PubMed Health⌕ Search

Biomedical subjects

Dorothy J Wiley

Publications and source records attributed to Dorothy J Wiley.

14 recordsLinked to original sources
PubMed2006

Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: Human papillomavirus (HPV) virus-like particle (VLP) vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of cervical intraepithelial neoplasia (CIN) 2-3 has not yet been established. We present results from an HPV16 L1 VLP vaccine trial through 48 months. METHODS: A total of 2,391 women, aged 16-23 years, participated in a randomized, double-blind, placebo-controlled trial. Either 40 mug HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. RESULTS: Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN2-3 (6 CIN2 and 6 CIN3). Among 755 vaccine recipients, there were no cases (vaccine efficacy 100%, 95% confidence interval [CI] 65-100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients (vaccine efficacy 94%, 95% CI 88-98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/mL), declined through month 18 (202 mMU/mL), and remained relatively stable between month 30 and month 48 (128-150 mMU/mL). CONCLUSION: The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2-3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer. LEVEL OF EVIDENCE: I.

Adolescent↗
PubMed2006

Will widespread human papillomavirus prophylactic vaccination change sexual practices of adolescent and young adult women in America?

Two virus-like particle human papillomavirus (HPV) vaccines have been shown to be nearly 100% effective in preventing type-specific persistent HPV infections and associated type-specific high-grade cervical intraepithelial neoplasia (CIN). Recently, it has been hypothesized that the administration of this vaccine to young girls in the United States might increase sexual promiscuity among adolescent women and/or young adults. Thus, it has been suggested that focused vaccine strategies either based on the risk of CIN or gender might be more rational or cost-effective. However, such strategies are unlikely to completely eradicate the burden of this disease and decrease the cost of cervical cancer screening. The suggestion that widespread vaccination will alter sexual practices is refuted and the rationale for the vaccination of all girls and boys is outlined.

Adolescent↗
PubMed2006

Reversible deficiency of antimicrobial polypeptides in bacterial vaginosis.

Bacterial vaginosis is a common condition associated with increased risk of sexually transmitted diseases, including human immunodeficiency virus infections. In contrast, vulvovaginal candidiasis has a much weaker association with sexually transmitted diseases. We found that vaginal lavage fluid from women with bacterial vaginosis is deficient in antimicrobial polypeptides and antimicrobial activity compared to fluid from healthy women or women with vulvovaginal candidiasis. Effective treatment normalized the concentrations of antimicrobial polypeptides in both bacterial vaginosis and in vulvovaginal candidiasis, suggesting that the abnormalities were a result of the diseases. Unlike in vulvovaginal candidiasis, the neutrophil attractant chemokine interleukin-8 (IL-8) was not increased in bacterial vaginosis, accounting for low concentrations of neutrophil-derived defensins in vaginal fluid. In organotypic cultures of human vaginal epithelium containing dendritic cells, treatment with Lactobacillus jensenii, a typical vaginal resident, induced the synthesis of IL-8 mRNA and the epithelial human beta-defensin-2 mRNA, but a typical bacterial vaginosis pathogen, Gardnerella vaginalis, had no effect. When the two bacteria were combined, Gardnerella vaginalis did not interfere with the immunostimulatory effect of Lactobacillus jensenii. The loss of normal immunostimulatory flora in bacterial vaginosis is thus associated with a local deficiency of multiple innate immune factors, and this deficiency could predispose individuals to sexually transmitted diseases.

Adult↗
PubMed2006

Smokers at higher risk for undetected antibody for oncogenic human papillomavirus type 16 infection.

