Stem Cells From Human Exfoliated Deciduous Teeth Attenuate Trigeminal Neuralgia in Rats By Inhibiting Endoplasmic Reticulum Stress

The treatment of trigeminal neuralgia remains a challenging issue. Stem cells from human exfoliated deciduous teeth (SHED) provide optimized therapy for chronic pain. This study aimed to investigate the mechanisms underlying the attenuation of trigeminal neuralgia by SHED. Our findings showed that local transplantation of SHED could relieve trigeminal neuralgia in rats. Further, transmission electron microscopy revealed swelling of endoplasmic reticulum in rats with trigeminal neuralgia. Moreover, SHED inhibited the tunicamycin-induced up-regulated expression of Bip mRNA and protein in vitro. Additionally, SHED decreased the up-regulated expression of Caspase12 mRNA and protein in the trigeminal ganglion of rats caused by trigeminal neuralgia after chronic constriction injury of the infraorbital nerve mode. Our findings demonstrated that SHED could alleviate pain by relieving endoplasmic reticulum stress which provide potential basic evidence for clinical pain treatment.

The Up-regulation of TNF-α Maintains Trigeminal Neuralgia by Modulating MAPKs Phosphorylation and BKCa Channels in Trigeminal Nucleus Caudalis

Trigeminal neuralgia (TN) is a severe chronic neuropathic pain. Despite numerous available medical interventions, the therapeutic effects are not ideal. To control the pain attacks, the need for more contemporary drugs continues to be a real challenge. Our previous study reported that Ca2+-activated K+ channels (BKCa) channels modulated by mitogen-activated protein kinases (MAPKs) in the trigeminal ganglia (TG) neurons play crucial roles in regulating TN, and some research studies demonstrated that inflammatory cytokine tumor necrosis factor alpha (TNF-α) could promote neuropathic pain. Meanwhile, the trigeminal nucleus caudalis (TNC), the first central site of the trigeminal nociceptive pathway, is responsible for processing sensory and pain signals from the peripheral orofacial area. Thus, this study is aimed to further investigate whether TNF-α and MAPKs phosphorylation in the TNC could mediate the pathogenesis of TN by modulating BKCa channels. The results showed that TNF-α of the TNC region is upregulated significantly in the chronic constriction injury of infraorbital nerve (ION-CCI) rats model, which displayed persistent facial mechanical allodynia. The normal rats with target injection of exogenous TNF-α to the fourth brain ventricle behaved just like the ION-CCI model rats, the orofacial mechanical pain threshold decreased clearly. Meanwhile, the exogenous TNF-α increased the action potential frequency and reduced the BKCa currents of TNC neurons significantly, which could be reversed by U0126 and SB203580, the inhibitors of MAPK. In addition, U0126, SB203580, and another MAPK inhibitor SP600125 could relieve the facial mechanical allodynia by being injected into the fourth brain ventricle of ION-CCI model rats, respectively. Taken together, our work suggests that the upregulation of TNF-α in the TNC region would cause the increase of MAPKs phosphorylation and then the negative regulation of BKCa channels, resulting in the TN.

Comparison of Functional Recovery of Infraorbital Nerve Paresthesia Following Open and Closed Reduction of Zygomaticomaxillary Complex Fractures

Objective: To compare the functional recovery of infraorbital nerve paresthesia following open reduction as compared to closed reduction in zygomaticomaxillary complex fracture management. Study Design: Randomized controlled trial. Place and Duration of Study: Oral and Maxillofacial Surgery Dept. Dentistry Section, Ayub Medical College & Teaching Hospital, Abbottabad from 1st April 2016 to 30th September 2016. Methodology: Eighty two patients of infraorbital nerve recovery were included. They were divided in two groups; group A was treated by closed reduction technique, and group B was treated by open reduction with internal fixation technique using mini plates. Permuted blocks of 6 were used to ensure equal representation in both groups. All patients were underwent surgical management within 1-7 days following trauma. Patients were assessed post-surgery for infraorbital nerve recovery. Results: There were 63.4% males and 36.6% females in group A while 60.9% males and 39.1% females were included in group B with mean age was 28.44±7.15 years in group A and 27.93±7.33 in group B respectively. 51.2% patients have infraorbial nerve recovery in group A while 65.8% have infraorbital nerve recovery in group B. Conclusion: Closed reduction approach was found to be the best reduction technique and open reduction was effective in terms of stability, prevention of relaps and functional recovery of infraorbital nerve injuries. Key words: Functional recovery, Infraorbital nerve, Paresthesia, Closed reduction, Zygomaticomaxillary complex fracture

