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 (p75), protein gene product 9.5 (PGP 9.5) and 4' ,6-diamidino-2-phenylindole (DAPI). 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 contained 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 3D 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.

Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits.

BACKGROUND: Understanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity. METHODS: Here, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals. RESULTS: First, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. CONCLUSIONS: Overall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

Brain expression profiles of two SCN1A antisense RNAs in children and adolescents with epilepsy.

Objective: Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. Methods: We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested. Results: The SCN1A related antisense RNAs SCN1A-dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A-usAS (upstream AS, SCN1A-AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A-usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A-dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A-dsAS transcripts. Conclusion: These findings support the role of SCN1A-dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A-dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

[Surgical management of burn injury patients : Comments on the guidelines on treatment of thermal injuries in adults]. / Chirurgisches Management des brandverletzten Patienten : Kommentar zur Leitlinie Behandlung thermischer Verletzungen des Erwachsenen.

The treatment of burn injury patients is a unique challenge for clinicians. The extent of thermal injuries ranges from very small burns to life-threatening burn injuries. Insufficient treatment can result in a substantial impairment in the quality of life. In order to avoid such sequelae a targeted treatment must be carried out. A precise diagnosis determines the necessary treatment. Superficial second-degree burns (2a) not involving the face, hand or joints with a total body surface area smaller than 10% can usually be treated with modern wound dressings in an outpatient setting. Deep second-degree burns (2b) are an indication for debridement. In addition to the classical surgical procedures with tangential excision, enzymatic debridement can also be employed. Similarly, indeterminate burns (2a/2b) are also considered to be an indication for enzymatic debridement. Third-degree burns are treated with early debridement and skin grafting. These patients can also benefit from special dermal replacement procedures for an improvement of the functional and esthetic results. Due to the long-term visible sequelae of burns, aftercare of these patients is indicated.

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.

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.

[Evaluation of the Charlson Comorbidity Index as a prognostic tool for assessing the severity of hand infections] / Evaluation des Charlson Komorbiditätsindex als prognostisches Hilfsmittel zur Einschätzung des Verlaufes von Handinfektionen.

BACKGROUND: The Charlson Comorbidity Index (CCI) is used for the prognostic analysis of comorbidities. Comorbidities, especially diabetes mellitus, are a decisive factor for the development and course of hand infections. This study aimed to determine the CCI in patients with hand infections in order to examine how comorbidities influence the course and severity of hand infections. MATERIAL AND METHODS: Ninety patients with hand infections requiring surgery but without previous antibiotic treatment were studied prospectively. The respective CCI was determined on admission to hospital. A total score of zero points was defined as "low", a score of one to three as "medium" and a score of four to nine points as a "high" index. Age, CRP level, duration of inpatient stay and the number of performed surgeries were documented and statistically evaluated. RESULTS: The median CCI was 0,5 points with a range of 0-9 points. The most common comorbidity was diabetes mellitus without end-organ damage, followed by heart failure and chronic lung disease. Patients with a low total score (median 51 years) were significantly younger than those with a medium score (median 60 years; p=0,018) or a high score (median 66,5 years; p=0,018). In addition, patients with a low or medium score had a shorter hospital stay (median 6 vs. 11,5 days; plow=0,003; pmean=0,005), required fewer surgeries (median 1 vs. 3 surgeries; plow=0,002; pmean=0,003) and had a lower CRP level (median 8,3 mg/l vs. 7,1 mg/l vs. 86,25 mg/l; plow=pmean=0,001) than those with a high index. A significant positive correlation was found between the CCI and patient age (Spearman's ρ=0,367; p<0,001) as well as the length of hospital stay (Spearman's ρ=0,261; p=0,013), the number of surgeries (Spearman's ρ=0,219; p=0,038) and the CRP level (Spearman's ρ=0,212; p=0,045). CONCLUSIONS: The CCI is an appropriate questionnaire for the prognostic assessment of the course and severity of hand infections, particularly with regard to the length of hospital stay, the number of surgeries and the CRP level.

Breast Implant-Associated Tumors.

In addition to anaplastic large T-cell lymphomas (BIA-ALCL), other implant-related tumors have been described for some years. Squamous cell carcinoma (SSC) and B-cell lymphomas occurred in very rare cases. The unexplained pathogenesis as well as the unclear individual risk profile is an ongoing source of uncertainty for patients and physicians. The pathogenesis of the tumors is still largely not understood. While BIA-ALCL occurs more frequently with textured breast implants, other tumors were also observed with smooth implants and at other implant sites. Multiple potential mechanisms are discussed. It is suspected that the etiology of a chronic inflammatory response and subsequently immunostimulation is multifactorial and appears to play a key role in the malignant transformation. Since there are currently no sufficiently valid data for a specific risk assessment, this must be done with caution. This article presents the incidence, pathogenesis, as well as the level of evidence according to the current state of knowledge, and evaluates and discusses the current literature.

[Surgical management of burn injury patients : Comments on the guidelines on treatment of thermal injuries in adults]. / Chirurgisches Management des brandverletzten Patienten : Kommentar zur Leitlinie Behandlung thermischer Verletzungen des Erwachsenen.

