Primary Nerve Research Articles

RhEPO Upregulates the PPARγ Pathway in Long-term Cultured Primary Nerve Cells via PI3K/Akt to Delay Cell Senescence.

Previous studies have confirmed that both recombinant human erythropoietin (rhEPO) and peroxisome proliferator-activated receptors γ (PPARγ) activator pioglitazone can protect senescent nerve cells, and their mechanisms involve enhancing cell antioxidant capacity and reducing cell apoptosis. However, whether the PPARγ pathway is involved in the rhEPO anti-aging process in neuronal cells is still unclear. In this study, to explore the relationship between rhEPO and the PPARγ pathway at the cellular level, primary nerve cells cultured for 22days were used to simulate the natural aging process of nerve cells. Starting on the 11th day of culture, rhEPO, LY294002, and GW9662 were added for treatment. Immunochemical methods and SA-β-gal staining were used to observe the changes in cellular antioxidant capacity and the fraction of senescent cells. The results showed that PPARγ blockade retarded the effect of rhEPO on the cellular antioxidant capacity and altered the fraction of senescent cells. It was confirmed that PPARγ was involved in rhEPO's anti-aging process in neuronal cells. Real-time fluorescent quantitative RT-PCR, Western blotting, and immunofluorescence staining were used to observe the changes in PPARγ pathway-related factors in nerve cells after rhEPO treatment. The results showed that rhEPO significantly upregulated the expression of PPARγ coactivator-1α (PGC-1α), PPARγ, and nuclear PPARγ in cells but did not affect the level of phosphorylated PPARγ protein, confirming that rhEPO has the ability to upregulate the PPARγ pathway. PI3K/Akt and PPARγ pathway blockade experiments were used to explore the relationships among rhEPO, PI3K/Akt, and PPARγ. The results showed that after PPARγ blockade, rhEPO had no significant effect on the PI3K/Akt pathway-related factor p-Akt, while after PI3K/Akt blockade, rhEPO's effects on PPARγ-related factors (PGC-1α, PPARγ, and nuclear PPARγ) were significantly decreased. It is suggested that rhEPO delays the PI3K/Akt pathway in the process of neuronal senescence, which is located upstream of PPARγ regulation. In conclusion, this study confirmed that rhEPO can upregulate the expression of PGC-1α and PPARγ in cells and the level of PPARγ protein in the nucleus to enhance the antioxidant capacity of cells and delay the senescence of nerve cells through the PI3K/Akt pathway. These findings will provide ideas for finding new targets for neuroprotection research and will also provide a theoretical basis and experimental evidence for rhEPO anti-aging research in neural cells.

The Pronator Quadratus Muscle – its Morphology and Functions

Knowledge of the architecture and nerve supply of the human pronator quadratus muscle (MPQ) appears to be rather scarce and is insufficient for a surgical approach of the muscle. In older French and more recent clinical studies it is stated that the MPQ consists of two or even three parts, each of them with an individual nerve supply and function. Former studies have described a superficial part that is active during pronation, and a deeper part which acts during supination. Furthermore, other authors described that the MPQ regulates the tension of the capsular complex at the distal radio‐ulnar joint.We studied the existence of subdivisions of the MPQ and their pattern of nerve supply from the anterior interosseous nerve in 15 cadaver forearms (8 M, 7 F, mean age 80 years). The dissection was carried out using a surgical microscope. In all 15 forearms the MPQ consisted of three parts: a superficial (pars superficialis; PQs), a deep proximal (pars profunda proximalis; PQpp) and a deep distal part (pars profunda distalis; PQpd).Three primary nerve branches were identified (ramus proximalis, ramus intermedius and ramus distalis) as they originated from the anterior interosseous nerve and at entry of the individual parts of the MPQ.We have not been able to conclude whether the ramus proximalis or the ramus intermedius supplies the superficial (PQs) or the deep proximal (PQpp) part of the MPQ. However, it could be established that the ramus distalis goes to the deep distal (PQpd) part of the MPQ. We could also confirm that only fibers of the deep distal part insert into the distal radio‐ulnar joint.On the basis of the existing division of the MPQ in three different parts, functional considerations can be made with regard to the complex functions of MPQ, i.e. pronation by the superficial part of the MPQ, fine‐tuning of motion of the radius during pronation and supination by the deep proximal part and capsular tension (stabilization) of the distal radio‐ulnar joint by the deep distal part of the MPQ.

