Publications by authors named "Dirk Winkler"

86 Publications

Striatal dopamine transporter availability and individual clinical course within the 1-year follow-up of deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

J Neurosurg 2021 Feb 19:1-7. Epub 2021 Feb 19.

2Neurosurgery, and.

Objective: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of this study was therefore to evaluate whether 1) DAT availability changes within 1 year of STN-DBS and 2) the clinical outcome can be predicted based on preoperative DAT availability.

Methods: Twenty-seven PD patients (mean age 62.7 ± 8.9 years; mean duration of illness 13.0 ± 4.9 years; PD subtypes: akinetic-rigid, n = 11; equivalence, n = 13; and tremor-dominant, n = 3) underwent [123I]FP-CIT SPECT preoperatively and after 1 year of STN-DBS. DAT availability as determined by the specific binding ratio (SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side.

Results: Unified Parkinson's Disease Rating Scale (UPDRS) III scores improved significantly (mean preoperative on medication 25.6 ± 12.3, preoperative off medication 42.3 ± 15.2, postoperative on medication/off stimulation 41.4 ± 13.2, and postoperative on medication/on stimulation 16.1 ± 9.4; preoperative on medication vs postoperative on medication/on stimulation, p = 0.006), while the levodopa-equivalent daily dose was reduced (mean preoperative 957 ± 440 mg vs postoperative 313 ± 189 mg, p < 0.001). The SBR did not differ significantly before and 1 year after DBS, regardless of PD subtype. Preoperative DAT availability was not related to the change in UPDRS III score, but the change in DAT availability was significantly correlated with the change in UPDRS III score (contralateral head of the caudate VOI, p = 0.014; contralateral putamen VOI, p = 0.018).

Conclusions: Overall, DAT availability did not change significantly after 1 year of STN-DBS. However, on an individual basis, the improvement in UPDRS III score was associated with an increase in DAT availability, whereas DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of preoperative DAT availability can become a reliable predictor of successful STN-DBS must be evaluated in larger study cohorts.
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http://dx.doi.org/10.3171/2020.8.JNS192740DOI Listing
February 2021

Differential dephosphorylation of CTP:phosphocholine cytidylyltransferase upon translocation to nuclear membranes and lipid droplets.

Mol Biol Cell 2020 05 18;31(10):1047-1059. Epub 2020 Mar 18.

Department of Pediatrics and Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS B3H 4R2, Canada.

CTP:phosphocholine cytidylyltransferase-alpha (CCTα) and CCTβ catalyze the rate-limiting step in phosphatidylcholine (PC) biosynthesis. CCTα is activated by association of its α-helical M-domain with nuclear membranes, which is negatively regulated by phosphorylation of the adjacent P-domain. To understand how phosphorylation regulates CCT activity, we developed phosphosite-specific antibodies for pS319 and pY359+pS362 at the N- and C-termini of the P-domain, respectively. Oleate treatment of cultured cells triggered CCTα translocation to the nuclear envelope (NE) and nuclear lipid droplets (nLDs) and rapid dephosphorylation of pS319. Removal of oleate led to dissociation of CCTα from the NE and increased phosphorylation of S319. Choline depletion of cells also caused CCTα translocation to the NE and S319 dephosphorylation. In contrast, Y359 and S362 were constitutively phosphorylated during oleate addition and removal, and CCTα-pY359+pS362 translocated to the NE and nLDs of oleate-treated cells. Mutagenesis revealed that phosphorylation of S319 is regulated independently of Y359+S362, and that CCTα-S315D+S319D was defective in localization to the NE. We conclude that the P-domain undergoes negative charge polarization due to dephosphorylation of S319 and possibly other proline-directed sites and retention of Y359 and S362 phosphorylation, and that dephosphorylation of S319 and S315 is involved in CCTα recruitment to nuclear membranes.
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http://dx.doi.org/10.1091/mbc.E20-01-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346725PMC
May 2020

Accuracy of a magnetic resonance imaging-based 3D printed stereotactic brain biopsy device in dogs.

J Vet Intern Med 2020 Mar 24;34(2):844-851. Epub 2020 Feb 24.

Department of Small Animal Medicine, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.

Background: Brain biopsy of intracranial lesions is often necessary to determine specific therapy. The cost of the currently used stereotactic rigid frame and optical tracking systems for brain biopsy in dogs is often prohibitive or accuracy is not sufficient for all types of lesion.

Objectives: To evaluate the application accuracy of an inexpensive magnetic resonance imaging-based personalized, 3D printed brain biopsy device.

Animals: Twenty-two dog heads from cadavers were separated into 2 groups according to body weight (<15 kg, >20 kg).

Methods: Experimental study. Two target points in each cadaver head were used (target point 1: caudate nucleus, target point 2: piriform lobe). Comparison between groups was performed using the independent Student's t test or the nonparametric Mann-Whitney U Test.

