An Overview of Oral Pain : Orofacial Pain and Concomitant Symptoms

口の痛みには歯原性歯痛・非歯原性歯痛などがある。前者は歯を原因とする歯痛であり，従来の歯科治療（つまり歯を削る・抜くなど）によって対応可能で，これまで問題視されることはなかった。後者は歯を原因としない歯痛であり，従来の歯科治療は奏効し難く，対応に苦慮することが多い。これに鑑み，米国において新しい疾患概念「口腔顔面痛」が提唱され，本邦においても，その対策は喫緊の課題とされる。また，口腔顔面痛は随伴症状を有することも多い。その原因や症状は歯科領域に止まらず，内科・外科・精神神経科領域など多岐にわたり，的確な判断と対応が求められる。Oral pain may be due to odontogenic toothache, non-odontogenic toothache, or other causes. Odontogenic toothaches can be resolved by conventional dental treatments, but non-odontogenic toothaches are refractory to such treatments; dental practitioners have not yet devised a way to deal with them. In light of these circumstances, a new disease concept, orofacial pain（OFP）, was advocated in the United States. OFP is an urgent issue to be resolved in Japan, too. Individuals with OFP frequently present with concomitant symptoms, and these causes and symptoms of OFP are associated not only with dentistry but also fields of study such as medicine, surgery, and psychology. Appropriate clinical judgements and actions are required to deal with cases of OFP

ゼッツウ オ ウッタエル カンジャ ニツイテ カンガエル : ゼッツウショウ オ チュウシン ニ

Many patients with tongue pain are frequently found in clinics of oral medicine and surgery. There is a possibility that they include various diseases such as glossitis, tongue tumor, tongue trauma, anemia, neuralgia, oral infection, xerostomia, temporomandibular disorder, galvanism, irritant substance and glossodynia. We conducted a survey on the clinical status of 58 patients with tongue pain, and found that they consisted of 30 cases of oral candidiasis, 17 cases of oral xerostomia, 16 cases of glossodynia, 13 cases of glossitis and so on in order of prevalence. Further survey on these patients with oral candidiasis and xerostomia revealed that a large number of patients suffering from oral candidiasis had no clinical appearance in their tongues, and those of xerostomia didn't complain of thirst. Thus, because all these patients without any symptoms except for tongue pain might be diagnosed and treated as glossodynia, thorough examination such as cultivation and salivation tests should be performed in these patients. Next, we employed a novel approach to diagnose glossodynia based on heart rate variability. We examined whether or not heart rate variability reflects curative effects of linear polarized near-infrared light irradiation near stellate ganglion. The result showed that a time-dependent change of autonomic activity correlated with that of VAS value. These findings suggest that heart rate variability is useful for monitoring curative effects and estimation of prognosis

ビスコクラウリン型アルカロイドであるセファランチンは、1次性シェーグレン症候群患者の唾液分泌量を著明に増加させる

Objective: Our previous findings suggested that the suppression of tumor necrosis factoralpha (TNF-α)-induced matrix metalloproteinase (MMP)-9 production by the biscoclaurine alkaloid cepharanthine could prevent the destruction of the acinar structure in the salivary glands of murine Sjögren's syndrome. Here, we examined the effect of cepharanthine on the salivary secretion in primary Sjögren's syndrome (pSS) patients. Methods: In this single-center, open-label pilot study, 29 patients with pSS (28 women, 1 man) received 6 mg/day orally cepharanthine for 12 months. Standard clinical assessments and stimulated salivary flow were examined at baseline and each month for 12 months in all 29 patients. In eight of the patients, inflammatory lesions in the salivary glands were histologically investigated before and after the cepharanthine treatment. We analyzed the expressions of p65, phosphorylated IκB-α, MMP-9, and type IV collagen immunohistochemically. Results: All patients completed the study without any adverse events. A significant increase in salivary flow was observed after the cepharanthine treatment compared to baseline. The serological analysis revealed that the 14 patients with an anti-Sjögren's-syndrome-related antigen A (anti-SSA/Ro) antibody value that was either negative or 64 U/ml did not. The immunohistochemical analysis demonstrated that although p65, phosphorylated IκB-α, and MMP-9 were more strongly stained in the acinar cells of the patients at baseline compared to the staining at the completion of cepharanthine treatment, the continuity of type IV collagen was observed following the cepharanthine treatment. These results indicate that cepharanthine could inhibit the phosphorylation of IκB-α, followed by the prevention of MMP-9 activation and the stabilization of type IV collagen. Conclusions: Our findings suggest that cepharanthine could be a promising agent for improving salivary secretion in pSS patients