Role of Magnetic Resonance Neurography on 3-Tesla in Brachial Plexus Injury Management

Objective: To study the effect of magnetic resonance neurography on 3 Tesla (MRN-3T) on the outcome of brachial plexus injury management.
 Study Design: Prospective comparative study.Place and Duration of Study: Department of Plastic Surgery, Combined Military Hospital Rawalpindi Pakistan, from Apr 2017 to Mar 2019.
 Methodology: Two groups of brachial plexus injury (BPI) were studied over two years. Group-A (n=29) cases whose operative intervention was decided based on history, examination, NCS/EMG and CT scan. Second group-B included (n=33) patients in which MRN-3T (magnetic resonance neurography on 3 Tesla) was the critical diagnostic tool. The comparison of preoperative diagnosis with intraoperative findings and outcome of surgery were made.
 Results: Out of 29 cases in group-A, 11 (37.93%) were explored. In these 11, neurolysis was done in one case, direct repair in one case, nerve grafting in 4 patients, nerve transfers with bridging grafts in 2 cases, whereas three patients had negative exploration. Of 33 cases in group-B, 21(63.64%) were explored. From these 21 cases, neurolysis was done in four patients; the direct repair was possible in 7 and in 10 cases bridging nerve grafts were used along with primary nerve transfers.
 Conclusion: MRN-3T brachial plexus has significantly improved the diagnosis, preoperative planning and surgical outcome of patients with brachial plexus injury.

Finger Drop: Cervical Radiculopathy, Peripheral Nerve Lesion, or Multifocal Neuropathy? A Case Report

Background Posterior interosseous nerve (PIN) lesions can result in finger drop. Multifocal neuropathy (MFN) occurs when a primary nerve disorder predisposes the nerve to further injury. Case Presentation A 69-year-old male presented with left-handed weakness and left-sided pain of the neck, upper trapezius, and medial scapular border 4 weeks after an asymptomatic fall. Findings regarding proximal pain were consistent with cervical radiculopathy (CR). Distal weakness indicated a PIN lesion: spared sensation/supination, limited finger extension, and radial deviation upon wrist extension. MFN was considered based on history/presentation. The care team included a physical therapist, a neurosurgeon, and a hand therapist. Outcome and Follow-up Resolution of CR pain occurred at 1 month; finger extension/grip strength improved at 3 months but was less than anticipated. Discussion With neurogenic weakness, one needs to consider central- and peripheral-mediated origins, MFN contributions, and appropriate referrals. JOSPT Cases 2022;2(2):112–116. doi:10.2519/josptcases.2022.10601

Clinical outcomes following neurolysis and porcine collagen extracellular matrix wrapping of scarred nerves in revision carpal tunnel decompression

Scar tether after primary nerve decompression can impair physiological nerve glide and vascularity of the nerve. Revision decompression in the setting of neurostenalgia should address the scarred mesoneurium in order to prevent further entrapment and tether. This study reports on the clinical outcomes of 12 patients with neurostenalgia following carpal tunnel decompression (CTD), treated with revision CTD and a porcine submucosa extracellular matrix nerve wrap (PECM) (Axoguard® nerve protector, Axogen Inc., Alachua, FL). Eleven patients had one primary decompression procedure prior to revision surgery; one patient previously had two operations for CTD. There was a significant reduction in visual analogue pain scores (VAS) and improvement in patients' satisfaction rating and symptom resolution. Patient-reported outcome measures were recorded using the Impact of Hand Nerve Disorders (I-HaND) Scale (Version 2), which demonstrated a significant reduction in hand disability. There were no complications attributable to the procedure and no re-revision procedures necessary at the latest follow-up.

