Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

Identification of the collar-like structure of the 30S ribosomal subunit from E. coli by dark field electron microscopy.

We have used dark field electron microscopy to study a fragment of the small (30S) subunit of the E. coli ribosome. This fragment is almost the same size as the parent particle but RNA sequencing studies have shown it to lack, as a major constituent, a 150-nucleotide stretch at the 3' end of the rRNA, and two minor sections constituting 20 nucleotides from the 5' end and the 15 nucleotides of the sequence 687-701. The protein composition of the fragment was essentially unchanged. Samples of this material, and controls, were examined in the electron microscope after treatment with a buffered uranyl acetate solution for positive staining. Careful comparison revealed the following differences. The structural feature that we call the "collar" was missing in the fragment. Of the three parallel uranyl-staining bands that we have observed in micrographs of whole 30S subunits, the fragment consistently lacked the uppermost band. These observations identify the top uranyl-adsorbing band as being the 3' end of the ribosomal RNA and show that it can be equated with the collar-like structure.

Multimeric complexes of differentiation-inducing protein bound to DNA.

Myeloid hematopoietic precursor cells are induced to differentiate by the macrophage and granulocyte differentiation-inducing protein MGI-2 (DF). This differentiation-inducing protein bound to double-stranded but not to single-stranded mammalian DNA. The bound MGI-2 was not eluted by high salt, but was eluted by sodium dodecyl sulfate (SDS). MGI-2 also bound to double-stranded E. coli DNA, but with this DNA the bound MGI-2 was eluted by high salt. This indicated a difference in the binding affinities of MGI-2 to mammalian and E. coli DNA. MGI-2 bound to DNA was examined by electron microscopy. The results indicate that MGI-2 formed a multimeric complex with double-stranded DNA and that the size of the complex was correlated with the strength of protein binding to the DNA. The multimeric complex bound to DNA was disrupted by deoxyribonuclease. The data indicated that binding of this differentiation-inducing protein to DNA involves the formation of a multimeric complex in which the monomers are held together by DNA. It is suggested that the formation of such multimeric complexes of MGI-2 and DNA may allow activation of the multiple pathways of gene expression that is required for differentiation.

A survey of 50 S ribosomal subunits by dark field electron microscopy.

A survey of dark field electron micrographs of the 50 S ribosomal subunit of E. coli has been performed and supplemented, for comparative purposes, by examination of negatively stained or metal shadowed specimens in the bright field mode. Attention was directed to the so-called "crown" and "kidney" views. The elongated appendage seen in negatively stained crown profiles was not observed in unstained or positively stained samples examined in dark field; these showed only symmetrical crown profiles regardless of changes in buffer type and drying method and of the presence or absence of uranyl acetate treatment and glutaraldehyde fixation. The crown view occasionally displayed a bifurcation in one of the lateral lobes, while the kidney profile showed a groove near the base of the convex edge. Uranyl acetate treatment produced delicate stripes which may give an indication of the surface RNA distribution.

Specific visualization of ribosomal RNA in the intact ribosome by electron spectroscopic imaging.

The recently developed electron microscopic technique of electron spectroscopic imaging has been used to map the distribution of phosphorus, and therefore of RNA, in situ in the ribosomal subunits of E. coli. The results indicate that the RNA moiety of both subunits is concentrated toward the centre of the particle somewhat more than is the total mass, but reaches the outer surface at several places. The micrographs also reveal certain distinctive features in the shape of the RNA component that may be related to the overall shape of the ribosome. The method yielded a reasonably accurate estimate of the phosphorus content of the 30 S ribosome.

Protein that induces cell differentiation causes nicks in double-stranded DNA.

The growth and differentiation of myeloid hematopoietic cells are regulated by different macrophage and granulocyte inducing proteins, those that induce growth and others that induce differentiation. The proteins that induce differentiation but not those that induce growth bind to double-stranded DNA. We now report that purified myeloid cell differentiation-inducing protein causes single strand breaks (nicks) in double-stranded DNA. This DNA nicking may initiate the changes in gene expression that are required for differentiation.

Does use of permanent suture material affect outcome of the modified Pereyra procedure?

OBJECTIVE: To determine the effect of absorbable versus permanent suture on outcome of the modified Pereyra procedure for stress urinary incontinence. METHODS: A review was performed of case-series reports of outcome of the modified Pereyra procedure for stress urinary incontinence that provided at least 1 year of follow-up and that specified the suture material used. Outcomes of cases in which permanent suture was used were compared with cases in which absorbable suture was used. The groups were further stratified according to whether success of the procedure was determined objectively or subjectively. Chi-square analysis was performed. RESULTS: Fourteen case-series reports were examined, representing a total of 988 modified Pereyra operations. Overall, the relative risk (RR) of failure when absorbable suture was used was 1.8 times higher than with permanent suture (95% confidence interval [CI] 1.4-2.3; P < .0001) using objective or subjective outcome criteria. The RR of failure using absorbable suture when judged by objective criteria only was 1.6 (95% CI 1.1-2.3; P = .03) and when judged by subjective outcome only was 2.3 (95% CI 1.5-3.4; P < .0001). CONCLUSION: Until a randomized controlled trial is done, the available evidence supports the use of permanent suture material whenever the modified Pereyra procedure is performed.

