Publications by authors named "Thomas Kremer"

120 Publications

Reduced real-life affective well-being and amygdala habituation in unmedicated community individuals at risk for depression and anxiety.

Biol Psychiatry Cogn Neurosci Neuroimaging 2022 Jun 24. Epub 2022 Jun 24.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address:

Background: Early identification of risk for depression and anxiety disorders is important for prevention, but real-life affective well-being and its biological underpinnings in the population remain understudied. Here, we combined methods from epidemiology, psychology, ecological momentary assessment (EMA) and functional magnetic resonance imaging (fMRI) to study real-life and neural affective functions in individuals with subclinical anxiety and depression from a population-based cohort of young adults.

Methods: We examined psychological measures, real-life affective valence, fMRI amygdala habituation to negative affective stimuli and the relevance of neural readouts for daily-life affective function in 132 non-help-seeking community individuals. We compared psychological and EMA measures of 61 unmedicated individuals at clinical risk for depression and anxiety (operationalized as subthreshold depression and anxiety symptoms or a former mood or anxiety disorder) to those of 48 non-risk individuals and 23 persons with a mood or anxiety disorder. We studied risk-associated fMRI signals in subsamples with balanced sociodemographic and image quality parameters (26 non-risk, 26 at-risk persons).

Results: Compared to non-risk persons, at-risk individuals showed significantly decreased real-life affective valence (p = .038), reduced amygdala habituation (p = .024, region of interest [ROI] corrected) and an intermediate psychological risk profile. Amygdala habituation predicted real-life affective valence in controls, but not in participants at risk (p = .005, ROI corrected).

Conclusions: Our data suggest real-life and neural markers for affective alterations in unmedicated community individuals at risk for depression and anxiety and highlight the significance of amygdala habituation measures for the momentary affective experience in real-world environments.
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http://dx.doi.org/10.1016/j.bpsc.2022.06.009DOI Listing
June 2022

[Reconstruction of Soft Tissue Defects of the Achilles Tendon Region: a Literature Review].

Handchir Mikrochir Plast Chir 2022 Jun 22. Epub 2022 Jun 22.

Städtisches Klinikum Sankt Georg Leipzig, Klinik für Plastische und Handchirurgie mit Schwerbrandverletztenzentrum.

Background: Soft tissue defects in the achilles tendon region occur after trauma, but also as a complication after open recon- struction of the tendon with subsequent infection.

Objectives: Recommendations for the treatment of soft tissue injuries involving the Achilles tendon are presented.

Materials And Methods: A search of the German, French and English literature on reconstruction of soft tissue defects of the Achilles tendon region was performed, which were differentiated into singular and combined tendocutaneous defects. Combined defects were further subdivided into three reconstructive principles: a simple soft tissue reconstruction without tendon repair or a combined reconstruction of the soft tissue as well as the tendon using either a vascularized tendon transplant or an avascular tendon graft.

Results: Local and distally-based pedicled flaps include a relatively high risk or perioperative morbidity, whereas free flaps are described with significantly lower complications rates. Therefore, the authors prefer free flaps for reconstruction. Potential donor sites are the Medial Sural Artery (MSAP-) flap for smaller defects or free fasciocutaneous or muscle flaps in patients with large defects. The standard for tendocutaneousreconstructions is the free anterolateral thigh flap including vascularized fascia. Non-vascularized tendon grafts are frequently applied from the flexor hallucis longus- or peroneus brevis tendon.

Conclusions: Reconstructions over the Achilles tendon require thin and stable reconstructions that additionally allow slippage of soft tissues. Moreover, the use of normal shoes should be possible. The postoperative strength and range of motion of the ankle joint show comparable functional results after vascularized and non-vascularized tendon reconstruction.
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http://dx.doi.org/10.1055/a-1794-5449DOI Listing
June 2022

Multi-platform quantitation of alpha-synuclein human brain proteoforms suggests disease-specific biochemical profiles of synucleinopathies.

Acta Neuropathol Commun 2022 06 3;10(1):82. Epub 2022 Jun 3.

Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.

Based on immunostainings and biochemical analyses, certain post-translationally modified alpha-synuclein (aSyn) variants, including C-terminally truncated (CTT) and Serine-129 phosphorylated (pSer129) aSyn, are proposed to be involved in the pathogenesis of synucleinopathies such as Parkinson's disease with (PDD) and without dementia (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, quantitative information about aSyn proteoforms in the human brain in physiological and different pathological conditions is still limited. To address this, we generated sequential biochemical extracts of the substantia nigra, putamen and hippocampus from 28 donors diagnosed and neuropathologically-confirmed with different synucleinopathies (PD/PDD/DLB/MSA), as well as Alzheimer's disease, progressive supranuclear palsy, and aged normal subjects. The tissue extracts were used to build a reverse phase array including 65 aSyn antibodies for detection. In this multiplex approach, we observed increased immunoreactivity in donors with synucleinopathies compared to controls in detergent-insoluble fractions, mainly for antibodies against CT aSyn and pSer129 aSyn. In addition, despite of the restricted sample size, clustering analysis suggested disease-specific immunoreactivity signatures in patient groups with different synucleinopathies. We aimed to validate and quantify these findings using newly developed immunoassays towards total, 119 and 122 CTT, and pSer129 aSyn. In line with previous studies, we found that synucleinopathies shared an enrichment of post-translationally modified aSyn in detergent-insoluble fractions compared to the other analyzed groups. Our measurements allowed for a quantitative separation of PDD/DLB patients from other synucleinopathies based on higher detergent-insoluble pSer129 aSyn concentrations in the hippocampus. In addition, we found that MSA stood out due to enrichment of CTT and pSer129 aSyn also in the detergent-soluble fraction of the SN and putamen. Together, our results achieved by multiplexed and quantitative immunoassay-based approaches in human brain extracts of a limited sample set point to disease-specific biochemical aSyn proteoform profiles in distinct neurodegenerative disorders.
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http://dx.doi.org/10.1186/s40478-022-01382-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164351PMC
June 2022

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome.

Mol Ther Nucleic Acids 2022 Jun 20;28:514-529. Epub 2022 Apr 20.

Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.

Angelman syndrome (AS) is a severe neurodevelopmental disorder featuring ataxia, cognitive impairment, and drug-resistant epilepsy. AS is caused by mutations or deletion of the maternal copy of the paternally imprinted gene, with current precision therapy approaches focusing on re-expression of . Certain phenotypes, however, are difficult to rescue beyond early development. Notably, a cluster of microRNA binding sites was reported in the untranslated transcript, including for miR-134, suggesting that AS may be associated with microRNA dysregulation. Here, we report levels of miR-134 and key targets are normal in the hippocampus of mice carrying a maternal deletion of ( ). Nevertheless, intracerebroventricular injection of an antimiR oligonucleotide inhibitor of miR-134 (Ant-134) reduced audiogenic seizure severity over multiple trials in 21- and 42-day-old AS mice. Interestingly, Ant-134 also improved distance traveled and center crossings of AS mice in the open-field test. Finally, we show that silencing miR-134 can upregulate targets of miR-134 in neurons differentiated from Angelman patient-derived induced pluripotent stem cells. These findings indicate that silencing miR-134 and possibly other microRNAs could be useful to treat clinically relevant phenotypes with a later developmental window in AS.
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http://dx.doi.org/10.1016/j.omtn.2022.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092865PMC
June 2022

Comparative histomorphological analysis of elbow ligaments and capsule.

