Noboru Takahashi

Long-term effect of submucous turbinectomy in patients with perennial allergic rhinitis

Objectives The long‐term effect of submucous turbinectomy for patients with perennial allergic rhinitis was assessed.

Timing for removal of tympanic ventilation tube in children

The medical records of 220 ears of 137 pediatric patients (85 male and 52 female) in which three kinds of ventilation tubes were inserted for treating otitis media with effusion (OME) were reviewed. The tubes selected were the Shepard grommet (75 ears), Goode-T (39 ears), and Paparella type II tube (106 ears). The criteria for tube placement were as follows: (1) continuous conductive hearing loss with over 25 dB air-bone gap, (2) resistance to conservative therapy for over 6 months, and (3) retracted and glue-colored tympanic membrane with type B tympanogram. The tubes that remained in place for over 18-24 months were removed intentionally in combination with a freshening of the perforation edge and tape-patch technique using Steri-Strip tape (3M) for preventing permanent eardrum perforation, because the incidence of persistent perforation became higher after long-term intubation. Shepard grommets tended to be extruded earlier, while Paparella type II tubes tended to stay longer. The OME recurrence rate decreased 12 months or more after tubal insertion. There was a tendency for the recurrence rate to decrease the longer the tube stayed in the eardrum. The number of recurrences decreased when the patients age at the tube removal or extrusion was 7-8 years old. Adenoidectomy did not influence the recurrence rate of OME. Although the Goode-T and Paparella tube II tubes showed high perforation rates, the perforation rate after extrusion or removal of the tube was decreased by the use of the tape patch technique in combination with a freshening of the perforation edge. From these findings, it was concluded that the appropriate intubation period for the treatment of OME in children is over 12 months with the use of a long-term tube, and that if the patients age at the time of tube insertion was below 6 years, it might be better that the removal of the tube is postponed until the patient is 8 years of age.

Poly(I:C) induces BLyS-expression of airway fibroblasts through phosphatidylinositol 3-kinase

B lymphocyte stimulator (BLyS), B cell activating factor (BAFF), a member of the tumor necrosis factor ligand superfamily has potent co-stimulatory activity on B cells, and BLyS-production in the airway mucosa is of potential importance as it triggers innate and adaptive immune responses. To investigate whether airway fibroblast could express BLyS, we examined BLyS-expression in human nasal airway fibroblasts and compared to its expression in tonsillar and skin fibroblasts as well as the effect of the Toll-like receptor (TLR) ligands on that in human nasal airway fibroblasts. The expression of BLyS by nasal fibroblasts in the presence of polyinocinic-polycytidykic acid (poly(I:C)) was markedly induced, to a level of more than 100 times higher than that observed in the absence of poly(I:C). In order to demonstrate the intracellular pathways involved in poly(I:C)-induced BLyS-expression, we used specific inhibitors of phosphatidylinositol 3-kinase (PI3-kinase), spleen tyrosine kinase (Syk), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and extracellular-signal related kinase (ERK)-signaling in these events. Pre-incubation with the PI3-kinase inhibitor LY294002 or Wortmanin reversed the poly(I:C)-induced production and expression of BLyS. Syk kinase inhibitor Piceatannol partially reduced its production and expression. Thus, we were able to show that PI3-kinase signaling is directly involved in poly(I:C)-induced BLyS-expression in nasal airway fibroblasts. These results indicate that human nasal airway fibroblasts strongly induce BLyS-expression and production by poly(I:C) through PI3-K signaling during airway immune responses.

Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancer.

To elucidate the molecular mechanisms for the enhancement of heat-induced apoptosis on exposure to acidic conditions, human maxillary carcinoma IMC-3 cells were heat-shocked at 44°C for 30 min at either pH 7.4 or 6.7. Analyses with cDNA arrays, the reverse transcription–polymerase chain reaction (RT–PCR), and Western blotting were performed. We found that histone deacetylase 3 (HDAC3) was specifically induced after hyperthermia at 44°C for 30 min at pH 6.7. Although the cytotoxicity of heating at 44°C for 30 min was enhanced by decreasing the pH from 7.4 to 6.7, it was enhanced even more by antisense RNA oligonucleotides for HDAC3. The induction of G2/M arrest after heating occurred earlier at pH 6.7 than at pH 7.4. The inhibition of HDAC3 by the antisense RNA oligonucleotides suppressed partially the induction of G2/M arrest, resulting in an enhancement of the apoptosis caused by the heating under acidic conditions. Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 43°C for 30 min in vivo. Analyses of p65 activity suggested that NF-κB is involved in this enhancement of hyperthermia. HDAC3 may be a novel target enhancing hyperthermia and combined treatment with hyperthermia and HDAC inhibitors is a possible modality for cancer therapy.

