高能聚焦超声在治疗晚期胰腺癌中的疗效分析

目的：通过对晚期胰腺癌患者行高强度聚焦超声治疗,观察其近期疗效,为晚期胰腺癌患者的临床治疗提供一种新的选择。方法：对15例晚期胰腺癌患者行高强度聚焦超声治疗,对比治疗前后的KPS评分,疼痛感受评分,CA199,三大常规,生化检查,B超观察肿瘤回声及血供,CT观察肿瘤大小改变。结果：HIFU治疗后,患者KPS评分升高,疼痛评分下降,肿瘤标志物下降,B超观察肿瘤回声,其中10例肿瘤回声增强,11例肿瘤血供减少或消失,CT示大部分患者治疗后肿瘤体积缩小或不变,治疗后三大常规、生化和电解质无明显改变。结论：运用高强度聚焦超声治疗晚期胰腺癌患者,在改善患者临床症状方面有明显疗效,并且能缩小肿瘤体积,减少或中断肿瘤血供,是一种很有发展前景的无创治疗方法。     

Optogenetic Functional MRI

The investigation of the functional connectivity of precise neural circuits across the entire intact brain can be achieved through optogenetic functional magnetic resonance imaging (ofMRI), which is a novel technique that combines the relatively high spatial resolution of high-field fMRI with the precision of optogenetic stimulation. Fiber optics that enable delivery of specific wavelengths of light deep into the brain in vivo are implanted into regions of interest in order to specifically stimulate targeted cell types that have been genetically induced to express light-sensitive trans-membrane conductance channels, called opsins. fMRI is used to provide a non-invasive method of determining the brain''s global dynamic response to optogenetic stimulation of specific neural circuits through measurement of the blood-oxygen-level-dependent (BOLD) signal, which provides an indirect measurement of neuronal activity. This protocol describes the construction of fiber optic implants, the implantation surgeries, the imaging with photostimulation and the data analysis required to successfully perform ofMRI. In summary, the precise stimulation and whole-brain monitoring ability of ofMRI are crucial factors in making ofMRI a powerful tool for the study of the connectomics of the brain in both healthy and diseased states.     

Modeling and Predicting Tissue Movement and Deformation for High Intensity Focused Ultrasound Therapy

PurposeIn ultrasound-guided High Intensity Focused Ultrasound (HIFU) therapy, the target tissue (such as a tumor) often moves and/or deforms in response to an external force. This problem creates difficulties in treating patients and can lead to the destruction of normal tissue. In order to solve this problem, we present a novel method to model and predict the movement and deformation of the target tissue during ultrasound-guided HIFU therapy.MethodsOur method computationally predicts the position of the target tissue under external force. This prediction allows appropriate adjustments in the focal region during the application of HIFU so that the treatment head is kept aligned with the diseased tissue through the course of therapy. To accomplish this goal, we utilize the cow tissue as the experimental target tissue to collect spatial sequences of ultrasound images using the HIFU equipment. A Geodesic Localized Chan-Vese (GLCV) model is developed to segment the target tissue images. A 3D target tissue model is built based on the segmented results. A versatile particle framework is constructed based on Smoothed Particle Hydrodynamics (SPH) to model the movement and deformation of the target tissue. Further, an iterative parameter estimation algorithm is utilized to determine the essential parameters of the versatile particle framework. Finally, the versatile particle framework with the determined parameters is used to estimate the movement and deformation of the target tissue.ResultsTo validate our method, we compare the predicted contours with the ground truth contours. We found that the lowest, highest and average Dice Similarity Coefficient (DSC) values between predicted and ground truth contours were, respectively, 0.9615, 0.9770 and 0.9697.ConclusionOur experimental result indicates that the proposed method can effectively predict the dynamic contours of the moving and deforming tissue during ultrasound-guided HIFU therapy.     

