Publications

Induction of primary B cell responses requires the presence of Ag and costimulatory signals by T cells. Innate signals further enhance B cell activation. The precise nature and kinetics of such innate immune signals and their functional effects are unknown. This study demonstrates that influenza virus-induced type I IFN is the main innate stimulus affecting local B cells within 48 h of infection. It alters the transcriptional profile of B cells and selectively traps them in the regional lymph nodes, presumably via up-regulation of CD69. Somewhat paradoxically, innate B cell stimulation inhibited the ability of regional lymph node B cells to clonally expand following BCR-mediated stimulation. This inhibition was due to IFNR-signaling independent B cell intrinsic, as well as IFNR-dependent B cell extrinsic, regulation induced following influenza infection. IFNR-mediated signals also reduced B cell migration to various chemotactic agents. Consistent with the lack of responsiveness to CCR7 ligands, unaltered or reduced expression of MHC class II and genes associated with MHC class II Ag processing/presentation and CD40, B cells were unable to induce proliferation of naive CD4 T cells. Instead, they showed increased expression of a subset of nonclassical MHC molecules that facilitate interaction with gammadelta T cells and NK T cells. We conclude that type I IFN is the main "third" B cell signal following influenza infection causing early trapping of B cells in regional lymph nodes and, at a time when cognate T cell help is rare, enhancing their propensity to interact with innate immune cells for noncognate stimulation.

Four new compounds, belonging to the tetranortriterpenoid family, named dysoxylins A-D (1-4), isolated from Dysoxylum gaudichaudianum, were found to exhibit potent antiviral activity against respiratory syncytial virus (RSV). These structures were determined by NMR spectroscopy and mass spectrometry and were shown to have anti-RSV EC50 activities in the range 1.0-4.0 microg/mL in cytopathic effect inhibition and plaque reduction assays.

T-cell activation has long been considered a central mediator of HIV pathogenesis. High T-cell activation levels predict more rapid disease progression in untreated patients and decreased treatment-mediated CD4+ T-cell gains during antiretroviral therapy, independent of plasma HIV RNA levels, and may be the primary feature distinguishing pathogenic from nonpathogenic primate models of HIV infection. Studies in animal models and individuals with HIV infection continue to enhance our understanding of how T-cell activation causes immunodeficiency during HIV infection. The goal of these studies is to identify specific mechanisms that can be targeted by novel immune-based therapies for patients who have thus far been unable to recover normal immune function despite years of antiretroviral therapy. Although most immune-based therapies targeting T-cell activation have been unsuccessful to date, recent scientific developments have focused attention on specific pathways that may be exploited by future generations of immune-based therapies.

Life-long exposure to estrogen is an established risk factor for breast cancer development. The underlying mechanism has been suggested to be the binding of estrogen-to-estrogen receptors in mammary tissue, which in turn promotes the proliferation and differentiation of breast tissue. Polymorphisms and haplotypes in estrogen receptor alpha (ESR1) have been reportedly associated with breast cancer risk; however, the results are not fully consistent. In this study, we investigated breast cancer risk associated with genotypes and haplotypes resulting from four ESR1 single nucleotide polymorphisms (SNPs), rs746432, rs2234693, rs9340799, and rs1801132. Genotyping has been performed on 393 breast cancer cases and 790 randomly selected controls in 1,183 Caucasian women over age 65 from the Study of Osteoporotic Fractures (SOF). We observed an allelic protective effect for SNP rs9340799 with an estimated odds ratio (OR) of 0.82 (95% CI = 0.68-1.00; P = 0.04) after adjustment for age, BMI and hip BMD. A protective effect of this SNP has been reported before in several different studies. We did not replicate the previously reported C-C-A-G haplotype association to breast cancer-the C-C-A-G haplotype from these SNPs was rare in this study (estimated frequency below 0.001% in cases and controls). No other statistically significant associations were observed between ESR1 haplotypes from the same four SNPs and the risk of breast cancer in older Caucasian women.

