Yuji Nakamaru

A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9

Inappropriate elevation of matrix metalloproteinase‐9 (MMP9) is reported to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The object of this study was to identify the molecular mechanism underlying this increase of MMP9 expression, and here we show that oxidative stress‐dependent reduction of a protein deacetylase, SIRT1, known as a putative antiaging enzyme, causes elevation of MMP9 expression. A sirtuin inhibitor, splitomycin, and SIRT1 knockdown by RNA interference led an increase in MMP9 expression in human monocytic U937 cells and in primary sputum macrophages, which was detected by RT‐PCR, Western blot, activity assay, and zymography. In fact, the SIRT1 level was significantly decreased in peripheral lungs of patients with COPD, and this increase was inversely correlated with MMP9 expression and MMP9 promoter activation detected by a chromatin immunoprecipitation assay. H2O2 reduced SIRT1 expression and activity in U937 cells;furthermore, cigarette smoke exposure also caused reduction of SIRT1 expression in lung tissue of A/J mice, with concomitant elevation of MMP9. Intranasal treatment of a selective and novel SIRT1 small molecule activator, SRT2172, blocked the increase of MMP9 expression in the lung as well as pulmonary neutrophilia and the reduction in exercise tolerance. Thus, SIRT1 is a negative regulator of MMP9 expression, and SIRT1 activation is implicated as a novel therapeutic approach to treating chronic inflammatory diseases, in which MMP9 is abundant.— Nakamaru, Y., Vuppusetty, C., Wada, H., Milne, J. C., Ito, M., Rossios, C., Elliot, M., Hogg, J., Kharitonov, S., Goto, H., Bemis, J. E., Elliott, P., Barnes, P. J., Ito, K. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase‐9. FASEB J. 23, 2810–2819 (2009).www.fasebj.org

Otologic Manifestations of Wegener's Granulomatosis

Objective/Hypothesis To evaluate the clinical features, treatment, and outcomes of otologic manifestations in Wegeners granulomatosis (WG) treated at Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Voice-Related Quality of Life After Treatment of Laryngeal Cancer

OBJECTIVE To determine patient-perceived voice-related quality of life in patients treated with various methods based on the results of Voice-Related Quality of Life (VRQOL) and Voice Handicap Index-10 (VHI-10) questionnaires. DESIGN The VRQOL and VHI-10 questionnaires. SETTING University hospital. PATIENTS One hundred thirty-seven patients who had received definitive treatment of laryngeal cancer were followed-up at Hokkaido University Hospital, Sapporo, Japan, and were alive with no evidence of malignancy at the time of the survey. MAIN OUTCOME MEASURE Patient-perceived voice-related quality of life based on the results of the VRQOL and VHI-10 questionnaires. RESULTS The mean VRQOL scores for patients who had undergone radiotherapy (n = 63), chemoradiotherapy (n = 29), laser surgery (n = 14), or total laryngectomy (n = 27) as final treatment of laryngeal cancer were 92.6, 92.9, 85.5, and 68.4, respectively; the mean VHI-10 scores were 2.87, 2.34, 5.43, and 11.26, respectively. CONCLUSION The VRQOL and VHI-10 questionnaires are important in judging the overall effectiveness of treatment options for laryngeal cancer.

Sublingual Immunotherapy with House Dust Extract for House Dust-Mite Allergic Rhinitis in Children

