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MITOCHONDRIAL FUNCTION AND TISSUE VIABILITY IN VIVO:FROM ANIMAL EXPERIMENTS TO CLINICAL APPLICATIONS.FORTY YEARS OF FRUITFUL COLLABORATION WITH BRITTON CHANCE

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Journal of Innovative Optical Health Sciences 2011年第4期4卷 337-359页

作者： Avraham Mayevsky The Mina and Everard Goodman Faculty of Life-Sciences The Leslie and Susan Gonda Multidisciplinary Brain Research Center Bar-Ilan University Ramat-Gan52900Israel

The involvement of mitochondrial dysfunction in many pathophysiological conditions and human diseases is well documented.In order to evaluate mitochondrial function in vitro,many experimental systems have been developed.Nevertheless the number of in vivo monitoring systems for the evaluation of mitochondrial activities in intact animals and patients is relatively limited.The pioneering development of the conceptual and technological aspects ofmitochondrial monitoring,in vitro and in vivo,was done by the late Prof.Britton Chance(July 24,1913November 16,2010)since the early 1950s.It was my privilege to join his laboratory in 1972 and collaborate with him for almost four decades.The main achievements of our collaboration are presented in this paper.Our activities included cycles of technology development,followed by its applications to study various pathophysiological conditions.In the initial stage,thefirstfiber-opticbased NADHfluorometer was developed.This device enabled us to monitor various organs in anesthetized animals aswell as the brain of nonanesthetized small animals.Later on,the addition of various physiological parameters to NADH monitoring enabled us to correlate mitochondrial function with other cellular functions.The application of the developed technology to clinical situations was a major interest of Prof.Chance and indeed this goal was achieved in the last decade.As of today,the basic tool forNADHmonitoring and the large database of results are available for large-scale experimental and clinical applications.

关键词： NADHfluorescence in vivo multiparametric brain monitoring mitochondrial redox state mitochondrial dysfunction tissue energy metabolism

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SHEDDING LIGHT ON LIFE:OPTICAL ASSESSMENT OF MITOCHONDRIAL FUNCTION AND TISSUE VITALITY IN BIOLOGY AND MEDICINE

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Journal of Innovative Optical Health Sciences 2008年第1期1卷 71-83页

作者： Avraham Mayevsky The Mina&Everard Goodman Faculty of Life-Sciences and The Gonda Multidisciplinary Brain Research Center Bar-Ilan University Ramat-Gan 52900Israel

The involvement of mitochondrial dysfunction in various pathophysiological conditions,developed in experimental and clinical situations,is widely documented.Nevertheless,real time monitoring of mitochondrial function In-vivo is very rare.The pressing question is how the mitochondria of intact tissues behave under In-vivo conditions as compared to isolated mitochondria that had been described by Chance and Williams over 50 years ago.This subject has been recently discussed in detail(mayevsky and Rogatsky 2007).We reviewed the subject of evaluating mitochondrial function by monitoring NADH fluorescence together with microcirculatory blood flow,Hemoglobin oxygenation and tissue reflectance.These 4 parameters represent the vitality of the tissue and could be monitored in vivo,using optical spectroscopy,in animal models as well as in clinical practice.It is a well known physiological hypothesis that,under emergency conditions,the sympathetic nervous system will give preference to the most vital organs in the body,namely the brain,heart and adrenal glands.The less vital organs,such as the skin,GI-tract,and Urethral wall,will become hypoperfused and their mitochondrial activity will be inhibited.The monitoring of the less vital organs may reveal critical tissue conditions that may manifest an early phase of body deterioration.The aim of the current presentation is to review the experimental and preliminary clinical results accumulated using a new integrated medical device–the“CritiView”which enabled,for the first time,monitoring 4 parameters from the tissue using a single optical probe.The CritiView is a computerized optical device that integrates hardware and software in order to provide real time information on tissue vitality.In preliminary clinical testing,we used a 3-way Foley catheter that includes a bundle of optical fibers enabling the monitoring of the 4 parameters,representing the vitality of the urethral wall(a less vital organ).We found that the exposure of patients to metabolic imbalances in the operation r

