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1.  Trajectory of body mass index before the development of type 2 diabetes in Japanese men: Toranomon Hospital Health Management Center Study 15 
We aimed to investigate the long-term trajectory of general adiposity assessed by the body mass index (BMI) before the onset of type 2 diabetes in Japanese individuals.
Materials and Methods
We retrospectively examined data on 1,553 Japanese men without diabetes. Mean BMI and incident cases of diabetes (diabetes indicated by fasting glucose concentrations ≥7.0 mmol/L, a self-reported history of clinician-diagnosed diabetes, or glycated hemoglobin ≥6.5% (≥48 mmol/mol) were assessed on an annual basis over a 10-year period after the baseline examination.
Mean (standard deviation) BMI at the time of diagnosis was 24.4 kg/m2 (3.1 kg/m2) among cases of diabetes (n = 191). An increasingly high BMI was associated with the early stage of the disease development, such as an 8- to 10-year prediagnosis period; individuals who developed diabetes experienced a prolonged and stable elevated BMI of ≥24.4 kg/m2 over the 8 years before the diagnosis of diabetes. The mean BMI among the non-cases of diabetes did not exceed 23.2 kg/m2 throughout the period.
These results suggested that Japanese men who eventually developed diabetes during the 10-year observation period were not characterized as obese, but had stable high-normal BMIs before the onset of diabetes. Previous evidence showed that values for glycemic markers rapidly increased before the development of diabetes; however, the present study showed a slight gain in BMI in the earlier stage of the natural history of diabetes followed by a prolonged period of overweight.
PMCID: PMC4420560  PMID: 25969713
Body mass index trajectory; Prediction; Type 2 diabetes
2.  Circulating Malondialdehyde-Modified LDL-Related Variables and Coronary Artery Stenosis in Asymptomatic Patients with Type 2 Diabetes 
Journal of Diabetes Research  2015;2015:507245.
Aims. To elucidate the levels of malondialdehyde-modified LDL (MDA-LDL)-related variables for predicting coronary artery stenosis (CAS) by coronary CT angiography (CCTA) in asymptomatic patients with type 2 diabetes (T2DM). Methods. Enrolled were 36 Japanese patients with T2DM who underwent CCTA and in whom MDA-LDL levels were measured. Definition of CAS was luminal narrowing of ≥50%. Trends through tertiles of each MDA-LDL-related variable were analyzed with a general linear model. The ability of each MDA-LDL-related variable to predict CAS was compared to areas under the curve (AUCs) in receiver operating characteristic curve (ROC) analysis. Results. Seventeen patients had CAS. Each MDA-LDL-related variable was an independent predictor of CAS (P = 0.039 for MDALDL, P = 0.013 for MDA-LDL/LDL-C, P = 0.047 for MDA-LDL/HDL-C, and P = 0.013 for (MDA-LDL/LDL-C)/HDL-C). AUCs of MDA-LDL, MDA-LDL/LDL-C, MDA-LDL/HDL-C, and (MDA-LDL/LDL-C)/HDL-C were 0.675 (95% CI 0.496–0.854), 0.765 (0.602–0.927), 0.752 (0.592–0.913), and 0.799 (0.643–0.955), respectively, for predicting CAS. Trends throughout the tertiles showed significant associations between MDA-LDL/LDL-C, MDA-LDL/HDL-C, or (MDALDL/LDL-C)/HDL-C and CAS (P = 0.003 for MDA-LDL/LDL-C, P = 0.042 for MDA-LDL/HDL-C, and P = 0.001 for (MDA-LDL/LDL-C)/HDL-C). Conclusions. Data suggest that measurements of MDA-LDL/LDL-C, MDA-LDL/HDLC, and (MDA-LDL/LDL-C)/HDL-C are useful for predicting CAS.
PMCID: PMC4391491  PMID: 25883985
3.  Simple self-reported behavioral or psychological characteristics as risk factors for future type 2 diabetes in Japanese individuals: Toranomon Hospital Health Management Center Study 14 
Depression, anger, sleep disorders and cognitive impairment are regarded as presenting a high risk for diabetes. We investigated whether responses to single statements on a self-report questionnaire on the presence of each of these four factors were associated with the development of type 2 diabetes.