BACKGROUND House dust extract is used in conventional immunotherapy for house dust-mite (HDM) allergic rhinitis in Japan. However, an alternative administration route is desired. The aims of the present double blind, placebo-controlled trial were to evaluate the therapeutic efficacy and safety of sublingual immunotherapy (SLIT) with house dust extract in pediatric patients with HDM allergic rhinitis. METHODS The study population comprised 31 subjects (21 males and 10 females) aged from 7 to 15 years old. Twenty patients (the active group) received house dust extract and 11 received placebo via sublingual administration. Extract or placebo (1 ml) was administered at 10-fold dilution once weekly for 40 weeks. During the study period, the subjects recorded their daily nasal symptoms and use (dose and frequency) of other medications in a nasal allergy diary. RESULTS The symptom scores in the active group began to decrease about 24 weeks after initiation of treatment and significant differences between the active and placebo groups were observed after 30 weeks. The average scores for the last four weeks of the study were significantly lower than those for the first four weeks in the active group but not in the placebo group. The only local adverse effect was a bitter taste reported by one patient. There were no other local or systemic adverse effects associated with SLIT. CONCLUSIONS Our results suggest that SLIT with house dust extract for more than 30 weeks is safe and effective treatment for HDM allergic rhinitis in children.

Diagnosis of the elongated styloid process by three-dimensional computed tomography

OBJECTIVE To examine whether the styloid process can be imaged by three-dimensional computer tomography reconstruction (3-DCT) distinctly enough to be used for diagnosis, and whether the image findings are explanatory of the symptoms. METHODS We performed 3-DCT in four patients suspected to have elongated styloid process in our hospital. The apparatus we used was X-vigor (Toshiba), and the processing software was X-tension; the slicing thickness was 1.0 mm and the shifting speed of CT table was 1.0 mm per rotation. One hundred and twenty images were reconstructed for a view. RESULTS In all cases, the 3-DCT showed the exact full length of the styloid process. Two cases were diagnosed as elongation of the styloid process by 3-DCT and their image findings were explanatory of the symptoms. In other two cases, the 3-DCT showed no difference between the right and the left styloid processes, and thus the diagnosis of elongation of the styloid process had to be excluded. CONCLUSION We suggest that 3-DCT is useful for the diagnosis, explanation to patients and selection of treatment in some cases of elongated styloid process, but further study in more cases is required before we can fully confirm the utility.

Nasal manifestations of immunoglobulin G4‐related disease

Immunoglobulin (Ig)G4‐related disease is a systemic syndrome, characterized by sclerosing lesions that mainly affect the exocrine tissue. Although some patients with IgG4‐related disease complain of nasal symptoms, there are few reports concerning the nasal manifestations of this disease. We investigated the clinical and pathological features of the nasal manifestations of IgG4‐related disease.

Immunological Hyperresponsiveness in HTLV-I LTR-env-pX Transgenic Rats: A Prototype Animal Model for Collagen Vascular and HTLV-I-Related Inflammatory Diseases

We have earlier reported that diverse collagen vascular diseases, including arthritis, arteritis, thrombosis, myocarditis, myositis, sialo-/dacryoadenitis and dermatitis develop with the advent of autoantibodies in transgenic rats carrying the LTR-env-pX gene of human T lymphocyte virus type I (LTR-env-pX rats). To clarify the pathogenesis of these collagen vascular diseases, immunological features of LTR-env-pX rats were examined. In LTR-env-pX rats affected with these diseases, expression of CD80/86 on both tissue-infiltrating and peripheral T cells increased, compared with findings in non-transgenic rats with experimental inflammatory diseases. CD80/86 was also upregulated on peripheral T cells in LTR-env-pX rats prior to the development of diseases. Lymphocytes from LTR-env-pX rats showed an increase in autologous proliferation and were hyperreactive against several mitogens, including concanavalin A, immobilized anti-CD3 antibodies, and superantigens in vitro. Antigen-specific immune response was also enhanced in LTR-env-pX rats. The collective evidence indicates that lymphocytes of LTR-env-pX rats constitutively express surface molecules related to T cell activation and are immunologically hyperresponsive. Bone marrow cell transfer from LTR-env-pX rats to lethally irradiated non-transgenic rats revealed that these immunologically pre-activated and hyperresponsive lymphocytes play a critical role in the pathogenesis of several collagen vascular diseases, especially of dermatitis in LTR-env-pX rats.