Sensitivity of the Papanicolaou smear in human immunodeficiency virus-infected women.

OBJECTIVE: To determine the sensitivity of the Papanicolaou smear in human immunodeficiency virus (HIV)-infected women. METHODS: Fifty-two HIV-seropositive women underwent colposcopy and had cytologic and histologic specimens obtained. Eighty-five consecutive women seen in our colposcopy clinic who stated that they were HIV-seronegative formed the comparison group. Demographic features of the groups and cytology and histology findings were compared. RESULTS: In HIV-infected patients, the prevalence of cervical dysplasia was 50%. An additional 15% had vulvar lesions alone. The sensitivity of cytologic smears for cervical dysplasia was 63% and specificity was 84%. These findings were not significantly different from those of a control group of women undergoing colposcopy for standard indications (P > .05). Twelve of 38 seropositive women for whom future appointments were scheduled were lost to follow-up. CONCLUSIONS: The sensitivity of the Papanicolaou test does not appear to be diminished in HIV-seropositive women. Screening colposcopy may be justified in view of the high prevalence of cervical and vulvar dysplasia, as well as the high noncompliance rate observed in this patient population.

Pelvic inflammatory disease in human immunodeficiency virus-infected women.

OBJECTIVE: To determine whether the clinical course of pelvic inflammatory disease differs between women with human immunodeficiency virus (HIV) infection and seronegative controls. METHODS: All admissions for acute pelvic inflammatory disease from January 1, 1986 to December 31, 1992 at San Francisco General Hospital were reviewed, identifying 23 HIV-seropositive women. Their clinical course was compared with a control group of 108 seronegative women admitted for acute pelvic inflammatory disease. RESULTS: Human immunodeficiency virus-seropositive women with acute pelvic inflammatory disease had significantly lower abdominal tenderness scores (P < .05), lower admission and discharge white blood cell counts (WBC) (P < .01, P < .05), and fewer gonococcal infections (odds ratio 0.3, 95% confidence interval [CI] 0.1-0.9; P < .05) than the seronegative controls. There were no significant differences in duration of treatment, length of hospitalization, or incidence of tubo-ovarian abscess. Significantly more HIV-positive women with acute pelvic inflammatory disease required surgical intervention than seronegative women (odds ratio 5.5, 95% CI 1.0-29.3; P < .05). CONCLUSION: Human immunodeficiency virus-seropositive women with acute pelvic inflammatory disease may have an altered immune response, resulting in inadequate response to antimicrobial agents and the need for more surgical intervention. Future studies must include larger numbers of HIV-infected women, and the results must be stratified for CD4 counts, clinical HIV stage, and other measures of immunocompromise.

Plasma cell endometritis in women with symptomatic bacterial vaginosis.

OBJECTIVE: To evaluate the endometrial microbiology and histopathology in women with symptomatic bacterial vaginosis but no signs or symptoms of upper genital tract disease or other vaginal or cervical infections. METHODS: Endometrial biopsies were performed on 41 women complaining of vaginal discharge or pelvic pain at a sexually transmitted disease clinic. These women had neither culture nor serologic evidence of Neisseria gonorrhoeae or Chlamydia trachomatis infection. Twenty-two women with bacterial vaginosis diagnosed by Gram stain examination of vaginal fluid, but with neither signs nor symptoms of upper genital tract infection, were compared with 19 women who had no evidence of bacterial vaginosis on vaginal fluid Gram stain. Endometrial biopsies were evaluated for histopathologic evidence of plasma cell endometritis and were cultured for N gonorrhoeae, C trachomatis, aerobic and anaerobic bacteria, Mycoplasma species, and Ureaplasma urealyticum. RESULTS: Ten of 22 women with bacterial vaginosis had plasma cell endometritis, compared with one of 19 controls (odds ratio [OR] 15, 95% confidence interval [CI] 2-686; P < .01). Bacterial vaginosis-associated organisms were cultured from the endometria of nine of 11 women with and eight of 30 women without plasma cell endometritis (OR 12.4, 95% CI 2-132; P = .002). CONCLUSION: Plasma cell endometritis was frequently present in women with bacterial vaginosis and without other vaginal or cervical infections. This suggests the possibility of an association between bacterial vaginosis and nonchlamydial, nongonococcal, upper genital tract infection.