Cavernous Hemangioma in the Orbital Cavity: Case Report

Cavernous hemangiomas are benign malformations of vascular origin, usually well circumscribed and slow to grow. These lesions can be asymptomatic, being discovered unintentionally in imaging exams or symptomatic, indicated mainly by the presence of proptosis, diplopia, and visual disturbances by optic nerve compression. The complementary exams involve computed tomography associated with contrast, color Doppler, magnetic resonance, and angiography. Treatment can be conservative or surgical depending on the case, and the open therapy usually involves lateral, supraorbital, transconjunctival, transantral, pterional, transnasal, and extradural endoscopic orbitotomy. The present study aims to report a recurrent case of hemangioma in the orbital cavity signaled by ocular proptosis, hyperemia, and ocular pain.The lesion was achieved through the Weber-Ferguson access with zygomatic osteotomy and preservation of the infraorbital nerve. The excision of the lesion was performed, and the previously displaced fragments were fixed with 1.5 mm mini plates. The patient has a chance of progressing with visual impairment due to considerable manipulation of the optic nerve and is being followed up.The reported case showed a successful diagnosis and therapeutic conduct, remaining now in the evolution and follow-up scenario.

Tissue-resident M2 macrophages directly contact primary sensory neurons in the sensory ganglia after nerve injury

Background Macrophages in the peripheral nervous system are key players in the repair of nerve tissue and the development of neuropathic pain due to peripheral nerve injury. However, there is a lack of information on the origin and morphological features of macrophages in sensory ganglia after peripheral nerve injury, unlike those in the brain and spinal cord. We analyzed the origin and morphological features of sensory ganglionic macrophages after nerve ligation or transection using wild-type mice and mice with bone-marrow cell transplants. Methods After protecting the head of C57BL/6J mice with lead caps, they were irradiated and transplanted with bone-marrow-derived cells from GFP transgenic mice. The infraorbital nerve of a branch of the trigeminal nerve of wild-type mice was ligated or the infraorbital nerve of GFP-positive bone-marrow-cell-transplanted mice was transected. After immunostaining the trigeminal ganglion, the structures of the ganglionic macrophages, neurons, and satellite glial cells were analyzed using two-dimensional or three-dimensional images. Results The number of damaged neurons in the trigeminal ganglion increased from day 1 after infraorbital nerve ligation. Ganglionic macrophages proliferated from days 3 to 5. Furthermore, the numbers of macrophages increased from days 3 to 15. Bone-marrow-derived macrophages increased on day 7 after the infraorbital nerve was transected in the trigeminal ganglion of GFP-positive bone-marrow-cell-transplanted mice but most of the ganglionic macrophages were composed of tissue-resident cells. On day 7 after infraorbital nerve ligation, ganglionic macrophages increased in volume, extended their processes between the neurons and satellite glial cells, and contacted these neurons. Most of the ganglionic macrophages showed an M2 phenotype when contact was observed, and little neuronal cell death occurred. Conclusion Most of the macrophages that appear after a nerve injury are tissue-resident, and these make direct contact with damaged neurons that act in a tissue-protective manner in the M2 phenotype. These results imply that tissue-resident macrophages signal to neurons directly through physical contact.