OBJECTIVE: To determine the association between tobacco smoking and serologic evidence of human papillomavirus type 16 (HPV16)-specific antibodies among HPV16 DNA-positive women. DESIGN, SETTING, AND PARTICIPANTS: Baseline health history, physical examination, and laboratory data for 205 HPV16 DNA-positive women with no prior cytologic evidence of squamous intraepithelial lesions who were enrolled subsequently in a randomized clinical trial. MAIN OUTCOME MEASURE: HPV16-L1 antibody (anti-HPV16 antibody) detected from serum using RIA or ELISA. RESULTS: Eighty-seven percent (179 of 205) of women tested positive for HPV16 DNA using cervicovaginal swabs or lavage specimens, and 26 women showed similar results using swab specimens of external genitalia alone. HPV16-infected women who reported increasingly greater levels of daily cigarette smoking were less likely to test positive for anti-HPV16 antibodies than nonsmoking women (P = 0.02). Smokers were twice as likely as nonsmokers to test negative for anti-HPV16 antibodies, even after controlling for the effects of other covariates in the analyses (adjusted odds ratio, 0.5; 95% confidence limits, 0.2-0.9). Although Papanicolaou test findings and smoking characteristics were poorly correlated (r(2) = 0.01), women who showed atypical cells of unknown significance or squamous intraepithelial lesion were twice as likely to test anti-HPV16 antibody positive as women who showed normal Papanicolaou tests (adjusted odds ratio, 2.0; 95% confidence limits, 1.1-3.7). CONCLUSION: These data suggest that smoking may influence the long-term risk for cancer by perturbing early immune responses to the virus and may increase the likelihood of persistent infection. Patient education messages should alert women to this additional risk of smoking. A clinical trial of smoking cessation should be explored as a therapeutic intervention for primary HPV16 infection.

Adolescent↗
PubMed2005

Methylation of human papillomavirus genomes in cells of anal epithelia of HIV-infected men.

Intra-anal malignancies disproportionately affect individuals who engage in anal intercourse because of infection with human papillomaviruses (HPVs), with an increased risk attributed to infection with HIV because of a declining immunity against HPVs. Long-term persistence of HPVs suggests yet other mechanisms that determine the clinical outcome, however. Because methylation of HPV DNA represses oncogene expression in cervical samples, we investigated whether this mechanism also occurs in HIV-positive men and studied the methylation of CpG dinucleotides overlapping with the HPV-16 enhancer and promoter in 16 anal samples. Similar to cervical infections, the average methylation frequency was 12.3%, with heterogeneities between clones from different and the same samples. In low-grade anal intraepithelial neoplasia (AIN), methylation was high in CpGs overlapping the viral enhancer but rare in promoter positions, whereas methylation was high in promoter regions in high-grade AIN, especially in samples with a high load of viral genomes. The viral replication origin was never methylated. We also detected de novo methylation at methylated (me) CpA, meCpT, and meCpC dinucleotides. Our study expands the observation and mapping of HPV DNA methylation to anal infections and the HIV-positive patient population. As observed at the cervix, DNA methylation may force HPVs into latency with functional replication but repressed transcription. Escape from this repression is a prerequisite for neoplastic progression; however, methylation resumes because of chromosomal integration of HPV genomes but spares some HPV genomes in each cell that maintain the transformed phenotype. DNA methylation, taken together with virus load, may be useful to diagnose the emergence of a population of tumor cells.

Anal Canal↗
PubMed2004

Genomic diversity of human papillomavirus-16, 18, 31, and 35 isolates in a Mexican population and relationship to European, African, and Native American variants.

Cervical cancer, mainly caused by infection with human papillomaviruses (HPVs), is a major public health problem in Mexico. During a study of the prevalence of HPV types in northeastern Mexico, we identified, as expected from worldwide comparisons, HPV-16, 18, 31, and 35 as highly prevalent. It is well known that the genomes of HPV types differ geographically because of evolution linked to ethnic groups separated in prehistoric times. As HPV intra-type variation results in pathogenic differences, we analyzed genomic sequences of Mexican variants of these four HPV types. Among 112 HPV-16 samples, 14 contained European and 98 American Indian (AA) variants. This ratio is unexpected as people of European ethnicity predominate in this part of Mexico. Among 15 HPV-18 samples, 13 contained European and 2 African variants, the latter possibly due to migration of Africans to the Caribbean coast of Mexico. We constructed phylogenetic trees of HPV-31 and 35 variants, which have never been studied. Forty-six HPV-31 isolates from Mexico, Europe, Africa, and the United States (US) contained a total of 35 nucleotide exchanges in a 428-bp segment, with maximal distances between any two variants of 16 bp (3.7%), similar to those between HPV-16 variants. The HPV-31 variants formed two branches, one apparently the European, the other one an African branch. The European branch contained 13 of 29 Mexican isolates, the African branch 16 Mexican isolates. These may represent the HPV-31 variants of American Indians, as a 55% prevalence of African variants in Mexico seems incomprehensible. Twenty-seven HPV-35 samples from Mexico, Europe, Africa, and the US contained 11 mutations in a 893-bp segment with maximal distances between any two variants of only 5 mutations (0.6%), including a characteristic 16-bp insertion/deletion. These HPV-35 variants formed several phylogenetic clusters rather than two- or three-branched trees as HPV-16, 18, and 31. An HPV-35 variant typical for American Indians was not identifiable. Our research suggests type specific patterns of evolution and spread of HPV-16, 18, 31, and 35 both before and after the worldwide migrations of the last four centuries. The high prevalence of highly carcinogenic HPV-16 AA variants, and the extensive diversity of HPV-18, 31, and 35 variants with unknown pathogenic properties raise the possibility that HPV intra-type variation contributes to the high cervical cancer burden in Mexico.