Clin Anat 2022 May 8. Epub 2022 May 8.

Department of Plastic and Hand Surgery with Burn Unit, Hospital Sankt Georg, Leipzig, Germany.

This study aimed to compare the histomorphology of the elbow capsule and its ligaments to gain a better understanding of the clinically relevant biomechanical stabilization. Eleven human elbows were dissected including the joint capsule with its anterior (AJC) and posterior (PJC) parts, the annular ligament (AL), the radial collateral ligament (RCL) and the ulnar collateral ligament with its anterior (AUCL), posterior (PUCL) and transverse (TUCL) parts. Hematoxylin-Eosin and Elastica van Gieson as conventional histology stainings were applied to determine collagenous and elastic fiber arrangements in transmission and polarization light microscopy. The radial collateral ligament and the anterior part of the ulnar collateral ligament showed significantly more densely packed parallel fiber arrangement than the anterior joint capsule, the posterior joint capsule, and the posterior part of the ulnar collateral ligament (p < 0.02, respectively). The PUCL had significantly more mixed tight and loose parallel arrangements than the PJC, the annular ligament, the RCL, the AUCL and the transverse part of the ulnar collateral ligamentp < 0.02, respectively), while the PJC showed significantly more interlaced mixed tight and loose fiber arrangement than the AL, the RCL and the AUCL (p < 0.003, respectively). The AJC had a significantly higher amount of elastic fibers as compared to the AL, the RCL, the AUCL and the TUCL in fascicular regions (p < 0.04, respectively), while the AUCL had significantly lesser elastic fibers than the AJC and the PJC (p < 0.004, respectively). The densely packed parallel fiber arrangement and few elastic fibers of the AUCL, RCL, and AL indicate a strong biomechanically stabilizing function. The fiber arrangement of the PUCL and the TUCL with few elastic fibers support the medial elbow stabilization. Crimping and elastic fibers provide the viscoelasticity of the joint capsule.
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http://dx.doi.org/10.1002/ca.23913DOI Listing
May 2022

A cross-species spatiotemporal proteomic analysis identifies UBE3A-dependent signaling pathways and targets.

Mol Psychiatry 2022 May 9;27(5):2590-2601. Epub 2022 Mar 9.

Neuroscience and Rare Diseases Discovery & Translational Area, Basel, Switzerland.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of neuronal E3 ligase UBE3A. Restoring UBE3A levels is a potential disease-modifying therapy for AS and has recently entered clinical trials. There is paucity of data regarding the molecular changes downstream of UBE3A hampering elucidation of disease therapeutics and biomarkers. Notably, UBE3A plays an important role in the nucleus but its targets have yet to be elucidated. Using proteomics, we assessed changes during postnatal cortical development in an AS mouse model. Pathway analysis revealed dysregulation of proteasomal and tRNA synthetase pathways at all postnatal brain developmental stages, while synaptic proteins were altered in adults. We confirmed pathway alterations in an adult AS rat model across multiple brain regions and highlighted region-specific differences. UBE3A reinstatement in AS model mice resulted in near complete and partial rescue of the proteome alterations in adolescence and adults, respectively, supporting the notion that restoration of UBE3A expression provides a promising therapeutic option. We show that the nuclear enriched transketolase (TKT), one of the most abundantly altered proteins, is a novel direct UBE3A substrate and is elevated in the neuronal nucleus of rat brains and human iPSC-derived neurons. Taken together, our study provides a comprehensive map of UBE3A-driven proteome remodeling in AS across development and species, and corroborates an early UBE3A reinstatement as a viable therapeutic option. To support future disease and biomarker research, we present an accessible large-scale multi-species proteomic resource for the AS community ( https://www.angelman-proteome-project.org/ ).
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http://dx.doi.org/10.1038/s41380-022-01484-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135630PMC
May 2022

Teaching Microsurgical Breast Reconstruction-A Retrospective Cohort Study.

J Clin Med 2021 Dec 14;10(24). Epub 2021 Dec 14.

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, Hand and Plastic Surgery of Heidelberg University, BG Clinic Ludwigshafen, Ludwig-Guttmann-Str. 13, 67071 Ludwigshafen, Germany.

Microsurgical breast reconstruction demands the highest level of expertise in both reconstructive and aesthetic plastic surgery. Implementation of such a complex surgical procedure is generally associated with a learning curve defined by higher complication rates at the beginning. The aim of this study was to present an approach for teaching deep inferior epigastric artery perforator (DIEP) and transverse upper gracilis (TUG) flap breast reconstruction, which can diminish complications and provide satisfying outcomes from the beginning. DIEP and TUG flap procedures for breast reconstruction were either performed by a senior surgeon (>200 DIEP/TUG, " "), or taught to one of five trainees (>80 breast surgeries; >50 free flaps) in a step-wise approach. The latter were either performed by the senior surgeon, and a trainee was assisting the surgery (""); by the trainee, and a senior surgeon was supervising (""); or by the trainee without a senior surgeon (""). Surgeries of each group were analyzed regarding OR-time, complications, and refinement procedures. A total of 95 DIEP and 93 TUG flaps were included into this study. Before the first DIEP/TUG flap without supervision, each trainee underwent a mean of 6.8 DIEP and 7.3 TUG training surgeries ( > 0.05). Outcome measures did not reveal any statistically significant differences (passive training/active training/after training/no-training: OR-time (min): DIEP: 331/351/338/304 ( > 0.05); TUG: 229/214/239/217 ( > 0.05); complications (n): DIEP: 6/13/16/11 ( > 0.05); TUG: 6/19/23/11 ( > 0.05); refinement procedures (n): DIEP:71/63/49/44 ( > 0.05); TUG: 65/41/36/56 ( > 0.05)), indicating safe and secure implementation of this step-wise training approach for microsurgical breast reconstruction in both aesthetic and reconstructive measures. Of note, despite being a perforator flap, DIEP flap required no more training than TUG flap, highlighting the importance of flap inset at the recipient site.
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http://dx.doi.org/10.3390/jcm10245875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707719PMC
December 2021

Revisionary soft tissue reconstruction of posterior midline defects after spinal surgery-plastic reconstructive options including perforator flaps.

J Spine Surg 2021 Sep;7(3):364-375

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Ludwigshafen, Germany.

Background: Chronic prevertebral soft tissue defects with exposed metal hardware following spinal surgery represent a challenging complication. Frequently patients underwent multiple previous operations due to wound complications. Surrounding soft tissues are often compromised due to malperfusion, severe subcutaneous scarring, previous local advancement flaps and therefore impair stable wound closure.

Methods: Patients after spinal surgery who received complex soft tissue reconstructions between 2011 and 2015 were analyzed retrospectively. Patient`s age, risk factors, wound size, cause and defect location as well as complication rates were evaluated. A focus was set on therapeutic strategies and decision-making concerning reconstructive techniques.