IgG4-related disease in patients with idiopathic orbital inflammation

Background To identify the prevalence of positive IgG4 immunostaining in orbital tissue among patients previously diagnosed with nongranulomatous idiopathic orbital inflammation (IOI) and to compare the clinical characteristics of patients with and without IgG4-positive cells. Methods A retrospective review of all patients with a histopathologic diagnosis of IOI was performed. Immunohistochemical staining was performed to identify IgG-positive cells and IgG4-positive cells. Multivariate analysis was performed using likelihood ratio-test logistic regression on the differences between IgG4-related disease (IgG4-RD) and non-IgG4-RD. Results Of the 45 patients included, 21 patients (46.7%) had IgG4-positive cells, with 52.4% being male and a mean age of 55.9 ± 13.4 years. Bilateral ocular adnexal involvement (adjusted odds ratio [aOR] = 9.45; P = 0.016) and infraorbital nerve enlargement (aOR = 12.11; P = 0.008) were frequently found in IgG4-RD patients. Complete remission occurred in 23.8% of IgG4-RD patients and 41.7% of non-IgG4-RD patients. IgG4-RD patients had more frequent recurrent disease than non-IgG4-RD patients. Conclusions Nearly 50% of IgG4-RD patients were previously diagnosed with biopsy-proven IOI. IgG4-RD was more frequent in patients with bilateral disease and infraorbital nerve enlargement, showing the importance of tissue biopsy in these patients. Immunohistochemistry studies of all histopathology slides showing nongranulomatous IOI are highly recommended to evaluate for IgG4-RD.

Malignancies in Immunoglobulin G4-Related Ophthalmic Disease

Purpose: Clinical phenotypes in Immunoglobulin G4-related disease (IgG4-RD) according to the affected organs affected have different risks of malignancies. We attempt to determine the association of malignances with IgG4-related ophthalmic disease (IgG4-ROD). Design: Retrospective cohort study. Methods: Review of medical records, orbital images and histopathology reports in a territory-wide cohort of patients fulfilling the “probable” or “definite” comprehensive diagnostic criteria of IgG4-RD from 2005-2019. Findings: Among 122 patients who had biopsies taken from adnexal lesions including lacrimal glands (n=108), orbital mass (n=30), infiltrated orbital fat (n=10), conjunctiva (n=2) or extraocular muscles (n=3), 16 (13%) developed malignancies over 73±48months’ follow-up. There were 9 cases of ocular adnexal lymphoma (OAL) and 7 extra-orbital malignancies. Compared with the general population, the incidence of OAL was significantly higher (standardized incidence ratios, SIRs=10.0, 95%CI=4.5-17.6) while that of extraorbital malignancy was similar. The SIR was highest within the first year (SIR=46.7, 95%CI=18.5-87.6) when 7 OAL were concomitantly diagnosed. Patients who developed OAL or extra-orbital malignancies were older than other patients when diagnosed of IgG4-ROD (64.9±7.1, 68.3±8.5 versus 55.2±15.0 years, p<0.05). Asymmetric lacrimal gland enlargement (78% versus 13%), lack of frontal (0% versus 12%) or infraorbital nerve enlargement (0% versus 36%)were associated with OAL (all p<0.05). Pre-treatment serum IgG4 level or pattern of extraorbital involvement was similar among patients with or without malignancies. Conclusion: In this biopsy-proven IgG4-ROD cohort, 7% developed OAL which was 10 times higher than the general population. Patients with asymmetric lacrimal gland enlargement or without trigeminal nerves involvement radiologically were associated with OAL.

Down-regulation of MAPK pathway alleviates TRPV4-mediated trigeminal neuralgia by inhibiting the activation of histone acetylation

Our objective of this study is to determine the molecular mechanism of MAPKs (mitogen activated protein kinase systems) on TRPV4 (transient receptor potential vanilloid 4)-mediated trigeminal neuralgia (TN). Partial chronic constriction injury of the infraorbital nerve (CCI-ION) ligation model was used in this research. When treated with antagonists of p38, JNK or ERK, the mechanical hyperalgesia threshold, nerve fiber disorder, myelinoclasis, and Schwann cells proliferation could be reversed. RT-PCR (real-time quantitative polymerase chain reaction), Western blot and IHC (immunohistochemistry) showed that TRPV4 mRNA and protein levels, TRPV4-positive cells and small positive neurons decreased remarkably in TN group treated with antagonists of p38, JNK or ERK. ELISA (enzyme-linked immunosorbent assay) was performed to discover inhibition of MAPK pathway can down-regulate the expression of HATs (histone acetyltransferases), and up-regulate the expression of HDACs (histone deacetylases) in TN, thus inhibiting histone acetylation. Finally, Western blot was performed to identify the phosphorylation status of p38, JNK and ERK, finding decreased phosphorylation forms in antagonists treated TN groups compared with TN groups. Based on the above investigation method, on a whole, our study showed that down-regulation of MAPK pathway could alleviate TRPV4-mediated trigeminal neuralgia, via inhibiting the activation of histone acetylation.