关键词： organs representing hardware

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HYPERBARIC HYPEROXIA AND THE BRAIN IN VIVO:THE BALANCE BETWEEN THERAPY AND TOXICITY

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Journal of Innovative Optical Health Sciences 2008年第2期1卷 185-193页

作者： JUDITH SONN ELHANAN MEIROVITHZ Avraham Mayevsky The Mina&Everard Goodman Faculty of Life Sciences and the Leslie and Susan Gonda Multidisciplinary Brain Research Center Bar-Ilan University Ramat-Gan 52900Israel

Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy and minimal toxicity is under controversy.However,it can be evaluated by monitoring oxygen delivery,saturation,and consumption.In this study,the monitoring system fixed on the rats’brain cortex included a time-sharing fluorometer-reflectometer for monitoring mitochondrial NADH and hemoglobin oxygenation(HbO_(2))combined with Laser Doppler Flowmetry(LDF)for blood-flow monitoring.Rats were located in a hyperbaric chamber and exposed to different pressures.The HBO pressure caused an increase in HbO_(2)and a decrease in NADH in proportion to the increase in hyperbaric pressure,up to a nearly maximum effect at 2.5ATA.At 6ATA,15 minutes before convulsions started,blood volume and NADH started to increase,while tissue O_(2)supply by hemoglobin remained stable.Oxygen pool includes oxygen dissolved in the plasma and also bounded to hemoglobin.Above 2.5ATA,hemoglobin is fully saturated and the oxygen pool nourishment derives only from the oxygen dissolved in the plasma,exceeding the physiological ability for autoregulation;hence,homeostasis is disturbed and convulsions appear.This information is vital because pressures around 2.5ATA–3ATA are standard clinically applied pressures used to treat most of the pathophysiological problems considering the potential benefit which must be balanced against the potential toxicity.This study enables,for the first time,to evaluate the oxygenation level of hemoglobin in the microcirculation.Furthermore,our study showed that additional oxygen pressure(above 2.5ATA)caused brain oxygen toxicity within a short variable period of time after the pressure elevation.

关键词： NADH redox state brain tissue hemoglobin oxygenation HBO therapy HBO toxicity

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Early identification of acute hypoxia based on brain NADH fluores cence and cerebral blood flow

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Journal of Innovative Optical Health Sciences 2014年第2期7卷 153-161页

作者： Hua Shi Nannan Sun Avraham Mayevsky Zhihong Zhang Qingning Luo Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for Optoelectronics-Huazhong University of Scienceand Technology Wuhan 430074 P.R.China MoE Key Laboratory for Biomedical Photonics Department of Biomedical Engineering Huazhong University of Science and Technology(HUST)Wuhan 430074P.R.China

Hypoxia is closely related to many diseases and often leads to death.Early detection andidentification of the hypoxia causes may help to promptly determine the right rescue plan andreduce the mortality.We proposed a new multiparametric monitoring method employingmitochondrial reduced nicotinamide adenine dinucleotide(NA DH)fluorescence,regional reflectance,regional cerebral blood flow(CBF),electrocardiography(ECG),and respiration under sixkinds of acute hypoxia in four categories to investigate a correlation bet ween the parametervariances and the hypoxia causes.The variation patterns of the paramet ers were discussed,andthe combination of NADH and CBF may contribute to the identification of the causes of hypoxia.

关键词： Nicotinamide adenine dinucleotide fuorescence acute hypoxia carly detection cer-ebral blood flow.

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REAL-TIME MONITORING OF MITOCHONDRIAL FUNCTION AND CEREBRAL BLOOD FLOW FOLLOWING FOCAL ISCHEMIA IN RATS

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Journal of Innovative Optical Health Sciences 2008年第1期1卷 63-69页

作者： AMIR LIVNAT MICHAEL TOLMASOV EFRAT BARBIRO-MICHAELY Avraham Mayevsky The Mina&Everard Goodman Faculty of Life-Sciences and The Gonda Multidisciplinary Brain Research Center Bar-Ilan University Ramat-Gan 52900Israel