Results: Fourteen patients receiving 27 pedicled and one free flap were included in the study. Patients mean age was 51.1 years, mean wound size was 144 cm. Defects were located in the lumbar spine [8], cervical spine [2] and thoracic spine [1], respectively. Three patients suffered from extensive defects affecting more than one area. Mean time of flap surgery was 213 minutes. Fifteen perforator-based flaps and 11 non-perforator (classic rotation-flaps), 1 pedicled and 1 free latissimus dorsi flap were used. In 9 patients (64.3%) different flaps had to be combined in a single-staged procedure due to large wounds. Implant material was removed completely in six patients (42.9%), whereas in five patients (35.7%) implants were replaced within the operation for soft tissue reconstruction. In three patients (21.4%) initial implant removal or replacement was not possible which leads to prolonged postoperative wound infections.

Conclusions: Most patients with exposed spinal hardware suffered from multiple comorbidities and showed a poor general condition. Due to the reduced soft tissue quality wound healing is significantly impaired. Exposed implant material should be replaced or removed when possible. Therefore, the complete armamentarium of plastic reconstructive techniques is required for wound closure. Today, perforator flaps play a prominent role due to the variability, excellent vascularization and sufficient subcutaneous filling capacities.
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http://dx.doi.org/10.21037/jss-20-688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511569PMC
September 2021

Intra- and Extrathoracic Malignant Tracheoesophageal Fistula-A Differentiated Reconstructive Algorithm.

Cancers (Basel) 2021 Aug 27;13(17). Epub 2021 Aug 27.

Department of General, Vascular and Thoracic Surgery, RoMed Klinikum, 83022 Rosenheim, Germany.

Background: Tracheoesophageal fistulae (TEF) after oncologic resections and multimodal treatment are life-threatening and surgically challenging. Radiation and prior procedures hamper wound healing and lead to high complication rates. We present an interdisciplinary algorithm for the treatment of TEF derived from the therapy of consecutive patients.

Patients And Methods: 18 patients (3 females, 15 males) treated for TEF from January 2015 to July 2017 were included. Two patients were treated palliatively, whereas reconstructions were attempted in 16 cases undergoing 24 procedures. Discontinuity resection and secondary gastric pull-up were performed in two patients. Pedicled reconstructions were pectoralis major ( = 2), sternocleidomastoid muscle ( = 2), latissimus dorsi ( = 1) or intercostal muscle (ICM, = 7) flaps. Free flaps were anterolateral thigh (ALT, = 4), combined anterolateral thigh/anteromedial thigh (ALT/AMT, = 1), jejunum ( = 3) or combined ALT-jejunum flaps ( = 2).

Results: Regarding all 18 patients, 11 of 16 reconstructive attempts were primarily successful (61%), whereas long-term success after multiple procedures was possible in 83% ( = 15). The 30-day survival was 89%. Derived from the experience, patients were divided into three subgroups (extrathoracic, cervicothoracic, intrathroracic TEF) and a treatment algorithm was developed. Primary reconstructions for extra- and cervicothoracic TEF were pedicled flaps, whereas free flaps were used in recurrent or persistent cases. Pedicled ICM flaps were mostly used for intrathoracic TEF.

Conclusion: TEF after multimodal tumor treatment require concerted interdisciplinary efforts for successful reconstruction. We describe a differentiated reconstructive approach including multiple reconstructive techniques from pedicled to chimeric ALT/jejunum flaps. Hereby, successful reconstructions are mostly possible. However, disease and patient-specific morbidity has to be anticipated and requires further interdisciplinary management.
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http://dx.doi.org/10.3390/cancers13174329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430587PMC
August 2021

[A systematic approach to plastic surgical foot reconstruction].

Unfallchirurg 2021 Oct 9;124(10):797-806. Epub 2021 Sep 9.

Klinik für Plastische und Handchirurgie mit Schwerbrandverletztenzentrum, Klinikum St. Georg gGmbH, Delitzscher Str. 141, 04129, Leipzig, Deutschland.

Background: Soft tissue defects of the foot are very common sequelae after trauma and require an individual reconstructive approach.

Objective: Recommendations for the treatment of soft tissue injuries to the foot are given.

Material And Methods: The criteria of soft tissue reconstruction, postoperative follow-up and complications are first discussed before the therapeutic approach is explained depending on the reconstruction site. Case examples are given for illustration.

Results: Decision making for soft tissue reconstruction of the foot is based on the location, the 3‑dimensional extent of the defect, the patient requirements and concomitant diseases. Standardized treatment algorithms are usually applied that need to be adapted according to individual patient factors. Randomized and local pedicled flaps can be applied for foot reconstruction; however, these options involve a significant risk of complications. Consequently, free flaps are frequently indicated after appropriate preoperative diagnostics of the perfusion of the foot. Due to the vast variety of donor sites, free flaps allow an individualized reconstruction, which is adapted to local and patient requirements.

Conclusion: Precise preoperative reconstructive planning and analysis of the vascularization form the foundation for a successful soft tissue reconstruction of the foot. The aims of the individualized approach to soft tissue reconstruction of the foot are stable soft tissue coverage, resistance to weight bearing of the sole of the foot, the ability to wear normal shoes and maintenance of sensibility.
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http://dx.doi.org/10.1007/s00113-021-01075-7DOI Listing
October 2021

Secreted retrovirus-like GAG-domain-containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology.

Cell Rep Med 2021 08 17;2(8):100360. Epub 2021 Aug 17.

Neuroscience and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal , a ubiquitin protein ligase E3A. Here, we study neurons derived from patients with AS and neurotypical individuals, and reciprocally modulate UBE3A using antisense oligonucleotides. Unbiased proteomics reveal proteins that are regulated by UBE3A in a disease-specific manner, including PEG10, a retrotransposon-derived GAG protein. PEG10 protein increase, but not RNA, is dependent on UBE3A and proteasome function. PEG10 binds to both RNA and ataxia-associated proteins (ATXN2 and ATXN10), localizes to stress granules, and is secreted in extracellular vesicles, modulating vesicle content. Rescue of AS patient-derived neurons by UBE3A reinstatement or PEG10 reduction reveals similarity in transcriptome changes. Overexpression of PEG10 during mouse brain development alters neuronal migration, suggesting that it can affect brain development. These findings imply that PEG10 is a secreted human UBE3A target involved in AS pathophysiology.
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http://dx.doi.org/10.1016/j.xcrm.2021.100360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385294PMC
August 2021

Antisense oligonucleotide treatment rescues UBE3A expression and multiple phenotypes of an Angelman syndrome mouse model.

JCI Insight 2021 08 9;6(15). Epub 2021 Aug 9.

Departments of Clinical Genetics and Neuroscience and.

Angelman syndrome (AS) is a severe neurodevelopmental disorder for which only symptomatic treatment with limited benefits is available. AS is caused by mutations affecting the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene. Previous studies showed that the silenced paternal Ube3a gene can be activated by targeting the antisense Ube3a-ATS transcript. We investigated antisense oligonucleotide-induced (ASO-induced) Ube3a-ATS degradation and its ability to induce UBE3A reinstatement and rescue of AS phenotypes in an established Ube3a mouse model. We found that a single intracerebroventricular injection of ASOs at postnatal day 1 (P1) or P21 in AS mice resulted in potent and specific UBE3A reinstatement in the brain, with levels up to 74% of WT levels in the cortex and a full rescue of sensitivity to audiogenic seizures. AS mice treated with ASO at P1 also showed rescue of established AS phenotypes, such as open field and forced swim test behaviors, and significant improvement on the reversed rotarod. Hippocampal plasticity of treated AS mice was comparable to WT but not significantly different from PBS-treated AS mice. No rescue was observed for the marble burying and nest building phenotypes. Our findings highlight the promise of ASO-mediated reactivation of UBE3A as a disease-modifying treatment for AS.
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http://dx.doi.org/10.1172/jci.insight.145991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410092PMC
August 2021

Systematic Assessment of 10 Biomarker Candidates Focusing on α-Synuclein-Related Disorders.

