Risk factors for otitis media in children with special emphasis on the role of colonization with bacterial airway pathogens: the Generation R study

Acute otitis media is the most frequent diagnosis in children visiting physicians’ offices. Risk factors for otitis media have been widely studied. Yet, the correlation between bacterial carriage and the development of otitis media is not entirely clear. Our aim was to study in a population-based prospective cohort the risk factors for otitis media in the second year of life with special emphasis on the role of colonization with Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. The study was embedded in the Generation R Study. Data on risk factors and doctor-diagnosed otitis media were obtained by midwives, hospital registries and postal questionnaires in the whole cohort (n = 7,295). Nasopharyngeal swabs were obtained at the age of 1.5, 6 and 14 months in the focus cohort (n = 1,079). Of these children, 2,515 (47.2%) suffered at least one period of otitis media in their second year of life. The occurrence of otitis media during the follow-up period in the first 6 months of life and between 6 and 12 months of age was associated with the risk of otitis media in the second year of life (aOR, 1.83 95% CI 1.24–2.71 and aOR 2.72, 95% CI 2.18–3.38, respectively). Having siblings was associated with an increased risk for otitis media in the second year of life (aOR 1.42, 95% CI 1.13–1.79). No associations were found between bacterial carriage in the first year of life and otitis media in the second year of life. In our study, otitis media in the first year of life is an independent risk factor for otitis media in the second year of life. Surprisingly, bacterial carriage in the first year of life did not add to this risk. Moreover, no association was observed between bacterial carriage in the first year of life and otitis in the second year of life

The enhanced expression of the matrix metalloproteinase 9 in nasal NK/T-cell lymphoma

<p>Abstract</p> <p>Background</p> <p>Nasal NK/T cell lymphoma is an aggressive disease and has a poor prognosis. Nasal NK/T cell lymphoma is refractory to conventional chemotherapy and has strong tendency of widespread relapse or dissemination into distant sites.</p> <p>Methods</p> <p>We immunohistochemically studied nasal NK/T-cell lymphoma to elucidate the unique characteristics of nasal NK/T-cell lymphoma, such as its higher metastatic tendency and its vast necrosis which leads to destruction of the involved tissues. The expression of P-glycoprotein and MMP-9 was evaluated in the 20 patients with nasal NK/T-cell lymphoma and 25 with nasal non-NK/T-cell lymphoma and the relationship between expression of these proteins and clinical results were analyzed in this report.</p> <p>Results</p> <p>Overall 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 51%, and 84%. Distant involvement free 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 53%, and 79%.</p> <p>Overall positivity for P-glycoprotein was observed in 10 of 19 patients with NTL and in 13 of 23 patients with non-NTL. When the overall survival rate was compared between patients with P-glycoprotein positive and negative, there was no difference between them.</p> <p>Sixteen of the 19 patients with nasal NK/T cell lymphoma expressed MMP-9. In contrast, only 8 of the 22 patients with nasal non-NK/T cell lymphoma expressed MMP-9. Distant involvement free 5-year survival rates for patients with MMP-9 negative, and MMP-9 positive were 92%, and 61%, respectively. The difference was statistically significant (p = 0.027).</p> <p>Conclusion</p> <p>Positive immunoreactivity for P-glycoprotein was not an independent prognostic factor in nasal NK/T-cell lymphomas, which stresses the importance of exploring other mechanisms of drug resistance. The strong expression of MMP-9 is uniquely characteristic of nasal NK/T cell lymphoma and may contribute to its strong tendency to disseminatate and the extensive necrosis which is always seen. However, our results are based on univariate comparisons, and as such, should be viewed with some caution.</p

Phosphorylcholine Allows for Evasion of Bactericidal Antibody by Haemophilus influenzae

The human pathogen Haemophilus influenzae has the ability to quickly adapt to different host environments through phase variation of multiple structures on its lipooligosaccharide (LPS), including phosphorylcholine (ChoP). During colonization with H. influenzae, there is a selection for ChoP+ phase variants. In a murine model of nasopharyngeal colonization, this selection is lost in the absence of adaptive immunity. Based on previous data highlighting the importance of natural antibody in limiting H. influenzae colonization, the effect of ChoP expression on antibody binding and its bactericidal activity was investigated. Flow cytometric analysis revealed that ChoP+ phase variants had decreased binding of antibody to LPS epitopes compared to ChoP− phase variants. This difference in antibody binding correlated with increased survival of ChoP+ phase variants in the presence of antibody-dependent, complement-mediated killing. ChoP+ phase variants were also more resistant to trypsin digestion, suggesting a general effect on the physical properties of the outer membrane. Moreover, ChoP-mediated protection against antibody binding correlated with increased resilience of outer membrane integrity. Collectively, these data suggest that ChoP expression provides a selective advantage during colonization through ChoP-mediated effects on the accessibility of bactericidal antibody to the cell surface

