Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness.

Mitochondrial dysfunction causes poorly understood tissue-specific pathology stemming from primary defects in respiration, coupled with altered reactive oxygen species (ROS), metabolic signaling, and apoptosis. The A1555G mtDNA mutation that causes maternally inherited deafness disrupts mitochondrial ribosome function, in part, via increased methylation of the mitochondrial 12S rRNA by the methyltransferase mtTFB1. In patient-derived A1555G cells, we show that 12S rRNA hypermethylation causes ROS-dependent activation of AMP kinase and the proapoptotic nuclear transcription factor E2F1. This retrograde mitochondrial-stress relay is operative in vivo, as transgenic-mtTFB1 mice exhibit enhanced 12S rRNA methylation in multiple tissues, increased E2F1 and apoptosis in the stria vascularis and spiral ganglion neurons of the inner ear, and progressive E2F1-dependent hearing loss. This mouse mitochondrial disease model provides a robust platform for deciphering the complex tissue specificity of human mitochondrial-based disorders, as well as the precise pathogenic mechanism of maternally inherited deafness and its exacerbation by environmental factors.

Not every knee tumour is a ganglion - retrospective analysis of benign and malign tumour entities around the knee.

BACKGROUND: Due to a lack of routine, there is often uncertainty regarding diagnostics of tumours around the knee joint. This study aimed to provide knowledge about the frequency, distribution and diagnostic algorithm of different bone and soft tissue tumour entities of the knee at a large referral university hospital in Germany. METHODS: Retrospective, longitudinal, single-centre study that reviewed adult patients from 2010 until 2020 with a suspected tumours diagnosis around the knee at a university cancer centre. Inclusion criteria were adults with true bone or soft-tissue tumours in the knee joint and in its adjacent compartments. Suspected diagnosis, histological tumour entity, localization and its surgical treatment by biopsy, resection, osteosynthesis or tumour endoprosthesis were investigated. RESULTS: A total number of 310 adult patients were included with a mean age of 54.2 ± 18.8 years. In total 160 (51.6%) soft-tissue tumours (69/43.1% benign; 74/46.2% malignant; 17/10.6% intermediate), 92 (29.6%) primary bone tumours (46/50% benign; 39/42.3% malignant; 7/7.6% intermediate), 36 (11.6%) metastases and 22 (7.1%) lymphomas were detected. 171 (55.1%) tumours were classified as malignant. Suspected diagnosis was matched with histology in 74.5% (231/310) of all cases. In 6 cases a primarily suspected benign diagnosis turned out to be malignant. The majority of primary bone tumours was cartilage derived (63.1%;58/92) and located in the distal 2/3 of the femur, whereas intracapsular tumours of the knee joint were rare (13.0%). Soft-tissue tumours were located primarily in the middle third of the thigh (36.8%). The MRI was the diagnostic tool of choice in 98.1% of soft tissue tumours and 82.6% bone tumours. CONCLUSION: Awareness is crucial for detecting rare and malignant tumours around the knee, with adipocytic tumours being the most common soft tissue tumour and chondrogenic tumours as the most prevalent malignant bone tumour. Accurate diagnosis of bone tumours necessitates radiographs and frequently an additional MRI scan, while soft tissue tumours require mandatory MRI scans. Incorrectly diagnosing a tumour can have severe consequences, emphasizing the need for histological confirmation in all cases. Additionally, malignant tumours within joint capsules in adults are infrequent.

Do You Really Need a Hand Surgeon? Hand Masses and Infections.

Hand masses and infections are commonly encountered by the community orthopaedic specialist, and maintaining an understanding of these ailments is important for diagnosis, treatment, and possible referral to a hand specialist. Hand masses are common, and it is important to provide the community orthopaedic specialist the knowledge needed for appropriate diagnostic workup and treatment as well as an understanding of when to refer to a hand specialist. Hand masses arise from soft tissue or bone. Specific types include ganglion cysts, mucoid cysts, giant cell tumors of the tendon sheath, lipomas, epidermal inclusions cysts, glomus tumors, and malignancies. Hand infections are also common, and their level of acuity can vary. It is important to define which infections necessitate urgent management and are associated with a risk of significant morbidity and mortality. From superficial cellulitis to deep space infections, it is important to provide an understanding of hand anatomy needed for appropriate treatment.

Ganglion cyst of temporomandibular joint - A systematic review.