Mammalian hepatic cytochromes P450 (P450s) are endoplasmic reticulum (ER)-anchored haemoproteins with the bulk of their catalytic domains exposed to the cytosol and engaged in the metabolism of numerous xeno- and endobiotics. The native P450s exhibit widely ranging half-lifes and predominantly turn over via either autophagic-lysosomal degradation (ALD) or ubiquitin-dependent 26S proteasomal degradation (UPD). The basis for this heterogeneity and differential proteolytic targeting is unknown. On the other hand, structurally/functionally inactivated P450s are predominantly degraded via UPD in a process known as ER-associated degradation (ERAD). ALD/UPD/ERAD pathways are evolutionarily highly conserved. The availability of Saccharomyces cerevisiae mutants with specific genetic defects/deletions in various ALD/UPD/ERAD-associated proteins and corresponding isogenic wild-type strains has enabled the molecular dissection of the degradation pathways for heterologously expressed mammalian P450s, leading to the identification of specific protein participants. These findings collectively attest to a highly versatile cellular system for the physiological disposal of native, senescent and/or inactivated, structurally damaged mammalian liver P450s.

BACKGROUND

A major health priority is to increase colorectal cancer screening, and colonoscopy has become an increasingly important method of screening. The Medicare program began coverage for colonoscopy for average risk individuals in 2001.

OBJECTIVES

We sought to examine whether overall colorectal cancer screening increased over time and whether these increases were a result of increased utilization of all methods or a result of greater use of colonoscopy but reduced use of other methods, whether the enactment of Medicare coverage was associated with an increase in colonoscopy among Medicare enrollees, and whether these trends equally affected subpopulations.

METHODS

We used nationally representative data from the 2000 and 2003 National Health Interview Surveys and analyzed data using used chi, difference-in-differences tests, and logistic regression analyses to examine whether screening rates differed between 2000 and 2003.

RESULTS

The percentage of individuals being screened for colorectal cancer using any method increased modestly from 2000 to 2003 (3%), with increases a result of increased use of colonoscopy and a reduction in the use of other methods. Increases in colonoscopy use were significant among all populations except the insured, non-Medicare population with low incomes. Among Medicare enrollees with high/middle incomes, colonoscopy use increased 14% from 2000 to 2003 compared with an increase of only 7% among low-income groups, which was a significant difference (P < 0.01). Similarly, among insured, non-Medicare enrollees with high/middle incomes, colonoscopy use increased 11% from 2000 to 2003 compared with an increase of only 4% among low-income groups, which also was a significant difference (P < 0.01).

CONCLUSIONS

Colorectal cancer screening utilization increased modestly from 2000 to 2003, with the increases that primarily were the result of increased colonoscopy use. Increases in colonoscopy use, however, were primarily among high/middle income groups. Although Medicare coverage may have indirectly facilitated the increase in colonoscopy, we could not determine that coverage directly increased screening rates. Screening rates remain modest and lower income individuals continue to be screened less. Topics for future research include approaches to facilitating screening among low-income individuals and evaluating the impact of policy coverage decisions.

A need exists for the development of applicable surveillance tools to detect fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) in urine samples. We describe here a real-time PCR assay for detecting mutations in the Ser91 codon of the gyrA gene of N. gonorrhoeae in urine specimens. We tested 96 urine samples collected along with Gonorrhea Isolate Surveillance Project (GISP) urethral swab samples and compared the results with matched MICs of ciprofloxacin, as reported by the regional GISP laboratory. We then tested 100 urine specimens, known to be gonorrhea positive by nucleic acid amplification testing, provided by females to challenge the real-time PCR assay with urine specimens containing potentially less target DNA content than specimens from symptomatic males. With an MIC threshold of 0.125 mug of ciprofloxacin/ml, our assay correctly identified resistance in 41 of 44 (93.2%; 95% confidence interval [CI] = 81.3 to 98.6%) corresponding resistant culture specimens and correctly identified 51 of 51 (100%; 95% CI = 93.0 to 100%) susceptible specimens. One specimen did not amplify. The assay successfully amplified the gyrA amplicon and determined a susceptibility genotype in 72 of 100 (72%) urine specimens collected from female patients. We developed an assay for detecting QRNG in urine specimens that correlated well with MIC results of cultured specimens and had moderate sensitivity with urine specimens. This methodology might fulfill the need for a QRNG detection system for urine specimens, a useful characteristic in the age of nucleic acid amplification testing for gonococcal infection.