Results: The total median target point deviation was 0.83 mm (range 0.09-2.76 mm). The separate median target point deviations for target points 1 and 2 in all dogs were 0.57 mm (range: 0.09-1.25 mm) and 0.85 mm (range: 0.14-2.76 mm), respectively.

Conclusion And Clinical Importance: This magnetic resonance imaging-based 3D printed stereotactic brain biopsy device achieved an application accuracy that was better than the accuracy of most brain biopsy systems that are currently used in veterinary medicine. The device can be applied to every size and shape of skull and allows precise positioning of brain biopsy needles in dogs.
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http://dx.doi.org/10.1111/jvim.15739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096628PMC
March 2020

Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group.

Leukemia 2020 04 10;34(4):1038-1051. Epub 2020 Feb 10.

Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin >3.5 mg/dL, lymphocyte doubling time (LDT) <12 months, and age >60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P < 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.
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http://dx.doi.org/10.1038/s41375-020-0727-yDOI Listing
April 2020

Evaluation of electroencephalography analysis methods.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:767-773

The extraction of expressive features from an electroencephalography (EEG) signal is necessary for classification of movement and movement imagination of the limbs. We introduce different preprocessing and feature extraction algorithms for this purpose and develop an algorithm that selects features by their feature importance. This selection is used as an evaluation measure for features, their preprocessing algorithms and the EEG electrodes. Our results show that most influential features for signal interpretation are: common spatial patterns, fractal dimensions, as well as, variance and standard deviation of the preprocessed data. We show that preprocessing with continuous wavelet transforms outperforms the other tested preprocessing algorithms. Furthermore, we show that high gamma frequencies (70-90 Hz) contain more information than the lower μ-rhythms (8-12 Hz) where event-related-desynchronization (ERD) is known to occur. The important EEG electrodes for this classification task are located in the left and right back of the motor-cortex. The proposed algorithm can be further used to create subject-specific and performance models for real-time classification.
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http://dx.doi.org/10.1109/EMBC.2019.8857230DOI Listing
July 2019

SPOT Synthesis: The Solid-Phase Peptide Synthesis on Planar Surfaces.

Authors:
Dirk F H Winkler

Methods Mol Biol 2020 ;2103:151-173

Kinexus Bioinformatics Corporation, Vancouver, BC, Canada.

Peptide libraries are a highly useful tool for drug development. While most preparations of peptide libraries are laborious during either the synthesis or its screening, the SPOT synthesis offers the possibility of directly synthesizing large numbers of peptides on a planar surface. As a positionally addressable, multiple solid-phase synthesis technique, the synthesis allows a very convenient handling during the screening of that peptide library in a form of an array. This publication will provide protocols for the basic procedures of the SPOT synthesis and references to some important literature regarding that technique and its application.
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http://dx.doi.org/10.1007/978-1-0716-0227-0_10DOI Listing
January 2021

Automated Solid-Phase Peptide Synthesis.

Authors:
Dirk F H Winkler

Methods Mol Biol 2020 ;2103:59-94

Kinexus Bioinformatics Corporation, Vancouver, BC, Canada.

The development of solid-phase peptide synthesis by Bruce Merrifield paved the way for a synthesis carried out by machines. Automated peptide synthesis is a fast and convenient way of synthesizing many peptides simultaneously. This chapter tries to give a general guidance for the development of synthesis protocols for the peptide synthesizer. It also provides some suggestions for the modification of the synthesized peptides. Additionally, many examples of possible challenges during and after the synthesis are given in order to support the reader in finding the best synthesis strategy. Numerous references are given to many of the described matters.
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http://dx.doi.org/10.1007/978-1-0716-0227-0_5DOI Listing
January 2021

A concept for a 3D-printed patient-specific stereotaxy platform for brain biopsy -a canine cadaver study.

Res Vet Sci 2019 Jun 25;124:79-84. Epub 2019 Feb 25.

Fraunhofer Institute for Machine Tools and Forming Technology, Nöthnitzer Straße 44, D-01187 Dresden, Germany.

The treatment of intracranial lesions requires a precise diagnosis with subsequent identification of an adequate therapeutic approach. Stereotactic tumor biopsy may be considered the safest neurosurgical procedure in terms of anticipated results and potential surgical complications. The aim of the present paper was to demonstrate a new method of stereotactic biopsy, based on a patient-specific 3D printed platform in dogs. The system was tested on two canine cadavers, a small (Shih Tzu) and a large (Labrador) breed. Imaginary biopsy targets were defined in a superficial (caudate nucleus) and a deep (piriform lobe) position. Based on 3 Tesla MRI, individualized stereotactic platforms were designed using a semi-automatic approach, and manufactured additively using ABS M30. A pre- and intra-operative CT was performed to compare the planned vs. the realized needle position for precision analyses of the procedure. The target points varied with a precision between 0.09 mm and 0.48 mm. Manufacturing time required 480 to 700 min per platform. The presented patient-specific stereotactic system seems a suitable instrument for application in small animal neurosurgery. In particular, the implementation of relevant stereotactic data may help performing the procedure in rapid sequence and with higher precision than currently-used systems. Required adjustments and adaptions to the respective anatomical conditions are omitted and make the procedure reliable and safe.
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http://dx.doi.org/10.1016/j.rvsc.2019.02.007DOI Listing
June 2019

Development of evidence-based quality indicators for deep brain stimulation in patients with Parkinson's disease and first year experience of implementation of a nation-wide registry.