Ganglion cyst of the temporomandibular joint (TMJ) is an uncommon pathology with uncertain etiology. There is no consensus on their management. The current systematic review aimed to discuss the clinical and histopathological features of ganglion cysts of TMJ, to aid in appropriate treatment. A literature search was done and a total of 20 cases were retrieved from published databases such as PubMed, SCOPUS, and Google Scholar. The cyst presented with swelling in all the cases followed by pain (50 %) and trismus (35 %) as other common symptoms. Though CT and MRI proved helpful in determining the location of the cyst, a histopathological examination was essential in concluding its final diagnosis. It is a pseudocyst lined by dense fibro-connective tissue with myxoid tissue degeneration. Histologically, it is essential to distinguish them from the clinically and radiographically similar true cyst of TMJ, synovial cyst. The lining of ganglion cyst is devoid of epithelium and synovial cells. Surgical excision was found to be the treatment of choice with minimal recurrence (10 %) being reported.

Does complete regression of intraneural ganglion cysts occur without surgery?

PURPOSE: The dynamic nature of intraneural ganglion cysts, including spontaneous expansion and regression, has been described. However, whether these cysts can regress completely in the absence of surgical management has important therapeutic implications. Therefore, we aim to review the literature for cyst regression without surgical intervention. METHODS: We reviewed our database of 970 intraneural ganglion cysts in the literature to search for evidence of complete regression based on strict radiologic confirmation, either spontaneously, or after percutaneous cyst aspiration or steroid injection. RESULTS: We did not find any examples of complete regression without surgical treatment that met inclusion criteria. Spontaneous regression was reported in four cases; however, only two cases had follow-up imaging, both of which demonstrated residual cysts. Nineteen cases of percutaneous intervention were found in the literature, 13 of which reported clinical improvement following aspiration/steroid injection; however, only seven cases had available imaging. Only two cases reported complete resolution of cyst on MR imaging at follow-up, but reinterpretation found residual intraneural cyst in both cases. CONCLUSION: We believe that pathology (structural abnormalities and/or increased joint fluid) always exists at the joint origin of intraneural ganglion cysts which persist even with regression of the cyst. The persistence of a capsular abnormality or defect can lead to recurrence of the cyst in the future, and while imaging may show dramatic decreases in cyst size, truly focused assessment of images will show a tiny focus of persistent intraneural cyst at the joint origin. Thus, expectant management or percutaneous intervention may lead to regression, but not complete resolution, of intraneural ganglion cysts.

Ganglion Cysts of the Proximal Tibiofibular Joint: Low Risk of Recurrence After Total Cyst Excision.

BACKGROUND: Peroneal nerve neuropathy due to compression from tumors or tumor-like lesions such as ganglion cysts is rare. Few case series have been published and reported local recurrence rates are high, while secondary procedures are frequently employed. QUESTIONS/PURPOSES: (1) What are the demographics of patients with ganglion cysts of the proximal tibiofibular joint, and what proportion of them present with intraneural cysts and peroneal nerve palsy? (2) What Musculoskeletal Tumor Society (MSTS) scores do patients with this condition achieve after decompression surgery with removal of the ganglion cyst, but no arthrodesis of the tibiofibular joint? (3) What proportion of patients experience local recurrence after surgery? METHODS: Between 2009 to 2018, 30 patients (29 primary cases) were treated for chronic peroneal palsy or neuropathy due to ganglion cysts of the proximal tibiofibular joint at two tertiary orthopaedic medical centers with total resection of the cystic lesion. MRI with contrast and electromyography (EMG) were performed preoperatively in all patients. The minimum follow-up for this series was 1 year (median 48 months, range 13 to 120); 14% (4 of 29) were lost to follow-up before that time. The MSTS score was recorded preoperatively, at 6 weeks postoperatively, and at most-recent follow-up. RESULTS: A total of 90% of the patients were male (26 of 29 patients) and the median age was 67 years (range 20 to 76). In all, 17% (5 of 29) were treated due to intraneural ganglia. Twenty-eight percent (8 of 29) presented with complete peroneal palsy (foot drop). The mean MSTS score improved from 67 ± 12% before surgery to 89 ± 12% at 6 weeks postoperative (p < 0.001) and to 92 ± 9% at final follow up (p = 0.003, comparison with 6 weeks postop). All patients improved their scores. A total of 8% (2 of 25 patients) experienced local recurrence after surgery. CONCLUSION: Ganglion cysts of the proximal tibiofibular joint occurred more often as extraneural lesions in older male patients in this small series. Total excision was associated with improved functional outcome and low risk of neurologic damage and local recurrence, and we did not use any more complex reconstructive procedures. Tendon transfers may be performed simultaneously in older patients to stabilize the ankle joint, while younger patients may recover after decompression alone, although larger randomized studies are needed to confirm our preliminary observations. LEVEL OF EVIDENCE: Level IV, therapeutic study.

