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Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants-Let's get even more personal

Translational Neurodegeneration 2020年第4期9卷 499-508页

作者： christian u.von linstow Ziv Gan-Or Patrik Brundin Center for Neurodegenerative Science Van Andel InstituteGrand RapidsMI 49503USA Montreal Neurological Institute McGill UniversityMontrealQC H3A 2B4Canada Department of Human Genetics McGill UniversityMontrealQC H3A 0C7Canada Department of Neurology and Neurosurgery McGill UniversityMontrealQC H3A 2B4Canada

Parkinson's disease(PD)is characterized by motor deficits and a wide variety of non-motor *** age of onset,rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual ***,the loss of substantia nigra dopaminergic neurons is a key feature of *** vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions,but there is also great variability in the neuropathology between *** the dopamine replacement therapies can reduce motor symptoms,current therapies do not modify the disease *** clinical trials using a wide variety of approaches have failed to achieve disease *** has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials,and that it is unlikely that a single treatment will be effective in all *** medicine,using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD,has been suggested as a way *** patients can be stratified according to whether they carry one of the risk variants associated with elevated PD *** this review we assess current clinical trials targeting two enzymes,leucine-rich repeat kinase 2(LRRK2)and glucocerebrosidase(GBA),which are encoded by two most common PD risk *** the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood,we ask if these precision medicinebased intervention strategies will prove"precise"or"personalized"enough to modify the disease process in PD *** also consider at what phases of the disease that such strategies might be effective,in light of the genes being primarily associated with the risk of developing disease in the first place,and less clearly linked to the rate of disease ***,we critically evaluate the notion that therapies target

关键词： Parkinson's disease Precision medicine Personalized medicine Glucocerebrosidase GCase Leucine-rich repeat kinase-2 Dopamine PD drug trials PD risk variants

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Analysis of Cartilage Creep Recovery using a Highly Dynamic Closed-loop Test System

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Journal of Bionic Engineering 2018年第6期15卷 1057-1066页

作者： Josef Stolberg-Stolberg Peter Foehr Iris Pflieger Lara Kuntz Constantin von Deimling Andreas Obermeier Peter M. Prodinger christian u. Grosse Rainer Burgkart Department of Orthopaedics and Sports Orthopaedics Klinikum rechts der Isar Technical University of Munich Munich 81675 Germany Department of Trauma Hand and Reconstructive Surgery University Hospital Muenster Albert-Schweitzer-Campus 1 Muenster 48149 Germany Chair of Non-destructive Testing Technical University of Munieh Munich 81245 Germany Department of Trauma Surgery Trauma Center Murnau Murnau 82418 Germany

The aim of this study was to analyze cartilage creep and creep recovery after static and cyclic loading. up to now technical limitations have hindered the measurement of creep recovery. For this reason, we developed a closed loop micro creep and creep-recovery indentation test system with active force control. Bovine osteochondral explants were tested under static （110 kPa） and cyclic （100 cycles, 350 kPa/35 kPa, 1 Hz） loading conditions and subsequently creep recovery was measured. The cartilage thickness was determined using needle indentation. For static loading, the creep and creep-recovery rates were significantly different during the first 60 seconds （p 〈 0.05）. Cyclic loading was assessed for the medial and lateral patella and resulted in a physiological patellar cartilage strain of 7.7% ± 2.6% and 8.2% ± 2.7%, respectively. We recorded a creep recovery of 97.8% ±2.1% for the medial and 98.3% ± 2.4% for the lateral patella. The advantage of this study over earlier in vitro studies is that we recorded creep-recovery profiles with an actively controlled setup. This allowed us to analyze creep recovery immediately after removing the creep load, in contrast to MRI-based in vivo studies. In future, the presented method will enable us to quantify spatial variations within articular joints.

