Damage associated molecular patterns within xenogeneic biologic scaffolds and their effects on host remodeling.

The immune response is an important determinant of the downstream remodeling of xenogeneic biologic scaffolds in vivo. Pro-inflammatory responses have been correlated with encapsulation and a foreign body reaction, while anti-inflammatory reactions are associated with constructive remodeling. However, the bioactive and bioinductive molecules within the extracellular matrix (ECM) that induce this polarization are unclear, although it is likely that cellular remnants such as damage associated molecular patterns (DAMPs) retained within the scaffold may play a role. The present study investigated the immunomodulatory effects of common ECM scaffolds. Results showed that tissue source, decellularization method and chemical crosslinking modifications affect the presence of the well characterized DAMP - HMGB1. In addition, these factors were correlated with differences in cell proliferation, death, secretion of the chemokines CCL2 and CCL4, and up regulation of the pro-inflammatory signaling receptor toll-like receptor 4 (TLR4). Inhibition of HMGB1 with glycyrrhizin increased the pro-inflammatory response, increasing cell death and up regulating chemokine and TLR4 mRNA expression. The present study suggests the importance of HMGB1 and other DAMPS as bioinductive molecules within the ECM scaffold. Identification and evaluation of other ECM bioactive molecules will be an area of future interest for new biomaterial development.

Otitis media and associations with overweight status in toddlers.

INTRODUCTION: Otitis media (OM) is a significant disease that affects nearly all children early in life. Recently, childhood overweight has become an epidemic. Past research has demonstrated that a history of OM is related to food preferences and overweight through proposed physiological mechanisms. The purpose of this study was to explore the relationship between recurrent OM (ROM)/tympanostomy tube treatment and overweight status. METHODS: Data were analyzed from a prospective cohort of mothers and children recruited from 1991-1996 from a local health maintenance organization. ROM and tympanostomy tube status were obtained through a combination of physical exam and medical record abstraction. ROM and tympanostomy tube status were analyzed as categorical variables with weight-for-length (WFL) data from well child checks. Chi-square and logistic regression for univariate and multivariate analyses were performed. RESULTS: 11.4% of children had a WFL measure at two years of age ≥ 95 th percentile. Those children with a history of tympanostomy tube treatment had a significantly increased risk of having a WFL ≥ 95 th percentile after controlling for birth weight, maternal prenatal smoking, maternal education, and family income (OR 3.32, 95% CI 1.43-7.72). The alternative hypothesis that children with larger WFL at two month of age would have a greater number of OM episodes by two years of age was not significant. CONCLUSION: The findings of this study are consistent with the hypothesis and prior research that OM treated with tympanostomy tubes is associated with overweight status.

Low cord blood pneumococcal antibody concentrations predict more episodes of otitis media.

OBJECTIVE: To determine if cord blood anticapsular polysaccharide pneumococcal IgG antibody concentration was related to the number of otitis media (OM) and acute OM episodes during the first year of life. DESIGN: Prospective study following infants from birth to 24 months. SETTING: Health maintenance organization. PATIENTS: The study population consisted of 415 infants whose mothers volunteered for the study during pregnancy. Cord blood samples were collected and infants were followed up for OM in the health maintenance organization. Ninety-seven percent of the infants were white, 49% male, 3% from households with annual incomes of less than $20 000, and 30% from households with annual incomes of more than $60 000. MAIN OUTCOME MEASURE: Number of physician-diagnosed OM episodes, including both OM with effusion and acute OM, and acute OM episodes from birth to 12 months. RESULTS: With univariate analysis, low cord blood antibody concentrations against serotypes 3 and 19F predicted more acute OM episodes (P =.04 and P =.05, respectively), and low antibody concentrations against serotypes 19F and 23F predicted more OM episodes (P =.04 and P =.05, respectively) over the first year of life. With Poisson regression, which adjusted for variables related to the recurrence of OM and having low cord blood antibody concentrations, serotype 19F remained significantly related to the number of OM episodes (relative risk for lowest quartiles vs upper 3 quartiles 1.23; 95% confidence interval, 1.02-1.50; P =.03). CONCLUSIONS: Low cord blood antibody concentrations to serotype 19F predicted more OM episodes over the first 12 months of life. These results suggest the potential benefit of maternal immunization to raise neonatal antipolysaccharide pneumococcal antibody concentration and delay the onset and reduce the number of OM episodes.