Focal ischemia due to reduction of cerebral blood flow(CBF),creates 2 zones of damage:the core area,which suffers severe damage,and penumbra area,which surrounds the core and suffers intermediate levels of injury.Objectives:A novel method is introduced,which evaluates mitochondrial function in the core and in the penumbra,during focal cerebral ischemia.Methods:Wistar rats underwent focal cerebral ischemia by middle cerebral artery occlusion(MCAO)for 60 minutes,followed by 60 minutes of reperfusion.Mitochondrial function was assessed by a unique Multi-Site—Multi-Parametric(MSMP)monitoring system,which measures mitochondrial NADH using fluorometric technique,and CBF using Laser Doppler Flowmetry(LDF).Results:At the onset of occlusion,CBF dropped and NADH increased significantly only in the right hemisphere.CBF levels were significantly lower and NADH significantly higher in the core than in the penumbra.After reperfusion,CBF and NADH recovered correspondingly to the intensity of ischemia.Conclusion:Application of the MSMP system can add significant information for the understanding of the cerebral metabolic state under ischemic conditions,with an emphasis on mitochondrial function.

关键词： Mitochondrial function cerebral blood flow focal ischemia

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基于NADH荧光的组织病理生理状态多参数在体监测与评价

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科学通报 2010年第25期55卷 2476-2486页

作者：施华 mayevsky avraham 华中科技大学武汉光电国家实验室(筹) Britton Chance生物医学光子学研究中心武汉430074

组织病理生理状态的实时多参数评价,无论在动物实验研究还是临床应用中均具有重要价值,一直是生命科学与医学研究者们广泛关注的热点.众所周知,临床手术过程或重症监护病房中,患者病理生理状态的实时监测是十分必需的.心、脑等重要组织... 详细信息

组织病理生理状态的实时多参数评价,无论在动物实验研究还是临床应用中均具有重要价值,一直是生命科学与医学研究者们广泛关注的热点.众所周知,临床手术过程或重症监护病房中,患者病理生理状态的实时监测是十分必需的.心、脑等重要组织脏器是否处于缺血缺氧等危急状态直接关系到病人的存活与否;早期发现术中和术后次要脏器的微循环障碍有助于提高器官移植等手术的成功率和降低术后并发症的发生率.临床常规使用的监测指标,如血压、心电、脉搏等,在生命指征的实时评价中发挥了重要作用.然而,目前的常规指标尚不足以从分子水平反映局部组织病理生理状态的早期改变.NADH是细胞线粒体中氧化还原呼吸链上的内源性关键分子,具有自发荧光性质,可作为一项灵敏的内源性含氧状态指标来反映机体的代谢状态和细胞活力.本文介绍了基于NADH自发荧光信号的细胞氧化还原状态在体监测方法,从分子水平预警机体的活力情况,结合微循环血流、血氧饱和度等多种生理参数的同步并行监测,不仅可在活体动物体内进行疾病的病理生理学机制研究和新药的药效评价,还有望应用于临床外科手术和重症监护病房,为机体活力和生命指征的实时监护提供分子水平的动态信息.目前,NADH荧光一维信号的获取技术发展最为成熟,可实现从离体、活细胞、活体动物乃至临床水平的实时动态监测,已处于临床推广应用阶段.二维动态成像也已经发展到活体动物实验阶段.三维成像由于受制于NADH荧光的穿透能力,只能在冷冻组织切片上实现.如何突破因高散射所致的荧光穿透能力受限的瓶颈,最大限度地减少环境因素对荧光信号的干扰,在分子水平实现组织病理生理状态的实时多参数评价,是生物医学光子学领域面临的巨大挑战.