Materials and Methods
We investigated 3,211 Japanese individuals without diabetes. Cumulative incidence rate and hazard ratios (HRs) for future type 2 diabetes over 7–13 years were evaluated according to the presence of lack of perseverance, anger, memory loss or sleep disorders.
Results of Cox regression analysis showed that lack of perseverance (age- and sex-adjusted HR 1.41, 95% confidence interval 1.07–1.84), anger, (HR 1.51, 95% confidence interval 1.07–2.12) or memory loss (HR 1.47, 95% confidence interval 1.14–1.90) was predictive of the development of diabetes. Even after adjustment for metabolic factors including glycemic measurements, anger was significantly associated with an increased risk of future diabetes. Individuals with both anger and memory loss had a 1.94-fold (95% confidence interval 1.19–3.15) increased risk of type 2 diabetes than those without those two symptoms.
Responses to a simple self-report questionnaire as to whether individuals were aware of anger or memory loss were associated with the development of type 2 diabetes independent of traditional risk factors for diabetes in this cohort of Japanese individuals.
PMCID: PMC4364859  PMID: 25802732
Behavioral or psychological risk factors; Type 2 diabetes
4.  An Endoscopic Endonasal Approach for Early-Stage Olfactory Neuroblastoma: An Evaluation of 2 Cases with Minireview of Literature 
Case Reports in Otolaryngology  2015;2015:541026.
We describe the clinical findings in two patients with pathologically diagnosed olfactory neuroblastoma (ONB) of the sinonasal area and the surgical methods used for its treatment. Using an endoscopic endonasal approach (EEA) without dura resection, along with radiotherapy, we successfully treated ONB at the Kadish stage A. One of our patients, however, experienced tumor recurrence 24 years after open surgery with radiotherapy that was conducted at another hospital. This patient was no longer eligible for radiotherapy, and the tumor was therefore resected with dura resection using an EEA combined with duraplasty. The dura resection with duraplasty using fascia lata and a pedicled nasal septal flap was minimally invasive. As with surgery without duraplasty, a postoperative computed tomography (CT) examination revealed that EEA with duraplasty led to quick improvement of the postoperative inflammatory response as well as pneumocranium. Here, we investigated whether to modify the method of surgery depending upon the primary site of early-stage ONB. We suggest that, in early-stage ONB, an endoscopic endonasal approach is an effective and less invasive method. It is also advisable to perform dura mater resection of the lesion site despite the absence of obvious intracranial invasions in image findings.
PMCID: PMC4305615  PMID: 25650131
5.  Effect of Postmenopausal Status and Age at Menopause on Type 2 Diabetes and Prediabetes in Japanese Individuals: Toranomon Hospital Health Management Center Study 17 (TOPICS 17) 
Diabetes Care  2013;36(12):4007-4014.
Findings on the effect of menopause or age at menopause on the presence of hyperglycemia are controversial, and why women after menopause have a higher probability of having hyperglycemia than men in the same age range remains unknown.
We reviewed data on 29,189 men, 6,308 premenopausal women, and 4,570 postmenopausal women in Japan. Odds ratios (ORs) for diabetes or prediabetes indicated by American Diabetes Association criteria were calculated for men and for pre- and postmenopausal women.
Compared with premenopausal women, women after natural menopause had an age-adjusted OR of 1.40 (95% CI 1.03–1.89) for diabetes, and women after menopause by surgical or other causes had an age-adjusted OR of 1.59 (1.07–2.37). The age-adjusted OR in men was 4.02 (3.15–5.14). Compared with premenopausal nondiabetic women, postmenopausal nondiabetic women had a significantly elevated OR of 1.33 (1.20–1.48) for prediabetes; nondiabetic men had an OR of 1.93 (1.77–2.10) independently of age and demographic and metabolic factors. Even among women aged <50 years, postmenopausal status was significantly associated with an elevated OR (1.50 [1.18–1.91]) for dysglycemia (either diabetes or prediabetes). Postmenopausal women aged ≥50 years had a particularly elevated OR for dysglycemia, regardless of age at menopause.