Parkinsonism Relat Disord 2019 03 5;60:3-9. Epub 2019 Feb 5.

Institute for Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany; Comprehensive Heart Failure Center, University Würzburg, Clincial Trial Center Würzburg, University Hospital Würzburg, Germany.

Introduction: Deep Brain Stimulation (DBS) is a complex, invasive and cost-intensive therapy that requires a high level of expertise. To date, data on quality of DBS in clinical routine in the German health care system are lacking.

Methods: The development of evidence-based QIs for DBS in PD patients was performed following a standardized process by a multidisciplinary board between 2014 and 2016. The process was initiated by the German Parkinson Society and followed international recommendations for developing QIs including: a systematic literature search; an appraisal of the published evidence; a consensus-based selection of the QI set; and a pilot study to assess the feasibility in implementing the QIs in clinical routine.

Results: A set of 28 QIs for determining the quality of DBS in PD was established by the board covering different dimensions of health care quality (structure, process, and outcome) in different treatment phases of DBS care (pre-operative, peri-operative, and post-operative). Implementation in clinical practice was tested in a pilot study comprising three hospitals delivering DBS care. The feasibility of the QI set was evaluated positively by the participating physicians and hospitals. Mean time to document one patient was 25 min. The German-wide implementation of the defined indicator set within a dedicated quality registry (QualiPa) started in June 2016.

Conclusion: QIs are a necessary requirement to monitor hospital performance in DBS care. The evidence-based approach to develop the proposed indicator set is expected to assure transparency, acceptance and long-term applicability of the QI set in Germany.
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http://dx.doi.org/10.1016/j.parkreldis.2019.01.016DOI Listing
March 2019

A technical concept of a computer game for patients with Parkinson's disease - a new form of PC-based physiotherapy.

Int J Neurosci 2019 Aug 20;129(8):770-775. Epub 2019 Feb 20.

b University Leipzig, Faculty of Medicine , Department of Neurosurgery , Leipzig , Germany.

At present, there are no meaningful and sophisticated computer games that simultaneously allow the treatment of movement disorders such as Parkinson's syndrome. In particular, there are no systems to consider the severity of the disease and the physical skills of the patient. A computer game using the Microsoft Kinect as markerless sensor for the 3 D recognition of the patient's movement was developed to support the rehabilitation. The scenario of a basketball game was created after determining that the movement like throwing a ball and the correct posture of the body are important. A study based on system usability was performed with 15 patients to evaluate the system. The technical feasibility of a computer-assisted training system for supporting patients with Parkinson's disease has been demonstrated. No markers on the patient are required for movement detection and allow a user-friendly handling. Regarding the usability study, the patients were accepting of such a system and its at-home use and symptoms like 'freezing' and the Pisa syndrome can be treated. The physiotherapist can be assisted by the developed rehabilitation system. An objective measurement of the patient's training progress delivers valuable information to adjust the training sessions for every patient individually. Due to its modular character, the system can also be applied to other diseases or sports injuries and offers the basis for further development.
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http://dx.doi.org/10.1080/00207454.2019.1567510DOI Listing
August 2019

3-Dimensional Aortic Model to Create a Fenestrated Stent Graft for the Urgent Treatment of a Paravisceral Penetrating Aortic Ulcer.

JACC Cardiovasc Interv 2019 Apr 12;12(8):793-795. Epub 2018 Dec 12.

Department of Neurosurgery, University of Leipzig, Leipzig, Germany; Fraunhofer Institute for Machine Tools and Forming Technology, Dresden, Germany.

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http://dx.doi.org/10.1016/j.jcin.2018.10.024DOI Listing
April 2019

Cervical vagus nerve morphometry and vascularity in the context of nerve stimulation - A cadaveric study.

Sci Rep 2018 05 22;8(1):7997. Epub 2018 May 22.

Department of Neurology, University of Leipzig, Leipzig, Germany.

