Impaired Proinflammatory Response in Stringently Defined Otitis-prone Children During Viral Upper Respiratory Infections.

BACKGROUND: Viral upper respiratory infections (URIs) are common and often precipitate acute otitis media (AOM), caused by bacterial otopathogens, in young children. Acute inflammatory responses initiated in the early phase of viral URI contribute to preventing the development of AOM. Stringently-defined otitis-prone (sOP) children are susceptible to recurrent AOM. METHODS: We assessed proinflammatory cytokine and chemokine levels in the nasopharynxes during viral URIs, and examined the different nasopharyngeal responses between viral URI events and the following AOM episodes in both sOP and non-otitis-prone (NOP) children. RESULTS: The sOP children exhibited significantly more AOM episodes per child (8.86-fold higher), viral URIs (P < .0001), and viral URIs followed by AOMs (P < .0001) than the NOP children. The sOP children had lower nasal proinflammatory levels of interleukin (IL)-6 (P = .05), IL-10 (P = .001), tumor necrosis factor (TNF)-α (P = .004), and regulated on activation, normal T-cell-expressed and -secreted (RANTES; P = .002) than NOP children during viral URIs. NOP children had higher levels of IL-6 (P = .02), IL-10 (P = .02), interferon-γ (P = .003), TNF-α (P = .006), IL-1ß (P = .022), monocyte chemoattractant protein 1 (P = .028), RANTES (P = .005), IL-2 (P = .002), and IL-17 (P = .007) during viral URIs versus AOMs following the URIs, when compared to sOP children. CONCLUSIONS: We conclude that sOP children have more frequent viral URIs than NOP children, due to deficient antiviral nasopharyngeal proinflammatory cytokine and chemokine responses.

Effect of oral sodium bicarbonate on fibroblast growth factor-23 in patients with chronic kidney disease: a pilot study.

BACKGROUND: The regulation of fibroblast growth factor-23 (FGF23) secretion in patients with chronic kidney disease (CKD) is incompletely understood. An in vitro study showed that metabolic acidosis increased FGF23 in mouse bone. The objective of this study is to evaluate the effect of oral sodium bicarbonate on circulating FGF23 levels in patients with CKD. METHODS: This was a single-blind pilot study. Twenty adults with estimated glomerular filtration rate between 15-45 mL/min/1.73 m(2) and serum bicarbonate between 20-24 mEq/L were treated with placebo for 2 weeks, followed by increasing doses of oral sodium bicarbonate (0.3, 0.6 and 1.0 mEq/kg/day) in 2 week intervals for a total of 6 weeks. C-terminal FGF23 levels were measured at the initial visit, after 2 weeks of placebo and after 6 weeks of bicarbonate therapy. Wilcoxon matched-pairs signed-rank test was used to compare FGF23 before and after sodium bicarbonate. RESULTS: After 6 weeks of oral sodium bicarbonate, the median FGF23 increased significantly from 150.9 RU/mL (IQR 107.7-267.43) to 191.4 RU/mL (IQR 132.6-316.9) (p = 0.048) and this persisted after excluding participants who received activated vitamin D. CONCLUSIONS: FGF23 increased after short-term oral sodium bicarbonate therapy in patients with CKD and mild metabolic acidosis. It is unclear whether this was due to the alkalinizing effect of sodium bicarbonate or other factors. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT00888290 ) on April 23, 2009.

Nef gene evolution from a single transmitted strain in acute SIV infection.

BACKGROUND: The acute phase of immunodeficiency virus infection plays a crucial role in determining steady-state virus load and subsequent progression of disease in both humans and nonhuman primates. The acute period is also the time when vaccine-mediated effects on host immunity are likely to exert their major effects on virus infection. Recently we developed a Monte-Carlo (MC) simulation with mathematical analysis of viral evolution during primary HIV-1 infection that enables classification of new HIV-1 infections originating from multiple versus single transmitted viral strains and the estimation of time elapsed following infection. RESULTS: A total of 322 SIV nef SIV sequences, collected during the first 3 weeks following experimental infection of two rhesus macaques with the SIVmac239 clone, were analyzed and found to display a comparable level of genetic diversity, 0.015% to 0.052%, with that of env sequences from acute HIV-1 infection, 0.005% to 0.127%. We confirmed that the acute HIV-1 infection model correctly identified the experimental SIV infections in rhesus macaques as "homogenous" infections, initiated by a single founder strain. The consensus sequence of the sampled strains corresponded to the transmitted sequence as the model predicted. However, measured sequential decrease in diversity at day 7, 11, and 18 post infection violated the model assumption, neutral evolution without any selection. CONCLUSION: While nef gene evolution over the first 3 weeks of SIV infection originating from a single transmitted strain showed a comparable rate of sequence evolution to that observed during acute HIV-1 infection, a purifying selection for the founder nef gene was observed during the early phase of experimental infection of a nonhuman primate.