A novel mechanism for the formation and propagation of neural tumors and lesions through neural highways.

By recognizing anatomic and radiologic patterns of rare and often misdiagnosed peripheral nerve tumors/lesions, we have defined mechanisms for the propagation of neural diseases. The novel concept of the nervous system serving as a complex system of "highways" driving the neural and perineural spread of these lesions is described in three examples: Intraneural dissection of joint fluid in intraneural ganglion cysts, perineural spread of cancer cells, and dissemination of unknown concentrations of neurotrophic/inhibitory factors for growth in hamartomas/choristomas of nerve. Further mapping of these pathways to identify the natural history of diseases, the spectrum of disease evolution, the role of genetic mutations, and how these neural pathways interface with the lymphatic, vascular, and cerebrospinal systems may lead to advances in targeted treatments.

Peripheral Neuronopathy Associated With Ebola Virus Infection in Rhesus Macaques: A Possible Cause of Neurological Signs and Symptoms in Human Ebola Patients.

Neurological signs and symptoms are the most common complications of Ebola virus disease. However, the mechanisms underlying the neurologic manifestations in Ebola patients are not known. In this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to Ebola virus (EBOV) disease from 5 to 8 days post exposure. Ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients.

Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome.

Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.

Extensive apoptosis during the formation of the terminal nerve ganglion by olfactory placode-derived cells with distinct molecular markers.

The terminal nerve ganglion (TNG) is a well-known structure of the peripheral nervous system in cartilaginous and teleost fishes. It derives from the olfactory placode during embryonic development. While the differentiation and migration of gonadotropin releasing hormone (GnRH)-expressing neurons from the olfactory placode has been well documented, the TNG has been neglected in birds and mammals, and its development is less well described. Here we describe the formation of a ganglion-like structure from migratory olfactory placodal cells in chicken. The TNG is surrounded by neural crest cells, but in contrast to other cranial sensory ganglia, we observed no neural crest corridor, and olfactory unsheathing cells appear only after the onset of neuronal migration. We identified Isl1 and Lhx2 as two transcription factors that label neuronal subpopulations in the forming TNG, distinct from GnRH1+ cells, thereby revealing a diversity of cell types during the formation of the TNG. We also provide evidence for extensive apoptosis in the terminal nerve ganglion shortly after its formation, but not in other cranial sensory ganglia. Moreover, at later stages placode-derived neurons expressing GnRH1, Isl1 and/or Lhx2 become incorporated in the telencephalon. The integration of TNG neurons into the telencephalon together with the earlier widespread apoptosis in the TNG might be an explanation why the TNG in mammals and birds is much smaller compared to other vertebrates.

Ganglion cysts developed from the flexor tendon sheaths in the fingers: Clinical and sonographic features.

PURPOSE: The purpose of this study was to assess the clinical and sonographic features of flexor tendon sheath ganglion cysts in the fingers. METHODS: We retrospectively reviewed the clinical and sonographic features of 35 cases of flexor tendon sheath ganglion cysts in the fingers in 34 patients that were pathologically confirmed between 2003 and 2018. RESULTS: The mean age of the patients was 44.2 years (range, 11-73 years). Lesions were located at the level of the metacarpophalangeal joint (n = 22 [63%]) and proximal phalanx (n = 11 [31%]), and involvement of the third finger was common (n = 19 [54%]). The mean lesion size was 6 mm and the mean volume was 90 mm3 . None of the lesions had a pedicle. Lesions were homogeneous (n = 24 [69%]) and anechoic (n = 23 [66%]). A septum was noted in 12 cases (34%). CONCLUSIONS: Flexor tendon sheath ganglion cysts are most commonly located in the third finger and at the level of the metacarpophalangeal joint and proximal phalanx. It usually presents as a simple cyst without a pedicle, but occasionally exhibits a mixed echogenicity and contains a septum.

Cystic Adventitial Disease of the Tibial Vein Arising From the Subtalar Joint: A Case Report.

