple sonications to cover the whole targeted area. Using MR compatible mechanical actuators could help the ultrasound beam to reach a wider treatment range than using electrical beam steering technique and more flexibility in position the transducer. An active MR tracking technique was combined into the MRgFUS system to help locating the position of the mechanical actuator and the FUS transducer. For this study, a precise agar reference model was designed and fabricated to test the performance of the active tracking technique when it was used on the MR-compatible robotics InnoMotion™ (IBSMM, Engineering spol. s r.o. / Ltd, Czech Republic). The precision, tracking range and positioning speed of the combined robotic FUS system were evaluated in this study. Compared to the existing MR guided HIFU systems, the combined robotic system with active tracking techniques provides a potential that allows the FUS treatment to operate in a larger spatial range and with a faster speed, which is one of the main challenges for organ motion tracking.

Non-invasive peripheral nerve stimulation via focused ultrasound in vivo

NASA Astrophysics Data System (ADS)

Downs, Matthew E.; Lee, Stephen A.; Yang, Georgiana; Kim, Seaok; Wang, Qi; Konofagou, Elisa E.

2018-02-01

Focused ultrasound (FUS) has been employed on a wide range of clinical applications to safely and non-invasively achieve desired effects that have previously required invasive and lengthy procedures with conventional methods. Conventional electrical neuromodulation therapies that are applied to the peripheral nervous system (PNS) are invasive and/or non-specific. Recently, focused ultrasound has demonstrated the ability to modulate the central nervous system and ex vivo peripheral neurons. Here, for the first time, noninvasive stimulation of the sciatic nerve eliciting a physiological response in vivo is demonstrated with FUS. FUS was applied on the sciatic nerve in mice with simultaneous electromyography (EMG) on the tibialis anterior muscle. EMG signals were detected during or directly after ultrasound stimulation along with observable muscle contraction of the hind limb. Transecting the sciatic nerve downstream of FUS stimulation eliminated EMG activity during FUS stimulation. Peak-to-peak EMG response amplitudes and latency were found to be comparable to conventional electrical stimulation methods. Histology along with behavioral and thermal testing did not indicate damage to the nerve or surrounding regions. The findings presented herein demonstrate that FUS can serve as a targeted, safe and non-invasive alternative to conventional peripheral nervous system stimulation to treat peripheral neuropathic diseases in the clinic.

Focused ultrasound thermal therapy system with ultrasound image guidance and temperature measurement feedback.

PubMed

Lin, Kao-Han; Young, Sun-Yi; Hsu, Ming-Chuan; Chan, Hsu; Chen, Yung-Yaw; Lin, Win-Li

2008-01-01

In this study, we developed a focused ultrasound (FUS) thermal therapy system with ultrasound image guidance and thermocouple temperature measurement feedback. Hydraulic position devices and computer-controlled servo motors were used to move the FUS transducer to the desired location with the measurement of actual movement by linear scale. The entire system integrated automatic position devices, FUS transducer, power amplifier, ultrasound image system, and thermocouple temperature measurement into a graphical user interface. For the treatment procedure, a thermocouple was implanted into a targeted treatment region in a tissue-mimicking phantom under ultrasound image guidance, and then the acoustic interference pattern formed by image ultrasound beam and low-power FUS beam was employed as image guidance to move the FUS transducer to have its focal zone coincident with the thermocouple tip. The thermocouple temperature rise was used to determine the sonication duration for a suitable thermal lesion as a high power was turned on and ultrasound image was used to capture the thermal lesion formation. For a multiple lesion formation, the FUS transducer was moved under the acoustic interference guidance to a new location and then it sonicated with the same power level and duration. This system was evaluated and the results showed that it could perform two-dimensional motion control to do a two-dimensional thermal therapy with a small localization error 0.5 mm. Through the user interface, the FUS transducer could be moved to heat the target region with the guidance of ultrasound image and acoustic interference pattern. The preliminary phantom experimental results demonstrated that the system could achieve the desired treatment plan satisfactorily.

Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities

PubMed Central

Curley, Colleen T.; Sheybani, Natasha D.; Bullock, Timothy N.; Price, Richard J.

2017-01-01

Immunotherapy is rapidly emerging as the cornerstone for the treatment of several forms of metastatic cancer, as well as for a host of other pathologies. Meanwhile, several new high-profile studies have uncovered remarkable linkages between the central nervous and immune systems. With these recent developments, harnessing the immune system for the treatment of brain pathologies is a promising strategy. Here, we contend that MR image-guided focused ultrasound (FUS) represents a noninvasive approach that will allow for favorable therapeutic immunomodulation in the setting of the central nervous system. One obstacle to effective immunotherapeutic drug delivery to the brain is the blood brain barrier (BBB), which refers to the specialized structure of brain capillaries that prevents transport of most therapeutics from the blood into brain tissue. When applied in the presence of circulating microbubbles, FUS can safely and transiently open the BBB to facilitate the delivery of immunotherapeutic agents into the brain parenchyma. Furthermore, it has been demonstrated that physical perturbations of the tissue microenvironment via FUS can modulate immune response in both normal and diseased tissue. In this review article, we provide an overview of FUS energy regimens and corresponding tissue bioeffects, followed by a review of the literature pertaining to FUS for therapeutic antibody delivery in normal brain and preclinical models of brain disease. We provide an overview of studies that demonstrate FUS-mediated immune modulation in both the brain and peripheral settings. Finally, we provide remarks on challenges facing FUS immunotherapy and opportunities for future expansion in this area. PMID:29109764

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity

PubMed Central

Daigle, J Gavin; Krishnamurthy, Karthik; Ramesh, Nandini; Casci, Ian; Monaghan, John; McAvoy, Kevin; Godfrey, Earl W; Daniel, Dianne C.; Johnson, Edward M.; Monahan, Zach; Shewmaker, Frank; Pasinelli, Piera; Pandey, Udai Bhan

2016-01-01

Amyotrophic lateral Sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA binding proteins, have been linked to ALS pathology. Recently, Pur-alpha a DNA/RNA binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells. Interestingly, shRNA mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics. PMID:26728149

A software tool for advanced MRgFUS prostate therapy planning and follow up

NASA Astrophysics Data System (ADS)

van Straaten, Dörte; Hoogenboom, Martijn; van Amerongen, Martinus J.; Weiler, Florian; Issawi, Jumana Al; Günther, Matthias; Fütterer, Jurgen; Jenne, Jürgen W.

2017-03-01

US guided HIFU/FUS ablation for the therapy of prostate cancer is a clinical established method, while MR guided HIFU/FUS applications for prostate recently started clinical evaluation. Even if MRI examination is an excellent diagnostic tool for prostate cancer, it is a time consuming procedure and not practicable within an MRgFUS therapy session. The aim of our ongoing work is to develop software to support therapy planning and post-therapy follow-up for MRgFUS on localized prostate cancer, based on multi-parametric MR protocols. The clinical workflow of diagnosis, therapy and follow-up of MR guided FUS on prostate cancer was deeply analyzed. Based on this, the image processing workflow was designed and all necessary components, e.g. GUI, viewer, registration tools etc. were defined and implemented. The software bases on MeVisLab with several implemented C++ modules for the image processing tasks. The developed software, called LTC (Local Therapy Control) will register and visualize automatically all images (T1w, T2w, DWI etc.) and ADC or perfusion maps gained from the diagnostic MRI session. This maximum of diagnostic information helps to segment all necessary ROIs, e.g. the tumor, for therapy planning. Final therapy planning will be performed based on these segmentation data in the following MRgFUS therapy session. In addition, the developed software should help to evaluate the therapy success, by synchronization and display of pre-therapeutic, therapy and follow-up image data including the therapy plan and thermal dose information. In this ongoing project, the first stand-alone prototype was completed and will be clinically evaluated.

Juvenile-onset Sporadic Amyotrophic Lateral Sclerosis with a Frameshift FUS Gene Mutation Presenting Unique Neuroradiological Findings and Cognitive Impairment.

PubMed

Hirayanagi, Kimitoshi; Sato, Masayuki; Furuta, Natsumi; Makioka, Kouki; Ikeda, Yoshio

2016-01-01

A 24-year-old Japanese woman developed anterocollis, weakness of the proximal arms, and subsequent cognitive impairment. A neurological examination revealed amyotrophic lateral sclerosis (ALS) without a family history. Systemic muscle atrophy progressed rapidly. Cerebral MRI clearly exhibited high signal intensities along the bilateral pyramidal tracts. An analysis of the FUS gene revealed a heterozygous two-base pair deletion, c.1507-1508delAG (p.G504WfsX515). A subset of juvenile-onset familial/sporadic ALS cases with FUS gene mutations reportedly demonstrates mental retardation or learning difficulty. Our study emphasizes the importance of conducting a FUS gene analysis in juvenile-onset ALS cases, even when no family occurrence is confirmed.

Real-time imaging and kinetics measurements of focused ultrasound-induced extravasation in skeletal muscle using SPECT/CT.

PubMed

Sanches, Pedro Gomes; Rossin, Raffaella; Böhmer, Marcel; Tiemann, Klaus; Grüll, Holger

2013-06-28

Drugs need to overcome several biological barriers such as the endothelium and cellular membranes in order to reach their target. Promising new therapeutics, many of which are charged and macromolecular, are not able to passively extravasate, let alone cross cell membranes, and stay mainly in the blood pool upon intravenous injection until clearance. Using focused ultrasound (fUS) in combination with circulating microbubbles (MBs) leads to temporary localized tissue permeabilization allowing extravasation of (macro) molecules from the vascular system. Thus, fUS is a promising approach for localized drug delivery. However, little is known about the permeabilization kinetics in skeletal muscle. In this study, we used single photon emission computed tomography (SPECT) to characterize the kinetics of extravasation of ¹¹¹In-labeled bovine serum albumin (BSA), a model macromolecular drug, in muscle treated with fUS and MBs. The same fUS protocol was applied to 6 groups of mice with different times, ∆t, between fUS application and BSA injection (∆t=-10, 2.5, 10, 30, 60, 90 min) followed by SPECT imaging. For ∆t ≤30min we observed an exponential accumulation of activity in an area of the treated muscle which extended to a volume larger than the fUS pattern with highest accumulation for short waiting times ∆t. The extent of extravasation decreased exponentially with increasing ∆t, with a calculated half-life of ca. 21 min, defining the time window of extravasation. The same treatment without MBs did not induce extravasation of BSA thus supporting MBs and drug co-injection strategies. These results provide essential information for the development of fUS based strategies for localized drug delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Arabidopsis cop8 and fus4 mutations define the same gene that encodes subunit 4 of the COP9 signalosome.

PubMed Central

Serino, G; Tsuge, T; Kwok, S; Matsui, M; Wei, N; Deng, X W

1999-01-01

The pleiotropic constitutive photomorphogenic/deetiolated/fusca (cop/det/fus) mutants of Arabidopsis exhibit features of light-grown seedlings when grown in the dark. Cloning and biochemical analysis of COP9 have revealed that it is a component of a multiprotein complex, the COP9 signalosome (previously known as the COP9 complex). Here, we compare the immunoaffinity and the biochemical purification of the COP9 signalosome from cauliflower and confirm its eight-subunit composition. Molecular cloning of subunit 4 of the complex revealed that it is a proteasome-COP9 complex-eIF3 domain protein encoded by a gene that maps to chromosome 5, near the chromosomal location of the cop8 and fus4 mutations. Genetic complementation tests showed that the cop8 and fus4 mutations define the same locus, now designated as COP8. Molecular analysis of the subunit 4-encoding gene in both cop8 and fus4 mutants identified specific molecular lesions, and overexpression of the subunit 4 cDNA in a cop8 mutant background resulted in complete rescue of the mutant phenotype. Thus, we conclude that COP8 encodes subunit 4 of the COP9 signalosome. Examination of possible molecular interactions by using the yeast two-hybrid assay indicated that COP8 is capable of strong self-association as well as interaction with COP9, FUS6/COP11, FUS5, and Arabidopsis JAB1 homolog 1, the latter four proteins being previously defined subunits of the Arabidopsis COP9 signalosome. A comparative sequence analysis indicated that COP8 is highly conserved among multicellular eukaryotes and is also similar to a subunit of the 19S regulatory particle of the 26S proteasome. PMID:10521526

Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can be increased through repeated applications.

PubMed

Burks, Scott R; Ziadloo, Ali; Kim, Saejeong J; Nguyen, Ben A; Frank, Joseph A

2013-11-01

Stem cells are promising therapeutics for cardiovascular diseases, and i.v. injection is the most desirable route of administration clinically. Subsequent homing of exogenous stem cells to pathological loci is frequently required for therapeutic efficacy and is mediated by chemoattractants (cell adhesion molecules, cytokines, and growth factors). Homing processes are inefficient and depend on short-lived pathological inflammation that limits the window of opportunity for cell injections. Noninvasive pulsed focused ultrasound (pFUS), which emphasizes mechanical ultrasound-tissue interactions, can be precisely targeted in the body and is a promising approach to target and maximize stem cell delivery by stimulating chemoattractant expression in pFUS-treated tissue prior to cell infusions. We demonstrate that pFUS is nondestructive to murine skeletal muscle tissue (no necrosis, hemorrhage, or muscle stem cell activation) and initiates a largely M2-type macrophage response. We also demonstrate that local upregulation of chemoattractants in pFUS-treated skeletal muscle leads to enhance homing, permeability, and retention of human mesenchymal stem cells (MSC) and human endothelial precursor cells (EPC). Furthermore, the magnitude of MSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily. This study demonstrates that pFUS defines transient "molecular zip codes" of elevated chemoattractants in targeted muscle tissue, which effectively provides spatiotemporal control and tunability of the homing process for multiple stem cell types. pFUS is a clinically translatable modality that may ultimately improve homing efficiency and flexibility of cell therapies for cardiovascular diseases. © AlphaMed Press.

Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1.

PubMed

Ederle, Helena; Funk, Christina; Abou-Ajram, Claudia; Hutten, Saskia; Funk, Eva B E; Kehlenbach, Ralph H; Bailer, Susanne M; Dormann, Dorothee

2018-05-04

TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology. Here we show that predicted nuclear export signals in TDP-43 and FUS are non-functional and that both proteins are exported independently of the export receptor CRM1/Exportin-1. Silencing of Exportin-5 or the mRNA export factor Aly/REF, as well as mutations that abrogate RNA-binding do not impair export of TDP-43 and FUS. However, artificially enlarging TDP-43 or FUS impairs their nuclear egress, suggesting that they could leave the nucleus by passive diffusion. Finally, we found that inhibition of transcription causes accelerated nuclear egress of TDP-43, suggesting that newly synthesized RNA retains TDP-43 in the nucleus, limiting its egress into the cytoplasm. Our findings implicate reduced nuclear retention as a possible factor contributing to mislocalization of TDP-43 in ALS/FTD.

Enhanced cavitation and heating of flowing polymer- and lipid-shelled microbubbles and phase-shift nanodroplets during focused ultrasound exposures

NASA Astrophysics Data System (ADS)

Zhang, Siyuan; Cui, Zhiwei; Li, Chong; Zhou, Fanyu; Zong, Yujin; Wang, Supin; Wan, Mingxi

2017-03-01

Cavitation and heating are the primary mechanisms of numerous therapeutic applications of ultrasound. Various encapsulated microbubbles (MBs) and phase-shift nanodroplets (NDs) have been used to enhance local cavitation and heating, creating interests in developing ultrasound therapy using these encapsulated MBs and NDs. This work compared the efficiency of flowing polymer- and lipid-shelled MBs and phase-shift NDs in cavitation and heating during focused ultrasound (FUS) exposures. Cavitation activity and temperature were investigated when the solution of polymer- and lipid-shelled MBs and NDs flowed through the vessel in a tissue-mimicking phantom with varying flow velocities when exposed to FUS at various acoustic power levels. The inertial cavitation dose (ICD) for the encapsulated MBs and NDs were higher than those for the saline. Temperature initially increased with increasing flow velocities of the encapsulated MBs, followed by a decrease of the temperature with increasing flow velocities when the velocity was much higher. Meanwhile, ICD showed a trend of increases with increasing flow velocity. For the phase-shift NDs, ICD after the first FUS exposure was lower than those after the second FUS exposure. For the encapsulated MBs, ICD after the first FUS exposure was higher than those after the second FUS exposure. Further studies are necessary to investigate the treatment efficiency of different encapsulated MBs and phase-shift NDs in cavitation and heating.

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model

PubMed Central

Baghirov, Habib; Snipstad, Sofie; Sulheim, Einar; Berg, Sigrid; Hansen, Rune; Thorsen, Frits; Mørch, Yrr; Åslund, Andreas K. O.

2018-01-01

The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma. PMID:29338016

TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update.

PubMed

Lattante, Serena; Rouleau, Guy A; Kabashi, Edor

2013-06-01

Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau-negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS. © 2013 Wiley Periodicals, Inc.

Intrinsically disordered RGG/RG domains mediate degenerate specificity in RNA binding

PubMed Central

Ozdilek, Bagdeser A.; Thompson, Valery F.; Ahmed, Nasiha S.; White, Connor I.

2017-01-01

Abstract RGG/RG domains are the second most common RNA binding domain in the human genome, yet their RNA-binding properties remain poorly understood. Here, we report a detailed analysis of the RNA binding characteristics of intrinsically disordered RGG/RG domains from Fused in Sarcoma (FUS), FMRP and hnRNPU. For FUS, previous studies defined RNA binding as mediated by its well-folded domains; however, we show that RGG/RG domains are the primary mediators of binding. RGG/RG domains coupled to adjacent folded domains can achieve affinities approaching that of full-length FUS. Analysis of RGG/RG domains from FUS, FMRP and hnRNPU against a spectrum of contrasting RNAs reveals that each display degenerate binding specificity, while still displaying different degrees of preference for RNA. PMID:28575444

Harmonic motion imaging for focused ultrasound (HMIFU): a fully integrated technique for sonication and monitoring of thermal ablation in tissues.

PubMed

Maleke, C; Konofagou, E E

2008-03-21

FUS (focused ultrasound), or HIFU (high-intensity-focused ultrasound) therapy, a minimally or non-invasive procedure that uses ultrasound to generate thermal necrosis, has been proven successful in several clinical applications. This paper discusses a method for monitoring thermal treatment at different sonication durations (10 s, 20 s and 30 s) using the amplitude-modulated (AM) harmonic motion imaging for focused ultrasound (HMIFU) technique in bovine liver samples in vitro. The feasibility of HMI for characterizing mechanical tissue properties has previously been demonstrated. Here, a confocal transducer, combining a 4.68 MHz therapy (FUS) and a 7.5 MHz diagnostic (pulse-echo) transducer, was used. The therapy transducer was driven by a low-frequency AM continuous signal at 25 Hz, producing a stable harmonic radiation force oscillating at the modulation frequency. A pulser/receiver was used to drive the pulse-echo transducer at a pulse repetition frequency (PRF) of 5.4 kHz. Radio-frequency (RF) signals were acquired using a standard pulse-echo technique. The temperature near the ablation region was simultaneously monitored. Both RF signals and temperature measurements were obtained before, during and after sonication. The resulting axial tissue displacement was estimated using one-dimensional cross correlation. When temperature at the focal zone was above 48 degrees C during heating, the coagulation necrosis occurred and tissue damage was irreversible. The HMI displacement profiles in relation to the temperature and sonication durations were analyzed. At the beginning of heating, the temperature at the focus increased sharply, while the tissue stiffness decreased resulting in higher HMI displacements. This was confirmed by an increase of 0.8 microm degrees C(-1)(r=0.93, p<.005). After sustained heating, the tissue became irreversibly stiffer, followed by an associated decrease in the HMI displacement (-0.79 microm degrees C(-1), r=-0.92, p<0.001). Repeated experiments showed a reproducible pattern of the HMI displacement changes with a temperature at a slope equal to 0.8+/-0.11 and -0.79+/-0.14 microm degrees C(-1), prior to and after lesion formation in seven bovine liver samples, respectively. This technique was thus capable of following the protein-denatured lesion formation based on the variation of the HMI displacements. This method could, therefore, be applied for real-time monitoring of temperature-related stiffness changes of tissues during FUS, HIFU or other thermal therapies.

Ultrasound-Induced Blood-Brain Barrier Opening

PubMed Central

Konofagou, Elisa E.; Tung, Yao-Sheng; Choi, James; Deffieux, Thomas; Baseri, Babak; Vlachos, Fotios

2014-01-01

Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions. PMID:22201586

Semiclassical treatment of fusion and breakup processes of ^{6,8}He halo nuclei

NASA Astrophysics Data System (ADS)

Majeed, Fouad A.; Abdul-Hussien, Yousif A.

2016-06-01

A semiclassical approach has been used to study the effect of channel coupling on the calculations of the total fusion reaction cross section σ _{fus}, and the fusion barrier distribution D_{fus} for the systems 6He +^{238}U and 8He +^{197}Au. Since these systems invloves light exotic nuclei, breakup states channel play an important role that should be considered in the calculations. In semiclassical treatment, the relative motion between the projectile and target nuclei is approximated by a classical trajectory while the intrinsic dynamics is handled by time-dependent quantum mechanics. The calculations of the total fusion cross section σ _{fus}, and the fusion barrier distribution D_{fus} are compared with the full quantum mechanical calculations using the coupled-channels calculations with all order coupling using the computer code and with the available experimental data.

Imbalance of mitochondrial dynamics in Drosophila models of amyotrophic lateral sclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Altanbyek, Volodya; Cha, Sun-Joo; Kang, Ga-Un

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease, characterized by progressive and selective loss of motor neurons in the brain and spinal cord. DNA/RNA-binding proteins such as TDP-43, FUS, and TAF15 have been linked with the sporadic and familial forms of ALS. However, the exact pathogenic mechanism of ALS is still unknown. Recently, we found that ALS-causing genes such as TDP-43, FUS, and TAF15 genetically interact with mitochondrial dynamics regulatory genes. In this study, we show that mitochondrial fission was highly enhanced in muscles and motor neurons of TDP-43, FUS, and TAF15-induced fly models of ALS. Furthermore, themore » mitochondrial fission defects were rescued by co-expression of mitochondrial dynamics regulatory genes such as Marf, Opa1, and the dominant negative mutant form of Drp1. Moreover, we found that the expression level of Marf was decreased in ALS-induced flies. These results indicate that the imbalance of mitochondrial dynamics caused by instability of Marf is linked to the pathogenesis of TDP-43, FUS, and TAF15-associated ALS. - Highlights: • Mitochondrial fission is highly enhanced in TDP-43, FUS, and TAF15-induced fly models of ALS. • Excessive mitochondrial fragmentation in fly models of ALS is restored by mitochondrial dynamics regulatory genes. • Level of Marf protein is decreased in TDP-43, FUS, and TAF15-mediated ALS. • Imbalance of mitochondrial dynamics caused by Marf instability is linked to the pathogenesis of ALS.« less

Transient disruption of vascular barriers using focused ultrasound and microbubbles for targeted drug delivery in the brain

NASA Astrophysics Data System (ADS)

Aryal, Muna

The physiology of the vasculature in the central nervous system (CNS) which includes the blood-brain-barrier (BBB) and other factors, prevents the transport of most anticancer agents to the brain and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels (blood-tumor barrier; BTB), along with several other factors, creates additional hurdles for drug treatment of brain tumors. Different methods have been used to bypass the BBB/BTB, but they have their own limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Magnetic Resonance Imaging guided Focused Ultrasound (MRIgFUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and BTB. The purpose of this thesis was to use this alternative approach to deliver chemotherapeutic agents through the BBB/BTB for brain tumor treatment in a rodent model to overcome the hinderances encountered in prior approaches tested for drug delivery in the CNS. The results presented in thesis demonstrate that MRIgFUS can be used to achieve consistent and reproducible BBB/BTB disruption in rats. It enabled us to achieve clinically-relevant concentrations of doxorubicin (~ 4.8+/-0.5 microg/g) delivered to the brain with the sonication parameters (0.69 MHz; 0.55 MPa; 10 ms bursts; 1 Hz PRF; 60 s duration), microbubble concentration (Definity, 10 microl/kg), and liposomoal doxorubicin (Lipo-DOX) dose (5.67 mg/kg) used. The resulting doxorubicin concentration was reduced by 32% when the agent was injected 10 minute after the last sonication. Three weekly sessions of FUS and Lipo-DOX appeared to be safe in the rat brain, despite some minor tissue damage. Importantly, the severe neurotoxicity seen in earlier works using other approaches does not appear to occur with delivery via FUS-BBB disruption. The resuls from three weekly treatments of FUS and Lipo-DOX in a rat glioma model are highly promising since they demonstrated that the method significantly inhibits tumor growth and improves survival. Animals that received three weekly sessions of FUS + Lipo-DOX (N = 8) had a median survival time that was increased significantly (P<0.001) compared to animals who received Lipo-DOX only (N = 6), FUS only (N = 8), or no treatment (N = 7). Median survival for animals that received FUS + Lipo-DOX was increased by 100% relative to untreated controls, whereas animals who received Lipo-DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS + Lipo-DOX group, and only a few tumor cells were detected in two animals. Tumor doxorubicin concentrations increased monotonically (823+/-600, 1817+/-732 and 2432+/-448 ng/g) in the control tumors at 9, 14 and 17 days respectively after administration of Lipo-DOX. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222+/-784, 3687+/-796 and 5658+/-821 ng/g) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (p<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery for Lipo-DOX are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da). Overall, this thesis research provides pre-clinical data toward the development of MRIgFUS as a noninvasive method for the delivery of agents such as Lipo-DOX across the BBB/BTB to treat patients with diseases of the central nervous system.

Pharmacokinetic analysis and drug delivery efficiency of the focused ultrasound-induced blood-brain barrier opening in non-human primates

PubMed Central

Samiotaki, Gesthimani; Karakatsani, Maria Eleni; Buch, Amanda; Papadopoulos, Stephanos; Wu, Shih Ying; Jambawalikar, Sachin; Konofagou, Elisa E.

2016-01-01

Purpose Focused Ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the Blood-Brain Barrier (BBB) locally, non-invasively and reversibly in rodents and non-human primates (NHP), suggesting the immense potential of this technique. The objective of this study entailed the investigation of the physiologic changes in the brain following the FUS-induced BBB opening and their relationship with the underlying anatomy. Materials and Methods Pharmacokinetic analysis was implemented in NHP’s that received FUS at various acoustic pressures. Relaxivity mapping enabled the robust quantitative detection of the BBB opening as well as gray and white matter segmentation. Drug delivery efficiency was measured for pre-clinical validation of the technique. Results Based on our results, the opening volume and the amount of the gadolinium delivered were found mostly contained in the grey matter, while FUS-induced permeability and drug concentration varied depending upon the underlying brain inhomogeneity, and increased with the acoustic pressure. Conclusions Overall, apart from the in vivo protocols for BBB analysis developed here, this study also suggests the important role that FUS can have in efficient drug delivery via localized and transient BBB opening. PMID:27916657

MRI-guided Focused Ultrasound Ablation of Lumbar Medial Branch Nerve: Feasibility and Safety Study in a Swine Model

PubMed Central

Kaye, Elena A; Monette, Sebastien; Srimathveeravalli, Govindarajan; Maybody, Majid; Solomon, Stephen B; Gulati, Amitabh

2016-01-01

Purpose About 10–40% of chronic low back pain cases involve facet joints, which are commonly treated with lumbar medial branch (MB) radiofrequency neurotomy. Magnetic Resonance Imaging-guided Focused Ultrasound (MRgFUS), a non-invasive, non-ionizing ablation modality used to treat tumors, neuropathic pain and painful bone metastasis, can also be used to disrupt nerve conduction. This work’s purpose was to study the feasibility and safety of direct MRgFUS ablation of the lumbar MB nerve in acute and subacute swine models. Materials and Methods In vivo MRgFUS ablation was performed in six swine (3 acute and 3 subacute) using a clinical MRgFUS system (ExAblate 2000®; InSightec Ltd., Haifa, Israel) and 3 T MRI scanner (SIGNA; GE Healthcare, Waukesha, WI, USA) combination. Behavioral assessment was performed, and imaging and histology were used to assess the treatment. Results and Conclusions Histological analysis of the in vivo studies confirmed thermal necrosis of the MB nerve could be achieved without damaging the spinal cord or adjacent nerve roots. MRgFUS did not cause changes in the animals’ behavior and ambulation. PMID:27443328

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage.

PubMed

Hill, Sarah J; Mordes, Daniel A; Cameron, Lisa A; Neuberg, Donna S; Landini, Serena; Eggan, Kevin; Livingston, David M

2016-11-29

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

PubMed Central

Hill, Sarah J.; Mordes, Daniel A.; Cameron, Lisa A.; Neuberg, Donna S.; Landini, Serena; Eggan, Kevin; Livingston, David M.

2016-01-01

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis. PMID:27849576

Real-Time Monitoring Of Regional Tissue Elasticity During FUS Focused Ultrasound Therapy Using Harmonic Motion Imaging

NASA Astrophysics Data System (ADS)

Maleke, Caroline; Pernot, Mathieu; Konofagou, Elisa

2006-05-01

The feasibility of the Harmonic Motion Imaging (HMI) technique for simultaneous monitoring and generation of focused ultrasound therapy using two separate focused ultrasound transducer elements has previously been shown. In this study, a new HMI technique is described that images tissue displacement induced by a harmonic radiation force induced using a single focused ultrasound element. First, wave propagation simulation models were used to compare the use of a single Amplitude-Modulated (AM) focused beam versus two overlapping focused beams as previously implemented for HMI. Simulation results indicated that, unlike in the two-beam configuration, the AM beam produced a consistent, stable focus for the applied harmonic radiation force. The AM beam thus offered the unique advantage of sustaining the application of the spatially-invariant radiation force. Experiments were then performed on gelatin gel phantoms and tissue in vitro bovine liver. The radiation force was generated by a 4.68 MHz focused transducer using a low-frequency Amplitude-Modulated (AM) RF-signal. RF data were acquired at 7.5 MHz with a PRF of 6.5 kHz and displacements were estimated using a 1D cross-correlation algorithm on successive RF signals. Furthermore, taking advantage of the real-time capability of our method, the change in the elastic properties was monitored during focused ultrasound (FUS) ablation of tissue in vitro bovine liver. Based on the harmonic displacements, their temperature-dependence, and the calculated acoustic radiation force, the change in the relative, regional stiffness could be monitored during heating and ablation, both using the displacement amplitude and the resulting phase shift change of the displacement relative to the radiation force temporal profile. In conclusion, the feasibility of using an AM radiation force for HMI for simultaneous monitoring and treatment during ultrasound therapy was demonstrated in phantoms and tissues in vitro. Further study of this method will include, ex vivo and in vivo, stiffness and temperature.

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets.

PubMed

Vyas, Urvi; Ghanouni, Pejman; Halpern, Casey H; Elias, Jeff; Pauly, Kim Butts

2016-09-01

In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen human subjects. Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. The simulated skull efficiency using individual-specific heterogeneous models predicts well (R(2) = 0.84) the experimental energy efficiency. This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible.

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets

PubMed Central

Vyas, Urvi; Ghanouni, Pejman; Halpern, Casey H.; Elias, Jeff; Pauly, Kim Butts

2016-01-01

Purpose: In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen human subjects. Methods: Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. Results: The simulated skull efficiency using individual-specific heterogeneous models predicts well (R2 = 0.84) the experimental energy efficiency. Conclusions: This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible. PMID:27587047

Predicting variation in subject thermal response during transcranial magnetic resonance guided focused ultrasound surgery: Comparison in seventeen subject datasets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vyas, Urvi, E-mail: urvi.vyas@gmail.com; Ghanouni,

Purpose: In transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) treatments, the acoustic and spatial heterogeneity of the skull cause reflection, absorption, and scattering of the acoustic beams. These effects depend on skull-specific parameters and can lead to patient-specific thermal responses to the same transducer power. In this work, the authors develop a simulation tool to help predict these different experimental responses using 3D heterogeneous tissue models based on the subject CT images. The authors then validate and compare the predicted skull efficiencies to an experimental metric based on the subject thermal responses during tcMRgFUS treatments in a dataset of seventeen humanmore » subjects. Methods: Seventeen human head CT scans were used to create tissue acoustic models, simulating the effects of reflection, absorption, and scattering of the acoustic beam as it propagates through a heterogeneous skull. The hybrid angular spectrum technique was used to model the acoustic beam propagation of the InSightec ExAblate 4000 head transducer for each subject, yielding maps of the specific absorption rate (SAR). The simulation assumed the transducer was geometrically focused to the thalamus of each subject, and the focal SAR at the target was used as a measure of the simulated skull efficiency. Experimental skull efficiency for each subject was calculated using the thermal temperature maps from the tcMRgFUS treatments. Axial temperature images (with no artifacts) were reconstructed with a single baseline, corrected using a referenceless algorithm. The experimental skull efficiency was calculated by dividing the reconstructed temperature rise 8.8 s after sonication by the applied acoustic power. Results: The simulated skull efficiency using individual-specific heterogeneous models predicts well (R{sup 2} = 0.84) the experimental energy efficiency. Conclusions: This paper presents a simulation model to predict the variation in thermal responses measured in clinical ctMRGFYS treatments while being computationally feasible.« less

A follow-up urine sample has limited value after treatment for urinary tract infection in children.

PubMed

Lytzen, Rebekka; Kaalund-Jørgensen, Kristine; Ahmed, Akhlaq; Abd-El-Redda, Haidar Karim; Thorup, Jørgen; Knudsen, Jenny Dahl; Cortes, Dina

2015-01-01

A routine follow-up urine sample (FUS) in the form of a midstream urine sample (MSU) is recommended after treatment for urinary tract infection (UTI) according to the Danish Paediatric Society (DPS) and "Lægehåndbogen" published by Danish Regions. We studied the effect of FUS with a focus on patients without symptoms at the time of FUS. Consecutive patients below 16.0 years treated for upper or lower UTI from 1 January 2009 to 31 December 2009 at Hvidovre Hospital in accordance with the guidelines of the department and the DPS. All patients were asked to provide a FUS within 21 days. A total of 87 patients were treated for upper UTI: 59 girls and 28 boys, the median age was 1.1 year (range: 0.1-15.6 years); and 42 girls were treated for lower UTI, their median age was 8.2 years (range: 2.5-15.3 years). After treatment, the risk of a UTI was 0% (0/87) after upper UTI versus 19% (8/42) after lower UTI (Fisher's exact test (FE), p < 0.0001). Among those without symptoms at FUS, the risk of a UTI was 0% (0/75) (95% confidence interval (CI): 0-4.9%) after upper UTI versus 4% (1/26) (95% CI: 0.1-19.6%) after lower UTI (FE, p = 0.2754). The cost of requesting a FUS in patients without symptoms was 166 euro after treatment for upper UTI and 66 euro after treatment of lower UTI. We do not recommend a FUS after treatment for UTI as the 95% CI of risk of missing UTI after treatment for upper UTI was below 5%. This strategy will save the patients/families and the health-care system. However, if a child has symptoms after treatment for UTI, it must be examined. not relevant. The study was approved by the Danish Data Protection Agency (J. no. 2007-58-0015).

A new polymorph of 4'-hydroxyvalerophenone revealed by thermoanalytical and X-ray diffraction studies

NASA Astrophysics Data System (ADS)

Lopes, Cátia S. D.; Bernardes, Carlos E. S.; Piedade, M. Fátima M.; Diogo, Hermínio P.; da Piedade, Manuel E. Minas

2017-04-01

A new polymorph of 1-(4-hydroxyphenyl)pentan-1-one (4'-hydroxyvalerophenone, HVP) was identified by using differential scanning calorimetry, hot stage microscopy, and X-ray powder diffraction. This novel crystal form (form II) was obtained by crystallization from melt. It has a fusion temperature of T fus = 324.3 ± 0.2 K and an enthalpy of fusion Δfus H m o = 18.14±0.18 kJ·mol-1. These values are significantly lower than those observed for the previously known phase (form I, monoclinic, space group P21/ c, T fus = 335.6 ± 0.7 K; Δfus H m o = 26.67±0.04 kJ·mol-1), which can be prepared by crystallization from ethanol. The results here obtained, therefore, suggest that form I is thermodynamically more stable than the newly identified form II and, furthermore, that the two polymorphs are monotropically related.

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

PubMed

Shin, Jaewoo; Kong, Chanho; Cho, Jae Sung; Lee, Jihyeon; Koh, Chin Su; Yoon, Min-Sik; Na, Young Cheol; Chang, Won Seok; Chang, Jin Woo

2018-02-01

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

Targeted Gene Transfer to the Brain via the Delivery of Brain-Penetrating DNA Nanoparticles with Focused Ultrasound

PubMed Central

Mead, Brian P.; Mastorakos, Panagiotis; Suk, Jung Soo; Klibanov, Alexander L.; Hanes, Justin; Price, Richard J.

2016-01-01

Gene therapy holds promise for the treatment of many pathologies of the central nervous system (CNS), including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracelluar matrix (ECM), which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact “brain penetrating” nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to ECM components. Here, we tested whether this combined approach could be utilized to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate localized, robust, and sustained transgene expression in the rat brain. Systemically administered DNA-BPN delivered through the BBB with FUS led to dose-dependent transgene expression only in the FUS-treated region that was evident as early as 24 h post administration and lasted for at least 28 days. In the FUS-treated region ~42% of all cells, including neurons and astrocytes, were transfected, while less than 6% were transfected in the contralateral non-FUS treated hemisphere. Importantly, this was achieved without any sign of toxicity or astrocyte activation. We conclude that the image-guided delivery of DNA-BPN with FUS and microbubbles constitutes a safe and non-invasive strategy for targeted gene therapy to the brain. PMID:26732553

FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.

PubMed

Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A; Munoz, David G; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R A

2011-09-01

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

PubMed Central

Coronas-Samano, Guillermo; Baker, Keeley L.; Tan, Winston J. T.; Ivanova, Alla V.; Verhagen, Justus V.

2016-01-01

Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology. Here we characterize and propose the Fus1 KO mice that lack a mitochondrial protein Fus1/Tusc2 as a new sAD model. To establish sAD relevance, we assessed sAD related deficits in Fus1 KO and WT adult mice of 4–5 months old, the equivalent human age when the earliest cognitive and olfactory sAD symptoms arise. Fus1 KO mice showed oxidative stress (increased levels of ROS, decreased levels of PRDX1), disruption of metabolic homeostasis (decreased levels of ACC2, increased phosphorylation of AMPK), autophagy (decreased levels of LC3-II), PKC (decreased levels of RACK1) and calcium signaling (decreased levels of Calb2) in the olfactory bulb and/or hippocampus. Mice were behaviorally tested using objective and accurate video tracking (Noldus), in which Fus1 KO mice showed clear deficits in olfactory memory (decreased habituation/cross-habituation in the short and long term), olfactory guided navigation memory (inability to reduce their latency to find the hidden cookie), spatial memory (learning impairments on finding the platform in the Morris water maze) and showed more sleep time during the diurnal cycle. Fus1 KO mice did not show clear deficits in olfactory perception (cross-habituation), association memory (passive avoidance) or in species-typical behavior (nest building) and no increased anxiety (open field, light-dark box) or depression/anhedonia (sucrose preference) at this relatively young age. These neurobehavioral deficits of the Fus1 KO mice at this relatively young age are highly relevant to sAD, making them suitable for effective research on pharmacological targets in the context of early intervention of sAD. PMID:27895577

Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain

NASA Astrophysics Data System (ADS)

Arvanitis, Costas D.; Livingstone, Margaret S.; McDannold, Nathan

2013-07-01

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation—the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies.

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.

PubMed

Downs, Matthew E; Buch, Amanda; Sierra, Carlos; Karakatsani, Maria Eleni; Teichert, Tobias; Chen, Shangshang; Konofagou, Elisa E; Ferrera, Vincent P

2015-01-01

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500 kHz, 200-400 kPa, 4-5 μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4-20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of' visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4-5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.

Nonthermal ablation in the rat brain using focused ultrasound and an ultrasound contrast agent: long-term effects

PubMed Central

McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia

2016-01-01

OBJECTIVE Thermal ablation with transcranial MRI-guided focused ultrasound (FUS) is currently under investigation as a less invasive alternative to radiosurgery and resection. A major limitation of the method is that its use is currently restricted to centrally located brain targets. The combination of FUS and a microbubble-based ultrasound contrast agent greatly reduces the ultrasound exposure level needed to ablate brain tissue and could be an effective means to increase the “treatment envelope” for FUS in the brain. This method, however, ablates tissue through a different mechanism: destruction of the microvasculature. It is not known whether nonthermal FUS ablation in substantial volumes of tissue can safely be performed without unexpected effects. The authors investigated this question by ablating volumes in the brains of normal rats. METHODS Overlapping sonications were performed in rats (n = 15) to ablate a volume in 1 hemisphere per animal. The sonications (10-msec bursts at 1 Hz for 60 seconds; peak negative pressure 0.8 MPa) were combined with the ultrasound contrast agent Optison (100 μl/kg). The rats were followed with MRI for 4–9 weeks after FUS, and the brains were examined with histological methods. RESULTS Two weeks after sonication and later, the lesions appeared as cyst-like areas in T2-weighted MR images that were stable over time. Histological examination demonstrated well-defined lesions consisting of a cyst-like cavity that remained lined by astrocytic tissue. Some white matter structures within the sonicated area were partially intact. CONCLUSIONS The results of this study indicate that nonthermal FUS ablation can be used to safely ablate tissue volumes in the brain without unexpected delayed effects. The findings are encouraging for the use of this ablation method in the brain. PMID:26848919

The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation.

PubMed

Liu, Xinxiu; Chen, Jiayu; Liu, Wenchao; Li, Xiaogang; Chen, Qi; Liu, Tao; Gao, Shaorong; Deng, Min

2015-07-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. Mutations in the fused in sarcoma (FUS) gene and abnormal aggregation of FUS protein have been reported in ALS. However, the mechanisms involved in ALS are poorly understood. Clinical drug trails have failed due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. Previous reports demonstrated that viral-based ALS-iPS cells generated from fibroblasts harvested from Caucasian populations are ideal for basic research; however, ALS-iPS cells are precluded from cell-based therapeutic applications because of the risks associated with the integration of viral sequences into the genome and inconvenience associated with dermal biopsies. To establish a model for use in clinical applications, using episomal vectors, we generated an integration-free iPS cell line from peripheral blood mononuclear cells (PBMCs) harvested from a familial ALS (FALS) patient carrying the FUS-P525L mutation and a healthy control. Furthermore, we successfully differentiated ALS patient-specific iPS cells into MNs and subsequently detected cytoplasmic mislocalization and formation of FUS protein aggregates in MNs due to the FUS-P525L mutation. Our findings offer a cell-based disease model for use in further elucidating ALS pathogenesis and provide a tool for exploring gene repair coupled with cell replacement therapy.

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts.

PubMed

Shen, Yuanyuan; Pi, Zhaoke; Yan, Fei; Yeh, Chih-Kuang; Zeng, Xiaojun; Diao, Xianfen; Hu, Yaxin; Chen, Siping; Chen, Xin; Zheng, Hairong

2017-01-01

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood-brain barrier (BBB) or blood-tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.

Transcranial functional ultrasound imaging of the brain using microbubble-enhanced ultrasensitive Doppler

PubMed Central

Errico, Claudia; Osmanski, Bruno-Félix; Pezet, Sophie; Couture, Olivier; Lenkei, Zsolt; Tanter, Mickael

2016-01-01

Functional ultrasound (fUS) is a novel neuroimaging technique, based on high-sensitivity ultrafast Doppler imaging of cerebral blood volume, capable of measuring brain activation and connectivity in rodents with high spatiotemporal resolution (100 μm, 1 ms). However, the skull attenuates acoustic waves, so fUS in rats currently requires craniotomy or a thinned-skull window. Here we propose a non-invasive approach by enhancing the fUS signal with a contrast agent, inert gas microbubbles. Plane-wave illumination of the brain at high frame rate (500 Hz compounded sequence with three tilted plane waves, PRF = 1500Hz with a 128 element 15 MHz linear transducer), yields highly-resolved neurovascular maps. We compared fUS imaging performance through the intact skull bone (transcranial fUS) versus a thinned-skull window in the same animal. First, we show that the vascular network of the adult rat brain can be imaged transcranially only after a bolus intravenous injection of microbubbles, which leads to a 9 dB gain in the contrast-to-tissue ratio. Next, we demonstrate that functional increase in the blood volume of the primary sensory cortex after targeted electrical-evoked stimulations of the sciatic nerve is observable transcranially in presence of contrast agents, with high reproducibility (Pearson's coefficient ρ = 0.7 ± 0.1, p = 0.85). Our work demonstrates that the combination of ultrafast Doppler imaging and injection of contrast agent allows non-invasive functional brain imaging through the intact skull bone in rats. These results should ease non-invasive longitudinal studies in rodents and open a promising perspective for the adoption of highly resolved fUS approaches for the adult human brain. PMID:26416649

Transcranial passive acoustic mapping with hemispherical sparse arrays using CT-based skull-specific aberration corrections: a simulation study

PubMed Central

Jones, Ryan M.; O’Reilly, Meaghan A.; Hynynen, Kullervo

2013-01-01

The feasibility of transcranial passive acoustic mapping with hemispherical sparse arrays (30 cm diameter, 16 to 1372 elements, 2.48 mm receiver diameter) using CT-based aberration corrections was investigated via numerical simulations. A multi-layered ray acoustic transcranial ultrasound propagation model based on CT-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm (Norton and Won 2000 IEEE Trans. Geosci. Remote Sens. 38 1337–43), simulated acoustic source fields representing the emissions from acoustically-stimulated microbubbles were spatially mapped through three digitized human skulls, with the transskull reconstructions closely matching the water-path control images. Image quality was quantified based on main lobe beamwidths, peak sidelobe ratio, and image signal-to-noise ratio. The effects on the resulting image quality of the source’s emission frequency and location within the skull cavity, the array sparsity and element configuration, the receiver element sensitivity, and the specific skull morphology were all investigated. The system’s resolution capabilities were also estimated for various degrees of array sparsity. Passive imaging of acoustic sources through an intact skull was shown possible with sparse hemispherical imaging arrays. This technique may be useful for the monitoring and control of transcranial focused ultrasound (FUS) treatments, particularly non-thermal, cavitation-mediated applications such as FUS-induced blood-brain barrier disruption or sonothrombolysis, for which no real-time monitoring technique currently exists. PMID:23807573

Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring.

PubMed

Konofagou, Elisa E; Maleke, Caroline; Vappou, Jonathan

2012-01-01

Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring.

Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring

PubMed Central

Maleke, Caroline; Vappou, Jonathan

2014-01-01

Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring. PMID:25364321

Spindle Cell Rhabdomyosarcoma of Bone with FUS-TFCP2 Fusion: Confirmation of a Very Recently Described Rhabdomyosarcoma Subtype.

PubMed

Dashti, Nooshin K; Wehrs, Rebecca N; Thomas, Brittany C; Nair, Asha; Davila, Jaime; Buckner, Jan C; Martinez, Anthony P; Sukov, William R; Halling, Kevin C; Howe, Benjamin M; Folpe, Andrew L

2018-05-14

Rhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harboring a FUS-TFCP2 fusion and involving both soft tissue and bone locations has very recently been reported. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma. A previously-well 72-year old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA-seq, RT-PCR and FISH confirmed the presence of the FUS-TFCP2 fusion. Spindle cell rhabdomyosarcomas carrying the FUS-TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/ sclerosing rhabdomyosarcoma are discussed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential into the Brain using MRI-Guided Focused Ultrasound

PubMed Central

Etame, Arnold B.; Diaz, Roberto J.; O’Reilly, Meaghan A.; Smith, Christian A.; Mainprize, Todd G.; Hynynen, Kullervo; Rutka, James T.

2014-01-01

The blood brain barrier (BBB) is a major impediment to the delivery of therapeutics into the central nervous system (CNS). Gold nanoparticles (AuNPs) have been successfully employed in multiple potential therapeutic and diagnostic applications outside the CNS. However, AuNPs have very limited biodistribution within the CNS following intravenous administration. Magnetic resonance imaging guided focused ultrasound (MRgFUS) is a novel technique that can transiently increase BBB permeability allowing delivery of therapeutics into the CNS. MRgFUS has not been previously employed for delivery of AuNPs into the CNS. This work represents the first demonstration of focal enhanced delivery of AuNPs into the CNS using MRgFUS in a rat model both safely and effectively. Histologic visualization and analytical quantification of AuNPs within the brain parenchyma suggest BBB transgression. These results suggest a role for MRgFUS in the delivery of AuNPs with therapeutic potential into the CNS for targeting neurological diseases. PMID:22349099

PET/CT imaging evidence of FUS-mediated (18)F-FDG uptake changes in rat brain

PubMed Central

Kim, Hyungmin; Park, Mi-Ae; Wang, Shuyan; Chiu, Alan; Fischer, Krisztina; Yoo, Seung-Schik

2013-01-01

Purpose: Transcranial focused ultrasound (FUS) delivers highly focused acoustic energy to a small region of the brain in a noninvasive manner. Recent studies have revealed that FUS, which is administered either in pulsed or continuous waves, can elicit or suppress neural tissue excitability. This neuromodulatory property of FUS has been demonstrated via direct motion detection, electrophysiological recordings, functional magnetic resonance imaging (fMRI), confocal imaging, and microdialysis sampling of neurotransmitters. This study presents new evidence of local increase in glucose metabolism induced by FUS to the rat brain using FDG (18-fludeoxyglucose) positron emission tomography (PET). Methods: Sprague–Dawley rats underwent sonication to a unilateral hemispheric area of the brain prior to PET scan. The pulsed sonication (350 kHz, tone burst duration of 0.5 ms, pulse repetition frequency of 1 kHz, and duration of 300 ms) was applied in 2 s intervals for 40 min immediately after the FDG injection via tail vein. Subsequently, the PET was acquired in dynamic list-mode to image FDG activity for an hour, and reconstructed into a single volume representing standardized uptake value (SUV). The raw SUV as well as its asymmetry index (AI) were measured from five different volume-of-interests (VOIs) of the brain for both hemispheres, and compared between sonicated and unsonicated groups. Results: Statistically significant hemispheric changes in SUV were observed only at the center of sonication focus within the FUS group [paired t-test; t(7) = 3.57, p < 0.05]. There were no significant hemispheric differences in SUV within the control group in any of the VOIs. A statistically significant elevation in AI (t-test; t(7) = 3.40, p < 0.05) was observed at the center of sonication focus (7.9 ± 2.5%, the deviations are in standard error) among the FUS group when compared to the control group (−0.8 ± 1.2%). Conclusions: Spatially distinct increases in the glucose metabolic activity in the rat brain is present only at the center of sonication focus, suggesting localized functional neuromodulation mediated by the sonication. PMID:23464343

Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging

NASA Astrophysics Data System (ADS)

Chu, Po-Chun; Chai, Wen-Yen; Tsai, Chih-Hung; Kang, Shih-Tsung; Yeh, Chih-Kuang; Liu, Hao-Li

2016-09-01

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

The investigation of genetic and clinical features in Chinese patients with juvenile amyotrophic lateral sclerosis.

PubMed

Liu, Z-J; Lin, H-X; Liu, G-L; Tao, Q-Q; Ni, W; Xiao, B-G; Wu, Z-Y

2017-09-01

Juvenile amyotrophic lateral sclerosis (JALS) occurs at an age of onset below 25 years with a heterogeneous disease onset location, variable progression and survival time. To investigate whether an ALS gene profile could resolve any aspects of clinical symptom heterogeneity, we have used targeted sequencing technology in a cohort of 12 JALS patients of Chinese descent. We detected 5 likely pathogenic mutations, 2 in familial probands and 3 in sporadic patients. One was a known TARDBP mutation (p.G348V) and 4 were FUS frameshift mutations including a known p.Gln519Ilefs*9 mutation and 3 novel mutations, p.Gly515Valfs*14, p.Gly486Profs*30, and p.Arg498Alafs*32. Of the 4 FUS mutations, 2 were able to be confirmed as de novo mutations. The TARDBP mutation carrier showed a classic ALS phenotype. All patients with FUS mutations experienced limb weakness at an early age and developed bulbar symptoms during the disease course. FUS mutations have previously been associated with increased JALS disease progression, however, we found a large range 12 to 84 months in disease survival (mean 58.2 months). Our results justify future screening for variants in FUS as it remains the most frequent genetic determinant of early onset, JALS (found in 30% of our patients). © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging.

