Seymour L. Romney

Preeclampsia and antioxidant nutrients: Decreased plasma levels of reduced ascorbic acid, α-tocopherol, and beta-carotene in women with preeclampsia

OBJECTIVE Our purpose was to investigate the plasma levels of three potent antioxidant nutrients in women with preeclampsia. STUDY DESIGN Fasting venous blood samples were collected from 30 women with preeclampsia and from 44 women with uncomplicated pregnancies. The criteria for recruitment included age 15 to 35 years, gestational age 28 to 42 weeks, singleton pregnancy, intact membranes, absence of labor contractions, and absence of any other medical complication concurrent with preeclampsia. Reduced ascorbic acid, alpha-tocopherol, and beta-carotene levels were assayed with high-pressure liquid chromatography. RESULTS Plasma levels of reduced ascorbic acid were significantly decreased in patients with mild and severe preeclampsia (p < 0.01). Plasma alpha-tocopherol and beta-carotene levels were significantly decreased only in severe preeclampsia compared with controls (p < 0.05 and p < 0.05, respectively). CONCLUSION In patients with preeclampsia antioxidant nutrients may be utilized to a greater extent to counteract free radical-mediated cell disturbances, resulting in a reduction in antioxidant plasma levels. Water-soluble antioxidant nutrients may initially be consumed, followed by lipid-soluble antioxidants.

HPV 16 and cigarette smoking as risk factors for high‐grade cervical intra‐epithelial neoplasia

Although genital human papillomavirus (HPV) infection is well established as the etiologic agent for cervical intra‐epithelial neoplasia (CIN), little is known about the cofactors involved in the development of high‐grade lesions or the progression of low‐grade to high‐grade lesions. In our study of HPV‐infected women with CIN (163 CIN I, 51 CIN II and 44 CIN III), women with CIN II or III were compared with those with CIN I for risk factors associated with high‐grade lesions. After controlling for age, education, ethnicity and frequency of Pap smear screening, infection with HPV 16, but not high viral load or infection with multiple types, was associated with high‐grade lesions (OR for CIN II = 11.96, OR for CIN III = 23.74). Risk of CIN III, but not CIN II, increased with number of cigarettes smoked per day (ORs = 1.49 and 3.35 for ≤10 and >10 cigarettes per day, respectively) and decreased with frequency of condom use during sex (ORs = 0.60 and 0.32 for women who used condoms occasionally/sometimes and most/all of the time, respectively). There were no associations between high‐grade lesions and plasma levels of micronutrients (retinol, β‐carotene, α‐tocopherol and reduced ascorbic acid). Our results indicate that infection with HPV 16 is associated with high‐grade lesions. Additional cofactors, such as cigarette smoking, may be required as a carcinogen to advance HPV‐infected cells toward neoplastic progression. Int. J. Cancer 78:281–285, 1998.© 1998 Wiley‐Liss, Inc.

Human papillomavirus infection of the cervix detected by cervicovaginal lavage and molecular hybridization: Correlation with biopsy results and Papanicolaou smear

Human papillomaviruses have previously been identified by molecular hybridization in the majority of dysplastic and cancerous lesions of the cervix. Since human papillomavirus types 16 and 18 have been strongly associated with cervical cancer, the identification of patients infected with these specific human papillomavirus types may provide useful prognostic information. We have developed a painless, noninvasive cervicovaginal lavage technique to collect exfoliated cervicovaginal cells, which can be reliably analyzed for the presence of human papillomavirus deoxyribonucleic acid by Southern blot analysis with the use of deoxyribonucleic acid cloned from human papillomaviruses 6, 11, 16, and 18. In a prospective study of 60 women referred to a colposcopy clinic for evaluation of abnormal Papanicolaou smears, we have detected human papillomavirus deoxyribonucleic acid in 16 of 17 (94%) women with a Class III (dysplasia) or IV (carcinoma in situ) Papanicolaou smear, five of 11 (45%) women with a Class II (atypical) Papanicolaou smear, and 10 of 34 (29%) women with a normal Papanicolaou smear. Detection of human papillomavirus deoxyribonucleic acid in cervicovaginal cells was indicative of a dysplastic cervical lesion in 19 of 20 (95%) patients irrespective of Papanicolaou smear results. We conclude that human papillomavirus deoxyribonucleic acid analysis in cervicovaginal cells is a sensitive method to detect dysplastic lesions of the cervix and may be useful in identifying patients with specific types of human papillomavirus infection, who are at risk to develop cervical cancer.

