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herbal hepatotoxicity:Challenges and pitfalls of causality assessment methods

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World Journal of Gastroenterology 2013年第19期19卷 2864-2882页

作者： Rolf Teschke christian Frenzel Johannes schulze Axel Eickhoff Division of Gastroenterology and hepatology Department of Internal Medicine ⅡKlinikum HanauD-63450 HanauGermany Academic Teaching hospital of the Medical Faculty Johann Wolfgang Goethe-Universit t Frankfurt am MainD-60590 Frankfurt am MainGermany Department of Medicine Ⅰ University Medical Center Hamburg EppendorfD-20246 HamburgGermany nstitute of Industrial Environmental and Social MedicineMedical FacultyJohann Wolfgang GoetheUniversitat Frankfurt am MainD-60590 Frankfurt am MainGermany

The diagnosis of herbal hepatotoxicity or herb induced liver injury(hILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality *** the day hILI is suspected in a patient,physicians should start assessing the quality of the used herbal product,optimizing the clinical data for completeness,and applying the Council for International Organizations of Medical Sciences(CIOMS) scale for initial causality *** scale is structured,quantitative,liver specific,and validated for hepatotoxicity *** items provide individual scores,which together yield causality levels of highly probable,probable,possible,unlikely,and *** completion by additional information including raw data,this scale with all items should be reported to regulatory agencies and manufacturers for further *** CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases,compared to numerous other causality assessment methods,which are inferior on various *** these disputed methods are the Maria and Victorino scale,an insufficiently qualified,shortened version of the CIOMS scale,as well as various liver unspecific methods such as thead hoc causality approach,the Naranjo scale,the World health Organization(WhO) method,and the Karch and Lasagna *** expert panel is required for the Drug Induced Liver Injury Network method,the WhO method,and other approaches based on expert opinion,which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the *** conclusion,hILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale,avoiding pitfalls commonly observed with other approaches.

关键词： herbal hepatotoxicity herb induced liver injury herbs Drug hepatotoxicity Drug induced liver injury Causality assessment

Targeting cell death signaling in colorectal cancer:Current strategies and future perspectives

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World Journal of Gastroenterology 2014年第8期20卷 1923-1934页

作者： Bruno christian Koehler Dirk Jger henning schulze-Bergkamen National Center for Tumor Diseases University Hospitals Heidelberg69120 HeidelbergGermany

The evasion from controlled cell death induction has been considered as one of the hallmarks of cancer cells. Defects in cell death signaling are a fundamental phenomenon in colorectal cancer. Nearly any non-invasive cancer treatment finally aims to induce cell death. however, apoptosis resistance is the major cause for insufficient therapeutic success and disease relapse in gastrointestinal oncology. Various compounds have been developed and evaluated with the aim to meet with this obstacle by triggering cell death in cancer cells. The aim of this review is to illustrate current approaches and future directions in targeting cell death signaling in colorectal cancer. The complex signaling network of apoptosis will be demonstrated and the “druggability” of targets will be identified. In detail, proteins regulating mitochondrial cell death in colorectal cancer, such as Bcl-2 and survivin, will be discussed with respect to potential therapeutic exploitation. Death receptor signaling and targeting in colorectal cancer will be outlined. Encouraging clinical trials including cell death based targeted therapies for colorectal cancer are under way and will be demonstrated. Our conceptual understanding of cell death in cancer is rapidly emerging and new types of controlled cellular death have been identified. To meet this progress in cell death research, the implication of autophagy and necroptosis for colorectal carcinogenesis and therapeutic approaches will also be depicted. The main focus of this topic highlight will be on the revelation of the complex cell death concepts in colorectal cancer and the bridging from basic research to clinical use.

关键词： Colorectal cancer Apoptosis Necroptosis Autophagy Clinical trial Bcl-2 proteins Bh-3 mimetics Inflammatory bowel disease

Inverted List Kinetic Monte Carlo with Rejection Applied to Directed Self-Assembly of Epitaxial Growth

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Communications in Computational Physics 2009年第8期6卷 553-564页

作者： Michael A.Saum Tim P.schulze christian Ratsch Department of Mathematics University of TennesseeKnoxvilleTennessee 37996USA Department of Mathematics and Institute for Pure and Applied Mathematics University of California in Los AngelesLos AngelesCalifornia 90095USA

We study the growth of epitaxial thin films on pre-patterned substrates that influence the surface diffusion of subsequently deposited material using a kinetic Monte Carlo algorithm that combines the use of inverted lists with *** resulting algorithm is well adapted to systems with spatially heterogeneous hopping *** evaluate the algorithm’s performance we compare it with an efficient,binary-tree based algorithm.A key finding is that the relative performance of the inverted list algorithm improves with increasing system size.