An Ultrasound Image-Based Dynamic Fusion Modeling Method for Predicting the Quantitative Impact of In Vivo Liver Motion on Intraoperative HIFU Therapies: Investigations in a Porcine Model

Organ motion is a key component in the treatment of abdominal tumors by High Intensity Focused Ultrasound (HIFU), since it may influence the safety, efficacy and treatment time. Here we report the development in a porcine model of an Ultrasound (US) image-based dynamic fusion modeling method for predicting the effect of in vivo motion on intraoperative HIFU treatments performed in the liver in conjunction with surgery. A speckle tracking method was used on US images to quantify in vivo liver motions occurring intraoperatively during breathing and apnea. A fusion modeling of HIFU treatments was implemented by merging dynamic in vivo motion data in a numerical modeling of HIFU treatments. Two HIFU strategies were studied: a spherical focusing delivering 49 juxtapositions of 5-second HIFU exposures and a toroidal focusing using 1 single 40-second HIFU exposure. Liver motions during breathing were spatially homogenous and could be approximated to a rigid motion mainly encountered in the cranial-caudal direction (f = 0.20Hz, magnitude >13mm). Elastic liver motions due to cardiovascular activity, although negligible, were detectable near millimeter-wide sus-hepatic veins (f = 0.96Hz, magnitude <1mm). The fusion modeling quantified the deleterious effects of respiratory motions on the size and homogeneity of a standard “cigar-shaped” millimetric lesion usually predicted after a 5-second single spherical HIFU exposure in stationary tissues (Dice Similarity Coefficient: DSC<45%). This method assessed the ability to enlarge HIFU ablations during respiration, either by juxtaposing “cigar-shaped” lesions with spherical HIFU exposures, or by generating one large single lesion with toroidal HIFU exposures (DSC>75%). Fusion modeling predictions were preliminarily validated in vivo and showed the potential of using a long-duration toroidal HIFU exposure to accelerate the ablation process during breathing (from 0.5 to 6 cm³·min^-1). To improve HIFU treatment control, dynamic fusion modeling may be interesting for assessing numerically focusing strategies and motion compensation techniques in more realistic conditions.     

Spontaneous regeneration of the central nervous system in gastropods

Of all organs in mammals including humans, the brain has the most limited regenerative capacity after injury or damage. In spite of extensive efforts to treat ischemic/stroke injury of the brain, thus far no reliable therapeutic method has been developed. However, some molluscan species show remarkable brain regenerative ability and can achieve full functional recovery following injury. The terrestrial pulmonates are equipped with a highly developed olfactory center, called the procerebrum, which is involved in olfactory discrimination and odor-aversion learning. Recent studies revealed that the procerebrum of the land slug can spontaneously recover structurally and functionally relatively soon after injury. Surprisingly, no exogenous interventions are required for this reconstitutive repair. The neurogenesis continues in the procerebrum in adult slugs as in the hippocampus and the olfactory bulb of mammals, and the reconstitutive regeneration seems to be mediated by enhanced neurogenesis. In this review, we discuss the relationship between neurogenesis and the regenerative ability of the brain, and also the evolutionary origin of the brain structures in which adult neurogenesis has been observed.     

Non-fluent aphasia and neural reorganization after speech therapy: insights from human sleep electrophysiology and functional magnetic resonance imaging

Stroke is associated with long-term functional deficits. Behavioral interventions are often effective in promoting functional recovery and plastic changes. Recent studies in normal subjects have shown that sleep, and particularly slow wave activity (SWA), is tied to local brain plasticity and may be used as a sensitive marker of local cortical reorganization after stroke. In a pilot study, we assessed the local changes induced by a single exposure to a therapeutic session of IMITATE (Intensive Mouth Imitation and Talking for Aphasia Therapeutic Effects), a behavioral therapy used for recovery in patients with post-stroke aphasia. In addition, we measured brain activity changes with functional magnetic resonance imaging (fMRI) in a language observation task before, during and after the full IMITATE rehabilitative program. Speech production improved both after a single exposure and the full therapy program as measured by the Western Aphasia Battery (WAB) Repetition subscale. We found that IMITATE induced reorganization in functionally-connected, speech-relevant areas in the left hemisphere. These preliminary results suggest that sleep hd-EEGs, and the topographical analysis of SWA parameters, are well suited to investigate brain plastic changes underpinning functional recovery in neurological disorders.     