Low cord blood type 14 pneumococcal IgG1 but not IgG2 antibody predicts early infant otitis media.

Type-specific IgG1 and IgG2 antibodies to Streptococcus pneumoniae capsular polysaccharides 14 and 19F were measured in cord blood samples from 425 neonates, to determine which antibody subclass was most strongly associated with otitis media (OM) during the first 6 months of life (early OM). Early OM was significantly associated with type 14 IgG1 antibody in the lowest antibody quartile (P=.055) but not with type 19F IgG1 antibody or with either IgG2 antibody. IgG1 and IgG2 antibodies were significantly intercorrelated for type 14 (r=.52, P<.001) and type 19F (r=.38, P<.001). Multivariate analysis revealed that having type 14 IgG1 antibody in the lowest quartile, child care attendance, and sibling and maternal OM history were independent risk factors for early OM. Although type-specific pneumococcal IgG2 antibody concentrations were significantly higher than IgG1 concentrations, IgG2 antibodies apparently are not protective against OM during early infancy.

Epidemiology of otitis media onset by six months of age.

OBJECTIVE: Although early otitis media (OM) onset predicts later recurrent and chronic OM, little research has been directed at illuminating the role of prenatal exposures in early OM. This prospective study examined prenatal, innate, and early environmental exposures associated with acute otitis media (AOM) onset and recurrent OM (ROM) by age 6 months. DESIGN AND METHODS: Prospective study of 596 infants from a health maintenance organization followed from birth to 6 months. Mothers completed monthly forms on prenatal exposures (diet, medications, and illnesses) and infant risk factors (eg, smoke exposure and child care) during pregnancy and until infants were 6 months old. Urine samples were collected when infants were 2 months of age and analyzed for cotinine and creatinine. Physicians and nurse practitioners examined infants at each clinic visit and completed standard ear examination forms. RESULTS: Thirty-nine percent had an episode of AOM and 20% had ROM by age 6 months. Using Cox's regression models to control for confounding, respiratory tract infection (relative risk [RR] 7.5), day care (RR 1. 7), >1 sibling (RR 1.4), maternal, paternal, and sibling OM history (RR 1.6, 1.5, and 1.7, respectively) were significantly related to early OM onset. ROM was related to respiratory tract infection (RR 9. 5), day care (RR 1.9), conjunctivitis (RR 2.0), maternal OM history (RR 1.9), and birth in the fall (RR 2.6). Among prenatal exposures, only high prenatal dietary vitamin C intake was significantly inversely related to early AOM with univariate but not multivariate analysis. CONCLUSION: Prenatal factors were not linked to early AOM onset with multivariate analysis, but environmental and innate factors play an important role in early AOM onset. Strategies to reduce exposure to environmental variables could reduce rates of early AOM, which could potentially result in declining rates of ROM and chronic OME.

Chronic otitis media with effusion.

Chronic OME, which arises from a complex series of inflammatory events in the middle ear, affects approximately 5% to 30% of children. The mean duration of MEE is 16 to 20 weeks during the first 2 years of life. This condition is diagnosed best with pneumatic otoscopy and tympanometry. The risk of chronic OME is increased by environmental factors and characteristics of the child, including disease history. Approximately 70% of MEE are culture-positive, with approximately 50% of these yielding S pneumoniae, H influenzae, or M catarrhalis. However, antibiotic treatment of acute otitis media and OME has only a minimal effect on the long-term resolution of MEE. Research has shown that 70% of children who have chronic OME suffer mild-to-moderate hearing loss, so a child who has bilateral MEE for 3 months should undergo hearing evaluation. If the child has hearing impairment, referral to an otolaryngologist for myringotomy and tympanostomy tube insertion is a treatment option that the AHCPR recommends after 4 months of effusion with hearing loss. Sequelae of chronic OME include deficient expressive language and poorer attention skills due to the temporary hearing loss associated with OME, high-frequency sensorineural hearing loss, tympanic membrane atrophy, perforation, retraction, atelectasis, and cholesteatoma.