关键词： Epitaxial growth kinetic Monte Carlo binary-tree search

The Influence of Edge Energy on Step Flow Instability for Crystals with Bravais Versus Non-Bravais Lattice Structures

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Communications in Computational Physics 2020年第1期27卷 70-86页

作者： Tim Krumwiede Khoa D.Dinh christian Ratsch Tim P.schulze Department of Mathematics Bringham Young UniversityUT 84602USA Department of Mathematics University of TennesseeTennessee 37996USA Institute for Pure and Applied Mathematics and Department of Mathematics University of CaliforniaLos AngelesCA 90095-1555USA

We examine the meandering instability for prismatic lattices formed from triangles,squares and hexagons using a nearest neighbor kinetic Monte Carlo *** the first two cases,which are Bravais lattices,we find that facets with the orientation favored in the equilibrium shape of isolated islands are most prone to this instability,while the analogous facet for the hexagonal lattice is the least *** argue that this is due to a significant difference in the reconstructed/equilibrium versus the non-reconstructed edge energy for non-Bravais ***/edge energy is typically modeled as a single-valued function of *** put forward a simple geometric argument that suggests this picture is inadequate for crystals with a non-Bravais lattice *** the case of a hexagonally structured lattice,our arguments indicate that the non-reconstructed edge energy can be viewed as both discontinuous and multi-valued for a subset of orientations that are commensurate with the crystal *** support these conclusions with density functional theory calculations that also reveal multivalued surface energies for the set of singular orientations.

关键词： KMC surface energy epitaxy

Lipid lowering in patients 75 years and older

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World Journal of Cardiology 2021年第10期13卷 526-532页

作者： Umidakhon Makhmudova P christian schulze harry R Davis Oliver Weingartner Klinik fur Innere Medizin I Universitatsklinikum JenaJena 07747Germany Synergy Partners RD Solutions Synergy Partners RD SolutionsGaithersburgMD 20850United States

More than twenty years ago,knowledge about the importance of cholesterol absorption and the potential therapeutic effect of its inhibition led to the discovery and clinical application of the first and only cholesterol absorption inhibitor to date–*** then,ezetimibe has become a well-recognized player in lipid-lowering *** findings of IMPROVE-IT and EWTOPIA 75 imply that elderly patients over the age of 75 years in particular benefit from *** review summarizes the evidence,discusses the possible underlying pathophysiological mechanisms and calls for a change in future dyslipidemia guidelines.

关键词： Cholesterol Cholesterol absorption Cholesterol synthesis Ezetimibe Elderly

herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

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World Journal of hepatology 2013年第7期5卷 353-363页

作者： Rolf Teschke christian Frenzel Johannes schulze Alexander Schwarzenboeck Axel Eickhoff Department of Internal Medicine Ⅱ Division of Gastroenterology and Hepatology Klinikum Hanau Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main Department of MedicineⅠ University Medical Center Hamburg Eppendorf Institute of Industrial Environmental and Social Medicine Medical Faculty of the Goethe University Frankfurt/Main

AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed herbalife hepatotoxicity with positive reexposure tests. METhODS: We searched the Medline database for suspected cases of herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase(ALT) h Nas the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n =

关键词： herbalife hepatotoxicity herbalife induced liver injury herbal hepatotoxicity herb induced liver injury herbs

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

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World Journal of hepatology 2014年第1期6卷 17-32页

作者： Rolf Teschke Albrecht Wolff christian Frenzel Alexander Schwarzenboeck Johannes schulze Axel Eickhoff Department of Internal Medicine Ⅱ Klinikum Hanau Academic Teaching Hospital of the Medical Faculty of the Goethe University of Frankfurt/Main Department of Internal Medicine Ⅱ Division of Gastroenterology Hepatology and Infectious Diseases Friedrich Schiller University Jena Department of Medicine Ⅰ University Medical Center Hamburg Eppendorf Institute of Industrial Environmental and Social Medicine Medical Faculty Goethe University

