The influence of multiple human papillomavirus types on the risk of genotype-concordant incident infections of the anus and cervix: the Hawaii HPV cohort study.

The influence of multiple human papillomavirus (HPV) types on detection of concordant incident HPV infections of the cervix or anus following infection at the other anatomic site was examined in a cohort of 897 women. Multiple HPV infections at the anus were not significantly associated with subsequent acquisition of a concordant cervical infection, whereas prior coinfections in the cervix increased risk of a new cervical HPV infection. Incident anal HPV infections following concordant cervical HPV infections increased significantly among women with preexisting cervical or anal coinfections. Potential synergy in acquisition of cervical and anal HPV infections has implications for prophylactic vaccine effectiveness.

Sequential acquisition of human papillomavirus (HPV) infection of the anus and cervix: the Hawaii HPV Cohort Study.

BACKGROUND: Relatively little is known about the epidemiology of anal human papillomavirus (HPV) infection in healthy women and its association with cervical HPV infection. METHODS: he association of an incident cervical (or anal) HPV infection with the subsequent risk of a genotype-concordant incident anal (or cervical) HPV infection was examined in a longitudinal cohort study of 751 sexually active women. Age-adjusted hazard ratios, obtained using Cox regression, served as measurements of relative risk (RR). RESULTS: Among women, the RR of acquiring an anal HPV infection after a cervical infection with HPV of the same genotype was 20.5 (95% confidence interval, 16.3-25.7), and the RR of acquiring a cervical HPV infection after an anal infection with HPV of the same genotype was 8.8 (95% confidence interval, 6.4-12.2), compared with women without a previous anal/cervical infection with HPV of a concordant genotype. RRs varied by phylogenetic species, with HPV alpha3/alpha15 and alpha1/alpha8/alpha10 types having a greater likelihood than other types of HPV infecting the anus among women with a previous infection at the cervix with HPV of the same genotype. CONCLUSIONS: It appears common for anal and cervical HPV infections to occur consecutively. The high degree of genotype-specific concordance suggests that the cervix (vagina) and anus may serve as reservoirs for HPV infection at the other anatomical site.

Duration and clearance of anal human papillomavirus (HPV) infection among women: the Hawaii HPV cohort study.

BACKGROUND: The association of anal cancer with human papillomavirus (HPV) infection is well established; however, little is known about the epidemiology of anal HPV in healthy women. We investigated patterns of duration and clearance of anal HPV infection in a cohort of healthy women in Hawaii. METHODS: Viral and nonviral determinants of anal HPV clearance were examined in a longitudinal cohort study of 431 sexually active women. At baseline and at 4-month intervals, interviews were conducted and cervical and anal cell specimens were obtained for detection of HPV DNA. RESULTS: Of the 431 women, 50% experienced a total of 414 incident anal HPV infections, reported at 1 clinic visits from baseline through a follow-up period of average duration of 1.2 years. Of these infections, 58% cleared during follow-up. The clearance rate for a high-risk anal infection was 9.2 per 100 woman-months (95% confidence interval [CI], 6.9-11.9 per 100 woman-months), with a median duration of 150 days (95% CI, 132-243 days). The slowest clearing high-risk HPV types were HPV-59 (median clearance time, 350 days) and HPV-58 (median clearance time, 252 days). The median clearance times for HPV-16 and HPV-18, the predominant types associated with anal cancer, were 132 days and 212 days, respectively. Nonviral factors that delayed clearance of anal HPV included douching, long-term tobacco smoking, and anal sex. CONCLUSIONS: The majority of anal HPV infections resolve in a relatively short time. Although anal HPV is commonly acquired in healthy women, its rapid clearance suggests limited efficacy of HPV testing as an anal cancer screening tool.

Novel micro-cavity substrates for improving the Raman signal from submicrometer size materials.