Serum antibody response to Moraxella catarrhalis proteins in stringently defined otitis prone children.

BACKGROUND: Moraxella catarrhalis (Mcat) is a frequent pathogen of acute otitis media (AOM) in young children. Here we prospectively assessed naturally-induced serum antibodies to four Mcat vaccine candidate proteins in stringently defined otitis prone (sOP) and non-otitis prone (NOP) children age 6-36months old following nasopharyngeal (NP) colonization, at onset of AOM and convalescence from AOM. METHODS: Serum IgG and IgM antibody against recombinant Mcat proteins, oligopeptide permease A (OppA), outer membrane protein (OMP) CD, hemagglutinin (Hag), and PilA clade 2 (PilA2), were quantitated by ELISA. RESULTS: During NP colonization by Mcat all four antigens were immunogenic in both sOP and NOP children. However, sOP children had lower antibody responses than NOP children across age 6-36months, similar to our findings for protein vaccine candidates of Streptococcus pneumoniae (Spn) and Nontypeable Haemophilus influenzae (NTHi). sOP children displayed a later and lower peak of antibody rise than NOP children for all four antigens during NP colonization of Mcat. The age-dependent increase of antibody ranked as OppA>Hag5-9>OMP CD>PilA2 in both sOP and NOP children. Lower serum antibody levels to the Mcat antigens were measured in sOP compared to NOP children at the onset of AOM. We did not find a consistent significant increase of antibody at the convalescence phase after an AOM event. CONCLUSIONS: sOP children is a highly vulnerable population that mount lower serum antibody responses to Mcat candidate vaccine proteins compared to NOP children during asymptomatic NP carriage and at onset of AOM.

Synchrony in serum antibody response to conserved proteins of Streptococcus pneumoniae in young children.

Conserved Streptococcus pneumoniae (Spn) proteins are currently under investigation as vaccine candidates. We recently identified a subset of children prone to frequent acute otitis media (AOM) that we refer to as stringently-defined otitis prone (sOP). We investigated the synchrony of serum antibody responses against 5 Spn protein vaccine antigens, PhtD, LytB, PcpA, PhtE, and PlyD1 resulting from nasopharyngeal colonization and AOM in sOP children (49 observations) and non-otitis prone (NOP) children (771 observations). Changes in serum IgG and IgM were quantitated with ELISA. IgG antibody concentrations against PhtD, PcpA, and PlyD1 rose in synchrony in sOP and NOP children; that is, the proteins appeared equally and highly immunogenic in children at age 6 to 15 months and then leveled off in their rise at 15 to 25 months. In contrast, rises in concentrations to PhtE and LytB were significantly slower and had not peaked in children even at 25 months of age, consistent with lower immunogenicity. Serum IgM responses against PhtD and PlyD1 were in synchrony in children at age 6-25 months old. PcpA did not induce a significant increase of serum IgM response in children, suggesting that primary responses to PcpA occurred prior to children attaining age 6 months old. PhtD, PcpA, and Ply elicit a synchronous natural acquisition of serum antibody in young children suggesting that a trivalent Spn protein vaccine combining PhtD, PcpA, and PlyD1 would be less likely to display antigen competition when administered as a combination vaccine in young children.

Familial and microbiological contribution to the otitis-prone condition.

OBJECTIVE: Our group has an ongoing clinical research project investigating the immunology of the otitis-prone (OP) phenotype. In light of evidence that this condition arises from underlying immunological defects, we examined our sample population of stringently defined OP (sOP) children suffering 3 episodes of acute otitis media within 6 months or 4 within a year for a familial association with the sOP phenotype. METHODS: We analyzed the frequency of sOP within and between families and the nasopharyngeal (NP) otopathogen colonization patterns within and between families. RESULTS: The presence of sOP siblings significantly predicted that additional children in the same family would likewise become sOP, with an odds ratio of 3.7 (95% CI 0.77-15.2, 95% lower bound 0.95). We further present evidence for an environmental contribution to this effect by means of prolonged exposure to otopathogens within family units. CONCLUSION: sOP children have a significant familial association. The tendency of siblings to share similar patterns of microbial NP colonization contributes to this association. Further research is necessary to determine whether and to what extent genetics are involved.