The postmenopausal state was significantly associated with the presence of dysglycemia independently of normal aging, although the increased probability in postmenopausal women did not equal that in men. Among women, menopause and older age might additively influence the elevated probability of dysglycemia.
PMCID: PMC3836104  PMID: 24170752
6.  Association of Helicobacter pylori Infection with Glycemic Control in Patients with Diabetes: A Meta-Analysis 
Journal of Diabetes Research  2014;2014:250620.
Objective. To assess the association between Helicobacter pylori (HP) infection and glycemic control in patients with diabetes through a meta-analytic approach. Research Design and Methods. Electronic literature searches were conducted for cross-sectional studies that examined the hemoglobin A1c (A1C) level by whether patients with diabetes were or were not carriers of HP. Mean differences in A1C between groups with and without HP infection were pooled with a random-effects model. Results. Thirteen eligible studies were included in this meta-analysis. Overall, the HP carriers did not have significantly higher A1C levels compared with HP noncarriers (mean difference (95% CI), 0.19% (−0.18 to 0.46), P = 0.16). When the analysis was limited to studies targeting patients with type 1 diabetes, there was also no significant difference in A1C (0.69% (−0.31 to 1.68), P = 0.18). Conclusions. There was insufficient evidence that HP infection worsened glycemic control in patients with diabetes.
PMCID: PMC4034768  PMID: 24901007
7.  Association Between Physical Activity and Risk of All-Cause Mortality and Cardiovascular Disease in Patients With Diabetes 
Diabetes Care  2013;36(2):471-479.
The association between habitual physical activity (PA) and lowered risk of all-cause mortality (ACM) and cardiovascular disease (CVD) has been suggested in patients with diabetes. This meta-analysis summarizes the risk reduction in relation to PA, focusing on clarifying dose-response associations.
Electronic literature searches were conducted for cohort studies that examined relative risk (RR) of ACM or CVD in relation to PA in patients with diabetes. For the qualitative assessment, RR for the highest versus the lowest PA category in each study was pooled with a random-effects model. We added linear and spline regression analyses to assess the quantitative relationship between increases in PA and ACM and CVD risk.
There were 17 eligible studies. Qualitatively, the highest PA category had a lower RR [95% CI] for ACM (0.61 [0.52–0.70]) and CVD (0.71 [0.60–0.84]) than the lowest PA category. The linear regression model indicated a high goodness of fit for the risk of ACM (adjusted R2 = 0.44, P = 0.001) and CVD (adjusted R2 = 0.51, P = 0.001), with the result that a 1 MET-h/day incrementally higher PA was associated with 9.5% (5.0–13.8%) and 7.9% (4.3–11.4%) reductions in ACM and CVD risk, respectively. The spline regression model was not significantly different from the linear model in goodness of fit (P = 0.14 for ACM risk; P = 0.60 for CVD risk).
More PA was associated with a larger reduction in future ACM and CVD risk in patients with diabetes. Nevertheless, any amount of habitual PA was better than inactivity.
PMCID: PMC3554302  PMID: 23349151
8.  The Relationship between Diabetic Neuropathy and Sleep Apnea Syndrome: A Meta-Analysis 
Sleep Disorders  2013;2013:150371.
Aims. High prevalence of sleep apnea syndrome (SAS) has been reported in patients with diabetes. However, whether diabetic neuropathy (DN) contributes to this high prevalence is controversial. Our aim of this study is to compare the prevalence of SAS between patients with and without DN. Methods. Systematic literature searches were conducted for cross-sectional studies that reported the number of patients with DN and SAS using MEDLINE (from 1966 to Nov 5, 2012) and EMBASE (from 1974 to Nov 5, 2012). Odds ratios (ORs) of SAS related to DN were pooled with the Mantel-Haenszel method. Results. Data were obtained from 5 eligible studies (including 6 data sets, 880 participants, and 429 cases). Overall, the pooled OR of SAS in patients with DN compared with that in non-DN patients was significant (OR (95% CI), −1.95 (1.03–3.70)). The pooled OR of SAS was 1.90 (0.97–3.71) in patients with type 2 diabetes. Excluding data on patients with type 1 diabetes, a higher OR was observed in younger patients (mean age <60 years) than in those ≥60 years among whom the OR remained significant (3.82; 95% CI, 2.24–6.51 and 1.17; 95% CI, 0.81–1.68). Conclusions. Current meta-analysis suggested the association of some elements of neuropathy with SAS in type 2 diabetes. Further investigations are needed to clarify whether the association is also true for patients with type 1 diabetes.