Cohort Studies↗
PubMed2004

Cervical cancer screening.

Although primary prevention of human papillomavirus (HPV) infections that are causally associated with invasive cervical cancer may be within our grasp, it is unlikely that these approaches will replace existing cervical cancer screening strategies for many years. Experts agree and data support periodic cytology screening for young-adult women using one of several technologies. Recent analyses of cost-effectiveness suggest that the addition of molecular HPV DNA testing for women aged over 30 years may allow the screening interval to be lengthened to 3 years for most women. Women at high risk for HPV infection and its associated cellular atypias warrant closer monitoring and follow-up. These patients would include organ transplant recipients, women exposed to diethylstilbestrol (DES), and HIV-infected women.

Adult↗
PubMed2004

Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence.

In an effort to examine changes that precede synapse loss, we have measured amyloid-beta and a series of damage markers in the synaptic compartment of Alzheimer's disease (AD) cases. Because localization of events to the terminal region in neurons is problematic with conventional methods, we prepared synaptosomes from samples of cryopreserved human association cortex, and immunolabeled terminals with a procedure for intracellular antigens. Fluorescence was quantified using flow cytometry. The viability dye calcein AM was unchanged in AD terminals compared to controls, and the fraction of large synaptosome particles did not change, although a striking loss of large terminals was observed in some AD cases. The percent positive fraction for a series of pre- and postsynaptic markers was not affected by AD in this cohort. However, the amyloid-beta-positive fraction increased from 16 to 27% (P < 0.02) in terminals from AD cortex. The expression level on a per-terminal basis is indicated in this assay by fluorescence (relative fluorescence units). The fluorescence of presynaptic markers did not change in AD terminals, but PSD-95 fluorescence was decreased by 19% (P < 0.03). Amyloid-beta fluorescence was increased by 132% (P < 0.01), and glial fibrillary acidic protein labeling by 31% (P < 0.01). These results suggest that synapse-associated amyloid-beta is prominent in regions relatively unaffected by AD lesions, and that amyloid accumulation in surviving terminals is accompanied by gliosis and alteration in the postsynaptic structure.

Aged↗
PubMed2004

Rapid annexin-V labeling in synaptosomes.

Distal neuronal terminals may be the site of apoptotic events and early synapse loss in neurodegenerative disease. To examine apoptosis in synaptic regions, we established a cell-free assay using a rat brain crude synaptosomal preparation (P-2 fraction) as a model system. The apoptosis marker annexin-V was used to measure phosphatidylserine (PS) exposure, and to ensure that only intact terminals were assayed, synaptosomes were dual labeled with a viability marker (calcein AM). Fluorescence was quantified by flow cytometry analysis. Annexin-V labeling increased rapidly in synaptosomes, following a 1 min incubation with staurosporine. However, increased caspase-3-like activity was not measured until 30 min with a fluorometric assay. The addition of a peptide inhibitor of caspase-3-like activity (Ac-DEVD-CHO) during homogenization was not able to block the initial increase in annexin labeling, but resulted in a partial blockade of annexin labeling after 30 min. These data demonstrate that PS externalization and caspase activation occur rapidly in this widely used neurochemical preparation.

Animals↗
PubMed2004

Conserved methylation patterns of human papillomavirus type 16 DNA in asymptomatic infection and cervical neoplasia.