基于频谱图像灰度共生矩阵的无损测温方法

本文提出了一种基于哈达玛变换的频谱图像灰度共生矩阵(Hadamard-GLCM)的高强度聚焦超声治疗无损测温方法。利用高强度聚焦超声辐照新鲜离体猪肉组织,获取辐照前后的B超图像的减影图像,采用Hadamard变换对其进行处理,获取频谱图像,将频谱图像的灰度共生矩阵惯性矩作为反应温度变化的信息参数。实验表明:不仅单组数据的Hadamard-GLCM惯性矩(HGMI)和温度能很好的线性拟合,而且多组数据的Hadamard-GLCM惯性矩与温度也成近似的线性关系,而且斜率非常接近,拟合度更接近1,误差小,对温度的分辨能力高,容错能力强,与传统的测温方法相比有着明显的优势,能为HIFU治疗过程中的无损测温提供有效的实时依据。     

The “Janus-Faced Role” of Autophagy in Neuronal Sickness: Focus on Neurodegeneration

The mature brain is a highly dynamic organ that constantly changes its organization by destroying and forming new connections. Collectively, these changes are referred to as brain plasticity and are associated with functional changes, such as memory, addiction, and recovery of function after brain damage. Neuronal plasticity is sustained by the fine regulation of protein synthesis and organelle biogenesis and their degradation to ensure efficient turnover. Thus, autophagy, as quality control mechanism of proteins and organelles in neurons, is essential to their physiology and pathology. Here, we review recent several findings proving that defects in autophagy affect neuronal function and impair functional recovery after brain insults, contributing to neurodegeneration, in chronic and acute neurological disorders. Thus, an understanding of the molecular mechanisms by which the autophagy machinery is finely regulated might accelerate the development of therapeutic interventions in many neurological disorders for which no cure is available.     

A Split-and-Merge-Based Uterine Fibroid Ultrasound Image Segmentation Method in HIFU Therapy

High-intensity focused ultrasound (HIFU) therapy has been used to treat uterine fibroids widely and successfully. Uterine fibroid segmentation plays an important role in positioning the target region for HIFU therapy. Presently, it is completed by physicians manually, reducing the efficiency of therapy. Thus, computer-aided segmentation of uterine fibroids benefits the improvement of therapy efficiency. Recently, most computer-aided ultrasound segmentation methods have been based on the framework of contour evolution, such as snakes and level sets. These methods can achieve good performance, although they need an initial contour that influences segmentation results. It is difficult to obtain the initial contour automatically; thus, the initial contour is always obtained manually in many segmentation methods. A split-and-merge-based uterine fibroid segmentation method, which needs no initial contour to ensure less manual intervention, is proposed in this paper. The method first splits the image into many small homogeneous regions called superpixels. A new feature representation method based on texture histogram is employed to characterize each superpixel. Next, the superpixels are merged according to their similarities, which are measured by integrating their Quadratic-Chi texture histogram distances with their space adjacency. Multi-way Ncut is used as the merging criterion, and an adaptive scheme is incorporated to decrease manual intervention further. The method is implemented using Matlab on a personal computer (PC) platform with Intel Pentium Dual-Core CPU E5700. The method is validated on forty-two ultrasound images acquired from HIFU therapy. The average running time is 9.54 s. Statistical results showed that SI reaches a value as high as 87.58%, and normHD is 5.18% on average. It has been demonstrated that the proposed method is appropriate for segmentation of uterine fibroids in HIFU pre-treatment imaging and planning.     

Default Mode Network,Motor Network,Dorsal and Ventral Basal Ganglia Networks in the Rat Brain: Comparison to Human Networks Using Resting State-fMRI

Rodent models are developed to enhance understanding of the underlying biology of different brain disorders. However, before interpreting findings from animal models in a translational aspect to understand human disease, a fundamental step is to first have knowledge of similarities and differences of the biological systems studied. In this study, we analyzed and verified four known networks termed: default mode network, motor network, dorsal basal ganglia network, and ventral basal ganglia network using resting state functional MRI (rsfMRI) in humans and rats. Our work supports the notion that humans and rats have common robust resting state brain networks and that rsfMRI can be used as a translational tool when validating animal models of brain disorders. In the future, rsfMRI may be used, in addition to short-term interventions, to characterize longitudinal effects on functional brain networks after long-term intervention in humans and rats.     