The effect of a gap concept on peripheral nerve recovery in modified epineurial neurorrhaphy: An experimental study in rats.

Several factors such as surgical approach that only consider topographic anatomy; inadequate fascicular alignment, extraepineurial sprouting in the repair zone; contact of axons with the suture area are the disadvantages of epineurial neurorrhaphy. Accordingly, axonal mismatch, neuroma, and unfavorable nerve recovery become inevitable. Neurotropism is the theory clarifying appropriate matching of the nerve fibers independently without needing surgical approach. The studies comparing the primary nerve repair with the nerve defects bridged in different ways demonstrated better outcomes of nerve recovery in the groups with a nerve gap. In this study, we aimed to demonstrate the effects of the gap concept in primary nerve repair bridged by own epineurium. We hypothesized that this technique will provide better results in terms of peripheral nerve recovery and will significantly eliminate the occurrence of a neuroma, which is quite possible in epineurial neurorrhaphy. A total of 35 Wistar female rats weighing 200 ~ 250 g were randomly divided into five groups each with seven rats. Sham controls constituted Group 1, while the rats with epineural neurorrhaphy were included in Group 2. The remaining three groups were the study groups. In Group 3, after the sciatic nerve transection, epineurium of the distal segment was sleeved and preserved. A 2-mm axonal segment was removed from the epineurium free distal ending and no any procedure was applied to the proximal ending of the transected sciatic nerve. Epineuriums of the both sides were approximated and repaired. In Group 4, a 2-mm axonal segment was removed from the proximal ending of the sciatic nerve after preservation of epineurium and no any procedure was applied to the distal part of sciatic nerve. Epineuriums of the both sides were approximated and repaired. In addition, in Group 5, after epineuriums were sleeved in the both distal and proximal stumps, a 1-mm nerve segment was removed from both endings and epineuriums were repaired in the middle bridging a 2-mm axonal gap again. After a 3months follow-up period Sciatic Functional Index (SFI) was measured by walking track analysis; the area under the evoked compound muscle action potential (CMAP) and latency periods were calculated via electromyographic (EMG) analysis; and histopathological evaluation were performed to compare the parameters of edema, fibrosis, inflammation, vascularization, axonal degeneration, axonal density, myelination, disorganization, and neuroma occurrence. Vascular structures and nerve fibers were counted at ×200 magnification: +1, +2, and +3 indicated the presence of 0-15, 16-30, and >30 structures, respectively. For uncountable parameters (edema, disorganization, myelination, fibrosis, and inflammation): +1 indicated mild, +2 indicated moderate, and +3 indicated severe. The differences between the groups with axonal gap repair and epineural neurorrhaphy were not significant regarding to SFI. The areas under CMAP were as follows: 27.9 ± 5.9 (Δ=12.1%) in Group 1; 16.5 ± 5.5 (Δ=6.3%) in Group 2; 14.1 ± 6.2 (Δ=4.8%) in group 3; 13.8 ± 2.3 (Δ=9.2%) in Group 4, and 22.5 ± 18.3 (Δ=2.2%) in Group 5. Group 5 (1 mm gap in the distal +1 mm gap in the proximal segments) had a significantly better result in terms of the area under CMAP with the value of 22.5 ± 18.3m/Mv (p=.031). Axonal density was 0.9 ± 0.6 (Δ=2.2%) in Group 2, 2.4 ± 0.3 (Δ=5.1%) in Group 3, 2.8 ± 0.1 (Δ=7.7%) in Group 4, and 2.8 ± 0.2 (Δ=4.8%) in Group 5. Myelination was 1.1 ± 0.5 (Δ=3.4%) in group 2, 2.2 ± 0.2 (Δ=6.7%) in group 3, 2.4 ± 0.4 (Δ=6.0%) in Group 4, and 2.7 ± 0.3 (Δ=4.6%) in Group 5. Disorganization was 2.3 ± 0.4 (Δ=4.1%) in Group 2, 1.2 ± 0.2 (Δ=7.7%) in Group 3, 1.3 ± 0.2 (Δ=6.5%) in Group 4, and 1 ± 0.3 (Δ=5.9%) in Group 5. And, neuroma occurrence was found 2.2 ± 0.6 (Δ=2.8%) in Group 2 and 0.3 ± 0.2 (Δ=0.1%) in Group 4 while neuroma was not encountered in Group 3 and Group 5. Comparison between the epineurial neurorrhaphy group and the groups with axonal defect revealed the statistically significant results in the factors of axonal density (p=.001), myelination (p=.028), disorganization (p=.016) and neuroma (p=.001). Creating axonal gap bridged by own epineurium showed favorable results comparing with epineurial neurorrhaphy. Resection of a 1 mm axonal segment from the proximal and distal stumps following the epineurial sleeve procedure and performing the epineurium- only repair can facilitate the nerve regeneration. The feasibility of the described technique has been demonstrated in a small rat model and must be further validated in larger animals before clinical testing.