关键词： articular cartilage indentation creep recovery arthritis regenerative tissue

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Influence of Reactive Alumina and Calcined Alumina on properties of Free Flowing Castables

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China's Refractories 2021年第3期30卷 7-10页

作者： christian DÜNZEN Nabaltec AG Schwandorf 92421Germany

Reactive alumina is a well-established group of raw materials for refractory castables to improve their rheological *** this article the influence of bimodal reactive alumina and standard(umina on workability,packing density and strength of alumina based castables is *** will be shown that there is a significant effect on water demand and apparent density of the castable,which is depending on the percentage of reactive alumina on the one hand and on the type of reactive alumina on the other *** effect of the alumina on setting time and cold crushing strength has shown to be insignificant in this set of experiments.

关键词： reactive alumina refractory castables calcined alumina rheological behavior

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Complications of dexamethasone implants:risk factors,prevention,and clinical management

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International Journal of Ophthalmology(English edition) 2020年第10期13卷 1612-1620页

作者： Nil Celik Ramin Khoramnia Gerd.u Auffarth Saadettin Sel christian S Mayer Department of Ophthalmology University Hospital of HeidelbergHeidelberg 69120Germany

AIM:To evaluate major complications after intravitreal injection of dexamethasone implants(Ozurdex)and their clinical ***:In a retrospective observational study between 2014 and 2016 at two university hospitals,we reviewed the clinical records of 1241 consecutive macular edema patients treated with the dexamethasone implant,and separated severe adverse events in the injection procedure from those that were post-injection *** evaluated the cause and the outcomes in each ***:In twenty-one procedures(1.69%)we noticed significant complications during and after intravitreal injection of the dexamethasone *** related to the injection procedure were in one case,that a second implant was injected by mistake in the same eye on the same *** another case,the implant lodged in the sclera during retraction of the injector *** scleral tunnel at the injection site led to hypotony in another *** were 10 cases of post-injection displacement of the implant into the anterior chamber and one case with a migrated and trapped device between the intraocular lens and an artificial *** typically occurred in patients with preexisting risk factors:eyes with complicated intraocular lens implantation,iris reconstruction or iris defects or pseudophakic eyes after vitrectomy were prone to develop this *** led to secondary corneal decompensation with *** case developed an endophthalmitis,and we observed four cases of retinal *** eyes presented with long-lasting hypotony due to ciliary ***:Treatment with the dexamethasone implant may cause various expected or unexpected complications that may have serious consequences for the patient and require further *** reduce complications,clinicians should evaluate certain risk factors before scheduling patients for dexamethasone implant treatment and use proper injection techniques.

关键词： intravitreal implants dexamethasone implants Ozurdex intravitreal injection slow release drug

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An independent practice validation of the Prostate Imaging Reporting and Data System version 2 scoring system and the introduction of PDP(prostate-specific antigen density×PI-RADSv2)score to assist with further risk assessment

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Current urology 2022年第4期16卷 213-217页

作者： Parth u.Patel David Bock christian A.Hettinger Department of urology University of MichiganAnn ArborMlUSA Kansas City urology Care Overland ParkKSUSA

Objectives:To provide concise information to clinicians on how to better interpret multiparametric magnetic resonance imaging for prostate cancer risk *** and methods:We analyzed 2 separate *** patients receiving a Prostate Imaging Reporting and Data System version 2(PI-RADSv2)score of 1 or 2,we reviewed the charts of 226 patients who underwent multiparametric magnetic resonance imaging of the prostate ordered from 2015 to 2017 to determine who developed clinically significant prostate cancer(csPCa)by August 27,*** patients receiving PI-RADSv2 a score of 3,4,or 5,we reviewed the results of 733 fusion biopsies on solitary *** analysis was used to further determine risk factors for ***:Ten percent of men with PI-RADSv2 a score of 1 eventually developed *** percent with a score of 2 were eventually diagnosed with *** 1 of 226 with a score of 1 or 2 developed *** PI-RADSv2 scores of 3,4,and 5,csPCa was detected in 16%,45%,and 67%of fusion *** zone(PZ)PI-RADSv2 score of 4 or 5 and prostate-specific antigen density(PSA-D)were significant predictors of csPCa on multivariable *** a PSA-D×PI-RADSv2 score of≤0.39,we identified 38%of men with a PI-RADSv2 score of 3 in the PZ or 3,4,or 5 in the transition zone who could have avoided a benign ***:The vast majority of patients with PI-RADSv2 scores 1 and 2 can be safely monitored with close *** with Pl-RADSv2 scores of 4 and 5 in the PZ should be *** zone lesions with a Pl-RADSv2 score of 3 and transition zone lesions with 3,4,or 5 can be risk-stratified using the PSA-D x PI-RADSv2 score to determine who may safely avoid a biopsy and who should proceed to fusion biopsy.