PubMed

Chu, Po-Chun; Chai, Wen-Yen; Tsai, Chih-Hung; Kang, Shih-Tsung; Yeh, Chih-Kuang; Liu, Hao-Li

2016-09-15

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

A cytoplasmic long noncoding RNA LINC00470 as a new AKT activator to mediate glioblastoma cell autophagy.

PubMed

Liu, Changhong; Zhang, Yan; She, Xiaoling; Fan, Li; Li, Peiyao; Feng, Jianbo; Fu, Haijuan; Liu, Qing; Liu, Qiang; Zhao, Chunhua; Sun, Yingnan; Wu, Minghua

2018-06-04

Despite the overwhelming number of investigations on AKT, little is known about lncRNA on AKT regulation, especially in GBM cells. RNA-binding protein immunoprecipitation assay (RIP) and RNA pulldown were used to confirm the binding of LINC00470 and fused in sarcoma (FUS). Confocal imaging, co-immunoprecipitation (Co-IP) and GST pulldown assays were used to detect the interaction between FUS and AKT. EdU assay, CCK-8 assay, and intracranial xenograft assays were performed to demonstrate the effect of LINC00470 on the malignant phenotype of GBM cells. RT-qPCR and Western blotting were performed to test the effect of LINC00470 on AKT and pAKT. In this study, we demonstrated that LINC00470 was a positive regulator for AKT activation in GBM. LINC00470 bound to FUS and AKT to form a ternary complex, anchoring FUS in the cytoplasm to increase AKT activity. Higher pAKT activated by LINC00470 inhibited ubiquitination of HK1, which affected glycolysis, and inhibited cell autophagy. Furthermore, higher LINC00470 expression was associated with GBM tumorigenesis and poor patient prognosis. Our findings revealed a noncanonical AKT activation signaling pathway, i.e., LINC00470 directly interacts with FUS, serving as an AKT activator to promote GBM progression. LINC00470 has an important referential significance to evaluate the prognosis of patients.

Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study.

PubMed

Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-04-28

Transcranial MRI-guided focused ultrasound is a rapidly advancing method for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). The method's main advantages are that it is both targeted and noninvasive, and that it can be easily repeated. Studies have shown that liposomal doxorubicin (Lipo-DOX), a chemotherapy agent with promise for tumors in the central nervous system, can be delivered into the brain across BBB. However, prior studies have suggested that doxorubicin can be significantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of Lipo-DOX administered after FUS-induced BBB disruption (FUS-BBBD) induces severe adverse events in the normal brain tissues. First, we used fluorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD to ensure that a clinically relevant doxorubicin concentration was achieved in the brain. Next, we performed three weekly sessions with FUS-BBBD±Lipo-DOX administration. Five to twelve targets were sonicated each week, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., 2013). Five rats received three weekly sessions where i.v. injected Lipo-DOX was combined with FUS-BBBD; an additional four rats received FUS-BBBD only. Animals were euthanized 70days from the first session and brains were examined in histology. We found that clinically-relevant concentrations of doxorubicin (4.8±0.5μg/g) were delivered to the brain with the sonication parameters (0.69MHz; 0.55-0.81MPa; 10ms bursts; 1Hz PRF; 60s duration), microbubble concentration (Definity, 10μl/kg), and the administered Lipo-DOX dose (5.67mg/kg) used. The resulting concentration of Lipo-DOX was reduced by 32% when it was injected 10min after the last sonication compared to cases where the agent was delivered before sonication. In histology, the severe neurotoxicity observed in some previous studies with doxorubicin by other investigators was not observed here. However, four of the five rats who received FUS-BBBD and Lipo-DOX had regions (dimensions: 0.5-2mm) at the focal targets with evidence of minor prior damage, either a small scar (n=4) or a small cyst (n=1). The focal targets were unaffected in rats who received FUS-BBBD alone. The result indicates that while delivery of Lipo-DOX to the rat brain might result in minor damage, the severe neurotoxicity seen in earlier works does not appear to occur with delivery via FUS-BBB disruption. The damage may be related to capillary damage produced by inertial cavitation, which might have resulted in excessive doxorubicin concentrations in some areas. Copyright © 2015 Elsevier B.V. All rights reserved.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function.

PubMed

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2013-11-01

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity--and thus a low microbubble concentration--some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function

PubMed Central

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2014-01-01

Object Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging–guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. Methods In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Results Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. Conclusions This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity—and thus a low microbubble concentration—some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures. PMID:24010975

Inverse effects of flowing phase-shift nanodroplets and lipid-shelled microbubbles on subsequent cavitation during focused ultrasound exposures.

PubMed

Zhang, Siyuan; Cui, Zhiwei; Xu, Tianqi; Liu, Pan; Li, Dapeng; Shang, Shaoqiang; Xu, Ranxiang; Zong, Yujin; Niu, Gang; Wang, Supin; He, Xijing; Wan, Mingxi

2017-01-01

This paper compared the effects of flowing phase-shift nanodroplets (NDs) and lipid-shelled microbubbles (MBs) on subsequent cavitation during focused ultrasound (FUS) exposures. The cavitation activity was monitored using a passive cavitation detection method as solutions of either phase-shift NDs or lipid-shelled MBs flowed at varying velocities through a 5-mm diameter wall-less vessel in a transparent tissue-mimicking phantom when exposed to FUS. The intensity of cavitation for the phase-shift NDs showed an upward trend with time and cavitation for the lipid-shelled MBs grew to a maximum at the outset of the FUS exposure followed by a trend of decreases when they were static in the vessel. Meanwhile, the increase of cavitation for the phase-shift NDs and decrease of cavitation for the lipid-shelled MBs had slowed down when they flowed through the vessel. During two discrete identical FUS exposures, while the normalized inertial cavitation dose (ICD) value for the lipid-shelled MB solution was higher than that for the saline in the first exposure (p-value <0.05), it decreased to almost the same level in the second exposure. For the phase-shift NDs, the normalized ICD was 0.71 in the first exposure and increased to 0.97 in the second exposure. At a low acoustic power, the normalized ICD values for the lipid-shelled MBs tended to increase with increasing velocities from 5 to 30cm/s (r>0.95). Meanwhile, the normalized ICD value for the phase-shift NDs was 0.182 at a flow velocity of 5cm/s and increased to 0.188 at a flow velocity of 15cm/s. As the flow velocity increased to 20cm/s, the normalized ICD was 0.185 and decreased to 0.178 at a flow velocity of 30cm/s. At high acoustic power, the normalized ICD values for both the lipid-shelled MBs and the phase-shift NDs increased with increasing flow velocities from 5 to 30cm/s (r>0.95). The effects of the flowing phase-shift NDs vaporized into gas bubbles as cavitation nuclei on the subsequent cavitation were inverse to those of the flowing lipid-shelled MBs destroyed after focused ultrasound exposures. Copyright © 2016 Elsevier B.V. All rights reserved.

Transcranial cavitation-mediated ultrasound therapy at sub-MHz frequency via temporal interference modulation

NASA Astrophysics Data System (ADS)

Sun, Tao; Sutton, Jonathan T.; Power, Chanikarn; Zhang, Yongzhi; Miller, Eric L.; McDannold, Nathan J.

2017-10-01

Sub-megahertz transmission is not usually adopted in pre-clinical small animal experiments for focused ultrasound (FUS) brain therapy due to the large focal size. However, low frequency FUS is vital for preclinical evaluations due to the frequency-dependence of cavitation behavior. To maximize clinical relevance, a dual-aperture FUS system was designed for low-frequency (274.3 kHz) cavitation-mediated FUS therapy. Combining two spherically curved transducers provides significantly improved focusing in the axial direction while yielding an interference pattern with strong side lobes, leading to inhomogeneously distributed cavitation activities. By operating the two transducers at slightly offset frequencies to modulate this interference pattern over the period of sonication, the acoustic energy was redistributed and resulted in a spatially homogenous treatment profile. Simulation and pressure field measurements in water were performed to assess the beam profiles. In addition, the system performance was demonstrated in vivo in rats via drug delivery through microbubble-mediated blood-brain barrier disruption. This design resulted in a homogenous treatment profile that was fully contained within the rat brain at a clinically relevant acoustic frequency.

Transcranial focused ultrasound stimulation of human primary visual cortex

NASA Astrophysics Data System (ADS)

Lee, Wonhye; Kim, Hyun-Chul; Jung, Yujin; Chung, Yong An; Song, In-Uk; Lee, Jong-Hwan; Yoo, Seung-Schik

2016-09-01

Transcranial focused ultrasound (FUS) is making progress as a new non-invasive mode of regional brain stimulation. Current evidence of FUS-mediated neurostimulation for humans has been limited to the observation of subjective sensory manifestations and electrophysiological responses, thus warranting the identification of stimulated brain regions. Here, we report FUS sonication of the primary visual cortex (V1) in humans, resulting in elicited activation not only from the sonicated brain area, but also from the network of regions involved in visual and higher-order cognitive processes (as revealed by simultaneous acquisition of blood-oxygenation-level-dependent functional magnetic resonance imaging). Accompanying phosphene perception was also reported. The electroencephalo graphic (EEG) responses showed distinct peaks associated with the stimulation. None of the participants showed any adverse effects from the sonication based on neuroimaging and neurological examinations. Retrospective numerical simulation of the acoustic profile showed the presence of individual variability in terms of the location and intensity of the acoustic focus. With exquisite spatial selectivity and capability for depth penetration, FUS may confer a unique utility in providing non-invasive stimulation of region-specific brain circuits for neuroscientific and therapeutic applications.

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

PubMed Central

Goedert, Michel; Ghetti, Bernardino; Spillantini, Maria Grazia

2012-01-01

Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are inherited in an autosomal-dominant manner. Mutations in seven genes cause FTD, with those in tau (MAPT), chromosome 9 open reading frame 72 (C9ORF72), and progranulin (GRN) being the most common. Mutations in MAPT give rise to FTLD-tau and mutations in C9ORF72 and GRN to FTLD-TDP. The other four genes are transactive response–DNA binding protein-43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). Mutations in TARDBP and VCP give rise to FTLD-TDP, mutations in FUS to FTLD-FUS, and mutations in CHMP2B to FTLD-UPS. The discovery that mutations in MAPT cause neurodegeneration and dementia has important implications for understanding Alzheimer disease. PMID:22355793

Towards multifocal ultrasonic neural stimulation: pattern generation algorithms

NASA Astrophysics Data System (ADS)

Hertzberg, Yoni; Naor, Omer; Volovick, Alexander; Shoham, Shy

2010-10-01

Focused ultrasound (FUS) waves directed onto neural structures have been shown to dynamically modulate neural activity and excitability, opening up a range of possible systems and applications where the non-invasiveness, safety, mm-range resolution and other characteristics of FUS are advantageous. As in other neuro-stimulation and modulation modalities, the highly distributed and parallel nature of neural systems and neural information processing call for the development of appropriately patterned stimulation strategies which could simultaneously address multiple sites in flexible patterns. Here, we study the generation of sparse multi-focal ultrasonic distributions using phase-only modulation in ultrasonic phased arrays. We analyse the relative performance of an existing algorithm for generating multifocal ultrasonic distributions and new algorithms that we adapt from the field of optical digital holography, and find that generally the weighted Gerchberg-Saxton algorithm leads to overall superior efficiency and uniformity in the focal spots, without significantly increasing the computational burden. By combining phased-array FUS and magnetic-resonance thermometry we experimentally demonstrate the simultaneous generation of tightly focused multifocal distributions in a tissue phantom, a first step towards patterned FUS neuro-modulation systems and devices.

Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation.

PubMed

Kovacs, Zsofia I; Kim, Saejeong; Jikaria, Neekita; Qureshi, Farhan; Milo, Blerta; Lewis, Bobbi K; Bresler, Michele; Burks, Scott R; Frank, Joseph A

2017-01-03

MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China.

PubMed

Hou, Lihua; Jiao, Bin; Xiao, Tingting; Zhou, Lu; Zhou, Zhifan; Du, Juan; Yan, Xinxiang; Wang, Junling; Tang, Beisha; Shen, Lu

2016-09-08

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.

Life-cycle and growth-phase-dependent regulation of the ubiquitin genes of Trypanosoma cruzi.

PubMed

Manning-Cela, Rebeca; Jaishankar, Sobha; Swindle, John

2006-07-01

Trypanosoma cruzi, the causative agent of Chagas disease, exhibits a complex life cycle that is accompanied by the stage-specific gene expression. At the molecular level, very little is known about gene regulation in trypanosomes. Complex gene organizations coupled with polycistronic transcription units make the analysis of regulated gene expression difficult in trypanosomes. The ubiquitin genes of T. cruzi are a good example of this complexity. They are organized as a single cluster containing five ubiquitin fusion (FUS) and five polyubiquitin (PUB) genes that are polycistronically transcribed but expressed differently in response to developmental and environmental changes. Gene replacements were used to study FUS and PUB gene expression at different stages of growth and at different points in the life cycle of T. cruzi. Based on the levels of reporter gene expression, it was determined that FUS1 expression was downregulated as the parasites approached stationary phase, whereas PUB12.5 polyubiquitin gene expression increased. Conversely, FUS1 expression increases when epimastigotes and amastigotes differentiate into trypomastigotes, whereas the expression of PUB12.5 decreases when epimastigotes differentiate into amastigotes and trypomastigotes. Although the level of CAT activity in logarithmic growing epimastigotes is six- to seven-fold higher when the gene was expressed from the FUS1 locus than when expressed from the PUB12.5 locus, the rate of transcription from the two loci was the same implying that post-transcriptional mechanisms play a dominant role in the regulation of gene expression.

Magnetic resonance-guided focused ultrasound treatment of facet joint pain: summary of preclinical phase

PubMed Central

2014-01-01

Study design A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted to test the feasibility, safety, and efficacy of magnetic resonance-guided focused ultrasound (MRgFUS) for treating facet joint pain. Objective The goal of the current study was to develop a novel method for accurate and safe noninvasive facet joint ablation using MRgFUS. Summary of background data Facet joints are a common source of chronic back pain. Direct facet joint interventions include medial branch nerve ablation and intra-articular injections, which are widely used, but limited in the short and long term. MRgFUS is a breakthrough technology that enables accurate delivery of high-intensity focused ultrasound energy to create a localized temperature rise for tissue ablation, using MR guidance for treatment planning and real-time feedback. Methods We validated the feasibility, safety, and efficacy of MRgFUS for facet joint ablation using the ExAblate 2000® System (InSightec Ltd., Tirat Carmel, Israel) and confirmed the system's ability to ablate the edge of the facet joint and all terminal nerves innervating the joint. A phantom experiment, two thermocouple experiments, three in vivo pig experiments, and a simulated treatment on a healthy human volunteer were conducted. Results The experiments showed that targeting the facet joint with energies of 150–450 J provides controlled and accurate heating at the facet joint edge without penetration to the vertebral body, spinal canal, or root foramina. Treating with reduced diameter of the acoustic beam is recommended since a narrower beam improves access to the targeted areas. Conclusions MRgFUS can safely and effectively target and ablate the facet joint. These results are highly significant, given that this is the first study to demonstrate the potential of MRgFUS to treat facet joint pain. PMID:24921048

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts

PubMed Central

Shen, Yuanyuan; Pi, Zhaoke; Yan, Fei; Yeh, Chih-Kuang; Zeng, Xiaojun; Diao, Xianfen; Hu, Yaxin; Chen, Siping; Chen, Xin; Zheng, Hairong

2017-01-01

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood–brain barrier (BBB) or blood–tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma. PMID:28848341

MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement.

PubMed

Doyle, Leona A; Wang, Wei-Lien; Dal Cin, Paola; Lopez-Terrada, Dolores; Mertens, Fredrik; Lazar, Alexander J F; Fletcher, Christopher D M; Hornick, Jason L

2012-10-01

Sclerosing epithelioid fibrosarcoma (SEF) is a rare aggressive fibroblastic neoplasm composed of cords of epithelioid cells embedded in a dense collagenous stroma. The reported immunophenotype of SEF is nonspecific. Some SEF cases show morphologic and molecular overlap with low-grade fibromyxoid sarcoma (LGFMS), suggesting a relationship between these tumor types. MUC4 has recently been identified as a sensitive and specific marker for LGFMS; MUC4 expression was also observed in 2 tumors with hybrid features of SEF and LGFMS. We investigated MUC4 expression in SEF and other epithelioid soft tissue tumors to determine (1) the potential diagnostic utility of MUC4 for SEF and (2) the association between MUC4 expression and FUS rearrangement in SEF. Whole sections of 180 tumors were evaluated: 41 cases of SEF (including 29 "pure" SEF and 12 hybrid LGFMS-SEF), 20 epithelioid sarcomas, 11 clear cell sarcomas, 11 metastatic melanomas, 10 perivascular epithelioid cell tumors, 10 alveolar soft part sarcomas, 10 epithelioid angiosarcomas, 10 epithelioid hemangioendotheliomas, 10 epithelioid gastrointestinal stromal tumors, 10 myoepithelial carcinomas, 17 ossifying fibromyxoid tumors, 10 leiomyosarcomas, and 10 biphasic synovial sarcomas. Immunohistochemical analysis was performed after antigen retrieval using a mouse anti-MUC4 monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed on 33 SEF cases using FUS break-apart probes. A subset of cases was also evaluated for EWSR1 and CREB3L2/L1 rearrangements by FISH. Strong diffuse cytoplasmic staining for MUC4 was observed in 32 of 41 (78%) cases of SEF, including all 12 hybrid tumors. FUS rearrangement was detected in 8 of 21 (38%) MUC4-positive cases of SEF with successful FISH studies. The prevalence of FUS rearrangement was similar in hybrid LGFMS-SEF (2 of 6; 33%) and SEF without an LGFMS component (6 of 15; 40%). FUS rearrangement was not detected in any cases of MUC4-negative SEF. Two hybrid tumors had both EWSR1 and CREB3L1 rearrangements. MUC4 expression was also seen in 9 of 10 (90%) biphasic synovial sarcomas, predominantly in the glandular component. All other tumor types were negative for MUC4, apart from focal reactivity in 5 ossifying fibromyxoid tumors, 2 epithelioid gastrointestinal stromal tumors, and 1 myoepithelial carcinoma. MUC4 is a sensitive and relatively specific marker for SEF among epithelioid soft tissue tumors. MUC4 expression occurs more frequently than FUS rearrangement in SEF. The finding of EWSR1 and CREB3L1 rearrangements in 2 cases of hybrid LGFMS-SEF suggests that SEFs are genetically heterogenous. MUC4-positive SEFs with FUS rearrangement are likely closely related to LGFMS. MUC4-positive SEFs that lack FUS rearrangement may be related to LGFMS but could have alternate fusion partners, including EWSR1. SEF without MUC4 expression may represent a distinct group of tumors. MUC4 expression correlates with glandular epithelial differentiation in biphasic synovial sarcoma and is very limited in other epithelioid soft tissue tumors.

Non-human primate skull effects on the cavitation detection threshold of FUS-induced blood-brain barrier opening

NASA Astrophysics Data System (ADS)

Wu, Shih-Ying; Tung, Yao-Sheng; Marquet, Fabrice; Chen, Cherry C.; Konofagou, Elisa E.

2012-11-01

Microbubble (MB)-assisted focused ultrasound is a promising technique for delivering drugs to the brain by noninvasively and transiently opening the blood-brain barrier (BBB), and monitoring BBB opening using passive cavitation detection (PCD) is critical in detecting its occurrence, extent as well as assessing its mechanism. One of the main obstacles in achieving those objectives in large animals is the transcranial attenuation. To study the effects, the cavitation response through the in-vitro non-human primate (NHP) skull was investigated. In-house manufactured lipid-shelled MB (medium diameter: 4-5 um) were injected into a 4-mm channel of a phantom below a degassed monkey skull. A hydrophone confocally aligned with the FUS transducer served as PCD during sonication (frequency: 0.50 MHz, peak rarefactional pressures: 0.05-0.60 MPa, pulse length: 100 cycles, PRF: 10 Hz, duration: 2 s) for four cases: water without skull, water with skull, MB without skull and MB with skull. A 5.1-MHz linear-array transducer was also used to monitor the MB disruption. The frequency spectra, spectrograms, stable cavitation dose (SCD) and inertial cavitation dose (ICD) were quantified. Results showed that the onset of stable cavitation and inertial cavitation in the experiments occurred at 50 kPa, and was detectable throught the NHP skull since the both the detection thresholds for stable cavitation and inertial cavitation remained unchanged compared to the non-skull case, and the SCD and ICD acquired transcranially may not adequately represent the true extent of stable and inertial cavitation due to the skull attenuation.

Amyotrophic Lateral Sclerosis after Receiving the Human Papilloma Virus Vaccine: A Case Report of a 15-year-old Girl.

PubMed

Hikiami, Ryota; Yamakado, Hodaka; Tatsumi, Shinsui; Ayaki, Takashi; Hashi, Yuichiro; Yamashita, Hirofumi; Sawamoto, Nobukatsu; Tsuji, Teruyuki; Urushitani, Makoto; Takahashi, Ryosuke

2018-02-09

We herein report a 15-year-old girl who developed rapid progressive muscle weakness soon after the third injection of a bivalent human papilloma virus (HPV) vaccine. Although immunotherapies were performed for possible vaccine-related disorders, she died of respiratory failure 14 months after the onset of the disease. A genetic analysis identified a heterozygous p.P525L mutation of the fused in sarcoma (FUS) gene, and a histopathological analysis was also consistent with FUS-associated amyotrophic lateral sclerosis (ALS) without any evidence of neuroinflammation. We concluded the diagnosis to be FUS-ALS, although we cannot completely rule out the possibility that the vaccination worked as a trigger.

Pharmacodynamic and Therapeutic Investigation of Focused Ultrasound-Induced Blood-Brain Barrier Opening for Enhanced Temozolomide Delivery in Glioma Treatment

PubMed Central

Liu, Hao-Li; Huang, Chiung-Yin; Chen, Ju-Yu; Wang, Hay-Yan Jack; Chen, Pin-Yuan; Wei, Kuo-Chen

2014-01-01

Focused ultrasound (FUS) exposure with the presence of microbubbles has been shown to transiently open the blood-brain barrier (BBB), and thus has potential to enhance the delivery of various kinds of therapeutic agents into brain tumors. The purpose of this study was to assess the preclinical therapeutic efficacy of FUS-BBB opening for enhanced temozolomide (TMZ) delivery in glioma treatment. FUS exposure with microbubbles was delivered to open the BBB of nude mice that were either normal or implanted with U87 human glioma cells. Different TMZ dose regimens were tested, ranging from 2.5 to 25 mg/kg. Plasma and brain samples were obtained at different time-points ranging from 0.5 to 4 hours, and the TMZ concentration within samples was quantitated via a developed LC-MS/MS procedure. Tumor progression was followed with T2-MRI, and animal survival and brain tissue histology were conducted. Results demonstrated that FUS-BBB opening caused the local TMZ accumulation in the brain to increase from 6.98 to 19 ng/mg. TMZ degradation time in the tumor core was found to increase from 1.02 to 1.56 hours. Improved tumor progression and animal survival were found at different TMZ doses (up to 15% and 30%, respectively). In conclusion, this study provides preclinical evidence that FUS-BBB opening increases the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting the potential for clinical application to improve current brain tumor treatment. PMID:25490097

Enhanced homing permeability and retention of bone marrow stromal cells (BMSC) by non-invasive pulsed focused ultrasound

PubMed Central

Ziadloo, Ali; Burks, Scott R.; Gold, Eric M.; Lewis, Bobbi K.; Chaudhry, Aneeka; Merino, Maria J.; Frenkel, Victor; Frank, Joseph A.

2012-01-01

Bone marrow stromal cells (BMSC) have shown significant promise in the treatment of disease, but their therapeutic efficacy is often limited by inefficient homing of systemically-administered cells, which results in low numbers of cells accumulating at sites of pathology. BMSC home to areas of inflammation where local expression of integrins and chemokine gradients are present. We demonstrated that non-destructive pulsed focused ultrasound (pFUS) exposures that emphasize the mechanical effects of ultrasound-tissue interactions induced local and transient elevations of chemoattractants (i.e., cytokines, integrins, and growth factors) in the murine kidney. pFUS-induced upregulation of cytokines occurred through approximately 1 day post-treatment and returned to contralateral kidney levels by day 3. This window of significant increases in cytokine expression was accompanied by local increases of other trophic factors and integrins that have been shown to promote BMSC homing. When BMSC were administered intravenously following pFUS treatment to a single kidney, enhanced homing, permeability, and retention of BMSC was observed in the treated kidney versus the contralateral kidney. Histological analysis revealed up to 8 times more BMSC in the peritubular regions of the treated kidneys on days 1 and 3 post-treatment. Furthermore, cytokine levels in pFUS-treated kidneys following BMSC administration were found to be similar to controls, suggesting modulation of cytokine levels by BMSC. pFUS could potentially improve cell-based therapies as a noninvasive modality to target BMSC homing by establishing local chemoattractant gradients and increasing expression of integrins to enhance tropism of BMSC toward treated tissues. PMID:22593018

Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response.

PubMed

Liu, Hao-Li; Hsieh, Han-Yi; Lu, Li-An; Kang, Chiao-Wen; Wu, Ming-Fang; Lin, Chun-Yen

2012-11-11

High-intensity focused-ultrasound (HIFU) has been successfully employed for thermal ablation of tumors in clinical settings. Continuous- or pulsed-mode HIFU may also induce a host antitumor immune response, mainly through expansion of antigen-presenting cells in response to increased cellular debris and through increased macrophage activation/infiltration. Here we demonstrated that another form of focused ultrasound delivery, using low-pressure, pulsed-mode exposure in the presence of microbubbles (MBs), may also trigger an antitumor immunological response and inhibit tumor growth. A total of 280 tumor-bearing animals were subjected to sonographically-guided FUS. Implanted tumors were exposed to low-pressure FUS (0.6 to 1.4 MPa) with MBs to increase the permeability of tumor microvasculature. Tumor progression was suppressed by both 0.6 and 1.4-MPa MB-enhanced FUS exposures. We observed a transient increase in infiltration of non-T regulatory (non-Treg) tumor infiltrating lymphocytes (TILs) and continual infiltration of CD8+ cytotoxic T-lymphocytes (CTL). The ratio of CD8+/Treg increased significantly and tumor growth was inhibited. Our findings suggest that low-pressure FUS exposure with MBs may constitute a useful tool for triggering an anticancer immune response, for potential cancer immunotherapy.

High Acceleration Cockpit Controller Locations. Volume 3. Onsite Pilot Evaluations

DTIC Science & Technology

1975-05-01

Ratings 31 9 Post Cockpit Questionnaire - Design Feature Ratings 32 VI A/A, A-A AAI A/C ACF ACM AFCS A/G CAP Chan CRT Coram DFC ...Negative Responses TASK RESPONSES NEGATIVE COMMENTS YES MAYBE NO MONITOR FBW STATUS 28 9 3 Obscured by throttles ACTIVATE FBW DFC , MVR, FUS AIM...4J 0 X O 4J O CO o Q UH U-l iH CJ i-H ^ i-1 TD CJ CO 4J CO 01 s c 0 O 4-1 o C 0 C X Si C 0) C -rl C cu C CO c

Combined Ultrasound and MR Imaging to Guide Focused Ultrasound Therapies in the Brain

PubMed Central

Arvanitis, Costas D.; Livingstone, Margaret S.; McDannold, Nathan

2013-01-01

Purpose Several emerging therapies with potential for use in the brain harness effects produced by acoustic cavitation – the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength, and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. Materials and Methods We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. Results The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. Conclusion While preliminary, these data clearly demonstrate, for the first time, that is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies. PMID:23788054

Registration of human skull computed tomography data to an ultrasound treatment space using a sparse high frequency ultrasound hemispherical array

DOE Office of Scientific and Technical Information (OSTI.GOV)

O’Reilly, Meaghan A., E-mail: moreilly@sri.utoront

Purpose: Transcranial focused ultrasound (FUS) shows great promise for a range of therapeutic applications in the brain. Current clinical investigations rely on the use of magnetic resonance imaging (MRI) to monitor treatments and for the registration of preoperative computed tomography (CT)-data to the MR images at the time of treatment to correct the sound aberrations caused by the skull. For some applications, MRI is not an appropriate choice for therapy monitoring and its cost may limit the accessibility of these treatments. An alternative approach, using high frequency ultrasound measurements to localize the skull surface and register CT data to themore » ultrasound treatment space, for the purposes of skull-related phase aberration correction and treatment targeting, has been developed. Methods: A prototype high frequency, hemispherical sparse array was fabricated. Pulse-echo measurements of the surface of five ex vivo human skulls were made, and the CT datasets of each skull were obtained. The acoustic data were used to rigidly register the CT-derived skull surface to the treatment space. The ultrasound-based registrations of the CT datasets were compared to the gold-standard landmark-based registrations. Results: The results show on an average sub-millimeter (0.9 ± 0.2 mm) displacement and subdegree (0.8° ± 0.4°) rotation registration errors. Numerical simulations predict that registration errors on this scale will result in a mean targeting error of 1.0 ± 0.2 mm and reduction in focal pressure of 1.0% ± 0.6% when targeting a midbrain structure (e.g., hippocampus) using a commercially available low-frequency brain prototype device (InSightec, 230 kHz brain system). Conclusions: If combined with ultrasound-based treatment monitoring techniques, this registration method could allow for the development of a low-cost transcranial FUS treatment platform to make this technology more widely available.« less

Registration of human skull computed tomography data to an ultrasound treatment space using a sparse high frequency ultrasound hemispherical array.

PubMed

O'Reilly, Meaghan A; Jones, Ryan M; Birman, Gabriel; Hynynen, Kullervo

2016-09-01

Transcranial focused ultrasound (FUS) shows great promise for a range of therapeutic applications in the brain. Current clinical investigations rely on the use of magnetic resonance imaging (MRI) to monitor treatments and for the registration of preoperative computed tomography (CT)-data to the MR images at the time of treatment to correct the sound aberrations caused by the skull. For some applications, MRI is not an appropriate choice for therapy monitoring and its cost may limit the accessibility of these treatments. An alternative approach, using high frequency ultrasound measurements to localize the skull surface and register CT data to the ultrasound treatment space, for the purposes of skull-related phase aberration correction and treatment targeting, has been developed. A prototype high frequency, hemispherical sparse array was fabricated. Pulse-echo measurements of the surface of five ex vivo human skulls were made, and the CT datasets of each skull were obtained. The acoustic data were used to rigidly register the CT-derived skull surface to the treatment space. The ultrasound-based registrations of the CT datasets were compared to the gold-standard landmark-based registrations. The results show on an average sub-millimeter (0.9 ± 0.2 mm) displacement and subdegree (0.8° ± 0.4°) rotation registration errors. Numerical simulations predict that registration errors on this scale will result in a mean targeting error of 1.0 ± 0.2 mm and reduction in focal pressure of 1.0% ± 0.6% when targeting a midbrain structure (e.g., hippocampus) using a commercially available low-frequency brain prototype device (InSightec, 230 kHz brain system). If combined with ultrasound-based treatment monitoring techniques, this registration method could allow for the development of a low-cost transcranial FUS treatment platform to make this technology more widely available.

Registration of human skull computed tomography data to an ultrasound treatment space using a sparse high frequency ultrasound hemispherical array

PubMed Central

O’Reilly, Meaghan A.; Jones, Ryan M.; Birman, Gabriel; Hynynen, Kullervo

2016-01-01

Purpose: Transcranial focused ultrasound (FUS) shows great promise for a range of therapeutic applications in the brain. Current clinical investigations rely on the use of magnetic resonance imaging (MRI) to monitor treatments and for the registration of preoperative computed tomography (CT)-data to the MR images at the time of treatment to correct the sound aberrations caused by the skull. For some applications, MRI is not an appropriate choice for therapy monitoring and its cost may limit the accessibility of these treatments. An alternative approach, using high frequency ultrasound measurements to localize the skull surface and register CT data to the ultrasound treatment space, for the purposes of skull-related phase aberration correction and treatment targeting, has been developed. Methods: A prototype high frequency, hemispherical sparse array was fabricated. Pulse-echo measurements of the surface of five ex vivo human skulls were made, and the CT datasets of each skull were obtained. The acoustic data were used to rigidly register the CT-derived skull surface to the treatment space. The ultrasound-based registrations of the CT datasets were compared to the gold-standard landmark-based registrations. Results: The results show on an average sub-millimeter (0.9 ± 0.2 mm) displacement and subdegree (0.8° ± 0.4°) rotation registration errors. Numerical simulations predict that registration errors on this scale will result in a mean targeting error of 1.0 ± 0.2 mm and reduction in focal pressure of 1.0% ± 0.6% when targeting a midbrain structure (e.g., hippocampus) using a commercially available low-frequency brain prototype device (InSightec, 230 kHz brain system). Conclusions: If combined with ultrasound-based treatment monitoring techniques, this registration method could allow for the development of a low-cost transcranial FUS treatment platform to make this technology more widely available. PMID:27587036

A study of novel bilateral thermal capsulotomy with focused ultrasound for treatment-refractory obsessive-compulsive disorder: 2-year follow-up.

PubMed

Kim, Se Joo; Roh, Daeyoung; Jung, Hyun Ho; Chang, Won Seok; Kim, Chan-Hyung; Chang, Jin Woo

2018-05-02

Recently, a new thermal lesioning approach using magnetic-resonance-guided focused ultrasound (MRgFUS) was introduced for the treatment of neurologic disorders. However, only 2 studies have used this approach for treatment-refractory obsessive-compulsive disorder (OCD), and follow-up was short-term. We investigated the efficacy and safety of bilateral thermal lesioning of the anterior limb of the internal capsule using MRgFUS in patients with treatment-refractory OCD and followed them for 2 years. Eleven patients with treatment-refractory OCD were included in the study. Clinical outcomes were evaluated using the Yale-Brown Obsessive Compulsive Scale, the Clinical Global Impression scale (including improvement and severity), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A) at 1 week and 1, 3, 6, 12 and 24 months following MRgFUS. Neuropsychological functioning, Global Assessment of Functioning and adverse events were also assessed. After MRgFUS, Yale-Brown Obsessive Compulsive Scale scores decreased significantly across the 24-month follow-up period (mean ± standard deviation, 34.4 ± 2.3 at baseline v. 21.3 ± 6.2 at 24 months, p < 0.001). Scores on the Hamilton rating scales for depression and anxiety also significantly decreased from baseline to 24 months (HAM-D, 19.0 ± 5.3 v. 7.6 ± 5.3, p < 0.001; HAM-A, 22.4 ± 5.9 v. 7.9 ± 3.9, p < 0.001). Global Assessment of Functioning scores improved significantly (35.8 ± 4.9 at baseline v. 56.0 ± 10.3 at 24 months, p < 0.001) and Memory Quotient significantly improved, but other neuropsychological functions were unchanged. The side effects of MRgFUS included headache and vestibular symptoms, but these were mild and transient. The main limitations of this study were the small sample size and the open-label design. Bilateral thermal lesioning of the anterior limb of the internal capsule using MRgFUS may improve obsessive-compulsive, depressive and anxiety symptoms in patients with treatment-refractory OCD, without serious adverse effects.

Cost-effectiveness of uterine-preserving procedures for the treatment of uterine fibroid symptoms in the USA.

PubMed

Cain-Nielsen, Anne H; Moriarty, James P; Stewart, Elizabeth A; Borah, Bijan J

2014-09-01

To evaluate the cost-effectiveness of the following three treatments of uterine fibroids in a population of premenopausal women who wish to preserve their uteri: myomectomy, magnetic resonance-guided focused ultrasound (MRgFUS) and uterine artery embolization (UAE). A decision analytic Markov model was constructed. Cost-effectiveness was calculated in terms of US$ per quality-adjusted life year (QALY) over 5 years. Two types of costs were calculated: direct costs only, and the sum of direct and indirect (productivity) costs. Women in the hypothetical cohort were assessed for treatment type eligibility, were treated based on eligibility, and experienced adequate or inadequate symptom relief. Additional treatment (myomectomy) occurred for inadequate symptom relief or recurrence. Sensitivity analysis was conducted to evaluate uncertainty in the model parameters.  In the base case, myomectomy, MRgFUS and UAE had the following combinations of mean cost and mean QALYs, respectively: US$15,459, 3.957; US$15,274, 3.953; and US$18,653, 3.943. When incorporating productivity costs, MRgFUS incurred a mean cost of US$21,232; myomectomy US$22,599; and UAE US$22,819. Using probabilistic sensitivity analysis (PSA) and excluding productivity costs, myomectomy was cost effective at almost every decision threshold. Using PSA and incorporating productivity costs, myomectomy was cost effective at decision thresholds above US$105,000/QALY; MRgFUS was cost effective between US$30,000 and US$105,000/QALY; and UAE was cost effective below US$30,000/QALY. Myomectomy, MRgFUS, and UAE were similarly effective in terms of QALYs gained. Depending on assumptions about costs and willingness to pay for additional QALYs, all three treatments can be deemed cost effective in a 5-year time frame.

MR-guided transcranial focused ultrasound safely enhances interstitial dispersion of large polymeric nanoparticles in the living brain

PubMed Central

Mohammadabadi, Ali; Nguyen, Ben A.; Guo, Sijia; Winkles, Jeffrey A.; Kim, Anthony J.; Gullapalli, Rao; Keller, Asaf; Frenkel, Victor

2018-01-01

Generating spatially controlled, non-destructive changes in the interstitial spaces of the brain has a host of potential clinical applications, including enhancing the delivery of therapeutics, modulating biological features within the tissue microenvironment, altering fluid and pressure dynamics, and increasing the clearance of toxins, such as plaques found in Alzheimer’s disease. Recently we demonstrated that ultrasound can non-destructively enlarge the interstitial spaces of the brain ex vivo. The goal of the current study was to determine whether these effects could be reproduced in the living brain using non-invasive, transcranial MRI-guided focused ultrasound (MRgFUS). The left striatum of healthy rats was treated using MRgFUS. Computer simulations facilitated treatment planning, and targeting was validated using MRI acoustic radiation force impulse imaging. Following MRgFUS treatments, Evans blue dye or nanoparticle probes were infused to assess changes in the interstitial space. In MRgFUS-treated animals, enhanced dispersion was observed compared to controls for 70 nm (12.8 ± 0.9 mm3 vs. 10.6 ± 1.0 mm3, p = 0.01), 200 nm (10.9 ± 1.4 mm3 vs. 7.4 ± 0.7 mm3, p = 0.01) and 700 nm (7.5 ± 0.4 mm3 vs. 5.4 ± 1.2 mm3, p = 0.02) nanoparticles, indicating enlargement of the interstitial spaces. No evidence of significant histological or electrophysiological injury was identified. These findings suggest that transcranial ultrasound can safely and effectively modulate the brain interstitium and increase the dispersion of large therapeutic entities such as particulate drug carriers or modified viruses. This has the potential to expand the therapeutic uses of MRgFUS. PMID:29415084

Cutoff values for bacteria and leukocytes for urine sediment analyzer FUS200 in culture-positive urinary-tract infections.

PubMed

Kocer, Derya; Sarıguzel, Fatma M; Karakukcu, Cıgdem

2014-08-01

The microscopic analysis of urine is essential for the diagnosis of patients with urinary tract infections. Quantitative urine culture is the 'gold standard' method for definitive diagnosis of urinary-tract infections, but it is labor-intensive, time consuming, and does not provide the same-day results. The aim of this study was to evaluate the analytical and diagnostic performance of the FUS200 (Changchun Dirui Industry, China), a new urine sedimentation analyzer in comparison to urine culture as the reference method. We evaluated 1000 urine samples, submitted for culture and urine analysis with a preliminary diagnosis of urinary-tract infection. Cut-off values for the FUS200 were determined by comparing the results with urine cultures. The cut-off values by the receiver operating characteristic (ROC) curve technique, sensitivity, and specificity were calculated for bacteria and white blood cells (WBCs). Among the 1000 urine specimens submitted for culture, 637 cultures (63.7%) were negative, and 363 were (36.3%) positive. The best cut-off values obtained from ROC analysis were 16/μL for bacteriuria (sensitivity: 82.3%, specificity: 58%), and 34/μL for WBCs (sensitivity: 72.3%, specificity: 65.2%). The area under the curve (AUC) for the bacteria and WBCs count were 0.71 (95% CI: 0.67-0.74) and, 0.72 (95% CI: 0.69-0.76) respectively. The most important requirement of a rapid diagnostic screening test is sensitivity, and, in this perspective, an unsatisfactory sensitivity by using bacteria recognition and quantification performed by the FUS200 analyzer has been observed. After further technical improvements in particle recognition and laboratory personnel training, the FUS200 might show better results.

MRI predictors of clinical success in MR-guided focused ultrasound (MRgFUS) treatments of uterine fibroids: results from a single centre.

PubMed

Mindjuk, Irene; Trumm, Christoph G; Herzog, Peter; Stahl, Robert; Matzko, Matthias

2015-05-01

To assess the technical and clinical results of MRgFUS treatment and factors affecting clinical treatment success. A total of 252 women (mean age, 42.1 ± 6.9 years) with uterine fibroids underwent MRgFUS. All patients underwent MRI before treatment. Results were evaluated with respect to post-treatment nonperfused volume (NPV), symptom severity score (SSS), reintervention rate, pregnancy and safety data. NPV ratio was significantly higher in fibroids characterized by low signal intensity in contrast-enhanced T1-weighted fat saturated MR images and in fibroids distant from the spine (>3 cm). NPV ratio was lower in fibroids with septations, with subserosal component and in skin-distant fibroids (p < 0.001). NPV ratio was highly correlated with clinical success: NPV of more than 80 % resulted in clinical success in more than 80 % of patients. Reintervention rate was 12.7 % (mean follow-up time, 19.4 ± 8 months; range, 3-38). Expulsion of fibroids (21 %) was significantly correlated with a high clinical success rate. No severe adverse events were reported. Adequate patient selection and correct treatment techniques, based on the learning curve of this technology, combined with technical advances of the system, lead to higher clinical success rates with low complications rate, comparable to other uterine-sparing treatment options. • MRgFUS appears to be a valid alternative to other uterus-preserving therapies • Patient selection is a significant factor in achieving high NPV ratios • MRI screening parameters correlate with the amount of fibroid ablation in MRgFUS • NPV results of more than 80 % correlate with higher clinical success rates.

Focused ultrasound facilitated thermo-chemotherapy for targeted retinoblastoma treatment: a modeling study.

PubMed

Wang, Shutao; Mahesh, Sankaranarayana P; Liu, Ji; Geist, Craig; Zderic, Vesna

2012-07-01

Retinoblastoma is the most common type of intraocular tumors in children. Currently, with early detection and improved systemic chemo-adjuvant therapies, treatment paradigm has shifted from survival to globe salvation/vision preservation. The objective of our work has been to explore the possible application of focused ultrasound (FUS) for targeted drug delivery in the posterior pole retinoblastoma. Specifically, theoretical models were implemented to evaluate the feasibility of using FUS to generate localized hyperthermia in retinal tumor areas, for potential triggering the chemotherapeutic agent deployment from heat-sensitive drug carriers. In-vitro experiments were conducted in tissue-mimicking phantoms with embedded excised rabbit eyes to validate the reliability of the modeling results. After confirming the reliability of our model, various FUS transducer parameters were investigated to induce maximal hyperthermia coverage in the tumor, while sparing adjacent eye structures (e.g. the lens). The evaluated FUS parameters included operating frequency, total acoustic power, geometric dimensions, transducer f-number, standoff distance, as well as different pulsing scenarios. Our modeling results suggest that the most suitable ultrasound frequency for this type of treatments was in the range of 2-3.5 MHz depending on the size of retinoblastoma. Appropriate transducer f-number (close to 1) and standoff distance could be selected to minimize the risks of over-heating undesired regions. With the total acoustic power of 0.4 W, 56.3% of the tumor was heated to hyperthermic temperature range (39-44 °C) while the temperature in lens was maintained below 41 °C. In conclusion, FUS-induced hyperthermia for targeted drug delivery may be a viable option in treatments of juxta-foveal or posterior pole retinoblastomas. Future in-vivo studies will allow us to determine the effectiveness and safety of the proposed approach. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effects of feeding a Fusarium toxin-contaminated diet to infectious bursal disease virus-infected broilers on the protein turnover of the bursa of Fabricius and spleen.

PubMed

Dänicke, Sven; Pappritz, Julia; Goyarts, Tanja; Xu, Bu; Rautenschlein, Silke

2011-02-01

Two experiments were carried out to examine the effects of feeding an uncontaminated control diet (CON) or a Fusarium toxin-contaminated diet (FUS; 10.7 mg deoxynivalenol [DON]/kg diet) to growing broilers, which were either uninfected or infected with infectious bursal disease virus (IBDV) beginning at 1 day post hatch. Broilers had been infected at three weeks post hatch with either a classical virulent infectious bursal disease virus (IBDV-IM, Exp. 1) or a very virulent IBDV (vvIBDV, Exp. 2) strain. The effects of the DON-contaminated diet in combination with the virus-infection on the bursa of Fabricius and spleen were determined at 3 and 6-7 days post infection. The transient development of the bursa oedema and the bursa atrophy was not significantly affected by the diet after infection with the different IBDV-strains. The histopathological lesions were more severe in IBDV-IM-infected birds at 6 days post infection when additionally exposed to the FUS diet as compared to the FUS-free feed. Most parameters of the bursa of Fabricius and spleen protein turnover (e.g. fractional protein synthesis rate, protein, DNA and RNA content and derived indices) were significantly and interactively influenced by infection and stage of infection. The vvIBDV-infected birds responded with a more pronounced depressing effect on the fractional protein synthesis rate after feeding the DON-containing FUS diet when compared to their IBDV-IM-infected counterparts, where the opposite effect was observed. It can be concluded that feeding a FUS diet to IBDV-infected broilers might modulate the virulence-dependent pathogenesis of an IBDV infection.

Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity

PubMed Central

Uzhachenko, Roman; Shanker, Anil; Yarbrough, Wendell G.; Ivanova, Alla V.

2015-01-01

Mitochondria present a unique set of key intracellular functions such as ATP synthesis, production of reactive oxygen species (ROS) and Ca2+ buffering. Mitochondria both encode and decode Ca2+ signals and these interrelated functions have a direct impact on cell signaling and metabolism. High proliferative potential is a key energy-demanding feature shared by cancer cells and activated T lymphocytes. Switch of a metabolic state mediated by alterations in mitochondrial homeostasis plays a fundamental role in maintenance of the proliferative state. Recent studies show that tumor suppressors have the ability to affect mitochondrial homeostasis controlling both cancer and autoimmunity. Herein, we discuss established and putative mechanisms of calcium–dependent regulation of both T cell and tumor cell activities. We use the mitochondrial protein Fus1 as a case of tumor suppressor that controls immune response and tumor growth via maintenance of mitochondrial homeostasis. We focus on the regulation of mitochondrial Ca2+ handling as a key function of Fus1 and highlight the mechanisms of a crosstalk between Ca2+ accumulation and mitochondrial homeostasis. Given the important role of Ca2+ signaling, mitochondrial Ca2+ transport and ROS production in the activation of NFAT and NF-κB transcription factors, we outline the importance of Fus1 activities in this context. PMID:26246474

Evaluation of mineral oil as an acoustic coupling medium in clinical MRgFUS.

PubMed

Gorny, K R; Hangiandreou, N J; Hesley, G K; Felmlee, J P

2007-01-07

We empirically evaluate mineral oil as an alternative to the mixture of de-gassed water and ultrasound gel, which is currently used as an acoustic coupling medium in clinical magnetic resonance guided focused ultrasound (MRgFUS) treatments. The tests were performed on an ExAblate 2000 MRgFUS system (InSightec Inc., Haifa, Israel) using a clinical patient set-up. Acoustic reflections, treatment temperatures, sonication spot dimensions and position with respect to target location were measured, using both coupling media, in repeated sonications in a tissue mimicking gel phantom. In comparison with the water-gel mix, strengths of acoustic reflections from coupling layers prepared with mineral oil were on average 39% lower and the difference was found to be statistically significant (p = 3.3 x 10(-8)). The treatment temperatures were found to be statistically equivalent for both coupling media, although temperatures corresponding to mineral oil tended to be somewhat higher (on average 1.9 degrees C) and their standard deviations were reduced by about 1 degrees C. Measurements of sonication spot dimensions and positions with respect to target location did not reveal systematic differences. We conclude that mineral oil may be used as an effective non-evaporating acoustic coupling medium for clinical MRgFUS treatments.

Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening

NASA Astrophysics Data System (ADS)

Wu, Sheng-Kai; Chu, Po-Chun; Chai, Wen-Yen; Kang, Shih-Tsung; Tsai, Chih-Hung; Fan, Ching-Hsiang; Yeh, Chih-Kuang; Liu, Hao-Li

2017-04-01

Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62-1.38 of mechanical index (MI) on rats. Evans blue, dynamic contrast-enhanced (DCE) MRI and small-animal ultrasound imaging were used as surrogates to allow molecule-penetrated quantification, BBB-opened observation, and MBs circulation/persistence. Cavitation activity was measured via the passive cavitation detection (PCD) setup to correlate with the exposure level and the histological effect. Under given and identical MB concentrations, the three MBs induced similar and equivalent BBB-opening effects and persistence. In addition, a treatment paradigm by adapting exposure time is proposed to compensate MB decay to retain the persistence of BBB-opening efficiency in multiple FUS exposures. The results potentially improve understanding of the equivalence among MBs in focused ultrasound CNS drug delivery, and provide an effective strategy for securing persistence in this treatment modality.

Acoustic characterization of Thiel liver for magnetic resonance-guided focused ultrasound treatment.

PubMed

Karakitsios, Ioannis; Joy, Joyce; Mihcin, Senay; Melzer, Andreas

2017-04-01

The purpose of this work was to measure the essential acoustic parameters, i.e., acoustic impedance, reflection coefficient, attenuation coefficient, of Thiel embalmed human and animal liver. The Thiel embalmed tissue can be a promising, pre-clinical model to study liver treatment with Magnetic Resonance-guided Focused Ultrasound (MRgFUS). Using a single-element transducer and the contact pulse-echo method, the acoustic parameters, i.e., acoustic impedance, reflection coefficient and attenuation coefficient of Thiel embalmed human and animal liver were measured. The Thiel embalmed livers had higher impedance, similar reflection and lower attenuation compared to the fresh tissue. Embalming liver with Thiel fluid affects its acoustic properties. During MRgFUS sonication of a Thiel organ, more focused ultrasound (FUS) will be backscattered by the organ, and higher acoustic powers are required to reach coagulation levels (temperatures >56 °C).

Trans-cranial opening of the blood-brain barrier in targeted regions using a stereotaxic brain atlas and focused ultrasound energy.

PubMed

Bing, Chenchen; Ladouceur-Wodzak, Michelle; Wanner, Clinton R; Shelton, John M; Richardson, James A; Chopra, Rajiv

2014-01-01

The blood-brain barrier (BBB) protects the brain by preventing the entry of large molecules; this poses a major obstacle for the delivery of drugs to the brain. A novel technique using focused ultrasound (FUS) energy combined with microbubble contrast agents has been widely used for non-invasive trans-cranial BBB opening. Traditionally, FUS research is conducted with magnetic resonance imaging (MRI) guidance, which is expensive and poses physical limitations due to the magnetic field. A system that could allow researchers to test brain therapies without MR intervention could facilitate and accelerate translational research. In this study, we present a novel FUS system that uses a custom-built FUS generator mounted on a motorized stereotaxic apparatus with embedded brain atlas to locally open the BBB in rodents. The system was initially characterized using a tissue-mimicking phantom. Rodent studies were also performed to evaluate whether non-invasive, localized BBB opening could be achieved using brain atlas-based targeting. Brains were exposed to pulsed focused ultrasound energy at 1.06 MHz in rats and 3.23 MHz in mice, with the focal pressure estimated to be 0.5-0.6 MPa through the skull. BBB opening was confirmed in gross tissue sections by the presence of Evans blue leakage in the exposed region of the brain and by histological assessment. The targeting accuracy of the stereotaxic system was better than 0.5 mm in the tissue-mimicking phantom. Reproducible localized BBB opening was verified with Evans blue dye leakage in 32/33 rats and had a targeting accuracy of ±0.3 mm. The use of higher frequency exposures in mice enabled a similar precision of localized BBB opening as was observed with the low frequency in the rat model. With this dedicated small-animal motorized stereotaxic-FUS system, we achieved accurate targeting of focused ultrasound exposures in the brain for non-invasive opening of the BBB. This system can be used as an alternative to MR-guided FUS and offers researchers the ability to perform efficient studies (30 min per experiment including preparation) at a reduced cost in a conventional laboratory environment.

Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound.

PubMed

Stavarache, Mihaela A; Petersen, Nicholas; Jurgens, Eric M; Milstein, Elizabeth R; Rosenfeld, Zachary B; Ballon, Douglas J; Kaplitt, Michael G

2018-04-27

OBJECTIVE Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain. METHODS Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses. RESULTS Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%-75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons. CONCLUSIONS This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.

A yeast functional screen predicts new candidate ALS disease genes

PubMed Central

Couthouis, Julien; Hart, Michael P.; Shorter, James; DeJesus-Hernandez, Mariely; Erion, Renske; Oristano, Rachel; Liu, Annie X.; Ramos, Daniel; Jethava, Niti; Hosangadi, Divya; Epstein, James; Chiang, Ashley; Diaz, Zamia; Nakaya, Tadashi; Ibrahim, Fadia; Kim, Hyung-Jun; Solski, Jennifer A.; Williams, Kelly L.; Mojsilovic-Petrovic, Jelena; Ingre, Caroline; Boylan, Kevin; Graff-Radford, Neill R.; Dickson, Dennis W.; Clay-Falcone, Dana; Elman, Lauren; McCluskey, Leo; Greene, Robert; Kalb, Robert G.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Ludolph, Albert; Robberecht, Wim; Andersen, Peter M.; Nicholson, Garth A.; Blair, Ian P.; King, Oliver D.; Bonini, Nancy M.; Van Deerlin, Vivianna; Rademakers, Rosa; Mourelatos, Zissimos; Gitler, Aaron D.

2011-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery. PMID:22065782

MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes.

PubMed

Fasano, Alfonso; Llinas, Maheleth; Munhoz, Renato P; Hlasny, Eugen; Kucharczyk, Walter; Lozano, Andres M

2017-08-22

To report the 6-month single-blinded results of unilateral thalamotomy with MRI-guided focused ultrasound (MRgFUS) in patients with tremors other than essential tremor. Three patients with tremor due to Parkinson disease, 2 with dystonic tremor in the context of cervicobrachial dystonia and writer's cramp, and 1 with dystonia gene-associated tremor underwent MRgFUS targeting the ventro-intermedius nucleus (Vim) of the dominant hemisphere. The primary endpoint was the reduction of lateralized items of the Tremor Rating Scale of contralateral hemibody assessed by a blinded rater. All patients achieved a statistically significant, immediate, and sustained improvement of the contralateral tremor score by 42.2%, 52.0%, 55.9%, and 52.9% at 1 week and 1, 3, and 6 months after the procedure, respectively. All patients experienced transient side effects and 2 patients experienced persistent side effects at the time of last evaluation: hemitongue numbness and hemiparesis with hemihypoesthesia. Vim MRgFUS is a promising, incision-free, but nevertheless invasive technique to effectively treat tremors other than essential tremor. Future studies on larger samples and longer follow-up will further define its effectiveness and safety. NCT02252380. This study provides Class IV evidence that for patients with tremor not caused by essential tremor, MRgFUS of the Vim improves the tremor of the contralateral hemibody at 6 months. © 2017 American Academy of Neurology.

Intra-operative feedback and dynamic compensation for image-guided robotic focal ultrasound surgery.

PubMed

Chauhan, S; Amir, H; Chen, G; Hacker, A; Michel, M S; Koehrmann, K U

2008-11-01

This paper describes a non-invasive remote temperature measurement technique integrated with a biomechatronic surgery system devised in our laboratory and named FUSBOT (Focal Ultrasound Surgery RoBOT). FUSBOTs use High-Intensity Focused Ultrasound (HIFU) for ablation of cancers/tumors and targets accessible through various soft-tissue acoustic windows in the human body. The focused ultrasound beam parameters are chosen so that biologically significant temperature rises are achieved only within the focal volume. In this paper, FUSBOT(BS), a customized system for breast surgery, is taken as a representative example to demonstrate the implementation and the results of non-invasive feedback during ablation. An 8-axis PC-based controller controls various sub-sections of the system within a safe constrained work envelope. Temperature is a prime target parameter in ablative procedures, and it is of paramount importance that means should be devised for its measurement and control in order to design optimal dose protocols and judge the efficacy of FUS systems. A customized sensory interface is devised and integrated with FUSBOT(BS), and dedicated software algorithms are embedded for surgical planning based on real-time guidance and feedback. Variations in the physical parameters of the tissue interacting with the incident modality are used as surgical feedback. The use of real-time ultrasound imaging and data processed from various sensors to deduce lesion position and thermal feedback during surgery, as integrated with the robotic system for online surgical planning, is described. Dynamic registration algorithms are developed for compensation and re-registration of the robotic end-effector with respect to the target, and representative empirical outcomes for lesion tracking and online temperature estimation in various biological tissues are presented.

Development, Characterization, and Implementation of a System for Focused Ultrasound-Mediated Blood-Brain Barrier Opening in Mice

NASA Astrophysics Data System (ADS)

Valdez, Michael Aaron

The blood-brain barrier BBB refers to the set of specialized endothelial cells that line the vasculature in the brain and effectively control movement of molecules into and out of the brain. While necessary for proper brain function, the BBB blocks 98% of drugs from entering the brain and is the most significant barrier to developing therapies for neurodegenerative diseases. Active transport allows some specific molecules to cross the BBB, but therapeutic development using this route has had limited success. A number of techniques have been used to bypass the BBB, but are often highly invasive and ineffective. Over the last two decades, a minimally invasive technique to transiently open the BBB has been under development that utilizes transcranial focused ultrasound (FUS) in combination with intravascular microbubble contrast agents. This method is often carried out in conjunction with magnetic resonance imaging (MRI) to guide and assess BBB opening and has been referred to as MRI guided FUS (MRgFUS). Because of the utility of mouse models of neurological disease and the exploratory nature of MRgFUS, systems that allow BBB opening in mice are a useful and necessary tool to develop and evaluate this method for clinical application. In this dissertation project, a custom built, cost-effective FUS system for opening the BBB in mice was developed, with the objective of using this device to deliver therapeutics to the brain. Being a custom device, it was necessary to evaluate the ultrasound output, verify in vivo safety, and anticipate the therapeutic effect. The scope of the work herein consists of the design, construction, and evaluation of system that fulfills these requirements. The final constructed system cost was an order of magnitude less than any commercially available MRgFUS system. At this low price point, the hardware could allow the implementation of the methodology in many more research areas than previously possible. Additionally, to anticipate the therapeutic effect, molecules of pharmacologically-relevant sizes were delivered to brain with a novel, multispectral approach. Results demonstrated that the device was able to safely open the BBB, and macromolecule delivery showed that both molecule size and FUS pressure both influence the amount and distribution of molecules in the brain. Using different ultrasound pressures, the threshold for BBB opening was found to be ≥ 180 kPa (0.13 MI). The threshold for damage was found to be ≥ 420 kPa (0.30 MI), and was minor at this pressure, but extensive for higher pressure (870 kPa, 0.62 MI), in which minor damage was caused by this pressure. Performing a novel implementation of a diffusion model on the fluorescence images of 500, 70, and 3 kDa dextran resulted in calculated diffusion coefficients of 0.032 +/- 0.015, 12 +/- 6.0, and 0.13 +/- 0.094 square microns per second, respectively.

Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

NASA Astrophysics Data System (ADS)

Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-03-01

Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P < 0.05, P < 0.01, and P < 0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222  ±  784, 3687  ±  796 and 5658  ±  821 ng g-1) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P < 0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.

Mutations in FUS cause FALS and SALS in French and French Canadian populations

PubMed Central

Belzil, V. V.; Valdmanis, P. N.; Dion, P. A.; Daoud, H.; Kabashi, E.; Noreau, A.; Gauthier, J.; Hince, P.; Desjarlais, A.; Bouchard, J. -P.; Lacomblez, L.; Salachas, F.; Pradat, P. -F.; Camu, W.; Meininger, V.; Dupré, N.; Rouleau, G. A.

2009-01-01

Background: The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. Methods: To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. Results: In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Conclusions: Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis. PMID:19741216

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

PubMed

Belzil, V V; Valdmanis, P N; Dion, P A; Daoud, H; Kabashi, E; Noreau, A; Gauthier, J; Hince, P; Desjarlais, A; Bouchard, J-P; Lacomblez, L; Salachas, F; Pradat, P-F; Camu, W; Meininger, V; Dupré, N; Rouleau, G A

2009-10-13

The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

Improving Thermal Dose Accuracy in Magnetic Resonance-Guided Focused Ultrasound Surgery: Long-Term Thermometry Using a Prior Baseline as a Reference

PubMed Central

Bitton, Rachel R.; Webb, Taylor D.; Pauly, Kim Butts; Ghanouni, Pejman

2015-01-01

Purpose To investigate thermal dose volume (TDV) and non-perfused volume (NPV) of magnetic resonance-guided focused ultrasound (MRgFUS) treatments in patients with soft tissue tumors, and describe a method for MR thermal dosimetry using a baseline reference. Materials and Methods Agreement between TDV and immediate post treatment NPV was evaluated from MRgFUS treatments of five patients with biopsy-proven desmoid tumors. Thermometry data (gradient echo, 3T) were analyzed over the entire course of the treatments to discern temperature errors in the standard approach. The technique searches previously acquired baseline images for a match using 2D normalized cross-correlation and a weighted mean of phase difference images. Thermal dose maps and TDVs were recalculated using the matched baseline and compared to NPV. Results TDV and NPV showed between 47%–91% disagreement, using the standard immediate baseline method for calculating TDV. Long-term thermometry showed a nonlinear local temperature accrual, where peak additional temperature varied between 4–13°C (mean = 7.8°C) across patients. The prior baseline method could be implemented by finding a previously acquired matching baseline 61% ± 8% (mean ± SD) of the time. We found 7%–42% of the disagreement between TDV and NPV was due to errors in thermometry caused by heat accrual. For all patients, the prior baseline method increased the estimated treatment volume and reduced the discrepancies between TDV and NPV (P = 0.023). Conclusion This study presents a mismatch between in-treatment and post treatment efficacy measures. The prior baseline approach accounts for local heating and improves the accuracy of thermal dose-predicted volume. PMID:26119129

Improving thermal dose accuracy in magnetic resonance-guided focused ultrasound surgery: Long-term thermometry using a prior baseline as a reference.

PubMed

Bitton, Rachel R; Webb, Taylor D; Pauly, Kim Butts; Ghanouni, Pejman

2016-01-01

To investigate thermal dose volume (TDV) and non-perfused volume (NPV) of magnetic resonance-guided focused ultrasound (MRgFUS) treatments in patients with soft tissue tumors, and describe a method for MR thermal dosimetry using a baseline reference. Agreement between TDV and immediate post treatment NPV was evaluated from MRgFUS treatments of five patients with biopsy-proven desmoid tumors. Thermometry data (gradient echo, 3T) were analyzed over the entire course of the treatments to discern temperature errors in the standard approach. The technique searches previously acquired baseline images for a match using 2D normalized cross-correlation and a weighted mean of phase difference images. Thermal dose maps and TDVs were recalculated using the matched baseline and compared to NPV. TDV and NPV showed between 47%-91% disagreement, using the standard immediate baseline method for calculating TDV. Long-term thermometry showed a nonlinear local temperature accrual, where peak additional temperature varied between 4-13°C (mean = 7.8°C) across patients. The prior baseline method could be implemented by finding a previously acquired matching baseline 61% ± 8% (mean ± SD) of the time. We found 7%-42% of the disagreement between TDV and NPV was due to errors in thermometry caused by heat accrual. For all patients, the prior baseline method increased the estimated treatment volume and reduced the discrepancies between TDV and NPV (P = 0.023). This study presents a mismatch between in-treatment and post treatment efficacy measures. The prior baseline approach accounts for local heating and improves the accuracy of thermal dose-predicted volume. © 2015 Wiley Periodicals, Inc.

LEC1 (NF-YB9) directly interacts with LEC2 to control gene expression in seed.

PubMed

Boulard, C; Thévenin, J; Tranquet, O; Laporte, V; Lepiniec, L; Dubreucq, B

2018-05-01

The LAFL transcription factors LEC2, ABI3, FUS3 and LEC1 are master regulators of seed development. LEC2, ABI3 and FUS3 are closely related proteins that contain a B3-type DNA binding domain. We have previously shown that LEC1 (a NF-YB type protein) can increase LEC2 and ABI3 but not FUS3 activity. Interestingly, FUS3, LEC2 and ABI3 contain a B2 domain, the function of which remains elusive. We showed that LEC1 and LEC2 partially co-localised in the nucleus of developing embryos. By comparing protein sequences from various species, we identified within the B2 domains a set of highly conserved residues (i.e. TKxxARxxRxxAxxR). This domain directly interacts with LEC1 in yeast. Mutations of the conserved amino acids of the motif in the B2 domain abolished this interaction both in yeast and in moss protoplasts and did not alter the nuclear localisation of LEC2 in planta. Conversely, the mutations of key amino acids for the function of LEC1 in planta (D86K) prevented the interaction with LEC2. These results provide molecular evidences for the binding of LEC1 to B2-domain containing transcription factors, to form heteromers, involved in the control of gene expression. Copyright © 2018 Elsevier B.V. All rights reserved.

Decreased seed oil production in FUSCA3 Brassica napus mutant plants.

PubMed

Elahi, Nosheen; Duncan, Robert W; Stasolla, Claudio

2015-11-01

Canola (Brassica napus L.) oil is extensively utilized for human consumption and industrial applications. Among the genes regulating seed development and participating in oil accumulation is FUSCA3 (FUS3), a member of the plant-specific B3-domain family of transcription factors. To evaluate the role of this gene during seed storage deposition, three BnFUSCA3 (BnFUS3) TILLING mutants were generated. Mutations occurring downstream of the B3 domain reduced silique number and repressed seed oil level resulting in increased protein content in developing seeds. BnFUS3 mutant seeds also had increased levels of linoleic acid, possibly due to the reduced expression of ω-3 FA DESATURASE (FAD3). These observed phenotypic alterations were accompanied by the decreased expression of genes encoding transcription factors stimulating fatty acid (FA) synthesis: LEAFY COTYLEDON1 and 2 (LEC1 and 2) ABSCISIC ACID-INSENSITIVE 3 (BnABI3) and WRINKLED1 (WRI1). Additionally, expression of genes encoding enzymes involved in sucrose metabolism, glycolysis, and FA modifications were down-regulated in developing seeds of the mutant plants. Collectively, these transcriptional changes support altered sucrose metabolism and reduced glycolytic activity, diminishing the carbon pool available for the synthesis of FA and ultimately seed oil production. Based on these observations, it is suggested that targeted manipulations of BnFUS3 can be used as a tool to influence oil accumulation in the economically important species B. napus. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Development of an Atmospheric Dispersion Model for Heavier-Than-Air Gas Mixtures. Volume 1.

DTIC Science & Technology

1985-05-01

aspirated concentration sensor used a balanced Wheatstone bridge to measure the heat loss from a sensing element placed in the sample stream. Shaded...a semipermeable membrane and electrochemical cell. A fast response sensor (10 Hz) basically aspirated a sample past the cell membrane. Reported...ramp function around the freezing point of water by X11., X= vap for T 273.15 K vap fus 263.15 for 263.15 <T < 273.15 Xvap +x fus for T < 263.15 (A-4

Fetal monitoring during nonobstetric surgery: revisiting guidelines: a case report.

PubMed

Rothschild, Tod J; Morel, Bruce; Pace, Benjamin; Fuks, Aleksandr M

2015-01-01

Nonobstetric surgery during pregnancy is not an infrequent occurrence. Guidelines for fetal monitoring during nonobstetric surgery are limited. We describe a case of appendectomy during third trimester, complicated by in utero fetal demise (IUFD). A 30-year-old, Caucasian woman underwent open appendectomy for suspected acute appendicitis. The procedure was complicated by IUFD. Fetal monitoring was done prior to but not during surgery. Guidelines for fetal monitoring were revised, recommending continuous electronic fetal monitoring when possible during third trimester nonobstetric surgery after appropriate patient counseling. A subsequent series of 5 uncomplicated appendectomies demonstrated no difficulty in implementing these guidelines. Continuous electronic fetal monitoring during third trimester nonobstetric surgery should be available and implemented after appropriate patient counseling. This approach reduces the risk of fetal mortality.

SU-E-J-03: Characterization of the Precision and Accuracy of a New, Preclinical, MRI-Guided Focused Ultrasound System for Image-Guided Interventions in Small-Bore, High-Field Magnets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellens, N; Farahani, K

2015-06-15

Purpose: MRI-guided focused ultrasound (MRgFUS) has many potential and realized applications including controlled heating and localized drug delivery. The development of many of these applications requires extensive preclinical work, much of it in small animal models. The goal of this study is to characterize the spatial targeting accuracy and reproducibility of a preclinical high field MRgFUS system for thermal ablation and drug delivery applications. Methods: The RK300 (FUS Instruments, Toronto, Canada) is a motorized, 2-axis FUS positioning system suitable for small bore (72 mm), high-field MRI systems. The accuracy of the system was assessed in three ways. First, the precisionmore » of the system was assessed by sonicating regular grids of 5 mm squares on polystyrene plates and comparing the resulting focal dimples to the intended pattern, thereby assessing the reproducibility and precision of the motion control alone. Second, the targeting accuracy was assessed by imaging a polystyrene plate with randomly drilled holes and replicating the hole pattern by sonicating the observed hole locations on intact polystyrene plates and comparing the results. Third, the practicallyrealizable accuracy and precision were assessed by comparing the locations of transcranial, FUS-induced blood-brain-barrier disruption (BBBD) (observed through Gadolinium enhancement) to the intended targets in a retrospective analysis of animals sonicated for other experiments. Results: The evenly-spaced grids indicated that the precision was 0.11 +/− 0.05 mm. When image-guidance was included by targeting random locations, the accuracy was 0.5 +/− 0.2 mm. The effective accuracy in the four rodent brains assessed was 0.8 +/− 0.6 mm. In all cases, the error appeared normally distributed (p<0.05) in both orthogonal axes, though the left/right error was systematically greater than the superior/inferior error. Conclusions: The targeting accuracy of this device is sub-millimeter, suitable for many preclinical applications including focused drug delivery and thermal therapy. Funding support provided by Philips Healthcare.« less

Image-guided Navigation of Single-element Focused Ultrasound Transducer

PubMed Central

Kim, Hyungmin; Chiu, Alan; Park, Shinsuk; Yoo, Seung-Schik

2014-01-01

The spatial specificity and controllability of focused ultrasound (FUS), in addition to its ability to modify the excitability of neural tissue, allows for the selective and reversible neuromodulation of the brain function, with great potential in neurotherapeutics. Intra-operative magnetic resonance imaging (MRI) guidance (in short, MRg) has limitations due to its complicated examination logistics, such as fixation through skull screws to mount the stereotactic frame, simultaneous sonication in the MRI environment, and restrictions in choosing MR-compatible materials. In order to overcome these limitations, an image-guidance system based on optical tracking and pre-operative imaging data is developed, separating the imaging acquisition for guidance and sonication procedure for treatment. Techniques to define the local coordinates of the focal point of sonication are presented. First, mechanical calibration detects the concentric rotational motion of a rigid-body optical tracker, attached to a straight rod mimicking the sonication path, pivoted at the virtual FUS focus. The spatial error presented in the mechanical calibration was compensated further by MRI-based calibration, which estimates the spatial offset between the navigated focal point and the ground-truth location of the sonication focus obtained from a temperature-sensitive MR sequence. MRI-based calibration offered a significant decrease in spatial errors (1.9±0.8 mm; 57% reduction) compared to the mechanical calibration method alone (4.4±0.9 mm). Using the presented method, pulse-mode FUS was applied to the motor area of the rat brain, and successfully stimulated the motor cortex. The presented techniques can be readily adapted for the transcranial application of FUS to intact human brain. PMID:25232203

Molecular determinants of Cytochrome C oxidase IV mRNA axonal trafficking

PubMed Central

Kar, Amar N.; Vargas, Jose Norberto S.; Chen, Cai-Yun; Kowalak, Jeffrey A; Gioio, Anthony E.; Kaplan, Barry B.

2017-01-01

In previous studies, we identified a putative 38-nucleotide stem-loop structure (zipcode) in the 3′ untranslated region of the cytochrome c oxidase subunit IV (COXIV) mRNA that was necessary and sufficient for the axonal localization of the message in primary superior cervical ganglion (SCG) neurons. However, little is known about the proteins that interact with the COXIV-zipcode and regulate the axonal trafficking and local translation of the COXIV message. To identify proteins involved in the axonal transport of the COXIV mRNA, we used the biotinylated 38-nucleotide COXIV RNA zipcode as bait in the affinity purification of COXIV zipcode binding proteins. Gel-shift assays of the biotinylated COXIV zipcode indicated that the putative stem-loop structure functions as a nucleation site for the formation of ribonucleoprotein complexes. Mass spectrometric analysis of the COXIV zipcode ribonucleoprotein complex led to the identification of a large number RNA binding proteins, including fused in sarcoma/translated in liposarcoma (FUS/TLS), and Y-box protein 1 (YB-1). Validation experiments, using western analyses, confirmed the presence of the candidate proteins in the COXIV zipcode affinity purified complexes obtained from SCG axons. Immunohistochemical studies show that FUS, and YB-1 are present in SCG axons. Importantly, RNA immunoprecipitation studies show that FUS, and YB-1 interact with endogenous axonal COXIV transcripts. siRNA-mediated downregulation of the candidate proteins FUS and YB-1 expression in the cell-bodies diminishes the levels of COXIV mRNA in the axon, suggesting functional roles for these proteins in the axonal trafficking of COXIV mRNA. PMID:28161363

Decay analysis of compound nuclei formed in reactions with exotic neutron-rich 9Li projectile and the synthesis of 217At* within the dynamical cluster-decay model

NASA Astrophysics Data System (ADS)

Kaur, Arshdeep; Kaushal, Pooja; Hemdeep; Gupta, Raj K.

2018-01-01

The decay of various compound nuclei formed via exotic neutron-rich 9Li projectile is studied within the dynamical cluster-decay model (DCM). Following the earlier work of one of us (RKG) and collaborators (M. Kaur et al. (2015) [1]), for an empirically fixed neck-length parameter ΔRemp, the only parameter in the DCM, at a given incident laboratory energy ELab, we are able to fit almost exactly the (total) fusion cross section σfus =∑x=16σxn for 9Li projectile on 208Pb and other targets, with σfus depending strongly on the target mass of the most abundant isotope and its (magic) shell structure. This result shows the predictable nature of the DCM. The neck-length parameter ΔRemp is fixed empirically for the decay of 217At* formed in 9Li + 208Pb reaction at a fixed laboratory energy ELab, and then the total fusion cross section σfus calculated for all other reactions using 9Li as a projectile on different targets. Apparently, this procedure could be used to predict σfus for 9Li-induced reactions where experimental data are not available. Furthermore, optimum choice of "cold" target-projectile combinations, forming "hot" compact configurations, are predicted for the synthesis of compound nucleus 217At* with 8Li + 209Pb as one of the target-projectile combination, or another (t , p) combination 48Ca + 169Tb, with a doubly magic 48Ca, as the best possibility.

Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections

PubMed Central

Fernandes, Prabhavathi

2016-01-01

Fusidic acid is an oral antistaphylococcal antibiotic that has been used in Europe for more than 40 years to treat skin infections as well as chronic bone and joint infections. It is a steroidal antibiotic and the only marketed member of the fusidane class. Fusidic acid inhibits protein synthesis by binding EF-G-GDP, which results in the inhibition of both peptide translocation and ribosome disassembly. It has a novel structure and novel mode of action and, therefore, there is little cross-resistance with other known antibiotics. Many mutations can occur in the FusA gene that codes for EF-G, and some of these mutations can result in high-level resistance (minimum inhibitory concentration [MIC] > 64 mg/L), whereas others result in biologically unfit staphylococci that require compensatory mutations to survive. Low-level resistance (<8 mg/L) is more common and is mediated by fusB, fusC, and fusD genes that code for small proteins that protect EF-G-GDP from binding fusidic acid. The genes for these proteins are spread by plasmids and can be selected mostly by topical antibiotic use. Reports of resistance have led to combination use of fusidic acid with rifampin, which is superseded by the development of a new dosing regimen for fusidic acid that can be used in monotherapy. It consists of a front-loading dose to decrease the potential for resistance development followed by a maintenance dose. This dosing regimen is now being used in clinical trials in the United States for skin and refractory bone and joint infections. PMID:26729758

Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound.

PubMed

Kaye, Elena A; Hertzberg, Yoni; Marx, Michael; Werner, Beat; Navon, Gil; Levoy, Marc; Pauly, Kim Butts

2012-10-01

To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat et al., "MR-guided adaptive focusing of ultrasound," IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734-1747 (2010)] was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients' phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR-ARFI-based focusing for a clinical transcranial MRgFUS therapy.

Application of Zernike polynomials towards accelerated adaptive focusing of transcranial high intensity focused ultrasound

PubMed Central

Kaye, Elena A.; Hertzberg, Yoni; Marx, Michael; Werner, Beat; Navon, Gil; Levoy, Marc; Pauly, Kim Butts

2012-01-01

Purpose: To study the phase aberrations produced by human skulls during transcranial magnetic resonance imaging guided focused ultrasound surgery (MRgFUS), to demonstrate the potential of Zernike polynomials (ZPs) to accelerate the adaptive focusing process, and to investigate the benefits of using phase corrections obtained in previous studies to provide the initial guess for correction of a new data set. Methods: The five phase aberration data sets, analyzed here, were calculated based on preoperative computerized tomography (CT) images of the head obtained during previous transcranial MRgFUS treatments performed using a clinical prototype hemispherical transducer. The noniterative adaptive focusing algorithm [Larrat , “MR-guided adaptive focusing of ultrasound,” IEEE Trans. Ultrason. Ferroelectr. Freq. Control 57(8), 1734–1747 (2010)]10.1109/TUFFC.2010.1612 was modified by replacing Hadamard encoding with Zernike encoding. The algorithm was tested in simulations to correct the patients’ phase aberrations. MR acoustic radiation force imaging (MR-ARFI) was used to visualize the effect of the phase aberration correction on the focusing of a hemispherical transducer. In addition, two methods for constructing initial phase correction estimate based on previous patient's data were investigated. The benefits of the initial estimates in the Zernike-based algorithm were analyzed by measuring their effect on the ultrasound intensity at the focus and on the number of ZP modes necessary to achieve 90% of the intensity of the nonaberrated case. Results: Covariance of the pairs of the phase aberrations data sets showed high correlation between aberration data of several patients and suggested that subgroups can be based on level of correlation. Simulation of the Zernike-based algorithm demonstrated the overall greater correction effectiveness of the low modes of ZPs. The focal intensity achieves 90% of nonaberrated intensity using fewer than 170 modes of ZPs. The initial estimates based on using the average of the phase aberration data from the individual subgroups of subjects was shown to increase the intensity at the focal spot for the five subjects. Conclusions: The application of ZPs to phase aberration correction was shown to be beneficial for adaptive focusing of transcranial ultrasound. The skull-based phase aberrations were found to be well approximated by the number of ZP modes representing only a fraction of the number of elements in the hemispherical transducer. Implementing the initial phase aberration estimate together with Zernike-based algorithm can be used to improve the robustness and can potentially greatly increase the viability of MR-ARFI-based focusing for a clinical transcranial MRgFUS therapy. PMID:23039661

Complex adenovirus-vectored vaccine protects guinea pigs from three strains of Marburg virus challenges.

PubMed

Wang, Danher; Hevey, Michael; Juompan, Laure Y; Trubey, Charles M; Raja, Nicholas U; Deitz, Stephen B; Woraratanadharm, Jan; Luo, Min; Yu, Hong; Swain, Benjamin M; Moore, Kevin M; Dong, John Y

2006-09-30

The Marburg virus (MARV), an African filovirus closely related to the Ebola virus, causes a deadly hemorrhagic fever in humans, with up to 90% mortality. Currently, treatment of disease is only supportive, and no vaccines are available to prevent spread of MARV infections. In order to address this need, we have developed and characterized a novel recombinant vaccine that utilizes a single complex adenovirus-vectored vaccine (cAdVax) to overexpress a MARV glycoprotein (GP) fusion protein derived from the Musoke and Ci67 strains of MARV. Vaccination with the cAdVaxM(fus) vaccine led to efficient production of MARV-specific antibodies in both mice and guinea pigs. Significantly, guinea pigs vaccinated with at least 5 x 10(7) pfu of cAdVaxM(fus) vaccine were 100% protected against lethal challenges by the Musoke, Ci67 and Ravn strains of MARV, making it a vaccine with trivalent protective efficacy. Therefore, the cAdVaxM(fus) vaccine serves as a promising vaccine candidate to prevent and contain multi-strain infections by MARV.

Functional ultrasound imaging of intrinsic connectivity in the living rat brain with high spatiotemporal resolution

PubMed Central

Osmanski, Bruno-Félix; Pezet, Sophie; Ricobaraza, Ana; Lenkei, Zsolt; Tanter, Mickael

2014-01-01

Long-range coherences in spontaneous brain activity reflect functional connectivity. Here we propose a novel, highly resolved connectivity mapping approach, using ultrafast functional ultrasound (fUS), which enables imaging of cerebral microvascular haemodynamics deep in the anaesthetized rodent brain, through a large thinned-skull cranial window, with pixel dimensions of 100 μm × 100 μm in-plane. The millisecond-range temporal resolution allows unambiguous cancellation of low-frequency cardio-respiratory noise. Both seed-based and singular value decomposition analysis of spatial coherences in the low-frequency (<0.1 Hz) spontaneous fUS signal fluctuations reproducibly report, at different coronal planes, overlapping high-contrast, intrinsic functional connectivity patterns. These patterns are similar to major functional networks described in humans by resting-state fMRI, such as the lateral task-dependent network putatively anticorrelated with the midline default-mode network. These results introduce fUS as a powerful novel neuroimaging method, which could be extended to portable systems for three-dimensional functional connectivity imaging in awake and freely moving rodents. PMID:25277668

Complex adenovirus-vectored vaccine protects guinea pigs from three strains of Marburg virus challenges

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Danher; Hevey, Michael; Juompan, Laure Y.

2006-09-30

The Marburg virus (MARV), an African filovirus closely related to the Ebola virus, causes a deadly hemorrhagic fever in humans, with up to 90% mortality. Currently, treatment of disease is only supportive, and no vaccines are available to prevent spread of MARV infections. In order to address this need, we have developed and characterized a novel recombinant vaccine that utilizes a single complex adenovirus-vectored vaccine (cAdVax) to overexpress a MARV glycoprotein (GP) fusion protein derived from the Musoke and Ci67 strains of MARV. Vaccination with the cAdVaxM(fus) vaccine led to efficient production of MARV-specific antibodies in both mice and guineamore » pigs. Significantly, guinea pigs vaccinated with at least 5 x 10{sup 7} pfu of cAdVaxM(fus) vaccine were 100% protected against lethal challenges by the Musoke, Ci67 and Ravn strains of MARV, making it a vaccine with trivalent protective efficacy. Therefore, the cAdVaxM(fus) vaccine serves as a promising vaccine candidate to prevent and contain multi-strain infections by MARV.« less

[Facial nerve monitoring during middle ear surgery: Results of a French survey].

PubMed

Mazzaschi, O; Juvanon, J-M; Mondain, M; Lavieile, J-P; Ayache, D

2014-01-01

Facial nerve injury is a rare complication of middle ear surgery. To date there is no widely accepted consensus on the use of intraoperative facial nerve monitoring during middle ear surgery, whereas its use has been proved as a valuable adjunct in neurotologic surgery. The purpose of our study was to identify introperative facial nerve monitoring practice patterns in France for middle ear surgery. A 19-item survey has been made up by three experienced otologists under the auspices of the French Otology and Neurotology Association. With the support of the French Society of Otolaryngology--Head and Neck Surgery, the survey was electronically sent by email to 1249 practicing ENT with a valid email address. Answers were analyzed two months later. Among 1249 email sent, 299 were opened (24%) and 83 answers were collected (6,6%). Of the respondents, 66% had access to intraoperative facial nerve monitoring. Otolaryngologists involved in academic setting were influenced by their teaching duty in 27%. Intraoperative facial nerve monitoring should not be required for stapes surgery, ossiculoplasty, myringoplasty for, respectively, 92%, 93 % and 98% of the respondents. In cochlear implantation, 78% of ear surgeons used facial nerve monitoring. Answers were more controversial for chronic ear surgery, ear atresia and middle ear implant. Revision surgery and CT scan can influence answers. Despite a low response rate, results of this national survey revealed interesting findings. For most of the respondents, intraoperative facial nerve monitoring was not indicated in stapes surgery, myringoplasty and ossiculoplasty. The use of intraoperative facial nerve monitoring for cochlear implantation was supported by the majority of respondents. Variations in response rate were more significant for chronic ear surgery, including middle ear cholesteatoma, and for ear atresia surgery.

Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging

NASA Astrophysics Data System (ADS)

Tian, Feng; Yang, Wenlong; Mordes, Daniel A.; Wang, Jin-Yuan; Salameh, Johnny S.; Mok, Joanie; Chew, Jeannie; Sharma, Aarti; Leno-Duran, Ester; Suzuki-Uematsu, Satomi; Suzuki, Naoki; Han, Steve S.; Lu, Fa-Ke; Ji, Minbiao; Zhang, Rosanna; Liu, Yue; Strominger, Jack; Shneider, Neil A.; Petrucelli, Leonard; Xie, X. Sunney; Eggan, Kevin

2016-10-01

The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics.

Cost comparison between uterine-sparing fibroid treatments one year following treatment

PubMed Central

2014-01-01

Background To compare one-year all-cause and uterine fibroid (UF)-related direct costs in patients treated with one of the following three uterine-sparing procedures: magnetic resonance-guided focused ultrasound (MRgFUS), uterine artery embolization (UAE) and myomectomy. Methods This retrospective observational cohort study used healthcare claims for several million individuals with healthcare coverage from employers in the MarketScan Database for the period 2003–2010. UF patients aged 25–54 on their first UF procedure (index) date with 366-day baseline experience, 366-day follow-up period, continuous health plan enrollment during baseline and follow-up, and absence of any baseline UF procedures were included in the final sample. Cost outcomes were measured by allowed charges (sum of insurer-paid and patient-paid amounts). UF-related cost was defined as difference in mean cost between study cohorts and propensity-score-matched control cohorts without UF. Multivariate adjustment of cost outcomes was conducted using generalized linear models. Results The study sample comprised 14,426 patients (MRgFUS = 14; UAE = 4,092; myomectomy = 10,320) with a higher percent of older patients in MRgFUS cohort (71% vs. 50% vs. 12% in age-group 45–54, P < 0.001). Adjusted all-cause mean cost was lowest for MRgFUS ($19,763; 95% CI: $10,425-$38,694) followed by myomectomy ($20,407; 95% CI: $19,483-$21,381) and UAE ($25,019; 95% CI: $23,738-$26,376) but without statistical significance. Adjusted UF-related costs were also not significantly different between the three procedures. Conclusions Adjusted all-cause and UF-related costs at one year were not significantly different between patients undergoing MRgFUS, myomectomy and UAE. PMID:25512868

Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo

PubMed Central

Choi, James J.; Wang, Shougang; Tung, Yao-Sheng; Morrison, Barclay; Konofagou, Elisa E.

2009-01-01

Focused ultrasound (FUS) is hereby shown to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened blood-brain barrier (BBB). A complete examination on the size of the FUS-induced BBB opening, the spatial distribution of the delivered agents and its dependence on the agent's molecular weight were imaged and quantified using fluorescence microscopy. BBB opening in mice (n=13) was achieved in vivo after systemic administration of microbubbles and subsequent application of pulsed FUS (frequency: 1.525 MHz, peak-rarefactional pressure in situ: 569 kPa) to the left murine hippocampus through the intact skin and skull. BBB-impermeant, fluorescent-tagged dextrans at three distinct molecular weights spanning over several orders of magnitude were systemically administered and acted as model therapeutic compounds. First, dextrans of 3 and 70 kDa were delivered trans-BBB while 2000 kDa dextran was not. Second, compared to 70 kDa dextran, a higher concentration of 3 kDa dextran was delivered through the opened BBB. Third, the 3 and 70 kDa dextrans were both diffusely distributed throughout the targeted brain region. However, high concentrations of 70 kDa dextran appeared more punctated throughout the targeted region. In conclusion, FUS combined with microbubbles opened the BBB sufficiently to allow passage of compounds of at least 70 kDa, but not greater than 2000 kDa, into the brain parenchyma. This noninvasive and localized BBB opening technique could thus provide a unique means for the delivery of compounds of several magnitudes of kDa that include agents with shown therapeutic promise in vitro, but whose in vivo translation has been hampered by their associated BBB impermeability. PMID:19900750

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.

PubMed

Luty, Agnes A; Kwok, John B J; Dobson-Stone, Carol; Loy, Clement T; Coupland, Kirsten G; Karlström, Helena; Sobow, Tomasz; Tchorzewska, Joanna; Maruszak, Aleksandra; Barcikowska, Maria; Panegyres, Peter K; Zekanowski, Cezary; Brooks, William S; Williams, Kelly L; Blair, Ian P; Mather, Karen A; Sachdev, Perminder S; Halliday, Glenda M; Schofield, Peter R

2010-11-01

Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.

A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up.

PubMed

Chang, Jin Woo; Park, Chang Kyu; Lipsman, Nir; Schwartz, Michael L; Ghanouni, Pejman; Henderson, Jaimie M; Gwinn, Ryder; Witt, Jennifer; Tierney, Travis S; Cosgrove, G Rees; Shah, Binit B; Abe, Keiichi; Taira, Takaomi; Lozano, Andres M; Eisenberg, Howard M; Fishman, Paul S; Elias, W Jeffrey

2018-01-01

Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET. A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55% at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64% at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year-each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114. © 2017 American Neurological Association.

Magnetic resonance-guided motorized transcranial ultrasound system for blood-brain barrier permeabilization along arbitrary trajectories in rodents.

PubMed

Magnin, Rémi; Rabusseau, Fabien; Salabartan, Frédéric; Mériaux, Sébastien; Aubry, Jean-François; Le Bihan, Denis; Dumont, Erik; Larrat, Benoit

2015-01-01

Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Magnetic resonance imaging (MRI) guidance enables to plan, monitor, and characterize the BBB disruption. Being able to precisely and remotely control the permeabilization location is of great interest to perform reproducible drug delivery protocols. In this study, we developed an MR-guided motorized focused ultrasound (FUS) system allowing the transducer displacement within preclinical MRI scanners, coupled with real-time transfer and reconstruction of MRI images, to help ultrasound guidance. Capabilities of this new device to deliver large molecules to the brain on either single locations or along arbitrary trajectories were characterized in vivo on healthy rats and mice using 1.5 MHz ultrasound sonications combined with microbubble injection. The efficacy of BBB permeabilization was assessed by injecting a gadolinium-based MR contrast agent that does not cross the intact BBB. The compact motorized FUS system developed in this work fits into the 9-cm inner diameter of the gradient insert installed on our 7-T preclinical MRI scanners. MR images acquired after contrast agent injection confirmed that this device can be used to enhance BBB permeability along remotely controlled spatial trajectories of the FUS beam in both rats and mice. The two-axis motor stage enables reaching any region of interest in the rodent brain. The positioning error when targeting the same anatomical location on different animals was estimated to be smaller than 0.5 mm. Finally, this device was demonstrated to be useful for testing BBB opening at various acoustic pressures (0.2, 0.4, 0.7, and 0.9 MPa) in the same animal and during one single ultrasound session. Our system offers the unique possibility to move the transducer within a high magnetic field preclinical MRI scanner, thus enabling the delivery of large molecules to virtually any rodent brain area in a non-invasive manner. It results in time-saving and reproducibility and could be used to either deliver drugs over large parts of the brain or test different acoustic conditions on the same animal during the same session, therefore reducing physiological variability.

Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound.

PubMed

Kobus, Thiele; Vykhodtseva, Natalia; Pilatou, Magdalini; Zhang, Yongzhi; McDannold, Nathan

2016-02-01

The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Occurrence and Characterization of Cronobacter spp. in Dehydrated Rice Powder from Chinese Supermarket

PubMed Central

Huang, Yan; Pang, Yiheng; Wang, Hong; Tang, Zhengzhu; Zhou, Yan; Zhang, Weiyu; Li, Xiugui; Tan, Dongmei; Li, Jian; Lin, Ying; Liu, Xiaoling; Huang, Weiyi; Shi, Yunliang

2015-01-01

Cronobacter spp. are emerging food-borne pathogens and have been identified as causative agents of meningitis and necrotizing enterocolitis in infants. Dehydrated rice is popular with a wide range of people and it is frequently used as a substitute for infant milk powder to baby older than four months. The occurrence of Cronobacter spp. was investigated in 1,012 samples of dehydrated rice powder collected from 14 manufacturers in China during 2010 to 2012. The isolates were identified using fusA allele sequencing and subtyped using pulsed-field gel electrophoresis. Seventy-six samples (7.5%) contained Cronobacter spp. The prevalence among manufacturers ranged from 0-28.8%. The 76 isolates included 4 species [Cronobacter sakazakii (52 isolates) Cronobacter malonaticus (14 isolates), Cronobacter dublinensis (7 isolates), and Cronobacter muytjensii (3 isolates)]. Twenty-three unique fusA alleles and sixty-six PFGE-patterns were detected. All isolated strains were observed to be sensitive or to show intermediate susceptibility to eight tested antimicrobial agents. The study revealed serious contamination of dehydrated rice powder by Cronobacter spp., with prevalence varying among manufacturers in China. Identified Cronobacter species, fusA alleles, and subtypes were diverse. PMID:26132635

Improved survival in rats with glioma using MRI-guided focused ultrasound and microbubbles to disrupt the blood-brain barrier and deliver Doxil

NASA Astrophysics Data System (ADS)

Aryal, Muna; Zhi Zhang, Yong; Vykhodtseva, Natalia; Park, Juyoung; Power, Chanikarn; McDannold, Nathan

2012-02-01

Blood-brain-barrier (BBB) limits the transportation of most neuropeptides, proteins (enzymes, antibodies), chemotherapeutic agents, and genes that have therapeutic potential for the treatment of brain diseases. Different methods have been used to overcome this limitation, but they are invasive, non-targeted, or require the development of new drugs. We have developed a method that uses MRI-guided focused ultrasound (FUS) combined with circulating microbubbles to temporarily open BBB in and around brain tumors to deliver chemotherapy agents. Here, we tested whether this noninvasive technique could enhance the effectiveness of a chemotherapy agent (Doxil). Using 690 kHz FUS transducer and microbubble (Definity), we induced BBB disruption in intracranially-implanted 9L glioma tumors in rat's brain in three weekly sessions. Animals who received BBB disruption and Doxil had a median survival time of 34.5 days, which was significantly longer than that found in control animals which is 16, 18.5, 21 days who received no treatment, BBB disruption only and Doxil only respectively This work demonstrates that FUS technique has promise in overcoming barriers to drug delivery, which are particularly stark in the brain due to the BBB.

Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins.

PubMed

Ratti, Antonia; Buratti, Emanuele

2016-08-01

The multiple roles played by RNA binding proteins in neurodegeneration have become apparent following the discovery of TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) involvement in amyotrophic lateral sclerosis and frontotemporal lobar dementia. In these two diseases, the majority of patients display the presence of aggregated forms of one of these proteins in their brains. The study of their functional properties currently represents a very promising target for developing the effective therapeutic options that are still lacking. This aim, however, must be preceded by an accurate evaluation of TDP-43 and FUS/TLS biological functions, both in physiological and disease conditions. Recent findings have uncovered several aspects of RNA metabolism that can be affected by misregulation of these two proteins. Progress has also been made in starting to understand how the aggregation of these proteins occurs and spreads from cell to cell. The aim of this review will be to provide a general overview of TDP-43 and FUS/TLS proteins and to highlight their physiological functions. At present, the emerging picture is that TDP-43 and FUS/TLS control several aspects of an mRNA's life, but they can also participate in DNA repair processes and in non-coding RNA metabolism. Although their regulatory activities are similar, they regulate mainly distinct RNA targets and show different pathogenetic mechanisms in amyotrophic lateral sclerosis/frontotemporal lobar dementia diseases. The identification of key events in these processes represents today the best chance of finding targetable options for therapeutic approaches that might actually make a difference at the clinical level. The two major RNA Binding Proteins involved in Amyotrophic Lateral Sclerosisi and Frontotemporal Dementia are TDP-43 and FUST/TLS. Both proteins are involved in regulating all aspects of RNA and RNA life cycle within neurons, from transcription, processing, and transport/stability to the formation of cytoplasmic and nuclear stress granules. For this reason, the aberrant aggregation of these factors during disease can impair multiple RNA metabolic pathways and eventually lead to neuronal death/inactivation. The purpose of this review is to provide an up-to-date perspective on what we know about this issue at the molecular level. This article is part of the Frontotemporal Dementia special issue. © 2016 International Society for Neurochemistry.

Immediate-type hypersensitivity reaction to ingestion of mycoprotein (Quorn) in a patient allergic to molds caused by acidic ribosomal protein P2.

PubMed

Hoff, Michael; Trüeb, Ralph M; Ballmer-Weber, Barbara K; Vieths, Stefan; Wuethrich, Brunello

2003-05-01

Quorn is the brand name for a line of foods made with so-called "mycoprotein," which springs from the mold Fusarium venenatum. Since the introduction on the food market, there have been complaints from consumers reporting adverse gastrointestinal reactions after ingestion of mycoprotein. To date, it is not clear whether the reported symptoms are IgE-mediated. The aim of the study was to describe for the first time a case history of an asthmatic patient with severe hypersensitivity reactions to ingested mycoprotein and to identify and characterize the potential allergen that might be responsible for this. The sensitization pattern of the asthmatic subject was characterized, and food allergy to mycoprotein was assessed by double-blinded placebo-controlled food challenge. Afterward, specific IgE antibodies of the serum of this patient were used to screen a Fusarium culmorum cDNA expression library. The coding sequence of one enriched cDNA-clone was expressed in Escherichia coli to produce a recombinant protein that was further purified and immunologically characterized. The patient showed high sensitization to many known aeroallergens but apart from Quorn not to any other tested food samples. The deduced amino acid sequence of the enriched cDNA-clone (Fus c 1) showed large identity to the 60S acidic ribosomal protein P2 which is highly conserved among several species and also described as minor allergen in other mold species. The frequency of IgE reactivity of sera from F culmorum -sensitized subjects to rFus c 1 was approximately 35%. By enzyme allergosorbent test inhibition, we found 65% inhibition of mycoprotein IgE reactivity by rFus c 1. On the opposite we found reduced IgE reactivity of rFus c 1 of 68% by using mycoprotein as inhibitor. Sensitization to mold allergens by the respiratory tract and subsequent oral ingestion of cross-reactive proteins may lead to severe food-allergic reactions. Thus, the 60S acidic ribosomal protein P2 of F venenatum probably is the reason for the described severe hypersensitivity reactions of the patient to Quorn-mycoprotein because of its potential cross-reactivity to the F culmorum allergen Fus c 1.

Full-wave acoustic and thermal modeling of transcranial ultrasound propagation and investigation of skull-induced aberration correction techniques: a feasibility study.

PubMed

Kyriakou, Adamos; Neufeld, Esra; Werner, Beat; Székely, Gábor; Kuster, Niels

2015-01-01

Transcranial focused ultrasound (tcFUS) is an attractive noninvasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of tcFUS therapy, as its heterogeneous nature and acoustic characteristics induce significant distortion of the acoustic energy deposition, focal shifts, and thermal gain decrease. Phased-array transducers allow for partial compensation of skull-induced aberrations by application of precalculated phase and amplitude corrections. An integrated numerical framework allowing for 3D full-wave, nonlinear acoustic and thermal simulations has been developed and applied to tcFUS. Simulations were performed to investigate the impact of skull aberrations, the possibility of extending the treatment envelope, and adverse secondary effects. The simulated setup comprised an idealized model of the ExAblate Neuro and a detailed MR-based anatomical head model. Four different approaches were employed to calculate aberration corrections (analytical calculation of the aberration corrections disregarding tissue heterogeneities; a semi-analytical ray-tracing approach compensating for the presence of the skull; two simulation-based time-reversal approaches with and without pressure amplitude corrections which account for the entire anatomy). These impact of these approaches on the pressure and temperature distributions were evaluated for 22 brain-targets. While (semi-)analytical approaches failed to induced high pressure or ablative temperatures in any but the targets in the close vicinity of the geometric focus, simulation-based approaches indicate the possibility of considerably extending the treatment envelope (including targets below the transducer level and locations several centimeters off the geometric focus), generation of sharper foci, and increased targeting accuracy. While the prediction of achievable aberration correction appears to be unaffected by the detailed bone-structure, proper consideration of inhomogeneity is required to predict the pressure distribution for given steering parameters. Simulation-based approaches to calculate aberration corrections may aid in the extension of the tcFUS treatment envelope as well as predict and avoid secondary effects (standing waves, skull heating). Due to their superior performance, simulationbased techniques may prove invaluable in the amelioration of skull-induced aberration effects in tcFUS therapy. The next steps are to investigate shear-wave-induced effects in order to reliably exclude secondary hot-spots, and to develop comprehensive uncertainty assessment and validation procedures.

Treatment with Saccharomyces boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in 5-fluorouracil-induced intestinal mucositis in mice.

PubMed

Justino, Priscilla F C; Melo, Luis F M; Nogueira, Andre F; Costa, Jose V G; Silva, Luara M N; Santos, Cecila M; Mendes, Walber O; Costa, Marina R; Franco, Alvaro X; Lima, Aldo A; Ribeiro, Ronaldo A; Souza, Marcellus H L P; Soares, Pedro M G

2014-05-01

Intestinal mucositis is an important toxic side effect of 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii is known to protect from intestinal injury via an effect on the gastrointestinal microbiota. The objective of the present study was to evaluate the effect of S. boulardii on intestinal mucositis induced by 5-FU in a murine model. Mice were divided into saline, saline (control)+5-FU or 5-FU+S. boulardii (16 × 10⁹ colony-forming units/kg) treatment groups, and the jejunum and ileum were removed after killing of mice for the evaluation of histopathology, myeloperoxidase (MPO) activity, and non-protein sulfhydryl group (mainly reduced glutathione; GSH), nitrite and cytokine concentrations. To determine gastric emptying, phenol red was administered orally, mice were killed 20 min after administration, and the absorbance of samples collected from the mice was measured by spectrophotometry. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following oral administration. S. boulardii significantly reversed the histopathological changes in intestinal mucositis induced by 5-FU and reduced the inflammatory parameters: neutrophil infiltration (control 1·73 (SEM 0·37) ultrastructural MPO (UMPO)/mg, 5-FU 7·37 (SEM 1·77) UMPO/mg and 5-FU+S. boulardii 4·15 (SEM 0·73) UMPO/mg); nitrite concentration (control 37·00 (SEM 2·39) μm, 5-FU 59·04 (SEM 11·41) μm and 5-FU+S. boulardii 37·90 (SEM 5·78) μm); GSH concentration (control 477·60 (SEM 25·25) μg/mg, 5-FU 270·90 (SEM 38·50) μg/mg and 5-FU+S. boulardii 514·00 (SEM 38·64) μg/mg). Treatment with S. Boulardii significantly reduced the concentrations of TNF-α and IL-1β by 48·92 and 32·21 % in the jejunum and 38·92 and 61·79 % in the ileum. In addition, S. boulardii decreased the concentrations of chemokine (C-X-C motif) ligand 1 by 5-fold in the jejunum and 3-fold in the ileum. Interestingly, S. boulardii reduced the delay in gastric emptying (control 25·21 (SEM 2·55) %, 5-FU 54·91 (SEM 3·43) % and 5-FU+S. boulardii 31·38 (SEM 2·80) %) and induced the recovery of intestinal permeability (lactulose:mannitol ratio: control 0·52 (SEM 0·03), 5-FU 1·38 (SEM 0·24) and 5-FU+S. boulardii 0·62 (SEM 0·03)). In conclusion, S. boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in intestinal mucositis induced by 5-FU.

Quantitative measurement and real-time tracking of high intensity focused ultrasound using phase-sensitive optical coherence tomography: Feasibility study.