Effects of macrolides on antigen presentation and cytokine production by dendritic cells and T lymphocytes

Elsevier, Ishida, Yoshiya ; Abe, Yusuke ; Harabuchi, Yasuaki, International Journal of Pediatric Otorhinolaryngology, 71(2), 2007, 297-305. authorMacrolides are effective therapeutic agents for chronic respiratory tract diseases, such as chronic sinusitis, sinobronchial syndrome and diffuse panbronchiolitis. Although only limited information is available about their mechanisms, suppression of various inflammatory cytokines (IL-8, etc.) and some transcription factors has been reported to be involved. Non-typeable Haemophilus influenzae (NTHI) is one of the most important pathogens of the respiratory tract. P6 is one of the outer membrane proteins of NTHI and the target antigen of protective antibodies. To analyze the influence of macrolides on human dendritic cells (DCs), we treated DCs with macrolides and used them as antigen-presenting cells (APCs). Clarithromycin, roxithromycin and prednisolone suppressed the in vitro proliferative response of CD4+ T cells to P6 and also the production of cytokines. As a control, we also cultured DCs alone and exposed them to the medicament, while conversely culturing T cells without adding any drugs to the cultures. The results showed similar tendencies for suppression of immune responses. These findings suggest that macrolides suppress the antigen-specific immune responses of DCs in vitro

Intranasal immunization with lipoteichoic acid and cholera toxin evokes specific pharyngeal IgA and systemic IgG responses and inhibits streptococcal adherence to pharyngeal epithelial cells in mice

ELSEVIER, Yokoyama, Y; Harabuchi, Y, INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY, 63(3), 235-241, 2002. authorObjective: Streptococcus (S.) pyogenes is common cause of acute tonsillitis. Lipoteichoic acid (LTA), which is a common constitute of the cell surface of most gram positive bacteria, is known to act as a substance of bacterial site for adherence to epithelium and antiserum to LTA is reported to inhibit bacterial attachment to epithelial cells in vitro. Cholera toxin subunit B (CT-B) is known to be a mucosal adjuvant. The purpose of this study is to investigate whether intranasal immunization with LTA and CT-B may be a possible candidate for vaccine formulation. Methods: Six-week-old male BALB/c mice were assigned to 3 experimental groups, mice immunized with LTA and CT-B, with LTA alone and with phosphate buffered saline (PBS) as a control. Immunizations were performed intranasally every 2 days for 2 weeks in every group. At the 21 days after immunization, sera, pharyngeal washings and pharyngeal epithelial cells were taken. The levels of serum IgG and pharyngeal IgA antibodies to LTA were measured by enzyme-linked immunosorbent assay (ELISA). The adherence rates of S. pyogenes pretreated by pharyngeal washings to pharyngeal epithelial cells from the mice were determined by in vitro adherence assay. Results: The serum anti-LTA IgG antibody levels of either mice immunized with LTA and CT-B or mice immunized with LTA alone were significantly higher than those of mice administered with PBS alone. The pharyngeal anti-LTA IgA antibody levels of the mice immunized with LTA and CT-B were significantly higher than those of either mice with LTA alone or mice with PBS alone. The streptococcal adherence rates to pharyngeal epithelial cells were significantly decreased by pretreatment with pharyngeal washings from the mice immunized with LTA and CT-B as compared to pretreatment with those from either mice with PBS or mice with LTA alone. Conclusions: These data shows that intranasal immunization with LTA nd CT-B evokes a good pharyngeal IgA response as well as systemic IgG response to LTA and inhibits streptococcal adherence to pharyngeal epithelial cells, suggesting that intranasal immunization with LTA and CT-B may be an effective approach to prevent streptococcal tonsillitis

Decreased serum and pharyngeal antibody levels specific to streptococcal lipoteichoic acid in children with recurrent tonsillitis