Plasma levels of antioxidant β‐carotene and α‐tocopherol in uterine cervix dysplasias and cancer

Abstract Chronic human health problems, namely arteriosclerosis, myocardial ischemia, and cancer, may be caused by highly active oxygen species and may be preventable by antioxidant vitamins. In humans, the sources of two major antioxidants, β‐carotene and α‐tocopherol, are dietary. In this study, we measured the plasma concentrations of s‐carotene and a‐tocopherol by reverse‐phase high‐pressure liquid chromatography in a cross‐sectional sampling of 116 women. Significantly reduced plasma levels of β‐carotene and α‐tocopherol were observed in women with histopathologically diagnosed cervical dysplasias or cancer (p < 0.0001 and p < 0.005, respectively). There was an inverse association between the plasma levels of both β‐carotene and α‐tocopherol and increasingly severe graded cervical histopathology. In groups with advanced dysplasias, the percentage of smokers was markedly increased and the women were comparatively older (p < 0.0001). A strong association was noted between smoking status and plasma β‐ca...

VIRAL CHARACTERISTICS OF HUMAN PAPILLOMAVIRUS INFECTION AND ANTIOXIDANT LEVELS AS RISK FACTORS FOR CERVICAL DYSPLASIA

Genital human papillomavirus (HPV) infection is the major causal factor of cervical intraepithelial neoplasia (CIN). The potential role of nutrition as an additional, independent risk factor for CIN has not been appropriately addressed in the context of HPV. This case‐control study evaluated the etiologic role of HPV in terms of viral type and load and examined the association between CIN and plasma levels of micronutrients adjusting for HPV. Cases (n = 378) with histo‐pathologically confirmed CIN and controls (n = 366) with no history of abnormal Pap smears were recruited from colposcopy and gynecology clinics, respectively. Risk of CIN was significantly increased among women who were infected with multiple HPV types (odds ratio [OR] = 21.06), a high viral load (OR = 13.08) and HPV 16 (OR = 62.49). After adjusting for HPV positivity and demographic factors, there was an inverse correlation between plasma α‐tocopherol and risk of CIN (OR = 0.15). Plasma ascorbic acid was protective at a high level of ≥ 0.803 mg/ dl (OR = 0.46). CIN was not associated with plasma retinol and β‐carotene levels. The effect of genital HPV infection on CIN development is highly influenced by oncogenic viral type and high viral load. Vitamins C and E may play an independent protective role in development of CIN that needs to be confirmed in prospective studies. Int. J. Cancer 78:594–599, 1998.

Human papillomaviruses of different types in precancerous lesions of the uterine cervix: Histologic, immunocytochemical and ultrastructural studies

In a prospective study of 34 women with abnormal Papanicolaou smears, biopsy and cervicovaginal lavage specimens were analyzed for the presence of human papillomaviruses (HPVs) by Southern blot analysis and probes for HPVs 6, 11, 16, and 18. In 22 of the 23 patients with cervical lesions (96%), HPV DNA was identified in one or more specimens. All patients in whom HPV DNA was found had either koilocytotic or dysplastic lesions on biopsy or Papanicolaou smear. Immunocytochemical demonstration of HPV in biopsy samples was associated with the presence of large amounts of HPV DNA and with the ultrastructural identification of viral particles. The presence of HPV DNA in cervical biopsy specimens was limited to discrete geographic areas of the cervix with histologic abnormalities. Although HPV 16 and other related HPV types were found in all cases of severe cervical intraepithelial neoplasia, the type of HPV present in a given specimen could not be predicted on the basis of morphologic, immunocytochemical, or electron microscopic findings. It is concluded that virtually all dysplastic lesions of the cervix contain HPV DNA, that HPV is thus likely to be a major etiologic agent in the pathogenesis of cervical dysplasia, and that histopathologic features are not predictive of HPV type.

Retinoids and the prevention of cervical dysplasias.

Women with abnormal cytology were matched with normal control subjects for age, parity, ethnicity, and socioeconomic class and participated in a blind case-control study focused on the role of nutrition in cervical dysplasia. Sucrose gradient ultracentrifugation studies for determination of the presence and concentration of the binding proteins for retinol and retinoic acid were performed on colposcopic biopsy tissue specimens. The nutritional survey revealed statistically significant differences for vitamins A and C and beta carotene. Retinol binding protein was absent or minimally detectable and inversely related to the severity of the dysplasia. It is proposed that a double-blind clinical trial be conducted to evaluate whether retinoids may pharmacologically inhibit, arrest, or reverse cervical dysplasia.