Challenges in preoperative diagnosis of glossopharyngeal nerve schwannoma: own findings analysis

Medical history, disease onset, clinical symptoms, and results of neuroimaging of 14 glossopharyngeal schwannoma patients, who were exa­mined and treated in the Subtentorial Neurooncology Department of the State Institution, Romodanov Institute of Neurosurgery of the NAMS of Ukraine (8 patients) and the Neurosurgery Department No. 2 of the Municipal Enterprise, Mechnikov Dnipropetrovsk Regional Clinical Hospital of Dnipropetrovsk Regional Council (6 patients) in 2018 to 2021 have been analyzed in details. The study inclusion criteria were as follows: patient’s age over 18, pre­sence of unilateral primary glossopharyngeal nerve schwannoma. Our study showed that most of clinical signs and symptoms of the glossopharyngeal nerve schwannoma are associated with otolaryngological disorders (such as hearing loss, tinnitus, hoarseness, or dizziness) or cerebellar disorders (such as ataxia, nystagmus, or dizziness). Neuroimaging cerebellopontine angle tumors diagnosis must include brain computed tomography (with mandatory assessment of the state of jugular foramen and internal auditory canal) and IV contrast brain magnetic resonance tomography and inclusion of high-resolution sequences, gradient echo (3D CISS, DRIVE, TRUFFI, B-FFE) with the aim of better visualization and differentiation of various cerebellopontine angle cranial nerves. The study demonstrates the com­plexity of a reliable preoperative diagnosis when using standard diagnostic tools. Preoperative jugular foramen and cerebellopontine angle tumors diagnosis should be based on a systematic approach and include a comparison of results of comprehensive clinical and instrumental examination and neuroimaging studies.

Successful Radiotherapy of Primary Malignant Peripheral Nerve Sheath Tumor of the Lung

A 71-year-old man presented with cough and bloody sputum. Computed tomography showed a mass in the lower lobe of the left lung. Histological findings in biopsy tissue revealed a malignant peripheral nerve sheath tumor (MPNST). The patient was diagnosed with primary lung MPNST based on a systemic examination. Although initial chemotherapy treatment with doxorubicin failed to control the disease, radiotherapy considerably shrank the tumor. Primary lung MPNSTs are rare, and there is no established treatment for inoperable cases. This case suggests that radiotherapy is a treatment option for primary lung MPNST.