PMCID: PMC3871907  PMID: 24381764
9.  Longitudinal Trajectories of HbA1c and Fasting Plasma Glucose Levels During the Development of Type 2 Diabetes 
Diabetes Care  2012;35(5):1050-1052.
To describe the trajectory of HbA1c and glucose concentrations before the diagnosis of diabetes.
The study comprised 1,722 nondiabetic Japanese individuals aged 26–80 years. Fasting plasma glucose (FPG) and HbA1c were measured annually for a mean of 9.5 (SD 1.8) years.
Diabetes occurred in 193 individuals (FPG ≥7.0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA1c ≥6.5%). Mean HbA1c values were >5.6% each year before diagnosis in diabetes cases. Mean HbA1c (5.69% [95% CI 5.50–5.88]) was higher in the 21 individuals who developed diabetes 10 years after the baseline examination than in nondiabetic individuals after 10 years (5.27% [5.25–5.28]). From 3 years to 1 year prediagnosis, HbA1c increased 0.09% (SE 0.01)/year, reaching 5.90% (5.84–5.96) 1 year prediagnosis. In the entire group, marked increases in HbA1c of 0.3% (SE 0.05%)/year and FPG of 0.63 (0.07) mmol/L/year predicted diabetes.
HbA1c trajectory increased sharply after gradual long-term increases in diabetic individuals.
PMCID: PMC3329827  PMID: 22456865
10.  Low Lung Function and Risk of Type 2 Diabetes in Japanese Men: The Toranomon Hospital Health Management Center Study 9 (TOPICS 9) 
Mayo Clinic Proceedings  2012;87(9):853-861.
To evaluate the effect of elevated fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) concentrations on lung dysfunction and to prospectively investigate whether reduced lung function would be independently predictive of diabetes.
Participants and Methods
From January 6, 1997, through December 22, 2008, we observed 5346 men with no history of diabetes or lung dysfunction. Hazard ratios (HRs) for incident diabetes (FPG ≥126 mg/dL, HbA1c ≥6.5%, or self-reported clinician-diagnosed diabetes) were estimated for spirometry indices as continuous and categorical variables.
Elevated HbA1c concentrations within the normal range were significantly and more strongly associated with reduced forced vital capacity and forced expiratory volume in the first second after expiration (FEV1) than were FPG concentrations. During a 4.0-year follow-up, diabetes developed in 214 individuals. A 10-point decrease in percentage of FEV1 predicted value was associated with an increased HR of 1.21 (95% confidence interval [CI], 1.09-1.34; P=.001) for diabetes after adjustment for demographic factors and body mass index. This association remained significant even after adjustment for metabolic factors, smoking status, and FPG or HbA1c concentrations but was attenuated substantially after adjustment for baseline HbA1c values (HR, 1.13; 95% CI, 1.01-1.26; P=.03). Lower quartile (Q) categories of percentage of FEV1 predicted value were associated with increased risk of diabetes independently of known predictors including HbA1c (HR, 1.73; 95% CI, 1.14-2.62 for Q1; and HR, 1.76; 95% CI, 1.15-2.69 for Q2).
Reduced lung function was significantly related to chronic glycemic exposure within a normal range. Relatively low pulmonary function was an independent risk factor for diabetes in apparently healthy Japanese men.
PMCID: PMC3538497  PMID: 22958989
CI, confidence interval; FEV1, forced expiratory volume in the first second of expiration; FEV1%pre, FEV1 for predicted values; FPG, fasting plasma glucose; FVC, forced vital capacity; FVC%pre, FVC for predicted values; HbA1c, hemoglobin A1c; HR, hazard ratio; OR, odds ratio
11.  Bilateral Endoscopic Medial Maxillectomy for Bilateral Inverted Papilloma 
Case Reports in Otolaryngology  2012;2012:215847.
