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Acta Neuropathologica Communications Jun 2024Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs)....
snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.
Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.
Topics: Humans; Schwann Cells; Skin Neoplasms; Benzimidazoles; Extracellular Matrix; Signal Transduction; Neurofibroma; Female; Male; RNA-Seq; Middle Aged; Adult; Neurofibromatosis 1; Protein Kinase Inhibitors; Transcriptome
PubMed: 38907342
DOI: 10.1186/s40478-024-01821-z -
Journal of Cardiothoracic Surgery Jun 2024The incidence of minimally invasive heart surgery via mini-thoracotomy (MT; right anterior thoracotomy) is on the rise, accompanied by an increase in post-MT intercostal...
BACKGROUND
The incidence of minimally invasive heart surgery via mini-thoracotomy (MT; right anterior thoracotomy) is on the rise, accompanied by an increase in post-MT intercostal nerve neuralgia and the risk of lung herniation through the incision site. While various methods have been proposed to address these issues, none have been commonly effective. In this case report, we attempted to simultaneously address these problems by performing intercostal cryoablation (IC) and mesh repair.
CASE PRESENTATION
A 43-year-old male was referred to our hospital for chronic post-thoracotomy neuralgia following heart surgery via MT, involving patch closure of an atrial septal defect and tricuspid annuloplasty. He presented with intercostal nerve neuralgia and lung herniation accompanied by severe pain. Despite medication and lidocaine injections, there was no relief. Consequently, he underwent surgical treatment with IC for chronic MT wound pain and simultaneously underwent mesh repair for a lung hernia. He was discharged from hospital free of complications. Subsequently, he no longer required further pain medication and experienced a favorable recovery.
CONCLUSION
Our findings suggest that concurrent IC and mesh repair can effectively relieve chronic post-MT intercostal nerve neuralgia and severe lung herniation pain in patients who underwent MT surgery, leading to a decrease in opioid medication usage.
Topics: Humans; Male; Adult; Cryosurgery; Thoracotomy; Surgical Mesh; Herniorrhaphy; Intercostal Nerves; Pain, Postoperative; Lung Diseases; Neuralgia; Hernia; Chronic Pain
PubMed: 38907312
DOI: 10.1186/s13019-024-02864-y -
Science Advances Jun 2024Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central...
Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the highly regenerative axolotl and found that the harmonized atlas also improves cell type annotation, particularly of sparse neuronal subtypes. We observed that the transcriptomes of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The resources presented here can guide future studies in comparative transcriptomics, simplify cell-type nomenclature differences across studies, and help prioritize targets for future analgesic development.
Topics: Animals; Humans; Ganglia, Spinal; Trigeminal Ganglion; Transcriptome; Single-Cell Analysis; Sensory Receptor Cells; Species Specificity; Mice; Atlases as Topic; Gene Expression Profiling; Rats
PubMed: 38905344
DOI: 10.1126/sciadv.adj9173 -
Science Advances Jun 2024Neuroblastoma is a childhood developmental cancer; however, its embryonic origins remain poorly understood. Moreover, in-depth studies of early tumor-driving events are...
Neuroblastoma is a childhood developmental cancer; however, its embryonic origins remain poorly understood. Moreover, in-depth studies of early tumor-driving events are limited because of the lack of appropriate models. Herein, we analyzed RNA sequencing data obtained from human neuroblastoma samples and found that loss of expression of trunk neural crest-enriched gene associates with advanced disease and worse outcome. Further, by using single-cell RNA sequencing data of human neuroblastoma cells and fetal adrenal glands and creating in vivo models of zebrafish, chick, and mouse, we show that MOXD1 is a determinate of tumor development. In addition, we found that expression is highly conserved and restricted to mesenchymal neuroblastoma cells and Schwann cell precursors during healthy development. Our findings identify as a lineage-restricted tumor-suppressor gene in neuroblastoma, potentiating further stratification of these tumors and development of novel therapeutic interventions.
Topics: Neuroblastoma; Animals; Humans; Mice; Genes, Tumor Suppressor; Gene Expression Regulation, Neoplastic; Zebrafish; Cell Line, Tumor; Cell Lineage; Neural Crest; Schwann Cells
PubMed: 38905335
DOI: 10.1126/sciadv.ado1583 -
Journal of Hand Surgery Global Online Mar 2024Neurofibromas are benign peripheral nerve sheath tumors that typically develop within cutaneous nerve branches but can involve major nerves as well. They can be sporadic...
Neurofibromas are benign peripheral nerve sheath tumors that typically develop within cutaneous nerve branches but can involve major nerves as well. They can be sporadic or associated with neurofibromatosis type 1. In this report, we describe the surgical treatment of a pediatric patient with neurofibromatosis type 1 presenting with a neurofibroma of a bifid median nerve. Involvement of the median nerve was not evident on preoperative examination or imaging, therefore altering the risk-benefit ratio of the procedure. After bifid nerve involvement was identified intraoperatively, the patient's parents were counseled on the risks and benefits of surgical excision before resuming the case. Ultimately, the neurofibroma was resected, and the patient experienced no neurological deficits after surgery.
PubMed: 38903847
DOI: 10.1016/j.jhsg.2023.12.001 -
Journal of Hand Surgery Global Online Mar 2024Articular comminuted fracture dislocations of the base of the middle phalanx represent a major challenge for the surgeon. The treatment goal is a nonpainful, stable, and...