Soft tissue ganglion cysts are a well-known cause of tibial nerve compression in the tarsal tunnel. We describe a patient who presented with tibial nerve symptoms and was found to have an adventitial cyst of the tibial vein arising from the subtalar joint, with the joint connection confirmed both on imaging and at surgery. Surgical decompression of the cyst with transection of the vascular pedicle arising from the subtalar joint improved her symptoms at 6 months, and postoperative magnetic resonance imaging showed resolution of the cyst. Cystic adventitial disease is a rare, poorly understood condition in which a cyst is identified in the adventitia of a vessel, usually an artery. Only 3 cases of adventitial cysts have been reported in the foot and ankle region, 2 in the lesser and 1 in the greater saphenous vein. None of the previous cases have been recognized to be joint connected. This case provides additional evidence for an articular origin for adventitial cysts and helps guide management strategies for these joint-connected cysts.

Intraoperative intravenous fluorescein as an adjunct during surgery for peroneal intraneural ganglion cysts.

The intraoperative use of intravenous fluorescein is presented in a case of peroneal intraneural ganglion cyst. When illuminated with the operative microscope and yellow filter, this fluorophore provided excellent visualization of the abnormal cystic peroneal nerve and its articular branch connection. The articular (synovial) theory for the pathogenesis of intraneural cysts is further supported by this pattern of fluorescence. Further, our report presents a novel use of fluorescein in peripheral nerve surgery.

Superficial radial intraneural ganglion cysts at the wrist.

Superficial radial intraneural ganglion cysts are rare. Only nine previous cases have been described. We provide two examples with a wrist joint connection and review the literature to provide further support for the unifying articular (synovial) theory for the pathogenesis and treatment of intraneural ganglia.

Ultrasound-guided synovial Tru-cut biopsy: indications, technique, and outcome in 111 cases.

OBJECTIVE: To investigate the diagnostic performance of ultrasound-guided synovial biopsy. METHODS: Clinical notes, pathology and microbiology reports, ultrasound and other imaging studies of 100 patients who underwent 111 ultrasound-guided synovial biopsies were reviewed. Biopsies were compared with the final clinical diagnosis established after synovectomy (n = 43) or clinical/imaging follow-up (n = 57) (mean 30 months). RESULTS: Other than a single vasovagal episode, no complication of synovial biopsy was encountered. One hundred and seven (96 %) of the 111 biopsies yielded synovium histologically. Pathology ± microbiology findings for these 107 conclusive biopsies comprised synovial tumour (n = 30, 28 %), synovial infection (n = 18, 17 %), synovial inflammation (n = 45, 42 %), including gouty arthritis (n = 3), and no abnormality (n = 14, 13 %). The accuracy, sensitivity, and specificity of synovial biopsy was 99 %, 97 %, and 100 % for synovial tumour; 100 %, 100 %, and 100 % for native joint infection; and 78 %, 45 %, and 100 % for prosthetic joint infection. False-negative synovial biopsy did not seem to be related to antibiotic therapy. CONCLUSION: Ultrasound-guided Tru-cut synovial biopsy is a safe and reliable technique with a high diagnostic yield for diagnosing synovial tumour and also, most likely, for joint infection. Regarding joint infection, synovial biopsy of native joints seems to have a higher diagnostic yield than that for infected prosthetic joints. KEY POINTS: • Ultrasound-guided Tru-cut synovial biopsy has high accuracy (99 %) for diagnosing synovial tumour. • It has good accuracy, sensitivity, and high specificity for diagnosis of joint infection. • Synovial biopsy of native joints works better than biopsy of prosthetic joints. • A negative synovial biopsy culture from a native joint largely excludes septic arthritis. • Ultrasound-guided Tru-cut synovial biopsy is a safe and well-tolerated procedure.

Joint Fluid, Bone Marrow Edemalike Changes, and Ganglion Cysts in the Pediatric Wrist: Features That May Mimic Pathologic Abnormalities-Follow-Up of a Healthy Cohort.