Lipopolysaccharides increase the amount of CXCR4, and modulate the morphology and invasive activity of oral cancer cells in a CXCL12-dependent manner.

Recently, it has been reported that bacterial infections play an important role in the development of cancers of the upper aero digestive tract. To examine the influence of bacterial infections on oral cancer, human oral carcinoma T3M-1 cells were treated with lipopolysaccharide (LPS) for 24 h as a model of infection. The LPS treatment increased the mRNA expression of CXCR4 and invasiveness in T3M-1 cells stimulated with CXCL12. The Rho family of small guanosine triphosphatases regulates the dynamics of the actin cytoskeleton that underlie cellular functions such as cell shape changes, migration and polarity. In T3M-1 cells treated with LPS and stimulated with CXCL12, Rac and Cdc42 were activated and caused an increase in the development of filopodia. The present findings suggest that bacterial infections enhance the invasiveness of T3M-1 cells via CXCL12/CXCR4 interaction and Cdc42-activation. Furthermore, filopodia are critical to this process.

Nasal challenge activates the mucociliary transport system on not only the ipsilateral but also the contralateral side of the nose in patients with perennial allergic rhinitis.

It is controversial whether the mucociliary transport system in the nasal mucosa of persons with allergic rhinitis is upregulated after an allergen challenge in vivo. The aim of this study was to assess the effect of a specific allergen challenge on the mucociliary transport system in allergic rhinitis. We used a challenge of house dust mites or a control substance on one side of the nose of 97 volunteers (54 with allergic rhinitis for house dust mites and 43 without allergies). The mucociliary transport system of the ipsilateral or contralateral side of the nose challenged was evaluated using the saccharin clearance time on the right side of the nose. The saccharin clearance time was significantly shortened after an allergen challenge not only on the ipsilateral (right) side of the nose (from 15.0 ± 11.6 to 10. 9 ± 9.2 min, mean ± SD, p = 0.041) but also on the contralateral (left) side of the nose (from 14.7 ± 10.1 to 8.1 ± 7.9 min, p = 0.013) in the allergic group. A reduction of the saccharin clearance time was also seen in the allergic group after a control challenge [ipsilateral (right) challenge: from 13.0 ± 10.0 to 11.6 ± 10.6 min, contralateral (left) challenge: from 13.5 ± 9.0 to 10.2 ± 10.1 min]. There were no reductions of the saccharin clearance time after an allergen or control challenge in the nonallergic groups. These results suggest that a unilateral nasal challenge accelerates the mucociliary transport system bilaterally in the nose of subjects with a hypersensitivity such as allergic rhinitis.

Infection of Haemophilus parainfluenzae in tonsils is associated with IgA nephropathy

We investigated the functions of tonsillar mononuclear cells (TMC) regarding whether a Haemophilus parainfluenzae (HP) outer membranes antigen (HPOM) enhances IgA-related cytokine (IFN-γ, IL-10, and TGF-β) production in vitro by TMC in IgA nephropathy (IgAN) patients. In addition, we examined the effect of synthetic oligodeoxynucleotide and HPOM stimulation by TMC on IgA production, whether the constant region antisense to IgA inhibits the production of IgA in vitro by TMC. Eighteen patients with IgAN and 25 patients with chronic tonsillitis (CT) from 6 to 45 years (mean age of 20.9 years) participated in this study. TMC were obtained from resected tonsils, and total and HP-specific IgA levels, along with the concentration of TGF-β, IL-10 and IFN-γ in the supernatant of stimulated TMC were measured by ELISA. Isolated TMC were cultured with HPOM in the presence of 23 oligodeoxynucleotides (ODNs), and the induction of total IgA and HP-specific IgA in the supernatant was also measured using ELISA. To investigate the inhibition of IgA production, TMC were cultured with HPOM and antisence to IgA. We found that IgA-related cytokine (IFN-γ, IL-10, and TGF-β) production by unstimulated or stimulated TMC was higher in IgAN patients than CT patients. Two types of synthetic oligodeoxynucleotides produced higher HP-specific IgA than with HPOM stimulation alone. HPOM and antisence IgA inhibited the production of total IgA and HP-specific IgA in dose-depend manner. In conclusion, IFN-γ, TGF-β, and IL-10 influence each other in the pathogenesis of IgAN, and infection by not only HP but other bacteria or viruses which possess specific DNA sequences such as CpG motifs induce the production of HP-specific IgA by TMC.