Articular comminuted fracture dislocations of the base of the middle phalanx represent a major challenge for the surgeon. The treatment goal is a nonpainful, stable, and functional proximal interphalangeal joint, which is achieved through concentric joint reduction and restoration of joint stability. Fracture pattern rarely results in sagittal bone loss involving the entire ulnar or radial pilon of the base of the second phalanx. In these cases, the choice of treatment can be particularly challenging as the loss of a pillar of the articular base causes angular deviation at the joint level, thus causing the loss of finger joint flexion and overlap of the adjacent finger. We present a novel nonvascularized osteochondral graft, which we named hemi--hamate osteochondral graft a modified version of the traditional hemi-hamate arthroplasty, that is suitable for the reconstruction of bone loss involving the whole anteroposterior hemiarticular surface of the base of the P2.
PubMed: 38903846
DOI: 10.1016/j.jhsg.2023.11.009 -
Ugeskrift For Laeger Jun 2024Ramsay Hunt syndrome (RHS) is an infection with the Varicella Zoster virus in the geniculate ganglion of the facial nerve. The syndrome consists of a triad of peripheral...
Ramsay Hunt syndrome (RHS) is an infection with the Varicella Zoster virus in the geniculate ganglion of the facial nerve. The syndrome consists of a triad of peripheral facial nerve palsy, ear pain and concurrent zoster rash in the ear canal. However, vesicles in the mouth can be seen. A rare complication of RHS is viral meningitis. This is a case report of a patient with orally manifested RHS and concurrent asymptomatic viral meningitis. This case aims to raise awareness of RHS with atypical presentation and concurrent viral meningitis and, thereby, the importance of a thorough neurological examination.
Topics: Humans; Herpes Zoster Oticus; Meningitis, Viral; Male; Female; Middle Aged
PubMed: 38903036
DOI: 10.61409/V02240092 -
Annals of Palliative Medicine Jun 2024Radiofrequency ablation (RFA), a minimally invasive procedure for pain reduction, is increasingly used for managing chronic neck pain and headaches. This article offers...
Radiofrequency ablation (RFA), a minimally invasive procedure for pain reduction, is increasingly used for managing chronic neck pain and headaches. This article offers a concise overview of cervical spine RFA. In the context of RFA, heat is applied to specific nerve tissues to interrupt pain signals. Wallarian degeneration occurs as a result of the thermal injury to the nerve. The heat generated by the RFA procedure can damage the nerve fibers, initiating the degenerative process. Wallarian degeneration is a process that occurs in a nerve axon due to the thermal injury, leading to the breakdown and eventual degradation of the axon and its myelin sheath. However, nerves have regeneration capacity, especially the peripheral nerves, which are often the target of RFA for pain management. After Wallarian degeneration takes place, the nerve sheath, or the connective tissue surrounding the nerve, can serve as a scaffold for the growth of new nerve fibers. Over time, these new fibers can regenerate and re-establish connections, potentially restoring nerve function. Three common types are traditional thermal, water-cooled, and pulsed radio frequency ablation. Given the regenerative potential of nerves, these procedures are typically effective for 1 to 2 years, with some variability. Despite a 112% increase in Medicare claims for RFA from 2009 to 2018, it's recommended for patients who respond positively to diagnostic medial branch blocks, with recent guidelines suggesting a single block may be sufficient. Although generally effective, the procedure carries risks, including nerve and tissue injury. Notably, the procedure's increased utilization notably surpasses the most commonly reported prevalence rates of conditions it aims to treat. Moreover, diagnostic blocks performed before cervical RFA also have their risks, such as inadvertent vascular injections leading to seizures or paralysis. In summary, the risks and benefits of cervical RFA must be considered with regards to the patient's comorbidities and specific pain issues. The skill and experience of the practitioner plays a significant role in minimizing these risks. Detailed discussions with healthcare providers about the risks, benefits, and alternatives can help in making an informed decision about the procedure.
PubMed: 38902987
DOI: 10.21037/apm-23-520 -
Translational Psychiatry Jun 2024Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying...
Whereas meta-analytical data highlight abnormal frontocortical macrostructure (thickness/surface area/volume) in Major Depressive Disorder (MDD), the underlying microstructural processes remain uncharted, due to the use of conventional MRI scanners and acquisition techniques. We uniquely combined Ultra-High Field MRI at 7.0 Tesla with Quantitative Imaging to map intracortical myelin (proxied by longitudinal relaxation time T) and iron concentration (proxied by transverse relaxation time T*), microstructural processes deemed particularly germane to cortical macrostructure. Informed by meta-analytical evidence, we focused specifically on orbitofrontal and rostral anterior cingulate cortices among adult MDD patients (N = 48) and matched healthy controls (HC; N = 10). Analyses probed the association of MDD diagnosis and clinical profile (severity, medication use, comorbid anxiety disorders, childhood trauma) with aforementioned microstructural properties. MDD diagnosis (p's < 0.05, Cohen's D = 0.55-0.66) and symptom severity (p's < 0.01, r = 0.271-0.267) both related to decreased intracortical myelination (higher T values) within the lateral orbitofrontal cortex, a region tightly coupled to processing negative affect and feelings of sadness in MDD. No relations were found with local iron concentrations. These findings allow uniquely fine-grained insights on frontocortical microstructure in MDD, and cautiously point to intracortical demyelination as a possible driver of macroscale cortical disintegrity in MDD.
Topics: Humans; Depressive Disorder, Major; Magnetic Resonance Imaging; Female; Male; Adult; Prefrontal Cortex; Gyrus Cinguli; Myelin Sheath; Middle Aged; Iron; Case-Control Studies
PubMed: 38902245
DOI: 10.1038/s41398-024-02976-y