Inverted papilloma (IP) is a benign tumor of the nasal cavity and paranasal sinuses that is unilateral in most cases. Bilateral IP, involving both sides of the nasal cavity and sinuses, is extremely rare. This paper describes a large IP that filled in both sides of the nasal cavity and sinuses, mimicking association with malignancy. The tumor was successfully treated by bilateral endoscopic medial maxillectomy (EMM). The patient is without evidence of the disease 24 months after surgery. If preoperative diagnosis does not confirm the association with malignancy in IP, endoscopic sinus surgery (ESS) should be selected, and ESS, including EMM, is a good first choice of the treatment for IP.
PMCID: PMC3420519  PMID: 22953103
12.  Endoscopic Endonasal Transturbinate Approach to the Pterygopalatine Fossa in the Management of Juvenile Nasopharyngeal Angiofibromas 
Case Reports in Otolaryngology  2012;2012:786262.
Pterygopalatine fossa (PPF) is a difficult-to-access anatomic area located behind the posterior wall of the maxillary sinus. Juvenile nasopharyngeal angiofibroma (JNA) often affects this area, and the management of feeding artery to the tumor is important in the surgery. Endoscopic endonasal approach to the PPF without endangering all other nasal structures is useful in the management of JNA. We describe a new approach to the PPF, endoscopic transturbinate approach, which is effective in the management of JNA. Submucous inferior turbinoplasty was performed, and sphenopalatine artery, the feeder to the tumor, was identified at the sphenopalatine foramen. The posterior wall of maxillary sinus was removed. Internal maxillary artery was identified in the PPF and was ligated with a hemoclip. The tumor in the PPF was pushed into the nasal cavity. These procedures were all performed via submucous turbinate tunnel. Then, the tumor was successfully removed in en bloc from the nasal cavity by transnasal approach without ethmoidectomy. This approach improves accessibility and visualization in the PPF and potential to reduce intraoperative bleeding due to ligation of the feeder safely without touching the tumor. Endoscopic transturbinate approach is effective in the management of early stage of JNA.
PMCID: PMC3420430  PMID: 22953122
13.  Wegener's Granulomatosis with Extensive Bone Abnormalities Mimicking Fungal Sinusitis 
Case Reports in Otolaryngology  2012;2012:103403.
Abnormalities of the underlying bone of the paranasal sinuses have sometimes been shown in Wegener's granulomatosis (WG). We describe an interesting case of WG with extensive bone abnormalities in the sinuses mimicking fungal sinusitis. A 30-year-old woman presented with intermittent unilateral epistaxis. Biopsy was performed for the granulation tissue in the right nasal cavity, and she was diagnosed as having WG. Computed tomography (CT) revealed a ring-like calcification, mimicking a fungus ball, in the right maxillary sinus. Endoscopic sinus surgery was performed to confirm the diagnosis. A spherical bony structure, surrounded by granulation tissue, was identified in the maxillary sinus. The wall of the “bony ball” was fragile, like an egg shell. No fungus was found in the sinus. Thus, the extensive bone abnormalities were due to WG.
PMCID: PMC3420613  PMID: 22953096
14.  Expression of bone morphogenic protein in sinonasal inverted papilloma with new bone formation 
Allergy & Rhinology  2011;2(1):16-20.
Inverted papilloma (IP) is a common benign tumor in the nose and sinus. Osteogenesis in sinonasal IP is extremely rare; to date, only five cases of IP with new bone formation appear in the literature. In addition, the mechanism of osteogenesis in IP remains unclear. Here, we describe three cases of IP with new bone formation and an investigation into a possible role for bone morphogenic protein (BMP) in osteogenesis. Of three patients with sinonasal IP with new bone formation, two were treated by endoscopic sinus surgery and one was followed up with watchful waiting. Tumor tissues were subjected to immunohistochemistry to detect BMP expression. The patients were successfully treated surgically and showed no evidence of recurrence postoperatively. Follow-up examination is ongoing. Immunohistochemically, the tumors expressed BMP-4 but not BMP-2 or BMP-7. ESS could be successfully used to achieve complete removal of the sinonasal IPs with new bone formation. BMP-4 might be associated with new bone formation in the tumor.