The treatment of burn injury patients is a unique challenge for clinicians. The extent of thermal injuries ranges from very small burns to life-threatening burn injuries. Insufficient treatment can result in a substantial impairment in the quality of life. In order to avoid such sequelae a targeted treatment must be carried out. A precise diagnosis determines the necessary treatment. Superficial second-degree burns (2a) not involving the face, hand or joints with a total body surface area smaller than 10% can usually be treated with modern wound dressings in an outpatient setting. Deep second-degree burns (2b) are an indication for debridement. In addition to the classical surgical procedures with tangential excision, enzymatic debridement can also be employed. Similarly, indeterminate burns (2a/2b) are also considered to be an indication for enzymatic debridement. Third-degree burns are treated with early debridement and skin grafting. These patients can also benefit from special dermal replacement procedures for an improvement of the functional and esthetic results. Due to the long-term visible sequelae of burns, aftercare of these patients is indicated.

Microbiologic Analysis of Hand Infections: A Prospective Study.

Background: Hand infections are a common problem in emergency departments. Staphylococcus aureus is the main pathogen of both hand and blood stream infections. Therefore, the aim of the present study was to evaluate the frequency and impact of bacteremia in patients with hand infections to improve the microbiologic diagnostics. Patients and Methods: A prospective study of 90 patients with acute hand infections without antimicrobial pre-treatment was performed. Blood cultures were taken pre-operatively. If positive, transesophageal echocardiography was performed to rule out infectious endocarditis. Tissue samples were microbiologically processed using standardized culture media. If negative, a broad-spectrum bacterial 16S ribosomal RNA (rRNA) gene polymerase chain reaction (PCR) was applied. The etiology and location of the infection, the length of hospital stay, the number of surgical interventions, and the inflammatory parameters were obtained. Results: Six patients with bacteremia (6.6%) were diagnosed, after animal bites (n = 3) and intra-articular empyema (n = 3). Pathogens included Staphylococcus pettenkoferi, Pasteurella multocida, Staphylococcus epidermidis, Staphylococcus aureus, and Bacteroides pyogenes. No case of infective endocarditis was detected. Patients with bacteremia required more surgical interventions (p = 0.002), had a longer hospital stay (p < 0.001), higher plasma C-reactive protein (CRP; p = 0.016), and a higher age (p = 0.002) compared with those without bacteremia. In 14 cases (15.6%) no pathogen was detected by culture, whereas the subsequent broad-spectrum PCR diagnosed three cases (21.4%). Conclusions: Pre-operative blood cultures in patients with hand infections are important to detect bacteremia as an essential marker of clinical severity. Those blood cultures are indicated after deep animal bites and joint empyema. A precise identification of pathogens is fundamental for an effective treatment of hand infections, for which a 16S rRNA gene PCR can contribute in culture-negative tissue samples.

Reduced Real-life Affective Well-being and Amygdala Habituation in Unmedicated Community Individuals at Risk for Depression and Anxiety.

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, and functional magnetic resonance imaging 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, functional magnetic resonance imaging 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 ecological momentary assessment 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) with those of 48 nonrisk individuals and 23 persons with a mood or anxiety disorder. We studied risk-associated functional magnetic resonance imaging signals in subsamples with balanced sociodemographic and image quality parameters (26 nonrisk, 26 at-risk persons). RESULTS: Compared with nonrisk persons, at-risk individuals showed significantly decreased real-life affective valence (p = .038), reduced amygdala habituation (familywise error-corrected p = .024, region of interest corrected), and an intermediate psychological risk profile. Amygdala habituation predicted real-life affective valence in control subjects but not in participants at risk (familywise error-corrected p = .005, region of interest 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.

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.

Fear, depression, and well-being during COVID-19 in German and South African students: A cross-cultural comparison.

Various studies have shown a decrease in well-being and an increase in mental health problems during the COVID-19 pandemic; however, only a few studies have explored fear, depression, and well-being cross-culturally during this time. Accordingly, we present the results of a cross-cultural study that (1) compares these mental health scores for German and South African students, (2) compares the correlations among them, and (3) identifies COVID-19 fear, well-being, and depression predictors. German and South African societies differ from each other socio-culturally, politically, and economically. Their university systems also differ to a large extent. University students in both countries completed the Fear of COVID-19 Scale, the World Health Organization-Five Well-Being Index (WHO-5), and the Patient Health Questionnaire-9 (PHQ-9). Welch's t-test, correlation, and multiple regression analyses were performed. (1) German students were found to have statistically lower levels of COVID-19 fear and depression, but lower levels of general well-being than South African students. (2) In both samples, fear of COVID-19 was negatively correlated with well-being and positively associated with female gender and depression. (3) Additionally, female gender, depression, and lower well-being were identified as predictors of COVID-19 fear in both samples. The findings indicate that the fear of COVID-19 is associated with and varies according to gender, depression, and well-being across cultures, and that the difference in the intensity of fear between German and South African students may be partly explained by cultural and contextual differences. These findings can create a deeper understanding of the pandemic's impact on student communities and may be used by mental health practitioners and researchers to develop and apply culture-specific interventions.

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

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.

[Reconstruction of Soft Tissue Defects of the Achilles Tendon Region: a Literature Review]. / Rekonstruktionen von Weichteildefekten der Achillessehnen region ­ eine Literaturübersicht.

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.

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

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 UBE3A gene, with current precision therapy approaches focusing on re-expression of UBE3A. Certain phenotypes, however, are difficult to rescue beyond early development. Notably, a cluster of microRNA binding sites was reported in the untranslated Ube3a1 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 Ube3a (Ube3a m-/p+ ). 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.

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.

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/ ).