Makoto Yokota

Modified transnasal endoscopic medial maxillectomy with medial shift of preserved inferior turbinate and nasolacrimal duct

Although transnasal endoscopic medial maxillectomy (TEMM) is effective for the treatment of inverted papilloma (IP) in maxillary sinus (MS), it involves resection of the inferior turbinate (IT). TEMM also involves resection of the nasolacrimal duct (ND) in many cases to gain better access. Therefore, we developed a novel procedure in which the preserved IT and ND are shifted medially for a complete resection of IP in the MS. Incision was made in the mucosa of the lateral wall along the anterior margin of the IT. After removal of the medial maxillary wall except the ND and the lateral nasal mucosa, the anterior lateral mucosa of the nose, including the IT and the ND, was shifted in the medial direction to allow wider access to the MS. The tumor was removed together with the attachment through the anterior side of the ND. This modified TEMM was performed in 10 patients with IP. The IT and ND were preserved in all patients. We have not observed epiphora after this surgery. The advantages of the novel approach presented herein include: 1) preservation of the IT, ND, and lateral nasal mucosa; 2) wide access to the MS by shifting the IT, ND, and lateral nasal mucosa in the medial direction; and 3) direct access to the MS through anterior space of the ND, resulting in easier operation with a straight endoscope and instruments. This approach is a safe and effective method to obtain wide and straight access to the MS and to resect IP in the MS.

Optimal duration of macrolide treatment for chronic sinusitis after endoscopic sinus surgery

OBJECTIVE The objective is to determine the appropriate duration of postoperative macrolide therapy for chronic rhinosinusitis to obtain a favourable outcome with endoscopic sinus surgery (ESS). METHODS The effectiveness of postoperative macrolide treatment was examined in patients with chronic rhinosinusitis who underwent ESS, by comparing 3-month (44 patients) and 6-month administration (66 patients) of clarithromycin (CAM) (200mg/day). Evaluation was made based on subjective symptoms and endoscopic findings at 3, 6 and 12 months after surgery. RESULTS Seventeen (3-month CAM group) and 22 (6-month CAM group) subjects were able to be followed up to 12 months after surgery. No difference in effectiveness was observed between the groups until 6 months after surgery, but the 6-month treatment group showed significantly higher disappearance rates and significantly lower visual analogue scale (VAS) scores in the subjective symptoms of rhinorrhea and postnasal drip at 12 months after surgery. The positive finding rate of postnasal drip by endoscopic examination was also significantly lower in the 6-month treatment group at 12 months after surgery. These changes over time indicated gradual deterioration after discontinuation of CAM treatment in the 3-month treatment group, whereas a small improvement was observed after discontinuation in the 6-month treatment group. CONCLUSION The results indicate that chronic sinusitis patients with rhinorrhea or postnasal drip should be treated with macrolides for 6 months after surgery in order to improve the long-term outcome of endoscopic sinus surgery.

Serum Periostin as a Biomarker for Comorbid Chronic Rhinosinusitis in Patients with Asthma

Rationale: Periostin is a matricellular protein that is involved in the pathophysiology of allergic rhinitis, chronic rhinosinusitis, and asthma. Associations of serum periostin with systemic and airway eosinophilic inflammation and comorbid chronic rhinosinusitis in patients with asthma have been demonstrated. Although serum periostin is positioned as a marker of helper T cell 2 immune responses, its implication regarding the presence of comorbid upper airway diseases in patients with asthma remains unclear. Objectives: To investigate the utility of serum periostin as a diagnostic biomarker for upper airway disease in patients with asthma. Methods: We prospectively enrolled 65 patients with stable asthma, 20 without upper airway disease, 22 with rhinitis, and 23 with chronic rhinosinusitis (13 with nasal polyps, 10 without). Serum periostin, eotaxin, total IgE, fractional exhaled nitric oxide, and blood and sputum eosinophil levels were measured and compared between upper airway disease subtypes. We evaluated the utility of each biomarker in detecting upper airway disease, associations among the biomarkers, and severity of upper airway disease as measured by the Lund‐Mackay score for sinus computed tomography. Results: Serum periostin levels were higher in patients with asthma who had chronic rhinosinusitis (109.6 ± 47.4 ng/ml) than in those without upper airway disease (83.2 ± 22.9 ng/ml) (P = 0.04). Serum periostin levels in patients with asthma who had chronic rhinosinusitis and nasal polyps were significantly higher (130.0 ± 46.6 ng/ml) than in those without nasal polyps (87.9 ± 37.7 ng/ml) (P = 0.001). Serum periostin levels were not associated with the presence or the severity of rhinitis. In contrast, receiver operating characteristic curve analyses showed moderate diagnostic accuracy for detecting chronic rhinosinusitis (area under the curve, 0.71; P = 0.01) and high accuracy for chronic rhinosinusitis with nasal polyps (area under the curve, 0.86; P = 0.0002). When we compared patients with asthma who had comorbid chronic rhinosinusitis and nasal polyps with patients with asthma without these comorbidities, we found serum periostin to be the sole biomarker among those tested for detecting the presence of nasal polyps. Serum periostin was also the sole biomarker that significantly correlated with Lund‐Mackay score in patients with chronic rhinosinusitis (r = 0.44; P = 0.04). Conclusions: Serum periostin is useful for detecting chronic rhinosinusitis with nasal polyps and predicting radiological chronic rhinosinusitis severity in patients with asthma. Clinical trial registered with the UMIN Clinical Trials Registry (UMIN000017533).