Serum antibody response to Moraxella catarrhalis proteins OMP CD, OppA, Msp22, Hag, and PilA2 after nasopharyngeal colonization and acute otitis media in children.

BACKGROUND: There is no licensed vaccine for Moraxella catarrhalis (Mcat), which is a prominent bacterium causing acute otitis media (AOM) in children and lower respiratory tract infections in adults. Nasopharyngeal (NP) colonization caused by respiratory bacteria results in natural immunization of the host. To identify Mcat antigens as vaccine candidates, we evaluated the development of naturally induced antibodies to 5 Mcat surface proteins in children 6-30 months of age during Mcat NP colonization and AOM. METHODS: Human serum IgG against the recombinant Mcat proteins, outer membrane protein (OMP) CD, oligopeptide permease (Opp)A, hemagglutinin (Hag), Moraxella surface protein (Msp)22, and PilA clade 2 (PilA2) was quantitated by using an ELISA assay. RESULTS: There were 223 Mcat NP colonization episodes documented in 111 (60%) of 184 children in the study. Thirty five Mcat AOM episodes occurred in 30 (16%) of 184 children. All 5 Mcat candidate vaccine antigens evaluated stimulated a significant rise in serum IgG levles over time from 6 to 36 months of age (P<0.001), with a rank order as follows: Msp22=OppA>OMP CD=Hag=PilA2. Children with no detectable Mcat NP colonization showed a higher serum IgG level against OppA, Hag, and Msp22 compared to those with Mcat NP colonization (P<0.05). Individual data showed that some children responded to AOM with an antibody increase to one or more of the studied Mcat proteins but some children failed to respond. CONCLUSIONS: Serum antibody to Mcat candidate vaccine proteins OMP CD, OppA, Msp22, Hag, and PilA2 increased with age in naturally immunized children age 6-30 months following Mcat NP colonization and AOM. High antibody levels against OppA, Msp22, and Hag correlated with reduced carriage. The results support further investigation of these vaccine candidates in protecting against Mcat colonization and infection.

Simulator assessment of innate endovascular aptitude versus empirically correct performance.

OBJECTIVE: Prior work has established that performance on an endovascular simulator incorporating tactile feedback (haptics) correlates with previous endovascular experience and can be improved by training. This study was designed to test the ability to define and measure innate endovascular aptitude and empirically correct performance and to determine whether these are two different things. METHODS: Subjects ranging in endovascular skill level from novice to expert were surveyed to determine video game experience and skill, endovascular level of training, and endovascular experience. They were then tested by using a standard protocol requiring timed advancement of a catheter and wire sequentially into each of three vessels arising from a simulated type I arch. Recorded trials were independently and blindly scored by two experienced endovascular faculty members by using a modification of a previously validated scale (Modified Reznick Scale; MRS). Summed scores were analyzed by frequency analysis and categorized as satisfactory and unsatisfactory on the basis of a clear bimodal distribution. Categorical outcome, time to task completion, and other variables were analyzed by means of linear regression, analysis of variance, and Welch modified two-sample t tests, as indicated. RESULTS: A total of 61 subjects were enrolled: 42% students, 8% technicians, 19% surgeons, 13% cardiologists, and 18% radiologists. Of these, 62% were considered novices and 30% experts on the basis of previous experience; 56% of subjects worked in an endovascular-related occupation. MRS scores were highly correlated between raters (P < .0001) and showed a clear bimodal distribution, with subjects in any endovascular occupation (including technicians) scoring significantly better than all others (P < .0001). Hours of video games played per week were correlated highly with completion times (P < .001) and MRS scores (P < .001). Measures of formal training (number of endovascular cases and occupation) correlated highly with completion times (all P < .03) and MRS scores (all P < .008). In comparing completion times vs MRS scores, three groups were apparent: unskilled-inexperienced, skilled-inexperienced, and skilled-experienced, corresponding primarily to senior subjects without endovascular experience, younger subjects without endovascular experience, and formally trained endovascular physicians, respectively. Those judged intermediate in aptitude reduced times to the lowest possible level before improving their MRS scores. CONCLUSIONS: Although inherently subjective, the MRS yields reproducible scores that correlate with endovascular experience and formal training. Experts and novices with extensive video game experience achieve short completion times, whereas high MRS scores are achieved only by formally trained subjects. Innate endovascular aptitude and empirically correct performance may be two separate things, and aptitude may be acquirable through (or identified by) extensive nonmedical video game experience.