Vagus nerve stimulation (VNS) has become a well-established therapy for epilepsy and depression, and is emerging to treat inflammatory disease, with the cervical vagus nerve (CVN) as major stimulation site. CVN morphometries are missing for VNS, considering its variability. Morphometric data were obtained from CVNs in 27 cadavers, including branching patterns and histology. Cross-sectional area, greater and lesser diameters averaged 7.2 ± 3.1 mm, 5.1 ± 1.5 and 4.1 ± 1.3 mm, and were ≤11.0 mm, ≤7.0 and ≤5.8 mm in 90% of the specimens, respectively. Midline distance (position lateral to the laryngeal eminence) and skin distance (anterior-posterior from skin) averaged 34.5 ± 6.2 and 36.2 ± 9.4 mm, ≤49.0 and ≤41.0 mm in 90%, respectively. Nerve dimensions and surface topography correlated closely, but without gender-, side- or branching-dependent differences. The nerve fascicle number averaged 5.2 ± 3.5. Vagal arteries were observed in 49% of the cases. Negative correlations were found for age and cross-sectional area, as well as subperineural vessel count. Detailed anatomical data on the CVN and its vascularity are given, forming the morphometric basis for VNS refinement, filling an evident gap in light of the CVN being a structure with variable positions and branching. A 35 × 35-mm rule may apply for the CVN position, irrespective of branching or positional variation.
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http://dx.doi.org/10.1038/s41598-018-26135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964190PMC
May 2018

Positional Relations of the Cervical Vagus Nerve Revisited.

Neuromodulation 2017 Jun 1;20(4):361-368. Epub 2017 Feb 1.

Faculty of Medicine, Department of Neurosurgery, University Clinic of Leipzig, Leipzig, Germany.

Objectives: The cervical part of the vagus nerve (CVN) has become an important target for stimulation therapy to treat epilepsy and psychiatric conditions. For this purpose, the CVN is visualized in the carotid sheath, assuming it to be localized dorsomedially between the carotid artery (CA) and the internal jugular vein (JV). The aim of our morphological study was therefore to revisit the CVN relationships to the CA and JV, hypothesizing it to have common variations to this classical textbook anatomy.

Materials And Methods: Positional relations of the CVN, CA and JV were investigated in the carotid sheath of 35 cadavers at the C3 to C6 level. Positional relations of the CVN, CA and JV were documented on the basis of a 3 × 3 chart.

Results: Eighteen different arrangements of the CVN, CA and JV were observed. The typical topographic relationship of the CVN dorsomedially between the CA and JV was only found in 42% of all cases. The CVN was located dorsally or (dorso-)laterally to the CA in 80% and dorsally or (dorso-)medially of the JV in 96% of all cases.

Conclusions: Classical textbook anatomy of the CVN is only present in a minority of cases. Positional variations in contrast to textbook anatomy are considerably more frequent than previously described, which might be a hypothetical morphological explanation for the lack of efficacy or side effects of CVN stimulation. Furthermore, the position of the CVN relative to the internal jugular vein is more consistent than to the CA.
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http://dx.doi.org/10.1111/ner.12557DOI Listing
June 2017

Subthalamic nucleus volumes are highly consistent but decrease age-dependently-a combined magnetic resonance imaging and stereology approach in humans.

Hum Brain Mapp 2017 02 11;38(2):909-922. Epub 2016 Oct 11.

Faculty of Medicine, Institute of Anatomy University of Leipzig, Leipzig, Germany.

The subthalamic nucleus (STN) is a main target structure of deep brain stimulation (DBS) in idiopathic Parkinson's disease. Nevertheless, there is an ongoing discussion regarding human STN volumes and neuron count, which could potentially have an impact on STN-DBS. Moreover, a suspected functional subdivision forms the basis of the tripartite hypothesis, which has not yet been morphologically substantiated. In this study, it was aimed to investigate the human STN by means of combined magnetic resonance imaging (MRI) and stereology. STN volumes were obtained from 14 individuals (ranging from 65 to 96 years, 25 hemispheres) in 3 T MRI and in luxol-stained histology slices. Neuron number and cell densities were investigated stereologically over the entire STN and in pre-defined subregions in anti-human neuronal protein HuC/D-stained slices. STN volumes measured with MRI were smaller than in stereology but appeared to be highly consistent, measuring on average 99 ± 6 mm (MRI) and 132 ± 20 mm (stereology). The neuron count was 431,088 ± 72,172. Both STN volumes and cell count decreased age-dependently. Neuron density was different for the dorsal, medial and ventral subregion with significantly higher values ventrally than dorsally. Small variations in STN volumes in both MRI and stereology contradict previous findings of large variations in STN size. Age-dependent decreases in STN volumes and neuron numbers might influence the efficacy of STN-DBS in a geriatric population. Though the study is limited in sample size, site-dependent differences for the STN subregions form a morphological basis for the tripartite theory. Hum Brain Mapp 38:909-922, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867036PMC
February 2017

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease.