A novel and simple method for improving the detection limit of conventional Raman spectra using a micro-Raman system and picoliter volumes is presented. A micro-cavity in a reflecting metal substrate uses various mechanisms that collectively improve the entire Raman spectrum from the sample. A micro-cavity with a radius of several micrometers acts as a very effective device that provides multiple excitation of the sample with the laser and couples the forward-scattered Raman photons toward the collection optics in the back-scattered Raman geometry. One of the important features of the micro-cavity substrate is that it enhances the entire Raman spectrum of the molecules under investigation and maintains the relative intensity ratios of the various Raman bands. This feature of maintaining the overall integrity of the Raman features during signal enhancement makes the micro-cavity substrate ideal for forensic science applications for chemical detection of residual traces and other applications requiring low sample concentrations. The spectra measured in these cavities are also observed to be highly reproducible and reliable. A simple method for fabricating micro-cavity substrates with precise sizes and shapes is described. It is further shown that micro-cavities coated with nanofilms of gold take advantage of both surface-enhanced Raman scattering (SERS) and micro-cavity methods and also significantly improve sample detection limits.

Hawaii cohort study of serum micronutrient concentrations and clearance of incident oncogenic human papillomavirus infection of the cervix.

The degree to which the resolution of human papillomavirus (HPV) infection parallels exposure to other factors, particularly those related to nutritional status, is a relatively unexplored area of research. We established a cohort of women for long-term follow-up to examine the association of serum retinol, carotenoid, and tocopherol concentrations with the clearance of incident cervical HPV infection. Interviews and biological specimens were obtained at baseline and at 4-month intervals. At each visit, a cervical cell specimen for HPV DNA analysis and cytology and a fasting blood sample to measure micronutrient levels were collected. A Cox proportional hazards model was used to study the relationship between clearance of 189 incident (type-specific) oncogenic HPV infections and the levels of 20 serum micronutrients among 122 women. Higher circulating levels of trans-zeaxanthin, total trans-lutein/zeaxanthin, cryptoxanthin (total and beta), total trans-lycopene and cis-lycopene, carotene (alpha, beta, and total), and total carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (120 days) was not significantly associated with circulating levels of carotenoids or tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.

Transmission of human papillomavirus in heterosexual couples.

We examined the transmission of human papillomavirus (HPV) in 25 heterosexual, monogamous couples (25 men, 25 women), followed up over an average of 7.5 months. A total of 53 heterosexual transmission events were observed among 16 couples (14 male-to-female and 39 female-to male). Sexual transmission involved 13 different oncogenic and nononcogenic HPV types; 8% were vaccine-covered types transmitted between partners. The overall rate of HPV transmission from the penis to the cervix was 4.9/100 person-months, which was substantially lower than that from the cervix to the penis (17.4/100 person-months). Transmission between the hands and genitals, as well as apparent self-inoculation events (primarily in men), were also observed. Couples who transmitted HPV were more sexually active and used condoms less frequently. These results have implications for HPV prevention and control strategies, including the targeting of prophylactic vaccines.

Anal human papillomavirus infection in women and its relationship with cervical infection.

Human papillomavirus (HPV), the primary cause of cervical cancer, is also associated with the development of anal cancer. Relatively little is known about the epidemiology of anal HPV infection among healthy females and its relationship to cervical infection. We sought to characterize anal HPV infection in a cohort of adult women in Hawaii. Overall, 27% (372 of 1,378) of women were positive for anal HPV DNA at baseline compared with 29% (692 of 2,372) with cervical HPV DNA. Among women with paired anal and cervical samples, anal infection without accompanying cervical infection was observed in 14% (190 of 1,363). Concurrent anal and cervical HPV infections were observed in 13% (178 of 1,363) of women. Women with cervical HPV infection had >3-fold increased risk of concurrent anal infection. Concurrent anal and cervical HPV infection was most prevalent among the youngest women and steadily decreased through age 50 years. By contrast, the prevalence of anal infection alone remained relatively steady in all age groups. Compared with cervical infections, the overall distribution of HPV genotypes in the anus was more heterogeneous and included a greater proportion of nononcogenic types. A high degree of genotype-specific concordance was observed among concurrent anal and cervical infections, indicating a common source of infection. Nevertheless, the association of anal intercourse with anal HPV infection was limited to those women without accompanying cervical infection. The relationship of anal to cervical infection as described in this study has implications for the development of anal malignancies in women.

HIV-associated mitochondrial toxicity in pregnancy.