PubMed

Le, Nhan; Song, ShaoZhen; Nabi, Ghulam; Wang, Ruikang; Huang, Zhihong

2016-09-01

Phase-sensitive optical coherence tomography (PhS-OCT) is proposed, as a new high intensity focused ultrasound (HIFU) imaging guidance to detect and track HIFU focus inside 1% agar samples in this work. The experiments studied the effect of varying HIFU power on the induction of shear wave, which can be implemented as a new technique to monitor focused ultrasound surgery (FUS). A miniature HIFU transducer (1.02 MHz, 20 mm aperture diameter, 15 mm radius of curvature) was produced in-house, pressure-field mapped, and calibrated. The transducer was then embedded inside a 1% agar phantom, which was placed under PhS-OCT for observation, under various HIFU power settings (acoustic power, and number of cycles per pulse). Shear wave was induced on the sample surface by HIFU and was captured in full under PhS-OCT. The lowest HIFU acoustic power output for the detection of shear wave was found to be 0.36 W (1.02 MHz, 100 cycles/pulse), or with the number of cycles/pulse as low as 20 (1.02 MHz, 0.98 W acoustic power output). A linear relationship between acoustic power output and the maximum shear wave displacement was found in the first study. The second study explores a non-linear correlation between the (HIFU) numbers of cycles per pulse, and the maximum shear wave displacement. PhS-OCT demonstrates excellent tracking and detection of HIFU-induced shear wave. The results could benefit other imaging techniques in tracking and guiding HIFU focus. Further studies will explore the relationship between the physical transducer characteristics and the HIFU-induced shear wave.

Effect of neurological monitoring in postoperative 5-15 days residual thyroidectomy after primary thyroid cancer surgery.

PubMed

Long, Miao-Yun; Diao, Fei-Yu; Peng, Li-Na; Tan, Lang-Ping; Zhu, Yue; Huang, Kai; Li, Hong-Hao

2018-05-16

To explore the application of intraoperative neurological monitoring in residual thyroidectomy 5-15 days after thyroid cancer operation and the influence on postoperative serum thyroglobulin (Tg), recurrent laryngeal nerve and function of parathyroid glands. Material of patients receiving thyroid surgery from January 2010 to December 2016 was retrospectively analyzed. Cases meeting with standards were enrolled for analysis and the patients were divided into neurological monitoring group and non-neurological monitoring group in line with the use of neurological monitoring during the operation. Recurrent laryngeal nerve-injured hoarseness, hypoparathyroidism and concentration of serum Tg before and after the surgery were collected and analyzed. Four-hundred and thirty-five patients met with standards, among which 227 from neurological monitoring group and 208 from non-neurological monitoring group. Temporary hoarseness rate of non-neurological monitoring group and neurological monitoring group was 8.67% and 2.2%. Permanent hoarseness rate of non-neurological monitoring group and neurological monitoring group was 1.92% and 0.44%. Temporary hypoparathyroidism rate of non-neurological monitoring group and neurological monitoring group was 18.75% and 7.48%. Permanent hypoparathyroidism rate of non-neurological monitoring group and neurological monitoring group was 1.92% and 0.88%. Average Tg concentration 1 month after the surgery in non-neurological monitoring group and neurological monitoring group was 2.82 and 1.37 ng/mL, respectively. Rate of average Tg concentration less than 1 ng/mL 1 month after the surgery in non-neurological monitoring group and neurological monitoring group was 45.06% and 67.4%. Intraoperative neurological monitoring can be adopted in residual thyroidectomy in postoperative 5-15 days after primary thyroid cancer surgery, as to reduce incidence rate of recurrent laryngeal nerve injury and hypoparathyroidism and to enhance thorough removal of thyroid tissues and cancer tissues. © 2018 John Wiley & Sons Australia, Ltd.

A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping

NASA Astrophysics Data System (ADS)

Deng, Lulu; O'Reilly, Meaghan A.; Jones, Ryan M.; An, Ran; Hynynen, Kullervo

2016-12-01

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612, and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning (-40, 40) and (-30, 50) mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi-foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning (-25, 25) mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in vivo experiments demonstrated the system’s ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non-thermal FUS brain therapy and concurrent microbubble cavitation monitoring through the availability of multiple frequencies.

A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping

PubMed Central

Deng, Lulu; O'Reilly, Meaghan A.; Jones, Ryan M.; An, Ran; Hynynen, Kullervo

2016-01-01

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612 and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning [−40, 40] and [−30, 50] mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi–foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning [−25, 25] mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in-vivo experiments demonstrated the system's ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non-thermal FUS brain therapy and concurrent microbubble cavitation monitoring through the availability of multiple frequencies. PMID:27845920

A multi-frequency sparse hemispherical ultrasound phased array for microbubble-mediated transcranial therapy and simultaneous cavitation mapping.

PubMed

Deng, Lulu; O'Reilly, Meaghan A; Jones, Ryan M; An, Ran; Hynynen, Kullervo

2016-12-21

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612, and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning (-40, 40) and (-30, 50) mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi-foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning (-25, 25) mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in vivo experiments demonstrated the system's ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non-thermal FUS brain therapy and concurrent microbubble cavitation monitoring through the availability of multiple frequencies.

Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles

NASA Astrophysics Data System (ADS)

Baseri, Babak; Choi, James J.; Deffieux, Thomas; Samiotaki, Gesthimani; Tung, Yao-Sheng; Olumolade, Oluyemi; Small, Scott A.; Morrison, Barclay, III; Konofagou, Elisa E.

2012-04-01

The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.

Microtubules as platforms for probing liquid-liquid phase separation in cells: application to RNA-binding proteins.

PubMed

Maucuer, Alexandre; Desforges, Bénédicte; Joshi, Vandana; Boca, Mirela; Kretov, Dmitry; Hamon, Loic; Bouhss, Ahmed; Curmi, Patrick A; Pastré, David

2018-05-04

Liquid-liquid phase separation enables compartmentalization of biomolecules in cells, notably RNA and associated proteins in the nucleus. Besides critical functions in RNA processing, there is a major interest in deciphering the molecular mechanisms of compartmentalization orchestrated by RNA-binding proteins such as TDP-43 and FUS due to their link to neuron diseases. However, tools for probing compartmentalization in cells are lacking. Here we developed a method to analyze the mixing:demixing of two different phases in a cellular context. The principle is the following: mRNA-binding proteins are confined on microtubules and quantitative parameters defining their spatial segregation are measured along the microtubule network. Through this approach, we found that four mRNA binding proteins, HuR, G3BP1, TDP-43 and FUS form mRNA-rich liquid-like compartments on microtubules. TDP-43 is partly miscible with FUS but immiscible with either HuR or G3BP1. We also demonstrate that mRNA is essential to capture the mixing:demixing behavior of RNA-binding proteins in cells. Altogether we show that microtubules can be used as platforms to understand the mechanisms underlying liquid-liquid phase separation and their deregulation in human diseases. © 2018. Published by The Company of Biologists Ltd.

Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound

PubMed Central

Miller, G. Wilson; Song, Ji; Louttit, Cameron; Klibanov, Alexander L; Shih, Ting-Yu; Swaminathan, Ganesh; Tamargo, Rafael J.; Woodworth, Graeme F.; Hanes, Justin; Price, Richard J.

2014-01-01

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer’s, Parkinson’s and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a noninvasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPN in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60 nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain. PMID:24979210

Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center.

PubMed

Chadi, Gerson; Maximino, Jessica Ruivo; Jorge, Frederico Mennucci de Haidar; Borba, Fabrício Castro de; Gilio, Joyce Meire; Callegaro, Dagoberto; Lopes, Camila Galvão; Santos, Samantha Nakamura Dos; Rebelo, Gabriela Natania Sales

2017-05-01

To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.

The conservative and interventional treatment of fibroids.

PubMed

Boosz, Alexander Stephan; Reimer, Peter; Matzko, Matthias; Römer, Thomas; Müller, Andreas

2014-12-22

Fibroids are the most common benign tumors in women. One-third of all women of reproductive age undergo treatment for symptomatic fibroids. In recent years, the spectrum of available treatments has been widened by the introduction of new drugs and interventional procedures. Selective literature review on the treatment of uterine fibroids, including consideration of several Cochrane Reviews. Fibroids can be treated with drugs, interventional procedures (uterine artery embolization [UAE] and focused ultrasound treatment [FUS]), and surgery. The evidence regarding the various available treatments is mixed. All methods improve symptoms, but only a few comparative studies have been performed. A meta-analysis revealed that recovery within 15 days is more common after laparoscopic enucleation than after open surgery (odds ratio [OR], 3.2). A minimally invasive hysterectomy, or one performed by the vaginal route, is associated with a shorter hospital stay and a more rapid recovery than open transabdominal hysterectomy. UAE is an alternative to hysterectomy for selected patients. The re-intervention rates after fibroid enucleation, hysterectomy, and UAE are 8.9-9%, 1.8-10.7%, and 7-34.6%, respectively. The main drugs used to treat fibroids are gonadotropin-releasing hormone analogs and selective progesterone receptor modulators. Multiple treatment options are available and enable individualized therapy for symptomatic fibroids. The most important considerations in the choice of treatment are the question of family planning and, in some cases, the technical limitations of the treatments themselves.

Micro-SPECT/CT-based pharmacokinetic analysis of 99mTc-diethylenetriaminepentaacetic acid in rats with blood-brain barrier disruption induced by focused ultrasound.

PubMed

Yang, Feng-Yi; Wang, Hsin-Ell; Lin, Guan-Liang; Teng, Ming-Che; Lin, Hui-Hsien; Wong, Tai-Tong; Liu, Ren-Shyan

2011-03-01

This study evaluated the pharmacokinetics of (99m)Tc-diethylenetriamine pentaacetate acid ((99m)Tc-DTPA) after intravenous administration in healthy and F98 glioma-bearing F344 rats in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). The pharmacokinetics of the healthy and tumor-containing brains after BBB-D were compared to identify the optimal time period for combined treatment. Healthy and F98 glioma-bearing rats were injected intravenously with Evans blue (EB) and (99m)Tc-DTPA; these treatments took place with or without BBB-D induced by transcranial FUS of 1 hemisphere of the brain. The permeability of the BBB was quantified by EB extravasation. Twelve rats were scanned for 2 h to estimate uptake of (99m)Tc radioactivity with respect to time for the pharmacokinetic analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed to examine tissue damage. The accumulations of EB and (99m)Tc-DTPA in normal brains or brains with a tumor were significantly elevated after the intravenous injection when BBB-D was induced. The disruption-to-nondisruption ratio of the brains and the tumor-to-ipsilateral brain ratio of the tumors in terms of radioactivity reached a peak at 45 and 60 min, respectively. EB injection followed by sonication showed that there was an increase of about 2-fold in the tumor-to-ipsilateral brain EB ratio of the target tumors (7.36), compared with the control tumors (3.73). TUNEL staining showed no significant differences between the sonicated tumors and control tumors. This study demonstrates that (99m)Tc-DTPA micro-SPECT/CT can be used for the pharmacokinetic analysis of BBB-D induced by FUS. This method should be able to provide important information that will help with establishing an optimal treatment protocol for drug administration after FUS-induced BBB-D in clinical brain disease therapy.

Quantitative Magnetic Resonance Thermometry and Its Use with MR-Guided Focused Ultrasound

NASA Astrophysics Data System (ADS)

Pauly, Kim

2014-03-01

Focused ultrasound (FUS) uses a large area array, typically outside the body, that is geometrically or electronically focused to a point deep in the body. Such focusing provides amplification of the ultrasound intensity, thereby allowing heating of tissue to the point of coagulation at the focus, without damage to the intervening tissue. Guidance of FUS treatments deep in the body can be done quantitatively with magnetic resonance (MR) thermometry, termed MRgFUS. The physics behind MR thermometry lie in the changes in hydrogen bonding with temperature. As tissue temperature rises, hydrogen bonds break, allowing the return of the electron cloud to shield water protons, reducing the magnetic field seen by the protons, and the resonant frequency. The change in resonant frequency is -0.01 ppm per degree C and is the same for all aqueous tissues. The result of the shift in proton resonant frequency is seen in the phase of gradient echo images. Subtraction of the phase of images acquired before and during heating allows the removal of background phase from other sources, yielding quantitative temperature maps. Temperature standard deviations less than 1 degree C are readily achievable and thermal dose maps are easily calculated. Thermal dose is found from a conversion of the whole temperature-time curve to an equivalent number of minutes at 43 degrees C. A thermal dose of 240 minutes is often taken as the threshold for tissue damage. MR thermometry is complicated by the motion of the target tissue and/or motion of other organs such as occurs during respiration. More sophisticated algorithms than the simple baseline subtraction take advantage of the facts that motion can be repetitive (in the case of respiratory motion) and/or the fact that the focal region in MRgFUS is small, allowing for extraction of the heat from the phase profile without subtraction of a background phase.

Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

PubMed

Zou, Zhang-Yu; Zhou, Zhi-Rui; Che, Chun-Hui; Liu, Chang-Yun; He, Rao-Li; Huang, Hua-Pin

2017-07-01

Genetic studies have shown that C9orf72 , SOD1 , TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the mutation frequencies of these major ALS-related genes in patients with ALS. We performed an extensive literature research to identify all original articles reporting frequencies of C9orf72 , SOD1 , TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis. 111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations. These findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis.

PubMed

Tibshirani, Michael; Zhao, Beibei; Gentil, Benoit J; Minotti, Sandra; Marques, Christine; Keith, Julia; Rogaeva, Ekaterina; Zinman, Lorne; Rouaux, Caroline; Robertson, Janice; Durham, Heather D

2017-11-01

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Barcode Sequencing Screen Identifies SUB1 as a Regulator of Yeast Pheromone Inducible Genes

PubMed Central

Sliva, Anna; Kuang, Zheng; Meluh, Pamela B.; Boeke, Jef D.

2016-01-01

The yeast pheromone response pathway serves as a valuable model of eukaryotic mitogen-activated protein kinase (MAPK) pathways, and transcription of their downstream targets. Here, we describe application of a screening method combining two technologies: fluorescence-activated cell sorting (FACS), and barcode analysis by sequencing (Bar-Seq). Using this screening method, and pFUS1-GFP as a reporter for MAPK pathway activation, we readily identified mutants in known mating pathway components. In this study, we also include a comprehensive analysis of the FUS1 induction properties of known mating pathway mutants by flow cytometry, featuring single cell analysis of each mutant population. We also characterized a new source of false positives resulting from the design of this screen. Additionally, we identified a deletion mutant, sub1Δ, with increased basal expression of pFUS1-GFP. Here, in the first ChIP-Seq of Sub1, our data shows that Sub1 binds to the promoters of about half the genes in the genome (tripling the 991 loci previously reported), including the promoters of several pheromone-inducible genes, some of which show an increase upon pheromone induction. Here, we also present the first RNA-Seq of a sub1Δ mutant; the majority of genes have no change in RNA, but, of the small subset that do, most show decreased expression, consistent with biochemical studies implicating Sub1 as a positive transcriptional regulator. The RNA-Seq data also show that certain pheromone-inducible genes are induced less in the sub1Δ mutant relative to the wild type, supporting a role for Sub1 in regulation of mating pathway genes. The sub1Δ mutant has increased basal levels of a small subset of other genes besides FUS1, including IMD2 and FIG1, a gene encoding an integral membrane protein necessary for efficient mating. PMID:26837954

Ultrashort echo-time MRI versus CT for skull aberration correction in MR-guided transcranial focused ultrasound: In vitro comparison on human calvaria.

PubMed

Miller, G Wilson; Eames, Matthew; Snell, John; Aubry, Jean-François

2015-05-01

Transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) brain treatment systems compensate for skull-induced beam aberrations by adjusting the phase and amplitude of individual ultrasound transducer elements. These corrections are currently calculated based on a preacquired computed tomography (CT) scan of the patient's head. The purpose of the work presented here is to demonstrate the feasibility of using ultrashort echo-time magnetic resonance imaging (UTE MRI) instead of CT to calculate and apply aberration corrections on a clinical TcMRgFUS system. Phantom experiments were performed in three ex-vivo human skulls filled with tissue-mimicking hydrogel. Each skull phantom was imaged with both CT and UTE MRI. The MR images were then segmented into "skull" and "not-skull" pixels using a computationally efficient, threshold-based algorithm, and the resulting 3D binary skull map was converted into a series of 2D virtual CT images. Each skull was mounted in the head transducer of a clinical TcMRgFUS system (ExAblate Neuro, Insightec, Israel), and transcranial sonications were performed using a power setting of approximately 750 acoustic watts at several different target locations within the electronic steering range of the transducer. Each target location was sonicated three times: once using aberration corrections calculated from the actual CT scan, once using corrections calculated from the MRI-derived virtual CT scan, and once without applying any aberration correction. MR thermometry was performed in conjunction with each 10-s sonication, and the highest single-pixel temperature rise and surrounding-pixel mean were recorded for each sonication. The measured temperature rises were ∼ 45% larger for aberration-corrected sonications than for noncorrected sonications. This improvement was highly significant (p < 10(-4)). The difference between the single-pixel peak temperature rise and the surrounding-pixel mean, which reflects the sharpness of the thermal focus, was also significantly larger for aberration-corrected sonications. There was no significant difference between the sonication results achieved using CT-based and MR-based aberration correction. The authors have demonstrated that transcranial focal heating can be significantly improved in vitro by using UTE MRI to compute skull-induced ultrasound aberration corrections. Their results suggest that UTE MRI could be used instead of CT to implement such corrections on current 0.7 MHz clinical TcMRgFUS devices. The MR image acquisition and segmentation procedure demonstrated here would add less than 15 min to a clinical MRgFUS treatment session.

ABA-dependent inhibition of the ubiquitin proteasome system during germination at high temperature in Arabidopsis.

PubMed

Chiu, Rex Shun; Pan, Shiyue; Zhao, Rongmin; Gazzarrini, Sonia

2016-12-01

During germination, endogenous and environmental factors trigger changes in the transcriptome, translatome and proteome to break dormancy. In Arabidopsis thaliana, the ubiquitin proteasome system (UPS) degrades proteins that promote dormancy to allow germination. While research on the UPS has focused on the identification of proteasomal substrates, little information is known about the regulation of its activity. Here we characterized the activity of the UPS during dormancy release and maintenance by monitoring protein ubiquitination and degradation of two proteasomal substrates: Suc-LLVY-AMC, a well characterized synthetic substrate, and FUSCA3 (FUS3), a dormancy-promoting transcription factor degraded by the 26S proteasome. Our data indicate that proteasome activity and protein ubiquitination increase during imbibition at optimal temperature (21°C), and are required for seed germination. However, abscisic acid (ABA) and supraoptimal temperature (32°C) inhibit germination by dampening both protein ubiquitination and proteasome activity. Inhibition of UPS function by high temperature is reduced by the ABA biosynthesis inhibitor, fluridone, and in ABA biosynthetic mutants, suggesting that it is ABA dependent. Accordingly, inhibition of FUS3 degradation at 32°C is also dependent on ABA. Native gels show that inhibition of proteasome activity is caused by interference with the 26S/30S ratio as well as free 19S and 20S levels, impacting the proteasome degradation cycle. Transfer experiments show that ABA-mediated inhibition of proteasome activity at 21°C is restricted to the first 2 days of germination, a time window corresponding to seed sensitivity to environmental and ABA-mediated growth inhibition. Our data show that ABA and high temperature inhibit germination under unfavourable growth conditions by repressing the UPS. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

TU-B-210-01: MRg HIFU - Bone and Soft Tissue Tumor Ablation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghanouni, P.

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advancedmore » techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips.« less

TU-B-210-02: MRg HIFU - Advanced Approaches for Ablation and Hyperthermia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moonen, C.

2015-06-15

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advancedmore » techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips.« less

Validation and Application of a Dried Blood Spot Assay for Biofilm-Active Antibiotics Commonly Used for Treatment of Prosthetic Implant Infections

PubMed Central

Knippenberg, Ben; Page-Sharp, Madhu; Clark, Ben; Dyer, John; Batty, Kevin T.; Davis, Timothy M. E.

2016-01-01

Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK)/pharmacodynamic (PD) studies in situations where venous blood sampling is logistically difficult. We sought to develop, validate, and apply a DBS assay for rifampin (RIF), fusidic acid (FUS), and ciprofloxacin (CIP). These antibiotics are considered active against organisms in biofilms and are therefore commonly used for the treatment of infections associated with prosthetic implants. A liquid chromatography-mass spectroscopy DBS assay was developed and validated, including red cell partitioning and thermal stability for each drug and the rifampin metabolite desacetyl rifampin (Des-RIF). Plasma and DBS concentrations in 10 healthy adults were compared, and the concentration-time profiles were incorporated into population PK models. The limits of quantification for RIF, Des-RIF, CIP, and FUS in DBS were 15 μg/liter, 14 μg/liter, 25 μg/liter, and 153 μg/liter, respectively. Adjusting for hematocrit, red cell partitioning, and relative recovery, DBS-predicted plasma concentrations were comparable to measured plasma concentrations for each antibiotic (r > 0.95; P < 0.0001), and Bland-Altman plots showed no significant bias. The final population PK estimates of clearance, volume of distribution, and time above threshold MICs for measured and DBS-predicted plasma concentrations were comparable. These drugs were stable in DBSs for at least 10 days at room temperature and 1 month at 4°C. The present DBS antibiotic assays are robust and can be used as surrogates for plasma concentrations to provide valid PK and PK/PD data in a variety of clinical situations, including therapeutic drug monitoring or studies of implant infections. PMID:27270283

TU-B-210-00: MR-Guided Focused Ultrasound Therapy in Oncology

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advancedmore » techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips.« less

Utility of intraoperative nerve monitoring in thyroid surgery: 20-year experience with 1418 cases.

PubMed

Kadakia, Sameep; Mourad, Moustafa; Hu, Shirley; Brown, Ryan; Lee, Thomas; Ducic, Yadranko

2017-09-01

The efficacy of intraoperative nerve monitoring is controversial in the literature. This study of a single surgeon's experience seeks to determine if the use of intraoperative nerve monitoring influences recurrent laryngeal nerve injury during thyroid surgery. Six hundred fifty-seven patients with normal pre-operative vocal fold function underwent thyroid surgery without the use of intraoperative nerve monitoring from September 1997 to January 2007, while 761 patients underwent thyroid surgery from February 2007 to February 2016 with routine use of nerve monitoring. Patients were followed for a minimum of 6 months after surgery, and postoperative nerve function was determined by fiberoptic laryngoscopy. A Fisher test was used to determine if nerve injury was statistically different between both groups. In patients operated on without nerve monitoring, 21 patients were found to have postoperative vocal fold paralysis with nine regaining functioning. In patients operated on with nerve monitoring, 27 were found to have vocal fold dysfunction with 17 regaining function. Fisher test analysis, both with and without patients regaining function, showed no difference in nerve injury between groups (p > 0.05, p > 0.05). Intraoperative monitoring during thyroidectomy may not prevent injury to the recurrent laryngeal nerve.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Intraoperative Cranial Nerve Monitoring in Vestibular Schwannoma Surgery.

PubMed

Vivas, Esther X; Carlson, Matthew L; Neff, Brian A; Shepard, Neil T; McCracken, D Jay; Sweeney, Alex D; Olson, Jeffrey J

2018-02-01

Does intraoperative facial nerve monitoring during vestibular schwannoma surgery lead to better long-term facial nerve function? This recommendation applies to adult patients undergoing vestibular schwannoma surgery regardless of tumor characteristics. Level 3: It is recommended that intraoperative facial nerve monitoring be routinely utilized during vestibular schwannoma surgery to improve long-term facial nerve function. Can intraoperative facial nerve monitoring be used to accurately predict favorable long-term facial nerve function after vestibular schwannoma surgery? This recommendation applies to adult patients undergoing vestibular schwannoma surgery. Level 3: Intraoperative facial nerve can be used to accurately predict favorable long-term facial nerve function after vestibular schwannoma surgery. Specifically, the presence of favorable testing reliably portends a good long-term facial nerve outcome. However, the absence of favorable testing in the setting of an anatomically intact facial nerve does not reliably predict poor long-term function and therefore cannot be used to direct decision-making regarding the need for early reinnervation procedures. Does an anatomically intact facial nerve with poor electromyogram (EMG) electrical responses during intraoperative testing reliably predict poor long-term facial nerve function? This recommendation applies to adult patients undergoing vestibular schwannoma surgery. Level 3: Poor intraoperative EMG electrical response of the facial nerve should not be used as a reliable predictor of poor long-term facial nerve function. Should intraoperative eighth cranial nerve monitoring be used during vestibular schwannoma surgery? This recommendation applies to adult patients undergoing vestibular schwannoma surgery with measurable preoperative hearing levels and tumors smaller than 1.5 cm. Level 3: Intraoperative eighth cranial nerve monitoring should be used during vestibular schwannoma surgery when hearing preservation is attempted. Is direct monitoring of the eighth cranial nerve superior to the use of far-field auditory brain stem responses? This recommendation applies to adult patients undergoing vestibular schwannoma surgery with measurable preoperative hearing levels and tumors smaller than 1.5 cm. Level 3: There is insufficient evidence to make a definitive recommendation.  The full guideline can be found at: https://www.cns.org/guidelines/guidelines-manage-ment-patients-vestibular-schwannoma/chapter_4. Copyright © 2017 by the Congress of Neurological Surgeons

Intraoperative Recurrent Laryngeal Nerve Monitoring in a Patient with Contralateral Vocal Fold Palsy.

PubMed

Na, Bub-Se; Choi, Jin-Ho; Park, In Kyu; Kim, Young Tae; Kang, Chang Hyun

2017-10-01

Recurrent laryngeal nerve injury can develop following cervical or thoracic surgery; however, few reports have described intraoperative recurrent laryngeal nerve monitoring. Consensus regarding the use of this technique during thoracic surgery is lacking. We used intraoperative recurrent laryngeal nerve monitoring in a patient with contralateral vocal cord paralysis who was scheduled for completion pneumonectomy. This case serves as an example of intraoperative recurrent laryngeal nerve monitoring during thoracic surgery and supports this indication for its use.

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models.

PubMed

Wong, Andrew W; Fite, Brett Z; Liu, Yu; Kheirolomoom, Azadeh; Seo, Jai W; Watson, Katherine D; Mahakian, Lisa M; Tam, Sarah M; Zhang, Hua; Foiret, Josquin; Borowsky, Alexander D; Ferrara, Katherine W

2016-01-01

Magnetic resonance-guided focused ultrasound (MRgFUS) facilitates noninvasive image-guided conformal thermal therapy of cancer. Yet in many scenarios, the sensitive tissues surrounding the tumor constrain the margins of ablation; therefore, augmentation of MRgFUS with chemotherapy may be required to destroy remaining tumor. Here, we used 64Cu-PET-CT, MRI, autoradiography, and fluorescence imaging to track the kinetics of long-circulating liposomes in immunocompetent mammary carcinoma-bearing FVB/n and BALB/c mice. We observed a 5-fold and 50-fold enhancement of liposome and drug concentration, respectively, within MRgFUS thermal ablation-treated tumors along with dense accumulation within the surrounding tissue rim. Ultrasound-enhanced drug accumulation was rapid and durable and greatly increased total tumor drug exposure over time. In addition, we found that the small molecule gadoteridol accumulates around and within ablated tissue. We further demonstrated that dilated vasculature, loss of vascular integrity resulting in extravasation of blood cells, stromal inflammation, and loss of cell-cell adhesion and tissue architecture all contribute to the enhanced accumulation of the liposomes and small molecule probe. The locally enhanced liposome accumulation was preserved even after a multiweek protocol of doxorubicin-loaded liposomes and partial ablation. Finally, by supplementing ablation with concurrent liposomal drug therapy, a complete and durable response was obtained using protocols for which a sub-mm rim of tumor remained after ablation.

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models

PubMed Central

Wong, Andrew W.; Fite, Brett Z.; Liu, Yu; Kheirolomoom, Azadeh; Seo, Jai W.; Watson, Katherine D.; Mahakian, Lisa M.; Tam, Sarah M.; Zhang, Hua; Foiret, Josquin; Borowsky, Alexander D.; Ferrara, Katherine W.

2015-01-01

Magnetic resonance–guided focused ultrasound (MRgFUS) facilitates noninvasive image-guided conformal thermal therapy of cancer. Yet in many scenarios, the sensitive tissues surrounding the tumor constrain the margins of ablation; therefore, augmentation of MRgFUS with chemotherapy may be required to destroy remaining tumor. Here, we used 64Cu-PET-CT, MRI, autoradiography, and fluorescence imaging to track the kinetics of long-circulating liposomes in immunocompetent mammary carcinoma–bearing FVB/n and BALB/c mice. We observed a 5-fold and 50-fold enhancement of liposome and drug concentration, respectively, within MRgFUS thermal ablation–treated tumors along with dense accumulation within the surrounding tissue rim. Ultrasound-enhanced drug accumulation was rapid and durable and greatly increased total tumor drug exposure over time. In addition, we found that the small molecule gadoteridol accumulates around and within ablated tissue. We further demonstrated that dilated vasculature, loss of vascular integrity resulting in extravasation of blood cells, stromal inflammation, and loss of cell-cell adhesion and tissue architecture all contribute to the enhanced accumulation of the liposomes and small molecule probe. The locally enhanced liposome accumulation was preserved even after a multiweek protocol of doxorubicin-loaded liposomes and partial ablation. Finally, by supplementing ablation with concurrent liposomal drug therapy, a complete and durable response was obtained using protocols for which a sub-mm rim of tumor remained after ablation. PMID:26595815

The BABY BOOM Transcription Factor Activates the LEC1-ABI3-FUS3-LEC2 Network to Induce Somatic Embryogenesis1[OPEN

PubMed Central

Weemen, Mieke

2017-01-01

Somatic embryogenesis is an example of induced cellular totipotency, where embryos develop from vegetative cells rather than from gamete fusion. Somatic embryogenesis can be induced in vitro by exposing explants to growth regulators and/or stress treatments. The BABY BOOM (BBM) and LEAFY COTYLEDON1 (LEC1) and LEC2 transcription factors are key regulators of plant cell totipotency, as ectopic overexpression of either transcription factor induces somatic embryo formation from Arabidopsis (Arabidopsis thaliana) seedlings without exogenous growth regulators or stress treatments. Although LEC and BBM proteins regulate the same developmental process, it is not known whether they function in the same molecular pathway. We show that BBM transcriptionally regulates LEC1 and LEC2, as well as the two other LAFL genes, FUSCA3 (FUS3) and ABSCISIC ACID INSENSITIVE3 (ABI3). LEC2 and ABI3 quantitatively regulate BBM-mediated somatic embryogenesis, while FUS3 and LEC1 are essential for this process. BBM-mediated somatic embryogenesis is dose and context dependent, and the context-dependent phenotypes are associated with differential LAFL expression. We also uncover functional redundancy for somatic embryogenesis among other Arabidopsis BBM-like proteins and show that one of these proteins, PLETHORA2, also regulates LAFL gene expression. Our data place BBM upstream of other major regulators of plant embryo identity and totipotency. PMID:28830937

Efficacy of sub-threshold focused ultrasound irradiation against pancreatic cancer xenografts evaluated using magnetic resonance imaging

PubMed Central

Chen, Yini; Gao, Yihui; Wu, Lei

2017-01-01

We investigated the efficacy and optimal period for using magnetic resonance imaging (MRI) to detect effects of sub-threshold focused ultrasound (FUS) irradiation. Nude mice bearing pancreatic cancer xenografts were subjected to MRI and pathology examnation before, and 24 h, 48 h, 2 weeks after irradiation, which were used to evaluate therapeutic effects of FUS. Tumor volumes were lower post-treatment than control group (P < 0.05). The T1WI turbo spin echo (T1WI-TSE) sequence was similar signal before and after treatment. On T1 enhanced scanning sequence (T1WI-SPIR) imaging, ablation lesions appeared as patchy areas of low signal after 24 h and 48 h. After 2 weeks, the ablation lesions contained low signal areas with clear borders. Hematoxylin and eosin (HE) staining revealed small vessels at ablation lesions with no obvious boundary between cell injury areas and normal tumor cells areas in early-stage, while revealed obvious boundaries 2 weeks post-treatment. Terminal deoxynucleotidyl transferase-modified, dUTP nick-end labeling (TUNEL) staining showed cell apoptosis in early-stage, and revealed reduced apoptotic cells and increased necrotic cell areas 2 weeks later. These findings indicate sub-threshold FUS induces pancreatic cancer cell apoptosis and inhibits tumor growth. Contrast-enhanced MRI delineated the ablation lesions better 2 weeks post-treatment than early stage. PMID:29113316

Investigation and Treatment of Fusidic Acid Resistance Among Methicillin-Resistant Staphylococcal Isolates from Egypt.

PubMed

Abouelfetouh, Alaa; Kassem, Mervat; Naguib, Marwa; El-Nakeeb, Moustafa

2017-01-01

Methicillin resistance among staphylococci isolated from patients in northern Egypt has escalated alarmingly in the past decade. Data about the prevalence of fusidic acid (FA) resistance in Egyptian clinical isolates are limited. This work investigates the prevalence and mechanism of FA resistance among 81 methicillin-resistant staphylococcal isolates from major hospitals of Alexandria, Egypt. Some combinations for treating infections due to resistant isolates were studied. Twenty-six isolates (32.1%) were FA resistant (minimum inhibitory concentrations [MICs] = 2-1,024 μg/ml), and fusB and fusC genes coding for FA resistance were detected in 30.77% and 34.62% of the FA-resistant strains, respectively. One highly resistant isolate, S502 (MIC = 1,024 μg/ml), possessed both genes. Plasmid curing resulted in fusB loss and MIC decrease by 16-64 folds. Conjugation caused acquisition of FA resistance among susceptible isolates. Serial passages in subinhibitory FA concentrations produced mutants with increased MIC by 4-32 folds. The combination of FA with rifampin, gentamicin, or ampicillin/sulbactam, in a subinhibitory concentration, was synergistic against the isolates, including serial passage mutants, decreasing number of survivors by an average of 2-4 logs. A relatively moderate rate of FA resistance was detected in Alexandria hospitals. Combination therapy with gentamicin, rifampin, or ampicillin/sulbactam is crucial to preserve the effectiveness of FA.

Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

NASA Astrophysics Data System (ADS)

Cho, Hongseok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-Ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

2016-08-01

Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

Intraoperative nerve monitoring in laryngotracheal surgery.

PubMed

Bolufer, Sergio; Coves, María Dolores; Gálvez, Carlos; Villalona, Gustavo Adolfo

Laryngotracheal surgery has an inherent risk of injury to the recurrent laryngeal nerves (RLN). These complications go from minor dysphonia to even bilateral vocal cord paralysis. The intraoperative neuromonitoring of the RLN was developed in the field of thyroid surgery, in order to preserve nerve and vocal cord function. However, tracheal surgery requires in-field intubation of the distal trachea, which limits the use of nerve monitoring using conventional endotracheal tube with surface electrodes. Given these challenges, we present an alternative method for nerve monitoring during laryngotracheal surgery through the insertion of electrodes within the endolaryngeal musculature by bilateral puncture. Copyright © 2016 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

Intensity dependence of focused ultrasound lesion position

NASA Astrophysics Data System (ADS)

Meaney, Paul M.; Cahill, Mark D.; ter Haar, Gail R.

1998-04-01

Knowledge of the spatial distribution of intensity loss from an ultrasonic beam is critical to predicting lesion formation in focused ultrasound surgery. To date most models have used linear propagation models to predict the intensity profiles needed to compute the temporally varying temperature distributions. These can be used to compute thermal dose contours that can in turn be used to predict the extent of thermal damage. However, these simulations fail to adequately describe the abnormal lesion formation behavior observed for in vitro experiments in cases where the transducer drive levels are varied over a wide range. For these experiments, the extent of thermal damage has been observed to move significantly closer to the transducer with increasing transducer drive levels than would be predicted using linear propagation models. The simulations described herein, utilize the KZK (Khokhlov-Zabolotskaya-Kuznetsov) nonlinear propagation model with the parabolic approximation for highly focused ultrasound waves, to demonstrate that the positions of the peak intensity and the lesion do indeed move closer to the transducer. This illustrates that for accurate modeling of heating during FUS, nonlinear effects must be considered.

Evaluation of a hygiene monitor for detection of contamination in dental surgeries.

PubMed

Douglas, C W; Rothwell, P S

1991-05-11

Routines for disinfecting working surfaces in dental surgeries are difficult to monitor without time-consuming and labour-intensive microbiological techniques, yet effective monitoring is a vital part of cross-infection control. Easy to use, on-site methods would be valuable in this context. This study evaluates a portable monitor, the Biotrace Hygiene Monitor, which uses bioluminescence to measure adenosine triphosphate (ATP) on surfaces. Under laboratory conditions, the ability of the monitor to detect whole saliva and Streptococcus sanguis was determined and, in the general practice environment, the level of ATP on surfaces in five dental surgeries was assessed. The minimum amount of saliva detectable was 0.5 microliters and in surgeries, the monitor readily identified numerous surfaces with fairly high levels of ATP. Routine cleaning methods sometimes left ATP on surfaces at levels which represented a cross-infection risk, if it is assumed that the ATP derived from patients' saliva. Modification of cleaning methods resulted in a reduction of ATP levels to within that which could be considered reasonably practicably safe. It is concluded that the Biotrace Hygiene Monitor offers a simple and valuable means of monitoring dental practice cleaning routines.

Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

NASA Astrophysics Data System (ADS)

Etame, Arnold B.

The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non-transport permissive and intact BBB, we also assessed the role of magnetic resonance imaging (MRI) guided focused ultrasound (MRgFUS) disruption of the BBB in enhancing permeation of AuNPs across the intact BBB and tumor BBB in vivo. MRgFUS is a novel technique that can transiently increase BBB permeability thereby allowing delivery of therapeutics into the CNS. We demonstrated enhanced delivery of AuNPs with therapeutic potential into the CNS via MRgFUS. Our study was the first to establish a definitive role for MRgFUS in delivering AuNPs into the CNS. In summary, this thesis describes results from a series of research projects that have contributed to our understanding of the influence of design features on AuNP permeation through the BBB and also the potential role of MRgFUS in AuNP permeation across the BBB.

A theranostic nrGO@MSN-ION nanocarrier developed to enhance the combination effect of sonodynamic therapy and ultrasound hyperthermia for treating tumor

NASA Astrophysics Data System (ADS)

Chen, Yu-Wei; Liu, Tse-Ying; Chang, Po-Hsueh; Hsu, Po-Hung; Liu, Hao-Li; Lin, Hong-Cheu; Chen, San-Yuan

2016-06-01

Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor.Sonodynamic therapy (SDT), which induces activation of sonosensitizers in cancer cells through ultrasound irradiation, has emerged as an alternative and promising noninvasive therapeutic approach to kill both superficial and deep parts of tumors. In this study, mesoporous silica (MSN) grown on reduced graphene oxide nanosheet (nrGO) capped with Rose Bengal (RB)-PEG-conjugated iron-oxide nanoparticles (IONs), nrGO@MSN-ION-PEG-RB, was strategically designed to have targeted functionality and therapeutic efficacy under magnetic guiding and focused ultrasound (FUS) irradiation, respectively. The singlet oxygen produced by ultrasound-activated RB and the ultrasound-induced heating effect was enhanced by rGO and IONs, which improved the cytotoxic effect in cancer cells. In an animal experiment, we demonstrated that the combination of sonodynamic/hyperthermia therapy with magnetic guidance using this nanocomposite therapeutic agent can produce remarkable efficacious therapy in tumor growth inhibition. Furthermore, the combination effect induced by FUS irradiation produces significant damage to both superficial and deep parts of the targeted tumor. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07782f

Non-invasive, neuron-specific gene therapy by focused ultrasound-induced blood-brain barrier opening in Parkinson's disease mouse model.

PubMed

Lin, Chung-Yin; Hsieh, Han-Yi; Chen, Chiung-Mei; Wu, Shang-Rung; Tsai, Chih-Hung; Huang, Chiung-Yin; Hua, Mu-Yi; Wei, Kuo-Chen; Yeh, Chih-Kuang; Liu, Hao-Li

2016-08-10

Focused ultrasound (FUS)-induced with microbubbles (MBs) is a promising technique for noninvasive opening of the blood-brain barrier (BBB) to allow targeted delivery of therapeutic substances into the brain and thus the noninvasive delivery of gene vectors for CNS treatment. We have previously demonstrated that a separated gene-carrying liposome and MBs administration plus FUS exposure can deliver genes into the brain, with the successful expression of the reporter gene and glial cell line-derived neurotrophic factor (GDNF) gene. In this study, we further modify the delivery system by conjugating gene-carrying liposomes with MBs to improve the GDNF gene-delivery efficiency, and to verify the possibility of using this system to perform treatment in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal disease model. FUS-BBB opening was verified by contrast-enhanced MRI, and GFP gene expression was verified via in vivo imaging system (IVIS). Western blots as well as enzyme-linked immunosorbent assay (ELISA) were conducted to measure protein expression, and immunohistochemistry (IHC) was conducted to test the Tyrosine hydroxylase (TH)-neuron distribution. Dopamine (DA) and its metabolites as well as dopamine active transporter (DAT) were quantitatively analyzed to show dopaminergic neuronal dopamine secretion/activity/metabolism. Motor performance was evaluated by rotarod test weekly. Results demonstrated that the LpDNA-MBs (gene-liposome-MBs) complexes successfully serve as gene carrier and BBB-opening catalyst, and outperformed the separated LpDNA/MBs administration both in terms of gene delivery and expression. TH-positive IHC and measurement of DA and its metabolites DOPAC and HVA confirmed improved neuronal function, and the proposed system also provided the best neuroprotective effect to retard the progression of motor-related behavioral abnormalities. Immunoblotting and histological staining further confirmed the expression of reporter genes in neuronal cells. This study suggests that FUS exposures with the administration of LpDNA-MBs complexes synergistically can serve as an effective gene therapy strategy for MPTP-animal treatment, and may have potential for further application to perform gene therapy for neurodegenerative disease. Copyright © 2016 Elsevier B.V. All rights reserved.

[Application of CWT to extract characteristic monitoring parameters during spine surgery].

PubMed

Chen, Penghui; Wu, Baoming; Hu, Yong

2005-10-01

It is necessary to monitor intraoperative spinal function in order to prevent spinal neurological deficit during spine surgery. This study aims to extract characteristic electrophysiological monitoring parameters during surgical treatment of scoliosis. The problem, "the monitoring parameters in time domain are of great variability and are sensitive to noise", may also be solved in this study. By use of continuous wavelet transform to analyze the intraoperative cortical somatosensory evoked potential (CSEP), three new characteristic monitoring parameters in time-frequency domain (TFD) are extracted. The results indicate that the variability of CSEP characteristic parameters in TFD is lower than the variability of those in time domain. Therefore, the TFD characteristic monitoring parameters are more stable and reliable parameters of latency and amplitude in time domain. The application of TFD monitoring parameters during spine surgery may avoid spinal injury effectively.

Monitoring of recurrent and superior laryngeal nerve function using an Airwayscope™ during thyroid surgery.

PubMed

Ijichi, Kei; Sasano, Hiroshi; Harima, Megumi; Murakami, Shingo

2017-10-01

In thyroid surgery, intraoperative identification and preservation of the recurrent laryngeal nerve (RLN) and superior laryngeal nerve external branch (SLNEB) are crucial. Several reports have proposed that electromyography (EMG) monitoring is an acceptable adjunct for identification and preservation of the RLN. However, a limited number of hospitals have access to an EMG monitoring system. Therefore, the development of another viable monitoring method is required. The aim of the present study was to design a new RLN and SLNEB monitoring method combining an Airwayscope™ (AWS) and a facial nerve stimulator. The facial nerve-stimulating electrode stimulates the RLN or SLNEB, so that the movement of the vocal cord may be observed with an AWS. This monitoring method was performed on 10 patients with a thyroid tumor. In all the cases, RLN and SLNEB were identified and vocal cord function was preserved. All the patients exhibited normal vocal cord function following surgery. Thus, the new RLN and SLNEB monitoring method using an AWS and a facial nerve stimulator is useful in thyroid surgery, and this method may be used as a reliable and available alternative to EMG monitoring to ensure the normal function of the vocal cord.

TU-EF-210-03: Real-Time Ablation Monitoring and Lesion Quantification Using Harmonic Motion Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Konofagou, E.

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

A novel type of EWS-CHOP fusion gene in myxoid liposarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsui, Yoshito; Ueda, Takafumi; Kubo, Takahiro

2006-09-22

The cytogenetic hallmark of myxoid type and round cell type liposarcoma consists of reciprocal translocation of t(12;16)(q13;p11) and t(12;22)(q13;q12), which results in fusion of TLS/FUS and CHOP, and EWS and CHOP, respectively. Nine structural variations of the TLS/FUS-CHOP chimeric transcript have been reported, however, only two types of EWS-CHOP have been described. We describe here a case of myxoid liposarcoma containing a novel EWS-CHOP chimeric transcript and identified the breakpoint occurring in intron 13 of EWS. Reverse transcription-polymerase chain reaction and direct sequence showed that exon 13 of EWS was in-frame fused to exon 2 of CHOP. Genomic analysis revealedmore » that the breaks were located in intron 13 of EWS and intron 1 of CHOP.« less

The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration.

PubMed

St George-Hyslop, Peter; Lin, Julie Qiaojin; Miyashita, Akinori; Phillips, Emma C; Qamar, Seema; Randle, Suzanne J; Wang, GuoZhen

2018-04-30

Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules. Using FUS as an example, this review examines the biophysics of this physiological process, and reports on how mutations and changes in post-translational state alter phase behaviour, and lead to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Copyright © 2018. Published by Elsevier B.V.

CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs.

PubMed

Wang, Lixia; Yi, Fei; Fu, Lina; Yang, Jiping; Wang, Si; Wang, Zhaoxia; Suzuki, Keiichiro; Sun, Liang; Xu, Xiuling; Yu, Yang; Qiao, Jie; Belmonte, Juan Carlos Izpisua; Yang, Ze; Yuan, Yun; Qu, Jing; Liu, Guang-Hui

2017-05-01

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts of familial ALS patients bearing SOD1 +/A272C and FUS +/G1566A mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq) analysis of motor neurons derived from SOD1 +/A272C and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

Breakdown of lung framework and an increase in pores of Kohn as initial events of emphysema and a cause of reduction in diffusing capacity.

PubMed

Yoshikawa, Akira; Sato, Shuntaro; Tanaka, Tomonori; Hashisako, Mikiko; Kashima, Yukio; Tsuchiya, Tomoshi; Yamasaki, Naoya; Nagayasu, Takeshi; Yamamoto, Hiroshi; Fukuoka, Junya

2016-01-01

Pulmonary emphysema is the pathological prototype of chronic obstructive pulmonary disease and is also associated with other lung diseases. We considered that observation with different approaches may provide new insights for the pathogenesis of emphysema. We reviewed tissue blocks of the lungs of 25 cases with/without emphysema and applied a three-dimensional observation method to the blocks. Based on the three-dimensional characteristics of the alveolar structure, we considered one face of the alveolar polyhedron as a structural unit of alveoli and called it a framework unit (FU). We categorized FUs based on their morphological characteristics and counted their number to evaluate the destructive changes in alveoli. We also evaluated the number and the area of pores of Kohn in FUs. We performed linear regression analysis to estimate the effect of these data on pulmonary function tests. In multivariable regression analysis, a decrease in the number of FUs without an alveolar wall led to a significant decrease in the diffusing capacity of the lung for carbon monoxide (DLCO) and DLCO per unit alveolar volume, and an increase in the area of pores of Kohn had a significant effect on an increase in residual capacity. A breakdown in the lung framework and an increase in pores of Kohn are associated with a decrease in DLCO and DLCO per unit alveolar volume with/without emphysema.

Vaginal-sparing ventral buccal mucosal graft urethroplasty for female urethral stricture: A novel modification of surgical technique.

PubMed

Hoag, Nathan; Gani, Johan; Chee, Justin

2016-07-01

To present a novel modification of surgical technique to treat female urethral stricture (FUS) by a vaginal-sparing ventral buccal mucosal urethroplasty. Recurrent FUS represents an uncommon, though difficult clinical scenario to manage definitively. A variety of surgical techniques have been described to date, yet a lack of consensus on the optimal procedure persists. We present a 51-year-old female with urethral stricture involving the entire urethra. Suspected etiology was iatrogenic from cystoscopy 17 years prior. Since then, the patient had undergone at least 25 formal urethral dilations and periods of self-dilation. In lithotomy position, the urethra was dilated to accommodate forceps, and ventral urethrotomy carried out sharply, exposing a bed of periurethral tissue. Buccal mucosa was harvested, and a ventral inlay technique facilitated by a nasal speculum, was used to place the graft from the proximal urethra/bladder neck to urethral meatus without a vaginal incision. Graft was sutured into place, and urethral Foley catheter inserted. The vaginal-sparing ventral buccal mucosal graft urethroplasty was deemed successful as of last follow-up. Flexible cystoscopy demonstrated patency of the repair at 6 months. At 10 months of follow-up, the patient was voiding well, with no urinary incontinence. No further interventions have been required. This case describes a novel modification of surgical technique for performing buccal mucosal urethroplasty for FUS. By avoiding incision of the vaginal mucosa, benefits may include reduced: morbidity, urinary incontinence, and wound complications including urethro-vaginal fistula.

Colorimetric TMPRSS2-ERG Gene Fusion Detection in Prostate Cancer Urinary Samples via Recombinase Polymerase Amplification.

PubMed

Koo, Kevin M; Wee, Eugene J H; Trau, Matt

2016-01-01

TMPRSS2 (Exon 1)-ERG (Exon 4) is the most frequent gene fusion event in prostate cancer (PC), and is highly PC-specific unlike the current serum prostate specific antigen (PSA) biomarker. However, TMPRSS2-ERG levels are currently measured with quantitative reverse-transcription PCR (RT-qPCR) which is time-consuming and requires costly equipment, thus limiting its use in clinical diagnostics. Herein, we report a novel rapid, cost-efficient and minimal-equipment assay named "FusBLU" for detecting TMPRSS2-ERG gene fusions from urine. TMPRSS2-ERG mRNA was amplified by isothermal reverse transcription-recombinase polymerase amplification (RT-RPA), magnetically-isolated, and detected through horseradish peroxidase (HRP)-catalyzed colorimetric reaction. FusBLU was specific for TMPRSS2-ERG mRNA with a low visual detection limit of 10(5) copies. We also demonstrated assay readout versatility on 3 potentially useful platforms. The colorimetric readout was detectable by naked eye for a quick yes/no evaluation of gene fusion presence. On the other hand, a more quantitative TMPRSS2-ERG detection was achievable by absorbance/electrochemical measurements. FusBLU was successfully applied to 12 urinary samples and results were validated by gold-standard RT-qPCR. We also showed that sediment RNA was likely the main source of TMPRSS2-ERG mRNA in urinary samples. We believe that our assay is a potential clinical screening tool for PC and could also have wide applications for other disease-related fusion genes.

Custom molded thermal MRg-FUS phantom

NASA Astrophysics Data System (ADS)

Eames, Matthew D. C.; Snell, John W.; Hananel, Arik; Kassell, Neal F.

2012-11-01

This article describes a method for creating custom-molded thermal phantoms for use with MR-guided focused ultrasound systems. The method is defined here for intracranial applications, though it may be modified for other anatomical targets.

MR-guided Focused Ultrasound for Uterine Fibroids

MedlinePlus

... Professions Site Index A-Z MR-guided Focused Ultrasound for Uterine Fibroids Magnetic Resonance-guided Focused Ultrasound ( ... are the limitations of MRgFUS? What is Focused Ultrasound of Uterine Fibroids? Magnetic Resonance-guided Focused Ultrasound ( ...

Neuromuscular blockade in cardiac surgery: an update for clinicians.

PubMed

Hemmerling, Thomas M; Russo, Gianluca; Bracco, David

2008-01-01

There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary) sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.

Comparison of the Wake-up Test and Combined TES-MEP and CSEP Monitoring in Spinal Surgery.

