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CNS Neuroscience & Therapeutics Oct 2023Nerve injury-induced maladaptive changes in gene expression in the spinal neurons are essential for neuropathic pain genesis. Circular RNAs (ciRNA) are emerging as key...
AIMS
Nerve injury-induced maladaptive changes in gene expression in the spinal neurons are essential for neuropathic pain genesis. Circular RNAs (ciRNA) are emerging as key regulators of gene expression. Here, we identified a nervous-system-tissues-specific ciRNA-Kat6 with conservation in humans and mice. We aimed to investigate whether and how spinal dorsal horn ciRNA-Kat6b participates in neuropathic pain.
METHODS
Unilateral sciatic nerve chronic constrictive injury (CCI) surgery was used to prepare the neuropathic pain model. The differentially expressed ciRNAs were obtained by RNA-Sequencing. The identification of nervous-system-tissues specificity of ciRNA-Kat6b and the measurement of ciRNA-Kat6b and microRNA-26a (miRNA-26a) expression level were carried out by quantitative RT-PCR. The ciRNA-Kat6b that targets miRNA-26a and miRNA-26a that targets Kcnk1 were predicted by bioinformatics analysis and verified by in vitro luciferase reports test and in vivo experiments including Western-blot, immunofluorescence, and RNA-RNA immunoprecipitation. The correlation between neuropathic pain and ciRNA-Kat6b, miRNA-26a, or Kcnk1 was examined by the hypersensitivity response to heat and mechanical stimulus.
RESULTS
Peripheral nerve injury downregulated ciRNA-Kat6b in the dorsal spinal horn of male mice. Rescuing this downregulation blocked nerve injury-induced increase of miRNA-26a, reversed the miRNA-26a-triggered decrease of potassium channel Kcnk1, a key neuropathic pain player, in the dorsal horn, and alleviates CCI-induced pain hypersensitivities. On the contrary, mimicking this downregulation increased the miRNA-26a level and decreased Kcnk1 in the spinal cord, resulting in neuropathic pain-like syndrome in naïve mice. Mechanistically, the downregulation of ciRNA-Kat6b reduced the accounts of miRNA-26a binding to ciRNA-Kat6b, and elevated the binding accounts of miRNA-26a to the 3' untranslated region of Kcnk1 mRNA and degeneration of Kcnk1 mRNA, triggering in the reduction of KCNK1 protein in the dorsal horn of neuropathic pain mice.
CONCLUSION
The ciRNA-Kat6b/miRNA-26a/Kcnk1 pathway in dorsal horn neurons regulates the development and maintenance of neuropathic pain, ciRNA-Kat6b may be a potential new target for analgesic and treatment strategies.
Topics: Humans; Mice; Male; Animals; RNA, Circular; Down-Regulation; MicroRNAs; Neuralgia; Spinal Cord Dorsal Horn; Spinal Cord; Chronic Pain; Peripheral Nerve Injuries; RNA, Messenger; Hyperalgesia
PubMed: 37144575
DOI: 10.1111/cns.14235 -
Nature Communications Nov 2023In vertebrate embryos, the canonical Wnt ligand primes the formation of dorsal organizers that govern dorsal-ventral patterns by secreting BMP antagonists. In contrast,...
In vertebrate embryos, the canonical Wnt ligand primes the formation of dorsal organizers that govern dorsal-ventral patterns by secreting BMP antagonists. In contrast, in Drosophila embryos, Toll-like receptor (Tlr)-mediated NFκB activation initiates dorsal-ventral patterning, wherein Wnt-mediated negative feedback regulation of Tlr/NFκB generates a BMP antagonist-secreting signalling centre to control the dorsal-ventral pattern. Although both Wnt and BMP antagonist are conserved among species, the involvement of Tlr/NFκB and feedback regulation in vertebrate organizer formation remains unclear. By imaging and genetic modification, we reveal that a negative feedback loop between canonical and non-canonical Wnts and Tlr4/NFκB determines the size of zebrafish organizer, and that Tlr/NFκB and Wnts switch initial cue and feedback mediator roles between Drosophila and zebrafish. Here, we show that canonical Wnt signalling stimulates the expression of the non-canonical Wnt5b ligand, activating the Tlr4 receptor to stimulate NFκB-mediated transcription of the Wnt antagonist frzb, restricting Wnt-dependent dorsal organizer formation.
Topics: Animals; Zebrafish; Feedback; Ligands; NF-kappa B; Drosophila; Wnt Signaling Pathway
PubMed: 37938219
DOI: 10.1038/s41467-023-42963-3 -
The Journal of Neuroscience : the... Aug 2023Aberrant activation of presynaptic NMDARs in the spinal dorsal horn is integral to opioid-induced hyperalgesia and analgesic tolerance. However, the signaling mechanisms...