Relationships between otitis media sequelae and age.

OBJECTIVES: To explore relationships between age and sequelae in two groups of children treated with tympanostomy tubes for chronic otitis media with effusion (OME). STUDY DESIGN: Cross-sectional study of sequelae among children, adolescents, and adults at 4 years and 9 to 23 years after tympanostomy tube treatment. METHODS: Group I was examined with otomicroscopy, tympanometry, and audiometry two to four times a year as part of a prospective study, and they were evaluated 4 years after initial tube treatment for this study. Group II received tubes while participating in a chronic OME study, but participants were not followed prospectively after treatment. Nine to 23 years after tube treatment, they were examined with otomicroscopy, tympanometry, and hearing screening. RESULTS: Among the 5- to 28- year-old subjects, cholesteatoma (< or = 1%) and perforation (< or = 2%) were rare. In Group I, tympanosclerosis increased with age (P < .01), and OME (flat tympanograms) decreased with age in Group II (P < .01). The older cohort was more likely to have severe retractions (18% vs. 4%, P = .02), hearing loss (21% vs. 10%, P < .01), and severe atrophy (24% vs. 0%, P < .01) than the younger cohort, but they were less likely to have flat tympanograms (2% vs. 12%, P < .01). CONCLUSIONS: Although OME became less prevalent with age, important sequelae (severe atrophy, severe tympanic membrane retraction, hearing loss, cholesteatoma, and chronic perforation) may develop in children with chronic OME as they become adolescents and young adults. Long-term prospective studies are important in defining the progression of sequelae in these children.

Use of electrocochleography in the diagnosis of Meniere's disease.

OBJECTIVE: The diagnosis of Meniere's disease has always been a source of confusion. There is no single test that is definitive for the diagnosis. Recent advances have enabled clinicians to noninvasively test the function of the inner ear and its associated neural pathways. The electrocochleogram (ECOG) has been advocated as a reliable test that is diagnostic for Meniere's disease. This study was undertaken to assess the value of ECOG in establishing the diagnosis of Meniere's disease. STUDY DESIGN: Patients who were suspected of having Meniere's disease were prospectively entered into a study of the diagnostic value of ECOG. Each patient had a complete evaluation including a detailed history, physical examination, laboratory studies, and audiometric tests. SETTING: University otolaryngology clinic. PATIENTS: A group of 199 patients who presented to a neurotology clinic and were suspected to have symptoms consistent with Meniere's disease. INTERVENTION: ECOG testing. MAIN OUTCOME MEASURES: Audiometric thresholds, action potential magnitude (AP), summating potential amplitude (SP), AP latency, and clinical evaluations were assessed. RESULTS: The ECOG was found to correlate with historical and audiometric criteria that are used to diagnose the disease. The percentage of abnormal ECOG did not correlate with stage of disease or duration of time that symptoms were present. CONCLUSIONS: The ECOG has limited value in the diagnosis of Meniere's disease. It appears to correlate with the length of time patients experience symptoms and their audiometric findings. It was not correlated with the number of symptoms that the patient experienced at the time that the study was conducted.

Extracting dynamic information from EXAFS: simultaneous analysis of multiple temperature-dependent data.

A new approach to the extraction of dynamic information from extended X-ray absorption fine-structure (EXAFS) spectra has been developed. With this method, a complete set of temperature-dependent spectra are fit simultaneously to one of a variety of pair-distribution functions. Distributions are calculated in r-space using the appropriate absorber-scatterer pair potential. The temperature-dependent EXAFS spectra are calculated by summing k-space models over a range of distances and angles weighted according to the relative contribution of each geometry to the distribution. This approach allows refinement of data using a full multiple-scattering analysis with only modest computational time.

Knowledge and attitudes about otitis media risk: implications for prevention.