PubMed

Chen, Bailing; Chen, Yuguang; Yang, Junlin; Xie, Denghui; Su, Haihua; Li, Fobao; Wan, Yong; Peng, Xinsheng; Zheng, Zhaomin

2015-11-01

A retrospective clinical analysis. The aim of this study was to compare the effectiveness of the wake-up test with that of combined monitoring of transcranial electrical stimulation motor evoked potentials (TES-MEP) and cortical somatosensory evoked potentials (CSEP) in spinal surgery. TES-MEP/CSEP combined monitoring is being increasingly recognized as the ideal approach to detect spinal neurophysiological compromise during spinal surgery; however, as a result the merit of the wake-up test is now in doubt. TES-MEP/CSEP combined monitoring was performed simultaneously in 426 patients who underwent spinal surgery at our department, and wake-up tests were conducted on 23 patients because of positive neurophysiological monitoring results with uncertain causes or persistent positive monitoring findings after all potential causes had been resolved. Preoperative and postoperative neurological examinations were performed as the gold standard to detect irreversible spinal function compromise. All data were collected to compare the efficiency of TES-MEP/CSEP combined monitoring with that of the wake-up test. Positive results of TES-MEP/CSEP combined monitoring were recorded in 64 cases. Among them, the positive monitoring findings agreed with the results of the neurological examination in 51 cases, and the monitoring results did not match that of neurological examination in 13 cases. No false-negative result was observed. The sensitivity of TES-MEP/CSEP monitoring was 100%, the specificity was 96.5%, and the Youden index was 0.965. Wake-up tests were conducted in 23 cases. In 8 patients the positive monitoring findings completely matched the postoperative neurological examination results. In contrast, in the other 15 cases with negative neurophysiological monitoring results, only 9 patients retained intact neurological function and 6 patients suffered compromised neurological function. The sensitivity of the wake-up test was 57.1%, the specificity was 100%, and the Youden index was 0.571. Combined TES-MEP and CSEP monitoring, with its high sensitivity and specificity, is an effective method for monitoring spinal function during surgery and should be the preferred choice. The wake-up test is a useful complementary method for monitoring because of its high specificity.

Delineation of Chondroid Lipoma: An Immunohistochemical and Molecular Biological Analysis

PubMed Central

de Vreeze, Ronald S. A.; van Coevorden, Frits; Boerrigter, Lucie; Nederlof, Petra M.; Haas, Rick L.; Bras, Johannes; Rosenwald, Andreas; Mentzel, Thomas; de Jong, Daphne

2011-01-01

Aims. Chondroid lipoma (CL) is a benign tumor that mimics a variety of soft tissue tumors and is characterized by translocation t(11;16). Here, we analyze CL and its histological mimics. Methods. CL (n = 4) was compared to a variety of histological mimics (n = 83) for morphological aspects and immunohistochemical features including cyclinD1(CCND1). Using FISH analysis, CCND1 and FUS were investigated as potential translocation partners. Results. All CLs were strongly positive for CCND1. One of 4 myoepitheliomas, CCND1, was positive. In well-differentiated lipomatous tumors and in chondrosarcomas, CCND1 was frequently expressed, but all myxoid liposarcomas were negative. FISH analysis did not give support for direct involvement of CCND1 and FUS as translocation partners. Conclusions. Chondroid lipoma is extremely rare and has several and more prevalent histological mimics. The differential diagnosis of chondroid lipomas can be unraveled using immunohistochemical and molecular support. PMID:21559269

Oophorectomy (Ovary Removal Surgery)

MedlinePlus

... also be robotically assisted in certain cases. During robotic surgery, the surgeon watches a 3-D monitor and ... weeks after surgery. Those who undergo laparoscopic or robotic surgery may return to full activity sooner — as early ...

A feasibility study of soft embalmed human breast tissue for preclinical trials of HIFU- preliminary results

NASA Astrophysics Data System (ADS)

Joy, Joyce; Yang, Yang; Purdie, Colin; Eisma, Roos; Melzer, Andreas; Cochran, Sandy; Vinnicombe, Sarah

2017-03-01

Breast cancer is the commonest cancer in women in the UK, accounting for 30% of all new cancers in women, with an estimated 49,500 new cases in 20101. With the widespread negative publicity around over-diagnosis and over-treatment of low risk breast cancers, interest in the application of non-invasive treatments such as magnetic resonance imaging (MRI) guided high intensity focused ultrasound (HIFU) has increased. Development has begun of novel US transducers and platforms specifically designed for use with breast lesions, so as to improve the range of breast lesions that can be safely treated. However, before such transducers can be evaluated in patients in clinical trials, there is a need to establish their efficacy. A particular issue is the accuracy of temperature monitoring of FUS with MRI in the breast, since the presence of large amounts of surrounding fat can hinder temperature measurement. An appropriate anatomical model that imposes similar physical constraints to the breast and that responds to FUS in the same way would be extremely advantageous. The aim of this feasibility study is to explore the use of Thiel embalmed cadaveric tissue for these purposes. We report here the early results of laboratory-based experiments sonicating dissected breast samples from a Thiel embalmed soft human cadaver with high body mass index (BMI). A specially developed MRI compatible chamber and sample holder was developed to secure the sample and ensure reproducible sonications at the transducer focus. The efficacy of sonication was first studied with chicken breast and porcine tissue. The experiments were then repeated with the dissected fatty breast tissue samples from the soft-embalmed human cadavers. The sonicated Thiel breast tissue was examined histopathologically, which confirmed the absence of any discrete lesion. To investigate further, fresh chicken breast tissue was embalmed and the embalmed tissue was sonicated with the same parameters. The results confirmed the inability to produce a discrete lesion in any of the Thiel embalmed samples.

Localised drug release using MRI-controlled focused ultrasound hyperthermia.

PubMed

Staruch, Robert; Chopra, Rajiv; Hynynen, Kullervo

2011-01-01

Thermosensitive liposomes provide a mechanism for triggering the local release of anticancer drugs, but this technology requires precise temperature control in targeted regions with minimal heating of surrounding tissue. The objective of this study was to evaluate the feasibility of using MRI-controlled focused ultrasound (FUS) and thermosensitive liposomes to achieve thermally mediated localised drug delivery in vivo. Results are reported from ten rabbits, where a FUS beam was scanned in a circular trajectory to heat 10-15 mm diameter regions in normal thigh to 43°C for 20-30 min. MRI thermometry was used for closed-loop feedback control to achieve temporally and spatially uniform heating. Lyso-thermosensitive liposomal doxorubicin was infused intravenously during hyperthermia. Unabsorbed liposomes were flushed from the vasculature by saline perfusion 2 h later, and tissue samples were harvested from heated and unheated thigh regions. The fluorescence intensity of the homogenised samples was used to calculate the concentration of doxorubicin in tissue. Closed-loop control of FUS heating using MRI thermometry achieved temperature distributions with mean, T90 and T10 of 42.9°C, 41.0°C and 44.8°C, respectively, over a period of 20 min. Doxorubicin concentrations were significantly higher in tissues sampled from heated than unheated regions of normal thigh muscle (8.3 versus 0.5 ng/mg, mean per-animal difference = 7.8 ng/mg, P < 0.05, Wilcoxon matched pairs signed rank test). The results show the potential of MRI-controlled focused ultrasound hyperthermia for enhanced local drug delivery with temperature-sensitive drug carriers.

Genomic characterization of a persistent rubella virus from a case of Fuch' uveitis syndrome in a 73 year old man.

PubMed

Abernathy, Emily; Peairs, Randall R; Chen, Min-hsin; Icenogle, Joseph; Namdari, Hassan

2015-08-01

Many cases of Fuchs' uveitis have been associated with persistent rubella virus infection. A 73-year-old male patient with typical Fuchs' Uveitis Syndrome (FUS) first experienced heterochromia of the left eye at the age fourteen, when rubella was endemic in the US. The purposes of this report are to describe the patient's FUS clinical presentations and to characterize the virus detected in the vitreous fluid. The patient underwent a therapeutic pars plana vitrectomy in May 2013. A real-time RT-PCR assay for rubella virus was performed on the vitreous fluid by Focus Diagnostics. Additional real-time RT-PCR assays for rubella virus detection and RT-PCR assays for generation of templates for sequencing were performed at the Centers for Disease Control and Prevention (CDC). The results from Focus Diagnostics were positive for rubella virus RNA. Real-time RT-PCR assays at CDC were also positive for rubella virus. A rubella virus sequence of 739 nucleotides was determined and phylogenetic analysis showed that the virus was the sole member of a new phylogenetic group when compared to reference virus sequences. While FUS remains a clinical diagnosis, findings in this case support the association between rubella virus and the disease. Phylogenetic analysis provided evidence that this rubella virus was likely a previously undetected genotype which is no longer circulating. Since the patient had rubella prior to 1955, this sequence is from the earliest rubella virus yet characterized. Copyright © 2015 Elsevier B.V. All rights reserved.

Sulcus reproduction with elastomeric impression materials: a new in vitro testing method.

PubMed

Finger, Werner J; Kurokawa, Rie; Takahashi, Hidekazu; Komatsu, Masashi

2008-12-01

Aim of this study was to investigate the depth reproduction of differently wide sulci with elastomeric impression materials by single- and double-mix techniques using a tooth and sulcus model, simulating clinical conditions. Impressions with one vinyl polysiloxane (VPS; FLE), two polyethers (PE; IMP and P2), and one hybrid VPS/PE elastomer (FUS) were taken from a truncated steel cone with a circumferential 2 mm deep sulcus, 50, 100 or 200 microm wide. The "root surface" was in steel and the "periodontal tissue" in reversible hydrocolloid. Single-mix impressions were taken with light-body (L) or monophase (M) pastes, double-mix impressions with L as syringe and M or heavy-body (H) as tray materials (n=8). Sulcus reproduction was determined by 3D laser topography of impressions at eight locations, 45 degrees apart. Statistical data analysis by ANOVA and multiple comparison tests (p<0.05). For 200 microm wide sulci, significant differences were found between impression materials only: FLE=IMP>FUS=P2. At 50 and 100 microm width, significant differences were found between materials (IMP>FUS=FLE>P2) and techniques (L+H=L+M>M>L). The sulcus model is considered useful for screening evaluation of elastomeric impression materials ability to reproduce narrow sulci. All tested materials and techniques reproduced 200 microm wide sulci to almost nominal depth. Irrespective of the impression technique used, IMP showed the best penetration ability in 50 and 100 microm sulci. Double-mix techniques are more suitable to reproduce narrow sulci than single-mix techniques.

Membrane fusion triggers rapid degradation of two gamete-specific, fusion-essential proteins in a membrane block to polygamy in Chlamydomonas.

PubMed

Liu, Yanjie; Misamore, Michael J; Snell, William J

2010-05-01

The plasma membranes of gametes are specialized for fusion, yet, once fusion occurs, in many organisms the new zygote becomes incapable of further membrane fusion reactions. The molecular mechanisms that underlie this loss of fusion capacity (block to polygamy) remain unknown. During fertilization in the green alga Chlamydomonas, the plus gamete-specific membrane protein FUS1 is required for adhesion between the apically localized sites on the plasma membranes of plus and minus gametes that are specialized for fusion, and the minus-specific membrane protein HAP2 is essential for completion of the membrane fusion reaction. HAP2 (GCS1) family members are also required for fertilization in Arabidopsis, and for the membrane fusion reaction in the malaria organism Plasmodium berghei. Here, we tested whether Chlamydomonas gamete fusion triggers alterations in FUS1 and HAP2 and renders the plasma membranes of the cells incapable of subsequent fusion. We find that, even though the fusogenic sites support multi-cell adhesions, triploid zygotes are rare, indicating a fusion-triggered block to the membrane fusion reaction. Consistent with the extinction of fusogenic capacity, both FUS1 and HAP2 are degraded upon fusion. The rapid, fusion-triggered cleavage of HAP2 in zygotes is distinct from degradation occurring during constitutive turnover in gametes. Thus, gamete fusion triggers specific degradation of fusion-essential proteins and renders the zygote incapable of fusion. Our results provide the first molecular explanation for a membrane block to polygamy in any organism.

Vaginal-sparing ventral buccal mucosal graft urethroplasty for female urethral stricture: A novel modification of surgical technique

PubMed Central

Gani, Johan; Chee, Justin

2016-01-01

Purpose To present a novel modification of surgical technique to treat female urethral stricture (FUS) by a vaginal-sparing ventral buccal mucosal urethroplasty. Recurrent FUS represents an uncommon, though difficult clinical scenario to manage definitively. A variety of surgical techniques have been described to date, yet a lack of consensus on the optimal procedure persists. Materials and Methods We present a 51-year-old female with urethral stricture involving the entire urethra. Suspected etiology was iatrogenic from cystoscopy 17 years prior. Since then, the patient had undergone at least 25 formal urethral dilations and periods of self-dilation. In lithotomy position, the urethra was dilated to accommodate forceps, and ventral urethrotomy carried out sharply, exposing a bed of periurethral tissue. Buccal mucosa was harvested, and a ventral inlay technique facilitated by a nasal speculum, was used to place the graft from the proximal urethra/bladder neck to urethral meatus without a vaginal incision. Graft was sutured into place, and urethral Foley catheter inserted. Results The vaginal-sparing ventral buccal mucosal graft urethroplasty was deemed successful as of last follow-up. Flexible cystoscopy demonstrated patency of the repair at 6 months. At 10 months of follow-up, the patient was voiding well, with no urinary incontinence. No further interventions have been required. Conclusions This case describes a novel modification of surgical technique for performing buccal mucosal urethroplasty for FUS. By avoiding incision of the vaginal mucosa, benefits may include reduced: morbidity, urinary incontinence, and wound complications including urethro-vaginal fistula. PMID:27437540

TU-G-210-03: Acoustic Simulations in Transcranial MRgFUS: Treatment Prediction and Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vyas, U.

Modeling can play a vital role in predicting, optimizing and analyzing the results of therapeutic ultrasound treatments. Simulating the propagating acoustic beam in various targeted regions of the body allows for the prediction of the resulting power deposition and temperature profiles. In this session we will apply various modeling approaches to breast, abdominal organ and brain treatments. Of particular interest is the effectiveness of procedures for correcting for phase aberrations caused by intervening irregular tissues, such as the skull in transcranial applications or inhomogeneous breast tissues. Also described are methods to compensate for motion in targeted abdominal organs such asmore » the liver or kidney. Douglas Christensen – Modeling for Breast and Brain HIFU Treatment Planning Tobias Preusser – TRANS-FUSIMO - An Integrative Approach to Model-Based Treatment Planning of Liver FUS Urvi Vyas – Acoustic Simulations in Transcranial MRgFUS: Treatment Prediction and Analysis Learning Objectives: Understand the role of acoustic beam modeling for predicting the effectiveness of therapeutic ultrasound treatments. Apply acoustic modeling to specific breast, liver, kidney and transcranial anatomies. Determine how to obtain appropriate acoustic modeling parameters from clinical images. Understand the separate role of absorption and scattering in energy delivery to tissues. See how organ motion can be compensated for in ultrasound therapies. Compare simulated data with clinical temperature measurements in transcranial applications. Supported by NIH R01 HL172787 and R01 EB013433 (DC); EU Seventh Framework Programme (FP7/2007-2013) under 270186 (FUSIMO) and 611889 (TRANS-FUSIMO)(TP); and P01 CA159992, GE, FUSF and InSightec (UV)« less

[Anaesthetic management of excision of a cervical intraspinal tumor with intraoperative neurophysiologic monitoring in a pregnant woman at 29 weeks].

PubMed

Guerrero-Domínguez, R; González-González, G; Rubio-Romero, R; Federero-Martínez, F; Jiménez, I

2016-05-01

The intraoperative neurophysiological monitoring is a technique used to test and monitor nervous function. This technique has become essential in some neurosurgery interventions, since it avoids neurological injuries during surgery and reduces morbidity. The experience of intraoperative neurophysiological monitoring is limited in some clinical cases due to the low incidence of pregnant women undergoing a surgical procedure. A case is presented of a 29-weeks pregnant woman suffering from a cervical intraspinal tumour with intense pain, which required surgery. The collaboration of a multidisciplinary team composed of anaesthesiologists, neurosurgeons, neurophysiologists and obstetricians, the continuous monitoring of the foetus, the intraoperative neurophysiological monitoring, and maintaining the neurophysiological and utero-placental variables were crucial for the proper development of the surgery. According to our experience and the limited publications in the literature, no damaging effects of this technique were detected at maternal-foetal level. On the contrary, it brings important benefits during the surgery and for the final result. Copyright © 2015 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

From “awake” to “monitored anesthesia care” thoracic surgery: A 15 year evolution

PubMed Central

Mineo, Tommaso C; Tacconi, Federico

2014-01-01

Although general anesthesia still represents the standard when performing thoracic surgery, the interest toward alternative methods is increasing. These have evolved from the employ of just local or regional analgesia techniques in completely alert patients (awake thoracic surgery), to more complex protocols entailing conscious sedation and spontaneous ventilation. The main rationale of these methods is to prevent serious complications related to general anesthesia and selective ventilation, such as tracheobronchial injury, acute lung injury, and cardiovascular events. Trends toward shorter hospitalization and reduced overall costs have also been indicated in preliminary reports. Monitored anesthesia care in thoracic surgery can be successfully employed to manage diverse oncologic conditions, such as malignant pleural effusion, peripheral lung nodules, and mediastinal tumors. Main non-oncologic indications include pneumothorax, emphysema, pleural infections, and interstitial lung disease. Furthermore, as the familiarity with this surgical practice has increased, major operations are now being performed this way. Despite the absence of randomized controlled trials, there is preliminary evidence that monitored anesthesia care protocols in thoracic surgery may be beneficial in high-risk patients, with non-inferior efficacy when compared to standard operations under general anesthesia. Monitored anesthesia care in thoracic surgery should enter the armamentarium of modern thoracic surgeons, and adequate training should be scheduled in accredited residency programs. PMID:26766966

Spatial and Temporal Control of Hyperthermia Using Real Time Ultrasonic Thermal Strain Imaging with Motion Compensation, Phantom Study

PubMed Central

Foiret, Josquin; Ferrara, Katherine W.

2015-01-01

Mild hyperthermia has been successfully employed to induce reversible physiological changes that can directly treat cancer and enhance local drug delivery. In this approach, temperature monitoring is essential to avoid undesirable biological effects that result from thermal damage. For thermal therapies, Magnetic Resonance Imaging (MRI) has been employed to control real-time Focused Ultrasound (FUS) therapies. However, combined ultrasound imaging and therapy systems offer the benefits of simple, low-cost devices that can be broadly applied. To facilitate such technology, ultrasound thermometry has potential to reliably monitor temperature. Control of mild hyperthermia was previously achieved using a proportional-integral-derivative (PID) controller based on thermocouple measurements. Despite accurate temporal control of heating, this method is limited by the single position at which the temperature is measured. Ultrasound thermometry techniques based on exploiting the thermal dependence of acoustic parameters (such as longitudinal velocity) can be extended to create thermal maps and allow an accurate monitoring of temperature with good spatial resolution. However, in vivo applications of this technique have not been fully developed due to the high sensitivity to tissue motion. Here, we propose a motion compensation method based on the acquisition of multiple reference frames prior to treatment. The technique was tested in the presence of 2-D and 3-D physiological-scale motion and was found to provide effective real-time temperature monitoring. PID control of mild hyperthermia in presence of motion was then tested with ultrasound thermometry as feedback and temperature was maintained within 0.3°C of the requested value. PMID:26244783

Electromyographic monitoring and its anatomical implications in minimally invasive spine surgery.

PubMed

Uribe, Juan S; Vale, Fernando L; Dakwar, Elias

2010-12-15

Literature review. The objective of this article is to examine current intraoperative electromyography (EMG) neurophysiologic monitoring methods and their application in minimally invasive techniques. We will also discuss the recent application of EMG and its anatomic implications to the minimally invasive lateral transpsoas approach to the spine. Minimally invasive techniques require that the same goals of surgery be achieved, with the hope of decreased morbidity to the patient. Unlike standard open procedures, direct visualization of the anatomy is decreased. To increase the safety of minimally invasive spine surgery, neurophysiological monitoring techniques have been developed. Review of the literature was performed using the National Center for Biotechnology Information databases using PUBMED/MEDLINE. All articles in the English language discussing the use of intraoperative EMG monitoring and minimally invasive spine surgery were reviewed. The role of EMG monitoring in special reference to the minimally invasive lateral transpsoas approach is also described. In total, 76 articles were identified that discussed the role of neuromonitoring in spine surgery. The majority of articles on EMG and spine surgery discuss the use of intraoperative neurophysiological monitoring (IOM) for safe and accurate pedicle screw placement. In general, there is a paucity of literature that pertains to intraoperative EMG neuromonitoring and minimally invasive spine surgery. Recently, EMG has been used during minimally invasive lateral transpsoas approach to the lumbar spine for interbody fusion. The addition of EMG to the lateral approach has contributed to decrease the complication rate from 30% to less than 1%. In minimally invasive approaches to the spine, the use of EMG IOM might provide additional safety, such as percutaneous pedicle screw placement, where visualization is limited compared with conventional open procedures. In addition to knowledge of the anatomy and image guidance, directional EMG IOM is crucial for safe passage through the psoas muscle during the minimally invasive lateral retroperitoneal approach.

Consideration of the effects of intense tissue heating on the RF electromagnetic fields during MRI: simulations for MRgFUS in the hip

NASA Astrophysics Data System (ADS)

Xuegang Xin, Sherman; Gu, Shiyong; Carluccio, Giuseppe; Collins, Christopher M.

2015-01-01

Due to the strong dependence of tissue electrical properties on temperature, it is important to consider the potential effects of intense tissue heating on the RF electromagnetic fields during MRI, as can occur in MR-guided focused ultrasound surgery. In principle, changes of the RF electromagnetic fields could affect both efficacy of RF pulses, and the MRI-induced RF heating (SAR) pattern. In this study, the equilibrium temperature distribution in a whole-body model with 2 mm resolution before and during intense tissue heating up to 60 °C at the target region was calculated. Temperature-dependent electric properties of tissues were assigned to the model to establish a temperature-dependent electromagnetic whole-body model in a 3T MRI system. The results showed maximum changes in conductivity, permittivity, ≤ft|\\mathbf{B}1+\\right|, and SAR of about 25%, 6%, 2%, and 20%, respectively. Though the B1 field and SAR distributions are both temperature-dependent, the potential harm to patients due to higher SARs is expected to be minimal and the effects on the B1 field distribution should have minimal effect on images from basic MRI sequences.

THE USE OF THE INTERNET BY THE PATIENT AFTER BARIATRIC SURGERY: CONTRIBUTIONS AND OBSTACLES FOR THE FOLLOW-UP OF MULTIDISCIPLINARY MONITORING

PubMed Central

MARTINS, Michele Pereira; ABREU-RODRIGUES, Marcela; SOUZA, Juciléia Rezende

2015-01-01

ABSTRACT Background : Bariatric surgery is presented as the last treatment option for obesity. It requires from all candidates a multidisciplinary evaluation and monitoring throughout treatment. The non-adherence to follow-up with health care teams is related to weight regain. It's possible that the use of internet influences the doctor-patient relationship and patients replace medical care or information provided by health professionals for information from the internet. Aim : Identify and analyze the pattern of internet use by patients after bariatric surgery and check the influence of such use in attending medical appointments with the multidisciplinary team. Method : Electronic questionnaire available on the Internet was used to verify patient´s patterns of Internet use and its influence on in attending multidisciplinary care after surgery. Results : Of the 103 participants, 95% were female, 64% married, 59% with children and 54% with higher education. The mean age was 35.69 years and the mean duration of performing surgery, 11.74 months. The surgical technique that prevailed was Roux-en-Y gastric by-pass (90.3%), the local monitoring concentrated in the private care (93.2%). In the preoperative, most participants consulted more than three times with the surgeon (n=81), nutritionists (n=70), psychologist (n=70). After the surgery, p most patients maintained monitoring with the surgeon and nutritionist. Concerning the internet use, 51.5% accessed the internet in search of information about health and bariatric surgery every day. Facebook and search tools were the most used sites. Conclusion - Data showed the influence of the information contained on the Internet and the adherence to multidisciplinary monitoring. This fact requires the team to consider the use of the Internet as a variable that may interfere and must be handled during follow-up. It is suggested that an active participation of professionals on their websites and social networks and the diversification of services and interventions to stimulate follow-up after surgery. PMID:26537274

Intraoperative Functional Mapping and Monitoring during Glioma Surgery

PubMed Central

SAITO, Taiichi; MURAGAKI, Yoshihiro; MARUYAMA, Takashi; TAMURA, Manabu; NITTA, Masayuki; OKADA, Yoshikazu

2015-01-01

Glioma surgery represents a significant advance with respect to improving resection rates using new surgical techniques, including intraoperative functional mapping, monitoring, and imaging. Functional mapping under awake craniotomy can be used to detect individual eloquent tissues of speech and/or motor functions in order to prevent unexpected deficits and promote extensive resection. In addition, monitoring the patient’s neurological findings during resection is also very useful for maximizing the removal rate and minimizing deficits by alarming that the touched area is close to eloquent regions and fibers. Assessing several types of evoked potentials, including motor evoked potentials (MEPs), sensory evoked potentials (SEPs) and visual evoked potentials (VEPs), is also helpful for performing surgical monitoring in patients under general anesthesia (GA). We herein review the utility of intraoperative mapping and monitoring the assessment of neurological findings, with a particular focus on speech and the motor function, in patients undergoing glioma surgery. PMID:25744346

Non-contact monitoring during laser surgery by measuring the incision depth with air-coupled transducers

NASA Astrophysics Data System (ADS)

Oyaga Landa, Francisco Javier; Deán-Ben, Xosé Luís.; Montero de Espinosa, Francisco; Razansky, Daniel

2017-03-01

Lack of haptic feedback during laser surgery hampers controlling the incision depth, leading to a high risk of undesired tissue damage. Here we present a new feedback sensing method that accomplishes non-contact realtime monitoring of laser ablation procedures by detecting shock waves emanating from the ablation spot with air-coupled transducers. Experiments in soft and hard tissue samples attained high reproducibity in real-time depth estimation of the laser-induced cuts. The advantages derived from the non-contact nature of the suggested monitoring approach are expected to greatly promote the general applicability of laser-based surgeries.

Study of the Dynamics of Transcephalic Cerebral Impedance Data during Cardio-Vascular Surgery

NASA Astrophysics Data System (ADS)

Atefi, S. R.; Seoane, F.; Lindecrantz, K.

2013-04-01

Postoperative neurological deficits are one of the risks associated with cardio vascular surgery, necessitating development of new techniques for cerebral monitoring. In this study an experimental observation regarding the dynamics of transcephalic Electrical Bioimpedance (EBI) in patients undergoing cardiac surgery with and without extracorporeal circulation (ECC) was conducted to investigate the potential use of electrical Bioimpedance for cerebral monitoring in cardio vascular surgery. Tetrapolar transcephalic EBI measurements at single frequency of 50 kHz were recorded prior to and during cardio vascular surgery. The obtained results show that the transcephalic impedance decreases in both groups of patients as operation starts, however slight differences in these two groups were also observed with the cerebral impedance reduction in patients having no ECC being less common and not as pronounced as in the ECC group. Changes in the cerebral impedance were in agreement with changes of haematocrit and temperature. The origin of EBI changes is still unexplained however these results encourage us to continue investigating the application of electrical bioimpedance cerebral monitoring clinically.

TU-EF-210-01: HIFU, Drug Delivery, and Immunotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferrara, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-04: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farahani, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-00: Therapeutic Strategies and Image Guidance

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-02: MRg Hyperthermia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chopra, R.

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

Brain Monitoring with Electroencephalography and the Electroencephalogram-Derived Bispectral Index During Cardiac Surgery

PubMed Central

Kertai, Miklos D.; Whitlock, Elizabeth L.; Avidan, Michael S.

2011-01-01

Cardiac surgery presents particular challenges for the anesthesiologist. In addition to standard and advanced monitors typically used during cardiac surgery, anesthesiologists may consider monitoring the brain with raw or processed electroencephalography (EEG). There is strong evidence that a protocol incorporating the processed EEG Bispectral Index (BIS) decreases the incidence intraoperative awareness compared with standard practice. However there is conflicting evidence that incorporating the BIS into cardiac anesthesia practice improves “fast-tracking,” decreases anesthetic drug use, or detects cerebral ischemia. Recent research, including many cardiac surgical patients, shows that a protocol based on BIS monitoring is not superior to a protocol based on end tidal anesthetic concentration monitoring in preventing awareness. There has been a resurgence of interest in the anesthesia literature in limited montage EEG monitoring, including nonproprietary processed indices. This has been accompanied by research showing that with structured training, anesthesiologists can glean useful information from the raw EEG trace. In this review, we discuss both the hypothesized benefits and limitations of BIS and frontal channel EEG monitoring in the cardiac surgical population. PMID:22253267

Isolation, molecular and phenotypic characterization of Cronobacter spp. in ready-to-eat salads and foods from Japanese cuisine commercialized in Brazil.

PubMed

Vasconcellos, Luiza; Carvalho, Carla Trece; Tavares, Rodrigo Overas; de Mello Medeiros, Valéria; de Oliveira Rosas, Carla; Silva, Júlia Nunes; Dos Reis Lopes, Silvia Maria; Forsythe, Stephen James; Brandão, Marcelo Luiz Lima

2018-05-01

The aim of this study was to detect Cronobacter from 30 samples of ready-to-eat (RTE) salads and 30 foods from Japanese cuisine as commercially available in Brazil. The detection of Cronobacter was as according to the ISO standard 22964:2017. The isolates were phenotypically characterized by Vitek 2.0 and the antibiotic susceptibility profile was determined using the standardized agar disc diffusion method. Molecular characterization was accomplished by real-time PCR targeting dnaG gene, multiplex-PCR targeting cgcA gene, and fusA allele sequencing. Twenty-seven samples (45.0%) contained Cronobacter, 14 (23.3%) samples of foods from Japanese cuisine and 13 (21.7%) samples of RTE salads. Twenty-nine unique Cronobacter isolates were selected from the 27 positive samples and were identified as C. sakazakii (n = 18), C. malonaticus (n = 8), and C. dublinensis (n = 3). A high genetic diversity was observed, with 29 Cronobacter strains being assigned to 11 different fusA alleles, a ratio of 2.6 strains by fusA allele was found. The cgcA multiplex-PCR failed to identify many of the Cronobacter isolates at the species level. Four (13.8%) Cronobacter isolates were resistant to one or more antibiotics tested (n = 12). The presence of Cronobacter in RTE foods could be a potential threat to human health and highlights the need for high levels of hygiene, particularly when preparing food for elderly, immunosuppressed persons or adults with prior underlying pathology. Epidemiological surveillance agencies should be aware of the risk that these RTE foods may represent, for these groups. Copyright © 2018 Elsevier Ltd. All rights reserved.

Sparsely-distributed organization of face and limb activations in human ventral temporal cortex

PubMed Central

Weiner, Kevin S.; Grill-Spector, Kalanit

2011-01-01

Functional magnetic resonance imaging (fMRI) has identified face- and body part-selective regions, as well as distributed activation patterns for object categories across human ventral temporal cortex (VTC), eliciting a debate regarding functional organization in VTC and neural coding of object categories. Using high-resolution fMRI, we illustrate that face- and limb-selective activations alternate in a series of largely nonoverlapping clusters in lateral VTC along the inferior occipital gyrus (IOG), fusiform gyrus (FG), and occipitotemporal sulcus (OTS). Both general linear model (GLM) and multivoxel pattern (MVP) analyses show that face- and limb-selective activations minimally overlap and that this organization is consistent across experiments and days. We provide a reliable method to separate two face-selective clusters on the middle and posterior FG (mFus and pFus), and another on the IOG using their spatial relation to limb-selective activations and retinotopic areas hV4, VO-1/2, and hMT+. Furthermore, these activations show a gradient of increasing face selectivity and decreasing limb selectivity from the IOG to the mFus. Finally, MVP analyses indicate that there is differential information for faces in lateral VTC (containing weakly- and highly-selective voxels) relative to non-selective voxels in medial VTC. These findings suggest a sparsely-distributed organization where sparseness refers to the presence of several face- and limb-selective clusters in VTC, and distributed refers to the presence of different amounts of information in highly-, weakly-, and non-selective voxels. Consequently, theories of object recognition should consider the functional and spatial constraints of neural coding across a series of nonoverlapping category-selective clusters that are themselves distributed. PMID:20457261

Comparison of the clinical and cognitive features of genetically positive ALS patients from the largest tertiary center in Serbia.

PubMed

Marjanović, Ivan V; Selak-Djokić, Biljana; Perić, Stojan; Janković, Milena; Arsenijević, Vladimir; Basta, Ivana; Lavrnić, Dragana; Stefanova, Elka; Stević, Zorica

2017-06-01

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes-among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients.

The Dependence of the Ultrasound-Induced Blood-Brain Barrier Opening Characteristics on Microbubble Size In Vivo

NASA Astrophysics Data System (ADS)

Choi, James J.; Feshitan, Jameel A.; Wang, Shougang; Tung, Yao-Sheng; Baseri, Babak; Borden, Mark A.; Konofagou, Elisa E.

2009-04-01

Recent neuropharmaceutical developments have led to potent disease-modifying drugs. In spite of these advancements, most agents cannot traverse the blood-brain barrier (BBB) and deposit in the brain. Focused ultrasound (FUS) with microbubbles has been shown to induce noninvasive, localized, and transient BBB opening. Although promising, safety and efficacy concerns still remain. Previously reported experiments used conventional imaging contrast agents that have a wide size distribution. In this study, we hypothesize that BBB opening characteristics are dependent on bubble diameter. A 25 μl bolus of in-house manufactured, lipid-shelled bubbles with either 1-2 or 4-5 μm diameter ranges was injected intravenously. Pulsed FUS (frequency: 1.5 MHz, peak-negative pressure: 146-607 kPa, duty cycle: 20%, duration: 1-min) was then applied to the left hippocampus of mice (n = 16) in vivo through the intact skin and skull. MRI or fluorescence microscopy was used to determine BBB opening. Contrast-enhanced (Omniscan™; 0.75 mL; molecular weight: 574 Da) MRI (9.4-T) was acquired on multiple days after sonication to determine BBB opening and closing. Fluorescence microscopy was also used to determine the feasibility of delivering large, 3 kDa dextran compounds through the BBB. The BBB opening acoustic pressure threshold for the 4-5μm bubbles was in the 146-304 kPa range while the threshold for the 1-2μm bubbles was higher. In conclusion, FUS-induced BBB opening and closing was shown to be dependent on the bubble diameter indicating the possibility of specifically designing bubbles to enhance this therapeutic application.

In-vivo imaging of blood-brain barrier permeability using positron emission tomography with 2-amino-[3-11C]isobutyric acid.

PubMed

Okada, Maki; Kikuchi, Tatsuya; Okamura, Toshimitsu; Ikoma, Yoko; Tsuji, Atsushi B; Wakizaka, Hidekatsu; Kamakura, Tomoo; Aoki, Ichio; Zhang, Ming-Rong; Kato, Koichi

2015-12-01

The blood-brain barrier (BBB) limits the entry of some therapeutics into the brain, resulting in reduced efficacy. BBB-opening techniques have been developed to enhance the entry into the brain. However, a noninvasive, highly sensitive and quantitative method for evaluating the changes in BBB permeability induced by such techniques is needed to optimize treatment protocols. We evaluated 2-amino-[3-C]isobutyric acid ([3-C]AIB) as a PET probe to quantify BBB permeability in model rats. BBB opening was induced by a lipopolysaccharide injection or focused ultrasound (FUS) sonication. [3-C]AIB distribution in the brain was evaluated by autoradiography and PET and compared with that of Evans blue, a traditional BBB permeability marker. Kinetics of [3-C]AIB was compared with that of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced MRI. The unidirectional blood-brain transfer constant (Ki) of [3-C]AIB was estimated using the Patlak plot. [3-C]AIB uptake in the lesion area was significantly higher than that in the control area and radioactivity colocalized with Evans blue in both models. [3-C]AIB uptake in the FUS-sonicated region decreased over time after sonication. The ratio of [3-C]AIB accumulation in the FUS-treated to the contralateral side increased during the experimental period, whereas that of the Gd-DTPA intensity reached a maximum at 10 min after injection and decreased thereafter. The [3-C]AIB Ki values were significantly higher in the lesion area than the control area. [3-C]AIB PET is a promising, highly sensitive and quantitative imaging method for assessment of BBB permeability.

Dynamical Cluster-decay Model (DCM) applied to 9Li+208Pb reaction

NASA Astrophysics Data System (ADS)

Kaur, Arshdeep; Hemdeep; Kaushal, Pooja; Behera, Bivash R.; Gupta, Raj K.

2017-10-01

The decay mechanism of 217At* formed in 9Li+208Pb reaction is studied within the dynamical cluster-decay model (DCM) at various center-of-mass energies. The aim is to see the behavior of a light neutron-rich radioactive beam on a doubly-magic target nucleus for the (total) fusion cross section σfus and the individual decay channel cross sections. Experimentally, only the isotopic yield of heavy mass residues * 211- 214At [equivalently, the light-particles (LPs) evaporation residue cross sections σxn for x = 3- 6 neutrons emission] are measured, with the fusion-fission (ff) component σff taken zero. For a fixed neck-length parameter ΔR, the only parameter in the DCM, we are able to fit σfus =∑x=16σxn almost exactly for 9Li on 208Pb at all E c . m .'s. However, the observed individual decay channels (3n-6n) are very poorly fitted, with unobserved channels (1n, 2n) and σff strongly over-estimated. Different ΔR values, meaning thereby different reaction time scales, are required to fit individually both the observed and unobserved evaporation residue channels (1n-6n) and σff, but then the compound nucleus (CN) contribution σCN is very small (< 1%), and the non-compound nucleus (nCN) decay cross section σnCN contributes the most towards total σfus (=σCN +σnCN). Thus, the 9Li induced reaction on doubly-magic 208Pb is more of a quasi-fission-like nCN decay, which is further analyzed in terms of the statistical CN formation probability PCN and CN survival probability Psurv. For the reaction under study, PCN < < 1 and Psurv → 1, in particular at above barrier energies.

HSI2/VAL1 Silences AGL15 to Regulate the Developmental Transition from Seed Maturation to Vegetative Growth in Arabidopsis[OPEN

PubMed Central

Abdelmageed, Haggag; Kang, Miyoung

2018-01-01

Gene expression during seed development in Arabidopsis thaliana is controlled by transcription factors including LEAFY COTYLEDON1 (LEC1) and LEC2, ABA INSENSITIVE3 (ABI3), FUSCA3 (FUS3), known as LAFL proteins, and AGAMOUS-LIKE15 (AGL15). The transition from seed maturation to germination and seedling growth requires the transcriptional silencing of these seed maturation-specific factors leading to downregulation of structural genes including those that encode seed storage proteins, oleosins, and dehydrins. During seed germination and vegetative growth, B3-domain protein HSI2/VAL1 is required for the transcriptional silencing of LAFL genes. Here, we report chromatin immunoprecipitation analysis indicating that HSI2/VAL1 binds to the upstream sequences of the AGL15 gene but not at LEC1, ABI3, FUS3, or LEC2 loci. Functional analysis indicates that the HSI2/VAL1 B3 domain interacts with two RY elements upstream of the AGL15 coding region and at least one of them is required for HSI2/VAL1-dependent AGL15 repression. Expression analysis of the major seed maturation regulatory genes LEC1, ABI3, FUS3, and LEC2 in different genetic backgrounds demonstrates that HSI2/VAL1 is epistatic to AGL15 and represses the seed maturation regulatory program through downregulation of AGL15 by deposition of H3K27me3 at this locus. This hypothesis is further supported by results that show that HSI2/VAL1 physically interacts with the Polycomb Repressive Complex 2 component protein MSI1, which is also enriched at the AGL15 locus. PMID:29475938

TU-G-210-02: TRANS-FUSIMO - An Integrative Approach to Model-Based Treatment Planning of Liver FUS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Preusser, T.

Modeling can play a vital role in predicting, optimizing and analyzing the results of therapeutic ultrasound treatments. Simulating the propagating acoustic beam in various targeted regions of the body allows for the prediction of the resulting power deposition and temperature profiles. In this session we will apply various modeling approaches to breast, abdominal organ and brain treatments. Of particular interest is the effectiveness of procedures for correcting for phase aberrations caused by intervening irregular tissues, such as the skull in transcranial applications or inhomogeneous breast tissues. Also described are methods to compensate for motion in targeted abdominal organs such asmore » the liver or kidney. Douglas Christensen – Modeling for Breast and Brain HIFU Treatment Planning Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Tobias Preusser – TRANS-FUSIMO – An Integrative Approach to Model-Based Treatment Planning of Liver FUS Learning Objectives: Understand the role of acoustic beam modeling for predicting the effectiveness of therapeutic ultrasound treatments. Apply acoustic modeling to specific breast, liver, kidney and transcranial anatomies. Determine how to obtain appropriate acoustic modeling parameters from clinical images. Understand the separate role of absorption and scattering in energy delivery to tissues. See how organ motion can be compensated for in ultrasound therapies. Compare simulated data with clinical temperature measurements in transcranial applications. Supported by NIH R01 HL172787 and R01 EB013433 (DC); EU Seventh Framework Programme (FP7/2007-2013) under 270186 (FUSIMO) and 611889 (TRANS-FUSIMO)(TP); and P01 CA159992, GE, FUSF and InSightec (UV)« less

The hemocyanin from a living fossil, the cephalopod Nautilus pompilius: protein structure, gene organization, and evolution.

PubMed

Bergmann, Sandra; Lieb, Bernhard; Ruth, Peter; Markl, Jürgen

2006-03-01

By electron microscopic and immunobiochemical analyses we have confirmed earlier evidence that Nautilus pompilius hemocyanin (NpH) is a ring-like decamer (M(r) = approximately 3.5 million), assembled from 10 identical copies of an approximately 350-kDa polypeptide. This subunit in turn is substructured into seven sequential covalently linked functional units of approximately 50 kDa each (FUs a-g). We have cloned and sequenced the cDNA encoding the complete polypeptide; it comprises 9198 bp and is subdivided into a 5' UTR of 58 bp, a 3' UTR of 365 bp, and an open reading frame for a signal peptide of 21 amino acids plus a polypeptide of 2903 amino acids (M(r) = 335,881). According to sequence alignments, the seven FUs of Nautilus hemocyanin directly correspond to the seven FU types of the previously sequenced hemocyanin "OdH" from the cephalopod Octopus dofleini. Thirteen potential N-glycosylation sites are distributed among the seven Nautilus hemocyanin FUs; the structural consequences of putatively attached glycans are discussed on the basis of the published X-ray structure for an Octopus dofleini and a Rapana thomasiana FU. Moreover, the complete gene structure of Nautilus hemocyanin was analyzed; it resembles that of Octopus hemocyanin with respect to linker introns but shows two internal introns that differ in position from the three internal introns of the Octopus hemocyanin gene. Multiple sequence alignments allowed calculation of a rather robust phylogenetic tree and a statistically firm molecular clock. This reveals that the last common ancestor of Nautilus and Octopus lived 415 +/- 24 million years ago, in close agreement with fossil records from the early Devonian.

Genetic link between Cabeza, a Drosophila homologue of Fused in Sarcoma (FUS), and the EGFR signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shimamura, Mai; Kyotani, Akane; Insect Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585

2014-08-01

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular weakness. Fused in Sarcoma (FUS) that has been identified in familial ALS is an RNA binding protein that is normally localized in the nucleus. However, its function in vivo is not fully understood. Drosophila has Cabeza (Caz) as a FUS homologue and specific knockdown of Caz in the eye imaginal disc and pupal retina using a GMR-GAL4 driver was here found to induce an abnormal morphology of the adult compound eyes, a rough eye phenotype. This was partially suppressed by expression of the apoptosis inhibitor P35. Knockdownmore » of Caz exerted no apparent effect on differentiation of photoreceptor cells. However, immunostaining with an antibody to Cut that marks cone cells revealed fusion of these and ommatidia of pupal retinae. These results indicate that Caz knockdown induces apoptosis and also inhibits differentiation of cone cells, resulting in abnormal eye morphology in adults. Mutation in EGFR pathway-related genes, such as rhomboid-1, rhomboid-3 and mirror suppressed the rough eye phenotype induced by Caz knockdown. Moreover, the rhomboid-1 mutation rescued the fusion of cone cells and ommatidia observed in Caz knockdown flies. The results suggest that Caz negatively regulates the EGFR signaling pathway required for determination of cone cell fate in Drosophila. - Highlights: • Knockdown of Cabeza induced rough eye phenotype. • Knockdown of Cabeza induced fusion of cone cells in pupal retinae. • Knockdown of Cabeza induced apoptosis in pupal retinae. • Mutation in EGFR pathway-related genes suppressed the rough eye phenotype. • Cabeza may negatively regulate the EGFR pathway.« less

Predicting intraoperative feasibility of combined TES-mMEP and cSSEP monitoring during scoliosis surgery based on preoperative neurophysiological assessment.

PubMed

Azabou, Eric; Manel, Véronique; Abelin-Genevois, Kariman; Andre-Obadia, Nathalie; Cunin, Vincent; Garin, Christophe; Kohler, Remi; Berard, Jérôme; Ulkatan, Sedat

2014-07-01

Combined monitoring of muscle motor evoked potentials elicited by transcranial electric stimulation (TES-mMEP) and cortical somatosensory evoked potentials (cSSEPs) is safe and effective for spinal cord monitoring during scoliosis surgery. However, TES-mMEP/cSSEP is not always feasible. Predictors of feasibility would help to plan the monitoring strategy. To identify predictors of the feasibility of TES-mMEP/cSSEP during scoliosis surgery. Prospective cohort study in a clinical neurophysiology unit and pediatric orthopedic department of a French university hospital. A total of 103 children aged 2 to 19 years scheduled for scoliosis surgery. Feasibility rate of intraoperative TES-mMEP/cSSEP monitoring. All patients underwent a preoperative neurological evaluation and preoperative mMEP and cSSEP recordings at both legs. For each factor associated with feasibility, we computed sensitivity, specificity, positive predictive value (PPV), and negative predictive value. A decision tree was designed. Presence of any of the following factors was associated with 100% feasibility, 100% specificity, and 100% PPV: idiopathic scoliosis, normal preoperative neurological findings, and normal preoperative mMEP and cSSEP recordings. Feasibility was 0% in the eight patients with no recordable mMEPs or cSSEPs during preoperative testing. A decision tree involving three screening steps can be used to identify patients in whom intraoperative TES-mMEP/cSSEP is feasible. Preoperative neurological and neurophysiological assessments are helpful for identifying patients who can be successfully monitored by TES-mMEP/cSSEP during scoliosis surgery. Copyright © 2014 Elsevier Inc. All rights reserved.

Stand-alone error characterisation of microwave satellite soil moisture using a Fourier method

USDA-ARS?s Scientific Manuscript database

Error characterisation of satellite-retrieved soil moisture (SM) is crucial for maximizing their utility in research and applications in hydro-meteorology and climatology. Error characteristics can provide insights for retrieval development and validation, and inform suitable strategies for data fus...

Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies

PubMed Central

Arvanitis, Costas D.; McDannold, Nathan

2013-01-01

Purpose: Ultrasound can be used to noninvasively produce different bioeffects via viscous heating, acoustic cavitation, or their combination, and these effects can be exploited to develop a wide range of therapies for cancer and other disorders. In order to accurately localize and control these different effects, imaging methods are desired that can map both temperature changes and cavitation activity. To address these needs, the authors integrated an ultrasound imaging array into an MRI-guided focused ultrasound (MRgFUS) system to simultaneously visualize thermal and mechanical effects via passive acoustic mapping (PAM) and MR temperature imaging (MRTI), respectively. Methods: The system was tested with an MRgFUS system developed for transcranial sonication for brain tumor ablation in experiments with a tissue mimicking phantom and a phantom-filled ex vivo macaque skull. In experiments on cavitation-enhanced heating, 10 s continuous wave sonications were applied at increasing power levels (30–110 W) until broadband acoustic emissions (a signature for inertial cavitation) were evident. The presence or lack of signal in the PAM, as well as its magnitude and location, were compared to the focal heating in the MRTI. Additional experiments compared PAM with standard B-mode ultrasound imaging and tested the feasibility of the system to map cavitation activity produced during low-power (5 W) burst sonications in a channel filled with a microbubble ultrasound contrast agent. Results: When inertial cavitation was evident, localized activity was present in PAM and a marked increase in heating was observed in MRTI. The location of the cavitation activity and heating agreed on average after registration of the two imaging modalities; the distance between the maximum cavitation activity and focal heating was −3.4 ± 2.1 mm and −0.1 ± 3.3 mm in the axial and transverse ultrasound array directions, respectively. Distortions and other MRI issues introduced small uncertainties in the PAM/MRTI registration. Although there was substantial variation, a nonlinear relationship between the average intensity of the cavitation maps, which was relatively constant during sonication, and the peak temperature rise was evident. A fit to the data to an exponential had a correlation coefficient (R2) of 0.62. The system was also found to be capable of visualizing cavitation activity with B-mode imaging and of passively mapping cavitation activity transcranially during cavitation-enhanced heating and during low-power sonication with an ultrasound contrast agent. Conclusions: The authors have demonstrated the feasibility of integrating an ultrasound imaging array into an MRgFUS system to simultaneously map localized cavitation activity and temperature. The authors anticipate that this integrated approach can be utilized to develop controllers for cavitation-enhanced ablation and facilitate the optimization and development of this and other ultrasound therapies. The integrated system may also provide a useful tool to study the bioeffects of acoustic cavitation. PMID:24320468

Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies.

PubMed

Arvanitis, Costas D; McDannold, Nathan

2013-11-01

Ultrasound can be used to noninvasively produce different bioeffects via viscous heating, acoustic cavitation, or their combination, and these effects can be exploited to develop a wide range of therapies for cancer and other disorders. In order to accurately localize and control these different effects, imaging methods are desired that can map both temperature changes and cavitation activity. To address these needs, the authors integrated an ultrasound imaging array into an MRI-guided focused ultrasound (MRgFUS) system to simultaneously visualize thermal and mechanical effects via passive acoustic mapping (PAM) and MR temperature imaging (MRTI), respectively. The system was tested with an MRgFUS system developed for transcranial sonication for brain tumor ablation in experiments with a tissue mimicking phantom and a phantom-filled ex vivo macaque skull. In experiments on cavitation-enhanced heating, 10 s continuous wave sonications were applied at increasing power levels (30-110 W) until broadband acoustic emissions (a signature for inertial cavitation) were evident. The presence or lack of signal in the PAM, as well as its magnitude and location, were compared to the focal heating in the MRTI. Additional experiments compared PAM with standard B-mode ultrasound imaging and tested the feasibility of the system to map cavitation activity produced during low-power (5 W) burst sonications in a channel filled with a microbubble ultrasound contrast agent. When inertial cavitation was evident, localized activity was present in PAM and a marked increase in heating was observed in MRTI. The location of the cavitation activity and heating agreed on average after registration of the two imaging modalities; the distance between the maximum cavitation activity and focal heating was -3.4 ± 2.1 mm and -0.1 ± 3.3 mm in the axial and transverse ultrasound array directions, respectively. Distortions and other MRI issues introduced small uncertainties in the PAM∕MRTI registration. Although there was substantial variation, a nonlinear relationship between the average intensity of the cavitation maps, which was relatively constant during sonication, and the peak temperature rise was evident. A fit to the data to an exponential had a correlation coefficient (R(2)) of 0.62. The system was also found to be capable of visualizing cavitation activity with B-mode imaging and of passively mapping cavitation activity transcranially during cavitation-enhanced heating and during low-power sonication with an ultrasound contrast agent. The authors have demonstrated the feasibility of integrating an ultrasound imaging array into an MRgFUS system to simultaneously map localized cavitation activity and temperature. The authors anticipate that this integrated approach can be utilized to develop controllers for cavitation-enhanced ablation and facilitate the optimization and development of this and other ultrasound therapies. The integrated system may also provide a useful tool to study the bioeffects of acoustic cavitation.

The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation.

PubMed

Buratti, Emanuele; Baralle, Francisco Ernesto

2010-01-01

Heterogeneous ribonucleoproteins (hnRNPs) are multifunctional RNA-binding proteins (RBPs) involved in many cellular processes. They participate in most gene expression pathways, from DNA replication and repair to mRNA translation. Among this class of proteins, TDP-43 (and more recently FUS/TLS) have received considerable attention due to their involvement in several neurodegenerative diseases. This finding has prompted many research groups to focus on the gene expression pathways that are regulated by these proteins. The results have uncovered a considerable complexity of TDP-43 and FUS/TLS functions due to the many independent mechanisms by which they may act to influence various cellular processes (such as DNA transcription, pre-mRNA splicing, mRNA export/import). The aim of this chapter will be to review especially some of the novel functions that have been uncovered, such as role in miRNA synthesis, regulation of transcript levels, and potential autoregulatory mechanisms in order to provide the basis for further investigations.