Aberrant activation of presynaptic NMDARs in the spinal dorsal horn is integral to opioid-induced hyperalgesia and analgesic tolerance. However, the signaling mechanisms responsible for opioid-induced NMDAR hyperactivity remain poorly identified. Here, we show that repeated treatment with morphine or fentanyl reduced monomeric mGluR5 protein levels in the dorsal root ganglion (DRG) but increased levels of mGluR5 monomers and homodimers in the spinal cord in mice and rats of both sexes. Coimmunoprecipitation analysis revealed that monomeric and dimeric mGluR5 in the spinal cord, but not monomeric mGluR5 in the DRG, directly interacted with GluN1. By contrast, mGluR5 did not interact with μ-opioid receptors in the DRG or spinal cord. Repeated morphine treatment markedly increased the mGluR5-GluN1 interaction and protein levels of mGluR5 and GluN1 in spinal synaptosomes. The mGluR5 antagonist MPEP reversed morphine treatment-augmented mGluR5-GluN1 interactions, GluN1 synaptic expression, and dorsal root-evoked monosynaptic EPSCs of dorsal horn neurons. Furthermore, CRISPR-Cas9-induced conditional mGluR5 knockdown in DRG neurons normalized mGluR5 levels in spinal synaptosomes and NMDAR-mediated EPSCs of dorsal horn neurons increased by morphine treatment. Correspondingly, intrathecal injection of MPEP or conditional mGluR5 knockdown in DRG neurons not only potentiated the acute analgesic effect of morphine but also attenuated morphine treatment-induced hyperalgesia and tolerance. Together, our findings suggest that opioid treatment promotes mGluR5 trafficking from primary sensory neurons to the spinal dorsal horn. Through dimerization and direct interaction with NMDARs, presynaptic mGluR5 potentiates and/or stabilizes NMDAR synaptic expression and activity at primary afferent central terminals, thereby maintaining opioid-induced hyperalgesia and tolerance. Opioids are essential analgesics for managing severe pain caused by cancer, surgery, and tissue injury. However, these drugs paradoxically induce pain hypersensitivity and tolerance, which can cause rapid dose escalation and even overdose mortality. This study demonstrates, for the first time, that opioids promote trafficking of mGluR5, a G protein-coupled glutamate receptor, from peripheral sensory neurons to the spinal cord; there, mGluR5 proteins dimerize and physically interact with NMDARs to augment their synaptic expression and activity. Through dynamic interactions, the two distinct glutamate receptors mutually amplify and sustain nociceptive input from peripheral sensory neurons to the spinal cord. Thus, inhibiting mGluR5 activity or disrupting mGluR5-NMDAR interactions could reduce opioid-induced hyperalgesia and tolerance and potentiate opioid analgesic efficacy.
Topics: Male; Female; Rats; Mice; Animals; Receptors, N-Methyl-D-Aspartate; Analgesics, Opioid; Hyperalgesia; Receptor, Metabotropic Glutamate 5; Rats, Sprague-Dawley; Morphine; Spinal Cord Dorsal Horn; Spinal Cord; Neuralgia; Sensory Receptor Cells
PubMed: 37451981
DOI: 10.1523/JNEUROSCI.0601-23.2023 -
Operative Neurosurgery (Hagerstown, Md.) Dec 2023The retrosigmoid intradural suprameatal approach is mostly indicated for tumors in the cerebellopontine angle extending toward the Meckel cave and supratentorial...
INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE
The retrosigmoid intradural suprameatal approach is mostly indicated for tumors in the cerebellopontine angle extending toward the Meckel cave and supratentorial regions, most frequently meningiomas and schwannomas. This approach was first established by the senior author in 1982.
ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT
Nervous structures: cranial nerves III to XII, cerebellum, and brainstem. Vascular structures: anterior inferior cerebellar artery, posterior inferior cerebellar artery, superior cerebellar artery, basilar artery, vertebral artery, transverse, sigmoid, and petrous sinus, petrosal vein/veins, basilar plexus, and the mastoid emissary vein. Bony structures: petrous bone with internal auditory canal, jugular foramen and suprameatal tubercle, petrous apex, dorsum sellae, and posterior clinoid process. Structures within the petrous bone: vestibule, semicircular canals, and jugular bulb.
ESSENTIALS STEPS OF THE PROCEDURE
After a suboccipital retrosigmoid craniectomy in the semisitting position and debulking of the tumor mass in the cerebellopontine angle, extension is achieved by drilling suprameatal tubercle above cranial nerve VII and VIII toward the petrous apex. The extent of bone drilling is tailored for each patient.