ELSEVIER, Yokoyama, Y; Harabuchi, Y, INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY, 63(3), 199-207, 2002. authorObjective: Streptococcus (S.) pyogenes is common causes of primary as well as recurrent tonsillitis (RT). Lipoteichoic acid (LTA) has been proposed as a possible candidate for vaccine formulation against streptococcal infections, because LTA is a common constituent of streptococci and the antibody to LTA inhibits bacterial attachment to epithelial cells in vitro. Streptolysin-O and streptococcal whole cell body are highly immunogenic and the antibodies to these antigens are reported to be better parameters for streptococcal infections The objective of the present study is to investigate how systemic and local immune activities against S. pyogenes may be associated with RT. Methods: Sera from 178 children with or without RT aged 1-15 years with a median age of 5 years were investigated for the levels of total immunoglobulins and antibodies specific to streptococcal antigens such as whole cell body, LTA, and streptolysin-O. Pharyngeal secretions from 67 children with or without RT aged 2-14 years with a median age of 6 years were subjects to secretory IgA (SIgA) antibody levels to streptococcal LTA. The antibodies to whole cell body and LTA were measured by enzyme-linked immunosorbent assay. Total immunoglobins and the antistreptolysin- O antibody were assayed by nephelometry. Results: An age-matched comparison revealed that either levels of serum IgG antibody or pharyngeal SIgA antibody to streptococcal LTA at 2-5 years of age were significantly lower in RT children than in non-RT children (1.39 vs. 5.14 μg/ml, p=0.001; 10.6 vs. 29.9 units/ng/ml total SIgA, p=0.015; respectively) and correlated inversely to episodes of tonsillitis (r=–0.242, p=0.024; r=–0.3, p=0.024; respectively). Either serum total immunoglobulin levels of IgG or IgA correlated positively to episodes of tonsillitis in children aged 2-5 years(r=0.293, p=0.011; r=0.361, p=0.002; respectively). No difference was found on either serum levels of IgG antibody tostreptococcal whole cell body or antibody to streptolysin-O between RT and non-RT children in any age-matched comparisons. High serum antibody levels to whole cell body was associated with high antibody levels to streptococcal LTA in non-RT children (r=0.198, p<0.05), but no association was found between these antibody levels in RT children. Conclusions: Selective immunologic failure in systemic and pharyngeal antibody response to streptococcal LTA may be a potential cause of RT in young children

Cochlear implantation in an adult patient with auditory neuropathy

The original publication is available at www.springerlink.com. authorWe present a case report of effective cochlear implantation for an adult patient with auditory neuropathy. A 34-year-old man developed bilateral hearing loss at approximately 10 years of age. His speech discrimination score was very severe despite only moderate sensorineural hearing loss. Absence of auditory brainstem responses (ABR) and preservation of distortion product otoacoustic emissions (DPOAE) were confirmed by our audiological examinations. After cochlear implantation, good responses for electrically evoked compound action potential (EAP) and electrically evoked ABR (EABR) were observed. Postoperatively, his audiological performance was significantly improved. We conclude that cochlear implantation can be a valid option for patients with auditory neuropathy

T-cell activation in tonsils of patients with pustulosis palmaris et plantaris

AuthorPustulosis palmaris et plantaris (PPP) is a well-known skin disease closely related to tonsillar focal infections, and tonsillectomy is very effective for treatment of this condition. However, etiology of PPP was unclear. In this study, we investigated the characteristics of tonsils from PPP patients by clinical, immunohistochemical, immunological, and molecular–biological approach, and considered the etiology of PPP. For 47 Japanese patients with PPP who have tonsillectomy in Asahikawa Medical College, the skin lesion of PPP was improved in 87% of PPP patients 12 months after tonsillectomy. In quantitative immunohistologic analysis by measurement of T-cell nodule areas on tonsillar sections from those patients, there was positive correlation between the enlargement and improvement of the skin lesion. These results suggested that the T-cell nodule expansion might be an important clue towards clarifying the pathogenesis of this tonsil related disease. In flow cytometric analysis, CD3+, CD4+ and CD4+CD25+ cells were significantly elevated in tonsillar lymphocyte from PPP patients. In reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analyses of TGF-beta, IL-10, and Smad group, Smad7 mRNA and protein in tonsillar CD3+ cells from PPP patients were expressed at higher level than those from obstructive sleep apnea syndrome (OSAS) patients. These results suggested that helper T cells may be frequently activated and proliferating in tonsils of PPP patients, and the activation and proliferation of helper T cells may be due to enhanced inhibition by Smad7 in intracellular signal-transduction of TGF-beta

Identification of human T-cell epitopes and highly immunogenic analog peptides on the non-typeable Haemophilus influenzae P6 outer membrane protein

authorP6 outer membrane protein is one of the candidates for a vaccine formulation against non-typeable Haemophilus influenzae (NTHi) infection. However, otitis-prone children who have recurrent episodes of acute otitis media due to NTHi fail to respond adequately to P6. An innovative approach to vaccination is therefore required to augment such children's immune response. To develop an effective peptide vaccine, we established P6-specific CD4^+ T-cell lines (TCLs) restricted by the human histocompatibility leukocyte antigen (HLA)-DR9 molecule, and revealed a human T-cell epitope on P6 and its core peptide sequence (p77–85; EYNIALGQR). Furthermore, we found that 3 analog peptides, E77D (the substitution of E at position 77 with D), N79G, and R85K, induced high proliferative responses as well as marked cytokine production when compared to the T-cell epitope peptide. These peptides may be candidates for a peptide vaccine formulation effective against NTHi infections, even in otitis-prone children