[AML(M7) associated with t(16;21)(p11;q22) showing relapse after unrelated bone marrow transplantation and disappearance of TLS/FUS-ERG mRNA].

PubMed

Fukushima, Y; Fujii, N; Tabata, Y; Nishimura, Y; Fusaoka, T; Yoshihara, T; Tsunamoto, K; Kasubuchi, Y; Morimoto, A; Hibi, S; Taketani, K; Hayashi, Y; Imashuku, S

2001-06-01

A 3-year-old boy with poorly prognostic acute megakaryoblastic leukemia (AML M7) showing t(16;21)(p11;q22) karyotype underwent unrelated bone marrow transplantation (U-BMT) during his first hematological remission. The conditioning regimen consisted of BU, VP-16 and L-PAM. Engraftment was smooth, but the patient developed grade I acute GVHD. During hematological remission before U-BMT, the TLS/FUS-ERG chimeric transcript of t(16;21)(p11;q22) was consistently detectable as minimal residual disease (MRD) by RT-PCR. However, after U-BMT it soon became undetectable. There was no detectable MRD until 7 months after U-BMT, but bone marrow relapse occurred 10 months after U-BMT. We consider that U-BMT is a promising treatment for t(16;21)(p11;q22) AML. However, an intensified conditioning regimen or modification of GVHD prophylaxis is needed.

Crystal Structure of the 3.8-MDa Respiratory Supermolecule Hemocyanin at 3.0 Å Resolution.

PubMed

Gai, Zuoqi; Matsuno, Asuka; Kato, Koji; Kato, Sanae; Khan, Md Rafiqul Islam; Shimizu, Takeshi; Yoshioka, Takeya; Kato, Yuki; Kishimura, Hideki; Kanno, Gaku; Miyabe, Yoshikatsu; Terada, Tohru; Tanaka, Yoshikazu; Yao, Min

2015-12-01

Molluscan hemocyanin, a copper-containing oxygen transporter, is one of the largest known proteins. Although molluscan hemocyanins are currently applied as immunotherapeutic agents, their precise structure has not been determined because of their enormous size. Here, we have determined the first X-ray crystal structure of intact molluscan hemocyanin. The structure unveiled the architecture of the 3.8-MDa supermolecule composed of homologous functional units (FUs), wherein the dimers of FUs hierarchically associated to form the entire cylindrical decamer. Most of the specific inter-FU interactions were localized at narrow regions in the FU dimers, suggesting that rigid FU dimers formed by specific interactions assemble with flexibility. Furthermore, the roles of carbohydrates in assembly and allosteric effect, and conserved sulfur-containing residues in copper incorporation, were revealed. The precise structural information obtained in this study will accelerate our understanding of the molecular basis of hemocyanin and its future applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fusion and elastic scattering of 6Li + 58Ni at low energies

NASA Astrophysics Data System (ADS)

Aguilera, Elí F.; Amador-Valenzuela, Paulina; Martinez-Quiroz, Enrique; Lizcano, David; Garcia-Flores, Araceli; Kolata, James J.

2017-11-01

Sub-barrier fusion cross sections (σfus) for the 6Li + 58Ni system, obtained from the respective evaporation protons, are examined in the present work. With respect to expectations of a simple one-dimensional barrier penetration model, a large enhancement of the data is observed. Good consistency with equivalent data reported previously for similar systems is found. A comparison with total reaction cross sections (σR), deduced from elastic scattering measurements reported previously, indicates that σfus is close to σR within the measured energy range. To estimate the contribution of complete fusion (CF), an optical model analysis of the elastic scattering data is performed where CF is identified with the absorption in a short range volume potential. A surface polarization potential is added to the bare nuclear potential to simulate the effect of peripheral reactions. The results obtained indicate that other mechanisms different from CF may be dominant, especially in the lower energy region.

Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: Potential for targeting experimental brain tumors

PubMed Central

Diaz, Roberto Jose; McVeigh, Patrick Z.; O’Reilly, Meaghan A.; Burrell, Kelly; Bebenek, Matthew; Smith, Christian; Etame, Arnold; Zadeh, Gelareh; Hynynen, Kullervo; Wilson, Brian C.; Rutka, James T.

2014-01-01

Spectral mapping of nanoparticles with surface enhanced Raman scattering (SERS) capability in the near-infrared range is an emerging molecular imaging technique. We used magnetic resonance image-guided transcranial focused ultrasound (TcMRgFUS) to reversibly disrupt the blood-brain barrier (BBB) adjacent to brain tumor margins in rats. Glioma cells were found to internalize SERS capable nanoparticles of 50 nm or 120 nm physical diameter. Surface coating with anti-epidermal growth factor receptor antibody or non-specific human immunoglobulin G, resulted in enhanced cell uptake of nanoparticles in-vitro compared to nanoparticles with methyl terminated 12-unit polyethylene glycol surface. BBB disruption permitted the delivery of SERS capable spherical 50 or 120 nm gold nanoparticles to the tumor margins. Thus, nanoparticles with SERS imaging capability can be delivered across the BBB non-invasively using TcMRgFUS and have the potential to be used as optical tracking agents at the invasive front of malignant brain tumors. PMID:24374363

The efficacy of intraoperative atrial radiofrequency ablation for atrial fibrillation during concomitant cardiac surgery-the Surgical Atrial Fibrillation Suppression (SAFS) Study.

PubMed

Veasey, Rick A; Segal, Oliver R; Large, Janet K; Lewis, Michael E; Trivedi, Uday H; Cohen, Andrew S; Hyde, Jonathan A J; Sulke, A Neil

2011-10-01

Studies assessing radiofrequency ablation (RFA) for atrial fibrillation (AF) performed at the time of concomitant cardiac surgery have reported high success rates. The efficacy of this treatment has primarily been determined by a single electrocardiogram (ECG) or 24-h Holter monitor at follow-up. We sought to assess the true efficacy of this procedure using prolonged cardiac rhythm monitoring. One hundred patients with paroxysmal (n = 47) and persistent AF (n = 53) requiring cardiac surgery were enrolled. Patients were clinically reviewed 6 weeks post-operatively and were monitored with 7-day Holter with full disclosure, 6 months post-surgery. A cohort of 50 patients also underwent 7 day Holter monitoring preoperatively. AF recurrence was defined as >30 s of AF. At 6 months, 75% of patients were in sinus rhythm according to a single ECG. However, only 62% of patients were free from AF on 7-day Holter; all AF episodes in these patients were asymptomatic. The procedure resulted in a significant decrease in AF burden from 56.2% at baseline to 27.5% at 6 months follow-up, (p < 0.001). Predictors of AF recurrence were (1) pre-operative AF duration; (2) persistent compared with paroxysmal AF; (3) increasing left atrial diameter and (4) requirement for mitral valve surgery. Surgical RFA for the treatment of AF, during concomitant cardiac surgery, is a successful procedure and significantly reduces AF burden. However, 13% of patients have asymptomatic AF episodes only identified with continuous monitoring. This has important implications for post-operative anti-arrhythmic and anticoagulant management and for the definition of surgical AF ablation success.

Multimodal intraoperative monitoring (MIOM) during cervical spine surgical procedures in 246 patients

PubMed Central

Sutter, Martin A.; Grob, Dieter; Jeszenszky, Dezsö; Porchet, François; Dvorak, Jiri

2007-01-01

A prospective study of 246 patients who received multimodal intraoperative monitoring during cervical spine surgery between March 2000 and December 2005. To determine the sensitivity and specificity of MIOM techniques used to monitor spinal cord and nerve root function during cervical spine surgery. It is appreciated that complication rate of cervical spine surgery is low, however, there is a significant risk of neurological injury. The combination of monitoring of ascending and descending pathways may provide more sensitive and specific results giving immediate feedback information and/or alert regarding any neurological changes during the operation to the surgeon. Intraoperative somatosensory spinal and cerebral evoked potentials combined with continuous EMG and motor-evoked potentials of the spinal cord and muscles were evaluated and compared with postoperative clinical neurological changes. A total of 246 consecutive patients with cervical pathologies, majority spinal stenosis due to degenerative changes of cervical spine were monitored by means of MIOM during the surgical procedure. About 232 patients presented true negative while 2 patients false negative responses. About ten patients presented true positive responses where neurological deficit after the operation was predicted and two patients presented false positive findings. The sensitivity of MIOM applied during cervical spine procedure (anterior and/or posterior) was 83.3% and specificity of 99.2%. MIOM is an effective method of monitoring the spinal cord functional integrity during cervical spine surgery and can help to reduce the risk of neurological deficit by alerting the surgeon when monitoring changes are observed. PMID:17610090

Value of Free-Run Electromyographic Monitoring of Extraocular Cranial Nerves during Expanded Endonasal Surgery (EES) of the Skull Base.

PubMed

Thirumala, Parthasarathy D; Mohanraj, Santhosh Kumar; Habeych, Miguel; Wichman, Kelley; Chang, Yue-Fang; Gardner, Paul; Snyderman, Carl; Crammond, Donald J; Balzer, Jeffrey

2013-06-01

Objective To evaluate the value of free-run electromyography (f-EMG) monitoring of extraocular cranial nerves (EOCN) III, IV, and VI during expanded endonasal surgery (EES) of the skull base in reducing iatrogenic cranial nerve (CN) deficits. Design We retrospectively identified 200 patients out of 990 who had at least one EOCN monitored during EES. We further separated patients into groups according to the specific CN monitored. In each CN group, we classified patients who had significant (SG) f-EMG activity as Group I and those who did not as Group II. Results A total of 696 EOCNs were monitored. The number of muscles supplied by EOCNs that had SG f-EMG activity was 88, including CN III = 46, CN IV = 21, and CN VI = 21. There were two deficits involving CN VI in patients who had SG f-EMG activity during surgery. There were 14 deficits observed, including CN III = 3, CN IV = 2, and CN VI = 9 in patients who did not have SG f-EMG activity during surgery. Conclusions f-EMG monitoring of EOCN during EES can be useful in identifying the location of the nerve. It seems to have limited value in predicting postoperative neurological deficits. Future studies to evaluate the EMG of EOCN during EES need to be done with both f-EMG and triggered EMG.

Value of Free-Run Electromyographic Monitoring of Extraocular Cranial Nerves during Expanded Endonasal Surgery (EES) of the Skull Base

PubMed Central

Thirumala, Parthasarathy D.; Mohanraj, Santhosh Kumar; Habeych, Miguel; Wichman, Kelley; Chang, Yue-fang; Gardner, Paul; Snyderman, Carl; Crammond, Donald J.; Balzer, Jeffrey

2013-01-01

Objective To evaluate the value of free-run electromyography (f-EMG) monitoring of extraocular cranial nerves (EOCN) III, IV, and VI during expanded endonasal surgery (EES) of the skull base in reducing iatrogenic cranial nerve (CN) deficits. Design We retrospectively identified 200 patients out of 990 who had at least one EOCN monitored during EES. We further separated patients into groups according to the specific CN monitored. In each CN group, we classified patients who had significant (SG) f-EMG activity as Group I and those who did not as Group II. Results A total of 696 EOCNs were monitored. The number of muscles supplied by EOCNs that had SG f-EMG activity was 88, including CN III = 46, CN IV = 21, and CN VI = 21. There were two deficits involving CN VI in patients who had SG f-EMG activity during surgery. There were 14 deficits observed, including CN III = 3, CN IV = 2, and CN VI = 9 in patients who did not have SG f-EMG activity during surgery. Conclusions f-EMG monitoring of EOCN during EES can be useful in identifying the location of the nerve. It seems to have limited value in predicting postoperative neurological deficits. Future studies to evaluate the EMG of EOCN during EES need to be done with both f-EMG and triggered EMG. PMID:23943720

Influence of neural monitoring during thyroid surgery on nerve integrity and postoperative vocal function.

PubMed

Engelsman, A F; Warhurst, S; Fraser, S; Novakovic, D; Sidhu, S B

2018-06-01

Integrity of the recurrent laryngeal nerve (RLN) and the external branch of the superior laryngeal nerve (EBSLN) can be checked by intraoperative nerve monitoring (IONM) after visualization. The aim of this study was to determine the prevalence and nature of voice dysfunction following thyroid surgery with routine IONM. Thyroidectomies were performed with routine division of strap muscles and nerve monitoring to confirm integrity of the RLN and EBSLN following dissection. Patients were assessed for vocal function before surgery and at 1 and 3 months after operation. Assessment included use of the Voice Handicap Index (VHI) 10, maximum phonation time, fundamental frequency, pitch range, harmonic to noise ratio, cepstral peak prominence and smoothed cepstral peak prominence. A total of 172 nerves at risk were analysed in 102 consecutive patients undergoing elective thyroid surgery. In 23·3 per cent of EBSLNs and 0·6 per cent of RLNs nerve identification required the assistance of IONM in addition to visualization. Nerve integrity was confirmed during surgery for 98·8 per cent of EBSLNs and 98·3 per cent of RLNs. There were no differences between preoperative and postoperative VHI-10 scores. Acoustic voice assessment showed small changes in maximum phonation time at 1 and 3 months after surgery. Where there is routine division of strap muscles, thyroidectomy using nerve monitoring confirmation of RLN and EBSLN function following dissection results in no clinically significant voice change.

Magnetic Enhancement of Stem Cell-Targeted Delivery into the Brain Following MR-Guided Focused Ultrasound for Opening the Blood-Brain Barrier.

PubMed

Shen, Wei-Bin; Anastasiadis, Pavlos; Nguyen, Ben; Yarnell, Deborah; Yarowsky, Paul J; Frenkel, Victor; Fishman, Paul S

2017-07-01

Focused ultrasound (FUS)-mediated blood-brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superparamagnetic iron oxide nanoparticles (SPIONs) in culture were attracted by an external magnetic field. In vivo, enhanced brain retention was observed near a magnet mounted on the skull in a rat model of traumatic brain injury, where BBBD also occurs. The goal of the current study was to determine whether magnetic attraction of SPION-loaded hNPCs would also enhance their retention in the brain after FUS-mediated BBBD. A small animal magnetic resonance imaging (MRI)-guided FUS system operating at 1.5 MHz was used to treat rats (∼120 g) without tissue damage or hemorrhage. Evidence of successful BBBD was validated with both radiologic enhancement of gadolinium on postsonication TI MRI and whole brain section visualization of Evans blue dye. The procedure was then combined with the application of a powerful magnet to the head directly after intravenous injection of the hNPCs. Validation of cells within the brain was performed by staining with Perls' Prussian blue for iron and by immunohistochemistry with a human-specific antigen. By injecting equal numbers of iron oxide (SPIONs) and noniron oxide nanoparticles-loaded hNPCs, each labeled with a different fluorophore, we found significantly greater numbers of SPIONs-loaded cells retained in the brain at the site of BBBD as compared to noniron loaded cells. This result was most pronounced in regions of the brain closest to the skull (dorsal cortex) in proximity to the magnet surface. A more powerful magnet and a Halbach magnetic array resulted in more effective retention of SPION-labeled cells in even deeper brain regions such as the striatum and ventral cortex. There, up to 90% of hNPCs observed contained SPIONs compared to 60% to 70% with the less powerful magnet. Fewer cells were observed at 24 h posttreatment compared to 2 h (primarily in the dorsal cortex). These results demonstrate that magnetic attraction can substantially enhance the retention of stem cells after FUS-mediated BBBD. This procedure could provide a safer and less invasive approach for delivering stem cells to the brain, compared to direct intracranial injections, substantially reducing the risk of bleeding and infection.

[Clinical research on the application of trans-esophageal echocardiography in monitoring Nuss surgery].

PubMed

Mou, Ling; Xu, Bing; Lan, Zhixun

2015-04-01

To investigate the validity and safety of trans-esophageal echocardiography (TEE) in monitoring of Nuss surgery. A total of 140 patients with pectus excavatum from Sichuan Provincial People's Hospital underwent Nuss surgery from August, 2011 to Aμgust, 2013. Among them, 72 patients received TEE monitoring while 68 patients didn't. The injury of heart and large vessels by the introducer and Nuss steel bar was observed by intraoperative TEE monitoring under middle-esophageal four chamber view and middle-esophageal aortic short axis view. The operation in all patients had been performed successfully without any severe complications. Satisfactory TEE images were obtained in all patients. The procedure of inserting the inducer and Nuss steel bar behind sternum and steel bar overturn could be seen clearly. No injury in heart and large vessels was detected. Local streak-like hemorrhage in 3 patients was observed under intra-operative TEE screen, but no further new bleeding was found in postoperative TEE examination. The blood was absorbed and couldn't see under trans-thoracic echocardiography in 1 month after the operation. The TEE is a non-invasive monitoring method. It is sensitive to detect the status of the heart and large vessels and can prevent the severe complications due to Nuss surgery.

Transcranial electric motor evoked potential monitoring during spine surgery: is it safe?

PubMed

Schwartz, Daniel M; Sestokas, Anthony K; Dormans, John P; Vaccaro, Alexander R; Hilibrand, Alan S; Flynn, John M; Li, P Mark; Shah, Suken A; Welch, William; Drummond, Denis S; Albert, Todd J

2011-06-01

Retrospective review. To report on the safety of repetitive transcranial electric stimulation (RTES) for eliciting motor-evoked potentials during spine surgery. Theoretical concerns over the safety of RTES have hindered broader acceptance of transcranial electric motor-evoked potentials (tceMEP), despite successful implementation of spinal cord monitoring with tceMEPs in many large spine centers, as well as their apparent superiority over mixed-nerve somatosensory-evoked potentials (SSEP) for detection of spinal cord injury. The records of 18,862 consecutive patients who met inclusion criteria and underwent spine surgery with tceMEP monitoring were reviewed for RTES-related complications. This large retrospective review identified only 26 (0.14%) cases with RTES-related complications; all but one of these were tongue lacerations, most of which were self-limiting. The results demonstrate that RTES is a highly safe modality for monitoring spinal cord motor tract function intraoperatively.

Autonomic predictors of recovery following surgery: A comparative study

PubMed Central

Williamson, John B.; Lewis, Greg; Grippo, Angela J.; Lamb, Damon; Harden, Emily; Handleman, Mika; Lebow, Jocelyn; Carter, C. Sue; Porges, Stephen W.

2015-01-01

Although heart rate and temperature are continuously monitored in patients during recovery following surgery, measures that extract direct manifestations of neural regulation of autonomic circuits from the beat-to-beat heart rate may be more sensitive to outcome. We explore the relationship between features of autonomic regulation and survival in the prairie vole, a small mammal, with features of vagal regulation of the heart similar to humans. Cardiac vagal regulation is manifested in the beat-to-beat heart rate variability (HRV) pattern and can be quantified by extracting measures of the amplitude of periodic oscillations associated with spontaneous breathing. Thus, monitoring beat-to-beat heart rate patterns post-surgery in the prairie vole may provide an opportunity to dynamically assess autonomic adjustments during recovery. Surgeries to implant telemetry devices to monitor body temperature and continuous ECG in prairie voles are routinely performed in our laboratory. Ten of these implanted prairie voles died within 48 h post-surgery. To compare the post-surgery autonomic trajectories with typical surviving prairie voles, the post-surgery data from 17 surviving prairie voles were randomly selected. The data are reported hourly for 27 prairie voles between 6 and 14 h (1 h before the demise of the first subject) post-surgery. Receiver operator curves were calculated hourly for each variable to evaluate sensitivity in discriminating survival. The data illustrate that measures of HRV are the most sensitive indicators. These findings provide a foundation for investigating further neural mechanisms of cardiovascular function. PMID:20451468

[Indicators of healthcare quality in day surgery (2010-2012)].

PubMed

Martínez Rodenas, F; Codina Grifell, J; Deulofeu Quintana, P; Garrido Corchón, J; Blasco Casares, F; Gibanel Garanto, X; Cuixart Vilamajó, L; de Haro Licer, J; Vazquez Dorrego, X

2014-01-01

Monitoring quality indicators in Ambulatory Surgery centers is fundamental in order to identify problems, correct them and prevent them. Given their large number, it is essential to select the most valid ones. The objectives of the study are the continuous improvement in the quality of healthcare of day-case surgery in our center, by monitoring selective quality parameters, having periodic information on the results and taking corrective measures, as well as achieving a percentage of unplanned transfer and cancellations within quality standards. Prospective, observational and descriptive study of the day-case surgery carried out from January 2010 to December 2012. Unplanned hospital admissions and cancellations on the same day of the operation were selected and monitored, along with their reasons. Hospital admissions were classified as: inappropriate selection, medical-surgical complications, and others. The results were evaluated each year and statistically analysed using χ(2) tests. A total of 8,300 patients underwent day surgery during the 3 years studied. The day-case surgery and outpatient index increased by 5.4 and 6.4%, respectively (P<.01). Unexpected hospital admissions gradually decreased due to the lower number of complications (P<.01). Hospital admissions, due to an extended period of time in locoregional anaesthesia recovery, also decreased (P<.01). There was improved prevention of nausea and vomiting, and of poorly controlled pain. The proportion of afternoon admissions was significantly reduced (P<.01). The cancellations increased in 2011 (P<.01). The monitoring of quality parameters in day-case surgery has been a useful tool in our clinical and quality management. Globally, the unplanned transfer and cancellations have been within the quality standards and many of the indicators analysed have improved. Copyright © 2013 SECA. Published by Elsevier Espana. All rights reserved.

Optimal ergonomics for laparoscopic surgery in minimally invasive surgery suites: a review and guidelines.

PubMed

van Det, M J; Meijerink, W J H J; Hoff, C; Totté, E R; Pierie, J P E N

2009-06-01

With minimally invasive surgery (MIS), a man-machine environment was brought into the operating room, which created mental and physical challenges for the operating team. The science of ergonomics analyzes these challenges and formulates guidelines for creating a work environment that is safe and comfortable for its operators while effectiveness and efficiency of the process are maintained. This review aimed to formulate the ergonomic challenges related to monitor positioning in MIS. Background and guidelines are formulated for optimal ergonomic monitor positioning within the possibilities of the modern MIS suite, using multiple monitors suspended from the ceiling. All evidence-based experimental ergonomic studies conducted in the fields of laparoscopic surgery and applied ergonomics for other professions working with a display were identified by PubMed searches and selected for quality and applicability. Data from ergonomic studies were evaluated in terms of effectiveness and efficiency as well as comfort and safety aspects. Recommendations for individual monitor positioning are formulated to create a personal balance between these two ergonomic aspects. Misalignment in the eye-hand-target axis because of limited freedom in monitor positioning is recognized as an important ergonomic drawback during MIS. Realignment of the eye-hand-target axis improves personal values of comfort and safety as well as procedural values of effectiveness and efficiency. Monitor position is an important ergonomic factor during MIS. In the horizontal plain, the monitor should be straight in front of each person and aligned with the forearm-instrument motor axis to avoid axial rotation of the spine. In the sagittal plain, the monitor should be positioned lower than eye level to avoid neck extension.

Comparison of entropy and bispectral index during propofol and fentanyl sedation in monitored anaesthesia care.

PubMed

Balci, Canan; Karabekir, H S; Kahraman, F; Sivaci, R G

2009-01-01

Comparison of entropy (state entropy [SE] and response entropy [RE]) with the bispectral index (BIS) during propofol sedation in monitored anaesthesia care (MAC) was carried out in patients undergoing hand surgery. Thirty candidates for elective hand surgery were pre-medicated with midazolam 0.06 mg/kg and atropine 0.01 mg/kg. Sedation was induced with intravenous propofol and fentanyl was also administered. The Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) was used to determine sedation level and pain was maintained at < 4 on a 0 - 10 verbal rating scale. The BIS, entropy, MOAA/S and pain values were recorded before initiation of sedation (control), during initiation of sedation, during surgery, and for 30 min after the end of surgery and anaesthesia. On initiation of sedation, entropy decreased more rapidly than BIS. At 10 min after initiation of sedation, the mean +/- SD values for MOAA/S, BIS, RE and SE were 3.00 +/- 0.36, 85.45 +/- 0.15, 74.00 +/- 0.60 and 72.02 +/- 0.12, respectively. During recovery, BIS and RE and SE increased in parallel with MOAA/S. It is concluded that entropy monitoring is as reliable as BIS monitoring in MAC.

Morphological, chemical and molecular differentiation of Fusarium equiseti isolated from Norwegian cereals.

PubMed

Kosiak, Elzbieta Barbara; Holst-Jensen, Arne; Rundberget, Thomas; Gonzalez Jaen, Maria Teresa; Torp, Mona

2005-03-15

The morphological variation, secondary metabolite profiles and restriction fragment length polymorphisms (RFLPs) of PCR amplified intergenic spacer (IGS) ribosomal DNA (rDNA) were studied in 27 isolates of Fusarium equiseti, 25 isolated from Norwegian cereals and 2 from soil obtained from the IBT culture collection (BioCentrum, Technical University of Denmark). All 27 isolates were tested for production of fusarochromanone (FUSCHR), zearalenone (ZEA) and the trichothecenes: 15-monoacetoxy-scirpentriol (MAS), diacetoxy-scirpenol (DAS), T-2 and HT-2 toxins, T2-triol, neosolaniol (NEO), deoxynivalenol (DON), nivalenol (NIV) and 4-acetylnivalenol (Fus-X). The trichothecenes were analysed by GC-MS in a selected ion monitoring mode, while FUSCHR was determined by ion pair HPLC with fluorometric detection and production of ZEA by TLC. For amplification of IGS rDNA primers CNL12 and CNS1 were applied. IGS rDNA was digested with the four restriction enzymes: AvaII, CfoI, EcoRI and Sau3A. In addition, we sequenced the IGS rDNA region of three of the Norwegian isolates. There were two morphological types among the Norwegian strains of F. equiseti, type I with short apical cells (dominating) and type II with long apical cells, with four haplotypes identified based on the RFLP data. Variation in secondary metabolite profiles within and between the morphological groups was observed and the levels of produced toxins were: FUSCHR 3000-42,500 and 25-30 ng/g, NIV 20-2500 and 120-700 ng/g, FUS-X 20-15,000 and 0 ng/g, DAS 30-7500 and 0-600 ng/g, and MAS 10-600 and 0-500 ng/g, for strains with short and long apical cells, respectively. NEO was detected in 16/27 strains tested (all morphotype I). All but four strains of type I (these four lacked a restriction site for EcoRI) had identical RFLP profiles. The isolates of type II had two haplotypes. The IGS sequence similarity data indicated differences between these morphotypes corresponding to two separate lineages apparently at the species level.

Design and evaluation of a 63 element 1.75-dimensional ultrasound phased array for treating benign prostatic hyperplasia

NASA Astrophysics Data System (ADS)

Saleh, Khaldon Y.; Smith, Nadine B.

2003-10-01

Focused ultrasound surgery (FUS) is a clinical method for treating benign prostatic hyperplasia (BPH) in which tissue is noninvasively necrosed by elevating the temperature at the focal point above 60°C using short sonications. With 1.75-dimensional (1.75-D) arrays, the power and phase to the individual elements can be controlled electronically for focusing and steering. This research describes the design, construction and evaluation of a 1.75-D ultrasound phased array to be used in the treatment of benign prostatic hyperplasia. The array was designed with a steering angle of +/-13.5 deg in the transverse direction, and can move the focus in three parallel planes in the longitudinal direction with a relatively large focus size. A piezoelectric ceramic (PZT-8) was used as the material of the transducer and two matching layers were built for maximum acoustic power transmission to tissue. To verify the capability of the transducer for focusing and steering, exposimetry was performed and the results correlated well with the calculated fields. In vivo experiments were performed to verify the capability of the transducer to ablate tissue using short sonications. [Work supported by the Whitaker Foundation and the Department of Defense Congressionally Directed Medical Prostate Cancer Research Program.

Monitoring trends in waiting periods in Canada for elective surgery: validation of a method using administrative data.

PubMed

Shortt, Samuel E D; Shaw, Ralph A; Elliott, David; Mackillop, William J

2004-06-01

Provincial governments require timely, economical methods to monitor surgical waiting periods. Although use of prospective procedure-specific registers would be the ideal method, a less elaborate system has been proposed that is based on physician billing data. This study assessed the validity of using the date of the last service billed prior to surgery as a proxy for the beginning of the post-referral, pre-surgical waiting period. We examined charts for 31,824 elective surgical encounters between 1992 and 1996 at an Ontario teaching hospital. The date of the last service before surgery (the last billing date) was compared with the date of the consultant's letter indicating a decision to book surgery (i.e., to begin waiting). Several surgical specialties (but excluding cardiac, orthopedic and gynecologic) had a close correlation between the dates of the last pre-surgery visit and those of the actual decision to place the patient on the waiting list. Similar results were found for 12 of 15 individually studied procedures, including some orthopedic and gynecological procedures. Used judiciously, billing data is a timely, inexpensive and generally accurate method by which provincial governments could monitor trends in waiting times for appropriately selected surgical procedures.

Intraoperative high-field magnetic resonance imaging, multimodal neuronavigation, and intraoperative electrophysiological monitoring-guided surgery for treating supratentorial cavernomas.

PubMed

Li, Fang-Ye; Chen, Xiao-Lei; Xu, Bai-Nan

2016-09-01

To determine the beneficial effects of intraoperative high-field magnetic resonance imaging (MRI), multimodal neuronavigation, and intraoperative electrophysiological monitoring-guided surgery for treating supratentorial cavernomas. Twelve patients with 13 supratentorial cavernomas were prospectively enrolled and operated while using a 1.5 T intraoperative MRI, multimodal neuronavigation, and intraoperative electrophysiological monitoring. All cavernomas were deeply located in subcortical areas or involved critical areas. Intraoperative high-field MRIs were obtained for the intraoperative "visualization" of surrounding eloquent structures, "brain shift" corrections, and navigational plan updates. All cavernomas were successfully resected with guidance from intraoperative MRI, multimodal neuronavigation, and intraoperative electrophysiological monitoring. In 5 cases with supratentorial cavernomas, intraoperative "brain shift" severely deterred locating of the lesions; however, intraoperative MRI facilitated precise locating of these lesions. During long-term (>3 months) follow-up, some or all presenting signs and symptoms improved or resolved in 4 cases, but were unchanged in 7 patients. Intraoperative high-field MRI, multimodal neuronavigation, and intraoperative electrophysiological monitoring are helpful in surgeries for the treatment of small deeply seated subcortical cavernomas.

Review of temperature dependence of thermal properties, dielectric properties, and perfusion of biological tissues at hyperthermic and ablation temperatures.

PubMed

Rossmanna, Christian; Haemmerich, Dieter

2014-01-01

The application of supraphysiological temperatures (>40°C) to biological tissues causes changes at the molecular, cellular, and structural level, with corresponding changes in tissue function and in thermal, mechanical and dielectric tissue properties. This is particularly relevant for image-guided thermal treatments (e.g. hyperthermia and thermal ablation) delivering heat via focused ultrasound (FUS), radiofrequency (RF), microwave (MW), or laser energy; temperature induced changes in tissue properties are of relevance in relation to predicting tissue temperature profile, monitoring during treatment, and evaluation of treatment results. This paper presents a literature survey of temperature dependence of electrical (electrical conductivity, resistivity, permittivity) and thermal tissue properties (thermal conductivity, specific heat, diffusivity). Data of soft tissues (liver, prostate, muscle, kidney, uterus, collagen, myocardium and spleen) for temperatures between 5 to 90°C, and dielectric properties in the frequency range between 460 kHz and 3 GHz are reported. Furthermore, perfusion changes in tumors including carcinomas, sarcomas, rhabdomyosarcoma, adenocarcinoma and ependymoblastoma in response to hyperthmic temperatures up to 46°C are presented. Where appropriate, mathematical models to describe temperature dependence of properties are presented. The presented data is valuable for mathematical models that predict tissue temperature during thermal therapies (e.g. hyperthermia or thermal ablation), as well as for applications related to prediction and monitoring of temperature induced tissue changes.

Review of temperature dependence of thermal properties, dielectric properties, and perfusion of biological tissues at hyperthermic and ablation temperatures

PubMed Central

Rossmann, Christian; Haemmerich, Dieter

2016-01-01

The application of supraphysiological temperatures (>40°C) to biological tissues causes changes at the molecular, cellular, and structural level, with corresponding changes in tissue function and in thermal, mechanical and dielectric tissue properties. This is particularly relevant for image-guided thermal treatments (e.g. hyperthermia and thermal ablation) delivering heat via focused ultrasound (FUS), radiofrequency (RF), microwave (MW), or laser energy; temperature induced changes in tissue properties are of relevance in relation to predicting tissue temperature profile, monitoring during treatment, and evaluation of treatment results. This paper presents a literature survey of temperature dependence of electrical (electrical conductivity, resistivity, permittivity) and thermal tissue properties (thermal conductivity, specific heat, diffusivity). Data of soft tissues (liver, prostate, muscle, kidney, uterus, collagen, myocardium and spleen) for temperatures between 5 to 90°C, and dielectric properties in the frequency range between 460 kHz and 3 GHz are reported. Furthermore, perfusion changes in tumors including carcinomas, sarcomas, rhabdomyosarcoma, adenocarcinoma and ependymoblastoma in response to hyperthmic temperatures up to 46°C are presented. Where appropriate, mathematical models to describe temperature dependence of properties are presented. The presented data is valuable for mathematical models that predict tissue temperature during thermal therapies (e.g. hyperthermia or thermal ablation), as well as for applications related to prediction and monitoring of temperature induced tissue changes. PMID:25955712

Major thoracic surgery in Jehovah's witness: A multidisciplinary approach case report

PubMed Central

Rispoli, Marco; Bergaminelli, Carlo; Nespoli, Moana Rossella; Esposito, Mariana; Mattiacci, Dario Maria; Corcione, Antonio; Buono, Salvatore

2016-01-01

Introduction A bloodless surgery can be desirable also for non Jehovah’s witnesses patients, but requires a team approach from the very first assessment to ensure adequate planning. Presentation of the case Our patient, a Jehovah’s witnesses, was scheduled for right lower lobectomy due to pulmonary adenocarcinoma. Her firm denies to receive any kind of transfusions, forced clinicians to a bloodless management of the case. Discussion Before surgery a meticulous coagulopathy research and hemodynamic optimization are useful to prepare patient to operation. During surgery, controlled hypotension can help to obtain effective hemostasis. After surgery, clinicians monitored any possible active bleeding, using continuous noninvasive hemoglobin monitoring, limiting the blood loss due to serial in vitro testing. The optimization of cardiac index and delivery of oxygen were continued to grant a fast recovery. Conclusion Bloodless surgery is likely to gain popularity, and become standard practice for all patients. The need for transfusion should be targeted on individual case, avoiding strictly fixed limit often leading to unnecessary transfusion. PMID:27107502

Monitoring the gingival regeneration after aesthetic surgery with optical coherence tomography

NASA Astrophysics Data System (ADS)

Fernandes, Luana O.; Graça, Natalia D. R. L.; Melo, Luciana S. A.; Silva, Claudio H. V.; Gomes, Anderson S. L.

2016-02-01

The aim of this study was to use the Optical Coherence Tomography (OCT) technique working in spectral domain (Swept Source OCT at 1325 nm, Thorlabs, New Jersey, USA) to monitor the tissue repair in patients undergoing periodontal plastic surgery. The evaluations were done over a period of 60 days. It was observed that 15 days after periodontal surgery the gum was still in different healing process as compared to the observation after 60 days. Thus it is clear that, despite some technical limitations, the OCT is an efficient method in the evaluation of regeneration gingival.

The relationship between addictions and bariatric surgery for nurses in recovery.

PubMed

Fogger, Susanne A; McGuinness, Teena M

2012-01-01

Determinants of morbid obesity are complex and numerous, yet understanding the neurobiological underpinnings improves our knowledge of this serious issue. Emerging science supports a comparison of disordered eating with other addictive substances. The study used a sub-analysis of a cross-sectional study of nurses in a state-monitoring program. A study of 173 participants in a state-monitoring program for impaired nurses revealed that 14% (n= 25) had undergone bariatric surgery. Of these, 17 developed an addiction after surgery. Evidence suggests that some individuals may require additional treatment, similar to those with pharmacological addictions. © 2011 Wiley Periodicals, Inc.

Intraoperative cranial nerve monitoring.

PubMed

Harper, C Michel

2004-03-01

The purpose of intraoperative monitoring is to preserve function and prevent injury to the nervous system at a time when clinical examination is not possible. Cranial nerves are delicate structures and are susceptible to damage by mechanical trauma or ischemia during intracranial and extracranial surgery. A number of reliable electrodiagnostic techniques, including nerve conduction studies, electromyography, and the recording of evoked potentials have been adapted to the study of cranial nerve function during surgery. A growing body of evidence supports the utility of intraoperative monitoring of cranial nerve nerves during selected surgical procedures.

Non-invasive hemoglobin monitoring.

PubMed

Joseph, Bellal; Haider, Ansab; Rhee, Peter

2016-09-01

Technology has transformed the practice of medicine and surgery in particular over the last several decades. This change in practice has allowed diagnostic and therapeutic tests to be performed less invasively. Hemoglobin monitoring remains one of the most commonly performed diagnostic tests in the United States. Recently, non-invasive hemoglobin monitoring technology has gained popularity. The aim of this article is to review the principles of how this technology works, pros and cons, and the implications of non-invasive hemoglobin technology particularly in trauma surgery. Copyright © 2015 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

A pernicious agent affecting avocado in Israel: a novel symbiotic Fusarium sp. associated with the ambrosia beetle Euwallacea fornicatus

USDA-ARS?s Scientific Manuscript database

Since first recorded in Israel in 2009, the ambrosia beetle, Euwallacea fornicatus Eichhoff, has been shown to vector a fusarial pathogen of avocado (Persea Americana Miller) in its mandibular mycangia. Multilocus molecular phylogenetic analyses indicate the pathogen represents a novel symbiotic Fus...

Multimodal intraoperative neuromonitoring in corrective surgery for adolescent idiopathic scoliosis: Evaluation of 354 consecutive cases

PubMed Central

Kundnani, Vishal K; Zhu, Lisa; Tak, HH; Wong, HK

2010-01-01

Background: Multimodal intraoperative neuromonitoring is recommended during corrective spinal surgery, and has been widely used in surgery for spinal deformity with successful outcomes. Despite successful outcomes of corrective surgery due to increased safety of the patients with the usage of spinal cord monitoring in many large spine centers, this modality has not yet achieved widespread popularity. We report the analysis of prospectively collected intraoperative neurophysiological monitoring data of 354 consecutive patients undergoing corrective surgery for adolescent idiopathic scoliosis (AIS) to establish the efficacy of multimodal neuromonitoring and to evaluate comparative sensitivity and specificity. Materials and Methods: The study group consisted of 354 (female = 309; male = 45) patients undergoing spinal deformity corrective surgery between 2004 and 2008. Patients were monitored using electrophysiological methods including somatosensory-evoked potentials and motor-evoked potentials simultaneously. Results: Mean age of patients was 13.6 years (±2.3 years). The operative procedures involved were instrumented fusion of the thoracic/lumbar/both curves, Baseline somatosensory-evoked potentials (SSEP) and neurogenic motor-evoked potentials (NMEP) were recorded successfully in all cases. Thirteen cases expressed significant alert to prompt reversal of intervention. All these 13 cases with significant alert had detectable NMEP alerts, whereas significant SSEP alert was detected in 8 cases. Two patients awoke with new neurological deficit (0.56%) and had significant intraoperative SSEP + NMEP alerts. There were no false positives with SSEP (high specificity) but 5 patients with false negatives with SSEP (38%) reduced its sensitivity. There was no false negative with NMEP but 2 of 13 cases were false positive with NMEP (15%). The specificity of SSEP (100%) is higher than NMEP (96%); however, the sensitivity of NMEP (100%) is far better than SSEP (51%). Due to these results, the overall sensitivity, specificity and positive predictive value of combined multimodality neuromonitoring in this adult deformity series was 100, 98.5 and 85%, respectively. Conclusion: Neurogenic motor-evoked potential (NMEP) monitoring appears to be superior to conventional SSEP monitoring for identifying evolving spinal cord injury. Used in conjunction, the sensitivity and specificity of combined neuromonitoring may reach up to 100%. Multimodality monitoring with SSEP + NMEP should be the standard of care. PMID:20165679

Perils of intraoperative neurophysiological monitoring: analysis of "false-negative" results in spine surgeries.

PubMed

Tamkus, Arvydas A; Rice, Kent S; McCaffrey, Michael T

2018-02-01

Although some authors have published case reports describing false negatives in intraoperative neurophysiological monitoring (IONM), a systematic review of causes of false-negative IONM results is lacking. The objective of this study was to analyze false-negative IONM findings in spine surgery. This is a retrospective cohort analysis. A cohort of 109 patients with new postoperative neurologic deficits was analyzed for possible false-negative IONM reporting. The causes of false-negative IONM reporting were determined. From a cohort of 62,038 monitored spine surgeries, 109 consecutive patients with new postoperative neurologic deficits were reviewed for IONM alarms. Intraoperative neurophysiological monitoring alarms occurred in 87 of 109 surgeries. Nineteen patients with new postoperative neurologic deficits did not have an IONM alarm and surgeons were not warned. In addition, three patients had no interpretable IONM baseline data and no alarms were possible for the duration of the surgery. Therefore, 22 patients were included in the study. The absence of IONM alarms during these 22 surgeries had different origins: "true" false negatives where no waveform changes meeting the alarm criteria occurred despite the appropriate IONM (7); a postoperative development of a deficit (6); failure to monitor the pathway, which became injured (5); the absence of interpretable IONM baseline data which precluded any alarm (3); and technical IONM application issues (1). Overall, the rate of IONM method failing to predict the patient's outcome was very low (0.04%, 22/62,038). Minimizing false negatives requires the application of a proper IONM technique with the limitations of each modality considered in their selection and interpretation. Multimodality IONM provides the most inclusive information, and although it might be impractical to monitor every neural structure that can be at risk, a thorough preoperative consideration of available IONM modalities is important. Delayed development of postoperative deficits cannot be predicted by IONM. Absent baseline IONM data should be treated as an alarm when inconsistent with the patient's preoperative neurologic status. Alarm criteria for IONM may need to be refined for specific procedures and deserves continued study. Copyright © 2017 Elsevier Inc. All rights reserved.

Phytotoxicity Evaluation of Type B Trichothecenes Using a Chlamydomonas reinhardtii Model System

PubMed Central

Suzuki, Tadahiro; Iwahashi, Yumiko

2014-01-01

Type B trichothecenes, which consist of deoxynivalenol (DON) and nivalenol (NIV) as the major end products, are produced by phytotoxic fungi, such as the Fusarium species, and pollute arable fields across the world. The DON toxicity has been investigated using various types of cell systems or animal bioassays. The evaluation of NIV toxicity, however, has been relatively restricted because of its lower level compared with DON. In this study, the Chlamydomonas reinhardtii testing system, which has been reported to have adequate NIV sensitivity, was reinvestigated under different mycotoxin concentrations and light conditions. The best concentration of DON and NIV, and their derivatives, for test conditions was found to be 25 ppm (2.5 × 10−2 mg/mL). In all light test conditions, DON, NIV, and fusarenon-X (FusX) indicated significant growth inhibition regardless of whether a light source existed, or under differential wavelength conditions. FusX growth was also influenced by changes in photon flux density. These results suggest that C. reinhardtii is an appropriate evaluation system for type B trichothecenes. PMID:24476708

Liposarcoma: multimodality management and future targeted therapies

PubMed Central

Crago, Aimee M.; Dickson, Mark A.

2016-01-01

SYNOPSIS There are three biologic groups of liposarcoma: well- and dedifferentiated liposarcoma (WD/DDLS), myxoid/round cell liposarcoma (M/RCLS) and pleomorphic liposarcoma. WD/DDLS is characterized by amplification of 12q13-15 (including the oncogenes MDM2 and CDK4), M/RCLS by FUS-DDIT3 translocations, and pleomorphic liposarcoma by loss of p53 and Rb. In all three groups, complete surgical resection is central in treatment aimed at cure and is based on grade. Radiation can reduce risk of local recurrence in high-grade lesions or minimize surgical morbidity in the highly radiosensitive M/RCLS group. The biologic groups differ greatly in their chemosensitivity, so adjuvant chemotherapy is selectively utilized in chemosensitive histologies with metastatic potential (i.e. round cell and pleomorphic liposarcomas) but not in the relatively resistant subtype DDLS. An improved understanding of the genetic aberrations that lead to liposarcoma initiation is also allowing for the rapid development of targeted therapies for liposarcoma. Among such therapies are CDK4 inhibitors in WD/DDLS and trabectedin, which prevents FUS-DDIT3 binding to DNA, in M/RCLS. PMID:27591497

Duplex Real-Time PCR Method for the Differentiation of Cronobacter sakazakii and Cronobacter malonaticus.

PubMed

Li, Xiaofang; Cui, Jinghua; Du, Xiaoli; Cui, Zhigang; Huang, Yibing; Kan, Biao

2017-01-01

Cronobacter sakazakii and Cronobacter malonaticus are the most common species of Cronobacter , so it is necessary to detect the two species as soon as possible in surveillance programs. We developed a real-time PCR method for identifying C. sakazakii and C. malonaticus from the genus Cronobacter . In this study, the two pairs of primers and probes were designed, targeting 16S rRNA and fusA, respectively. The specificity of the real-time PCR assay was validated with 112 strains of Cronobacter , including 56 C. sakazakii , 32 C. malonaticus , 16 Cronobacter dublinensis , 6 Cronobacter turicensis , and 2 Cronobacter muytjensii . The results showed that C. sakazakii and C. malonaticus were all correctly identified, consistent with the results of another method by analyzing the clustering of the fusA sequence. The detection limit for pure culture was 10 2 CFU/ml and 10 3 CFU/g for artificially contaminated rehydrated powdered infant formula. Therefore, the developed real-time PCR was a rapid, sensitive, and reliable method for the identification of C. sakazakii and C. malonaticus .

Thermodynamic Investigation of Carbamazepine-Saccharin Co-Crystal Polymorphs.

PubMed

Pagire, Sudhir K; Jadav, Niten; Vangala, Venu R; Whiteside, Benjamin; Paradkar, Anant

2017-08-01

Polymorphism in active pharmaceutical ingredients can be regarded as critical for the potential that crystal form can have on the quality, efficacy, and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII has been performed using thermokinetic methods and systematically characterized by differential scanning calorimetry, powder X-ray diffraction, solubility, and slurry measurements. According to the heat of fusion rule by Burger and Ramberger, FI (ΔH fus  = 121.1 J/g; melting point, 172.5°C) and FII (ΔH fus  = 110.3 J/g; melting point, 164.7°C) are monotropically related. The solubility and van't Hoff plot results suggest FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat-induced stresses; however, FII converts to FI during solution-mediated transformation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Prion-like domains in RNA binding proteins are essential for building subnuclear paraspeckles

PubMed Central

Hennig, Sven; Kong, Geraldine; Mannen, Taro; Sadowska, Agata; Kobelke, Simon; Blythe, Amanda; Knott, Gavin J.; Iyer, K. Swaminathan; Ho, Diwei; Newcombe, Estella A.; Hosoki, Kana; Goshima, Naoki; Kawaguchi, Tetsuya; Hatters, Danny; Trinkle-Mulcahy, Laura; Hirose, Tetsuro; Bond, Charles S.

2015-01-01

Prion-like domains (PLDs) are low complexity sequences found in RNA binding proteins associated with the neurodegenerative disorder amyotrophic lateral sclerosis. Recently, PLDs have been implicated in mediating gene regulation via liquid-phase transitions that drive ribonucleoprotein granule assembly. In this paper, we report many PLDs in proteins associated with paraspeckles, subnuclear bodies that form around long noncoding RNA. We mapped the interactome network of paraspeckle proteins, finding enrichment of PLDs. We show that one protein, RBM14, connects key paraspeckle subcomplexes via interactions mediated by its PLD. We further show that the RBM14 PLD, as well as the PLD of another essential paraspeckle protein, FUS, is required to rescue paraspeckle formation in cells in which their endogenous counterpart has been knocked down. Similar to FUS, the RBM14 PLD also forms hydrogels with amyloid-like properties. These results suggest a role for PLD-mediated liquid-phase transitions in paraspeckle formation, highlighting this nuclear body as an excellent model system for understanding the perturbation of such processes in neurodegeneration. PMID:26283796

Transducer design and characterization for dorsal-based ultrasound exposure and two-photon imaging of in vivo blood-brain barrier disruption in a rat model.

PubMed

Nhan, Tam; Burgess, Alison; Hynynen, Kullervo

2013-07-01

Focused ultrasound (FUS) and microbubbles have been used effectively for transient, noninvasive blood¿ brain barrier disruption (BBBD). The use of two-photon microscopy (2PM) imaging of BBBD can provide valuable insights into the associated cellular mechanisms and fundamental biological effects. Coupling a thin ring-shaped transducer to a coverslip offers a robust solution for simultaneous dorsal application of FUS for BBBD and in vivo 2PM imaging of the cerebral microvasculature under treatment conditions. Two modes of vibration (thickness and height) from the transducer configuration were investigated for BBBD in an animal model. With the transducer operating in the thickness mode at 1.2 MHz frequency, shallow and localized BBBD near the cortical surface of animal brain was detected via 2PM and confirmed by Evans blue (EB) extravasation. Acoustic pressures ranging from 0.2 to 0.8 MPa were tested and the probability for successful BBBD was identified. Two distinct types of disruption characterized by different leakage kinetics were observed and appeared to be dependent on acoustic pressure.

Real time monitoring of risk-adjusted paediatric cardiac surgery outcomes using variable life-adjusted display: implementation in three UK centres

PubMed Central

Pagel, Christina; Utley, Martin; Crowe, Sonya; Witter, Thomas; Anderson, David; Samson, Ray; McLean, Andrew; Banks, Victoria; Tsang, Victor; Brown, Katherine

2013-01-01

Objective To implement routine in-house monitoring of risk-adjusted 30-day mortality following paediatric cardiac surgery. Design Collaborative monitoring software development and implementation in three specialist centres. Patients and methods Analyses incorporated 2 years of data routinely audited by the National Institute of Cardiac Outcomes Research (NICOR). Exclusion criteria were patients over 16 or undergoing non-cardiac or only catheter procedures. We applied the partial risk adjustment in surgery (PRAiS) risk model for death within 30 days following surgery and generated variable life-adjusted display (VLAD) charts for each centre. These were shared with each clinical team and feedback was sought. Results Participating centres were Great Ormond Street Hospital, Evelina Children's Hospital and The Royal Hospital for Sick Children in Glasgow. Data captured all procedures performed between 1 January 2010 and 31 December 2011. This incorporated 2490 30-day episodes of care, 66 of which were associated with a death within 30 days.The VLAD charts generated for each centre displayed trends in outcomes benchmarked to recent national outcomes. All centres ended the 2-year period within four deaths from what would be expected. The VLAD charts were shared in multidisciplinary meetings and clinical teams reported that they were a useful addition to existing quality assurance initiatives. Each centre is continuing to use the prototype software to monitor their in-house surgical outcomes. Conclusions Timely and routine monitoring of risk-adjusted mortality following paediatric cardiac surgery is feasible. Close liaison with hospital data managers as well as clinicians was crucial to the success of the project. PMID:23564473

Beyond Sociocultural Influence: Self-monitoring and Self-awareness as Predictors of Women's Interest in Breast Cosmetic Surgery.

PubMed

Matera, Camilla; Nerini, Amanda; Giorgi, Claudia; Baroni, Duccio; Stefanile, Cristina

2015-06-01

The aim of the present research was to analyze the role of self-awareness, self-monitoring, perceived media pressures, and peer attributions on the consideration of breast cosmetic surgery among women. The internalization of thin ideals was taken into account as a key moderating variable. Participants were 132 Italian women (mean age = 33.62), who completed a questionnaire aimed at measuring the variables of interest. Path analysis was used to test our hypotheses. The results indicated that perceived media pressure, self-monitoring, and peer attributions influenced participants' interest in breast modification procedures through the internalization of thin ideals. Self-awareness (both private and public) had a direct effect on women's consideration of breast cosmetic surgery. This research is one of few analyzing how specific aspects of the self could influence women's interest in cosmetic surgery. These findings contribute to the understanding of the reasons that trigger women's interest in cosmetic surgery. Not only sociocultural influences contribute to the development of favorable attitudes toward cosmetic surgery, but also specific aspects of the self have a relevant role. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the table of contents or the online Instructions to Authors www.springer.com/00266 .

