For the first time, in 2002, the Advisory Committee on Immunization Practices encouraged the vaccination of healthy children 6 to 23 months against influenza, whenever feasible. Participating ...inner-city health centers designed interventions to introduce influenza vaccination among this group of children. The study was designed to assess parents’ attitudes toward the vaccine.
Following the 2002–2003 influenza vaccination season, parents were surveyed to identify barriers to and facilitators of influenza vaccination. A low-literacy level, 19-question survey was mailed to parents in three waves, 4 weeks apart. A subset of children had medical record data available to confirm vaccination status. Measures of validity were calculated. This paper focused only on the children whose parent-reported vaccination status was concordant with that reported in medical records (
n=193). Associations of responses to vaccination status were calculated in 2004, using chi-square and logistic regression procedures.
Sensitivity was 85.7% and specificity was 66% (κ=0.50), assessing the ability of parents to recall receipt or nonreceipt of influenza vaccine. The most important factors related to immunization of healthy infants were perceived doctor’s recommendation (odds ratio OR=5.5; 95% confidence interval CI=2.4–12.3;
p<0.001) and belief that getting an influenza shot is a smart idea (OR=3.5; 95% CI=1.3–8.9;
p<0.01) for those with medical record–confirmed vaccination status.
A clear message that the doctor recommends influenza vaccination for a child is an important factor for ensuring vaccination, and may foster the idea that vaccination is “smart.”
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Two members of the recently identified FcR homolog (FcRH) family in mice demonstrate preferential B cell expression. One of these, FcRH3, encodes a type I transmembrane protein with five ...extracellular Ig domains and a cytoplasmic tail with a consensus ITIM and a noncanonical ITAM. Analysis of full-length cDNAs from five different mouse strains defines two FcRH3 alleles. A panel of FcRH3-specific mAbs was generated to define its expression pattern and functional potential on B lineage cells. Although poorly detected on the majority of bone marrow or peripheral blood cells, FcRH3 was readily identified on splenic marginal zone (MZ) and MZ precursor B cells, but not on the bulk of newly formed B cells, follicular B cells, germinal center B cells, and plasma cells. In the peritoneal cavity, FcRH3 was found on B1 cells, and not on the majority of B2 cells. Consistent with its possession of an ITIM and ITAM-like sequence, FcRH3 was tyrosine phosphorylated following pervanadate treatment, and its coligation with the BCR inhibited calcium mobilization. These results suggest FcRH3 is a novel immunoregulatory marker of MZ and B1 B lineage cells.
The short splice variant of mouse terminal deoxynucleotidyl transferase (TdTS) catalyzes the addition of nontemplated nucleotides (N addition) at the coding joins of B cell and T cell antigen ...receptor genes. However, the activity and function of the long isoform of TdT (TdTL) have not been determined. We show here, in vitro and in vivo, that TdTL is a 3'-->5' exonuclease that catalyzes the deletion of nucleotides at coding joins. These findings suggest that the two TdT isoforms may act in concert to preserve the integrity of the variable region of antigen receptors while generating diversity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding the selection and decay of drug-resistant HIV-1 variants is important for designing optimal antiretroviral therapy.
To develop a high-throughput, real-time reverse transcriptase (RT) ...polymerase chain reaction (PCR) assay to quantify non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants K103N (AAT or AAC alleles) at frequencies as low as 0.1%, and to apply this to monitor these variants before, during, and after NNRTI therapy.
HIV-1 RNA in longitudinal plasma samples obtained from patients starting and stopping NNRTI therapy was converted to cDNA and the target sequence region amplified and quantified by real-time PCR. Approximately 10 copies/reaction provided a template for a second round of PCR using primers that discriminated between the mutant and wild-type alleles. Amplification specificity was confirmed by thermal denaturation analysis.
Frequencies of 103N similar to assay background (0.029%) were observed in longitudinal samples from 9 of 12 treatment-naive patients; three patients had transient increases in 103N frequency to a range of 0.21-0.48%, which was 7-16.5 times assay background. Analysis of longitudinal plasma samples from six NNRTI-experienced patients showed three patterns: persistence of 103N variants after stopping NNRTI therapy, codon switching of 103N between AAC and AAT during NNRTI therapy, and decay of 103N variants to below assay background after cessation of NNRTI therapy.
Allele-specific RT-PCR quantified the emergence and decay of drug-resistant variants in patients over a broad range of frequencies (0.1-100%). The rate of decay of K103N variants after stopping NNRTI therapy was highly variable.