Current Trainee and Workforce Patterns for Thyroid and Parathyroid Surgery in the United States

ObjectiveThyroid and parathyroid surgery is performed by both general surgeons and otolaryngologists. We describe the proportion of surgeries performed by specialty, providing data to support decisions about when and to whom to direct research, education, and quality improvement interventions.MethodsWe tabulated case numbers for privately insured patients undergoing thyroid and parathyroid surgery in Marketscan: 2010–2016 and trainee case logs for residents and fellows in general surgery and otolaryngology. Summary statistics and tests for trends and differences were calculated.ResultsMarketscan data captured 114 500 thyroid surgeries. The proportion performed by each specialty was not significantly different. Otolaryngologists performed 58 098 and general surgeons performed 56 402. Otolaryngologists more commonly performed hemithyroidectomy (n = 25 148, 43.29% of all thyroid surgeries performed by otolaryngologists) compared to general surgeons (n = 20 353, 36.09% of all thyroid surgeries performed by general surgeons). Marketscan data captured 21 062 parathyroid surgeries: 6582 (31.25%) were performed by otolaryngologists, and 14 480 (68.75%) were performed by general surgeons. The case numbers of otolaryngology and general surgery trainees completing residency and fellowship varied 6- to 9-fold across different sites. The wide variation may reflect both the level of exposure a particular training program offers and trainee level of interest.ConclusionThyroid surgical care is equally provided by general surgeons and otolaryngologists. Both specialties contribute significantly to parathyroid surgical care. Both specialties should provide input into and be targets of research, quality, and education interventions.     

High-Intensity Focused Ultrasound (HIFU) for Dissolution of Clots in a Rabbit Model of Embolic Stroke

It is estimated that only 2-6% of patients receive thrombolytic therapy for acute ischemic stroke suggesting that alternative therapies are necessary. In this study, we investigate the potential for high intensity focused ultrasound (HIFU) to initiate thrombolysis in an embolic model of stroke. Iron-loaded blood clots were injected into the middle cerebral artery (MCA) of New Zealand White rabbits, through the internal carotid artery and blockages were confirmed by angiography. MRI was used to localize the iron-loaded clot and target the HIFU beam for treatment. HIFU pulses (1.5 MHz, 1 ms bursts, 1 Hz pulse repetition frequency, 20 s duration) were applied to initiate thrombolysis. Repeat angiograms and histology were used to assess reperfusion and vessel damage. Using 275 W of acoustic power, there was no evidence of reperfusion in post-treatment angiograms of 3 rabbits tested. In a separate group of animals, 415 W of acoustic power was applied and reperfusion was observed in 2 of the 4 (50%) animals treated. In the last group of animals, acoustic power was further increased to 550 W, which led to the reperfusion in 5 of 7 (～70%) animals tested. Histological analysis confirmed thatthe sonicated vessels remained intact after HIFU treatment. Hemorrhage was detected outside of the sonication site, likely due to the proximity of the target vessel with the base of the rabbit skull. These results demonstrate the feasibility of using HIFU, as a stand-alone method, to cause effective thrombolysis without immediate damage to the targeted vessels. HIFU, combined with imaging modalities used to identify and assess stroke patients, could dramatically reduce the time to achieve flow restoration in patients thereby significantly increasing the number of patients which benefit from thrombolysis treatments.     

Can ultrasound be used to stimulate nerve tissue?

Background  

The stimulation of nerve or cortical tissue by magnetic induction is a relatively new tool for the non-invasive study of the brain and nervous system. Transcranial magnetic stimulation (TMS), for example, has been used for the functional mapping of the motor cortex and may have potential for treating a variety of brain disorders.     