Multi-modality safety assessment of blood-brain barrier opening using focused ultrasound and definity microbubbles: a short-term study.

PubMed

Baseri, Babak; Choi, James J; Tung, Yao-Sheng; Konofagou, Elisa E

2010-09-01

As a potentially viable method of brain drug delivery, the safety profile of blood-brain barrier (BBB) opening using focused ultrasound (FUS) and ultrasound contrast agents (UCA) needs to be established. In this study, we provide a short-term (30-min or 5-h survival) histological assessment of murine brains undergoing FUS-induced BBB opening. Forty-nine mice were intravenously injected with Definity microbubbles (0.05 microL/kg) and sonicated under the following parameters: frequency of 1.525 MHz, pulse length of 20 ms, pulse repetition frequency of 10 Hz, peak rarefactional acoustic pressures of 0.15-0.98 MPa and two 30-s sonication intervals with an intermittent 30-s delay. The BBB opening threshold was found to be 0.15-0.3 MPa based on fluorescence and magnetic resonance imaging of systemically injected tracers. Analysis of three histological measures in hematoxylin and eosin-stained sections revealed the safest acoustic pressure to be within the range of 0.3-0.46 MPa in all examined time periods post sonication. Across different pressure amplitudes, only the samples 30 min post opening showed significant difference (p < 0.05) in the average number of distinct damaged sites, microvacuolated sites, dark neurons and sites with extravasated erythrocytes. Enhanced fluorescence around severed microvessels was also noted and found to be associated with the largest tissue effects, whereas mildly diffuse BBB opening with uniform fluorescence in the parenchyma was associated with no or mild tissue injury. Region-specific areas of the sonicated brain (thalamus, hippocampal fissure, dentate gyrus and CA3 area of hippocampus) exhibited variation in fluorescence intensity based on the position, orientation and size of affected vessels. The results of this short-term histological analysis demonstrated the feasibility of a safe FUS-UCA-induced BBB opening under a specific set of sonication parameters and provided new insights on the mechanism of BBB opening.

The reduction in treatment efficiency at high acoustic powers during MR-guided transcranial focused ultrasound thalamotomy for Essential Tremor.

PubMed

Hughes, Alec; Huang, Yuexi; Schwartz, Michael L; Hynynen, Kullervo

2018-05-14

To analyze clinical data indicating a reduction in the induced energy-temperature efficiency relationship during transcranial focused ultrasound (FUS) Essential Tremor (ET) thalamotomy treatments at higher acoustic powers, establish its relationship with the spatial distribution of the focal temperature elevation, and explore its cause. A retrospective observational study of patients (n = 19) treated between July 2015 and August 2016 for (ET) by FUS thalamotomy was performed. These data were analyzed to compare the relationships between the applied power, the applied energy, the resultant peak temperature achieved in the brain, and the dispersion of the focal volume. Full ethics approval was received and all patients provided signed informed consent forms before the initiation of the study. Computer simulations, animal experiments, and clinical system tests were performed to determine the effects of skull heating, changes in brain properties and transducer acoustic output, respectively. All animal procedures were approved by the Animal Care and Use Committee and conformed to the guidelines set out by the Canadian Council on Animal Care. MATLAB was used to perform statistical analysis. The reduction in the energy efficiency relationship during treatment correlates with the increase in size of the focal volume at higher sonication powers. A linear relationship exists showing that a decrease in treatment efficiency correlates positively with an increase in the focal size over the course of treatment (P < 0.01), supporting the hypothesis of transient skull and tissue heating causing acoustic aberrations leading to a decrease in efficiency. Changes in thermal conductivity, perfusion, absorption rates in the brain, as well as ultrasound transducer acoustic output levels were found to have minimal effects on the observed reduction in efficiency. The reduction in energy-temperature efficiency during high-power FUS treatments correlated with observed increases in the size of the focal volume and is likely caused by transient changes in the tissue and skull during heating. © 2018 American Association of Physicists in Medicine.

Identifying the Inertial Cavitation Pressure Threshold and Skull Effects in a Vessel Phantom Using Focused Ultrasound and Microbubbles

NASA Astrophysics Data System (ADS)

Tung, Yao-Sheng; Choi, James J.; Konofagou, Elisa E.

2010-03-01

Using Focused Ultrasound (FUS) and microbubbles to open the blood-brain barrier (BBB) has been shown promising for brain drug delivery. However, the exact mechanism behind the opening remains unknown. Here, the effects of the murine skull on the threshold of inertial cavitation were investigated. In order to investigate the pressure threshold for inertial cavitation of preformed microbubbles during sonication, passive cavitation detection in conjunction with B-mode imaging was used. A cylindrical vessel with a 610-μm diameter inside a polyacrylamide gel was generated within a polyacrylamide gel to simulate large blood vessels. Definity® (Lantheus Medical Imaging, MA, USA) microbubbles with a 1.1-3.3 μm in diameter at 2.5×107 bubbles/mL were injected into the channel before sonication (frequency: 1.525 MHz; pulse length: 100 cycles; PRF: 10 Hz; sonication duration: 2 s) through an excised mouse skull. A cylindrically focused hydrophone, confocal with the FUS transducer, acted as a passive cavitation detector (PCD) to identify the threshold. A 7.5 MHz linear array with the field-of-view perpendicular to the axial length of the FUS beam was also used to image the occurrence of bubble fragmentation. The broadband spectral response acquired at the passive cavitation detector (PCD) and the B-mode images identified the occurrence and location of the inertial cavitation, respectively. Findings indicated that the peak-rarefactional pressure threshold was approximately equal to 0.45 MPa at the presence or the absence of the skull. However, the skull induced 10-50% lower inertial cavitation dose. Mouse skulls did not affect the pressure threshold of inertial cavitation but resulted in a lower inertial cavitation dose. The broadband response could be captured through the murine skull, so the same PCD setup can be used in future in vivo applications.

Intraoperative cerebral blood flow imaging of rodents

NASA Astrophysics Data System (ADS)

Li, Hangdao; Li, Yao; Yuan, Lu; Wu, Caihong; Lu, Hongyang; Tong, Shanbao

2014-09-01

Intraoperative monitoring of cerebral blood flow (CBF) is of interest to neuroscience researchers, which offers the assessment of hemodynamic responses throughout the process of neurosurgery and provides an early biomarker for surgical guidance. However, intraoperative CBF imaging has been challenging due to animal's motion and position change during the surgery. In this paper, we presented a design of an operation bench integrated with laser speckle contrast imager which enables monitoring of the CBF intraoperatively. With a specially designed stereotaxic frame and imager, we were able to monitor the CBF changes in both hemispheres during the rodent surgery. The rotatable design of the operation plate and implementation of online image registration allow the technician to move the animal without disturbing the CBF imaging during surgery. The performance of the system was tested by middle cerebral artery occlusion model of rats.

Incidence of intraoperative seizures during motor evoked potential monitoring in a large cohort of patients undergoing different surgical procedures.

PubMed

Ulkatan, Sedat; Jaramillo, Ana Maria; Téllez, Maria J; Kim, Jinu; Deletis, Vedran; Seidel, Kathleen

2017-04-01

OBJECTIVE The purpose of this study was to investigate the incidence of seizures during the intraoperative monitoring of motor evoked potentials (MEPs) elicited by electrical brain stimulation in a wide spectrum of surgeries such as those of the orthopedic spine, spinal cord, and peripheral nerves, interventional radiology procedures, and craniotomies for supra- and infratentorial tumors and vascular lesions. METHODS The authors retrospectively analyzed data from 4179 consecutive patients who underwent surgery or an interventional radiology procedure with MEP monitoring. RESULTS Of 4179 patients, only 32 (0.8%) had 1 or more intraoperative seizures. The incidence of seizures in cranial procedures, including craniotomies and interventional neuroradiology, was 1.8%. In craniotomies in which transcranial electrical stimulation (TES) was applied to elicit MEPs, the incidence of seizures was 0.7% (6/850). When direct cortical stimulation was additionally applied, the incidence of seizures increased to 5.4% (23/422). Patients undergoing craniotomies for the excision of extraaxial brain tumors, particularly meningiomas (15 patients), exhibited the highest risk of developing an intraoperative seizure (16 patients). The incidence of seizures in orthopedic spine surgeries was 0.2% (3/1664). None of the patients who underwent surgery for conditions of the spinal cord, neck, or peripheral nerves or who underwent cranial or noncranial interventional radiology procedures had intraoperative seizures elicited by TES during MEP monitoring. CONCLUSIONS In this largest such study to date, the authors report the incidence of intraoperative seizures in patients who underwent MEP monitoring during a wide spectrum of surgeries such as those of the orthopedic spine, spinal cord, and peripheral nerves, interventional radiology procedures, and craniotomies for supra- and infratentorial tumors and vascular lesions. The low incidence of seizures induced by electrical brain stimulation, particularly short-train TES, demonstrates that MEP monitoring is a safe technique that should not be avoided due to the risk of inducing seizures.

Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab.

PubMed

Papamichael, Konstantinos; Chachu, Karen A; Vajravelu, Ravy K; Vaughn, Byron P; Ni, Josephine; Osterman, Mark T; Cheifetz, Adam S

2017-10-01

Monitoring serum concentrations of tumor necrosis factor antagonists in patients receiving these drugs as treatment for inflammatory bowel disease (IBD), also called therapeutic drug monitoring, is performed either after patient loss of response (reactive drug monitoring) or in patients in clinical remission in which the drug is titrated to a target concentration (proactive drug monitoring). We compared long-term outcomes of patients with IBD undergoing proactive vs reactive monitoring of serum concentrations of infliximab. We performed a multicenter, retrospective study of 264 consecutive patients with IBD (167 with Crohn's disease) receiving infliximab maintenance therapy. The subjects received proactive (n = 130) or reactive (n = 134) drug monitoring, based on measurements of first infliximab concentration and antibodies to infliximab, from September 2006 to January 2015; they were followed through December 2015 (median time of 2.4 years). We analyzed time to treatment failure, first IBD-related surgery or hospitalization, serious infusion reaction, and detection of antibodies to infliximab. Treatment failure was defined as drug discontinuation for loss of response or serious adverse event, or need for surgery. Multiple Cox regression analysis independently associated proactive drug monitoring, compared with reactive monitoring, with reduced risk for treatment failure (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.09-0.27; P < .001), IBD-related surgery (HR, 0.30; 95% CI, 0.11-0.80; P = .017), IBD-related hospitalization (HR, 0.16; 95% CI, 0.07-0.33; P < .001), antibodies to infliximab (HR, 0.25; 95% CI, 0.07-0.84; P = .025), and serious infusion reaction (HR, 0.17; 95% CI, 0.04-0.78; P = .023). In a retrospective analysis of patients with IBD receiving proactive vs reactive monitoring of serum concentration of infliximab, proactive monitoring was associated with better clinical outcomes, including greater drug durability, less need for IBD-related surgery or hospitalization, and lower risk of antibodies to infliximab or serious infusion reactions. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Early Experience with Combining Awake Craniotomy and Intraoperative Navigable Ultrasound for Resection of Eloquent Region Gliomas.

PubMed

Moiyadi, Aliasgar; Shetty, Prakash

2017-03-01

Introduction  Optimal resection of tumors in eloquent locations requires a combination of intraoperative imaging and functional monitoring during surgery. Combining awake surgery with intraoperative magnetic resonanceis logistically challenging. Navigable ultrasound (US) is a useful alternative in such cases. Methods  A total of 22 subjects with eloquent tumors were operated on (1 intended biopsy and 21 intended radical resections) using combined modality three-dimensional (3D) US and awake craniotomy with intraoperative clinical monitoring. We describe the technical details for these cases specifically addressing the feasibility of combining the two modalities. Results  US was used for resection control in 18 cases. There were technical limitations in three cases. Transient intraoperative worsening was encountered in eight, necessitating premature termination of the procedure. All patients tolerated the awake procedure well. Mean duration of the surgery was 3.2 hours. Radical resections were obtained in 14 of 18 where this was intended and in 12 of the 13 where there was no adverse intraoperative monitoring event prompting premature termination of the resection. Conclusions  Combining awake surgery with 3DUS is feasible and beneficial. It does not entail any additional surgical workflow modification or patient discomfort. This combined modality intraoperative monitoring can be beneficial for eloquent region tumors. Georg Thieme Verlag KG Stuttgart · New York.

Clinical guidelines for management of diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion after pituitary surgery.

PubMed

Lamas, Cristina; del Pozo, Carlos; Villabona, Carles

2014-04-01

Changes in water metabolism and regulation of vasopressin (AVP) or antidiuretic hormone (ADH) are common complications of pituitary surgery. The scarcity of studies comparing different treatment and monitoring strategies for these disorders and the lack of prior clinical guidelines makes it difficult to provide recommendations following a methodology based on grades of evidence. This study reviews the pathophysiology of diabetes insipidus and inappropriate ADH secretion after pituitary surgery, and is intended to serve as a guide for their diagnosis, differential diagnosis, treatment, and monitoring. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

Use of viscoelastic haemostatic assay in emergency and elective surgery.

PubMed

Yeung, Maximus C F; Tong, Steven Y T; Tong, Paul Y W; Cheung, Billy H H; Ng, Joanne Y W; Leung, Gilberto K K

2015-02-01

To review the current evidence for the use of viscoelastic haemostatic assays in different surgical settings including trauma, cardiac surgery, liver transplantation, as well as the monitoring of antiplatelet agents and anticoagulants prior to surgery. PubMed database. Key words for the literature search were "thromboelastography" or "ROTEM" in combination with "trauma", "antiplatelet", "cardiac surgery", "liver transplantation" or "anticoagulants". Original and major review articles related to the use of viscoelastic haemostatic assays. Haemostatic function is a critical factor determining patient outcomes in emergency or elective surgery. The increasing use of antiplatelet agents and anticoagulants has potentially increased the risks of haemorrhages and the need for transfusion. Conventional coagulation tests have limitations in detecting haemostatic dysfunctions in subgroups of patients and are largely ineffective in diagnosing hyperfibrinolysis. The viscoelastic haemostatic assays are potentially useful point-of-care tools that provide information on clot formation, clot strength, and fibrinolysis, as well as to guide goal-directed transfusion and antifibrinolytic therapy. They may also be used to monitor antiplatelet and anticoagulant therapy. However, standardisation of techniques and reference ranges is required before these tests can be widely used in different clinical settings. Viscoelastic haemostatic assays, as compared with conventional coagulation tests, are better for detecting coagulopathy and are the only tests that can provide rapid diagnosis of hyperfibrinolysis. Goal-directed administration of blood products based on the results of viscoelastic haemostatic assays was associated with reduction in allogeneic blood product transfusions in trauma, cardiac surgery, and liver transplantation cases. However, there is currently no evidence to support the routine use of viscoelastic haemostatic assays for monitoring platelet function prior to surgery.

Postoperative vocal fold palsy in patients undergoing thyroid surgery with continuous or intermittent nerve monitoring.

PubMed

Schneider, R; Sekulla, C; Machens, A; Lorenz, K; Nguyen Thanh, P; Dralle, H

2015-10-01

Continuous monitoring of electromyographic (EMG) amplitudes of the vocal muscles detects impending injury of the recurrent laryngeal nerve (RLN) during thyroid operations earlier than intermittent EMG monitoring. This may alert the surgeon to stop a manoeuvre causing stretching or pressure on the RLN, with better recovery of nerve function. Patients with intact preoperative RLN function who underwent thyroid surgery for benign disease between January 2011 and September 2014 under continuous intraoperative nerve monitoring (CIONM) or intermittent intraoperative nerve monitoring (IIONM) were included in this observational study conducted at a tertiary surgical centre. For CIONM, combined EMG events indicative of imminent nerve injury were defined as an EMG amplitude decrease of 50 per cent or more and a latency increase of 10 per cent relative to baseline values. The rates of early and permanent palsy for the two groups of patients were compared. There were 1526 patients, 788 of whom (1314 nerves at risk) underwent thyroid surgery using CIONM and 738 (965 nerves at risk) had IIONM. With the use of CIONM, 63 (82 per cent) of 77 combined events were reversible during the operation. No permanent vocal fold palsy occurred with CIONM, whereas four unilateral permanent vocal fold palsies (0·4 per cent) were diagnosed after IIONM (P = 0·019). Operation with CIONM resulted in fewer permanent vocal fold palsies compared with IIONM after thyroid surgery in patients with benign disease. © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.

Ergonomics in thoracoscopic surgery: results of a survey among thoracic surgeons†

PubMed Central

Welcker, Katrin; Kesieme, Emeka B.; Internullo, Eveline; Kranenburg van Koppen, Laura J.C.

2012-01-01

OBJECTIVES The frequent and prolonged use of thoracoscopic equipment raises ergonomic risks which may cause physical distress. We aimed to determine the relationship between ergonomic problems encountered in thoracoscopic surgery and physical distress among thoracic surgeons. METHODS An online questionnaire which investigated personal factors, product factors, interaction factors and physical discomfort was sent to all members of the European Society of Thoracic Surgeons (ESTS). RESULTS Of the respondents, 2.4% indicated that a one arm's length should be the optimal distance between the surgeon and the monitor. Only 2.4% indicated that the monitor should be positioned below the eye level of the surgeon. Most of the respondents agreed, partially to fully, that they experienced neck discomfort because of inappropriate monitor height, bad monitor position and bad table height. Most respondents experienced numb fingers and shoulder discomfort due to instrument manipulation. Most of the respondents (77.1%) experienced muscle fatigue to some extent due to a static posture during thoracoscopic surgery. The majority of respondents (81.9, 76.3 and 83.2% respectively) indicated that they had varying degrees of discomfort mainly in the neck, shoulder and back. Some 94.4% of respondents were unaware of any guidelines concerning table height, monitor and instrument placement for endoscopic surgery. CONCLUSIONS Most thoracic surgeons in Europe are unaware of ergonomic guidelines and do not practise them, hence they suffer varying degrees of physical discomfort arising from ergonomic issues. PMID:22586071

Monitoring trends in waiting periods in Canada for elective surgery: validation of a method using administrative data

PubMed Central

Shortt, Samuel E.D.; Shaw, Ralph A.; Elliott, David; Mackillop, William J.

2004-01-01

Background Provincial governments require timely, economical methods to monitor surgical waiting periods. Although use of prospective procedure-specific registers would be the ideal method, a less elaborate system has been proposed that is based on physician billing data. This study assessed the validity of using the date of the last service billed prior to surgery as a proxy for the beginning of the post-referral, pre-surgical waiting period. Method We examined charts for 31 824 elective surgical encounters between 1992 and 1996 at an Ontario teaching hospital. The date of the last service before surgery (the last billing date) was compared with the date of the consultant's letter indicating a decision to book surgery (i.e., to begin waiting). Results Several surgical specialties (but excluding cardiac, orthopedic and gynecologic) had a close correlation between the dates of the last pre-surgery visit and those of the actual decision to place the patient on the waiting list. Similar results were found for 12 of 15 individually studied procedures, including some orthopedic and gynecological procedures. Conclusion Used judiciously, billing data is a timely, inexpensive and generally accurate method by which provincial governments could monitor trends in waiting times for appropriately selected surgical procedures. PMID:15264378

Post-Surgical Clinical Monitoring of Soft Tissue Wound Healing in Periodontal and Implant Surgery

PubMed Central

Pippi, Roberto

2017-01-01

Clinical features of surgical soft tissue wound healing in dentistry have been rarely discussed in the international literature. The aim of the present paper is to highlight both the main clinical findings of surgical wound healing, especially in periodontal and implant dentistry, and the wound healing monitoring procedures which should be followed. Wound inspection after careful food and plaque debridement is the essential part of wound healing monitoring. Periodontal and peri-implant probing should be performed only after tissue healing has been completed and not on a weekly basis in peri-implant tissue monitoring. Telephone follow-up and patient self-assessment scales can also be used the days following surgery to monitor the most common surgical complications such as pain, swelling, bleeding, and bruising. Wound healing monitoring is an important concern in all surgical procedures since it allows to identify signs or/and symptoms possibly related to surgical complications. PMID:28824306

Post-Surgical Clinical Monitoring of Soft Tissue Wound Healing in Periodontal and Implant Surgery.

PubMed

Pippi, Roberto

2017-01-01

Clinical features of surgical soft tissue wound healing in dentistry have been rarely discussed in the international literature. The aim of the present paper is to highlight both the main clinical findings of surgical wound healing, especially in periodontal and implant dentistry, and the wound healing monitoring procedures which should be followed. Wound inspection after careful food and plaque debridement is the essential part of wound healing monitoring. Periodontal and peri-implant probing should be performed only after tissue healing has been completed and not on a weekly basis in peri-implant tissue monitoring. Telephone follow-up and patient self-assessment scales can also be used the days following surgery to monitor the most common surgical complications such as pain, swelling, bleeding, and bruising. Wound healing monitoring is an important concern in all surgical procedures since it allows to identify signs or/and symptoms possibly related to surgical complications.

Cardiac surgery during pregnancy: continuous fetal monitoring using umbilical artery Doppler flow velocity indices.

PubMed

Mishra, Manisha; Sawhney, Ravindra; Kumar, Anil; Bapna, Kumar Ramesh; Kohli, Vijay; Wasir, Harpreet; Trehan, Naresh

2014-01-01

The fetal death rate associated with cardiac surgery with cardiopulmonary bypass (CPB) is as high as 9.5-29%. We report continuous monitoring of fetal heart rate and umbilical artery flow-velocity waveforms by transvaginal ultrasonography and their analyses in relation to events of the CPB in two cases in second trimester of pregnancy undergoing mitral valve replacement. Our findings suggest that the transition of circulation from corporeal to extracorporeal is the most important event during surgery; the associated decrease in mean arterial pressure (MAP) at this stage potentially has deleterious effects on the fetus, which get aggravated with the use of vasopressors. We suggest careful management of CPB at this stage, which include partial controlled CPB at initiation and gradual transition to full CPB; this strategy maintains high MAP and avoids the use of vasopressors. Maternal and fetal monitoring can timely recognize the potential problems and provide window for the required treatment.

[Recent advances of monitoring and glycaemia control during early postoperative period in patients after pancreas surgery].

PubMed

Lishova, E A; Nikoda, V V; Bondarenko, A V; Ragozin, A K; Skipenko, O G

2013-01-01

Recently new technologies of diagnostics and correction of carbohydrates metabolism disturbances are introduced in the ICU to improve the safety for patients during intensive care. 33 patients after pancreas surgery were included into the study 13 patients (39%) had underlying diabetes mellitus. Glucose level changes in the interstitial liquid of the subcutaneous fat during postoperative period were monitored by system of CGM Medtronic MiniMed Guardian RT, MiniMed Paradigm Real-time. Valid values of glucose were from 4.1 to 10.1 mmol/L. Episodes of glucose level increasing occurred in 94% of patients in postoperative period after pancreas surgery. Average level of glucose was within the limits of valid values. However in 64% of cases patients needed insulin therapy Used systems of continuous glucose monitoring in the ICU allow improving the safety for patients receiving artificial nutrition and intravenous insulin therapy.

Efficacy of intraoperative monitoring of transcranial electrical stimulation-induced motor evoked potentials and spontaneous electromyography activity to identify acute-versus delayed-onset C-5 nerve root palsy during cervical spine surgery: clinical article.

PubMed

Bhalodia, Vidya M; Schwartz, Daniel M; Sestokas, Anthony K; Bloomgarden, Gary; Arkins, Thomas; Tomak, Patrick; Gorelick, Judith; Wijesekera, Shirvinda; Beiner, John; Goodrich, Isaac

2013-10-01

Deltoid muscle weakness due to C-5 nerve root injury following cervical spine surgery is an uncommon but potentially debilitating complication. Symptoms can manifest upon emergence from anesthesia or days to weeks following surgery. There is conflicting evidence regarding the efficacy of spontaneous electromyography (spEMG) monitoring in detecting evolving C-5 nerve root compromise. By contrast, transcranial electrical stimulation-induced motor evoked potential (tceMEP) monitoring has been shown to be highly sensitive and specific in identifying impending C-5 injury. In this study the authors sought to 1) determine the frequency of immediate versus delayed-onset C-5 nerve root injury following cervical spine surgery, 2) identify risk factors associated with the development of C-5 palsies, and 3) determine whether tceMEP and spEMG neuromonitoring can help to identify acutely evolving C-5 injury as well as predict delayed-onset deltoid muscle paresis. The authors retrospectively reviewed the neuromonitoring and surgical records of all patients who had undergone cervical spine surgery involving the C-4 and/or C-5 level in the period from 2006 to 2008. Real-time tceMEP and spEMG monitoring from the deltoid muscle was performed as part of a multimodal neuromonitoring protocol during all surgeries. Charts were reviewed to identify patients who had experienced significant changes in tceMEPs and/or episodes of neurotonic spEMG activity during surgery, as well as those who had shown new-onset deltoid weakness either immediately upon emergence from the anesthesia or in a delayed fashion. Two hundred twenty-nine patients undergoing 235 cervical spine surgeries involving the C4-5 level served as the study cohort. The overall incidence of perioperative C-5 nerve root injury was 5.1%. The incidence was greatest (50%) in cases with dual corpectomies at the C-4 and C-5 spinal levels. All patients who emerged from anesthesia with deltoid weakness had significant and unresolved changes in tceMEPs during surgery, whereas only 1 had remarkable spEMG activity. Sensitivity and specificity of tceMEP monitoring for identifying acute-onset deltoid weakness were 100% and 99%, respectively. By contrast, sensitivity and specificity for spEMG were only 20% and 92%, respectively. Neither modality was effective in identifying patients who demonstrated delayed-onset deltoid weakness. The risk of new-onset deltoid muscle weakness following cervical spine surgery is greatest for patients undergoing 2-level corpectomies involving C-4 and C-5. Transcranial electrical stimulation-induced MEP monitoring is a highly sensitive and specific technique for detecting C-5 radiculopathy that manifests immediately upon waking from anesthesia. While the absence of sustained spEMG activity does not rule out nerve root irritation, the presence of excessive neurotonic discharges serves both to alert the surgeon of such potentially injurious events and to prompt neuromonitoring personnel about the need for additional tceMEP testing. Delayed-onset C-5 nerve root injury cannot be predicted by intraoperative neuromonitoring via either modality.

Best Practices for Robotic Surgery Programs

PubMed Central

Goldenberg, David; Winder, Joshua S.; Juza, Ryan M.; Lyn-Sue, Jerome R.

2017-01-01

Background and Objectives: Robotic surgical programs are increasing in number. Efficient methods by which to monitor and evaluate robotic surgery teams are needed. Methods: Best practices for an academic university medical center were created and instituted in 2009 and continue to the present. These practices have led to programmatic development that has resulted in a process that effectively monitors leadership team members; attending, resident, fellow, and staff training; credentialing; safety metrics; efficiency; and case volume recommendations. Results: Guidelines for hospitals and robotic directors that can be applied to one's own robotic surgical services are included with examples of management of all aspects of a multispecialty robotic surgery program. Conclusion: The use of these best practices will ensure a robotic surgery program that is successful and well positioned for a safe and productive environment for current clinical practice. PMID:28729780

A Pilot Study of a Novel Automated Somatosensory Evoked Potential (SSEP) Monitoring Device for Detection and Prevention of Intraoperative Peripheral Nerve Injury in Total Shoulder Arthroplasty Surgery.

PubMed

Chui, Jason; Murkin, John M; Drosdowech, Darren

2018-05-21

Peripheral nerve injury is a potentially devastating complication after total shoulder arthroplasty (TSA) surgery. This pilot study aimed to assess the feasibility of using an automated somatosensory evoked potential (SSEP) device to provide a timely alert/intervention to minimize intraoperative nerve insults during TSA surgery. A prospective, single-arm, observational study was conducted in a single university hospital. The attending anesthesiologist monitored the study participants using the EPAD automated SSEP device and an intervention was made if there was an alert during TSA surgery. The median, radial, and ulnar nerve SSEP on the operative arm, as well as the median nerve SSEP of the nonoperative arm were monitored for each patient. All patients were evaluated for postoperative neurological deficits 6 weeks postoperatively. In total, 21 patients were consented and were successfully monitored. In total, 4 (19%) patients developed intraoperative abnormal SSEP signal changes in the operative arm, in which 3 were reversible and 1 was irreversible till the end of surgery. Median and radial nerves were mostly involved (3/4 patients). The mean cumulative duration of nerve insult (abnormal SSEP) was 21.7±26.2 minutes. Univariate analysis did not identify predictor of intraoperative nerve insults. No patients demonstrated postoperative peripheral neuropathy at 6 weeks. A high incidence (19%) of intraoperative nerve insult was observed in this study demonstrating the feasibility of using an automated SSEP device to provide a timely alert and enable an intervention in order to minimize peripheral nerve injury during TSA. Further randomized studies are warranted.

Head-mounted display for use in functional endoscopic sinus surgery

NASA Astrophysics Data System (ADS)

Wong, Brian J.; Lee, Jon P.; Dugan, F. Markoe; MacArthur, Carol J.

1995-05-01

Since the introduction of functional endoscopic sinus surgery (FESS), the procedure has undergone rapid change with evolution keeping pace with technological advances. The advent of low cost charge coupled device 9CCD) cameras revolutionized the practice and instruction of FESS. Video-based FESS has allowed for documentation of the surgical procedure as well as interactive instruction during surgery. Presently, the technical requirements of video-based FESS include the addition of one or more television monitors positioned strategically in the operating room. Thought video monitors have greatly enhanced surgical endoscopy by re- involving nurses and assistants in the actual mechanics of surgery, video monitors require the operating surgeon to be focused on the screen instead of the patient. In this study, we describe the use of a new low-cost liquid crystal display (LCD) based device that functions as a monitor but is mounted on the head on a visor (PT-O1, O1 Products, Westlake Village, CA). This study illustrates the application of these HMD devices to FESS operations. The same surgeon performed the operation in each patient. In one nasal fossa, surgery was performed using conventional video FESS methods. The contralateral side was operated on while wearing the head mounted video display. The device had adequate resolution for the purposes of FESS. No adverse effects were noted intraoperatively. The results on the patients ipsalateral and contralateral sides were similar. The visor did eliminated significant torsion of the surgeon's neck during the operation, while at the same time permitted simultaneous viewing of both the patient and the intranasal surgical field.

Motor evoked potential monitoring of the vagus nerve with transcranial electrical stimulation during skull base surgeries.

PubMed

Ito, Eiji; Ichikawa, Masahiro; Itakura, Takeshi; Ando, Hitoshi; Matsumoto, Yuka; Oda, Keiko; Sato, Taku; Watanabe, Tadashi; Sakuma, Jun; Saito, Kiyoshi

2013-01-01

Dysphasia is one of the most serious complications of skull base surgeries and results from damage to the brainstem and/or cranial nerves involved in swallowing. Here, the authors propose a method to monitor the function of the vagus nerve using endotracheal tube surface electrodes and transcranial electrical stimulation during skull base surgeries. Fifteen patients with skull base or brainstem tumors were enrolled. The authors used surface electrodes of an endotracheal tube to record compound electromyographic responses from the vocalis muscle. Motor neurons were stimulated using corkscrew electrodes placed subdermally on the scalp at C3 and C4. During surgery, the operator received a warning when the amplitude of the vagal motor evoked potential (MEP) decreased to less than 50% of the control level. After surgery, swallowing function was assessed clinically using grading criteria. In 5 patients, vagal MEP amplitude permanently deteriorated to less than 50% of the control level on the right side when meningiomas were dissected from the pons or basilar artery, or when a schwannoma was dissected from the vagal rootlets. These 5 patients had postoperative dysphagia. At 4 weeks after surgery, 2 patients still had dysphagia. In 2 patients, vagal MEPs of one side transiently disappeared when the tumors were dissected from the brainstem or the vagal rootlets. After surgery, both patients had dysphagia, which recovered in 4 weeks. In 7 patients, MEP amplitude was consistent, maintaining more than 50% of the control level throughout the operative procedures. After surgery all 7 patients were neurologically intact with normal swallowing function. Vagal MEP monitoring with transcranial electrical stimulation and endotracheal tube electrode recording was a safe and effective method to provide continuous real-time information on the integrity of both the supranuclear and infranuclear vagal pathway. This method is useful to prevent intraoperative injury of the brainstem corticobulbar tract or the vagal rootlets and to avoid the postoperative dysphagia that is often associated with brainstem or skull base surgeries.

Perioperative Near-Infrared Spectroscopy Monitoring in Neonates With Congenital Heart Disease: Relationship of Cerebral Tissue Oxygenation Index Variability With Neurodevelopmental Outcome.

PubMed

Spaeder, Michael C; Klugman, Darren; Skurow-Todd, Kami; Glass, Penny; Jonas, Richard A; Donofrio, Mary T

2017-03-01

To evaluate the value of perioperative cerebral near-infrared spectroscopy monitoring using variability analysis in the prediction of neurodevelopmental outcomes in neonates undergoing surgery for congenital heart disease. Retrospective cohort study. Urban, academic, tertiary-care children's hospital. Neonates undergoing surgery with cardiopulmonary bypass for congenital heart disease. Perioperative monitoring of continuous cerebral tissue oxygenation index by near-infrared spectroscopy and subsequent neurodevelopmental testing at 6, 15, and 21 months of age. We developed a new measure, cerebral tissue oxygenation index variability, using the root mean of successive squared differences of averaged 1-minute cerebral tissue oxygenation index values for both the intraoperative and first 24-hours postoperative phases of monitoring. There were 62 neonates who underwent cerebral tissue oxygenation index monitoring during surgery for congenital heart disease and 44 underwent subsequent neurodevelopmental testing (12 did not survive until testing and six were lost to follow-up). Among the 44 monitored patients who underwent neurodevelopmental testing, 20 (45%) had abnormal neurodevelopmental indices. Patients with abnormal neurodevelopmental indices had lower postoperative cerebral tissue oxygenation index variability when compared with patients with normal indices (p = 0.01). Adjusting for class of congenital heart disease and duration of deep hypothermic circulatory arrest, lower postoperative cerebral tissue oxygenation index variability was associated with poor neurodevelopmental outcome (p = 0.02). We found reduced postoperative cerebral tissue oxygenation index variability in neonatal survivors of congenital heart disease surgery with poor neurodevelopmental outcomes. We hypothesize that reduced cerebral tissue oxygenation index variability may be a surrogate for impaired cerebral metabolic autoregulation in the immediate postoperative period. Further research is needed to investigate clinical implications of this finding and opportunities for using this measure to drive therapeutic interventions.

Measurement of total hemoglobin reduces red cell transfusion in hospitalized patients undergoing cardiac surgery: a retrospective database analysis.

PubMed

Craver, Christopher; Belk, Kathy W; Myers, Gerard J

2018-01-01

Historically, perioperative hemoglobin monitoring has relied on calculated saturation, using blood gas devices that measure plasma hematocrit (Hct). Co-oximetry, which measures total hemoglobin (tHb), yields a more comprehensive assessment of hemodilution. The purpose of this study was to examine the association of tHb measurement by co-oximetry and Hct, using conductivity with red blood cell (RBC) transfusion, length of stay (LOS) and inpatient costs in patients having major cardiac surgery. A retrospective study was conducted on patients who underwent coronary artery bypass graft (CABG) and/or valve replacement (VR) procedures from January 2014 to June 2016, using MedAssets discharge data. The patient population was sub-divided by the measurement modality (tHb and Hct), using detailed billing records and Current Procedural Terminology coding. Cost was calculated using hospital-specific cost-to-charge ratios. Multivariable logistic regression was performed to identify significant drivers of RBC transfusion and resource utilization. The study population included 18,169 cardiovascular surgery patients. Hct-monitored patients accounted for 66% of the population and were more likely to have dual CABG and VR procedures (10.4% vs 8.9%, p=0.0069). After controlling for patient and hospital characteristics, as well as patient comorbidities, Hct-monitored patients had significantly higher RBC transfusion risk (OR=1.26, CI 1.15-1.38, p<0.0001), longer LOS (IRR=1.08, p<0.0001) and higher costs (IRR=1.15, p<0.0001) than tHb-monitored patients. RBC transfusions were a significant driver of LOS (IRR=1.25, p<0.0001) and cost (IRR=1.22, p<0.0001). tHb monitoring during cardiovascular surgery could offer a significant reduction in RBC transfusion, length of stay and hospital cost compared to Hct monitoring.

The use of electrophysiological monitoring in the intraoperative management of intracranial aneurysms

PubMed Central

Lopez, J.; Chang, S.; Steinberg, G.

1999-01-01

OBJECTIVES—Somatosensory evoked potentials (SSEPs) and brainstem auditory evoked potentials (BAEPs) have been increasingly utilised during surgery for intracranial aneurysms to identify cerebral ischaemia. Between July 1994 and April 1996, we surgically treated 70 aneurysms in 49 consecutive patients (58 operations) with the aid of intraoperative evoked potential monitoring. This study sought to evaluate the usefulness of SSEP and BAEP monitoring during intracranial aneurysm surgery.
METHODS—Mean patient age was 51.9 (range 18-79) years. The sizes of the aneurysms were 3-4 mm (15), 5-9 mm (26), 10-14 mm (11), 15-19 mm (seven), 20-24 mm (six), and >25 mm (five). SSEPs were monitored in 58 procedures (100%) and BAEPs in 15 (26%). The neurological status of the patients was evaluated before and after surgery.
RESULTS—Thirteen of the 58 procedures (22%) monitored with SSEPs had SSEP changes (12 transient, one persistent); 45 (78%) had no SSEP changes. Three of 15 patients (20%) monitored with BAEPs had changes (two transient, one persistent); 12 (80%) had no BAEP changes. Of the 14 patients with transient SSEP or BAEP changes, these changes resolved with adjustment or removal of aneurysm clips (nine), elevating MAP (four), or retractor adjustment (one). Mean time from precipitating event to electrophysiological change was 8.9 minutes (range 3-32), and the mean time for recovery of potentials in patients with transient changes was 20.2 minutes (range 3-60). Clinical outcome was excellent in 39 patients, good in five, and poor in three (two patients died), and was largely related to pretreatment grade.
CONCLUSIONS—SSEPs and BAEPs are useful in preventing clinical neurological injury during surgery for intracranial aneurysms and in predicting which patients will have unfavourable outcomes.

 PMID:10071098

Evaluation of the monitor cursor-line method for measuring pulmonary artery and central venous pressures.

PubMed

Pasion, Editha; Good, Levell; Tizon, Jisebelle; Krieger, Staci; O'Kier, Catherine; Taylor, Nicole; Johnson, Jennifer; Horton, Carrie M; Peterson, Mary

2010-11-01

To determine if the monitor cursor-line feature on bedside monitors is accurate for measuring central venous and pulmonary artery pressures in cardiac surgery patients. Central venous and pulmonary artery pressures were measured via 3 methods (end-expiratory graphic recording, monitor cursor-line display, and monitor digital display) in a convenience sample of postoperative cardiac surgery patients. Pressures were measured twice during both mechanical ventilation and spontaneous breathing. Analysis of variance was used to determine differences between measurement methods and the percentage of monitor pressures that differed by 4 mm Hg or more from the measurement obtained from the graphic recording. Significance level was set at P less than .05. Twenty-five patients were studied during mechanical ventilation (50 measurements) and 21 patients during spontaneous breathing (42 measurements). Measurements obtained via the 3 methods did not differ significantly for either type of pressure (P > .05). Graphically recorded pressures and measurements obtained via the monitor cursor-line or digital display methods differed by 4 mm Hg or more in 4% and 6% of measurements, respectively, during mechanical ventilation and 4% and 11%, respectively, during spontaneous breathing. The monitor cursor-line method for measuring central venous and pulmonary artery pressures may be a reasonable alternative to the end-expiratory graphic recording method in hemodynamically stable, postoperative cardiac surgery patients. Use of the digital display on the bedside monitor may result in larger discrepancies from the graphically recorded pressures than when the cursor-line method is used, particularly in spontaneously breathing patients.

Repeated sugammadex reversal of muscle relaxation during lumbar spine surgery with intraoperative neurophysiological multimodal monitoring.

PubMed

Errando, C L; Blanco, T; Díaz-Cambronero, Ó

2016-11-01

Intraoperative neurophysiological monitoring during spine surgery is usually acomplished avoiding muscle relaxants. A case of intraoperative sugammadex partial reversal of the neuromuscular blockade allowing adequate monitoring during spine surgery is presented. A 38 year-old man was scheduled for discectomy and vertebral arthrodesis throughout anterior and posterior approaches. Anesthesia consisted of total intravenous anesthesia plus rocuronium. Intraoperatively monitoring was needed, and the muscle relaxant reverted twice with low dose sugammadex in order to obtain adequate responses. The doses of sugammadex used were conservatively selected (0.1mg/kg boluses increases, total dose needed 0.4mg/kg). Both motor evoqued potentials, and electromyographic responses were deemed adequate by the neurophysiologist. If muscle relaxation was needed in the context described, this approach could be useful to prevent neurological sequelae. This is the first study using very low dose sugammadex to reverse rocuronium intraoperatively and to re-establish the neuromuscular blockade. Copyright © 2016 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

The impact on post-operative shoulder function of intraoperative nerve monitoring of cranial nerve XI during modified radical neck dissection.

PubMed

Lanišnik, Boštjan; Žitnik, Lidija; Levart, Primož; Žargi, Miha; Rodi, Zoran

2016-12-01

Intraoperative monitoring of the cranial nerve XI (CN XI) may decrease shoulder disability following modified radical neck dissection. Prospective study was designed comparing results of Constant Shoulder Score (CSS), Shoulder Pain and Disability Index (SPADI) and EMG score of the trapezius muscle (mT) before and after surgery. One side of the neck was monitored during surgery with intraoperative nerve monitor. EMG scores of the mT 6 months postoperatively were statistically better on monitored as compared to the non-monitored side of the neck (p = 0.041), while the differences of the CSS and SPADI were not statistically significant. Patients with better EMG scores of the mT at 6 weeks recuperated better and with smaller decrease of the CSS. Intraoperative monitoring is beneficial at the beginning of the surgeon's learning curve and in the process of familiarizing with anatomical variation of the CN XI.

A monitoring tool for performance improvement in plastic surgery at the individual level.

PubMed

Maruthappu, Mahiben; Duclos, Antoine; Orgill, Dennis; Carty, Matthew J

2013-05-01

The assessment of performance in surgery is expanding significantly. Application of relevant frameworks to plastic surgery, however, has been limited. In this article, the authors present two robust graphic tools commonly used in other industries that may serve to monitor individual surgeon operative time while factoring in patient- and surgeon-specific elements. The authors reviewed performance data from all bilateral reduction mammaplasties performed at their institution by eight surgeons between 1995 and 2010. Operative time was used as a proxy for performance. Cumulative sum charts and exponentially weighted moving average charts were generated using a train-test analytic approach, and used to monitor surgical performance. Charts mapped crude, patient case-mix-adjusted, and case-mix and surgical-experience-adjusted performance. Operative time was found to decline from 182 minutes to 118 minutes with surgical experience (p < 0.001). Cumulative sum and exponentially weighted moving average charts were generated using 1995 to 2007 data (1053 procedures) and tested on 2008 to 2010 data (246 procedures). The sensitivity and accuracy of these charts were significantly improved by adjustment for case mix and surgeon experience. The consideration of patient- and surgeon-specific factors is essential for correct interpretation of performance in plastic surgery at the individual surgeon level. Cumulative sum and exponentially weighted moving average charts represent accurate methods of monitoring operative time to control and potentially improve surgeon performance over the course of a career.

A comparison of retrobulbar block, sub-Tenon block, and topical anesthesia during cataract surgery.

PubMed

Ryu, Jung-Hee; Kim, Minsuk; Bahk, Jae-Hyon; Do, Sang-Hwan; Cheong, Il-Young; Kim, Yong-Chul

2009-01-01

This randomized, double-blinded, prospective study was performed to compare the intraoperative hemodynamic variables and the patient-reported outcomes, such as intra- and postoperative analgesia and patient satisfaction, of retrobulbar block, sub-Tenon block, and topical anesthesia during cataract surgery under monitored anesthesia care. Eighty-one patients, ASA physical status I-III, undergoing elective cataract surgery under monitored anesthesia care, aged between 43 and 78 years, were randomly assigned to three groups: retrobulbar block (group R), sub-Tenon block (group S), or topical anesthesia (group T). Three minutes after the start of monitored anesthesia care with lidocaine-propofol-remifentanil mixture, an ophthalmologist performed regional anesthesia. Intraoperative hemodynamics, pain score, and patients' satisfaction with the anesthetic experiences were recorded by a study-blinded anesthesiologist. Mean arterial pressure and heart rate in group R were significantly higher than those in groups S and T during and just after the regional block (p<0.05). Group R required smaller dosage of patient controlled sedation and fewer supplemental bolus doses than groups S and T (p<0.05). On the other hand, group S showed the highest satisfaction scores among the three groups (p<0.05). Sub-Tenon block seems to be better than retrobulbar block and topical anesthesia in patient satisfaction though adequate analgesia was achieved after retrobulbar block during cataract surgery under monitored anesthesia care.

Neuronavigated microvascular Doppler sonography for intraoperative monitoring of blood flow velocity changes during aneurysm surgery - a feasible monitoring technique.

PubMed

Malinova, Vesna; von Eckardstein, Kajetan; Rohde, Veit; Mielke, Dorothee

2015-10-01

The intraoperative microvascular Doppler sonography (iMDS) is a well-established tool in vascular surgery for blood flow velocity (BFV) monitoring, capable of detecting vessel occlusion. However, identification of subtotal vessel compromise is more difficult, since the measured BFV may substantially vary with changing insonation angles and insonated vessel segments. To keep these parameters constant we combined neuronavigation with iMDS (niMDS). The question was if niMDS allows the detection of subtotal vessel compromise in aneurysm surgery. During surgery, the 3-dimensional reconstruction of the CT-angiography, which was obtained routinely prior to surgery, was displayed by the neuronavigational system. Prior to clipping, neuronavigation was used to define target point and trajectory, which, by coupling the neuronavigational pointer with the Doppler probe, correspond to the insonated vessel segment and the insonation angle. After clipping, for each vessel segment, the same trajectory was used for all consecutive measurements. The mean BFVs pre- and post-clipping were documented. We performed 82 BFV-measurements in 39 aneurysm surgeries. Mean deviation between pre- and post-clipping BFV values was 2.12cm/s. There was a significant correlation between the mean BFV values before and after clipping (r=0.45 [95% CI 17-66%]; p=0.002). One patient experienced new neurological deficits due to occlusion of a perforating vessel that was not insonated. The study could not answer the question if niMDS can detect BFV changes after clipping indicating vessel compromise, as no subtotal vessel occlusion occurred in the 39 operations. However, we proofed that niMDS-measured BFVs only varied minimally in uncompromised vessels pre- and post-clipping, suggesting that vessel compromises might be easily detected during aneurysm surgery. Copyright © 2015 Elsevier B.V. All rights reserved.

Detection of recurrent Cushing's disease: proposal for standardized patient monitoring following transsphenoidal surgery.

PubMed

Ayala, Alejandro; Manzano, Alex J

2014-09-01

Transsphenoidal surgery (TSS) is first-line treatment for Cushing's disease (CD), a devastating disorder of hypercortisolism resulting from overproduction of adrenocorticotropic hormone by a pituitary adenoma. Surgical success rates vary widely and disease may recur years after remission is achieved. Recognizing CD recurrence can be challenging; although there is general acceptance among endocrinologists that patients need lifelong follow-up, there are currently no standardized monitoring guidelines. To begin addressing this need we created a novel, systematic algorithm by integrating information from literature on relapse rates in surgically-treated CD patients and our own clinical experiences. Reported recurrence rates range from 3 to 47 % (mean time to recurrence 16-49 months), emphasizing the need for careful post-surgical patient monitoring. We recommend that patients with post-operative serum cortisol <2 µg/dL (measured 2-3 days post-surgery) be monitored semiannually for 3 years and annually thereafter. Patients with post-operative cortisol between 2 and 5 µg/dL may experience persistent or subclinical CD and should be evaluated every 2-3 months until biochemical control is achieved or additional treatment is initiated. Post-operative cortisol >5 µg/dL often signifies persistent disease and second-line treatment (e.g., immediate repeat pituitary surgery, radiotherapy, and/or medical therapy) may be considered. This follow-up algorithm aims to (a) enable early diagnosis and treatment of recurrent CD, thereby minimizing the detrimental effects of hypercortisolism, and (b) begin addressing the need for standardized guidelines for vigilant monitoring of CD patients treated by TSS, as demonstrated by the reported rates of recurrence.

Effect of invasive EEG monitoring on cognitive outcome after left temporal lobe epilepsy surgery.

PubMed

Busch, Robyn M; Love, Thomas E; Jehi, Lara E; Ferguson, Lisa; Yardi, Ruta; Najm, Imad; Bingaman, William; Gonzalez-Martinez, Jorge

2015-10-27

The objective of this cohort study was to compare neuropsychological outcomes following left temporal lobe resection (TLR) in patients with epilepsy who had or had not undergone prior invasive monitoring. Data were obtained from an institutional review board-approved, neuropsychology registry for patients who underwent epilepsy surgery at Cleveland Clinic between 1997 and 2013. A total of 176 patients (45 with and 131 without invasive EEG) met inclusion criteria. Primary outcome measures were verbal memory and language scores. Other cognitive outcomes were also examined. Outcomes were assessed using difference in scores from before to after surgery and by presence/absence of clinically meaningful decline using reliable change indices (RCIs). Effect of invasive EEG on cognitive outcomes was estimated using weighting and propensity score adjustment to account for differences in baseline characteristics. Linear and logistic regression models compared surgical groups on all cognitive outcomes. Patients with invasive monitoring showed greater declines in confrontation naming; however, when RCIs were used to assess clinically meaningful change, there was no significant treatment effect on naming performance. No difference in verbal memory was observed, regardless of how the outcome was measured. In secondary outcomes, patients with invasive monitoring showed greater declines in working memory, which were no longer apparent using RCIs to define change. There were no outcome differences on other cognitive measures. Results suggest that invasive EEG monitoring conducted prior to left TLR is not associated with greater cognitive morbidity than left TLR alone. This information is important when counseling patients regarding cognitive risks associated with this elective surgery. © 2015 American Academy of Neurology.

Force-Free Time-Harmonic Plasmoids

DTIC Science & Technology

1992-10-01

effect of currents or vortical motion are absolutely required for stability. What makes the present model attractive is the minimization of the body ...radiative-mode effects may be very fruitful in the future. For example: Rigid non-radiative composite "particles" containing large numbers of fus- able...12 7. The neutral plasma .......... .......................... 12 8. Forces on a moving electron ....... ......... .............. 13 9. Effects of

An MBS-Assisted Femtocell Transmit Power Control Scheme with Mobile User QoS Guarantee in 2-Tier Heterogeneous Femtocell Networks

PubMed Central

Yang, Chih-Cheng; Sheu, Shiann-Tsong

2013-01-01

This study investigates how to adjust the transmit power of femto base station (FBS) to mitigate interference problems between the FBSs and mobile users (MUs) in the 2-tier heterogeneous femtocell networks. A common baseline of deploying the FBS to increase the indoor access bandwidth requires that the FBS operation will not affect outdoor MUs operation with their quality-of-service (QoS) requirements. To tackle this technical problem, an FBS transmit power adjustment (FTPA) algorithm is proposed to adjust the FBS transmit power (FTP) to avoid unwanted cochannel interference (CCI) with the neighboring MUs in downlink transmission. FTPA reduces the FTP to serve its femto users (FUs) according to the QoS requirements of the nearest neighboring MUs to the FBS so that the MU QoS requirement is guaranteed. Simulation results demonstrate that FTPA can achieve a low MU outage probability as well as serve FUs without violating the MU QoS requirements. Simulation results also reveal that FTPA has better performance on voice and video services which are the major trend of future multimedia communication in the NGN. PMID:24391461

A random phased-array for MR-guided transcranial ultrasound neuromodulation in non-human primates

NASA Astrophysics Data System (ADS)

Chaplin, Vandiver; Phipps, Marshal A.; Caskey, Charles F.