PITFALLS/AVOIDANCE OF COMPLICATIONS
Avoid damage to cranial nerves, arteries, and veins during drilling, dissection, and tumor removal or by retraction.
VARIANTS AND INDICATIONS FOR THEIR USE
In case of extreme supratentorial extensions laterally and dorsally, the opening of the tentorium may be helpful. For inferior extensions toward the upper spinal canal, opening of the foramen magnum and hemilaminectomy of C1 may be necessary.The patient consented to the procedure and to the publication of his/her image. Institutional logo in title slide, © 2023, INI Hannover. Used with permission.
PubMed: 38084947
DOI: 10.1227/ons.0000000000001030 -
Aesthetic Plastic Surgery Jun 2024The prerequisite of a well-shaped dorsum with proper dorsal aesthetic lines that needs no modifications in its width and symmetry is key to letdown and push-down... (Review)
Review
BACKGROUND
The prerequisite of a well-shaped dorsum with proper dorsal aesthetic lines that needs no modifications in its width and symmetry is key to letdown and push-down techniques as classically described. The common current concept is that total preservation of the middle vault is obligatory. This, however, obviously limits the indications, since nasal dorsum with natural aesthetic dorsal lines per se is relatively few. The recent, impressive, revival of letdown and push-down procedures has progressively generated numerous technical variations, but all those essentially still left the middle vault unmodified. The concept of splitting the middle vault and modifying its width and symmetry, while leaving the crucial dorsal (central) and lateral Keystone area intact, represents a new hybrid approach to the nasal dorsum. The structural benefits of classical component separation are combined with the major advantage of preserving the flexible chondro-osseous joint at the keystone junction. Osteotomies and/or osteoplasty can be done as necessary to modify the bony dorsum and at the same time any type of septal deformity can be addressed according to the time-tested L-strut principle, a Cottle septoplasty included. This hybrid approach expands indications beyond those of the conventional push-down/letdown technique, including moderate asymmetries of the bony and cartilaginous dorsum. Although splitting the middle vault along the septal T will also facilitate middle vault reshaping in cases where a full letdown procedure is indicated, this paper will clarity address only those instances where no circumferential osteotomy is done.
METHODS AND MATERIALS
The dorsal bony nasal pyramid is always addressed first by rhinosculpture (osteoplasty) with piezoelectric inserts and/or burrs, in combination with different types of osteotomies as needed. This will allow narrowing of the bridge and correction of bony asymmetries. The osseous-cartilaginous connection of the central dorsal keystone area (DKA) is totally preserved. At this point, three main variations are possible: Type 1) preservation of the septal T and push-down by a high-middle septal strip resection, two different variations (1A and 1B) are possible here, Type 2) reduction in width of the septal T-segment and middle vault restoration by spreader flaps without any push-down of the septal T and Type 3) preservation of the septal T and letdown by low strip resection.
CONCLUSION
Hybrid Dorsal Preservation involves concepts of Structure and Preservation Rhinoplasty. Dorsal and lateral keystone area are preserved, and the middle vault could be modified splitting the septal T in the anatomical plane, expanding patient indications and improve outcomes.
LEVEL OF EVIDENCE V
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
PubMed: 38839611
DOI: 10.1007/s00266-024-04120-z -
Aesthetic Plastic Surgery Aug 2023There has recently been a resurgence of interest in preservation rhinoplasty (PR) for dorsal hump elimination or dorsal projection reduction. However, no studies have...
BACKGROUND
There has recently been a resurgence of interest in preservation rhinoplasty (PR) for dorsal hump elimination or dorsal projection reduction. However, no studies have scrutinized aesthetic outcomes to identify common pattern of flaws seen in published images to aid those with ardent enthusiasm for this technique to become aware of the frequency of these flaws and find ways to reduce imperfections.
METHODS
A systematic literature review was performed using search terms ("preservation" OR "let down", "push down") AND "rhinoplasty" on PubMed, Cochrane, SCOPUS, and EMBASE databases for studies between January 2000 and December 2022. Patient images from these studies were analyzed by three reviewers (MWW, IAC, and BG) for dorsal flaws. Raw interrater agreement percentage and Krippendorff's alpha were calculated to determine interrater reliability. A descriptive and comparative analysis with Fisher's exact test was performed for the aggregate data.
RESULTS
There were 59 patient images with 464 views from 24 studies included for final analysis. Optimal dorsal aesthetic lines (DAL) were noted in 12 patients (20.3%), while optimal profile was observed in 15 patients (25.4%) (p = 0.66). Combined ideal front and profile view of dorsum was not observed on any patients. The most common flaws were DAL irregularities (n = 45; 78.0%), dorsal deviation (n = 32, 54.2%), and residual hump (n = 25, 42.4%). There was excellent interrater agreement.