The Value of Proton Magnetic Resonance Spectroscopy in High-Intensity Focused Ultrasound Treatment of Experimental Liver Cancer

High-intensity focused ultrasound (HIFU) is a rapidly developing, non-invasive technique for local treatment of solid tumors that produce coagulative tumor necrosis. This study is aimed to investigate the feasibility of proton magnetic resonance spectroscopy (MRS) on early assessing treatment of HIFU ablation in rabbit with VX2 liver tumor. HIFU ablation was performed on normal liver and VX2 tumor in rabbit, and MRS was performed on normal liver and VX2 tumor before and 2 days after 100% HIFU ablation or 80% ablation in tumor volume. Choline (Cho) and choline/lipid (Cho/Lip) ratios between complete and partial HIFU ablation of tumor were compared. Tissues were harvested and sequentially sliced to confirm the necrosis. In normal liver, the Cho value liver was not obviously changed after HIFU (P > .05), but the Cho/Lip ratio was decreased (P < .05). Cho in liver VX2 tumor was much higher than that in normal liver (P < .001). Cho and Cho/Lip ratio were significantly decreased in tumor after complete HIFU ablation and partial HIFU ablation, and the Cho value in complete HIFU tumor ablation did not show any difference from that in normal liver after HIFU (P > .05); however, the Cho value in partial ablation was still higher than that in normal liver before or in tumor after complete HIFU treatment due to the residual part of tumors, and Cho/Lip ratio is lower than that in complete HIFU treatment (P < .001). The changes in MRS parameters were consistent with histopathologic changes of the tumor tissues after treatment. MRS could differentiate the complete tumor necrosis from residual tumor tissue, when combined with magnetic resonance imaging. We conclude that MRS may be applied as an important, non-invasive biomarker for monitoring the thoroughness of HIFU ablation.     

Experimental focal ischemic injury: behavior-brain interactions and issues of animal handling and housing

In experimental neurological models of brain injury, behavioral manipulations before and after the insult can have a major impact on molecular, anatomical, and functional outcome. Investigators using animals for preclinical research should keep in mind that people with brain injury have lived in, and will continue to live in, an environment that is far more complex than that of the typical laboratory rodent. To yield more reliable and relevant behavioral assessment, it may be appropriate in some cases to house animals in environments that allow for motor enrichment and to handle animals in ways that promote tameness. Experience can affect mechanisms of plasticity and degeneration beneficially or adversely. Behavioral interventions that have been found to modulate postinjury brain events are reviewed. The timing and interaction of biological and motor therapies and the potential contribution of experience-dependent and drug-induced trophic factor expression are discussed.     

Inducing occlusion effect in Y-shaped vessels using high-intensity focused ultrasound: finite element analysis and phantom validation

High-intensity focused ultrasound (HIFU) surgery offers a truly non-invasive treatment method with no skin incision, but precise targeting of tumour tissues for thermotherapy. Clinical experience reveals that the efficacy of tumour destruction not only involves in coagulating necrosis, but also involves in damaging the tumour vessels, which play an important role in tumour progression. These vessels take the elevated temperature away by perfusion, resulting in uncertainty of the occlusion effect during HIFU treatment. In this study, a Y-shaped vessel model comprising common and tumour vessels and an indirect fabrication method are proposed. The physical properties of the fabricated vessel phantom are measured and compared with human tissue. Simulation is performed using finite element modelling according to the tissue parameter, perfusion rate of the tumour vessel and treatment parameters including power intensity and exposure duration. The phantom experiments are carried out with perfusion of egg white to validate the threshold time prediction obtained from the simulation results. Our findings reveal that the threshold time obtained from experiments is consistent with the simulated one.     

Estrogen synthesis in fetal sheep brain: effect of maternal treatment with an aromatase inhibitor

The aim of the present study was to determine whether the fetal lamb brain has the capacity to aromatize androgens to estrogens during the critical period for sexual differentiation. We also determined whether administration of the aromatase-inhibitor 1,4,6-androstatriene-3,17-dione (ATD) could cross the placenta and inhibit aromatase activity (AA) in fetal brain. Eight pregnant ewes were utilized. On Day 50 of pregnancy, four ewes were given ATD-filled Silastic implants, and the other four ewes received sham surgeries. The fetuses were surgically delivered 2 wk later (Day 64 of gestation). High levels of AA (0.8-1.4 pmol/h/mg protein) were present in the hypothalamus and amygdala. Lower levels (0.02-0.1 pmol/h/mg protein) were measured in brain stem regions, cortex, and olfactory bulbs. The Michaelis-Menten dissociation constant (K(m)) for aromatase in the fetal sheep brain was 3-4 nM. No significant sex differences in AA were observed in brain. Treatment with ATD produced significant inhibition of AA in most brain areas but did not significantly alter serum profiles of the major sex steroids in maternal and fetal serum. Concentrations of testosterone in serum from the umbilical artery and vein were significantly greater in male than in female fetuses. No other sex differences in serum steroids were observed. These data demonstrate that high levels of AA are found in the fetal sheep hypothalamus and amygdala during the critical period for sexual differentiation. They also demonstrate that AA can be inhibited in the fetal lamb brain by treating the mother with ATD, without harming fetal development.     