Preservation, reconstruction, and rehabilitation of the facial nerve

Der Umgang mit dem N. facialis ist bei der Operation eines Parotiskarzinoms wichtig für die Langzeitlebensqualität des Patienten. In etwa 2 Drittel der Fälle ist der N. facialis nicht vom Tumor befallen. In diesen Fällen sind neben vollständiger Tumorentfernung die Identifizierung und der Erhalt des Nervs für eine erfolgreiche Operation wesentlich. Ist der Nerv vom Tumor infiltriert, muss der betroffene Teil des Nervs im Rahmen einer radikalen Parotidektomie reseziert werden. Die primäre Nervenrekonstruktion, sofern möglich, führt zu den besten funktionellen und kosmetischen Langzeitergebnissen. Das individuell optimale Therapiekonzept basiert zum einen auf der klinischen Prüfung der Gesichtsbeweglichkeit, zum anderen auf der präoperativen Bildgebung, um die Lagebeziehung zwischen Tumor und Nerv zu verstehen, und schließlich auf einer elektrophysiologischen Untersuchung zur Funktion des Nervs. Intraoperativ hilft ein standardisiertes Vorgehen, um den Nerv zu identifizieren und zu erhalten. Wenn eine radikale Parotidektomie indiziert ist, kann bereits die präoperative Diagnostik helfen, neben der einzeitigen Rekonstruktion auch die adjuvante postoperative Therapie zu planen. Das Ziel der Rehabilitation ist die Wiederherstellung von Tonus, Symmetrie und Bewegung des gelähmten Gesichts. Die Wiederherstellung des Augenschlusses hat hohe Priorität. Bei der chirurgischen Therapie von Gesichtslähmungen gab es in den letzten Jahren viele Verbesserungen. Die vorliegende Arbeit gibt einen Überblick über die jüngsten Fortschritte in der Diagnostik, den Operationstechniken und weiteren Möglichkeiten zur Protektion des gesunden N. facialis. Anderseits wird die Rehabilitation des tumorinfiltrierten N. facialis im Kontext der Behandlung von Speicheldrüsenmalignomen beschrieben.

Minimally invasive retroperitoneal lymph node dissection for men with testis cancer: a retrospective cohort study of safety and feasibility

To describe the perioperative safety, functional and immediate post-operative oncological outcomes of minimally invasive RPLND (miRPLND) for testis cancer. We performed a retrospective multi-centre cohort study on testis cancer patients treated with miRPLND from 16 institutions in eight countries. We measured clinician-reported outcomes stratified by indication. We performed logistic regression to identify predictors for maintained postoperative ejaculatory function. Data for 457 men undergoing miRPLND were studied. miRPLND comprised laparoscopic (n = 56) or robotic (n = 401) miRPLND. Indications included pre-chemotherapy in 305 and post-chemotherapy in 152 men. The median retroperitoneal mass size was 32mm and operative time 270min. Intraoperative complications occurred in 20 (4%) and postoperative complications in 26 (6%). In multivariable regression, nerve sparing, and template resection improved ejaculatory function significantly (template vs bilateral resection [odds ratio (OR) 19.4, 95% confidence interval (CI) 6.5-75.6], nerve sparing vs non-nerve sparing [OR 5.9, 95% CI 2.3-16.1]). In 91 men treated with primary RPLND, nerve sparing and template resection, normal postoperative ejaculation was reported in 96%. During a median follow-up of 33months, relapse was detected in 39 (9%) of which one with port site (< 1%), one with peritoneal recurrence and 10 (2%) with retroperitoneum recurrences. The low proportion of complications or peritoneal recurrences and high proportion of men with normal postoperative ejaculatory function supports further miRPLND studies.

Does hyperbaric oxygen therapy facilitate peripheral nerve recovery in upper extremity injuries? A prospective study of 74 patients.

Several experimental studies have investigated the effects of hyperbaric oxygen therapy (HBOT) on peripheral nerve regeneration. However, to the best of our knowledge, clinical studies to evaluate the effects of HBOT on peripheral nerve recovery are seldom performed. The aim of our study was to investigate the efficacy of HBOT following primary nerve repair in patients with upper extremity nerve injuries. Patients admitted to our hospital between 2015 and 2019 with ulnar and median nerve injuries were included in the study. Patients were randomized based on their application dates and divided into two different groups. Patients who received HBOT following standard epineural nerve repair were included in group 1, while patients who only underwent epineural nerve repair were included in group 2. All patients were followed up at 3, 6, and 12months post-treatment and evaluated through electroneuromyography analysis of the traumatized nerve, injured nerve-related muscle strength, and two-point discrimination test. Impulse transmission of injured nerves to the end organ was faster in group 1. Further, ENMG parameters demonstrated that injured nerves of patients in group 1 recovered faster. Patients in group 1 also reached higher power score and had significantly more rapid motor recovery than patients in group 2. This prospective study of upper extremity injuries demonstrated the favorable effects of HBOT on nerve recovery both clinically and electrophysiologically following nerve repair. One HBOT session each day for 5days after surgical treatment can decrease morbidity and facilitate recovery.