Mov Disord 2021 12 7;36(12):2874-2887. Epub 2021 Aug 7.

Paracelsus-Elena-Klinik, Kassel, Germany.

Background: Objective diagnostic biomarkers are needed to support a clinical diagnosis.

Objectives: To analyze markers in various neurodegenerative disorders to identify diagnostic biomarker candidates for mainly α-synuclein (aSyn)-related disorders (ASRD) in serum and/or cerebrospinal fluid (CSF).

Methods: Upon initial testing of commercially available kits or published protocols for the quantification of the candidate markers, assays for the following were selected: total and phosphorylated aSyn (pS129aSyn), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), tau protein (tau), ubiquitin C-terminal hydrolase L1 (UCHL-1), glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM-2), and chitinase-3-like protein 1 (YKL-40). The cohort comprised participants with Parkinson's disease (PD, n = 151), multiple system atrophy (MSA, n = 17), dementia with Lewy bodies (DLB, n = 45), tau protein-related neurodegenerative disorders (n = 80, comprising patients with progressive supranuclear palsy (PSP, n = 38), corticobasal syndrome (CBS, n = 16), Alzheimer's disease (AD, n = 11), and frontotemporal degeneration/amyotrophic lateral sclerosis (FTD/ALS, n = 15), as well as healthy controls (HC, n = 20). Receiver operating curves (ROC) with area under the curves (AUC) are given for each marker.

Results: CSF total aSyn was decreased. NfL, pNfH, UCHL-1, GFAP, S100B, and sTREM-2 were increased in patients with neurodegenerative disease versus HC (P < 0.05). As expected, some of the markers were highest in AD (i.e., UCHL-1, GFAP, S100B, sTREM-2, YKL-40). Within ASRD, CSF NfL levels were higher in MSA than PD and DLB (P < 0.05). Comparing PD to HC, interesting serum markers were S100B (AUC: 0.86), sTREM2 (AUC: 0.87), and NfL (AUC: 0.78). CSF S100B and serum GFAP were highest in DLB.

Conclusions: Levels of most marker candidates tested in serum and CSF significantly differed between disease groups and HC. In the stratification of PD versus other tau- or aSyn-related conditions, CSF NfL levels best discriminated PD and MSA. CSF S100B and serum GFAP best discriminated PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28738DOI Listing
December 2021

The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson's disease brain as revealed by multicolor STED microscopy.

Acta Neuropathol 2021 09 11;142(3):423-448. Epub 2021 Jun 11.

Department of Anatomy and Neurosciences, Clinical Neuroanatomy and Biobanking, Amsterdam Neuroscience, Amsterdam UMC, Location VU University Medical Center, O2 building, room 13 E11, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.

Various post-translationally modified (PTM) proteoforms of alpha-synuclein (aSyn)-including C-terminally truncated (CTT) and Serine 129 phosphorylated (Ser129-p) aSyn-accumulate in Lewy bodies (LBs) in different regions of the Parkinson's disease (PD) brain. Insight into the distribution of these proteoforms within LBs and subcellular compartments may aid in understanding the orchestration of Lewy pathology in PD. We applied epitope-specific antibodies against CTT and Ser129-p aSyn proteoforms and different aSyn domains in immunohistochemical multiple labelings on post-mortem brain tissue from PD patients and non-neurological, aged controls, which were scanned using high-resolution 3D multicolor confocal and stimulated emission depletion (STED) microscopy. Our multiple labeling setup highlighted a consistent onion skin-type 3D architecture in mature nigral LBs in which an intricate and structured-appearing framework of Ser129-p aSyn and cytoskeletal elements encapsulates a core enriched in CTT aSyn species. By label-free CARS microscopy we found that enrichments of proteins and lipids were mainly localized to the central portion of nigral aSyn-immunopositive (aSyn+) inclusions. Outside LBs, we observed that 122CTT aSyn+ punctae localized at mitochondrial membranes in the cytoplasm of neurons in PD and control brains, suggesting a physiological role for 122CTT aSyn outside of LBs. In contrast, very limited to no Ser129-p aSyn immunoreactivity was observed in brains of non-neurological controls, while the alignment of Ser129-p aSyn in a neuronal cytoplasmic network was characteristic for brains with (incidental) LB disease. Interestingly, Ser129-p aSyn+ network profiles were not only observed in neurons containing LBs but also in neurons without LBs particularly in donors at early disease stage, pointing towards a possible subcellular pathological phenotype preceding LB formation. Together, our high-resolution and 3D multicolor microscopy observations in the post-mortem human brain provide insights into potential mechanisms underlying a regulated LB morphogenesis.
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http://dx.doi.org/10.1007/s00401-021-02329-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357756PMC
September 2021

The predictive role of Interleukin 6 in burn patients with positive blood cultures.

Int J Burns Trauma 2021 15;11(2):123-130. Epub 2021 Apr 15.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, St. Georg Hospital gGmbH Leipzig Germany.

Interleukin 6 (IL-6) is an established biomarker of inflammation with one of the earliest responses in sepsis. Serum levels can easily be measured within a few hours. The clinical significance of IL-6 in the early stage of sepsis in burned patients has not yet been confirmed. The purpose of our research was to investigate the predictive value of IL-6 for positive blood cultures in comparison to Procalcitonin (PCT), white blood cell (WBC) count, body temperature and the Sequential Organ Failure Assessment (SOFA) score in the presence of suspected sepsis in burn patients. In a retrospective study, we included all patients admitted to a regional burn centre in a 7-year period. Patients with a clinical suspicion of sepsis and complete laboratory tests underwent further analysis. Patients were categorized following culture results into either positive or negative bloodstream infection (BSI or non-BSI) groups. 39 of the 101 included patients had positive blood cultures (BSI). The serum IL-6 levels were significantly higher in the BSI group [1047 (339.9; 9000.5) vs. 198.5 (112.4; 702.5) ng/l; P = 0.001]. Receiver operating characteristic (ROC) curve analysis showed an AUC of 0.7 (59; 80.8%). The optimal IL-6 cut-off level was 312.8 ng/l (sensitivity 79.5%, specificity 56.5%). Other biomarkers (PCT, WBC), the maximum body temperature and increase of SOFA score were not different between the groups. IL-6 can be used to predict a positive blood culture even in the early stage of suspected sepsis in burned patients. In this context, other biomarkers (PCT, WBC) and body temperature are of limited clinical utility.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166662PMC
April 2021

[The free serratus carpaccio flap: indications and technique].

Handchir Mikrochir Plast Chir 2021 Dec 19;53(6):543-547. Epub 2021 May 19.

Klinikum Sankt Georg, Klinik für Plastische und Handchirurgie mit Schwerbrandverletztenzentrum, Leipzig.