Blood-brain barrier and new approaches to brain drug delivery.

Morbidity caused by brain dysfunction affects more than 50 million persons in the United States. Although new neuropharmaceuticals have the potential for treating specific brain diseases, they may not effectively enter brain from blood. Safe strategies are needed for drug delivery through the brain capillary wall, which makes up the blood-brain barrier in vivo. Two of these strategies are reviewed, as are related new developments in the molecular and cell biology of the brain capillary endothelium. The production of chimeric peptides represents a physiologic-based strategy for drug delivery. It entails the covalent coupling of the neuropharmaceutical to a brain transport vector, allowing transportation through the blood-brain barrier. Another strategy is biochemical opening of the blood-brain barrier: intracarotid leukotriene infusion is a method for selectively increasing blood-brain barrier permeability in brain tumors without affecting barrier permeability in normal brain tissue.     

Echinococcus granulosus: Protoscolicidal effect of high intensity focused ultrasound

High intensity focused ultrasound (HIFU) is a new non-invasive technique which can cause cell death and tissue necrosis by focusing high-energy ultrasonic waves on a single location. The aim of our work is to investigate the damaging effect of HIFU on Echinococcus granulosus protoscolices, as well as its inhibitory effect on growth of hydatid cysts derived from protoscolices. The damaging effect of HIFU on protoscolices was investigated by following parasite mortality after irradiation, while the inhibitory effect was investigated by infection experiments in vivo. The results demonstrated that HIFU was able to damage protoscolices and the protoscolicidal effect was dose-dependent and showed late-onset. The growth of protoscolices that survived the exposure to HIFU was obviously suppressed in vitro, and the mean weight of hydatid cysts resulting from such protoscolices in the experimental group was less than that in controls. Evidences including the protoscolicidal effect, fragmentized protoscolices and low post exposure temperatures, suggest that cavitation may contribute to the protoscolicidal effect of HIFU. In addition, the structure of the germinal membrane in cysts developing from the irradiated protoscolices was not as normal or intact as that from non-irradiated ones, and morphological changes related to degeneration were observed, suggesting that HIFU could prevent protoscolices from developing normal germinal membrane and consequently stop the proliferation of secondary hydatid cysts. HIFU demonstrated damaging effect on protoscolices, inhibited the growth of protoscolices in vitro and in vivo, and could be a possible therapeutic option for cystic echinococcosis.     

Polyphenolic compounds for treating neurodegenerative disorders involving protein misfolding

A diverse group of neurodegenerative diseases are characterized by progressive, age-dependent intracellular formation of misfolded protein aggregates. These include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and a number of tau-mediated disorders. There is no effective treatment for any of these disorders; currently approved interventions are designed to treat disease symptoms and generally lead to modest modulation of clinical symptoms. None are known to mitigate underlying neuropathologic mechanisms and, thus, it is not unexpected that existing treatments appear ineffective in modulating disease progression. We note that these neurodegenerative disorders all share a common mechanistic theme in that depositions of misfolded protein in the brain is a key molecular feature underlying disease onset and/or progression. While previous studies have identified a number of drugs and nutraceuticals capable of interfering with the formation and/or stability of misfolded protein aggregates, none have been demonstrated to be effective in vivo for treating any of the neurodegenerative disorders. We hereby review accumulating evidence that a select nutraceutical grape-seed polyphenolic extract (GSPE) is effective in vitro and in vivo in mitigating certain misfolded protein-mediated neuropathologic and clinical phenotypes. We will also review evidence implicating bioavailability of GSPE components in the brain and the tolerability as well as safety of GSPE in animal models and in humans. Collectively, available information supports continued development of the GSPE for treating a variety of neurodegenerative disorders involving misfolded protein-mediated neuropathologic mechanisms.