Periarticular Proprioception: Analyzing the Three-Dimensional Structure of Corpuscular Mechanosensors in the Dorsal Part of the Scapholunate Ligament.

INTRODUCTION: Sensory nerve endings transmit mechanical stimuli into afferent neural signals and form the basis of proprioception, giving rise to the self-perception of dynamic stability of joints. We aimed to analyze the three-dimensional structure of periarticular corpuscular sensory nerve endings in a carpal ligament to enhance our understanding of their microstructure. METHODS: Two dorsal parts of the scapholunate ligament were excised from two human cadaveric wrist specimens. Consecutive cryosections were stained with immunofluorescence markers protein S100B, neurotrophin receptor p75, protein gene product 9.5 (PGP 9.5), and 4',6-diamidino-2-phenylindole. Three-dimensional images of sensory nerve endings were obtained using confocal laser scanning microscopy, and subsequent analysis was performed using Imaris software. RESULTS: Ruffini endings were characterized by a PGP 9.5-positive central axon, with a median diameter of 4.63 µm and a median of 25 cells. The p75-positive capsule had a range in thickness of 0.94 µm and 15.5 µm, consisting of single to three layers of lamellar cells. Ruffini endings were significantly smaller in volume than Pacini corpuscles or Golgi-like endings. The latter contained a median of three intracorpuscular structures. Ruffini endings and Golgi-like endings presented a similar structural composition of their capsule and subscapular space. The central axon of Pacini corpuscles was surrounded by S100-positive cells forming the inner core which was significantly smaller than the outer core, which was immunoreactive for p75 and PGP 9.5. CONCLUSION: This study reports new data regarding the intricate outer and intracorpuscular three-dimensional morphology of periarticular sensory nerve endings, including the volume, number of cells, and structural composition. These results may form a basis to differ between normal and pathological morphological changes in periarticular sensory nerve endings in future studies.

Conjoined Free Fibula Transplantation and First Carpometacarpal Joint Prosthesis for Functional Thumb Reconstruction-A Case Report.

BACKGROUND: Giant cell tumors grow locally invasive with osseous and soft tissue destruction, requiring wide resection to avoid recurrence. Stable reconstruction of the first carpometacarpal (CMC-1) joint remains a challenge due to its high range of mobility. The latter is of paramount for the functionality of the hand. PURPOSE: Therefore, the aim of this study was to report our approach for a combined reconstruction of the first metacarpal and the CMC-1 joint. METHODS: A 58-year-old woman underwent wide resection of a benign giant cell tumor at the base and shaft of the first metacarpal of the left thumb. Because of the loss of the CMC-1 joint and the instability of the thumb, an osseous reconstruction using a vascularized fibular graft combined with a TOUCH Dual Mobility CMC-1 prosthesis was performed to reconstruct the CMC-1 joint. RESULTS: Osseous healing was observed after 3 months. No tumor recurrence and good joint function were documented at the follow-up investigation after 1 year. The patient reported only minor restrictions during activities of daily living. Thumb opposition was possible with a Kapandji score of 8/10. A slight pain while walking remained as a donor-side morbidity at the right lower leg. CONCLUSION: Metacarpal reconstruction with vascularized fibula bone grafts allowed a combined joint reconstruction with a commercially available prosthesis, which is an approach to restore the complex range of motion of the thumb.

Non degradation of chitosan and initial degradation of collagen nerve conduits used for protection of nerve coaptations.