Pregnancy is associated with a variety of physiologic and metabolic changes designed to support the fetoplacental unit. In the presence of maternal human immunodeficiency virus (HIV) infection, the use of combination antiretroviral therapy including the nucleoside analog reverse transcriptase inhibitor (NRTI) zidovudine to prevent perinatal HIV transmission, has resulted in a dramatic decrease in perinatally acquired HIV. Human and animal studies during pregnancy report a possible association between NRTI containing antiretroviral regimens and mitochondrial toxicity in the newborn and mother. However, the possible long-term consequences on the fetus and mother of these NRTI containing regimens during pregnancy are largely unknown. This review will examine the data available on NRTI-induced mitochondrial toxicity associated with combination antiretroviral regimens used to prevent perinatal HIV transmission.

Pelvic examination teaching: linking medical student professionalism and clinical competence.

The Professional Patient teaching program is an essential part of assuring competency in the performance of the pelvic examination and professional behaviors. Through a series of integrated teaching sessions from the first year reproductive anatomy laboratory, the second year basic clinical pelvic examination teaching program, to the third year teaching program, students perform at an enhanced level of clinical competency and professional behavior. A Professional Patient commented: "We create a safe environment where medical students not only learn the clinical portion of the exam, but also focus on the patient as the primary source of information on patient comfort. Students receive immediate feedback from us and have ample opportunity to ask questions about aspects of the clinical pelvic examination or doctor/patient communication skills. We guide them, teach them, and help them prepare for examinations with other patients who will not be as open or in tune with their bodies as we are."

Cervical and anal human papillomavirus infection in adult women in American Samoa.

The prevalence of cervical and anal human papillomavirus (HPV) and risk factors associated with infections were evaluated in a cross-sectional study of 211 adult women in American Samoa. Overall, 53% of women reported ever having a Pap smear. Cervical and anal HPV was detected in 10% and 16% of women, respectively; 4% of women had concurrent cervical and anal HPV. The most common cervical genotypes were HPV 6, HPV 16, and HPV 53. Cutaneous HPV types were detected in 40% of anal infections. Cervical HPV infection was associated with anal HPV (age-adjusted odds ratio = 3.32, 1.10-10.00). After age adjustment, cervical HPV was associated with being unmarried, postsecondary education, hot running water at home, multiple sexual partners, nulliparity, condom use, and other contraceptive methods. In multivariate analyses, only age remained associated with cervical HPV and anal HPV. Cervical and anal HPV was more prevalent among younger women; only anal HPV was detected in older women.

Acute chorioamnionitis at term caused by the oral pathogen Fusobacterium nucleatum.

Fusobacterium nucleatum is an oral pathogen associated with preterm birth. Presented is a case of acute chorioamnionitis that progressed to maternal sepsis in a term patient with intact membranes. In addition to its role in periodontal disease and preterm birth, our case demonstrates that intrauterine infection with Fusobacterium nucleatum can result in severe disease at term.

Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188.

BACKGROUND: Pharmacokinetic (PK) interactions between lopinavir/ritonavir (LPV/r) and transdermally delivered ethinyl estradiol (EE) and norelgestromin (NGMN) are unknown. METHODS: Using a standard noncompartmental PK analysis, we compared EE area under the time-concentration curve (AUC) and NGMN AUC during transdermal contraceptive patch administration in HIV-1-infected women on stable LPV/r to a control group of women not on highly active antiretroviral therapy (HAART). In addition, EE AUC after a single dose of a combination oral contraceptive pill including EE and norethindrone was measured before patch placement and was compared with patch EE AUC in both groups. Contraceptive effects on LPV/r PKs were estimated by measuring LPV/r AUC at baseline and during week 3 of patch administration. RESULTS: Eight women on LPV/r, and 24 women in the control group were enrolled. Patch EE median AUC0-168 h was 45% lower at 6010.36 pg·h·mL in those on LPV/r versus 10911.42 pg·h·mL in those on no HAART (P = 0.064). Pill EE median AUC0-48 hours was similarly 55% lower at 344.67 pg·h·mL in those on LPV/r versus 765.38 pg·h·mL in those on no HAART (P = 0.003). Patch NGMN AUC0-168 h however, was 138.39 ng·h·mL, 83% higher in the LPV/r group compared with the control AUC of 75.63 ng·h·mL (P = 0.036). After 3 weeks on the patch, LPV AUC0-8 h decreased by 19%, (P = 0.156). CONCLUSIONS: Although PKs of contraceptive EE and NGMN are significantly altered with LPV/r, the contraceptive efficacy of the patch is likely to be maintained. Larger studies are indicated to fully assess contraceptive efficacy versus risks of the transdermal contraceptive patch when co-administered with protease inhibitors.