PMCID: PMC3390124  PMID: 22852110
Bone formation; bone morphogenic protein; endoscopic sinus surgery; inverted papilloma; sinonasal
15.  Sinonasal Schwannoma with New Bone Formation Expressing Bone Morphogenic Protein 
Schwannoma is a benign tumor that arises from the sheath of myelinated nerve fibers and may occur in any part of the body. Osteogenesis in schwannoma is extremely rare and, to date, new bone formation in sinonasal schwannoma has not yet been reported. Here, we describe the first reported case of sinonasal schwannoma with new bone formation. The tumor was successfully treated by endoscopic sinus surgery, and the patient showed no evidence of recurrence 24 months postoperatively. Immunohistochemically, the tumor expressed bone morphogenic protein 4, indicating a possible role of this protein in the new bone formation in schwannomas.
PMCID: PMC3010644  PMID: 21197441
16.  Association Between Serum Uric Acid and Development of Type 2 Diabetes 
Diabetes Care  2009;32(9):1737-1742.
To systematically evaluate the association between serum uric acid (SUA) level and subsequent development of type 2 diabetes.
We searched Medline (31 March from 1966 to 2009) and Embase (31 March from 1980 to 2009) for observational cohort studies examining the association between SUA and the risk of type 2 diabetes by manual literature search. Relative risks (RRs) for each 1 mg/dl increase in SUA were pooled by using a random-effects model. The studies included were stratified into subgroups representing different study characteristics, and meta-regression analyses were performed to investigate the effect of these characteristics on the association between SUA level and type 2 diabetes risk.
The search yielded 11 cohort studies (42,834 participants) that reported 3,305 incident cases of type 2 diabetes during follow-up periods ranging from 2.0 to 13.5 years. The pooled RR of a 1 mg/dl increase in SUA was 1.17 (95% CI 1.09–1.25). Study results were consistently significant (i.e., >1) across characteristics of participants and study design. Publication bias was both visually and statistically suggested (P = 0.03 for Egger's test, 0.06). Adjustment for publication bias attenuated the pooled RR per mg/dl increase in SUA (RR 1.11 [95% CI 1.03–1.20]), but the association remained statistically significant (P = 0.009).
The current meta-analysis suggests that SUA level is positively associated with the development of type 2 diabetes regardless of various study characteristics. Further research should attempt to determine whether it is effective to utilize SUA level as a predictor of type 2 diabetes for its primary prevention.
PMCID: PMC2732137  PMID: 19549729
17.  Influence of Fat and Carbohydrate Proportions on the Metabolic Profile in Patients With Type 2 Diabetes: A Meta-Analysis 
Diabetes Care  2009;32(5):959-965.
The effects of dietary macronutrient composition on metabolic profiles in patients with type 2 diabetes have been inconsistent. This meta-analysis aimed to elucidate the effect of replacing dietary fat with carbohydrate on glucose and lipid parameters in patients with type 2 diabetes.
We searched for randomized trials that investigated the effects of two kinds of prescribed diets (a low-fat, high-carbohydrate [LFHC] diet and a high-fat, low-carbohydrate [HFLC] diet); in these studies, energy and protein intake did not differ significantly between the two dietary groups. Nineteen studies that included 306 patients met our inclusion criteria. Median diet composition of carbohydrate/fat in the LFHC and HFLC diets was 58%/24% and 40%/40%, respectively.
Changes in values for A1C, fasting plasma glucose (FPG), and total and LDL cholesterol did not differ significantly between the LFHC and HFLC groups. However, the LFHC diet significantly increased fasting insulin and triglycerides by 8% (P = 0.02) and 13% (P < 0.001), respectively, and lowered HDL cholesterol by 6% (P < 0.001) compared with the HFLC diet. There were positive associations among the magnitude of changes in FPG, fasting insulin, and triglycerides for the diets analyzed. However, stratified analysis indicated that the increase in triglycerides was insignificant when accompanied by energy intake restriction.