Modified transnasal endoscopic medial maxillectomy through prelacrimal duct approach

We previously reported a modified endoscopic medial maxillectomy (modified transnasal endoscopic medial maxillectomy through prelacrimal duct approach [MTEMMPDA]) to resect inverted papilloma (IP), for which the inferior turbinate (IT) and nasolacrimal duct (ND) can be preserved. MTEMMPDA is a safe and effective method to obtain wide, straight access to the maxillary sinus (MS). However, there are few reported cases of patients who underwent MTEMMPDA, and even fewer of patients who underwent partial osteotomy of the apertura piriformis and the anterior wall of the MS. In this study, we analyzed the outcomes of 51 patients who underwent MTEMMPDA.

Treatment of allergic rhinitis with intranasal infusion of botulinum toxin type A in mice

AIMS To determine whether intranasal infusion of botulinum toxin type A (BTX-A) relieves symptoms of ovalbumin (OVA)-induced allergic rhinitis (AR) and reduces nasal inflammation in mice. MAIN METHODS AR was induced via intraperitoneal injection of OVA followed by daily intranasal challenge with OVA. Five weeks after the initiation of OVA sensitization, nasal cavities were exposed to a single intranasal infusion of BTX-A. The behavior of mice was observed before and 1, 3, 5, 7, 14, 21, and 28days after infusion. Mice were sacrificed after 28days and late histological findings were examined. PBS was administered to control mice. RESULTS On Day 3, the frequency of typical AR symptoms, including sneezing and nose scratching, significantly decreased in the BTX-A-treated group (n=6) compared to the control group (n=6). Although the AR-inhibiting effects of BTX-A persisted until Day 21, AR symptoms re-appeared in response to daily OVA stimulation. Histological findings of the nasal mucosa also improved following BTX-A administration. Although capillary dilatation and eosinophil infiltration decreased by Day 3, these effects disappeared by Day 28. In contrast, the number and size of the secretary glands in the nasal mucosa did not change following BTX-A administration. PBS had no effect on nasal symptoms or histology. CONCLUSIONS Topical treatment with BTX-A efficiently and temporarily ameliorates AR symptoms. Intranasal infusion does not cause pain or bleeding, and the effects of a single infusion of BTX-A last for at least three weeks. This treatment might be a promising therapeutic strategy for the treatment of AR.

The Role of Atoh1 in Mucous Cell Metaplasia

A key issue in otitis media is mucous cell metaplasia which is responsible for mucous hypersecretion and persistence of the disease. However, little is known about the molecular mechanisms of mucous cell metaplasia in otitis media. Numerous studies of intestinal epithelial homeostasis have shown that Atonal homolog 1 (Atoh1), a basic helix-loop-helix (bHLH) transcription factor, is essential for the intestinal goblet cell differentiation. On the other hand, SAM-pointed domain-containing Ets transcription factor (SPDEF), a member of the “Ets” transcription factor family, has been reported to trigger the mucous cell metaplasia of pulmonary infectious diseases or athsma. Recent studies have demonstrated the relation of these factors, that is, Spdef functions downstream of Atoh1. We could take the adventages of these findings for the study of otitis media because both middle ear and pulmonary epithelia belong to the same respiratory tract. Atoh1 and SPDEF could be the therapeutic targets for otitis media associated with mucous cell metaplasia which is frequently considered “intractable” in the clinical settings.