Reconsideration of Diagnosis of Glossalgia

舌の痛みを伴う疾患（舌痛関連疾患）は数多く，それらを正確に鑑別診断することは必ずしも容易ではない。なかでも，舌痛症は舌痛などの舌症状を訴えるものの，それに見合う肉眼的変化がないものとされ，一次性（原因が明らかでないもの）と二次性（原因が明らかなもの）に分類される。二次性舌痛症は原因療法によって緩解または治癒が期待されるが，奏効しないこともある。今般，われわれが経験した五苓散（ゴレイサン）と加工附子末（ブシマツ）製剤を併用した本症の3例を参考にして，舌痛症の診断を考察した。 患者は女性3名，53～78歳，舌痛を自覚して来院した。二次性舌痛症（口腔乾燥症）の診断下に五苓散が投与されるも著変なかった。次いで，加工附子末製剤が投与されると，痛みは緩解した。これら漢方薬の併用は本症に対して有効であった。したがって，本症例の病態は口腔乾燥よりも難治性の痛みが反映されているものと考えられた。There are many kinds of diseases that can cause glossalgia, and it is not always easy to determine the differential diagnosis. Glossalgia is characterized by tongue pain without pathological changes, and divided into primary and secondary glossalgia. Secondary glossalgia is defined as glossalgia that has a clear cause. Causal therapies for secondary glossalgia are expected to relieve or cure its symptoms; however, they do not produce favorable responses in refractory cases. We treated several patients with secondary glossalgia treated with concomitant goreisan and powdered processed aconite roots (PA), and considered diagnosis of glossalgia. The patients were 3 females aged 53 to 78 years who presented at our hospital due to glossalgia. They were diagnosed with secondary glossalgia caused by xerostomia. The administration of goreisan did not produce a favorable response in any of these patients. The addition of PA remarkably relieved the glossalgia in each patient. This concomitant medicines may be useful for secondary glossalgia. Therefore, pathological conditions of these cases may be featured by intractable pain rather than xerostomia

MMP-9 Inhibition Suppresses Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells

Gene expression profiling of lip salivary gland (LSG) has shown that C-X-C motif chemokine 10 (CXCL10) and matrix metalloproteinase 9 (MMP9) expression is up-regulated in primary Sjögren's syndrome (pSS) patients. Although CXCL10 and MMP-9 are both associated with pSS pathogenesis, the potential relationship between these two factors has not been investigated. In this study, we used LSG sections from pSS patients and human salivary gland cell lines to investigate the relationship between CXCL10 and MMP-9. Immunofluorescence analyses revealed that CXCL10 and MMP-9 were co-expressed in the LSG of pSS patients, particularly in expanded ductal cells. Furthermore, RT-qPCR analyses on human salivary gland ductal NS-SV-DC cells confirmed that CXCL10 expression was induced by interferon (IFN)-γ, whereas that of MMP9 was stimulated by IFN-α, tumor necrosis factor-α, and interleukin 1β. Remarkably, MMP-9 inhibition in IFN-γ-stimulated NS-SV-DC cells significantly decreased CXCL10 mRNA and secreted protein levels. Further analyses established that MMP-9 inhibition in IFN-γ-stimulated NS-SV-DC cells decreased STAT1 phosphorylation and hence suppressed IFN-γ signaling. Collectively, these results suggest that in addition to its reported role in the destruction of acinar structures, MMP-9 is involved in the IFN-γ-induced production of CXCL10 in pSS lesions. We believe that our findings open the door to the development of novel treatments for pSS, based on the modulation of MMP-9 activity

Baricitinib Inhibits CXCL10 Production in Salivary Gland Cells

Sjögren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n=12) and healthy controls (n=3). We then evaluated effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS

Management of tooth extraction in a patient with ELANE gene mutation-induced cyclic neutropenia

Introduction: Cyclic neutropenia (CyN) is a rare hematological disease, and patients with CyN often experience an early onset of severe periodontitis and are forced to undergo tooth extraction. Here, we report a case of a patient with CyN who showed different periodicity and oscillations of neutrophil count compared with her mother, despite sharing the same novel genetic mutation. Patient concerns: A 17-year-old Japanese girl who had been diagnosed with CyN shortly after birth presented to our hospital with a complaint of mobility of her teeth and gingivitis. Upon presentation, an intraoral examination was performed and revealed redness and swelling of the marginal and attached gingiva. Radiographs revealed extreme resorption of the alveolar bone and apical lesions in her mandibular lateral incisors. The patient's hematologic data demonstrated a lack of blood neutrophils (0/μL). The patient had no history of dental extraction, and her mother also had a history of CyN. Diagnoses: The patient was diagnosed with severe periodontitis that was associated with CyN. Gene testing showed a novel heterozygous mutation in exon 4 of the ELANE gene (c.538delC, p.Leu180Ser fsX11). Interventions: Based on the clinical findings, we planned to extract the patient's mandibular lateral incisors. Although the tooth extraction was scheduled considering the cyclic variation in neutrophil count, the patient's neutrophil count was 0/μL on the day before the planned extraction. Therefore, granulocyte-colony stimulating factor (G-CSF) was administered to increase the patient's neutrophil count. On the day of the patient's admission for the tooth extraction, she presented with fever (body temperature, 38.5°C), tonsillitis, and stomatitis. The extraction was subsequently delayed, and the patient was administered antibiotics and G-CSF for 4 days. At this time, the neutrophil count increased to 750/μL, and the tooth extraction was carried out safely. Outcomes: The postoperative course was uneventful, and the healing process at the extraction site was excellent. Conclusion: There is a possibility that the periodicity and oscillations of neutrophil count may change with growth in patients with CyN. Therefore, it is important to frequently examine and treat patients with fluctuating neutrophil levels for the management of invasive dental treatment in patients with CyN

Prediction of Tsunami and Related Damage to Dental Clinics Caused by the Nankai Trough Earthquake in the Tokushima Prefecture

発災が危惧されている南海トラフ大地震において，徳島県は甚大な被害を受ける可能性が高く，歯科医療分野においても同様である。発災時に歯科医院等が多数被害を受け，災害時に求められる歯科の役割を果たすのに支障をきたす可能性もある。そこでわれわれはGISを用いて，歯科医院の浸水被害予測や発災後に必要な歯科医師数などのシミュレーションを行った。その結果，特に発災直後に大幅な人員不足が予測され，歯科的身元識別の遠隔支援などの必要性が考えられた