Publications

We investigated whether early life chronic exposure to woodsmoke, using personal passive 48-h carbon monoxide (CO) as an indicator, is associated with children's neurodevelopmental and behavioral performance. CO measures were collected every 3 months from 2002 to 2005 among mother-child dyads during the Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) stove intervention trial in San Marcos, Guatemala. From March to June, 2010, study children of age 6-7 years, performed a follow-up non-verbal, culturally adapted neurodevelopmental assessment. We found inverse associations between CO exposure of pregnant mothers during their 3rd trimesters (m=3.8ppm ± 3.0ppm; range: 0.6-12.5 ppm) and child neuropsychological performance. Scores on 4 out of 11 neuropsychological tests were significantly associated with mothers' 3rd trimester CO exposures, including visuo-spatial integration (p<0.05), short-term memory recall (p<0.05), long-term memory recall (p<0.05), and fine motor performance (p<0.01) measured using the Bender Gestalt-II's Copy, Immediate Recall, and an adapted version of a Delayed Recall Figures drawing, and the Reitan-Indiana's Finger Tapping Tests, respectively. These 4 significant finding persisted with adjustment for child sex, age, visual acuity, and household assets (socio-economic status). Summary performance scores were also significantly associated with maternal 3rd trimester CO when adjusted for these covariates. Other variables accounting for variance but were excluded in our final multiple regression models included the following: HOME environment stimulation score, child examiner, WHO height-for-age percentile, and age that the infant stopped breastfeeding. This seems to be the first study on woodsmoke exposure and neurodevelopment, and the first longitudinal birth cohort study on chronic early life CO exposures, determined by high quality measures of mothers' and infants' personal CO exposures, and using well-established, reliable child neuropsychological tests. Further research is needed to replicate our results and inform future interventions and air quality standards for woodsmoke and CO.

OBJECTIVE AND DESIGN

Increasing evidence supports a parallel between HIV-1 infection and immune aging, which is particularly apparent with common changes in naive versus memory T-cell proportions. Here, we aimed at refining the value of common T-cell-associated markers of immunosenescence during HIV disease progression or aging, and at exploring further the impact in this context of old age as well as cytomegalovirus (CMV) co-infection, which is predominant in HIV-1-infected individuals.

METHODS

Frequencies of naive or CD57(+) memory T cells as well as the magnitude of CMV-pp65 T cells were measured in HIV-1-infected patients grouped according to disease progression status, treatment and age.

RESULTS

Our results indicate that the decline in naive T-cell levels rather than the accumulation of CD57(+) senescent T cells identifies best the premature development of an immunosenescence phenotype with HIV disease progression. Moreover, advanced age or mounting of strong CMV-specific responses impact independently on CD4(+) T-cell counts and recovery with antiretroviral therapy.

CONCLUSIONS

The present findings indicate that HIV-1 infection amplifies the effect of age on naive T-cell levels, and highlight the constraint on the capacity of treated patients to reconstitute their CD4(+) T-cell compartment due to age and CMV co-infection.

AIM

Prior studies have reported conflicting results on the yield of esophagogastroduodenoscopy (EGD) in patients with a positive fecal occult blood test (FOBT). Our aim was to compare the yield between EGD and colonoscopy performed in a racially diverse population with a positive FOBT.

METHODS

A retrospective, cross-sectional study of FOBT positive patients who underwent EGD and colonoscopy from January 1, 1999 to November 1, 2008. Endoscopic lesions deemed responsible for GI bleeding were identified.

RESULTS

Two hundred and eighty-seven patients met entry criteria, among which, 63% were Asian and 81% were immigrants to the U.S. Forty-four patients had EGD findings deemed responsible for a positive FOBT, the most common being esophagitis (25.0%) and gastric ulceration (15.9%). Forty-two patients had colonoscopic findings likely responsible for a positive FOBT with the most frequent lesion being colonic polyps ≥9 mm in diameter (76.2%). Prevalence of lower and upper GI tract lesions responsible for positive FOBT was similar (14.6% vs. 15.3%, p = 0.2). There was no association between a patient reporting upper GI symptoms, or the presence of anemia and the detection of upper GI tract lesions on endoscopy. Gastric adenocarcinoma (n = 3) was as prevalent as colorectal adenocarcinoma (n = 4). All three patients with gastric adenocarcinomas were Asian (prevalence 1.6%).

CONCLUSIONS

In our racially diverse population evaluated for a positive FOBT, gastric adenocarcinoma was as prevalent as colorectal adenocarcinoma; however, gastric adenocarcinoma was limited to Asian patients. EGD and colonoscopy should be considered in the evaluation of patient populations similar to ours, particularly Asian immigrants.

BACKGROUND

Streptococcus oralis, Streptococcus mitis, and Streptococcus sanguinis are members of the Mitis group of streptococci and agents of oral biofilm, dental plaque and infective endocarditis, disease processes that involve bacteria-bacteria and bacteria-host interactions. Their close relative, the human pathogen S. pneumoniae uses pilus-islet 2 (PI-2)-encoded pili to facilitate adhesion to eukaryotic cells.