DNA methylation contributes to the chromatin conformation that represses transcription of human papillomavirus type16 (HPV-16), which is prevalent in the etiology of cervical carcinoma. In an effort to clarify the role of this phenomenon in the regulation and carcinogenicity of HPV-16, 115 clinical samples were studied to establish the methylation patterns of the 19 CpG dinucleotides within the long control region and part of the L1 gene by bisulfite modification, PCR amplification, DNA cloning, and sequencing. We observed major heterogeneities between clones from different samples as well as between clones from individual samples. The methylation frequency of CpGs was measured at 14.5%. In addition, 0.21 and 0.23%, respectively, of the CpA and CpT sites, indicators of de novo methylation, were methylated. Methylation frequencies exceeded 30% in the CpGs overlapping with the L1 gene and were about 10% for most other positions. A CpG site located in the linker between two nucleosomes positioned over the enhancer and promoter of HPV-16 had minimal methylation. This region forms part of the HPV replication origin and is close to binding sites of master-regulators of transcription during epithelial differentiation. Methylation of most sites was highest in carcinomas, possibly due to tandem repetition and chromosomal integration of HPV-16 DNA. Methylation was lowest in dysplasia, likely reflecting the transcriptional activity in these infections. Our data document the efficient targeting of HPV genomes by the epithelial methylation machinery, possibly as a cellular defense mechanism, and suggest involvement of methylation in HPV oncogene expression and the early-late switch.

Cell Line, Tumor↗
PubMedDate not supplied

Magnetic resonance imaging and the neonate.

Over the past decade, advances in neuroimaging have given birth to a new field of diagnostic pediatric neurologic assessment that includes magnetic resonance imaging (MRI). This invaluable tool helps medical professionals to resolve many clinical and research questions related to neonatal neurodevelopment that other imaging technology cannot explain. Nurses and others who accompany infants to MRI would benefit from a better understanding of early neurodevelopment and of the neuroimaging procedure. Knowing the advantages and disadvantages of MRI techniques can help nurses be better patient advocates, parent liaisons, and caregivers to infants having MRI scans.

Brain↗
PubMedDate not supplied

Perinatal corticosteroids: A review of research. Part I: Antenatal administration.

The premature infant may receive therapeutic glucocorticoid drugs while in utero or in the postnatal period. This article (part I of a two-part series) discusses the benefits and risks of in utero, or antenatal, corticosteroids (ACS) for the premature infant. Part II addresses the benefits and risks of postnatal corticosteroid (PCS) use. There are numerous clinical studies on the therapeutic use of these steroids for the prevention of respiratory distress syndrome and chronic lung disease in the premature infant, although research results on the efficacy of repeated steroid exposure among premature infants vary. Premature infants who are exposed to repeated courses of ACS and/or high-cumulative-dose PCS may show no neurologic side effects until later in life. Research in newborn animal models focused on the timing, duration, and amounts of ACS and PCS. Current clinical research includes examination of the neurodevelopment of infants who are therapeutically exposed to perinatal corticosteroids, to identify safer minimal dose protocols. Over the past 30 years, corticosteroids have been increasingly prescribed before and after birth. Understanding the potential treatment benefits and risks to human fetuses and neonates is vital to clinical practice. This review presents historic and pharmacokinetic information about prenatal use of corticosteroids. It also offers scientific evidence of the benefits and risks identified in animal models and clinical trials, to stimulate thought that gtiides neonatal clinical practice.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Sexual intercourse and the age difference between adolescent females and their romantic partners.

CONTEXT: The age difference between a female and her partner may influence relationship dynamics in ways that put the female at increased risk of unintended pregnancies and sexually transmitted diseases. Very little is known, however, about how romantic involvement progresses to intercourse, particularly among adolescent females with older male partners. METHODS: Data from 1,975 female participants in the National Longitudinal Study of Adolescent Health were analyzed using logistic regression to determine whether the age difference between an adolescent female and her romantic partner is a risk factor for sexual intercourse. RESULTS: Adolescent females involved with an older partner have higher odds of having intercourse with that partner than females with partners their own age, after adjustment for demographic covariates. The magnitude of this association is most dramatic among the youngest females--for example, the odds of intercourse among 13-year-old females with a partner six years older are more than six times the odds among 13-year-old females with a same-age partner (odds ratio, 6.4), while 17-year-old females with partners six years older have about twice the odds of intercourse when compared with those who have a same-age partner (2.1). CONCLUSIONS: Young adolescent females with substantially older partners are much more likely than their peers to have sex with their partner, which exposes them to the risks of pregnancy and sexually transmitted diseases.

Adolescent↗