Immunoregulatory defects of Vα24+Vβ11+ NKT cells in development of Wegener's granulomatosis and relapsing polychondritis

The frequency of either CD4–8– (double negative; DN) or CD4+ Vα24+Vβ11+ NKT cells, the expression of CD1d and the binding of CD1d‐tetramer loaded with α‐galactosylceramide (α‐GalCer) to NKT cells were analysed in peripheral blood mononuclear cells (PBMCs) of patients with Wegeners granulomatosis (WG), relapsing polychondritis (RP) and healthy subjects (HS). DN and CD4+ Vα24+Vβ11+ NKT cells as well as CD1d‐α‐GalCer tetramer‐positive NKT cells, were significantly decreased in number in both WG and RP patients compared to those from HS. When cytokine profiles were analysed in these PBMCs upon stimulation with phorbol ester and calcium ionophore, CD4+ T cells from patients with WG and RP exhibited a Th1 bias, whereas CD4+ NKT cells from WG patients in remission showed a Th2 bias. These findings suggest that NKT cells (especially CD4+ NKT cells) play a regulatory role in Th1 autoimmunity in patients with WG and RP. The reduction in NKT cell counts appears to be associated with the low responsiveness to α‐GalCer. The dysfunction of NKT cells to recognize ligands such as α‐GalCer may also contribute to the defects observed in NKT cells from WG and RP patients.

Preoperative Staging and Surgical Approaches for Sinonasal Inverted Papilloma

Objectives: We sought to determine the value of preoperative staging by magnetic resonance imaging (MRI) assessment in the surgical management of sinonasal inverted papillomas (IPs). Methods: Preoperative MRI staging was used to assess 22 patients with IPs. In addition to the Krouse staging system, T3 cases were categorized as subgroup T3-B if tumors extended into the frontal sinus or the supraorbital recess; otherwise, they were categorized as T3-A. Standard endoscopic sinus surgery (ESS) was the first choice for T1 and T2 cases. Endoscopic approaches, including ESS combined with endoscope-assisted transantral approach and endoscopic medial maxillectomy, were considered in T3-A cases, and external approaches were considered in T3-B cases. Patients were followed for a minimum of 1 year after surgery. Results: Preoperative MRI staging and postoperative staging were coincident in 21 of the 22 patients (95%). All 8 T2 cases were treated by an endoscopic approach. Of 10 T3-A cases, 9 (90%) were treated by an endoscopic approach and 1 (residual case) was treated by an external approach. All 3 of the T3-B cases underwent an external approach. One T4 case with malignant transformation underwent an external approach followed by radiotherapy. After a median follow-up period of 22 months, none of the 22 patients had had a recurrence. No major complications were observed after endoscopic approaches, but epiphora or hemorrhage requiring transfusion occurred in 3 of the 5 patients (60%) who underwent external approaches. Conclusions: Preoperative staging of IP by MRI is useful for selecting cases that can be managed by endoscopic approaches, resulting in lower rates of tumor recurrence and morbidity.

Preservation of the nasolacrimal duct during endoscopic medial maxillectomy for sinonasal inverted papilloma.

BACKGROUND To assess the efficacy of a new endonasal medial maxillectomy technique (EMM) for the treatment of inverted papilloma (IP). METHODOLOGIES A prospective series of 55 consecutive patients diagnosed with IP between March 2002 and April 2009 were entered into this study. The new surgical technique was applied to tumors arising from the anterior part of the maxillary sinus. After conventional EMM, the entire nasolacrimal duct was separated from the bony component of the nasolacrimal canal and preserved. Schirmer`s test and a visual analog scale (VAS) score were used to assess the lacrimal duct function after surgery. RESULTS Ten of the 55 patients underwent the new surgical procedure. All patients were categorized with stage T3 or T4 tumors. No patients suffered tumor recurrence. There was no difference in lacrimal duct function between the diseased side and healthy side of the nasolacrimal duct. The mean VAS score was 2.8/100. CONCLUSIONS This new surgical technique preserves the whole length of the nasolacrimal unit. It also offers several advantages including good visualization, nasolacrimal function after surgery and fewer adverse effects such as facial numbness and epiphora.