Bacillary angiomatosis of the cervix and vulva in a patient with AIDS.

BACKGROUND: Bacillary angiomatosis is a clinicopathologic entity that most often is identified in the skin of patients with AIDS. This report presents an example of bacillary angiomatosis of the female genital tract. CASE: Bacillary angiomatosis presented as red-purple nodules of the vulva and cervix in a 32-year-old woman with AIDS. Histologic examination revealed the lobular epithelioid vascular proliferation and hazy clumps of bacteria that characterize bacillary angiomatosis. The diagnosis was confirmed on Warthin-Starry-stained issue and by blood cultures, which were positive for Bartonella (Rochalimaea) henselae. CONCLUSION: Accurate diagnosis of this infection is important because 1) bacillary angiomatosis is commonly mistaken for Kaposi sarcoma, 2) it is effectively treated with inexpensive antibiotics, and 3) undiagnosed and/or untreated bacillary angiomatosis may lead to overwhelming disseminated infection and death.

Operations for stress urinary incontinence in the United States, 1988-1992.

OBJECTIVES: To determine the frequency and cost of operations for stress urinary incontinence in the United States. METHODS: We reviewed data from the 1988-1992 National Hospital Discharge Surveys and the 1991 California Office of Statewide Health Planning Survey. We determined the frequency and type of surgical procedures performed for stress urinary incontinence and estimated the total direct costs of these operations in the United States. RESULTS: From 1988 to 1992, the total number of operations for stress incontinence increased from 78,000 to over 100,000. The rate of operations increased most in women older than 65 years of age. The total direct cost for treatment of stress urinary incontinence in the United States in 1991 was about $0.5 billion. CONCLUSIONS: Operations for treatment of stress urinary incontinence are increasing in frequency in the United States. They are both more commonly performed and more costly than have been previously reported.

Does vaginal cuff closure decrease the infectious morbidity associated with abdominal hysterectomy?

BACKGROUND: Infectious morbidity after total abdominal hysterectomy includes fever (31%) and antibiotic administration (45%). Whether vaginal cuff closure reduces postoperative infectious morbidity remains unresolved. STUDY DESIGN: We reviewed the records of 172 consecutive abdominal hysterectomies for nonmalignant disease performed at an inner-city hospital. We identified potential risk factors for infectious morbidity by univariate analysis and determined adjusted odds ratios by multiple logistic regression analysis. RESULTS: The open vaginal cuff technique was associated with an increased risk of wound infection. Use of prophylactic antibiotics was associated with a decreased risk of febrile morbidity and a decreased risk of prolonged hospitalization. Body weight in the heaviest quartile was associated with increased risk of wound infection, increased risk of prolonged hospitalization, and decreased risk of postoperative vaginal cuff granulation tissue. Older age was associated with an increased risk of prolonged hospitalization. CONCLUSIONS: Closure of the vaginal cuff and use of prophylactic antibiotics at total abdominal hysterectomy were associated with decreased infectious morbidity in a high-risk population.

Charge redistribution in proteins via linear hydrogen-bond chains.

It is proposed that proteins might activate specific atomic positions within bound substrates or co-factors by means of hydrogen-bond chains. As a result of a concerted proton (tautomeric) shift in the linked residues of the hydrogen-bond chain, which includes the bound molecule, a charge separation occurs. The charge thus generated at a specific atom of the bound molecule renders it nucleophilic or electrophilic, as the case may be, and hence 'activated' towards subsequent chemical events. To test the feasibility of the theory a survey of published X-ray diffraction determined structures was performed. A search was made for hydrogen-bond chains which emanate away from bound substrates, co-factors or metal ions in order to validate the existence of such structural arrangements. Secondly, an attempt was made to incorporate the proposed proton dynamics into the proteins' mechanisms of action. Examples in which these criteria were satisfied are carboxypeptidase A, carbonic anhydrase, haemoglobin, dihydrofolate reductase, glutathione reductase and p-hydroxybenzoate hydroxylase.

Lower genital tract neoplasia in women with HIV infection.

Women who are infected with human immunodeficiency virus (HIV) are at greater risk for the development of lower genital tract neoplasia than are HIV-negative women. Among HIV-positive women, those who are more severely immunosuppressed appear to be at higher risk for cervical intraepithelial neoplasia (CIN), also known as squamous intraepithelial lesions (SILs). Women who are HIV-positive also are more likely than HIV-negative women to have multifocal lower genital tract neoplasia. Cervical cancer is one of the most important acquired immune deficiency syndrome (AIDS)--related malignancies in women. Cancer and intraepithelial neoplasia of the lower genital tract can be persistent, progressive, recurrent, and difficult to treat in HIV-positive women. The most effective method for treating SILs has not been determined. Regular performance of Pap smears in HIV-positive women is of critical importance, as is careful examination of the entire lower genital tract. Also, women with high-grade intraepithelial or cervical cancer should be tested for HIV.