Exp Neurol 2016 08 6;282:99-118. Epub 2016 May 6.

CHDI Foundation/CHDI Management Inc., Los Angeles, USA. Electronic address:

Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently modulates the Kyn pathway in peripheral tissues and in the central nervous system. The administration of CHDI-340246 leads to an inhibition of the formation of 3-OH-Kyn and Quin, and to an elevation of Kyn and Kynurenic acid (KynA) levels in brain tissues. We show that administration of CHDI-340246 or of Kyn and of KynA can restore several electrophysiological alterations in mouse models of HD, both acutely and after chronic administration. However, using a comprehensive panel of behavioral tests, we demonstrate that the chronic dosing of a selective KMO inhibitor does not significantly modify behavioral phenotypes or natural progression in mouse models of HD.
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http://dx.doi.org/10.1016/j.expneurol.2016.05.005DOI Listing
August 2016

Determination of the Substrate Specificity of Protein Kinases with Peptide Micro- and Macroarrays.

Methods Mol Biol 2016 ;1360:183-202

Kinexus Bioinformatics Corporation, Suite 1, 8755 Ash Street, Vancouver, British Columbia, Canada, V6P 6T3.

Elucidation of the key determinants for the phosphorylation site specificities of protein kinases facilitates identification of their physiological substrates, and serves to better define their critical roles in the signaling networks that underlie a multitude of cellular activities. Albeit with some apparent limitations, such as the lack of contextual information for secondary substrate-binding sites, the synthetic peptide-based approach has been adopted widely for the kinase specificity profiling studies, especially when they are used in an array format, which permits the screening of large numbers of potential peptide substrates in parallel. In this chapter, we present detailed protocols for determining protein kinase substrate specificity using an approach that involves both peptide microarrays and macroarrays. In particular, SPOT synthesis on macroarrays can be used to follow up on in silico predictions of protein kinase substrate specificity with predictive algorithms.
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http://dx.doi.org/10.1007/978-1-4939-3073-9_14DOI Listing
August 2016

Analysis of the Inhibitory Elements in the p5 Peptide Fragment of the CDK5 Activator, p35, CDKR1 Protein.

J Alzheimers Dis 2015 ;48(4):1009-17

National Institute of Neurological Disorders and Strokes, National Institutes of Health, Bethesda, MD, USA.

Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles, it is well documented that cyclin-dependent kinase 5 (CDK5), a critical neuronal protein kinase in nervous system development, function, and survival, when deregulated and hyperactivated induces Alzheimer's disease (AD) and amyotrophic lateral sclerosis and Parkinson's disease-like phenotypes in mice. In a recent study, we demonstrated that p5, a small, truncated fragment of 24 amino acid residues derived from the CDK5 activator protein 35 (NCK5A, p35), selectively inhibited deregulated CDK5 hyperactivity and ameliorated AD phenotypes in model mice. In this study, we identified the most inhibitory elements in the p5 peptide fragment. Each amino acid residue in p5 was systematically replaced with its homologous residues that may still be able to functionally substitute. The effects of these p5 peptide analogs were studied on the phosphotransferase activities of CDK5/p35, CDK5/p25, ERK1, and GSK3β. The mimetic p5 peptide (A/V substitution at the C-terminus of the peptide) in the sequence, KNAFYERALSIINLMTSKMVQINV (p5-MT) was the most effective inhibitor of CDK5 kinase activity of 79 tested mimetic peptides including the original p5 peptide, KEAFWDRCLSVINLMSSKMLQINA (p5-WT). Replacement of the residues in C-terminus end of the peptide affected CDK5 phosphotransferase activity most significantly. These peptides were strong inhibitors of CDK5, but not the related proline-directed kinases, ERK1 and GSK3β.
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http://dx.doi.org/10.3233/JAD-150412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927891PMC
August 2016

Pelvic Belt Effects on Health Outcomes and Functional Parameters of Patients with Sacroiliac Joint Pain.

PLoS One 2015 25;10(8):e0136375. Epub 2015 Aug 25.

Clinics for Orthopedics, Osteology and Pain Treatment, Kirchberg, Germany.

Introduction: The sacroiliac joint (SIJ) is a common source of low back pain. However, clinical and functional signs and symptoms correlating with SIJ pain are widely unknown. Pelvic belts are routinely applied to treat SIJ pain but without sound evidence of their pain-relieving effects. This case-control study compares clinical and functional data of SIJ patients and healthy control subjects and evaluates belt effects on SIJ pain.

Methods: 17 SIJ patients and 17 healthy controls were included in this prospective study. The short-form 36 survey and the numerical rating scale were used to characterize health-related quality of life in patients in a six-week follow-up and the pain-reducing effects of pelvic belts. Electromyography data were obtained from the gluteus maximus, biceps femoris, rectus femoris and medial vastus. Alterations of muscle activity, variability and gait patterns were compared in patients and controls along with the belts' effects in a dynamic setting when walking.