Psychogenic Hearing Loss with Panic Anxiety Attack after the Onset of Acute Inner Ear Disorder

A very rare case of a 50-year-old female showing psychogenic hearing loss with a panic anxiety attack that complicated an acute organic sensorineural hearing loss is reported. At the first visit to our clinic, the patient showed left sensorineural hearing loss with an inner ear disorder pattern. Five days after the onset, her left hearing threshold markedly increased without any subjective signs. On the next day, she suddenly experienced a severe panic attack with anxiety. After the attack, she felt mildly anxious and depressed. A combined therapy using primary corticosteroid therapy for the acute inner ear disorder, psychiatric counseling based on cognitive therapy and the administration of a minor tranquilizer was performed. Her left hearing threshold recovered to within normal ranges except in the high-frequency ranges immediately after the treatment. This case was considered very rare because: (1) the panic anxiety attack occurred in the conversion disorder as psychogenic hearing loss and (2) the psychogenic hearing loss complicated the primary sudden deafness. We suggest that otorhinolaryngologists should have psychiatric knowledge and be able to treat psychogenic hearing loss as a primary care.

Suppression of histone deacetylase 3 (HDAC3) enhances apoptosis induced by paclitaxel in human maxillary cancer cells in vitro and in vivo.

Inclusion of chemotherapeutic drugs in treatment of patients with newly diagnosed head and neck cancer has improved response rates and prolonged median survival. Nevertheless, most patients with advanced head and neck cancer are destined to relapse and to develop resistance to initially used drugs such as paclitaxel. Consequently, it has been more important in cancer therapy to determine the molecular mechanisms that are related to cell-killing effects of anti-cancer agents or cancer resistance against them. Consequently, we examined whether abrogation of histone deacetylase 3 (HDAC3) expression by anti-sense oligonucleotides (ASOs) potentiates the efficacy of paclitaxel in human maxillary cancer IMC-3 cells. Here, we showed that paclitaxel-induced apoptosis was enhanced significantly by addition of ASOs for HDAC3 in cultured cells. Furthermore, paclitaxel-induced apoptosis in IMC-3 tumors transplanted in nude mice was enhanced significantly by administration of ASOs for HDAC3, thereby suppressing tumor growth. We provide new evidence that HDAC3 is a novel molecular target whose inactivation can potentiate the efficacy of anti-cancer drugs disrupting microtubules such as paclitaxel.

Long-term sublingual immunotherapy for Japanese cedar pollinosis and the levels of IL-17A and complement components 3a and 5a

Allergen-specific immunotherapy is the only treatment that can alter the natural course of allergic disease. We performed long-term sublingual immunotherapy (SLIT) for patients with seasonal allergic rhinitis caused by Japanese cedar pollen (SAR-JCP), screened molecules as candidate biomarkers, and investigated serum IL-17A and complement components 3a (C3a) and C5a in order to evaluate whether these molecules show changes correlated to symptom scores. In this study, we found that the long-term SLIT reduced the serum levels of IL-17A and C3a and C5a. The levels of C3a in the patients significantly decreased from year 1 compared with those at the baseline, and their levels of IL-17A significantly decreased from year 2 compared with those at baseline. The levels of IL-17A, C3a, and C5a at year 4 of SLIT were significantly lower than not only those at baseline, but also those at year 1. A significant positive correlation was found between the symptom medication scores and the levels of IL-17A at year 4. The symptom medication scores in the group in which IL-17A levels decreased at year 4 were significantly lower than those in the group without such a decrease. The serum level of IL-17A might prove useful as a biological parameter to ascertain the effectiveness of SLIT for patients with SAR-JCP. It is necessary to produce new therapeutics for non-responders in whom serum IL-17A levels are still higher against long-term SLIT.