OBJECTIVES: To investigate maternal knowledge and attitudes about otitis media (OM) risk, to estimate the prevalence of risk factors in the first year of life, and to identify barriers to the reduction of risk factors (eg, formula feeding, day care attendance, and exposure to passive smoke). METHODS: Questionnaires mailed to a systematic sample of 504 Minnesota women >/=18 years old identified through 1994 birth certificates. RESULTS: Eighty percent returned a completed survey. According to maternal report, 29% of infants (age 8 to 13 months) had recurrent OM (>/=3 episodes) and 2% had tympanostomy tubes. Forty-six percent attended day care, 29% had >/=1 smoking parent, and 49% breastfed for

Low cord blood pneumococcal immunoglobulin G (IgG) antibodies predict early onset acute otitis media in infancy.

Low maternally derived serum immunoglobulin G (IgG) antibodies to Streptococcus pneumoniae capsular polysaccharides (PS) combined with the inability of infants to produce anti-PS antibody may explain onset of otitis media in the first 6 months of life. To explore this relation, cord blood samples were assayed for anti-PS IgG antibodies from 414 of 592 infants enrolled in a study of early onset otitis media between 1991 and 1994. Infants' ears were examined at health supervision and illness visits for the first 6 months of life in a large Minneapolis-St. Paul, Minnesota, health maintenance organization. Antibodies to seven common pneumococcal serotypes (3, 4, 6B, 14, 18C, 19F, and 23F) were measured by enzyme-linked immunoabsorbent assay (ELISA). Cox's regression analysis revealed that among infants with a sibling otitis media history, those with low concentrations of type 14 or 19F anti-PS cord blood antibody had earlier otitis media onset than those with higher cord blood antibody concentrations (relative risks (RR) (95% confidence intervals (CI)) = 1.77 (1.05-2.99) and 1.89 (1.11-3.23), respectively). Day care attendance also increased risk (RR = 1.56, 95% CI 0.96-2.52). Breastfeeding, parental smoking, and low anti-PS antibody to pneumococcal serotypes 3, 4, 6B, 18C, and 23F did not significantly affect the risk of early otitis media.

High frequency hearing loss associated with otitis media.

OBJECTIVE: Long-term effects of otitis media (OM) on hearing in both conventional and high frequency (HF) regions in children were studied. DESIGN: Children with OM were enrolled in a prospective study of sequelae after tympanostomy tube insertion (intubation) and were examined serially at 6-mo intervals with audiometry and multifrequency tympanometry, and every 3 mo with tympanometry and otoscopy for at least 3, and up to 5 yr. Hearing thresholds in conventional and HF regions were compared with those of an age-matched control group of children who had 2 or fewer documented episodes of any type of OM since birth. Frequency of OM during follow-up, number of intubations, use of ototopical eardrops, age, and sex along with several other factors were analyzed for a relationship to HF hearing loss. RESULTS: Otitis media history was associated with poorer HF hearing, but the presence of subtle residual middle ear dysfunction was not associated with an additional effect on HF hearing. Active middle ear disease significantly affected both conventional and HF thresholds. The number of intubations and frequency of OM during follow-up were significantly and positively associated with poorer HF thresholds. Several other factors, including middle ear appearance at intubation, presence of tympanosclerosis, age, male gender, and use of ototopical eardrops, were also associated with poorer HF hearing but failed to reach significance after their intercorrelation with number of intubations and frequency of OM was considered. CONCLUSIONS: High frequency hearing loss was associated with OM after middle ear disease resolved and after middle ear dysfunction was excluded. Relatively poorer HF hearing thresholds found for older children with OM histories appeared to be attributable to time spent with ear disease. Children at greatest risk for HF hearing loss were those who required multiple intubations. Older children tended to have poorer hearing in both conventional and HF regions, suggesting that the effects of OM on hearing thresholds may be progressive.

The family study of otitis media: design and disease and risk factor profiles.