Detection of human papillomavirus deoxyribonucleic acid in exfoliated cervicovaginal cells as a predictor of cervical neoplasia in a high-risk population

Specific types of human papillomavirus are currently implicated as etiologic agents of precancerous and cancerous lesions of the cervix. We have previously described the use of cervicovaginal lavage and molecular hybridization to detect human papillomavirus infections of the cervix. We report here the predictive value of this method of human papillomavirus detection to identify women with biopsy proved dysplastic and cancerous lesions of the cervix. One hundred ninety-one women from a city hospital colposcopy clinic underwent concurrent Papanicolaou smear, cervicovaginal lavage, and coloposcopically directed cervical biopsy. Human papillomavirus deoxyribonucleic acid was detected in 114 (59.7%) of these women. Of the positive results, human papillomavirus type 16 accounted for 23.7%, human papillomavirus type 18 for 10.5%, human papillomavirus type six or 11 for 6.2%, related human papillomavirus types for 52.6%, and 7.0% contained more than one type. The distribution of human papillomavirus types was similar in both women younger than 40 years of age and in older women. Eighty-nine of 128 (69.5%) women less than 40 years old with cervical lesions had positive findings of human papillomavirus, and 18 of 29 (62.1%) older women with cervical lesions had positive findings of human papillomavirus. Detection of human papillomavirus types 16 and 18 identified only 35 of 157 (22.3%) women with cervical lesions. The sensitivity of detecting all types of human papillomavirus as a predictor of a biopsy proved lesion (68.0%) was comparable with the sensitivity of cytologic examination alone (74.0%). However, human papillomavirus detection combined with the Papanicolaou smear provided an increased overall sensitivity of 89.3% (p less than 0.01). In fact, women either positive for human papillomavirus or having abnormal cytologic findings were 11.8 times more likely to have a biopsy proved cervical lesion than human papillomavirus-negative women with negative cytologic results (95% confidence interval for odds ratio: 5.3 to 26.6). We conclude that the sensitivity of cytologic examination plus human papillomavirus detection is superior to the use of either cytologic studies or human papillomavirus detection alone in identifying patients with cervical lesions.

Placental and serum levels of carotenoids in preeclampsia.

OBJECTIVE We compared placental tissue, maternal serum, and umbilical cord venous blood levels of four dietary carotenoids (α‐carotene, β‐carotene, lycopene, and canthaxanthin) in normal pregnant women and those with preeclampsia. METHODS Levels of α‐carotene, β‐carotene, lycopene, and canthaxanthin were measured in placental tissue, maternal serum, and umbilical cord venous blood from 22 normal pregnant women and 19 women with preeclampsia. The criteria for recruitment included gestational age of 30–42 weeks, singleton pregnancy, intact membranes, absence of labor contractions, and absence of any other medical complication concurrent with preeclampsia. Carotenoids were measured using high‐pressure liquid chromatography. RESULTS All four carotenoids were detectable in human placental tissue, maternal serum, and umbilical cord venous blood samples. The levels of β‐carotene, lycopene, and canthaxanthin in placentas from preeclamptic women were significantly lower (P = .032, .009, and .013, respectively, by Mann‐Whitney test) than those from normal pregnant women. Maternal serum levels of β‐carotene and lycopene were significantly lower (P = .004 and .008, respectively, by Mann‐Whitney test) in women with preeclampsia. However, umbilical cord venous blood levels of these carotenoids were not significantly different between the two groups. CONCLUSION Lower placental tissue and maternal serum carotenoid levels in women with preeclampsia suggest that oxidative stress or a dietary antioxidant influence might have an effect on the pathophysiology of preeclampsia.

Plasma vitamin C and uterine cervical dysplasia

Plasma concentrations of vitamin C were determined in a case-control study of women (n = 80) who had sought a Papanicolaou test in the Bronx Municipal Hospital Center. Controls (n = 34) were women having negative cytologic tests, negative colposcopic findings, and no known gynecologic dysfunction. Cases (n = 46) were defined as women who had either one positive or two consecutive suspicious Papanicolaou smears in a 12-month period. The mean concentration of vitamin C in the plasma was significantly lower in the cases than in the controls (0.36 versus 0.75 mg/dl, p less than 0.0001). Cases were further stratified according to the histopathologic diagnosis. The data direct attention to a possible etiologic association of vitamin C in human cervical epithelial abnormalities. A clinical trial with vitamin C intervention is suggested.