关键词：病理生理氧化还原在体监测线粒体 NADH 自发荧光

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EFFECTS OF SEVERE HEMORRHAGE ON IN VIVO BRAIN AND SMALL INTESTINE MITOCHONDRIAL NADH AND MICROCIRCULATORY BLOOD FLOW

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Journal of Innovative Optical Health Sciences 2008年第2期1卷 177-183页

作者： MIRA M.MANDELBAUM EFRAT BARBIRO-MICHAELY MICHAEL TOLMASOV Avraham Mayevsky The Mina&Everard Goodman Faculty of Life-Sciences and The Gonda Multidisciplinary Brain Research Center Bar-Ilan University Ramat-Gan52900Israel

Severe body stress induced by hypoxemia and hypotension may lead to total body energy state deterioration.The perfusion of the most vital organs is maintained at the expense of“less vital”organs.In the present study,we used a multi-site multiparametric(MSMP)monitoring system for real-time evaluation of tissue blood flow(TBF)and mitochondrial NADH fluorescence of the brain and the small intestine following hemorrhage.In Group 1,uncontrolled hemorrhage,mean arterial pressure(MAP)was decreased to 40mmHg within 2 minutes and shed blood was re-infused after 30minutes.In Group 2,controlled hemorrhage,during the 30minutes of hemorrhage,MAP was kept at 40mmHg.During hemorrhage,in both groups,the intestinal TBF and NADH deteriorated,while the brain remained relatively well protected.In Group 1,all parameters partly recovered within the hemorrhage phase,while in Group 2,complete recovery occurred only after resuscitation.At the end of the experiment,both models showed a decrease in intestinal viability(TBF decreased,NADH increased),while the brain metabolic state in Group 2 declined slightly.Our unique multi-parametric monitoring device demonstrated that,under hemorrhage,the small intestine responded entirely differently from the brain.This may suggest the potential usefulness of the monitoring of less vital organs,as proxy organs,in critical conditions such as massive hemorrhage.The present study also highlights the importance of mitochondrial function monitoring in similar conditions in the clinical environment.

关键词： Mitochondrial dysfunction multiparametric monitoring Laser Doppler Flowmetery fluorometric NADH monitoring

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用光学方法解释活体线粒体功能:总结与展望

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光学与光电技术 2012年第1期10卷 1-7页

作者： Avraham Mayevsky 孙楠楠施华 Bar-Ilan University 武汉光电国家实验室

为什么要研究线粒体？人的许多疾病与线粒体功能失调直接相关，如癌症、帕金森氏病、阿尔兹海默症、肝病、肾病、败血症等。因此，我们需要研究线粒体，发现疾病发生的规律，从而找到应对这些疾病的治疗手段和药物。

关键词：体功能光学方法展望活体疾病发生帕金森氏病线粒体败血症

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HOW DOES ANESTHESIA AFFECT VARIOUS LEVELS OF EXPERIMENTAL TRAUMATIC BRAIN INJURY?

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Journal of Innovative Optical Health Sciences 2011年第4期4卷 409-420页

作者： BARBIRO-MICHAELY EFRAT MANOR TAMAR ROGATSKY GENNADY mayevsky avraham The Mina and Everard Goodman Faculty of Life-Sciences The Leslie and Susan Gonda Multidisciplinary Brain Research Center Bar-Ilan University Ramat-Gan52900Israel

The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithesin on brain vitality in these models.Traumatic Brain Injury(TBI)was induced using thefluid percussion injury model in four levels:mild,moderate and two levels of severe TBI.Brain real-time evaluation was performed by the multiparametric monitoring assembly(MPA)which enable cerebral bloodflow(CBF)monitoring by laser Dopplerflowmetry,mitochondrial NADH(Nicotinamide adenine dinucleotide)monitoring by thefluorometric technique,ionic homehostasis using special mini-electrodes,intracranial pressure(ICP)by the ICP camino device and needle electrodes for ECoG(Electrocorticogram)recording.Our results showed high correlation between the level of impact and the extent of changes in the physiological properties of the injury as indicated by the changes in all parameters monitored using the MPA device.Moreover,Equithesin improved CBF,ionic extracellular level and mitochondrial redox state following mild and moderate TBI while in severe TBI,Equithesin did not improve the metabolic state of the cerebral cortex,although it decreased the mortality rate from 66%to 20%,and following extra-severe TBI level,Equithesin did not improve survival rate.In conclusion it seems that Equithesin's protective effect exists under mild to moderate levels of injury and not in case of severe injuries.

关键词： Cerebral bloodflow mitochondrial NADH multiparametric monitoring

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