Purpose: Soft tissue reconstructions of the hand require a thin and resistant flap palmarly as well as sliding abilities between the extensor tendons and the flap on the dorsum of the hand. Elasticity is required to maintain the normal wrist range of motion. One option in these cases is the free serratus fascia flap that sometimes shows limitations regarding resistance as well as reliability. Here, we describe an easy modification including a thin muscle cuff in the serratus fascia flap - the serratus carpaccio flap - that improves the ease of flap harvest and morbidity rates.

Methods: The indications for the serratus carpaccio flap, the technique of flap harvest and contouring as well as flap inset are described in detail. Clinical examples are given.

Results: The main advantage of the serratus carpaccio flap is the ability of the surgeon to adapt the flap thickness to the recipient site requirements. This allows excellent results regarding contour and function. Split thickness skin grafting fromthe instep region of the foot additionally allows optimal results for palmar as well as plantar defect reconstruction. Eighteen flaps for soft tissue defects of the hand (n = 5), foot (n = 10), and lower leg (n = 3) were performed. Complications included one flap loss, one venous re-anastomosis, two partial wound dehiscences and one postoperative hematoma at the donor site. Seventeen flaps survived completely. Secondary thinning procedures were not required.

Conclusions: The serratus carpaccio flap is an excellent option for the reconstruction of medium-sized skin and soft tissue defects of the dorsum of the hand or foot, the palm, and the distal forearm.
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http://dx.doi.org/10.1055/a-1439-9873DOI Listing
December 2021

Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson's Disease.

Mov Disord 2021 08 4;36(8):1972-1978. Epub 2021 May 4.

Paracelsus-Elena-Klinik, Kassel, Germany.

Background: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).

Objective: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.

Methods: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies.

Results: Baseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug-naive individuals, but some changed on starting levodopa treatment.

Conclusions: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453505PMC
August 2021

[Lesions of the anterior interosseous nerve: differentiating between compression neuropathy and neuritis].

Handchir Mikrochir Plast Chir 2021 Feb 15;53(1):31-39. Epub 2021 Feb 15.

Klinikum Sankt Georg gGmbH Klinik für Plastische und Handchirurgie mit Schwerbrandverletztenzentrum.

Background: In cases of anterior interosseous nerve (AIN) syndrome, it is often difficult to differentiate between compression neuropathy and neuritis.

Material And Methods: This review analyses the clinical aspects of the neuritic AIN syndrome and the different diagnostic tools for securing the diagnosis and differentiating the condition from compression neuropathy. Based on these data, the current therapeutic options are proposed.

Results: The AIN syndrome often results from neuritis of the AIN fascicles within the trunk of the median nerve. The differentiation between neuritis and compression neuropathy of the AIN is based on dedicated neurophysiological examinations as well as nerve sonography and MRI neurography. Although conservative treatment is the gold standard, microsurgical interventions have become more important in recent years.

Conclusion: A dedicated diagnostic workup of the AIN syndrome is paramount for optimal treatment. Conservative treatment remains the standard to date. However, if torsions and constrictions of nerve fascicles are detected, intrafascicular neurolysis should be considered, as current research shows the potential for an improved outcome in such cases.
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http://dx.doi.org/10.1055/a-1349-4989DOI Listing
February 2021

Degeneration of the articular disc in the human triangular fibrocartilage complex.

Arch Orthop Trauma Surg 2021 Apr 6;141(4):699-708. Epub 2021 Feb 6.

Sächsischen Krankenhaus Altscherbitz, Department of Neurology, Leipziger Straße 59, 04435, Schkeuditz, Germany.

Introduction: Traumatic injuries of the triangular fibrocartilage complex (TFCC) are frequent reasons for ulnar wrist pain. The assessment of the extent of articular disc (AD) degeneration is important for the differentiation of acute injuries versus chronic lesions.

Materials And Methods: The AD of the TFCC of eleven human cadaver wrists was dissected. Degeneration was analyzed according to the grading of Krenn et al. Hematoxylin-eosin was used to determine the tissue morphology. Degeneration was evaluated using the staining intensity of alcian blue, the immunohistochemistry of the proteoglycan versican and the immunoreactivity of NITEGE, an aggrecan fragment.

Results: The staining homogeneity of HE decreased with higher degeneration of the AD and basophilic tissue areas were more frequently seen. Two specimens were characterized as degeneration grade 1, five specimens as grade 2, and four specimens as grade 3, respectively. Staining intensity of alcian blue increased with higher degeneration grade of the specimens. Immunoreactivity for NITEGE was detected around tissue fissures and perforations as well as matrix splits. Immunoreactivity for versican was found concentrated in the tissue around matrix fissures and lesions as well as loose connective tissue at the ulnar border of the AD. Specimens with degeneration grade 2 had the strongest immunoreactivity of NITEGE and versican. Cell clusters were observed in specimens with degeneration grade 2 and 3, which were stained by alcian blue and immunoreactive for NITEGE and versican. Increasing age of the cadaver wrists correlated with a higher degree of degeneration (p < 0.0001, r = 0.68).

Conclusions: The fibrocartilage of degenerated ADs contains NITEGE and versican. The amount of the immunoreactivity of these markers allows the differentiation of degenerative changes into three grades. The degeneration of the AD increases with age and emphasizes its important mechanical function.
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http://dx.doi.org/10.1007/s00402-021-03795-2DOI Listing
April 2021

Immunohistochemical Detection of Synuclein Pathology in Skin in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinsonism.

Mov Disord 2021 04 24;36(4):895-904. Epub 2020 Nov 24.

Department of Neurology, McGill University-Montreal General Hospital, Montreal, Quebec, Canada.

Background: Recent studies reported abnormal alpha-synuclein deposition in biopsy-accessible sites of the peripheral nervous system in Parkinson's disease (PD). This has considerable implications for clinical diagnosis. Moreover, if deposition occurs early, it may enable tissue diagnosis of prodromal PD.

Objective: The aim of this study was to develop and test an automated bright-field immunohistochemical assay of cutaneous pathological alpha-synuclein deposition in patients with idiopathic rapid eye movement sleep behavior disorder, PD, and atypical parkinsonism and in control subjects.

Methods: For assay development, postmortem skin biopsies were taken from 28 patients with autopsy-confirmed Lewy body disease and 23 control subjects. Biopsies were stained for pathological alpha-synuclein in automated stainers using a novel dual-immunohistochemical assay for serine 129-phosphorylated alpha-synuclein and pan-neuronal marker protein gene product 9.5. After validation, single 3-mm punch skin biopsies were taken from the cervical 8 paravertebral area from 79 subjects (28 idiopathic rapid eye movement sleep behavior disorder, 20 PD, 10 atypical parkinsonism, and 21 control subjects). Raters blinded to clinical diagnosis assessed the biopsies.

Results: The immunohistochemistry assay differentiated alpha-synuclein pathology from nonpathological-appearing alpha-synuclein using combined phosphatase and protease treatments. Among autopsy samples, 26 of 28 Lewy body samples and none of the 23 controls were positive. Among living subjects, punch biopsies were positive in 23 (82%) subjects with idiopathic rapid eye movement sleep behavior disorder, 14 (70%) subjects with PD, 2 (20%) subjects with atypical parkinsonism, and none (0%) of the control subjects. After a 3-year follow-up, eight idiopathic rapid eye movement sleep behavior disorder subjects phenoconverted to defined neurodegenerative syndromes, in accordance with baseline biopsy results.