Results: Significant improvements were observed in the short-form 36 survey of the SIJ patients, especially in the physical health subscores. Minor declines were also observed in the numerical rating scale on pain. Belt-related changes of muscle activity and variability were similar in patients and controls with one exception: the rectus femoris activity decreased significantly in patients with belt application when walking. Further belt effects include improved cadence and gait velocity in patients and controls.

Conclusions: Pelvic belts improve health-related quality of life and are potentially attributed to decreased SIJ-related pain. Belt effects include decreased rectus femoris activity in patients and improved postural steadiness during locomotion. Pelvic belts may therefore be considered as a cost-effective and low-risk treatment of SIJ pain.

Trial Registration: ClinicalTrials.gov NCT02027038.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549265PMC
May 2016

A comparison of two surgical approaches in functional neurosurgery: individualized versus conventional stereotactic frames.

Comput Aided Surg 2015 20;20(1):34-40. Epub 2015 Aug 20.

a Department of Neurosurgery, University of Leipzig , Leipzig , Germany .

Object: The individualized Starfix® miniframe belongs to a new generation of stereotactic systems enabling high-precision electrode placement with considerably better time-efficiency in deep brain stimulation (DBS). We evaluated the usability and reliability of this novel technique in patients with idiopathic Parkinson's disease (IPD) and compared surgical and clinical results with those obtained in a historical group in which a conventional stereotactic frame was employed.

Methods: Sixty patients underwent surgery for implantation of DBS electrodes in the subthalamic nucleus. In 31 of them (group I) a conventional Zamorano-Dujovny frame was used and in 29 of them (group II) a Starfix® miniframe was used. Image fusion of preoperatively acquired 3D T1w and T2w 1.5 T MR-image series was used for the targeting procedure. Placement of the test electrodes and permanent electrodes corresponded to standard functional neurosurgery and included microelectrode recording and macrostimulation. Clinical (L-Dopa equivalent dose, United Parkinson's disease rating scale part III) and time for surgical electrode implantation were evaluated postoperatively in a 3-, 6- and 12-month follow-up.

Results: Twelve months postoperatively, L-Dopa dose was significantly reduced from 685.19 to 205.88 mg/day and from 757.92 to 314.42 mg/day in groups I and II, respectively. A comparable reduction of the LED could be observed 1 year after surgery. Motor function has improved in a significant and identical manner with 59% (group I) and 61% (group II). Besides clinical effects by stimulation therapy there was a significantly reduced surgery time required for electrode implantation using the Starfix® miniframe (group I: 234.1 min, group II: 173.6 min; p < 0.001).

Conclusions: Individualized miniframes such as the Starfix® miniframe allow implantation of DBS electrodes in IPD that is equally effective as conventional systems. The time efficiency achieved in surgery using of the Starfix® system helps to minimize patients' discomfort during DBS surgery.
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http://dx.doi.org/10.3109/10929088.2015.1076042DOI Listing
April 2016

Pelvic belt effects on pelvic morphometry, muscle activity and body balance in patients with sacroiliac joint dysfunction.

PLoS One 2015 17;10(3):e0116739. Epub 2015 Mar 17.

Institute of Anatomy, University of Leipzig, Faculty of Medicine, Leipzig, Germany; Department of Trauma and Reconstructive Surgery, University of Leipzig, Faculty of Medicine, Leipzig, Germany.

Introduction: The sacroiliac joint (SIJ) is frequently involved in low back and pelvic girdle pain. However, morphometrical and functional characteristics related to SIJ pain are poorly defined. Pelvic belts represent one treatment option, but evidence still lacks as to their pain-reducing effects and the mechanisms involved. Addressing these two issues, this case-controlled study compares morphometric, functional and clinical data in SIJ patients and healthy controls and evaluates the effects of short-term pelvic belt application.

Methods: Morphometric and functional data pertaining to pelvic belt effects were compared in 17 SIJ patients and 17 controls. Lumbar spine and pelvis morphometries were obtained from 3T magnetic resonance imaging. Functional electromyography data of pelvis and leg muscles and center of pressure excursions were measured in one-leg stance. The numerical rating scale was used to evaluate immediate pain-reducing effects.

Results: Pelvic morphometry was largely unaltered in SIJ patients and also by pelvic belt application. The angle of lumbar lateral flexion was significantly larger in SIJ patients without belt application. Muscle activity and center of pressure were unaffected by SIJ pain or by belt application in one-leg stance. Nine of 17 patients reported decreased pain intensities under moderate belt application, four reported no change and four reported increased pain intensity. For the entire population investigated here, this qualitative description was not confirmed on a statistical significant level.