Gynecology and family planning care for the woman infected with HIV.

This article reviews the interactions between HIV infection and a variety of gynecologic conditions, including lower genital tract neoplasia, pelvic inflammatory disease, menstrual disorders, sexually transmitted diseases, and vaginitis. Important considerations in choosing a family planning method for women infected with HIV-infected women will respond to standard therapy, but require multiple courses of treatment or use of innovative treatment methods. All HIV-infected women deserve careful evaluation for and treatment of gynecologic diseases.

PIP: The US Centers for Disease Control's revised (1993) case definition for HIV infection now includes several gynecologic diseases. Clinical category B illnesses (attributable to or complicated by HIV) include persistent, frequent, or poorly responsive vaginal candidiasis; moderate or severe cervical intraepithelial neoplasia; and pelvic inflammatory disease. Clinical category C illnesses (AIDS-defining) include chronic herpes simplex virus ulcers and invasive cervical cancer. This article reviews current knowledge on the interrelationship of each of these gynecologic diseases and HIV infection. Also discussed are contraceptive options for women with HIV. Until data on the impact of contraceptives on the clinical course of HIV are available, a combination of barrier and hormonal methods or tubal ligation is recommended. All HIV-infected women deserve careful, nonjudgmental evaluation for gynecologic disease and contraception.

Pelvic inflammatory disease in women infected with HIV.

Pelvic inflammatory disease (PID) and HIV infection are frequently coincident. The diagnosis of PID can be more difficult to make in HIV-infected than in uninfected women. In general, HIV-infected women with PID have a good response to standard intravenous antibiotic therapy. However, surgical therapy is more frequently required for HIV-infected women with PID, especially those with more severe degrees of immunosuppression, than for uninfected women.

Vulvar intraepithelial neoplasia in women with HIV.

The increasing incidence of lower genital tract neoplasia in HIV-infected women and the inherent difficulties in diagnosis and treatment have undermined effective management and contributed significantly to the morbidity of this population. The Centers for Disease Control and Prevention has included high-grade squamous intraepithelial lesions, as well as cervical carcinoma in situ, as part of the classification of HIV, with invasive cervical cancer as an AIDS-defining condition. The incidence of vulvar intraepithelial neoplasia (VIN) nearly doubled between 1973 and 1987. In one study, VIN has been reported to occur 29 times more frequently in HIV-infected women than in a control group of self-identified non-HIV-infected women. Because women with HIV are now living longer, they face an increased possibility of the development of these infections along with the long-term sequelae and the risk of transformation to cancer. Treatment of VIN is guided by the size and location of the lesion, the grade of the dysplasia, and identification of coexisting disease in other sites. The case study presented exemplifies many of the management and education issues encountered following women with HIV disease and lower genital tract neoplasia, one of the most difficult issues being that the best mode of treatment for VIN has yet to be determined. Screening of the entire lower genital tract, including the vulva for dysplasia, is recommended for early detection and timely initiation of management.

Importance of atypical glandular cells of uncertain significance in cervical cytologic smears.

OBJECTIVE: To determine the clinical implications of atypical glandular cells of uncertain significance (AGCUS) in cervical cytologic smears. STUDY DESIGN: Retrospective analysis. RESULTS: Eighty-eight of 32,181 (0.27%) cervical smears obtained during the study period contained AGCUS. Of the 47 women with AGCUS, 16 had intraepithelial or invasive neoplasms (34%; 95% confidence interval, 21-49%), including 9 low or high grade squamous intraepithelial lesions, 1 adenocarcinoma in situ of the cervix, 3 adenocarcinomas of the cervix, 2 adenocarcinomas of the endometrium and 1 adenoid basal cell carcinoma of the cervix. CONCLUSION: The high prevalence of cervical and endometrial neoplasia among women with the isolated finding of AGCUS on cervical cytologic smears warrants a thorough diagnostic evaluation.

Multifocal lower genital tract neoplasia in women with HIV disease.

Lower genital tract neoplasia appears to occur often and in multiple sites in women infected with the human immunodeficiency virus (HIV). To describe the prevalence of lower genital tract neoplasia in HIV-infected women in our clinic we performed a retrospective chart review of 38 HIV-infected women who had received screening colposcopy. Fourteen percent of the women had VIN on biopsy. In addition, 50% of the women had abnormal Pap smears and 24% had CIN on biopsy. In this study, lower genital tract neoplasia was multifocal in nature and included a relatively high prevalence of VIN not previously reported in the literature.