Conclusion: Even with a single 3-mm punch biopsy, there is considerable promise for using pathological alpha-synuclein deposition in skin to diagnose both clinical and prodromal PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28399DOI Listing
April 2021

[Implementation of treatment by enzymatic debridement in burns: results of an interprofessional German-speaking expert workshop].

Handchir Mikrochir Plast Chir 2021 Apr 17;53(2):175-184. Epub 2020 Nov 17.

Klinik für Hand-, Plastische und Rekonstruktive Chirurgie, Mikrochirurgie, Schwerbrandverletztenzentrum, BG Klinik Ludwigshafen, Universität Heidelberg.

Introduction:  Since its introduction in 2013 Bromelain-based Enzymatic Debridement (ED) is increasingly used in burn centers. Published evidence shows its efficiency in eschar removal as well as a superiority in blood loss and necessity of further surgical procedures compared to standard-of-care. While the procedure is safe and shows reliable results in experienced hands, some practical and logistical issues must be challenged that are not described sufficiently in available literature.

Method:  A multi-professional panel, consisting of experienced users of ED from German-speaking burn units has been invited to an expert workshop. Topics concerning indication, definition of treatment pathways, practical issues, post-treatment and handling of complications have been coordinated in advance to allow discussion during the workshop.

Results:  To each topic practical recommendations were developed and consented. Summarizing key messages have been additionally highlighted. They aim on helping to achieve optimal results after establishing the technique by new users as well as optimizing results by experienced users. Amongst others, the resulting recommendations deal with indications for ED beyond the classic domain, different treatment pathways depending on burn depth and primary result after ED with adapted post-treatment, management of treatment failure and implementation of infrastructural conditions.

Discussion:  While efficiency of ED as well as superiority in some aspects of treatment of burn wounds could be shown in available literature, user-oriented recommendations for practical implementation are scarce. Although the recommendations and experts opinions published here are only partly evidenced based, they are still based on the pooled experienced of the panelists that easily outnumbers the cases published in literature so far and allow valuable support for a successful implementation of the technique.
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http://dx.doi.org/10.1055/a-1294-9895DOI Listing
April 2021

Perforator-Based Flaps for Defect Reconstruction of the Posterior Trunk.

Ann Plast Surg 2021 01;86(1):72-77

From the Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Ludwigshafen.

Introduction: Full-thickness soft tissue defects of the back remain challenging clinical problems for reconstructive surgeons. Among a vast variety of local flap options, perforator-based local flaps gain increasing popularity lately. Because mostly heterogeneous patient cohort comparison of different perforator flaps is difficult and decision-making algorithms are lacking.

Methods: Patients, who received a local perforator-based soft tissue reconstruction between 2012 and 2019, were evaluated retrospectively. Patients' data were evaluated in terms of flap type and dimension, wound size and cause, surgery time, postoperative complications, and hospitalization. A focus was set on decision making concerning reconstructive techniques and flap choice for defect closure.

Results: Thirty-six patients (17 women, 19 men) were included, who received 40 perforator-based local flaps to reconstruct extended defects of the posterior trunk. Mean patient age was 56.3 years and mean hospitalization was 29 days. Average time of flap surgery was 179.7 minutes. Mean flap size was 160.8 cm and average defect size was 110 cm. Defects occurred because of tumor resection (50%), orthopedic/trauma surgery (16.7%), or pressure sores (33.3%). Twenty-eight propeller flaps (PPFs, 70%) and 12 perforator-based VY-advancement flaps (P-VYF, 30%) were transferred. In 4 patients, a bilateral approach using more than one flap was necessary. Revision surgery was required in 9 patients (25%) because of postoperative hematoma (n = 3), postoperative wound infection (n = 3), partial flap necrosis (1× P-VYF) and 2 flap losses (2× PPFs).

Conclusions: Pedicled perforator flaps are a reliable option for soft tissue reconstruction of complex wounds of the posterior trunk. A flexible surgical strategy is mandatory, and the individual perforator anatomy has to be considered. In most cases, P-VYFs or PPFs are reliably possible and allow sufficient defect reconstruction. However, skin incisions should always be performed in a way that classic random pattern flaps are still possible. Even in large defects combined, local perforator flaps may lead to sustainable soft tissue reconstructions without functional donor site deficits.
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http://dx.doi.org/10.1097/SAP.0000000000002439DOI Listing
January 2021

Structural topography of the interosseous membrane of the human forearm.

Ann Anat 2020 Sep 5;231:151547. Epub 2020 Jun 5.

Department of Plastic and Hand Surgery, Burn Unit, Klinikum Sankt Georg, Delitzscher Straße 141, 04129 Leipzig, Germany.

The aim of this study was to evaluate the morphology of the six different parts of the interosseous membrane (IOM) in 11 human cadaver forearms, including the distal oblique bundle (DOB), the distal accessory band (DAB), the central band (CB), the proximal accessory band (PAB), the dorsal oblique accessory cord (DOAC), and the proximal oblique cord (POC). Hematoxylin-eosin and Elastica van Gieson stained slices were used to investigate the tissue morphology. The DOB and DOAC were absent in one IOM and the POB in two IOMs, respectively. The CB and DAB were longer than all other structures except for each other. The DOAC was longer than the DOB. The DAB, CB, and PAB, were broader than the DOB, DOAC, and POC. No significant differences were observed regarding structure thickness. All structures were found to consist of densely packed parallel collagen fiber arrangement. The DOB and POC had a higher amount of elastic fibers in the fascicular collagen tissue than the other structures. Elastic fibers were more often equally distributed throughout the structures than condensed epifascicular or at the insertion into bone. The tight parallel collagen composition within the different structures reflects the central stabilizing role of the IOM in the forearm. The higher amount of elastic fibers within the DOB and POC can be attributed to their location close to the distal and proximal radioulnar joints, respectively. Here elastic fibers allow adaption to forearm rotation, whereas the structures of the central part of IOM have less elasticity reflecting the predominant stabilizing function.
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http://dx.doi.org/10.1016/j.aanat.2020.151547DOI Listing
September 2020

Safety, Pharmacodynamics, and Efficacy of High- Versus Low-Dose Ascorbic Acid in Severely Burned Adults.

J Burn Care Res 2020 07;41(4):871-877

Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Plastic and Hand Surgery, University of Heidelberg, Ludwigshafen, Germany.