2018-05-01

Transcranial focused ultrasound (FUS) is a non-invasive technique for therapy and study of brain neural activation. Here we report on the design and characterization of a new MR-guided FUS transducer for neuromodulation in non-human primates at 650 kHz. The array is randomized with 128 elements 6.6 mm in diameter, radius of curvature 7.2 cm, opening diameter 10.3 cm (focal ratio 0.7), and 46% coverage. Simulations were used to optimize transducer geometry with respect to focus size, grating lobes, and directivity. Focus size and grating lobes during electronic steering were quantified using hydrophone measurements in water and a three-axis stage. A novel combination of optical tracking and acoustic mapping enabled measurement of the 3D pressure distribution in the cortical region of an ex vivo skull to within ~3.5 mm of the surface, and allowed accurate modelling of the experiment via non-homogeneous 3D acoustic simulations. The data demonstrates acoustic focusing beyond the skull bone, with the focus slightly broadened and shifted proximal to the skull. The fabricated design is capable of targeting regions within the S1 sensorimotor cortex of macaques.

Riluzole does not improve lifespan or motor function in three ALS mouse models.

PubMed

Hogg, Marion C; Halang, Luise; Woods, Ina; Coughlan, Karen S; Prehn, Jochen H M

2018-08-01

Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1 G93A model, the TDP-43 A315T model, and the recently developed FUS (1-359) model. Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset. Lifespan was assessed and motor function tests were carried out twice weekly to determine whether riluzole slowed disease progression. Riluzole treatment had no significant benefit on lifespan in any of the ALS mouse models tested. Riluzole had no significant impact on decline in motor performance in the FUS (1-359) and SOD1 G93A transgenic mice as assessed by Rotarod and stride length analysis. Riluzole is widely prescribed for ALS patients despite questions surrounding its efficacy. Our data suggest that if riluzole was identified as a therapeutic candidate today it would not progress past pre-clinical assessment. This raises questions about the standards used in pre-clinical assessment of therapeutic candidates for the treatment of ALS.

Investigation of standing wave formation in a human skull for a clinical prototype of a large-aperture, transcranial MR-guided Focused Ultrasound (MRgFUS) phased array: An experimental and simulation study

PubMed Central

Song, Junho; Pulkkinen, Aki; Huang, Yuexi; Hynynen, Kullervo

2014-01-01

Standing wave formation in an ex vivo human skull was investigated using a clinical prototype of a 30 cm diameter with 15 cm radius of curvature, low frequency (230 kHz), hemispherical transcranial Magnetic Resonance guided Focused Ultrasound (MRgFUS) phased-array. Experimental and simulation studies were conducted with changing aperture size and f-number configurations of the phased array, and qualitatively and quantitatively examined the acoustic pressure variation at the focus due to standing waves. The results demonstrated that the nodes and anti-nodes of standing wave produced by the small aperture array were clearly seen at approximately every 3 mm. The effect of the standing wave became more pronounced as the focus was moved closer to skull base. However, a sharp focus was seen for the full array, and there was no such standing wave pattern in the acoustic plane or near the skull base. This study showed that the fluctuation pressure amplitude would be greatly reduced by using a large-scale, hemispherical phased array with a low f-number. PMID:22049360

A random phased-array for MR-guided transcranial ultrasound neuromodulation in non-human primates.

PubMed

Chaplin, Vandiver; Phipps, Marshal A; Caskey, Charles F

2018-05-17

Transcranial focused ultrasound (FUS) is a non-invasive technique for therapy and study of brain neural activation. Here we report on the design and characterization of a new MR-guided FUS transducer for neuromodulation in non-human primates at 650 kHz. The array is randomized with 128 elements 6.6 mm in diameter, radius of curvature 7.2 cm, opening diameter 10.3 cm (focal ratio 0.7), and 46% coverage. Simulations were used to optimize transducer geometry with respect to focus size, grating lobes, and directivity. Focus size and grating lobes during electronic steering were quantified using hydrophone measurements in water and a three-axis stage. A novel combination of optical tracking and acoustic mapping enabled measurement of the 3D pressure distribution in the cortical region of an ex vivo skull to within ~3.5 mm of the surface, and allowed accurate modelling of the experiment via non-homogeneous 3D acoustic simulations. The data demonstrates acoustic focusing beyond the skull bone, with the focus slightly broadened and shifted proximal to the skull. The fabricated design is capable of targeting regions within the S1 sensorimotor cortex of macaques.

Changes in cat urinary glycosaminoglycans with age and in feline urologic syndrome.

PubMed

Pereira, Daionety A; Aguiar, Jair A K; Hagiwara, Mitika K; Michelacci, Yara M

2004-04-07

The aim of the present study was to characterize the urinary excretion of glycosaminoglycans in kittens and adult healthy cats, as well as in cats with a low urinary tract disease, the feline urologic syndrome (FUS). The main urinary glycosaminoglycan in cats was found to be chondroitin sulfate, with smaller amounts of dermatan sulfate and heparan sulfate. There was no difference in the urinary glycosaminoglycan concentration with sex, but a marked decrease occurred with age, due to chondroitin sulfate. Trace amounts of keratan sulfate were also detected in the urine of kittens, but not of healthy adult cats. Dermatan sulfate and heparan sulfate were the only glycosaminoglycans found in the urinary tract and kidney, and chondroitin sulfate was the only glycosaminoglycan found in the plasma. These data suggest that the main urinary glycosaminoglycan chondroitin sulfate is of systemic origin and filtered in the kidney, while the minor components dermatan sulfate and heparan sulfate may come from the urinary tract. The urinary glycosaminoglycan concentration was greatly decreased in animals with FUS, as compared to normal adults. We hypothesize that these low glycosaminoglycan levels reflect a damage to the bladder surface, resulting in absorption and/or degradation of the endogenous urinary glycosaminoglycans.

Improvement of constraint-based flux estimation during L-phenylalanine production with Escherichia coli using targeted knock-out mutants.

PubMed

Weiner, Michael; Tröndle, Julia; Albermann, Christoph; Sprenger, Georg A; Weuster-Botz, Dirk

2014-07-01

Fed-batch production of the aromatic amino acid L-phenylalanine was studied with recombinant Escherichia coli strains on a 15 L-scale using glycerol as carbon source. Flux Variability Analysis (FVA) was applied for intracellular flux estimation to obtain an insight into intracellular flux distribution during L-phenylalanine production. Variability analysis revealed great flux uncertainties in the central carbon metabolism, especially concerning malate consumption. Due to these results two recombinant strains were genetically engineered differing in the ability of malate degradation and anaplerotic reactions (E. coli FUS4.11 ΔmaeA pF81kan and E. coli FUS4.11 ΔmaeA ΔmaeB pF81kan). Applying these malic enzyme knock-out mutants in the standardized L-phenylalanine production process resulted in almost identical process performances (e.g., L-phenylalanine concentration, production rate and byproduct formation). This clearly highlighted great redundancies in central metabolism in E. coli. Uncertainties of intracellular flux estimations by constraint-based analyses during fed-batch production of L-phenylalanine were drastically reduced by application of the malic enzyme knock-out mutants. © 2014 Wiley Periodicals, Inc.

An MBS-assisted femtocell transmit power control scheme with mobile user QoS guarantee in 2-tier heterogeneous femtocell networks.

PubMed

Chen, Jenhui; Yang, Chih-Cheng; Sheu, Shiann-Tsong

2013-01-01

This study investigates how to adjust the transmit power of femto base station (FBS) to mitigate interference problems between the FBSs and mobile users (MUs) in the 2-tier heterogeneous femtocell networks. A common baseline of deploying the FBS to increase the indoor access bandwidth requires that the FBS operation will not affect outdoor MUs operation with their quality-of-service (QoS) requirements. To tackle this technical problem, an FBS transmit power adjustment (FTPA) algorithm is proposed to adjust the FBS transmit power (FTP) to avoid unwanted cochannel interference (CCI) with the neighboring MUs in downlink transmission. FTPA reduces the FTP to serve its femto users (FUs) according to the QoS requirements of the nearest neighboring MUs to the FBS so that the MU QoS requirement is guaranteed. Simulation results demonstrate that FTPA can achieve a low MU outage probability as well as serve FUs without violating the MU QoS requirements. Simulation results also reveal that FTPA has better performance on voice and video services which are the major trend of future multimedia communication in the NGN.

Improved Design of Stellarator Coils for Current Carrying Plasmas

NASA Astrophysics Data System (ADS)

Drevlak, M.; Strumberger, E.; Hirshman, S.; Boozer, A.; Brooks, A.; Valanju, P.

1998-11-01

The method of automatic optimization (P. Merkel, Nucl. Fus. 27), (1987) 867; P. Merkel, M. Drevlak, Proc 25th EPS Conf. on Cont. Fus. and Plas. Phys., Prague, in print. for the design of stellarator coils consists essentially of determining filaments such that the average relative field error int dS [ (B_coil + B_j) \\cdot n]^2/B^2_coil is minimized on the prescribed plasma boundary. Bj is the magnetic field produced by the plasma currents of the given finite β fixed boundary equilibrium. For equilibria of the W7-X type, Bj can be neglected, because of the reduced parallel plasma currents. This is not true for quasi-axisymmetric stellarator (QAS) configurations (A. Reiman, et al., to be published.) with large equilibrium and net plasma (bootstrap) currents. Although the coils for QAS exhibit low values of the field error, free boundary calculations indicate that the shape of the plasma is usually not accurately reproduced , particularly when saddle coils are used. We investigate if the surface reconstruction can be improved by introducing a modified measure of the field error based on a measure of the resonant components of the normal field.

An examination of the thermodynamics of fusion, vaporization, and sublimation of several parabens by correlation gas chromatography.

PubMed

Umnahanant, Patamaporn; Chickos, James

2011-05-01

The vaporization, fusion, and sublimation enthalpies of methyl, ethyl, propyl, and butyl paraben are reported and compared with literature values. The vaporization enthalpies were measured by correlation gas chromatography and the fusion enthalpies by differential scanning calorimetry. Adjusted to T = 298.15 K, these enthalpies were combined to yield the sublimation enthalpy. The results compare favorably to some of the literature values but do not support the reversal in magnitude of both the vaporization and sublimation enthalpy previously reported for propyl and butyl paraben. The following fusion and vaporization enthalpies were measured for methyl through to butyl paraben, respectively: ΔH(fus) (T(fus) ) 26.3 ± 0.1 (398.6 K), 26.5 ± 0.1 (388.5 K), 27.3 ± 0.1 (368.8), and 25.9 ± 0.3 (340.7 K) kJ·mol(-1); ΔH(vap) (298.15 K) 79.5 ± 0.5, 84.0 ± 0.5, 89.7 ± 0.6, and 95.8 ± 0.6 kJ·mol(-1). The results are believed to be accurate to ± 4 kJ·mol(-1). Copyright © 2011 Wiley-Liss, Inc.

Diagnostic accuracy of motor evoked potentials to detect neurological deficit during idiopathic scoliosis correction: a systematic review.

PubMed

Thirumala, Parthasarathy D; Crammond, Donald J; Loke, Yoon K; Cheng, Hannah L; Huang, Jessie; Balzer, Jeffrey R

2017-03-01

OBJECTIVE The goal of this study was to evaluate the efficacy of intraoperative transcranial motor evoked potential (TcMEP) monitoring in predicting an impending neurological deficit during corrective spinal surgery for patients with idiopathic scoliosis (IS). METHODS The authors searched the PubMed and Web of Science database for relevant lists of retrieved reports and/or experiments published from January 1950 through October 2014 for studies on TcMEP monitoring use during IS surgery. The primary analysis of this review fit the operating characteristic into a hierarchical summary receiver operating characteristic curve model to determine the efficacy of intraoperative TcMEP-predicted change. RESULTS Twelve studies, with a total of 2102 patients with IS were included. Analysis found an observed incidence of neurological deficits of 1.38% (29/2102) in the sample population. Of the patients who sustained a neurological deficit, 82.8% (24/29) also had irreversible TcMEP change, whereas 17.2% (5/29) did not. The pooled analysis using the bivariate model showed TcMEP change with sensitivity (mean 91% [95% CI 34%-100%]) and specificity (mean 96% [95% CI 92-98%]). The diagnostic odds ratio indicated that it is 250 times more likely to observe significant TcMEP changes in patients who experience a new-onset motor deficit immediately after IS correction surgery (95% CI 11-5767). TcMEP monitoring showed high discriminant ability with an area under the curve of 0.98. CONCLUSIONS A patient with a new neurological deficit resulting from IS surgery was 250 times more likely to have changes in TcMEPs than a patient without new deficit. The authors' findings from 2102 operations in patients with IS show that TcMEP monitoring is a highly sensitive and specific test for detecting new spinal cord injuries in patients undergoing corrective spinal surgery for IS. They could not assess the value of TcMEP monitoring as a therapeutic adjunct owing to the limited data available and their study design.

[Motor evoked potentials in thoracoabdominal aortic surgery].

PubMed

Magro, Cátia; Nora, David; Marques, Miguel; Alves, Angela Garcia

2012-01-01

Thoracoabdominal aortic disease (aneurysm or dissection) has increased in recent decades. Surgery is the curative treatment but is associated to high perioperative morbidity and mortality risks. Paraplegia is one of the most severe complications, whose incidence has decreased significantly with the implementation of spinal cord protection strategies. No single method or combination of methods has proven to be fully effective in preventing paraplegia. This review is intended to analyse the scientific evidence available on the role of intraoperative monitoring with motor evoked potentials in the neurological outcome of patients undergoing thoracoabdominal aortic surgery. An online search (PubMed) was conducted. Relevant references were selected and reviewed. Intraoperative monitoring with motor evoked potentials (MEP) allows early detection of ischemic events and a targeted intervention to prevent the development of spinal cord injury, significantly reducing the incidence of postoperative paraplegia. MEP monitoring may undergo several intraoperative interferences which may compromise their interpretation. Neuromuscular blockade is the main limiting factor of anesthetic origin. It is essential to strike a balance between monitoring conditions and surgical and anesthetic needs as well as to evaluate the risks and benefits of the technique for each patient. MEP monitoring improves neurological outcome when integrated in a multidisciplinary strategy which must include multiple protective mechanisms that should be tailored to each hospital reality.

Surgical and immediate postrelease mortality of harlequin ducks (Histrionicus histrionicus) implanted with abdominal radio transmitters with percutaneous antennae

USGS Publications Warehouse

Mulcahy, Daniel M.; Esler, Daniel N.

1999-01-01

Radiotelemetry is an essential tool in the study of free-ranging bird populations, and a variety of transmitter-attachment methods have been developed. A promising new method is abdominal implantation of a transmitter with a percutaneous antenna. Researchers using this technique should be concerned about and aware of mortality during surgery and during the immediate postrelease period (the 14-day period following surgery). Of 307 radio-implant surgeries performed between 1995 and 1997 in harlequin ducks (Histrionicus histrionicus), 7 (2.3%) deaths were documented during surgery or anesthetic recovery. Of 295 birds released with implanted radios, 10 (3.4%) died during the immediate postrelease period. Modifications to anesthetic procedures used in the 204 surgeries performed in 1996 and 1997 reduced mortality to 1.5% during surgery and 1.5% during the immediate postrelease period. Anesthetic modifications included intubation of all birds, placement of birds on an elevated platform that allowed the head to rest at a level lower than the body during surgery, placement of a heated water blanket under the birds during surgery, monitoring of body temperature, and use of electrocardiogram and Doppler ultrasound to monitor heart rates and arrhythmias. Low levels of mortality associated with abdominal implantation of radio transmitters may be unavoidable, but mortality can be minimized with adjustments to anesthetic technique.

Uterine fibroids: current perspectives

PubMed Central

Khan, Aamir T; Shehmar, Manjeet; Gupta, Janesh K

2014-01-01

Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman’s menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge. PMID:24511243

Feasibility of real-time location systems in monitoring recovery after major abdominal surgery.

PubMed

Dorrell, Robert D; Vermillion, Sarah A; Clark, Clancy J

2017-12-01

Early mobilization after major abdominal surgery decreases postoperative complications and length of stay, and has become a key component of enhanced recovery pathways. However, objective measures of patient movement after surgery are limited. Real-time location systems (RTLS), typically used for asset tracking, provide a novel approach to monitoring in-hospital patient activity. The current study investigates the feasibility of using RTLS to objectively track postoperative patient mobilization. The real-time location system employs a meshed network of infrared and RFID sensors and detectors that sample device locations every 3 s resulting in over 1 million data points per day. RTLS tracking was evaluated systematically in three phases: (1) sensitivity and specificity of the tracking device using simulated patient scenarios, (2) retrospective passive movement analysis of patient-linked equipment, and (3) prospective observational analysis of a patient-attached tracking device. RTLS tracking detected a simulated movement out of a room with sensitivity of 91% and specificity 100%. Specificity decreased to 75% if time out of room was less than 3 min. All RTLS-tagged patient-linked equipment was identified for 18 patients, but measurable patient movement associated with equipment was detected for only 2 patients (11%) with 1-8 out-of-room walks per day. Ten patients were prospectively monitored using RTLS badges following major abdominal surgery. Patient movement was recorded using patient diaries, direct observation, and an accelerometer. Sensitivity and specificity of RTLS patient tracking were both 100% in detecting out-of-room ambulation and correlated well with direct observation and patient-reported ambulation. Real-time location systems are a novel technology capable of objectively and accurately monitoring patient movement and provide an innovative approach to promoting early mobilization after surgery.

The role of ICP monitoring in patients with persistent cerebrospinal fluid leak following spinal surgery: a case series.

PubMed

Craven, Claudia; Toma, Ahmed K; Khan, Akbar A; Watkins, Laurence D

2016-09-01

Cerebrospinal fluid (CSF) leak following spinal surgery is a relatively common surgical complication. A disturbance in the underlying CSF dynamics could be the causative factor in a small group of patients with refractory CSF leaks that require multiple surgical repairs and prolonged hospital admission. A retrospective case series of patients with persistent post spinal surgery CSF leak referred to the hydrocephalus service for continuous intracranial pressure (ICP) monitoring. Patients' notes were reviewed for medical history, ICP data, radiological data, and subsequent management and outcome. Five patients (two males/three females, mean age, 35.4 years) were referred for ICP monitoring over a 12-month period. These patients had prolonged CSF leak despite multiple repair attempts 252 ± 454 days (mean ± SD). On ICP monitoring, all five patients had abnormal results, with the mean ICP 8.95 ± 4.41 mmHg. Four had abnormal pulse amplitudes, mean 6.15 mmHg ± 1.22 mmHg. All five patients underwent an intervention. Three patients underwent insertion of ventriculoperitoneal (VP) shunts. One patient had venous sinus stent insertion and one patient underwent medical management with acetazolamide. All five of the patients' CSF leak resolved post intervention. The mean time to resolution of CSF leak post intervention was 10.8  ± 12.9 days. Abnormal cerebrospinal fluid dynamics could be the underlying factor in patients with a persistent and treatment-refractory CSF leak post spinal surgery. Treatments aimed at lowering ICP may be beneficial in this group of patients. Whether abnormal pressure and dynamics represent a pre-existing abnormality or is induced by spinal surgery should be a subject of further study.

Video-assisted thoracoscopic surgery lobectomy via confronting upside-down monitor setting

PubMed Central

Ichinose, Junji; Matsuura, Yosuke; Nakao, Masayuki; Okumura, Sakae

2017-01-01

Video-assisted thoracoscopic surgery (VATS) has been widely accepted as a minimally invasive surgery for treatment of early-stage lung cancer. However, various VATS approaches are available. In patients with lung cancer, VATS should achieve not only minimal invasiveness but also safety and oncological clearance. In this article, we introduce our method of VATS lobectomy. PMID:29078689

Strategic hospital partnerships: improved access to care and increased epilepsy surgical volume.

PubMed

Vadera, Sumeet; Chan, Alvin Y; Mnatsankanyan, Lilit; Sazgar, Mona; Sen-Gupta, Indranil; Lin, Jack; Hsu, Frank P K

2018-05-01

OBJECTIVE Surgical treatment of patients with medically refractory focal epilepsy is underutilized. Patients may lack access to surgically proficient centers. The University of California, Irvine (UCI) entered strategic partnerships with 2 epilepsy centers with limited surgical capabilities. A formal memorandum of understanding (MOU) was created to provide epilepsy surgery to patients from these centers. METHODS The authors analyzed UCI surgical and financial data associated with patients undergoing epilepsy surgery between September 2012 and June 2016, before and after institution of the MOU. Variables collected included the length of stay, patient age, seizure semiology, use of invasive monitoring, and site of surgery as well as the monthly number of single-surgery cases, complex cases (i.e., staged surgeries), and overall number of surgery cases. RESULTS Over the 46 months of the study, a total of 104 patients underwent a total of 200 operations; 71 operations were performed in 39 patients during the pre-MOU period (28 months) and 129 operations were performed in 200 patients during the post-MOU period (18 months). There was a significant difference in the use of invasive monitoring, the site of surgery, the final therapy, and the type of insurance. The number of single-surgery cases, complex-surgery cases, and the overall number of cases increased significantly. CONCLUSIONS Partnerships with outside epilepsy centers are a means to increase access to surgical care. These partnerships are likely reproducible, can be mutually beneficial to all centers involved, and ultimately improve patient access to care.

Monitoring of brain oxygen saturation (INVOS) in a protocol to direct blood transfusions during cardiac surgery: a prospective randomized clinical trial.

PubMed

Vretzakis, George; Georgopoulou, Stavroula; Stamoulis, Konstantinos; Tassoudis, Vassilios; Mikroulis, Dimitrios; Giannoukas, Athanasios; Tsilimingas, Nikolaos; Karanikolas, Menelaos

2013-06-07

Blood transfusions are common in cardiac surgery, but have been associated with increased morbidity and long-term mortality. Efforts to reduce blood product use during cardiac surgery include fluid restriction to minimize hemodilution, and protocols to guide transfusion decisions. INVOS is a modality that monitors brain tissue oxygen saturation, and could be useful in guiding decisions to transfuse. However, the role of INVOS (brain tissue oxygen saturation) as part of an algorithm to direct blood transfusions during cardiac surgery has not been evaluated. This study was conducted to investigate the value of INVOS as part of a protocol for blood transfusions during cardiac surgery. Prospective, randomized, blinded clinical trial, on 150 (75 per group) elective cardiac surgery patients. The study was approved by the Institution Ethics committee and all patients gave written informed consent. Data were initially analyzed based on "intention to treat", but subsequently were also analyzed "per protocol". When protocol was strictly followed ("per protocol analysis"), compared to the control group, significantly fewer patients monitored with INVOS received any blood transfusions (46 of 70 patients in INVOS group vs. 55 of 67 patients in the control group, p = 0.029). Similarly, patients monitored with INVOS received significantly fewer units of red blood cell transfusions intraoperatively (0.20 ± 0.50 vs. 0.52 ± 0.88, p = 0.008) and overall during hospital stay (1.31 ± 1.20 vs. 1.82 ± 1.46, p = 0.024). When data from all patients (including patient with protocol violation) were analyzed together ("intention to treat analysis"), the observed reduction of blood transfusions in the INVOS group was still significant (51 of 75 patients transfused in the INVOS group vs. 63 of 75 patients transfused in the control group, p = 0.021), but the overall number of units transfused per patient did not differ significantly between the groups (1.55 ± 1.97 vs. 1.84 ± 1.41, p = 0.288). Our data suggest that INVOS could be a useful tool as part of an algorithm to guide decisions for blood transfusion in cardiac surgery. Additional data from rigorous, well designed studies are needed to further evaluate the role of INVOS in guiding blood transfusions in cardiac surgery, and circumvent the limitations of this study.

Anaesthetic considerations for pectus repair surgery

PubMed Central

Patvardhan, Chinmay

2016-01-01

Repair of pectus is one of the most common congenital abnormality for which patient presents for thoracic surgery. In recent years, innovative minimally invasive techniques involving video assisted thoracoscopy for pectus repair have become the norm. Similarly, anaesthetic techniques have evolved to include principles of enhanced recovery, multimodal analgesia and innovative ultrasound guided neuraxial and nerve blocks. Adequate anaesthetic set up and monitoring including the use of real time intraoperative monitoring with transesophageal echocardiography (TOE) has enabled the anaesthetist to enhance patient safety by providing instantaneous imaging of cardiac compression and complications during surgery. In this review article we aim to provide non-systematic review and institutional experience of our anaesthetic strategy to provide effective peri-operative care in this patient group. PMID:29078504

Oxygen supply (HbO2) in beating hearts of 14 coronary patients obtained by tissue monitoring with optical sensors

NASA Astrophysics Data System (ADS)

Frank, Klaus H.; Kloevekorn, P.; Zuendorf, J.; Kessler, Manfred D.

2002-06-01

Local intra capillary HbO2 was monitored in beating hearts of 14 patients undergoing coronary bypass surgery. The spectra were measured in the epicardium of the left ventricle, supplied by the left coronary artery (LAD). All selected patients suffered form stenosis or occlusion of two to three vessels. The patients suffered from severe angina and showed hypokinesia in the angiography. Micro-light guide fibers with a diameter of 75micrometers were used for monitoring before and after bypass surgery. These light guides were connected to the Erlanger Micro Light guide Spectro Photometer EMPHO for registration. Local measurements were performed in the epicardium of the left ventricle in 25 areas 2.25cm2 each. Integrated gradient fields were plotted for each of the 14 patients before and after bypass surgery. The mean values of HbO2 in the respective areas were calculated and evaluated against the local value distribution.

Brain function monitoring during off-pump cardiac surgery: a case report

PubMed Central

Zanatta, Paolo; Bosco, Enrico; Di Pasquale, Piero; Nivedita, Agarwal; Valfrè, Carlo; Sorbara, Carlo

2008-01-01

Background Early postoperative stroke is an adverse syndrome after coronary bypass surgery. This report focuses on overcoming of cerebral ischemia as a result of haemodynamic instability during heart enucleation in off-pump procedure. Case presentation A 67 year old male patient, Caucasian race, with a body mass index of 28, had a recent non-Q posterolateral myocardial infarction one month before and recurrent instable angina. His past history includes an uncontrolled hypertension, dyslipidemia, insulin dependent diabetes mellitus, epiaortic vessel stenosis. The patient was scheduled for an off-pump procedure and monitored with bilateral somatosensory evoked potentials, whose alteration signalled the decrement of the cardiac index during operation. The somatosensory evoked potentials appeared when the blood pressure was increased with a pharmacological treatment. Conclusion During the off-pump coronary bypass surgery, a lower cardiac index, predisposes patients, with multiple stroke risk factors, to a reduction of the cerebral blood flow. Intraoperative somatosensory evoked potentials monitoring provides informations about the functional status of somatosensory cortex to reverse effects of brain ischemia. PMID:18706094

Intermittent neural monitoring of the recurrent laryngeal nerve in surgery for recurrent goiter

PubMed Central

Barczyński, Marcin

2016-01-01

Reoperative thyroid surgery is still challenging even for skilled surgeons, and is associated with a higher incidence of complications, such as hypoparathyroidism and recurrent laryngeal nerve (RLN) palsy. Displacement of the RLN, scar tissue from previous neck surgery and difficulty in maintaining good hemostasis are risk factors in reoperations. The prevalence of RLN injury in reoperative thyroid surgery ranges as high as 12.5% for transient injury and up to 3.8% for permanent injury. Bilateral paresis can also occur during reoperations, and is a dangerous complication influencing the quality of life, sometimes requiring tracheostomy. RLN identification is the gold standard during thyroidectomy, and the use of intraoperative neuromonitoring (IONM) can be a valuable adjunct to visual identification. This technique can be used to identify the RLN and the external branch of the superior laryngeal nerve (EBSLN), both of which are standardized procedures. The aim of this review was to evaluate the use of intermittent neural monitoring of the RLN in surgery for recurrent goiter, and to assess the prevalence of RLN injury while using IONM reported in the current literature. PMID:27867862

Optimizing sonication protocols for transthoracic focused ultrasound surgery

NASA Astrophysics Data System (ADS)

Gao, J.; Volovick, A.; Cao, R.; Nabi, G.; Cochran, S.; Melzer, A.; Huang, Z.

2012-11-01

During transthoracic focused ultrasound surgery (TFUS), the intervening ribs absorb and reflect the majority of the ultrasound energy excited by an acoustic source, resulting in pain, bone injuries and insufficient energy delivered to the target organs of liver, kidney, and pancreas. Localized hot spots may also exist at the interfaces between the ribs and soft tissue and in the highly absorptive regions such as the skin and connective tissue. The aims of this study were to clarify the effects of focal beam distortion and frequency-dependent rib heating in TFUS and to propose possible techniques to reduce the side-effects of rib heating and increase ultrasound efficacy. Frequency-dependent heating at the target and the ribs were estimated using finite element analysis (PZFlex, Weidlinger Associates Inc, USA) along with experimental verification on a range of different phantoms. The ratio of ultrasonic power density at the target and the ribs, the time-varying spatial distribution of temperature, and the ablated focus of each sonication were taken as key indicators to determine the optimal operating frequency. Comparison with a patient specific model was also made. TFUS seems to be useful to treat tumours that are small and near the surface of the abdominal organs. For targets deep inside these organs, severe attenuation of energy occurs, suggesting that purely ultrasound thermal ablation with advanced heating patterns will have limited effects in improving the treatment efficacy. Results demonstrate that the optimal ultrasound frequency is around 0.8 MHz for the configurations considered, but this may shift to higher frequencies with changes in the axial and lateral positions of the tumours relative to the ribs. To date, we have elucidated the most important effects and correlated these with idealised anatomical geometry. The changes in frequency and other techniques such as selection of excited element patterns in FUS arrays had some effect. However, more advanced techniques need to be explored for further enhanced localised heating in the TFUS study, if this is to prove fully effective.

An Intelligent Decision System for Intraoperative Somatosensory Evoked Potential Monitoring.

PubMed

Fan, Bi; Li, Han-Xiong; Hu, Yong

2016-02-01

Somatosensory evoked potential (SEP) is a useful, noninvasive technique widely used for spinal cord monitoring during surgery. One of the main indicators of a spinal cord injury is the drop in amplitude of the SEP signal in comparison to the nominal baseline that is assumed to be constant during the surgery. However, in practice, the real-time baseline is not constant and may vary during the operation due to nonsurgical factors, such as blood pressure, anaesthesia, etc. Thus, a false warning is often generated if the nominal baseline is used for SEP monitoring. In current practice, human experts must be used to prevent this false warning. However, these well-trained human experts are expensive and may not be reliable and consistent due to various reasons like fatigue and emotion. In this paper, an intelligent decision system is proposed to improve SEP monitoring. First, the least squares support vector regression and multi-support vector regression models are trained to construct the dynamic baseline from historical data. Then a control chart is applied to detect abnormalities during surgery. The effectiveness of the intelligent decision system is evaluated by comparing its performance against the nominal baseline model by using the real experimental datasets derived from clinical conditions.

Comparison of visual evoked potential monitoring during spine surgeries under total intravenous anesthesia versus balanced general anesthesia.

PubMed

Uribe, Alberto A; Mendel, Ehud; Peters, Zoe A; Shneker, Bassel F; Abdel-Rasoul, Mahmoud; Bergese, Sergio D

2017-10-01

To determine the comparison of its clinical utility and safety profile for visual evoked potential (VEP) monitoring during prone spine surgeries under total intravenous anesthesia (TIVA) versus balanced general anesthesia using the SightSaver™ visual stimulator. The protocol was designed asa pilot, single center, prospective, randomized, and double-arm study. Subjects were randomized to receive either TIVA or balanced general anesthesia. Following induction and intubation, 8 electrodes were placed subcutaneously to collect VEP recordings. The SightSaver™ visual stimulator was placed on the subject's scalp before prone positioning. VEP waveforms were recorded every 30min and assessed by a neurophysiologist throughout the length of surgery. A total of 19 subjects were evaluated and VEP waveforms were successfully collected. TIVA group showed higher amplitude and lower latency than balanced anesthesia. Our data suggested that TIVA is associated with higher VEP amplitude and shorter latencies than balanced general anesthesia; therefore, TIVA could be the most efficient anesthesia regimen for VEP monitoring. The findings help to better understand the effect of different anesthesia regimens on intra-operative VEP monitoring. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

The effect of temperature correction of blood gas values on the accuracy of end-tidal carbon dioxide monitoring in children after cardiac surgery.

PubMed

Suominen, Pertti K; Stayer, Stephen; Wang, Wei; Chang, Anthony C

2007-01-01

We evaluated accuracy of end-tidal carbon dioxide tension (PETco2) monitoring and measured the effect of temperature correction of blood gas values in children after cardiac surgery. Data from 49 consecutive mechanically ventilated children after cardiac surgery in the cardiac intensive care unit were prospectively collected. One patient was excluded from the study. Four arterial-end-tidal CO2 pairs in each patient were obtained. Both the arterial carbon dioxide tension (Paco2) values determined at a temperature of 37 degrees C and values corrected to body temperature (Patcco2) were compared with the PETco2 values. After the surgical correction 28 patients had biventricular, acyanotic (mean age 2.7 +/- 4.8 years) and 20 patients had a cyanotic lesion (mean age 1.0 +/- 1.7 years). The body temperature ranged from 35.2 degrees C to 38.9 degrees C. The Pa-PETco2 discrepancy was affected both by the type of cardiac lesion and by the temperature correction of Paco2 values. Correlation slopes of the Pa-PETco2 and Patc-PETco2 discrepancies were significantly different (p = 0.040) when the body temperature was higher or lower than 37 degrees C. In children, after cardiac surgery, end-tidal CO2 monitoring provided a clinically acceptable estimate of arterial CO2 value, which remained stabile in repeated measurements. End-tidal CO2 monitoring more accurately reflects temperature-corrected blood gas values.

Preclinical evaluation of a low-frequency transcranial MRI-guided focused ultrasound system in a primate model

NASA Astrophysics Data System (ADS)

McDannold, Nathan; Livingstone, Margaret; Barış Top, Can; Sutton, Jonathan; Todd, Nick; Vykhodtseva, Natalia

2016-11-01

This study investigated thermal ablation and skull-induced heating with a 230 kHz transcranial MRI-guided focused ultrasound (TcMRgFUS) system in nonhuman primates. We evaluated real-time acoustic feedback and aimed to understand whether cavitation contributed to the heating and the lesion formation. In four macaques, we sonicated thalamic targets at acoustic powers of 34-560 W (896-7590 J). Tissue effects evaluated with MRI and histology were compared to MRI-based temperature and thermal dose measurements, acoustic emissions recorded during the experiments, and acoustic and thermal simulations. Peak temperatures ranged from 46 to 57 °C, and lesions were produced in 5/8 sonicated targets. A linear relationship was observed between the applied acoustic energy and both the focal and brain surface heating. Thermal dose thresholds were 15-50 cumulative equivalent minutes at 43 °C, similar to prior studies at higher frequencies. Histology was also consistent with earlier studies of thermal effects in the brain. The system successfully controlled the power level and maintained a low level of cavitation activity. Increased acoustic emissions observed in 3/4 animals occurred when the focal temperature rise exceeded approximately 16 °C. Thresholds for thermally-significant subharmonic and wideband emissions were 129 and 140 W, respectively, corresponding to estimated pressure amplitudes of 2.1 and 2.2 MPa. Simulated focal heating was consistent with the measurements for sonications without thermally-significant acoustic emissions; otherwise it was consistently lower than the measurements. Overall, these results suggest that the lesions were produced by thermal mechanisms. The detected acoustic emissions, however, and their association with heating suggest that cavitation might have contributed to the focal heating. Compared to earlier work with a 670 kHz TcMRgFUS system, the brain surface heating was substantially reduced and the focal heating was higher with this 230 kHz system, suggesting that a reduced frequency can increase the treatment envelope for TcMRgFUS and potentially reduce the risk of skull heating.

In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice.

PubMed

Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E

2010-10-21

The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity® microbubbles (mean diameter range: 1.1-3.3 µm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 µm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity® microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without craniotomy in mice and IC may not be required for BBB opening at relatively low pressures.

Multimodal intraoperative monitoring: an overview and proposal of methodology based on 1,017 cases

PubMed Central

Eggspuehler, Andreas; Muller, Alfred; Dvorak, Jiri

2007-01-01

To describe different currently available tests of multimodal intraoperative monitoring (MIOM) used in spine and spinal cord surgery indicating the technical parameters, application and interpretation as an easy understanding systematic overview to help implementation of MIOM and improve communication between neurophysiologists and spine surgeons. This article aims to give an overview and proposal of the different MIOM-techniques as used daily in spine and spinal cord surgery at our institution. Intensive research in neurophysiology over the past decades has lead to a profound understanding of the spinal cord, nerve functions and their intraoperative functional evaluation in anaesthetised patients. At present, spine surgeons and neurophysiologist are faced with 1,883 publications in PubMed on spinal cord monitoring. The value and the limitations of single monitoring methods are well documented. The diagnostic power of the multimodal approach in a larger study population in spine surgery, as measured with sensitivity and specificity, is dealt with elsewhere in this supplement (Sutter et al. in Eur Spine J Suppl, 2007). This paper aims to give a detailed description of the different modalities used in this study. Description of monitoring techniques of the descending and ascending spinal cord and nerve root pathways by motor evoked potentials of the spinal cord and muscles elicited after transcranial electrical motor cortex, spinal cord, cauda equina and nerve root stimulation, continuous EMG, sensory cortical and spinal evoked potentials, as well as direct spinal cord evoked potentials applied on 1,017 patients. The method of MIOM, continuously adapted according to the site, stage of surgery and potential danger to nerve tissues, proved to be applicable with online results, reliable and furthermore teachable. PMID:17653777

Indocyanine green fluorescence angiography for free flap monitoring: A pilot study.

PubMed

Hitier, Marine; Cracowski, Jean-Luc; Hamou, Cynthia; Righini, Christian; Bettega, Georges

2016-11-01

We evaluated the feasibility and the tolerance of repeated fluorescent indocyanine green angiography in free flap monitoring, and determined the intraoperative predictive values of flap vitality. The free flap failure rate has been significantly reduced, but free flap loss still occurs and remains a costly disaster. Repeated clinical examinations are commonly used for flap monitoring, but they can be unreliable because of their subjectivity. Laser-induced fluorescence of indocyanine green is a new method for assessing tissue perfusion. 20 patients undergoing microsurgical reconstruction were monitored by indocyanine green fluorescence angiography, intraoperatively, and during 4 days after surgery, with 18 injections. Monitoring was made by clinical examination, and then compared to angiographic findings. The vascular complication rate was 15% (3/20) with 2 cases of venous thrombosis and one case of partial necrosis of the flap skin paddle. Both cases of venous thrombosis were salvaged by secondary surgery. There was no total flap loss. ICG angiography allowed detecting each intra and postoperative complication, earlier than clinical examination. The mean per-operative intensity of fluorescence was significantly lower in flaps with vascular complications (23.8 GL/ms; p = 0.008). The postoperative slope (p = 0.02) and amplitude (p = 0.03) of the fluorescent signal were both significantly lower than for uncomplicated flaps, before surgical revision. These 2 parameters came back to normal values after secondary surgery. There was no adverse effect of ICG despite the repeated injections. ICG angiography is a feasible and safe technique for the detection of free flap vascular complications. Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Comparison of false-negative/positive results of intraoperative evoked potential monitoring between no and partial neuromuscular blockade in patients receiving propofol/remifentanil-based anesthesia during cerebral aneurysm clipping surgery: A retrospective analysis of 685 patients.

PubMed

Kim, Sung-Hoon; Jin, Seok-Joon; Karm, Myong-Hwan; Moon, Young-Jin; Jeong, Hye-Won; Kim, Jae-Won; Ha, Seung-Il; Kim, Joung-Uk

2016-08-01

Although the elicited responses of motor evoked potential (MEP) monitoring are very sensitive to suppression by anesthetic agents and muscle relaxants, the use of neuromuscular blockade (NMB) during MEP monitoring is still controversial because of serious safety concerns and diagnostic accuracy. Here, we evaluated the incidence of unacceptable movement and compared false-negative MEP results between no and partial NMB during cerebral aneurysm clipping surgery. We reviewed patient medical records for demographic data, anesthesia regimen, neurophysiology event logs, MEP results, and clinical outcomes. Patients were divided into 2 groups according to the intraoperative use of NMB: no NMB group (n = 276) and partial NMB group (n = 409). We compared the diagnostic accuracy of MEP results to predict postoperative outcomes between both groups. Additionally, we evaluated unwanted patient movement during MEP monitoring in both groups. Of the 685 patients, 622 (90.8%) manifested no intraoperative changes in MEP and no postoperative motor deficits. Twenty patients showed postoperative neurologic deficits despite preserved intraoperative MEP. False-positive MEP results were 3.6% in the no NMB group and 3.9% in the partial NMB group (P = 1.00). False-negative MEP results were 1.1% in the no NMB group and 4.2% in the partial NMB group (P = 0.02). No spontaneous movement or spontaneous respiration was observed in either group. Propofol/remifentanil-based anesthesia without NMB decreases the stimulation intensity of MEPs, which may reduce the false-negative ratio of MEP monitoring during cerebral aneurysm surgery. Our anesthetic protocol enabled reliable intraoperative MEP recording and patient immobilization during cerebral aneurysm clipping surgery.

Trans-falcine and contralateral sub-frontal electrode placement in pediatric epilepsy surgery: technical note.

PubMed

Pindrik, Jonathan; Hoang, Nguyen; Tubbs, R Shane; Rocque, Brandon J; Rozzelle, Curtis J

2017-08-01

Phase II monitoring with intracranial electroencephalography (ICEEG) occasionally requires bilateral placement of subdural (SD) strips, grids, and/or depth electrodes. While phase I monitoring often demonstrates a preponderance of unilateral findings, individual studies (video EEG, single photon emission computed tomography [SPECT], and positron emission tomography [PET]) can suggest or fail to exclude a contralateral epileptogenic onset zone. This study describes previously unreported techniques of trans-falcine and sub-frontal insertion of contralateral SD grids and depth electrodes for phase II monitoring in pediatric epilepsy surgery patients when concern about bilateral abnormalities has been elicited during phase I monitoring. Pediatric patients with medically refractory epilepsy undergoing stage I surgery for phase II monitoring involving sub-frontal and/or trans-falcine insertion of SD grids and/or depth electrodes at the senior author's institution were retrospectively reviewed. Intra-operative technical details of sub-frontal and trans-falcine approaches were studied, while intra-operative complications or events were noted. Operative techniques included gentle subfrontal retraction and elevation of the olfactory tracts (while preserving the relationship between the olfactory bulb and cribriform plate) to insert SD grids across the midline for coverage of the contralateral orbito-frontal regions. Trans-falcine approaches involved accessing the inter-hemispheric space, bipolar cauterization of the anterior falx cerebri below the superior sagittal sinus, and sharp dissection using a blunt elevator and small blade scalpel. The falcine window allowed contralateral SD strip, grid, and depth electrodes to be inserted for coverage of the contralateral frontal regions. The study cohort included seven patients undergoing sub-frontal and/or trans-falcine insertion of contralateral SD strip, grid, and/or depth electrodes from February 2012 through June 2015. Five patients (71%) experienced no intra-operative events related to contralateral ICEEG electrode insertion. Intra-operative events of frontal territory venous engorgement (1/7, 14%) due to sacrifice of anterior bridging veins draining into the SSS and avulsion of a contralateral bridging vein (1/7, 14%), probably due to prior anterior corpus callosotomy, each occurred in one patient. There were no intra-operative or peri-operative complications in any of the patients studied. Two patients required additional surgery for supplemental SD strip and/or depth electrodes via burr hole craniectomy to enhance phase II monitoring. All patients proceeded to stage II surgery for resection of ipsilateral epileptogenic onset zones without adverse events. Trans-falcine and sub-frontal insertion of contralateral SD strip, grid, and depth electrodes are previously unreported techniques for achieving bilateral frontal coverage in phase II monitoring in pediatric epilepsy surgery. This technique obviates the need for contralateral craniotomy and parenchymal exposure with limited, remediable risks. Larger case series using the method described herein are now necessary.

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer.

PubMed

Hamdy, Freddie C; Donovan, Jenny L; Lane, J Athene; Mason, Malcolm; Metcalfe, Chris; Holding, Peter; Davis, Michael; Peters, Tim J; Turner, Emma L; Martin, Richard M; Oxley, Jon; Robinson, Mary; Staffurth, John; Walsh, Eleanor; Bollina, Prasad; Catto, James; Doble, Andrew; Doherty, Alan; Gillatt, David; Kockelbergh, Roger; Kynaston, Howard; Paul, Alan; Powell, Philip; Prescott, Stephen; Rosario, Derek J; Rowe, Edward; Neal, David E

2016-10-13

The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Self-monitoring for atrial fibrillation recurrence in the discharge period post-cardiac surgery using an iPhone electrocardiogram.

PubMed

Lowres, Nicole; Mulcahy, Georgina; Gallagher, Robyn; Ben Freedman, Saul; Marshman, David; Kirkness, Ann; Orchard, Jessica; Neubeck, Lis

2016-07-01

Postoperative atrial fibrillation (POAF) occurs in 25-40% of patients following cardiac surgery, and is associated with a significant increased risk of stroke and mortality. Routine surveillance is not performed post-discharge; however, recurrence of POAF can occur in up to 30% of patients discharged in sinus rhythm. This study aimed to determine the feasibility of patients self-monitoring with an iPhone handheld electrocardiogram (iECG) to identify recurrence of POAF in the post-discharge period following cardiac surgery. Patients with POAF following cardiac surgery were eligible for participation if they had no prior history of atrial fibrillation (AF) and were discharged home in stable sinus rhythm. Participants were provided with an iECG and asked to record a 30-s iECG, four times per day for 4 weeks post-discharge. iECGs were automatically transmitted to a secure server, and reviewed for the presence of AF by the research team and a validated algorithm. All participants also received brief education on AF. Forty-two participants completed the intervention (mean age 69 ± 9 years, 80% male). Self-monitoring for POAF recurrence using an iECG was feasible and acceptable, and participants felt empowered. Self-monitoring identified 24% (95% confidence interval, 12-39%) with an AF recurrence within 17 days of hospital discharge. These participants were significantly younger than those without AF recurrence (64 ± 7 vs 70 ± 10 years; P = 0.025), and had a significantly lower CHA2DS2-VASc score (2.3 ± 1.2 vs 3.7 ± 2.3; P = 0.007). However, 80% were at high enough stroke risk to warrant consideration of anticoagulation, i.e. CHA2DS2-VASc score ≥2. Only 30% of recurrences were associated with palpitations. Participation also improved AF knowledge from 6.4 ± 1.8 to 7.3 ± 1.8 (P = 0.02), of a total score of 10. Providing patients with an iECG is a non-invasive, inexpensive, convenient and feasible way to monitor for AF recurrence in post-cardiac surgery patients. It also provides a mechanism to provide knowledge about the condition and also potentially reduce anxiety. The success of patients using this technology also has implications for extending the use of iECG self-monitoring to other patient groups such as those undergoing antiarrhythmic interventions for AF. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

[Evaluation of the role of combined TES-MEP and CSEP monitoring during the spinal surgery].

PubMed

Chen, Yu-guang; Peng, Xin-sheng; Wan, Yong; Yang, Jun-lin; Zheng, Zhao-min; Zou, Xue-nong; Li, Fo-bao; Shu, Hai-hua; Xia, Jie-hua; Dou, Yun-ling

2010-02-01

To evaluate of the role of transcranial electrical stimulation motor evoked potential (TES-MEP) in combination with cortical somatosensory evoked potential (CSEP) monitoring during the spinal surgery. TES-MEP on bilateral anterior tibial muscle and flexor hallucal brevis and CSEP on bilateral posterior tibial nerve were observed simultaneously on 293 patients during spinal surgery from July 2006 to April 2009. Intravenous anesthesia was employed in all the patients, a part of which were added low dose of sevoflurane or muscle relaxant. The results of TES-MEP, CSEP and combined monitoring were analyzed statistically. Pre-operative and post-operative motor and sensory functions of spinal cord were compared. Success rate of TES-MEP, CSEP and combined monitoring was 90.8%, 96.9% and 100% respectively. For the judgment of motor function of spinal cord, the sensitivity of TES-MEP and CSEP was 100% and 89.3% respectively and the specificity of 98.4% and 96.9%. The Youden index of the two methods was 0.984 and 0.862. For sensory function, the sensitivity of them was 76.7% and 93.3% respectively and the specificity of 98.7% and 98.0%. The Youden index was 0.754 and 0.913. The sensitivity of combined monitoring was 100%, with the specificity of 96.9%. The Youden index was 0.969. The precision of monitoring motor function of spinal cord with TES-MEP is higher than that with CSEP, however, for sensory function, CSEP is more precise. The sensitivity and precision of combined monitoring for spinal cord function were apparently better than that of unitary TES-MEP or CSEP. The combined TES-MEP and CSEP monitoring is a relatively ideal method.

In vivo swine myocardial tissue characterization and monitoring during open chest surgery by time-resolved diffuse near-infrared spectroscopy

NASA Astrophysics Data System (ADS)

Spinelli, Lorenzo; Contini, Davide; Farina, Andrea; Torricelli, Alessandro; Pifferi, Antonio; Cubeddu, Rinaldo; Ascari, Luca; Potì, Luca; Trivella, Maria Giovanna; L'Abbate, Antonio; Puzzuoli, Stefano

2011-03-01

Cardiovascular diseases are the main cause of death in industrialized countries. Worldwide, a large number of patients suffering from cardiac diseases are treated by surgery. Despite the advances achieved in the last decades with myocardial protection, surgical failure can still occur. This is due at least in part to the imperfect control of the metabolic status of the heart in the various phases of surgical intervention. At present, this is indirectly controlled by the electrocardiogram and the echographic monitoring of cardiac mechanics as direct measurements are lacking. Diffuse optical technologies have recently emerged as promising tools for the characterization of biological tissues like breast, muscles and bone, and for the monitoring of important metabolic parameters such as blood oxygenation, volume and flow. As a matter of fact, their utility has been demonstrated in a variety of applications for functional imaging of the brain, optical mammography and monitoring of muscle metabolism. However, due to technological and practical difficulties, their potential for cardiac monitoring has not yet been exploited. In this work we show the feasibility of the in-vivo determination of absorption and scattering spectra of the cardiac muscle in the 600-1100 nm range, and of monitoring myocardial tissue hemodynamics by time domain near-infrared spectroscopy at 690 nm and 830 nm. Both measurements have been performed on the exposed beating heart during open chest surgery in pigs, an experimental model closely mimicking the clinical cardio-surgical setting.

Commonly Prescribed Blood Thinner Associated with Higher Risk of Post-Surgery Complications

MedlinePlus

... via an injection, requires no monitoring or blood tests, according to the study. Previous, single-site studies have suggested that there may be an association between preventive anticoagulant use and post-surgery infections or other problems, but this is ...

A Brief Review of Non-invasive Monitoring of Respiratory Condition for Extubated Patients with or at Risk for Obstructive Sleep Apnea after Surgery

PubMed Central

Zhang, Xuezheng; Kassem, Mahmoud Attia Mohamed; Zhou, Ying; Shabsigh, Muhammad; Wang, Quanguang; Xu, Xuzhong

2017-01-01

Obstructive sleep apnea (OSA) is one of the important risk factors contributing to postoperative airway complications. OSA alters the respiratory physiology and increases the sensitivity of muscle tone of the upper airway after surgery to residual anesthetic medication. In addition, the prevalence of OSA was reported to be much higher among surgical patients than the general population. Therefore, appropriate monitoring to detect early respiratory impairment in postoperative extubated patients with possible OSA is challenging. Based on the comprehensive clinical observation, several equipment have been used for monitoring the respiratory conditions of OSA patients after surgery, including the continuous pulse oximetry, capnography, photoplethysmography (PPG), and respiratory volume monitor (RVM). To date, there has been no consensus on the most suitable device as a recommended standard of care. In this review, we describe the advantages and disadvantages of some possible monitoring strategies under certain clinical conditions. According to the literature, the continuous pulse oximetry, with its high sensitivity, is still the most widely used device. It is also cost-effective and convenient to use but has low specificity and does not reflect ventilation. Capnography is the most widely used device for detection of hypoventilation, but it may not provide reliable data for extubated patients. Even normal capnography cannot exclude the existence of hypoxia. PPG shows the state of both ventilation and oxygenation, but its sensitivity needs further improvement. RVM provides real-time detection of hypoventilation, quantitative precise demonstration of respiratory rate, tidal volume, and MV for extubated patients, but no reflection of oxygenation. Altogether, the sole use of any of these devices is not ideal for monitoring of extubated patients with or at risk for OSA after surgery. However, we expect that the combined use of continuous pulse oximetry and RVM may be promising for these patients due to their complementary function, which need further study. PMID:28337439