BACKGROUND: Nerve conduits are either used to bridge nerve gaps of up to 3 cm or to protect nerve coaptations. Biodegradable nerve conduits, which are currently commercially available, include Chitosan or collagen-based ones. As histological aspects of their degradation are highly relevant for the progress of neuronal regeneration, the aim of this study was to report the histopathological signs of such nerve conduits, which were removed during revision surgery. MATERIALS AND METHODS: Either Chitosan (n = 2) or collagen (n = 2) nerve conduits were implanted after neuroma resection and nerve grafting (n = 2) or traumatic nerve lesion after cut (n = 1) or crush injury (n = 1) in two females and two men, aged between 17 and 57 years. Revision surgery with removal of the nerve conduits was indicated due to persisting neuropathic pain and sensorimotor deficits, limited joint motion, or neurolysis with hardware removal at a median time of 17 months (range: 5.5-48 months). Histopathological analyses of all removed nerve conduits were performed. RESULTS: A scar neuroma was diagnosed in one out of four patients. Mechanical complication occurred in one patient after nerve conduit implantation bridged over finger joints. Intraoperatively no or only initial signs of degradation of the nerve conduits were observed. Chitosan conduits revealed largely unchanged shape and structure of chitosan, and coating of the conduit by a vascularized fibrous membrane. The latter contained deposits taken up by macrophages, most likely representing dissolved chitosan. Characteristic histopathologic features of the degradation of collagen conduits were a disintegration of the compact collagen into separate fine circular strands, No foreign body reaction was observed in all removed nerve conduits. CONCLUSIONS: Both Chitosan nerve conduits have not been degraded. The collagen nerve conduits showed a beginning degradation process. Furthermore, wrapping the repaired nerve with a nerve conduit did neither prevent adhesions nor improved nerve gliding. Therefore, biodegradation in time should be particularly addressed in further developments of nerve conduits.

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

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/ ).

Soft Tissue Reconstruction of Complex Infrainguinal Wounds Following Revisionary Vascular Surgery.

BACKGROUND: Large, full-thickness infrainguinal wounds following revision revascularization procedures of the lower extremity are a challenging complication for reconstructive surgery. Frequently, these patients present with various comorbidities and after several previous reconstructive attempts. Therefore no straightforward soft tissue reconstruction is likely. METHODS: Patients who presented with large, complex inguinal wounds for soft tissue reconstruction were analyzed retrospectively in terms of flap choice, outcome, and complication rates. A focus was set on the reconstructive technique and a subgroup analysis was assessed. RESULTS: Nineteen patients (11 men, 8 women) who received 19 flaps (17 pedicled, 2 free flaps) were included in this retrospective study. Average patient age was 73.3 years (range: 53-88). Ten fasciocutaneous flaps (anterolateral thigh [ALT], 52.6%) and 9 muscle flaps (47.4%) were applied. Among muscle flaps, 3 pedicled gracilis flaps, 4 pedicled rectus abdominis flaps, and 2 free latissimus dorsi flaps were used. No flap losses were observed except 1 case of limited distal flap necrosis (gracilis group). Body mass index ranged from 19 to 37, mean 26.8. Mean surgery time in all patients was 165.9 min (range: 105-373). Revision surgery due to local wound healing problems averaged 1.6 in all patients. In all cases sufficient soft tissue reconstruction was achieved and bypasses were preserved. Lengths of stay averaged 27.2 days (range: 14-59). Mortality was considerably (10.5%) due to systemic complications (one patient died due to a heart attack 4 weeks postoperatively, another patient died due to an extensive pulmonary embolism 2 weeks postoperatively). CONCLUSIONS: Soft tissue reconstruction of complex inguinal wounds after revision vascular surgery is challenging and wound healing problems are expectable. In addition to the rectus abdominis flap the pedicled ALT flap is feasible in a broad variety of medium to large wounds. Free flap reconstruction is recommended for very large defects. A structured interdisciplinary approach is required for the management of complex wounds after vascular surgery to prevent and to deal with complications and perioperative morbidity.

Immunofluorescence analysis of sensory nerve endings in the periarticular tissue of the human elbow joint.

INTRODUCTION: To investigate the dynamic aspects of elbow stability, we aimed to analyze sensory nerve endings in the ligaments and the capsule of elbow joints. MATERIALS AND METHODS: The capsule with its anterior (AJC) and posterior (PJC) parts, the radial collateral ligament (RCL), the annular ligament (AL), and the ulnar collateral ligament with its posterior (PUCL), transverse (TUCL) and anterior parts (AUCL) were dissected from eleven human cadaver elbow joints. Sensory nerve endings were analyzed in two levels per specimen as total cell amount/ cm2 after immunofluorescence staining with low-affinity neurotrophin receptor p75, protein gene product 9.5, S-100 protein and 4',6-Diamidin-2-phenylindol, Carbonic anhydrase II and choline acetyltransferase on an Apotome microscope according to Freeman and Wyke's classification. RESULTS: Free nerve endings were the predominant mechanoreceptor in all seven structures followed by Ruffini, unclassifiable, Golgi-like, and Pacini corpuscles (p ≤ 0.00001, respectively). Free nerve endings were observed significant more often in the AJC than in the RCL (p < 0.00002). A higher density of Ruffini endings than Golgi-like endings was observed in the PJC (p = 0.004). The RCL contained significant more Ruffini endings than Pacini corpuscles (p = 0.004). Carbonic anhydrase II was significantly more frequently positively immunoreactive than choline acetyltransferase in all sensory nerve endings (p < 0.05). Sensory nerve endings were significant more often epifascicular distributed in all structures (p < 0.006, respectively) except for the AJC, which had a pronounced equal distribution (p < 0.00005). CONCLUSION: The high density of free nerve endings in the joint capsule indicates that it has pronounced nociceptive functions. Joint position sense is mainly detected by the RCL, AUCL, PUCL, and the PJC. Proprioceptive control of the elbow joint is mainly monitored by the joint capsule and the UCL, respectively. However, the extreme range of motion is primarily controlled by the RCL mediated by Golgi-like endings.