关键词： Biopsy Magnetic resonance imaging Prostate cancer

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Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure

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World Journal of Gastroenterology 2017年第9期23卷 1576-1585页

作者： Karolin Thiel Wilfried Klingert Kathrin Klingert Matthias H Morgalla Martin u Schuhmann Pamela Leckie Yalda Sharifi Nathan A Davies Rajiv Jalan Andreas Peter christian Grasshoff Alfred Konigsrainer Martin Schenk christian Thiel Department of General Visceral and Transplant SurgeryTuebingen University Hospital Department of Anaesthesiology Tuebingen University Hospital Department of Neurosurgery Tuebingen University Hospital Institute for Liver and Digestive Health University College London Division of Endocrinology DiabetologyAngiologyNephrologyPathobiochemistry and Clinical ChemistryDepartment of Internal MedicineTuebingen University Hospital

To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen *** pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon *** liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P udy end. Thrombocyte values (baseline 307 × 10up>3up>/µL ± 34 × 10up>3up>/µL) of intoxicated animals declined slowly to values of 145 × 10up>3up>/µL ± 46 × 10up>3up>/µL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 10up>3up>/µL ± 3 × 10up>3up>/µL preceding fatality within few hours which was significant (P > 0.01).CONCLuSIONDeclining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model.

关键词： Acetaminophen intoxication Acute liver failure Portal blood flow Thrombocytopenia Animal model Porcine model

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Existence of global solutions to isentropic gas dynamics equations with a source term

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Science China Mathematics 2010年第1期53卷 115-124页

作者： KLINGENBERG christian Institut fr angewandte Mathematik Universitt WrzburgAm Hubland97074 WrzburgGermany

In this paper we prove existence of isentropic gas dynamic equations with a source term (1.2). To this end we construct a sequence of regular hyperbolic systems (1.1) to approximate the inhomogeneous system of isentropic gas dynamics (1.2). First,for each fixed approximation parameter δ and very general condition on P (ρ),we establish the existence of entropy solutions for the Cauchy problem (1.1) with bounded initial date (1.4). Second,letting=o(δ),we obtain a complete proof of the H-1loc compactness of weak entropy pairs of system (1.2) in the form η(ρ,u) =ρH(ρ,u) given in Chen-LeFloch (2003). Finally,for the conditions of P(ρ) given in Chen-LeFloch (2003),applied to the results in Theorems 1 and 2,we obtain the global existence of entropy solutions for the Cauchy problem (1.2) with bounded initial date (1.4).

关键词： isentropic gas dynamics system global entropy solution compactness in H-loc1 compensated compactness method

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Efficient Algorithm forMany-Electron Angular Momentum and Spin Diagonalization on Atomic Subshells

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Communications in Computational Physics 2016年第1期19卷 192-204页

作者： christian B.Mendl Zentrum Mathematik Technische Universitat MunchenBoltzmannstraße 385748 Garching bei MunchenGermany

We devise an efficient algorithm for the symbolic calculation of irreducible angular momentum and spin(LS)eigenspaces within the n-fold antisymmetrized tensor product∧^(n)V_(u),where n is the number of electrons and u=s,p,d,…denotes the atomic *** is an essential step for dimension reduction in configurationinteraction(CI)methods applied to atomic many-electron quantum *** algorithm relies on the observation that each Lz eigenstate with maximal eigenvalue is also an L2 eigenstate(equivalently for Sz and S2),as well as the traversal of LS eigenstates using the lowering operators L−and S−.Iterative application to the remaining states in∧^(n)V_(u)leads to an implicit simultaneous diagonalization.A detailed complexity analysis for fixed n and increasing subshell number u yields run time O(u^(3n−2)).A symbolic computer algebra implementation is available online.