Intranasal Therapy with CpG DNA Alone for the Control of Allergic Rhinitis

Many people all over the world suffer from allergic rhinitis, induced by Th2 responses. CpG DNA, containing a central unmethylated C-G dinucleotide, promotes Th1 responses. Consequently, Th2 responses decrease. Systemic administration of CpG DNA could attenuate allergic rhinitis. However, studies investigating the effects of intranasal therapy with CpG DNA alone on allergic rhinitis are rare. Therefore, we estimated the effectiveness of intranasal administration of CpG DNA alone on allergic rhinitis compared with intradermal administration. Mice were sensitized intraperitoneally and challenged intranasally with Cryptomeria japonica. Therapy with CpG DNA alone was performed during the challenge, either intranasally or intradermally. Immunologic variables and nasal symptoms were examined. Intranasal administration of CpG DNA alone significantly reduced nasal symptoms, nasal eosinophilia, and the levels of IgE as well as IL-5 production from nasal lymphocytes and splenocytes, although intradermal administration of CpG DNA alone did not show a significant reduction. This study demonstrated that CpG DNA has effects not only on splenocytes but also on nasal lymphocytes, and that the intranasal administration of CpG DNA alone is useful in the management of allergic rhinitis.

Sleep Disturbance and Hyperactivity Detected by Actigraphy in Rats with Allergic Rhinitis or Attention-Deficit Hyperactivity Disorder

Actigraphy is an easy and noninvasive method used to monitor human ultradian cycles. However, to our knowledge, it has been not applied to experiments with rodents. Therefore, using actigraphy, we assessed the ultradian cycles and behavior of rats. Rats with or without allergic rhinitis wore an actigraphy device, and triaxial acceleration was recorded. The counts that represent physical activity were lower from 8:00 to 20:00 than those from 20:00 to 8:00 in control rats, suggesting that their sleep phase was from 8:00 to 20:00 and their awake phase from 20:00 to 8:00. The counts from 8:00 to 10:00 were significantly higher in allergic rhinitis rats than in control rats (p < 0.01), suggesting the presence of difficulty with sleep induction in rats with allergic rhinitis. The counts from 18:00 to 20:00 were also significantly higher in allergic rhinitis rats than in control rats (p < 0.05), suggesting the presence of early awakening in rats with allergic rhinitis. Moreover, the counts were significantly higher in allergic rhinitis rats than in control rats from 20:00 to 8:00. These results suggest that rats with allergic rhinitis experienced hyperactivity disorder during the daytime. Additionally, hyperreactivity and difficulty with sleep induction were observed in 6-hydroxydopamine-lesioned rats, an animal model of attention-deficit hyperactivity disorder. This study shows for the first time that actigraphy can be successfully used for behavioral analysis in rodents. These rat models could be useful for analyzing the mechanisms involved in sleep disturbances and hyperactivity disorder.

A novel allergen-specific therapy with CD40-silenced B cells and dendritic cells

CD40-silenced B cells, induced by siRNA, inhibited allergic responses and symptoms antigen-specifically even after allergic rhinitis had been established. CD40-silenced B cells and CD40-silenced dendritic cells also have independent mechanisms with a synergic effect.

Combined measurements of fractional exhaled nitric oxide and nasal nitric oxide levels for assessing upper airway diseases in asthmatic patients

ABSTRACT Background: Despite the close linkage between rhinitis, chronic rhinosinusitis (CRS) and asthma, relevant biomarkers of both upper and lower airway inflammation are rare. Methods: Patients with asthma (without upper airway disease [UAD; n = 24], with rhinitis [n = 25], CRS [n = 24], and nasal polyps [n = 2]), isolated rhinitis (n = 13), isolated CRS (n = 13), and 10 healthy controls were prospectively recruited. Fractional exhaled nitric oxide (NO) levels at 50 mL/s (FeNO50), nasal NO levels, Lund–Macay-scores of sinus computed tomography and an asthma control questionnaire (ACQ) were evaluated. Results: Asthma was associated with higher FeNO50 levels irrespective of the UAD category. FeNO50 levels were higher in asthmatics with CRS (median: 54.0 ppb) than those with rhinitis (35.2 ppb, p = 0.02) and those without UAD (34.3 ppb, p = 0.002). Nasal NO levels were higher in rhinitis patients than other UAD categories, irrespective of the asthma concomitance. Nasal NO levels were higher in asthmatics with rhinitis (112.8 ppb) than those without UAD (67.2 ppb, p = 0.001) and those with CRS (57.6 ppb, p < 0.0001). A receiver-operating-characteristic curve analysis for detecting comorbid allergic rhinitis (AR) in asthmatics showed a high area under the curve (0.87). Nasal NO levels were positively correlated with FeNO50 levels (ρ = 0.56, p = 0.003) in asthmatics with rhinitis. In contrast, they were negatively correlated with the Lund–Macay (ρ = −0.46, p = 0.03) and ACQ scores (ρ = −0.52, p = 0.009) in asthmatics with CRS. Conclusions: Higher nasal NO levels reflect the presence of AR, irrespective of asthma concomitance. Higher FeNO50 levels reflect the presence of CRS and asthma. These NO measurements are useful for assessing comorbid UAD in asthmatics.