Discussion: Minute changes were observed in the alignment of the lumbar spine in the frontal plane in SIJ patients. The potential pain-decreasing effects of pelvic belts could not be attributed to altered muscle activity, pelvic morphometry or body balance in a static short-term application. Long-term belt effects will therefore be of prospective interest.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116739PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364533PMC
February 2016

Human vagus nerve branching in the cervical region.

PLoS One 2015 13;10(2):e0118006. Epub 2015 Feb 13.

Department of Neurosurgery, University Clinic of Leipzig, Faculty of Medicine, Leipzig, Germany.

Background: Vagus nerve stimulation is increasingly applied to treat epilepsy, psychiatric conditions and potentially chronic heart failure. After implanting vagus nerve electrodes to the cervical vagus nerve, side effects such as voice alterations and dyspnea or missing therapeutic effects are observed at different frequencies. Cervical vagus nerve branching might partly be responsible for these effects. However, vagus nerve branching has not yet been described in the context of vagus nerve stimulation.

Materials And Methods: Branching of the cervical vagus nerve was investigated macroscopically in 35 body donors (66 cervical sides) in the carotid sheath. After X-ray imaging for determining the vertebral levels of cervical vagus nerve branching, samples were removed to confirm histologically the nerve and to calculate cervical vagus nerve diameters and cross-sections.

Results: Cervical vagus nerve branching was observed in 29% of all cases (26% unilaterally, 3% bilaterally) and proven histologically in all cases. Right-sided branching (22%) was more common than left-sided branching (12%) and occurred on the level of the fourth and fifth vertebra on the left and on the level of the second to fifth vertebra on the right side. Vagus nerves without branching were significantly larger than vagus nerves with branches, concerning their diameters (4.79 mm vs. 3.78 mm) and cross-sections (7.24 mm2 vs. 5.28 mm2).

Discussion: Cervical vagus nerve branching is considerably more frequent than described previously. The side-dependent differences of vagus nerve branching may be linked to the asymmetric effects of the vagus nerve. Cervical vagus nerve branching should be taken into account when identifying main trunk of the vagus nerve for implanting electrodes to minimize potential side effects or lacking therapeutic benefits of vagus nerve stimulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118006PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332499PMC
December 2015

Investigation of the automated solid-phase synthesis of a 38mer peptide with difficult sequence pattern under different synthesis strategies.

Amino Acids 2015 Apr 17;47(4):787-94. Epub 2015 Jan 17.

Peptide Facility, Kinexus Bioinformatics Corporation, 8755 Ash Street, Suite 1, Vancouver, BC, V6P 6T3, Canada,

Difficult peptides are a constant challenge in solid-phase peptide synthesis. In particular, hydroxyl amino acids such as serine can cause severe breakdowns in coupling yields even several amino acids after the insertion of the critical amino acid. This paper investigates several methods of improving synthesis yields of difficult peptides including the use of different resins, activators and the incorporation of a structure-breaking pseudoproline dipeptide building block both alone and in combination with each other.
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http://dx.doi.org/10.1007/s00726-014-1909-6DOI Listing
April 2015

Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.

J Med Chem 2015 Feb 23;58(3):1159-83. Epub 2015 Jan 23.

Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, U.K.

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
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http://dx.doi.org/10.1021/jm501350yDOI Listing
February 2015

Takotsubo cardiomyopathy - An unexpected complication in spine surgery.

Int J Surg Case Rep 2015 11;6C:172-4. Epub 2014 Dec 11.

Department of Neurosurgery, University of Leipzig, Liebigstraße 20, D-04103 Leipzig, Germany. Electronic address:

Introduction: Takotsubo cardiomyopathy is an apical ballooning syndrome, which can be triggered by stress. Only few case reports describe the onset of Takotsubo as a complication of neurosurgery procedures.

Clinical Presentation: A case of a 53 year-old female with a spinal neurinoma and surgery-associated Takotsubo cardiomyopathy is demonstrated. The patient developed typical signs of a myocardial infarction with circulation depression and ST elevation, but normal cardiac enzymes at the end of surgery. Cardiac catheterization and levocardiography confirmed the absence of any critical coronary disease but the presence of a typical apical ballooning and midventricular hypokinesis. The patient recovered completely under supportive conservative and cardiological therapy, showing regular left ventricular pump function.

Conclusion: Interventions in neurosurgery and perioperative care should be kept as stress free as possible. Due to the possibility of neurogenic mechanisms related to cardiomyopathy, Takotsubo cardiomyopathy as an entity of stress-induced complications should be taken into consideration.
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http://dx.doi.org/10.1016/j.ijscr.2014.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334960PMC
January 2015

Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors.

J Med Chem 2014 Jul 27;57(13):5714-27. Epub 2014 Jun 27.

Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.

Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.
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http://dx.doi.org/10.1021/jm500550eDOI Listing
July 2014

Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.