Near-infrared micro-Raman spectroscopy for in vitro detection of cervical cancer.

Near-infrared Raman spectroscopy is a powerful analytical tool for detecting critical differences in biological samples with minimum interference in the Raman spectra from the native fluorescence of the samples. The technique is often suggested as a potential screening tool for cancer. In this article we report in vitro Raman spectra of squamous cells in normal and cancerous cervical human tissue from seven patients, which have good signal-to-noise ratio and which were found to be reproducible. These preliminary results show that several Raman features in these spectra could be used to distinguish cancerous cervical squamous cells from normal cervical squamous cells. In general, the Raman spectra of cervical cancer cells show intensity differences compared to those of normal squamous cell spectra. For example, several well-defined Raman peaks of collagen in the 775 to 975 cm(-1) region are observed in the case of normal squamous cells, but these are below the detection limit of normal Raman spectroscopy in the spectra of invasive cervical cancer cells. In the high frequency 2800 to 3100 cm(-1) region, it is found that the peak area under the CH stretching band is lower by a factor of approximately six in the spectra of cervical cancer cells as compared with that of the normal cells. The Raman chemical maps of regions of cancer and normal cells in the cervical epithelium made from the spectral features in the 775 to 975 cm(-1) and 2800 to 3100 cm(-1) regions are also found to show good correlation with each other.

Acquisition of anal human papillomavirus (HPV) infection in women: the Hawaii HPV Cohort study.

BACKGROUND: The majority of anal cancer is associated with human papillomavirus (HPV) infection, yet little is known about women's risk of acquisition of anal HPV infection. METHODS: Risk factors for the acquisition of anal HPV infection were examined in a longitudinal cohort study of 431 women, via repeated measurement of HPV DNA. RESULTS: Seventy percent of women were positive for anal HPV infection at one or more clinic visits from baseline through a follow-up period that averaged 1.3 years. The incidence of a high-risk (HR) infection was 19.5 (95% confidence interval [CI], 16.0-23.6) per 1000 woman-months. The most common incident HR HPV types were HPV-53, -52 and -16. The presence of an HR anal HPV infection at baseline increased the risk of an incident anal infection by 65%. Baseline HR cervical HPV infection also predicted the acquisition of an HR anal HPV infection (odds ratio, 1.81 [95% CI, 1.09-3.02]). Nonviral risk factors for acquisition of HR HPV infection included younger age, lower socioeconomic status, greater lifetime number of sexual partners, past use of hormones, and condom use. CONCLUSIONS: The results of this study suggest that women's risk of anal HPV infection is as common as their risk of cervical HPV infection.

Prevalence, acquisition, and clearance of cervical human papillomavirus infection among women with normal cytology: Hawaii Human Papillomavirus Cohort Study.

Few natural history studies of cervical human papillomavirus (HPV) incidence and duration have been conducted among older women, especially from multiethnic populations. Viral and nonviral determinants of HPV acquisition and clearance were examined among 972 sexually active women, ages 18 to 85 years, recruited from clinics on Oahu, Hawaii, and followed for a mean duration of 15 months (range, 2-56 months). Interviews and cervical cell specimens for cytology and HPV DNA detection by PCR, using the PGMY09/PGMY11 primer system, were obtained at baseline and at 4-month intervals. The prevalence of cervical HPV infection was 25.6% at study entry. A total of 476 incident genotype-specific infections were observed during the follow-up period. The incidence of high-risk (HR) HPV types (9.26 per 1,000 woman-months) was similar to low-risk (LR) HPV types (8.24 per 1,000 woman-months). The most commonly acquired HR-HPV types were HPV-52, HPV-16, and HPV-31; and their incidence was increased significantly with a coexisting cervical HPV infection. Cervical HPV acquisition decreased with age, income, and long-term use of oral contraceptives and increased with number of sexual partners, use of hormonal creams, alcohol drinking, and condom use by a sexual partner. Cohort participants cleared 265 of the 476 incident infections during follow-up. LR-HPV infections cleared more rapidly than did HR-HPV infections (median, 180 days versus 224 days). Clearance times were enhanced among older women and women with multiple infections. Our data suggest several viral and nonviral determinants of cervical HPV acquisition and clearance that might be used in cervical cancer prevention programs.

