Structural insights into the evolution of the pantothenate-biosynthesis pathway.

Pantothenate is synthesized in bacteria, fungi and plants, and as vitamin B5 is a dietary requirement in animals. The three-dimensional structures of the four Escherichia coli enzymes involved in the production of pantothenate have been determined. We describe the use of comparative analyses of the sequences and structures to identify distant homologues of the four enzymes in an attempt to understand the evolution of the pathway. We conclude that it is likely to have evolved via a patchwork mechanism, whereby the individual enzymes were recruited separately.

Identification of Tyr58 as the proton donor in the aspartate-alpha-decarboxylase reaction.

The decarboxylation of L-aspartate by E. coli L-aspartate-alpha-decarboxylase (ADC) is shown to occur with retention of configuration; analysis of the protein structure identifies Tyr58 as the proton donor in the decarboxylation mechanism.

The relationship between contraceptives, sexual practices, and cervical human papillomavirus infection among a college population.

Four hundred and sixty-five college women were evaluated to determine if specific variables of social and sexual behavior correlated with the presence of human papillomavirus (HPV) DNA in the genital tract, and if these associations differed between women who were HPV DNA positive, HPV DNA positive/clinically (cytologically) negative, or who reported previous HPV-related disease by a history of an abnormal Papanicolaou (Pap) smear or genital warts. HPV positive women had more sexual partners in the recent past, more sexual episodes per month, and used spermacides less commonly than controls. Similarly, self-reporters were more likely to have more lifetime sexual partners and earlier age of onset for sexual activity. Cytologically negative HPV positive women were distinguished only by more sexual episodes per month and sexual partners in the past year (borderline significance). Alcohol use was significantly more frequent in all groups, underscoring this variable as a risk factor for both HPV DNA positivity and related disease in young women. Potential explanations for differences between women with clinically and non-clinically related HPV positivity are discussed, with emphasis on the need for followup studies to determine if an epidemiologically distinct subset of HPV DNA positive but clinically negative women are at risk for subsequent cervical disease.

PIP: Cancer of the cervix is strongly associated with sexual behavior, and the risk of acquiring both cervical cancer and its precursor lesions increases with the number of sex partners, early age at first intercourse, increasing parity, and cigarette smoking. Low dietary intake of vitamin A and long-term use of oral contraceptives have also been suspected of elevating the risk of cervical intraepithelial neoplasia and cervical cancer. Human papillomavirus (HPV) has been studied intensively in recent years with regard to its role in the genesis of cervical cancer. Cervical infection by the virus occurs sexually and HPV has been isolated from cervical warts, precancers, and invasive carcinomas. Certain HPV types have been associated with cervical neoplasia and extensive experimental data indicate that HPV is an oncogenic virus. The prevalence of clinical HPV infection among young women has increased over the past decade. 465 women enrolled at the University of Virginia were evaluated to determine if certain variables of social and sexual behavior correlated with the presence of HPV DNA in the genital tract, and if the associations differed between women who were HPV DNA positive, HPV DNA positive/clinically negative, or who reported previous HPV-related disease by a history of an abnormal Pap smear or genital warts. The women were of mean age 22.7 years in the range of 17-39 years, 89% White, 91% single, and 65% undergraduate. This study population did not differ significantly from the university population. HPV-positive women had more sex partners in the recent past, more sexual episodes per month, and used spermicides less commonly than controls. Self-reporters were more likely to have more lifetime sex partners and earlier age of onset for sexual activity. Cytologically negative HPV-positive women were distinguished only by more sexual episodes per month and sex partners in the past year. Alcohol use was significantly more frequent in all groups, highlighting that variable as a risk factor for both HPV DNA positivity and related disease in young women. Potential explanations for differences between women with clinically and non-clinically related HPV positivity are discussed, with emphasis upon the need for follow-up studies to determine if an epidemiologically distinct subset of HPV DNA-positive, but clinically negative women are at risk for subsequent cervical disease.

Cytologic correlates of cervical papillomavirus infection.

A fundamental question in Papanicolaou smear screening is the specificity of cytologic criteria for the recognition of genital human papillomavirus (HPV) infection. To address this problem, we conducted a two-phase study of routinely screened women to determine the efficiency with which cytologic findings identified the presence of HPV DNA, focusing on the criteria for identifying smears as "atypical." In phase 1, 25 of 290 (8.6%) smears were designated atypical, but only 3 (12%) of the samples contained HPV nucleic acids. Four of five (80%) smears designated as diagnostic of HPV/cervical HPV infection were associated with HPV nucleic acids. By applying more stringent criteria for the diagnosis of atypical in phase 2, only 3 of 166 (1.8%) were identified as atypical. Of these, two (67%) contained HPV nucleic acids. The criteria that most efficiently correlated with HPV nucleic acids included prominent nuclear enlargement with either multiple nuclei or nuclear hyperchromatism. On review of the 19 HPV-positive and 20 control HPV-negative smears originally diagnosed as cytologically negative, the above criteria identified an additional 3 cytologically atypical/positive smears versus none (0 of 20) in the control group. This study supports the concept that cytologic abnormalities suggesting "subtle" HPV infection may be extremely difficult to distinguish from non-HPV-related changes, and that criteria used to imply "suggestive but not diagnostic for HPV infection" should be continually reevaluated. The potential role of HPV DNA analysis in Papanicolaou smear interpretation is discussed.