Blood 2014 May 20;123(21):3247-54. Epub 2014 Mar 20.

Department of Internal Medicine III, Ulm University, Ulm, Germany;

Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.
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http://dx.doi.org/10.1182/blood-2014-01-546150DOI Listing
May 2014

Median nerve fascicular anatomy as a basis for distal neural prostheses.

Ann Anat 2014 May 12;196(2-3):144-9. Epub 2013 Dec 12.

Department of Neurosurgery, University of Leipzig, Liebigstraße 20a, D-04103 Leipzig, Germany.

Introduction: Functional electrical stimulation (FES) serves as a possible therapy to restore missing motor functions of peripheral nerves by means of cuff electrodes. FES is established for improving lower limb function. Transferring this method to the upper extremity is complex, due to a lack of anatomical data on the physiological configuration of nerve fascicles. Our study's aim was to provide an anatomical basis for FES of the median nerve in the distal forearm and hand.

Methods: We investigated 21 distal median nerves from 12 body donors. The peripheral fascicles were traced back by removing the external and interfascicular epineurium and then assigned to 4 quadrants.

Results: A distinct motor and sensory distribution was observed. The fascicles innervating the thenar eminence and the first lumbrical muscle originated from the nerves' radial parts in 82%. The fascicle supplying the second lumbrical muscle originated from the ulnar side in 78%. No macroscopically visible plexus formation was observed for the distal median nerve in the forearm.

Conclusions: The findings on the distribution of the motor branches of the median nerve and the missing plexus formation may likely serve as an anatomical basis for FES of the distal forearm. However, due to the considerable variability of the motor branches, cuff electrodes will need to be adapted individually in FES. Taking into account the sensory distribution of the median nerve, FES may also possibly be applied in the treatment of regional pain syndromes.
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http://dx.doi.org/10.1016/j.aanat.2013.11.002DOI Listing
May 2014

Implementing conventional Zamorano Dujovny frames versus individually manufactured microTargeting platforms--a comparative study on deep brain stimulation in Parkinson patients.

Stereotact Funct Neurosurg 2013 9;91(6):392-8. Epub 2013 Oct 9.

Department of Neurosurgery, University of Leipzig, Leipzig, Germany.

Background And Objectives: Individually manufactured microTargeting™ platforms (MT) provide a novel generation of stereotactic systems based on preoperatively implanted bone markers and screws. The feasibility and reliability of these frames were evaluated for bilateral deep brain stimulation (DBS) in patients with idiopathic Parkinson's disease (IPD). Surgical and clinical results were compared to conventional Zamorano Dujovny frames (ZD) in this prospective study.

Materials And Methods: Twenty-six IPD patients undergoing surgery for DBS were divided into 2 groups. In group I, electrode implantation was accomplished using conventional ZD. Group II underwent electrode implantation using MT. Microrecording and macrostimulation were performed and surgery time was measured. The clinical outcome was determined using the Unified Parkinson's Disease Rating Scale Part III (UPDRS III) and L-dopa-equivalent doses for a 12-month follow-up postoperatively.

Results: Clinical evaluation confirmed comparable outcomes for both targeting procedures and electrode positioning. Surgical time was lower in group II than in group I. Significant improvements were determined for both groups in UPDRS III and L-dopa-equivalent dose.

Conclusions: Both systems allow for reliable and safe neurosurgical procedures, yielding comparable clinical results. MT improved handling and automatic adjustment of frame coordinates. Surgery time was reduced markedly compared to conventional frames.
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http://dx.doi.org/10.1159/000351522DOI Listing
July 2014

NOTCH1, SF3B1, and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG.

Blood 2013 Aug 2;122(7):1266-70. Epub 2013 Jul 2.

Department of Internal Medicine III, Ulm University, Ulm, Germany.

We studied the incidences, associations, and prognostic roles of NOTCH1 and SF3B1 mutations (NOTCH1(mut), SF3B1(mut)) as compared with TP53(mut) in fludarabine-refractory chronic lymphocytic leukemia (CLL) patients treated with alemtuzumab in the CLL2H trial. We found NOTCH1(mut), SF3B1(mut), and TP53(mut) in 13.4%, 17.5%, and 37.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) were mutually exclusive, whereas TP53(mut) were evenly distributed within both subgroups. Apart from correlation of SF3B1(mut) with 11q deletion (P = .029), there were no other significant associations of the mutations with any baseline characteristics or response rates. However, NOTCH1(mut) cases had a significantly longer progression-free survival (PFS) compared with wild-type cases (15.47 vs 6.74 months; P = .025), although there was no significant difference with overall survival (OS). SF3B1(mut) had no significant impact on PFS and OS. In multivariable analyses, NOTCH1(mut) was identified as an independent favorable marker for PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00274976.
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http://dx.doi.org/10.1182/blood-2013-03-488197DOI Listing
August 2013