Comparative histomorphological analysis of elbow ligaments and capsule.

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

[A systematic approach to plastic surgical foot reconstruction]. / Systematik der plastischen Defektrekonstruktion am Fuß.

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 3­dimensional 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.

Donor site morbidity of vascularized bone grafts from the medial femoral condyle for osseous revascularization.

BACKGROUND: Vascularized bone grafts from the medial femoral condyle (MFC) are used to gain surgical revascularization of osseous defects. To date objective data regarding the donor site morbidity are limited. This study aims to evaluate the donor site associated outcome after MFC flap harvest. PATIENTS AND METHODS: From 2008 to 2016, 22 patients who underwent MFC bone flap harvest for osseous revascularization of 9 talus, 8 scaphoids, 2 metacarpals, 1 phalanx, 1 pilon tibiale, and 1 distal femur were included. Outcome analysis was performed for the whole cohort as well as for two subgroups (recipient site upper [group A] and lower extremity [group B]) by the lower extremity functional scale (LEFS), the OAK-score of the Swiss Orthopedic Society and the visual analog scale (VAS). Additionally, a 3D gait analysis was performed for four patients. RESULTS: The mean flap size was 1 × 1 × 3 cm. No flap loss was observed. One minor surgical revision was performed due to donor site hematoma. Mean follow-up was 35.8 (12-98) months. Mean LEFS-score was 74.9 ± 9.5 (A: 74.3 ± 7.9; B: 75.6 ± 11.2, p > .05) and OAK-score was 92.8 ± 9.4 (A: 93.2 ± 5.8; B: 92.4 ± 12.3, p > .05). At follow-up examination, pain at rest was stated with 0.1 ± 0.2 (A: 0.1 ± 0.3; B 0 ± 0, p > .05) and with activity 0.6 ± 1.4 (A: 1.2 ± 1.8; B: 0 ± 0, p > .05) on VAS. The 3-D gait analysis showed normative walking patterns. CONCLUSION: After MFC flap harvest knee function and gait pattern were almost unimpaired. Donor site morbidity can be considered as being of minor concern in the decision-making for this microvascular procedure.

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

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 [n = 217]; cohort 2 [n = 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 (p < 0.05) and also surgical complications showed a positive trend (p = 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.

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

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.

Path mediation analysis reveals GBA impacts Lewy body disease status by increasing α-synuclein levels.

Synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal α-synuclein in intraneuronal inclusions, named Lewy bodies. Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase, have been identified as the most common genetic risk factor for PD and DLB. However, despite extensive research, the mechanism by which glucocerebrosidase dysfunction increases the risk for PD or DLB still remains elusive. In our study we expand the toolbox for PD-DLB post-mortem studies by introducing new quantitative biochemical assays for glucocerebrosidase and α-synuclein. Applying causal modelling, we determine how these parameters are interrelated and ultimately impact disease manifestation. We developed quantitative immuno-based assays for glucocerebrosidase and α-synuclein (total and phosphorylated at Serine 129) protein levels, as well as a liquid chromatography-mass spectrometry method for the detection of the glucocerebrosidase lipid substrate glucosylsphingosine. These assays were applied on tissue samples from frontal cortex, putamen and substantia nigra of PD (n = 15) and DLB (n = 15) patients and age-matched non-demented controls (n = 15). Our results confirm elevated p-129 over total α-synuclein levels in the insoluble fraction of PD and DLB post-mortem brain tissue and we found significantly increased α-synuclein levels in the soluble fractions in PD and DLB. Furthermore, we identified an inverse correlation between reduced glucocerebrosidase enzyme activity and protein levels with increased glucosylsphingosine levels. In the substantia nigra, a brain region particularly vulnerable in Parkinson's disease, we found a significant correlation between glucocerebrosidase protein reduction and increased p129/total α-synuclein ratios. We assessed the direction and strength of the interrelation between all measured parameters by confirmatory path analysis. Interestingly, we found that glucocerebrosidase dysfunction impacts the PD-DLB status by increasing α-synuclein ratios in the substantia nigra, which was partly mediated by increasing glucosylsphingosine levels. In conclusion, we show that the introduced immuno-based assays enable the quantitative assessment of glucocerebrosidase and α-synuclein parameters in post-mortem brain. In the substantia nigra, reduced glucocerebrosidase levels contribute to the increase in α-synuclein levels and to PD-DLB disease manifestation partly by increasing its glycolipid substrate glucosylsphingosine. This interrelation between glucocerebrosidase, glucosylsphingosine and α-synuclein parameters supports the hypothesis that glucocerebrosidase acts as a modulator of PD-DLB.

Sliding free transverse rectus abdominis myocutaneous flap for closure of a massive abdominal wall defect: A case report.

Despite considerable advances in reconstructive surgery, massive abdominal wall defects continue to pose a significant surgical challenge. We report the case of a 72-year-old morbidly obese female patient with Clostridium septicum-related gas gangrene of the abdominal wall. After multidisciplinary treatment and multiple extensive debridements, a massive full-thickness defect (40 cm × 35 cm) of the right abdominal wall was present. The abdominal contents were covered with a resorbable mesh to prevent evisceration. Finally, the composite defect was successfully reconstructed through a contralateral extended free transverse rectus abdominis myocutaneus (TRAM) flap (50 cm × 38 cm). An arterio-venous loop to the superficial femoral vessels using the great saphenous vein was necessary to allow the flap to reach the defect. Postoperatively, a minor wound healing disorder of the flap was successfully treated with split skin grafting. Six month after surgery, the patient presented with a completely healed flap coverage area and a small abdominal hernia without the need of further surgical revision. This case illustrates the use of a sliding free TRAM flap for closure of a massive abdominal wall defect.

Evaluation of smartphone-based testing to generate exploratory outcome measures in a phase 1 Parkinson's disease clinical trial.

BACKGROUND: Ubiquitous digital technologies such as smartphone sensors promise to fundamentally change biomedical research and treatment monitoring in neurological diseases such as PD, creating a new domain of digital biomarkers. OBJECTIVES: The present study assessed the feasibility, reliability, and validity of smartphone-based digital biomarkers of PD in a clinical trial setting. METHODS: During a 6-month, phase 1b clinical trial with 44 Parkinson participants, and an independent, 45-day study in 35 age-matched healthy controls, participants completed six daily motor active tests (sustained phonation, rest tremor, postural tremor, finger-tapping, balance, and gait), then carried the smartphone during the day (passive monitoring), enabling assessment of, for example, time spent walking and sit-to-stand transitions by gyroscopic and accelerometer data. RESULTS: Adherence was acceptable: Patients completed active testing on average 3.5 of 7 times/week. Sensor-based features showed moderate-to-excellent test-retest reliability (average intraclass correlation coefficient = 0.84). All active and passive features significantly differentiated PD from controls with P < 0.005. All active test features except sustained phonation were significantly related to corresponding International Parkinson and Movement Disorder Society-Sponsored UPRDS clinical severity ratings. On passive monitoring, time spent walking had a significant (P = 0.005) relationship with average postural instability and gait disturbance scores. Of note, for all smartphone active and passive features except postural tremor, the monitoring procedure detected abnormalities even in those Parkinson participants scored as having no signs in the corresponding International Parkinson and Movement Disorder Society-Sponsored UPRDS items at the site visit. CONCLUSIONS: These findings demonstrate the feasibility of smartphone-based digital biomarkers and indicate that smartphone-sensor technologies provide reliable, valid, clinically meaningful, and highly sensitive phenotypic data in Parkinson's disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.