Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of γδ T cells.

Bisphosphonates distributed to bone exert toxic effects specifically towards osteoclasts. On the other hand, intravenous administration of a nitrogen-containing bisphosphonate (N-BP) such as zoledronate induces acute-phase reactions (APRs), including influenza-like fever 1 day later, indicating an interaction with immunocompetent cells circulating blood. Although it has been reported that activation of γδ T cells is pivotal to induce an APR following treatment with zoledronate, downstream events, including the production of inflammatory cytokines after activation of γδ T cells, remain obscure. We investigated the effects of zoledronate on inflammatory cytokine expression in human peripheral blood mononuclear cells (PBMCs) in vitro. While zoledronate induced mRNA expressions of tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and interferon-γ (IFN-γ) in PBMC, depletion of γδ T cells abolished that zoledronate-induced expression of those cytokines, indicating the necessity of γδ T cells for expression induction by zoledronate. However, which types of cells were responsible for the production of those cytokines in blood remained unclear. As it is generally accepted that monocytes and macrophages are primary sources of inflammatory cytokines, CD14+ cells from PBMC were exposed to zoledronate in the presence of PBMC, which resulted in induced expression of mRNAs for IL-1ß, IL-6 and IFN-γ, but not for TNF-α. These results indicate that CD14+ cells are responsible, at least in part, for the production of IL-1ß, IL-6 and IFN-γ in blood exposed to zoledronate. This suggests that CD14+ cells play an essential role in the occurrence of APRs following N-BP administration.

Phorbol-12-myristate 13-acetate inhibits Nephronectin gene expression via Protein kinase C alpha and c-Jun/c-Fos transcription factors.

Nephronectin (Npnt) is an extracellular matrix protein and ligand of integrin α8ß1 known to promote differentiation of osteoblasts. A search for factors that regulate Npnt gene expression in osteoblasts revealed that phorbol 12-myristate 13-acetate (PMA), which activates protein kinase C (PKC), had a strong effect to suppress that expression. Research was then conducted to elucidate the signaling pathway responsible for regulation of Npnt gene expression by PMA in osteoblasts. Treatment of MC3T3-E1 cells with PMA suppressed cell differentiation and Npnt gene expression. Effects were noted at a low concentration of PMA, and were time- and dose-dependent. Furthermore, treatment with the PKC signal inhibitor Gö6983 inhibited down-regulation of Npnt expression, while transfection with small interfering RNA (siRNA) of PKCα, c-Jun, and c-Fos suppressed that down-regulation. The present results suggest regulation of Npnt gene expression via the PKCα and c-Jun/c-Fos pathway.

Two Cases of Nonsuicidal Self-Injury Comprising Partial Autoamputation of the Apex of the Tongue.

The prevalence of nonsuicidal self-injury (NSSI) in adults is lower than that in adolescents and it is more prevalent in patients with psychiatric disorders. Sleep disturbances such as nightmares are associated with NSSI after accounting for depression; thus, persons with major NSSI sometimes present at medical institutions during the night seeking emergency treatment. Gingival tissues comprise the most frequent target of self-injury of the oral cavity using oral hygiene tools. Most NSSI in the oral cavity is minor because such tools are blunt. Major NSSI such as autoamputation of the tongue is rare. We describe two patients who partially autoamputated the apex of their own tongues using edged tools. Case 1 was a 55-year-old female with depression who had defaulted from psychiatric intervention. She had cut off her tongue using a Japanese kitchen knife and presented with the dry, necrotic amputated portion and blood oozing from the remainder of her tongue. We debrided and sutured the remainder of the tongue without reattaching the amputated portion. Her postoperative course was uneventful, and she was free of adverse events such as functional disability and wound infection. Case 2 was a 69-year-old female with schizophrenia who had defaulted from psychiatric intervention and had cut off her tongue using scissors. The amputated portion of the tongue was lost and the remainder, which was oozing blood, was debrided and sutured. She defaulted on a follow-up appointment. Neither of these patients had suicidal intent. The prevalence of NSSI across all age groups has recently increased, and the risk that self-injury will become normalized has become a concern. Thus, dentists as well as oral and maxillofacial surgeons should be aware of the possibility that patients will present with major NSSI requiring emergency treatment.