METHODOLOGY/PRINCIPAL FINDINGS

PI-2 pilus-encoding genetic islets were identified in S. oralis, S. mitis, and S. sanguinis, but were absent from other isolates of these species. The PI-2 islets resembled the genetic organization of the PI-2 islet of S. pneumoniae, but differed in the genes encoding the structural pilus proteins PitA and PitB. Two and three variants of pitA (a pseudogene in S. pneumoniae) and pitB, respectively, were identified that showed ≈20% difference in nucleotide as well as corresponding protein sequence. Species-independent combinations of pitA and pitB variants indicated prior intra- and interspecies horizontal gene transfer events. Polyclonal antisera developed against PitA and PitB of S. oralis type strain ATCC35037 revealed that PI-2 pili in oral streptococci were composed of PitA and PitB. Electronmicrographs showed pilus structures radiating >700 nm from the bacterial surface in the wild type strain, but not in an isogenic PI-2 deletion mutant. Anti-PitB-antiserum only reacted with pili containing the same PitB variant, whereas anti-PitA antiserum was cross-reactive with the other PitA variant. Electronic multilocus sequence analysis revealed that all PI-2-encoding oral streptococci were closely-related and cluster with non-PI-2-encoding S. oralis strains.

CONCLUSIONS/SIGNIFICANCE

This is the first identification of PI-2 pili in Mitis group oral streptococci. The findings provide a striking example of intra- and interspecies horizontal gene transfer. The PI-2 pilus diversity provides a possible key to link strain-specific bacterial interactions and/or tissue tropisms with pathogenic traits in the Mitis group streptococci.

The toxic dinoflagellate, Karenia brevis, forms dense blooms in the Gulf of Mexico that persist for many months in coastal waters, where they can cause extensive marine animal mortalities and human health impacts. The mechanisms that enable cell survival in high density, low growth blooms, and the mechanisms leading to often rapid bloom demise are not well understood. To gain an understanding of processes that underlie chronological aging in this dinoflagellate, a microarray study was carried out to identify changes in the global transcriptome that accompany the entry and maintenance of stationary phase up to the onset of cell death. The transcriptome of K. brevis was assayed using a custom 10,263 feature oligonucleotide microarray from mid-logarithmic growth to the onset of culture demise. A total of 2958 (29%) features were differentially expressed, with the mid-stationary phase timepoint demonstrating peak changes in expression. Gene ontology enrichment analyses identified a significant shift in transcripts involved in energy acquisition, ribosome biogenesis, gene expression, stress adaptation, calcium signaling, and putative brevetoxin biosynthesis. The extensive remodeling of the transcriptome observed in the transition into a quiescent non-dividing phase appears to be indicative of a global shift in the metabolic and signaling requirements and provides the basis from which to understand the process of chronological aging in a dinoflagellate.

We previously found an association between faster CD4+ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-α (IL-7Rα) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n=352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Rα single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n=57). Soluble (s)IL-7Rα levels were measured by ELISA. In UARTO, IL-7Rα haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P=0.020) and no association was found with LMM (P=0.958). The tagging-SNP for IL-7Rα haplotype-2 (rs6897932) was associated with decreased sIL-7Rα (P<0.001). The haplotypes for the IL-7Rα were significantly different in Africans and Caucasians. Using IL-7Rα genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P=0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P=0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Rα haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Rα SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

RATIONALE

Forced vital capacity (FVC) is an established measure of pulmonary function in idiopathic pulmonary fibrosis (IPF). Evidence regarding its measurement properties and minimal clinically important difference (MCID) in this population is limited.

OBJECTIVES

To assess the reliability, validity, and responsiveness of FVC and estimate the MCID in patients with IPF.

METHODS

The study population included all 1,156 randomized patients in two clinical trials of IFN-γ1b. FVC and other measures of functional status were measured at screening or baseline and 24-week intervals thereafter. Reliability was assessed based on two proximal measures of FVC, validity was assessed based on correlations between FVC and other measures of functional status, and responsiveness was assessed based on the relationship between 24-week changes in FVC and other measures of functional status. Distribution-based and anchor-based methods were used to estimate the MCID.

MEASUREMENTS AND MAIN RESULTS

Correlation of percent-predicted FVC between measurements (mean interval, 18 d) was high (r = 0.93; P < 0.001). Correlations between FVC and other parameters were generally weak, with the strongest observed correlation between FVC and carbon monoxide diffusing capacity (r = 0.38; P < 0.001). Correlations between change in FVC and changes in other parameters were slightly stronger (range, r = 0.16-0.37; P < 0.001). Importantly, 1-year risk of death was more than twofold higher (P < 0.001) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%.

CONCLUSIONS

FVC is a reliable, valid, and responsive measure of clinical status in patients with IPF, and a decline of 2-6%, although small, represents a clinically important difference.