In sepsis and burns, ascorbic acid (AA) is hypothesized advantageous during volume resuscitation. There is uncertainty regarding its safety and dosing. This study evaluated high dose AA (HDAA: 66 mg/kg/h for 24 hours) versus low dose AA (LDAA: 3.5 g/days) administration during the first 24 hours in severely burned adults. We conducted a retrospective study comparing fluid administration before and after switching from low dose to HDAA in severely burned adults. A total of 38 adults with burns >20% TBSA, who received either HDAA or LDAA were included in this retrospective study. AA serum concentrations were quantified at 0, 24, and 72 hours postburn. HDAA impact on hemodynamics, acid-base homeostasis, acute kidney injury, vasopressor use, resuscitation fluid requirement, urinary output, and the incidence of adverse effects was evaluated; secondary clinical outcomes were analyzed. AA plasma levels were 10-fold elevated in the LDAA and 150-fold elevated in the HDAA group at 24 hours and decreased in both groups afterwards. HDAA was not associated with a significantly increased risk of any complications. A significant reduction in colloid fluid requirements was noted (LDAA: 947 ± 1722 ml/24 hours vs HDAA: 278 ± 667 ml/24 hours, P = 0.029). Other hemodynamic and resuscitation measures, as well as secondary clinical outcomes were comparable between groups. HDAA was associated with higher AA levels and lower volumes of colloids in adults with severe burns. The rate of adverse events was not significantly higher in patients treated with HDAA. Future studies should consider prolonged administration of AA.
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http://dx.doi.org/10.1093/jbcr/iraa041DOI Listing
July 2020

Vascularized Medial Femoral Condyle Autografts for Osteochondral Lesions of the Talus: A Preliminary Prospective Randomized Controlled Trial.

J Foot Ankle Surg 2020 Mar - Apr;59(2):307-313

Head of Department and Professor, Department of Hand, Plastic and Reconstructive Surgery, Burn Center-Hand and Plastic Surgery, University of Heidelberg, BG Trauma Center Ludwigshafen, Germany; Head of Department and Professor, Department of Plastic and Hand Surgery, Burn Center-Sankt Georg Hospital Leipzig, BG Trauma Center Ludwigshafen, Leipzig, Germany.

Talar osteochondral lesions (OCLs) lead to progressive stages of talar destruction. Core decompression with cancellous bone grafting (CBG) is a common treatment for Berndt and Harty stages II and III. However, in a subset of patients, talar revascularization may fail. Surgical angiogenesis using vascularized medial femoral condyle (MFC) autografts may improve on these outcomes. These 2 treatment strategies were directly compared via a prospective preliminary randomized trial including 20 participants with talar core decompression followed by either cancellous (CBG group, n = 10) or vascularized MFC (MFC group, n = 10) bone grafting. Outcome analysis was performed with visual analog scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, Lower Extremity Functional Scale (LEFS), and contrast-enhanced magnetic resonance imaging (MRI) scans. At 12 months of follow-up, the mean VAS score was reduced from 6.6 ± 2.5 preoperatively to 4 ± 1.9 in the CBG group and from 5.2 ± 2.9 preoperatively to 1 ± 1.1 in the MFC group (p < .001). The LEFS improved from 53.4 ± 13.1 to 62.6 ± 16.2 CBG and from 53 ± 9.3 to 72.4 ± 7.4 MFC (p = .114). AOFAS improved from 71 ± 12.1 to 84.1 ± 12.5 in CBG and from 70.5 ± 7.4 to 95.1 ± 4.8 in MFC (p = .019). The MRI scans in the CBG group demonstrated 9 partial malperfusions and 1 hypervascularized bone graft, whereas the MFC group had 8 well-vascularized grafts incorporated into the talus and 1 partial malperfusion. Vascularized MFC autografts provide superior pain relief along with improvement of physical function in patients with talar OCL stage II and III compared with CBG. To confirm these promising results, further multicenter randomized controlled trials are required.
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http://dx.doi.org/10.1053/j.jfas.2019.03.025DOI Listing
January 2021

Association of a Reproducible Epigenetic Risk Profile for Schizophrenia With Brain Methylation and Function.

JAMA Psychiatry 2020 06;77(6):628-636

Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Importance: Schizophrenia is a severe mental disorder in which epigenetic mechanisms may contribute to illness risk. Epigenetic profiles can be derived from blood cells, but to our knowledge, it is unknown whether these predict established brain alterations associated with schizophrenia.

Objective: To identify an epigenetic signature (quantified as polymethylation score [PMS]) of schizophrenia using machine learning applied to genome-wide blood DNA-methylation data; evaluate whether differences in blood-derived PMS are mirrored in data from postmortem brain samples; test whether the PMS is associated with alterations of dorsolateral prefrontal cortex hippocampal (DLPFC-HC) connectivity during working memory in healthy controls (HC); explore the association between interactions between polygenic and epigenetic risk with DLPFC-HC connectivity; and test the specificity of the signature compared with other serious psychiatric disorders.

Design, Setting, And Participants: In this case-control study conducted from 2008 to 2018 in sites in Germany, the United Kingdom, the United States, and Australia, blood DNA-methylation data from 2230 whole-blood samples from 6 independent cohorts comprising HC (1238 [55.5%]) and participants with schizophrenia (803 [36.0%]), bipolar disorder (39 [1.7%]), major depressive disorder 35 [1.6%]), and autism (27 [1.2%]), and first-degree relatives of all patient groups (88 [3.9%]) were analyzed. DNA-methylation data were further explored from 244 postmortem DLPFC samples from 136 HC and 108 patients with schizophrenia. Neuroimaging and genome-wide association data were available for 393 HC. The latter data was used to calculate a polygenic risk score (PRS) for schizophrenia. The data were analyzed in 2019.

Main Outcomes And Measures: The accuracy of schizophrenia control classification based on machine learning using epigenetic data; association of schizophrenia PMS scores with DLPFC-HC connectivity; and association of the interaction between PRS and PMS with DLPFC-HC connectivity.

Results: This study included 7488 participants (4395 men [58.7%]), of whom 3158 (2230 men [70.6%]) received a diagnosis of schizophrenia. The PMS signature was associated with schizophrenia across 3 independent data sets (area under the curve [AUC] from 0.69 to 0.78; P value from 0.049 to 1.24 × 10-7) and data from postmortem DLPFC samples (AUC = 0.63; P = 1.42 × 10-4), but not with major depressive disorder (AUC = 0.51; P = .16), autism (AUC = 0.53; P = .66), or bipolar disorder (AUC = 0.58; P = .21). Pathways contributing most to the classification included synaptic processes. Healthy controls with schizophrenia-like PMS showed significantly altered DLPFC-HC connectivity (validation methylation/magnetic resonance imaging, t < -3.81; P for familywise error, <.04; validation magnetic resonance imaging, t < -3.54; P for familywise error, <.02), mirroring the lack of functional decoupling in schizophrenia. There was no significant association of the interaction between PMS and PRS with DLPFC-HC connectivity (P > .19).

Conclusions And Relevance: We identified a reproducible blood DNA-methylation signature specific for schizophrenia that was correlated with altered functional DLPFC-HC coupling during working memory and mapped to methylation differences found in DLPFC postmortem samples. This indicates a possible epigenetic contribution to a schizophrenia intermediate phenotype and suggests that PMS could be of interest to be studied in the context of multimodal biomarkers for disease stratification and treatment personalization.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.4792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042900PMC
June 2020

Evaluation of proprioception in denervated and healthy wrist joints.

J Hand Surg Eur Vol 2020 May 13;45(4):408-413. Epub 2020 Jan 13.

Department of General, Visceral and Vascular Surgery, Hospital Vivantes Spandau, Berlin, Germany.