OBJECTIVE: The presence of findings at wrist MRI that may mimic disease is a diagnostic problem. The purpose of this study is to examine the occurrence of bone marrow changes resembling edema, joint fluid, and ganglion cysts over time, in a cohort of healthy children. MATERIALS AND METHODS: Seventy-four of 89 healthy children included in a study of normal MRI findings of the wrists were reexamined after a period of 4 years, using the same 1.5-T MRI technique-namely, a coronal T1-weighted and a T2-weighted fat-saturated sequence. A history of handedness, diseases, and sports activity was noted. RESULTS: Bone marrow edema or edemalike changes were seen in 29 of 74 (39.2%) wrists in 2013 as compared with 35 of 72 (48.6%) wrists in 2009 (p = 0.153), all in different locations. Changes were found in central parts of the bone, on both sides of a joint, or near bony depressions. Fifty percent of all subjects had at least one fluid pocket greater than or equal to 2 mm. The location was unchanged in 47% of the joints. In 24% of the individuals, at least one ganglion cyst was seen. Six ganglion cysts present on the first scan were not seen on the follow-up scan, and 11 new ganglion cysts had appeared. CONCLUSION: Awareness of normal MRI appearances of the growing skeleton is crucial when interpreting MRI of children, and such findings must not be interpreted as pathologic abnormalities.

Synchronous ganglioneuroma and schwannoma of the vagal inferior ganglion.

Neurogenic neoplasms resulting from autonomic nerves are considerably rare. In this paper, we report a case of a 41-year-old woman with composite tumor of synchronous ganglioneuroma and schwannoma in the vagal inferior ganglion. Ultrasonography and computed tomography showed a well-defined mass, which extruded from the internal and external carotid arteries. Two tumors were closely attached but with an evident boundary. The small tumor was composed of spindle cells and numerous mature ganglion cells, and the large one consisted entirely of differentiated neoplastic Schwann cells. Results showed that these tumors were a schwannoma arising in a ganglioneuroma of the vagal inferior ganglion. Our case is the first to demonstrate the occurrence of schwannoma in benign ganglioneuroma. We also provided clinical and pathological evidence that such transformation can occur spontaneously.
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Cystic degeneration of the tibial nerve: magnetic resonance neurography and sonography appearances of an intraneural ganglion cyst.

Extra- and intraneural ganglion cysts have been described in the literature. The tibial nerve ganglion is uncommon and its occurrence without intra-articular extension is atypical. The pathogenesis of cystic degeneration localized to connective and perineural tissue secondary to chronic mechanical irritation or idiopathic mucoid degeneration is hypothesized. Since the above pathology is extremely rare and the magnetic resonance imaging examination detects the defining characteristics of the intrinsic alterations of the tibial nerve, the authors illustrate such a case of tibial intaneural ganglion cyst with its magnetic resonance neurography and sonography appearances.

Recognition of peroneal intraneural ganglia in an historical cohort with "negative" MRIs.

BACKGROUND: The objective of this study was to review an historical cohort of patients with peroneal neuropathy and magnetic resonance imaging (MRI) read as negative for mass or cyst to determine if occult peroneal intraneural ganglion cysts can be identified on subsequent imaging review and to use this as an estimation of how under-recognized this pathologic entity is. METHOD: The patient cohort utilized in this study was a previously published control cohort of 11 patients with peroneal neuropathy and MRI read as negative for mass or cyst. Clinical history, neurologic examination, and MRI studies of the knee were reviewed for each of the included patients. The primary outcome of interest was the presence of peroneal intraneural ganglion cyst on MRI. RESULTS: Overall, 7 of 11 (64%) patients in this historical "normal" cohort had evidence of a peroneal intraneural ganglion cyst on subsequent review of imaging. Deep peroneal-predominant weakness, knee pain, and tibialis anterior-predominant denervation/atrophy were seen more commonly in patients in whom an intraneural cyst was identified. CONCLUSIONS: This retrospective cohort study provides evidence that peroneal intraneural ganglion cysts are an historically under-recognized cause of peroneal neuropathy, with 64% of this historical "negative" cohort having evidence of a cyst on subsequent imaging review. Larger studies are needed to determine the treatment ramifications of identifying small cysts and to determine the clinical features suggestive of an intraneural ganglion cyst.

Ultrasound-Guided Therapy for Knee and Foot Ganglion Cysts.

The present study evaluated the effectiveness of ultrasound-guided aspiration/injection of ganglion cysts in the lower extremities (knee and foot) that required referral to the radiology department for precise localization. The present study is the first series to describe such results. The study population consisted of 15 patients who had undergone treatment from April 2012 to January 2015. Follow-up was by telephone survey, which was performed at a mean of 15 ± 6 months after treatment. Almost 90% of patients experienced immediate improvement in symptoms (mostly pain), and 77% of these patients had not experienced a recurrence of symptoms at a mean follow-up time of 14 ± 6 months. In conclusion, ultrasound-guided therapy is a safe and potentially effective treatment for most cases of symptomatic lower extremity ganglion cysts.