Recurrent acute otitis media (RAOM) and chronic otitis media with effusion (COME) exhibit familial aggregation, but environmental risk factors (day care attendance, cigarette smoke exposure, and bottle feeding) are also important in their development. The Family Study of OM was designed to ascertain the RAOM/ COME status of families whose children participated in Otitis Media Research Center studies between 1978 and 1984. Probands were treated with tympanostomy tubes, and had their RAOM/COME status ascertained as criteria for entry into these studies. For the Family Study of OM parents were interviewed about their otitis media and risk factor history; mothers were interviewed about their children's history, and pertinent medical records were obtained. Members of 173 families were examined with otomicroscopy and multifrequency tympanometry; 19% of parents and 32% of siblings were classified as affected, which is substantially higher than RAOM/COME rates from previous reports. Risk factor profiles differed significantly (P < .001) between parents and their children. Younger generation (adjusted odds ratio [OR] = 4.18, 95% confidence interval [CI], 2.74, 6.36) day care attendance (OR = 1.96, 95% CI, 1.32, 2.91) and male gender (OR = 1.42, 95% CI, 1.03, 1.97) were significantly related to RAOM/ COME using logistic regression. Analyses confirm 1) higher disease rates in families with an affected member compared to existing studies of the general population, 2) increased risk of RAOM/COME associated with known risk factors, and 3) increased risk for parents irrespective of risk factors. Additional analyses will explore competing models of disease susceptibility using genetic models and known risk factors.

Randomized trial of the efficacy of trimethoprim-sulfamethoxazole and prednisone in preventing post-tympanostomy tube morbidity.

This study was designed to determine whether treatment with prednisone and trimethoprim-sulfamethoxazole would reduce first year post-operative morbidity in children with chronic otitis media with effusion undergoing tympanostomy tube insertion (intubation). Eighty children ages 6 months to 8 years were enrolled at intubation and randomized from age strata to receive active drugs or placebos for 14 days after surgery. They were examined with pneumatic otoscopy and tympanometry preoperatively and at 3 weeks and 3, 6, 9 and 12 months after surgery. Active drug treatment significantly reduced tube obstruction or extrusion in the first 3 postoperative months compared with placebos (4% vs. 17%, P = .01). However, rates of repeat intubation, otorrhea and recurrence of otitis media did not differ significantly in the two groups. Children with chronic otitis media with effusion treated with intubation may benefit from a 2-week course of prednisone and trimethoprim-sulfamethoxazole at the time of surgery. However, there is no apparent long term benefit of this treatment.

Tobacco smoke and otitis media in the chinchilla model.

To determine whether tobacco smoke contributes to the pathogenesis of acute otitis media, chinchillas were exposed to mainstream tobacco smoke or sham conditions (cigarettes not lit) in a Walton smoke exposure machine for 20-minute cycles two or three times daily. After 6 to 8 weeks of daily exposure, 12 chinchillas were nasally injected with Streptococcus pneumoniae, and 18 chinchillas were injected into both middle ears with nontypable Haemophilus influenzae. Smoke or sham exposures were continued for 2 to 4 weeks after injection. Otitis media developed in none of the 12 nasally injected chinchillas and in all 18 chinchillas whose middle ears were injected with nontypable Haemophilus influenzae. Persistence of middle ear effusion and persistence of nontypable Haemophilus influenzae in the middle ear effusion were not different between the smoke- and sham-exposed groups. This suggests that mainstream smoke exposure does not change the natural course of otitis media in the chinchilla model.

Validity of parental report of a child's medical history in otitis media research.

The authors compared parental reports with medical records for 157 children enrolled in a prospective study of chronic otitis media with effusion between 1987 and 1991. Parents completed a questionnaire about the child's past health history, and the research nurse abstracted history information from the clinic's medical record. Previous insertion of a tympanostomy tube (kappa = 0.96) and premature birth (kappa = 0.68) were accurately reported, but there was a substantial proportion of missing data for age at first episode of otitis media, occurrence of otitis media the previous summer, and number of episodes in the previous 18 months. Data were significantly more likely to be missing for male children, children with siblings, and those with more episodes. Parents who reported six or more previous episodes for their child overestimated the number compared with the medical record (8.7 vs. 7.4, respectively; p = 0.01), while those who reported fewer episodes underestimated the number (3.1 vs. 4.6, respectively; p = 0.01). Episodes of otitis media during the 3 months between study visits were also accurately reported (kappa = 0.94). The accuracy and completeness of parental report of the child's health history was influenced by the chronicity of otitis media, the duration of recall, and the seriousness of the event being recalled.