Causality assessment of suspected drug induced liver injury(DILI) and herb induced liver injury(hILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences(CIOMS) scale as a standard tool for causality assessment in DILI and hILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and hILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and hILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and hILI cases, applicable primarily at all assessing levels involved. 2014 Baishideng Publishing Group Co., Limited. All

关键词： Drug induced liver injury Drug hepatotox-icity herb induced liver injury herbal hepatotoxicity Causality assessment

A cost driven predictive maintenance policy for structural airframe maintenance

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Chinese Journal of Aeronautics 2017年第3期30卷 1242-1257页

作者： Yiwei WANG christian GOGU Nicolas BINAUD christian BES Raphael T.hAFTKA Nam h.KIM Universite de Toulouse INSA/UPS/ISAE/Mines Albi ICA UMR CNRS 5312 Toulouse 31400 Frallce Department of Mechanical & Aerospace Engineering University of Florida Gainesville 32611 USA

Airframe maintenance is traditionally performed at scheduled maintenance *** decision to repair a fuselage panel is based on a fixed crack size threshold,which allows to ensure the aircraft safety until the next scheduled maintenance *** progress in sensor technology and data processing techniques,structural health monitoring（ShM） systems are increasingly being considered in the aviation *** systems track the aircraft health state continuously,leading to the possibility of planning maintenance based on an actual state of aircraft rather than on a fixed *** paper builds upon a model-based prognostics framework that the authors developed in their previous work,which couples the Extended Kalman filter（EKF） with a firstorder perturbation（FOP） *** using the information given by this prognostics method,a novel cost driven predictive maintenance（CDPM） policy is proposed,which ensures the aircraft safety while minimizing the maintenance *** proposed policy is formally derived based on the trade-off between probabilities of occurrence of scheduled and unscheduled maintenance.A numerical case study simulating the maintenance process of an entire fleet of aircrafts is *** the condition of assuring the same safety level,the CDPM is compared in terms of cost with two other maintenance policies：scheduled maintenance and threshold based ShM *** comparison results show CDPM could lead to significant cost savings.

关键词： Extended Kalman filter First-order perturbation method Model-based prognostic Predictive maintenance Structural airframe maintenance

Low-complexity online correction and calibration of pedestrian dead reckoning using map matching and GPS

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Geo-Spatial Information Science 2019年第2期22卷 114-127,I0004页

作者： Fabian hölzke Johann-P.Wolff Frank Golatowski christian haubelt Institute of Applied Microelectronics and CE University of RostockRostockGermany

Dead Reckoning is a relative positioning scheme that is used to infer the change of position relative to a point of origin by measuring the traveled distance and orientation *** Dead Reckoning(PDR)applies this concept to walking *** method can be used to track someone's movement in a building after a known landmark like the building's entrance is ***,the movement of a foot and the corresponding direction change is measured and summed up,to infer the current *** and integrating the corresponding physical parameters,*** inertial sensors,introduces small errors that accumulate quickly into large distance *** of a buildings geography may reduce these errors as it can be used to keep the estimated position from moving through walls and onto likely *** this paper,we use building maps to improve localization based on a single foot-mounted inertial *** describe our localization method using zero velocity updates to accurately compute the length of individual steps and a Madgwick filter to determine the step *** though the computation of individual steps is quite accurate,small errors still accumulate in the long *** show how correction algorithms using likely and unlikely paths can rectify errors intrinsic to pedestrian dead reckoning tasks,such as orientation and displacement drift,and discuss restrictions and disadvantages of these *** also present a method of deriving the initial position and orientation from GPS *** verify our PDR correction methods analyzing the corrected and raw trajectories of six participants walking four routes of varying length and complexity through an office building,walking each route three *** quantitative results show an endpoint accuracy improvement of up to 60%when using likely paths and 23%when using unlikely ***,both approaches can also decrease accuracy in certain *** identify those scenarios and

关键词： Indoor localization Pedestrian Dead Reckoning(PDR) Inertial Navigation System(INS) map matching Zero Velocity Update(ZUPT)