关键词： Angular momentum and spin symmetry atomic many-electron quantum systems symbolic computation

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GLOBAL WEAK SOLuTIONS FOR A NONLINEAR HYPERBOLIC SYSTEM

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Acta Mathematica Scientia 2020年第5期40卷 1185-1194页

作者： Qingyou SuN Yunguang Lu christian KLINGENBERG K.K.Chen Institute for Advanced Studies Hangzhou Normal UniversityHangzhou 311121China Department of Mathematics Wuerzburg UniversityWuerzburg 97070Germany

In this paper, we study the global existence of weak solutions for the Cauchy problem of the nonlinear hyperbolic system of three equations(1.1) with bounded initial data(1.2). When we fix the third variable s, the system about the variables ρ and u is the classical isentropic gas dynamics in Eulerian coordinates with the pressure function P(ρ, s) = ese-1/ρ,which, in general, does not form a bounded invariant region. We introduce a variant of the viscosity argument, and construct the approximate solutions of(1.1) and(1.2) by adding the artificial viscosity to the Riemann invariants system(2.1). When the amplitude of the first two Riemann invariants(w1(x, 0), w2(x, 0)) of system(1.1) is small,(w1(x, 0), w2(x, 0)) are nondecreasing and the third Riemann invariant s(x, 0) is of the bounded total variation, we obtained the necessary estimates and the pointwise convergence of the viscosity solutions by the compensated compactness theory. This is an extension of the results in [1].

关键词： global weak solutions viscosity method compensa ted compac tn ess

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Post-orogenic transients and relict landforms of the Bafoussam–Mamfe region(West-Cameroon Highland margin)

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Journal of Mountain Science 2022年第8期19卷 2180-2201页

作者： Pascal Landry WABO DEFO Sébastien OWONA Moussa NSANGOu NGAPNA christian BALLA ATEBA christian MWABANuA MuTABI The university of Douala Faculty of ScienceDepartment of Earth SciencesDouala 24157Cameroon The university of Lubumbashi Faculty of ScienceDepartment of GeologyLubumbashi 1825Democratic Republic of Congo

The Bafoussam-Mamfe Region(BMR)belongs to the Western Cameroon Highland margin,an amalgam of transient landscape that evolved from the interactions between tectonics,lithology and climate *** area is tectonically active and shows differential tectonic uplift,contrasting relief,variations in erosion rates,in river incision,and in channel *** order to appraise the BMR tectono-geomorphic evolution,it is essential to understand relationships between internal and external processes and their geomorphic expression at a river basin *** this purpose,we use drainage texture(Dt),stream frequency(Fs),drainage density(Dd),asymmetry factor(AF),the transverse topographic symmetry factor(TTSF),the mean of mountain front sinuosity per unit(Smf),concavity factor(Cf),hypsometry integral(HI)and streamlength gradient index(SL-index)based on 30 m Digital Elevation Models(DEM)and field *** results reveal considerable variations in geology,relief,topography and geomorphic indices values differentiated into three geomorphic units;the Mamfe unit developed on the Mamfe Cretaceous basin,the Nguti and Bafoussam high plateau units build up on the Precambrian granito-gneissic basement overlaid by a volcanic *** stepped(longitudinal and normalized)river profiles and complex hypsometric curves show the lithostructural control of the hydrographic ***(from~1.21 to~4.59),Fs(from~0.26 to~1.91),Dd(from~0.66 to~1.71)geomorphic indice values indicate a part of lithologic control on this morphology while the AF(from~1.16to~24.91),TTSF(from~0.20 to~0.71),Smf(u2=1.11 and u3=1.19),Cf(from~-20.91 to~78.93),HI(from~0.12 to~0.52)and SL-index designate the active tectonics as the main factor that had controlled the morphology of this same *** results pinpoint the combined post-Pan-African to Recent tectonic features,lithologic heterogeneities and the differential erosion processes as main factors that have controlled the BMR *** results highlight how

关键词： Geomorphic indices Tectonic,Lithology Differential erosion Bafoussam-Mamfe Cameroon

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