CONCLUSIONS
While PR may have some advantages, it has shortcomings in outcomes, particularly dorsal irregularities, dorsal deviation, and residual humps. Awareness of these imperfections may compel those performing this procedure to modify their techniques and improve their results.
LEVEL OF EVIDENCE III
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Topics: Humans; Follow-Up Studies; Reproducibility of Results; Treatment Outcome; Rhinoplasty; Plastic Surgery Procedures; Esthetics; Nose
PubMed: 37328654
DOI: 10.1007/s00266-023-03437-5 -
The Journal of Comparative Neurology Mar 2024The thalamus is one of the most important divisions of the forebrain because it serves as the major hub for transmission of information between the brainstem and...
The thalamus is one of the most important divisions of the forebrain because it serves as the major hub for transmission of information between the brainstem and telencephalon. While many studies have investigated the thalamus in mammals, comparable analyses in reptiles are incomplete. To fill this gap in knowledge, the thalamus was investigated in crocodiles using a variety of morphological techniques. The thalamus consists of two parts: a dorsal and a ventral division. The dorsal thalamus was defined by its projections to the telencephalon, whereas the ventral thalamus lacked this circuit. The complement of nuclei in each part of the thalamus was identified and characterized. Alar and basal components of both the dorsal and ventral thalamus were distinguished. Although some alar-derived nuclei in the dorsal thalamus shared certain features, no grouping could account for all of the known nuclei. However, immunohistochemical observations suggested a subdivision of alar-derived ventral thalamic nuclei. In view of this, a different approach to the organization of the dorsal thalamus should be considered. Development of the dorsal thalamus is suggested to be one way to provide a fresh perspective on its organization.
Topics: Animals; Alligators and Crocodiles; Thalamus; Mammals; Ventral Thalamic Nuclei; Telencephalon; Thalamic Nuclei
PubMed: 38427380
DOI: 10.1002/cne.25595 -
BioRxiv : the Preprint Server For... Aug 2023Hemispherectomy is a surgical procedure in which an entire hemisphere of a patient's brain is resected or functionally disconnected to manage seizures in individuals...
Hemispherectomy is a surgical procedure in which an entire hemisphere of a patient's brain is resected or functionally disconnected to manage seizures in individuals with drug-resistant epilepsy. Despite the extensive loss of input from both ventral and dorsal visual pathways of one hemisphere, pediatric patients who have undergone hemispherectomy show a remarkably high degree of perceptual function across many domains. In the current study, we sought to understand the extent to which functions of the ventral and dorsal visual pathways reorganize to the contralateral hemisphere following childhood hemispherectomy. To this end, we collected fMRI data from an equal number of left and right hemispherectomy patients who completed tasks that typically elicit lateralized responses from the ventral or the dorsal pathway, namely, word (left ventral), face (right ventral), tool (left dorsal), and global form (right dorsal) perception. Overall, there was greater evidence of functional reorganization in the ventral pathway than in the dorsal pathway. Importantly, because ventral and dorsal reorganization was tested in the very same patients, these results cannot be explained by idiosyncratic factors such as disease etiology, age at the time of surgery, or age at testing. These findings suggest that because the dorsal pathway may mature earlier, it may have a shorter developmental window of plasticity than the ventral pathway and, hence, be less malleable.
PubMed: 37577633
DOI: 10.1101/2023.08.03.551494 -
Journal of Anatomy Dec 2023Mormyridae are well known and intensively studied for their weak electric organ discharges, which facilitate communication and orientation. The Gemminger bones of...
Mormyridae are well known and intensively studied for their weak electric organ discharges, which facilitate communication and orientation. The Gemminger bones of Mormyridae are located next to the electrical organ in the caudal peduncle; however, they have not attracted much interest until recently. Therefore, we investigated the diversity of Gemminger bones in mormyrids and studied their ontogenetic development in Mormyrus rume proboscirostris. Gemminger bones are paired, thin, elongated ossifications lying on the dorsal and ventral sides of the caudal peduncle, and usually reach anterior well below the dorsal and anal fin bases. Ontogeny revealed that they are not intermuscular ossifications, as suspected based on the anatomical position of this structure and the systematic position of the mormyrids. Instead, they are membrane ossifications that originate from the fin stays of the dorsal and anal fins.
Topics: Animals; Electric Fish; Bone and Bones; Osteogenesis
PubMed: 37491873
DOI: 10.1111/joa.13935