Supracondylar Fractures of the Humerus: Association of Neurovascular Lesions with Degree of Fracture Displacement in Children-A Retrospective Study.

Supracondylar humerus fractures (ScHF) account for 60% of fractures of the elbow region in children. We assessed the relationship between neurovascular complications and the degree of fracture displacement as rated on the basis of modified Gartland classification. Moreover, we aimed to evaluate predisposing factors, e.g., age and gender, and outcomes of neurovascular complications in ScHF. Between 2004 and 2019, we treated 329 patients with ScHF at the Department of Traumatology and Orthopedics of the Upper Silesian Child Centre, Katowice, Poland. Mean age of patients (189 boys and 140 girls) was 7.2 years (Confidence interval: 6.89, 7.45). Undisplaced fractures were treated conservatively with a cast. Displaced fractures were managed by closed reduction and percutaneous Kirschner wire fixation using two pins inserted laterally. We retrospectively assessed the number of neurovascular lesions at baseline and recorded any iatrogenic injury resulting from the surgical intervention. Acute neurovascular lesions occurred in 44 of 329 ScHF patients (13.4%). The incidence of accompanying neurovascular injuries was positively associated with the severity of fracture displacement characterized by Gartland score. Vascular injuries occurred mainly in Gartland type IV ScHF, while nerve lesions occurred in both Gartland type III and IV ScHF. We noted a significantly higher mean Gartland score and mean age at injury in the group of children suffering from neurovascular injuries when compared to those in the group without such injuries (p = 0.045 and p = 0.04, respectively). We observed no secondary nerve lesions after surgical treatment. For the treatment of ScHF in children, we recommend closed reduction and stabilization of displaced fractures with K-wires inserted percutaneously from the lateral aspect of the upper arm. We advocate vessel exploration in case of absent distal pulses after closed reduction but do not consider primary nerve exploration necessary, unless a complete primary sensomotoric nerve lesion is present.

Autologous Muscle-Derived Nerve Wrap for Prevention of Symptomatic Microneuromas in Primary Nerve Repair.

Regeneration of peripheral nerves after repair is incomplete. Painful microneuromas may form at the site of an appropriately performed primary microsurgical nerve repair leading to a persistent Tinel’s sign and hypersensitivity in that location. Here, we describe an autologous option using a free muscle-derived nerve wrap with the intent to capture axonal escape at the site of primary nerve coaptation. We demonstrate this technique on a patient undergoing primary nerve repair of a laceration to the superficial branch of the radial nerve using extensor digitorum communis muscle as a donor graft. This has become our preferred technique over commercially available nerve wraps as the muscle wrap is autologous, not limited by cost, and has the potential to limit microneuroma formation at the coaptation site.

Upregulation of transient receptor potential cation channel subfamily M member-3 in bladder afferents is involved in chronic pain in cyclophosphamide-induced cystitis.