We recruited 25 patients after complete wrist denervation and 60 healthy adults to investigate conscious and unconscious proprioception of the wrist. Ipsi- and contralateral joint-position sense, force sense, and wrist reflexes were measured. The latter were triggered by a trapdoor, recording electromyographic signals from the extensor carpi radialis brevis, extensor carpi ulnaris, flexor carpi radialis, and flexor carpi ulnaris muscles. No significant differences were found for joint position sense, force sense, and wrist reflexes between both groups, except for reflex time of the flexor carpi ulnaris after denervation of the left wrist as compared with the left flexor carpi ulnaris in controls or in right operated wrists. At a mean follow-up of 32 months (range 8 to 133), we found no proprioceptive deficit of the conscious proprioceptive qualities of joint position sense, force sense, and the unconscious proprioceptive neuromuscular control of wrist reflex time for most muscles after complete wrist denervation. We conclude from this study that complete wrist denervation does not affect the proprioceptive senses of joint position, force sense, and reflex time of the wrist.
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http://dx.doi.org/10.1177/1753193419897192DOI Listing
May 2020

A 'metabolic bundle' including Oxandrolone in optimising the metabolic status of severely burn injured patients: a retrospective analysis of the first 50 patients.

GMS Interdiscip Plast Reconstr Surg DGPW 2019 15;8:Doc17. Epub 2019 Nov 15.

Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, St. Georg Hospital gGmbH Leipzig, Germany.

Severe burn injuries are associated with a rapid escalating hypermetabolic state and catabolism of muscle mass. To ameliorate this process a standardized approach using pharmacological and non-pharmacological interventions was implemented within a single burns center. Whilst individual components of this standardized package are well documented in the literature, their collective or bundled effect has not as yet been assessed. The aim of this study was to evaluate the efficacy of this standardized bundle of metabolic modulators and assess the safety of including the anabolic steroid oxandrolone within it. This retrospective observational study constituted all patients in whom the metabolic bundle including oxandrolone therapy was applied. The other elements of the metabolic bundle consisted of early surgical burn excision within seven days to completion, early active mobilization, increased ambient room temperature, expediated carbohydrate and protein rich enteral feeding with glutamine and trace element supplements (such as copper and zinc). Finally, administration of propranolol as a non-selective beta-blocker. Data collection was through review of the patient data management system focusing on the outcome criteria and hepatic blood values. The study looked at fifty consecutive patients meeting the inclusion criteria. Median patient age and burned total body surface area (TBSA) were 62 years [51.75; 73] and 33.75% [24.75; 51] respectively with an abbreviated burn severity index (ABSI) of 10 [9; 10.25]. Definitive surgical burn wound excision was completed in 44 patients [88%] within 7 days. 39 patients (78%) received propranolol over a therapeutic period of 29 days [19; 44]. Glutamine was supplemented in 45 patients (90%), while zinc and copper were applied to 42 (84%) and 31 (62%) respectively. Significant low zinc values were noted at therapeutic onset (6.5 mmol/l [4.7; 7.9]) requiring sustained substitution over 37.5 days [22; 46.75]). In respect of the inclusion criteria, all patients received oxandrolone at 20 mg/day [20; 20]. This was commenced on day 6.5 [4; 14] post burn injury and continued over 26 days [19; 31]. Despite a transitory elevation of hepatic enzyme values (ALT, GGT), these were only clinically relevant (>10 µmol/l*S) in 2.4% and 4.6% of all measurements respectively. None were sufficiently of concern to merit cessation of treatment. The application of a standardised bundle of metabolic treatment options of severe burns injured patients is reliable, repeatable and safe. Potential concerns of oxandrolone treatment regarding hepatic compromise remain unfounded.
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http://dx.doi.org/10.3205/iprs000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883381PMC
November 2019

[Consensus of the German-Speaking Society for Microsurgery of Peripheral Nerves and Vessels (DAM) on minimum standards for microsurgical training courses and accreditation - Minimum Standards for Microsurgical Training Courses and Accreditation].

Handchir Mikrochir Plast Chir 2020 Apr 16;52(2):135-139. Epub 2019 Oct 16.

Klinik für Plastische und Handchirurgie mit Schwerbrandverletztenzentrum, Klinikum St. Georg, Leipzig.

Microsurgical training courses are an integral part of surgical education and training. Due to the changes in the surgical everyday routine, the competence and skills training outside the operating room has an increasingly important status. Multi-day, hands-on exercises with different models of increasing difficulty use artificial, avital and vital microsurgical models. The skills are evaluated with regard to fine motor skills as well as orientation in space and low-tremor motion sequences as well as bimanual manipulation exercises by means of "lobal rating scales". However, with numerous course offerings in German-speaking countries, there are no uniform and transparent contents and evaluation standards to reflect the quality of the courses. At a consensus meeting, minimum requirements for the contents of microsurgical training courses in the context of continuing medical education were defined and drafted as a German-language consensus in order to award a DAM quality seal. The parameters include the definition of targets, the existence of a scripts, the number of hours used, models used, practical exercise time on the microscope, trainer to participant ratio, types of anastomosis or coaptation (artery, vein, nerve, lymph vessel), application of a global rating scale , examination (grade/passed - failed), participant certificate and course evaluation. With the aim to meet the available courses/course concepts to maintain or improve the quality of education and training, the assignment of a "Basic" and an "Advanced" quality seal has been defined. The further stepwise development of the courses is necessary to sustain all skills and competencies for future microsurgeons. Integration of validated microsurgical simulators may reduce animal use and thus contribute to the ethical responsibility. The introduction of quality seals for microsurgical training courses should strengthen the transparency and commitment of participants and provide support to course providers with appropriately substantiated content through DAM.
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http://dx.doi.org/10.1055/a-1017-3688DOI Listing
April 2020

Geriatric Patients with Free Flap Reconstruction: A Comparative Clinical Analysis of 256 Cases.

J Reconstr Microsurg 2020 Feb 23;36(2):127-135. Epub 2019 Sep 23.

Department of Hand-, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany.

Background:  In elderly patients, complex soft tissue defects are increasingly observed due to the prolonged life expectancy and accompanying comorbidities. The aim of this study is to evaluate whether free tissue transfer is safe in very old patients without additional risk and complications.

Methods:  All patients older than 65 years undergoing free tissue transfer between November 2007 and September 2016 were reviewed in a retrospective study. Two cohorts were compared regarding perioperative morbidity and postoperative outcome (cohort 1 [old patients, ages 65-79]; cohort 2 [very old patients, ages ≥ 80]).

Results:  In total, 256 patients were included in the study (cohort 1 [ = 217]; cohort 2 [ = 39]). Overall, 262 free flaps were performed due to a second microsurgical reconstruction in six cases. No statistically significant differences between cohorts were observed regarding surgical complications, total flap losses, and mortality. Detailed evaluation of cohort 2 revealed a significant learning curve during the observation period regarding the perioperative management and procedure of soft tissue reconstruction: operation length as well as postoperative intensive care unit stay decreased significantly over time ( < 0.05) and also surgical complications showed a positive trend ( = 0.07). We ascertained a shift toward a "more reliable" flap selection from predominantly anterolateral thigh flap) to axial flaps such as rectus abdominis and latissimus dorsi flaps.

Conclusion:  Our study showed that age is not associated with an increased risk of postoperative complications. Reliable muscle free flaps, two-stage procedures, and safe vascular supply are important strategic aspects to achieve microvascular tissue transfer with high success rates in geriatric patients.
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http://dx.doi.org/10.1055/s-0039-1697646DOI Listing
February 2020
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