V(D)J recombination generates a remarkably diverse repertoire of antigen receptors through the rearrangement of germline DNA. Terminal deoxynucleotidyl transferase (TdT), a polymerase that adds ...random nucleotides (N regions) to recombination junctions, is a key enzyme contributing to this diversity. The current model is that TdT adds N regions during V(D)J recombination by random collision with the DNA ends, without a dependence on other cellular factors. We previously demonstrated, however, that V(D)J junctions from Ku80-deficient mice unexpectedly lack N regions, although the mechanism responsible for this effect remains undefined in the mouse system. One possibility is that junctions are formed in these mice during a stage in development when TdT is not expressed. Alternatively, Ku80 may be required for the expression, nuclear localization or enzymatic activity of TdT. Here we show that V(D)J junctions isolated from Ku80-deficient fibroblasts are devoid of N regions, as were junctions in Ku80-deficient mice. In these cells TdT protein is abundant at the time of recombination, localizes properly to the nucleus and is enzymatically active. Based on these data, we propose that TdT does not add to recombination junctions through random collision but is actively recruited to the V(D)J recombinase complex by Ku80.
To study the dynamics of wild-type and drug-resistant HIV-1 RT variants, we developed a methodology that follows the fates of individual genomes over time within the viral quasispecies. Single genome ...sequences were obtained from 3 pigtail macaques infected with a recombinant simian immunodeficiency virus containing the RT coding region from HIV-1 (RT-SHIV) and treated with short-course efavirenz monotherapy 13 weeks post-infection followed by daily combination antiretroviral therapy (ART) beginning at week 17. Bioinformatics tools were constructed to trace individual genomes from the beginning of infection to the end of the treatment.
A well characterized challenge RT-SHIV inoculum was used to infect three monkeys. The RT-SHIV inoculum had 9 variant subpopulations and the dominant subpopulation accounted for 80% of the total genomes. In two of the three monkeys, the inoculated wild-type virus was rapidly replaced by new wild type variants. By week 13, the original dominant subpopulation in the inoculum was replaced by new dominant subpopulations, followed by emergence of variants carrying known NNRTI resistance mutations. However, during ART, virus subpopulations containing resistance mutations did not outgrow the wide-type subpopulations until a minor subpopulation carrying linked drug resistance mutations (K103N/M184I) emerged. We observed that persistent viremia during ART is primarily made up of wild type subpopulations. We also found that subpopulations carrying the V75L mutation, not known to be associated with NNRTI resistance, emerged initially in week 13 in two macaques. Eventually, all subpopulations from these two macaques carried the V75L mutation.
This study quantitatively describes virus evolution and population dynamics patterns in an animal model. The fact that wild type subpopulations remained as dominant subpopulations during ART treatment suggests that the presence or absence of at least some known drug resistant mutations may not greatly affect virus replication capacity in vivo. Additionally, the emergence and prevalence of V75L indicates that this mutation may provide the virus a selective advantage, perhaps escaping the host immure system surveillance. Our new method to quantitatively analyze viral population dynamics enabled us to observe the relative competitiveness and adaption of different viral variants and provided a valuable tool for studying HIV subpopulation emergence, persistence, and decline during ART.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Minorities and those living in the inner city have a higher respiratory disease burden than other groups. Yet, influenza vaccination rates among all children with chronic medical conditions remain ...low.
Parents of 2-13-year-old children with high-risk medical conditions from health centers in low-income urban neighborhoods completed a mailed survey. Immunization status from medical records was used to calculate validity measures. Survey data are presented for those whose vaccination status was concordant between parental report and the medical record (n=183).
Parent-reported influenza vaccination versus medical record review showed 84.9% sensitivity, 68.7% specificity, 49.1% positive predictive value and 92.7% negative predictive value, with a kappa of 0.43. Vaccination rate was 30.6%. Medical record-verified influenza vaccination was associated with parental beliefs that the doctor recommends a flu shot (OR, 40.9; 95% Cl, 9.0-184.9) and that relatives recommend a flu shot (OR, 4.3; 95% Cl, 1.7-10.5), and was less likely if the parent believed that the child will get the flu if a household member is infected (OR, 0.2; 95% Cl, 0.1-0.6).
The message that influenza vaccination is important to protect children with chronic medical conditions may be relayed through physician recommendation or a relative's suggestion and may be more effective if it addresses vaccine efficacy issues.
A 5-week-old female infant with vertical HIV-1 exposure, progressive cough, and failure to thrive was given a diagnosis of bilateral diffuse nodular lung lesions. The child was without fever, ...leukocytosis, anemia, peripheral adenopathy, or hepatosplenomegaly, and the results of repeated blood tests for HIV-1 DNA were negative. A needle biopsy of the lungs revealed granulomatous inflammation and giant cells, with fungal organisms suggestive of Aspergillus species. A nitroblue tetrazolium dye test performed on the patient's blood specimen demonstrated absence of dye reduction, suggesting a diagnosis of chronic granulomatous disease. Further analysis revealed that the child had a deficiency of the p47phox component of the nicotinamide adenine dinucleotide phosphate oxidase system. Thus this child with vertical HIV-1 exposure and diffuse pulmonary nodules actually had an autosomal recessive form of chronic granulomatous disease. This case study clearly demonstrates that children with suspected HIV-1 infection might also need evaluation for primary immunodeficiency and that the clinical immunology laboratory is a powerful adjunct in coming to a correct diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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