The transient receptor potential cation channel subfamily M member-3 (TRPM3) channel is a recently recognized noxious heat sensor that is involved in inflammatory thermal hyperalgesia. To examine its involvement in the development of hyperalgesia in interstitial cystitis/painful bladder syndrome (IC/PBS), rats with cyclophosphamide (CYP)-induced chronic cystitis were used as a model of IC/PBS. Mechanical and thermal hyperalgesia in lower abdominal region overlying the bladder in CYP rats were measured using von Frey filaments and radiant heat, respectively. Transient receptor potential cation channel subfamily M member-3 expression at the mRNA, protein, and functional levels in dorsal root ganglion neurons innervating the bladder was detected using RNA in situ hybridization (RNAscope), Western blotting, immunohistochemistry, and Ca 2+ imaging, respectively. Transient receptor potential cation channel subfamily M member-3 channels were expressed on most of the bladder primary afferent nerve terminals containing calcitonin gene-related peptide and their cell bodies in L6-S1 dorsal root ganglion. Activation of TRPM3 in the bladder wall by its specific agonist pregnenolone sulphate or CIM0216 induced spontaneous bladder pain, calcitonin gene-related peptide release, and neurogenic inflammation that was evidenced by edema, plasma extravasation, inflammatory cell accumulation, and mast cell infiltration. In CYP rats, pretreatment with the TRPM3 antagonist primidone (2 mg/kg, i.p.) significantly alleviated the mechanical and thermal hyperalgesia, bladder submucosal edema, mast cell infiltration, and bladder hyperactivity. Cyclophosphamide-induced cystitis was associated with TRPM3 upregulation at the mRNA, protein, and functional levels in bladder afferent neurons. Our results suggest that upregulation of TRPM3 channels is involved in the development of chronic pain in CYP-induced cystitis, and targeting TRPM3 may be a pharmacological strategy for treating bladder pain in IC/PBS.

Visceral Mediastinal Primary Nerve Sheath Tumor Located near the Right Brachiocephalic Vein

Visceral Mediastinal Primary Nerve Sheath Tumor Located near the Right Brachiocephalic Vein

Primary malignant peripheral nerve sheath tumors of bone: a clinicopathologic reappraisal of 8 cases

Primary spindle cell and pleomorphic sarcomas of bone represent an exceedingly rare group of mesenchymal malignancies that include soft tissuehistotypes, as malignant peripheral nerve sheath tumor. Outside the head and neck region, only 36 cases of primary malignant peripheral nerve sheath tumor of bone have been described. We retrieved from our archives eight cases of primary malignant peripheral nerve sheath tumor of bone arising outside the head and neck region, describing their clinical, radiological, and morphologic features. Our series, in which all but one patient died of diseases after a median of seven months, confirms that primary malignant peripheral nerve sheath tumors of bone are aggressive tumors. Pathologists should be aware of this rare histotype. More aggressive and active adjuvant treatments should be investigated.

Recombinant human erythropoietin protects long-term cultured ageing primary nerve cells by upregulating the PI3K/Akt pathway.

ObjectivePrevious studies have found that recombinant human erythropoietin (rhEPO) protects long-term cultured ageing primary nerve cells by enhancing the endogenous antioxidant capacity of cells; however, its signalling pathways are not clear. This study aimed to explore the relationship between the rhEPO and PI3K/Akt pathways in the protection of senescent nerve cells at the cellular level.MethodsPrimary nerve cells were cultured for 22 days to mimic the natural ageing process of nerve cells. rhEPO and LY294002 were administered as an intervention on the 11th day of culture. Western blot, immunochemistry, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide, immunofluorescence double-labelling staining, Annexin V-FITC/PI double-labelling flow cytometry, and SA-β-gal staining experiments were used to observe the expression levels of erythropoietin receptor (EPOR) and phosphorylated Akt (p-Akt) protein and the related indices of nerve cell senescence.ResultsWestern blot experiments showed that in ageing long-term cultured primary neurons, the EPOR and p-Akt decreased and rhEPO upregulated the expression levels of EPOR and p-Akt protein. The rest showed that the PI3K/Akt pathway blockade reduced the antioxidation capacity, cell viability, cell morphology, and ratio of apoptotic cells and senescent cells of rhEPO on ageing long-term cultured primary nerve cells.ConclusionsThis study explored the relationship between the rhEPO and PI3K/Akt pathways in the protection of ageing nerve cells at the cellular level and found that rhEPO protects long-term cultured ageing primary nerve cells by upregulating the PI3K/Akt pathway. These findings provide a theoretical basis and experimental evidence for the antiaeging mechanism of EPO in the nervous system.

Heat-dependent opening of TRPV1 in the presence of capsaicin

Noxious heat (> 42°C) and capsaicin are two well-known stimuli for nociception. Our ability to sense noxious heat and spiciness is owed to the transient receptor potential vanilloid member 1 (TRPV1), a calcium-permeable ion channel expressed in primary sensory nerve terminals. TRPV1 also serves as a sensor for other vanilloid compounds and is a member of the TRP channel superfamily. Here we present six high-resolution cryo-EM structures of apo and capsaicin-bound full-length TRPV1 reconstituted into lipid nanodiscs over a range of temperatures.

Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide's Motor-Stimulating and Prosecretory Function in the Intestine.

The development of small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and of monoclonal antibodies targeting the CGRP system has been a major advance in the management of migraine. In the randomized controlled trials before regulatory approval, the safety of these anti-CGRP migraine therapeutics was considered favorable and to stay within the expected profile. Post-approval real-world surveys reveal, however, constipation to be a major adverse event which may affect more than 50% of patients treated with erenumab (an antibody targeting the CGRP receptor), fremanezumab or galcanezumab (antibodies targeting CGRP). In this review article we address the question whether constipation caused by inhibition of CGRP signaling can be mechanistically deduced from the known pharmacological actions and pathophysiological implications of CGRP in the digestive tract. CGRP in the gut is expressed by two distinct neuronal populations: extrinsic primary afferent nerve fibers and distinct neurons of the intrinsic enteric nervous system. In particular, CGRP is a major messenger of enteric sensory neurons which in response to mucosal stimulation activate both ascending excitatory and descending inhibitory neuronal pathways that enable propulsive (peristaltic) motor activity to take place. In addition, CGRP is able to stimulate ion and water secretion into the intestinal lumen. The motor-stimulating and prosecretory actions of CGRP combine in accelerating intestinal transit, an activity profile that has been confirmed by the ability of CGRP to induce diarrhea in mice, dogs and humans. We therefore conclude that the constipation elicited by antibodies targeting CGRP or its receptor results from interference with the physiological function of CGRP in the small and large intestine in which it contributes to the maintenance of peristaltic motor activity, ion and water secretion and intestinal transit.

Addition of 2 mg dexamethasone to improve the anesthetic efficacy of 2% lidocaine with 1:80,000 epinephrine administered for inferior alveolar nerve block to patients with symptomatic irreversible pulpitis in the mandibular molars: a randomized double-blind clinical trial.

IntroductionThis clinical trial aimed to evaluate the anesthetic effect of the addition of 2 mg (4 mg/ml) of dexamethasone to 2% lidocaine (plain or with 1:80,000 epinephrine). The solutions were injected for a primary inferior alveolar nerve block (IANB) to provide mandibular anesthesia for the endodontic treatment of mandibular molars with symptomatic irreversible pulpitis.MethodsIn a double-blinded setup, 124 patients randomly received either of the following injections: 2% lidocaine with 1:80,000 epinephrine, 2% lidocaine with 1:80,000 epinephrine mixed with 2 mg dexamethasone, or plain 2% lidocaine mixed with 2 mg dexamethasone, which were injected as a primary IANB. Ten minutes after injection, patients with profound lip numbness underwent electric and thermal pulp sensibility tests. Patients who responded positively to the tests were categorized as “failed” anesthesia and received supplemental anesthesia. The remaining patients underwent endodontic treatment using a rubber dam. Anesthetic success was defined as “no pain or faint/weak/mild pain” during endodontic access preparation and instrumentation (HP visual analog scale score < 55 mm). The effect of the anesthetic solutions on the maximum change in heart rate was also evaluated. The Pearson chi-square test at 5% and 1% significance was used to analyze anesthetic success rates.ResultsThe 2% lidocaine with 1:80,000 epinephrine, 2% lidocaine with 1:80,000 epinephrine mixed with 2 mg dexamethasone, and plain 2% lidocaine mixed with 2 mg dexamethasone groups had anesthetic success rates of 34%, 59%, and 29%, respectively. The addition of dexamethasone resulted in significantly better results (P < 0.001, χ2 = 9.07, df = 2).ConclusionsThe addition of dexamethasone to 2% lidocaine with epinephrine, administered as an IANB, can improve the anesthetic success rates during the endodontic management of symptomatic mandibular molars with irreversible pulpitis.