Our findings suggested that replacing fat with carbohydrate could deteriorate insulin resistance while the adverse effect on triglycerides from the LFHC diet could be avoided by restricting energy intake to a degree sufficient for the attainment of weight reduction.
PMCID: PMC2671123  PMID: 19407076
18.  Intranasal Immunization Enhances Clearance of Nontypeable Haemophilus influenzae and Reduces Stimulation of Tumor Necrosis Factor Alpha Production in the Murine Model of Otitis Media 
Infection and Immunity  2001;69(5):2964-2971.
Nontypeable Haemophilus influenzae (NTHi) is a major pathogen causing otitis media (OM). One of the outer membrane proteins of NTHi, P6, is a common antigen to all strains and is considered a candidate for mucosal vaccine. We have previously reported that intranasal immunization with P6 and cholera toxin (CT) could induce P6-specific immunoglobulin A (IgA) antibodies in the middle ear. In the present study, we assessed the effect of intranasal immunization for the protection against NTHi-induced OM. Mice were immunized intranasally with P6 and CT as an adjuvant on days 0, 7, and 14. Control mice were given phosphate-buffered saline (PBS) without antigen. One week after the final immunization, a suspension of live NTHi (107 CFU) was injected into the tympanic cavity to induce experimental OM. On days 3 and 7 after bacterial challenge, mice were killed and middle ear effusions (MEEs) were collected. All immunized mice showed elevated titers of P6-specific antibodies in MEEs. The rank order of specific antibody included, from highest to lowest levels, IgG, IgA, and IgM. In addition, immunized mice showed enhanced clearance of NTHi from the middle ear and the number of NTHi in MEEs of immunized mice was reduced by 97% on day 3 and by 92% on day 7 after bacterial challenge relative the number in the MEEs of control mice. The protective effect of intranasal immunization on the incidence of NTHi-induced experimental OM was evident on day 7 after challenge. By day 7, the number of MEEs in immunized mice was 64% less than that in control mice and the incidence of NTHi culture-positive MEEs in immunized mice was 56% less than that in control mice. Less stimulation of tumor necrosis factor alpha (TNF-α) production in the middle ear was evident on day 3 after challenge. Immunized mice showed lower concentrations of TNF-α in MEEs. These results indicate that intranasal immunization affords protection against experimental OM as evidenced by enhanced clearance of NTHi and less stimulation of TNF-α production in the middle ear. These findings suggest that a nasal vaccine might be useful for preventing OM.
PMCID: PMC98249  PMID: 11292713
19.  Induction of Specific Immunoglobulin A and Th2 Immune Responses to P6 Outer Membrane Protein of Nontypeable Haemophilus influenzae in Middle Ear Mucosa by Intranasal Immunization 
Infection and Immunity  2000;68(4):2294-2300.
Nontypeable Haemophilus influenzae (NTHI) is a major pathogen of otitis media. One of the outer membrane proteins of NTHI, P6, is an antigen common to all strains and is considered as a candidate for mucosal vaccine. To elucidate the possibility of developing a nasal vaccine against nontypeable Haemophilus influenzae (NTHI) and to investigate mucosal immune responses in the middle ear, mice were immunized intranasally with the P6 outer membrane protein of NTHI, and P6-specific immune responses in the middle ear mucosa were examined. Mice were given with P6 and cholera toxin intranasally as an adjuvant on days 0, 7, and 14 and were killed on day 21. The P6-specific immunoglobulin A (IgA) antibody titer in ear wash was significantly elevated. Mononuclear cells were isolated from middle ear mucosa, and an increase in P6-specific IgA-producing cells was shown with an enzyme-linked immunospot assay. In addition, an increase in memory T cells in middle ear mucosa was detected with flow cytometric analysis after intranasal immunization. Moreover, in vitro stimulation with P6 resulted in proliferation of purified CD4+ T cells from immunized mice, and these T cells expressed Th2 cytokine mRNA. These results indicate that P6-specific IgA–B-cell immune responses and selected Th2 cytokine expressing Th cells were induced in middle ear mucosa by intranasal immunization. These findings suggest that a nasal vaccine is useful for preventing otitis media with effusion.
PMCID: PMC97416  PMID: 10722632

Results 1-19 (19)