Obstetrics and gynecology medical student outcomes: longitudinal multispecialty clerkship versus traditional block rotations.

OBJECTIVE: To evaluate outcomes of students in a longitudinal clerkship. STUDY DESIGN: Clerkship grades, written examination scores, and clinical evaluations were compared between students participating in a longitudinal clerkship and students in block rotations. The percent of students pursuing an obstetrics and gynecology residency from each group was evaluated. RESULTS: There was no difference in clerkship grade (3.3 versus 3.5, P = .158). Longitudinal and block students received similar clinical evaluations with no significant difference in any category. The average written examination score was lower for students in the longitudinal clerkship (76.9% versus 80.0%, P = .008). A higher percent of students in the longitudinal program chose an obstetrics and gynecology residency, 12.5% versus 6.17% (odds ratio = 2.17, 95% confidence interval 0.57-6.89, P = .18). CONCLUSIONS: Longitudinally trained students received similar clinical evaluations to their colleagues but may need assistance in acquiring the knowledge needed for the written examination. This program should be examined closely for factors influencing a higher percent of students to pursue a residency in obstetrics and gynecology.

Diet and premalignant lesions of the cervix: evidence of a protective role for folate, riboflavin, thiamin, and vitamin B12.

OBJECTIVE: A case-control study was conducted among a population of multiethnic women identified from clinics on Oahu, Hawaii between 1992 and 1996 to explore the relationship between diet and cervical dysplasia. METHODS: Two-hundred and fourteen women with biopsy-confirmed high and low grade squamous intraepithelial lesions of the cervix (SIL) and 271 controls were identified. Exfoliated cervical cells were collected for HPV DNA testing. Surveys were administered to assess non-dietary risk factors and intake of nutrients from over 250 specific food items as well as nutritional supplements. RESULTS: Riboflavin and thiamin from food sources, vitamin B12 supplements, and total (food and supplements) folate displayed inverse, dose-responsive associations with high-grade SIL (HSIL). Riboflavin from food sources and total folate also demonstrated inverse, dose-responsive associations with low-grade SIL (LSIL). The odds ratios for LSIL and HSIL were reduced by 50-90% for the highest compared to the lowest levels of intake of these nutrients. A number of major food sources of these vitamins, including all types of breads, bran cereal, and fruit juice, also demonstrated inverse associations with HSIL. There was some evidence that the increased risk of HSIL associated with low nutrient intake was most pronounced among drinkers and smokers. CONCLUSIONS: This investigation provides evidence that thiamin, riboflavin, folate, and vitamin B12 may play a protective role in cervical carcinogenesis.

Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy.

Recent studies of pregnant women and animal models have raised concerns regarding potentially serious mitochondrial toxicity-related side effects in infants born to mothers who received nucleoside reverse transcriptase inhibitors (NRTIs) during their pregnancy to prevent HIV-1 perinatal transmission. The aim of this study was to assess mitochondrial DNA (mtDNA) content of cord blood and placenta in HIV-infected pregnant women receiving NRTI compared with HIV-negative women, hypothesizing that placenta and cord blood mtDNA copies per cell would be decreased in women on NRTI therapy. Immediately following delivery, placenta and cord blood were obtained from eight HIV-infected pregnant women on NRTIs and five HIV-negative women. Assessment of mtDNA copies per cell was accomplished by quantitative real-time PCR. The mean mtDNA copies per cell from the placenta of the HIV-infected women compared with HIV-negative women was 152 +/- 119 and 880 +/- 136 ( =.0016), respectively. Similarly, the mean mtDNA copies per cell from the cord blood of the HIV-positive women compared with HIV-negative women was 144 +/- 101 and 865 +/- 331 ( =.0026), respectively. There was a statistically significant decrease in mtDNA copies per cell in placenta and cord blood between the HIV-infected women on NRTIs compared with HIV-negative women. Further studies are needed to better understand the morbidity to infants and mothers treated with NRTI to prevent vertical transmission of HIV.