TH1 and TH2 cytokine mRNA and protein levels in human immunodeficiency virus (HIV)-seropositive and HIV-seronegative youths

The roles of cytokines in the progression of human immunodeficiency virus (HIV)-associated disease are controversial. The patterns of innate cytokine production have been postulated to shift from TH1- to TH2-type cytokines with the progression of HIV-associated disease. Although there have been studies of cytokines in children and adults, no data are available on cytokine production in healthy or HIV-infected adolescents. We analyzed and characterized cytokine mRNA and protein levels for gamma interferon, interleukin 2 (IL-2), IL-4, and tumor necrosis factor alpha and protein levels of IL-6 in both stimulated and unstimulated peripheral blood mononuclear cells obtained from a large longitudinal, observational cohort study of HIV-seropositive and -seronegative adolescents. We correlated cytokine results with viral load and CD4(+)-T-cell counts as critical markers of disease progression in HIV-infected adolescents. These data were used to examine hypotheses related to the TH1-to-TH2 cytokine shift in a sample of HIV-infected adolescents. Five hundred twenty subjects participating in the REACH (Reaching for Excellence in Adolescent Care and Health) Project of the Adolescent Medicine HIV/AIDS Research Network contributed blood samples. Samples selected for the cross-sectional data set analyzed had to meet selection criteria developed to minimize the potential confounding effects of acute intercurrent illnesses or infections, recent vaccination for hepatitis, and altered hormone status and to optimize congruence of cytokine measurements with assays of viral load and CD4(+)-T-cell counts. Group differences in the proportions of subjects with detectable levels of each cytokine marker were compared. In the subset of subjects with detectable cytokine values, differences in detected values were compared across subgroups defined by HIV serostatus and among HIV-seropositive subjects by three viral load classifications. The study sample was 65% HIV seropositive, 71% African-American, and 75% female with a mean age of 17.4 years. HIV-seropositive subjects were relatively healthy with mean and median CD4(+)-T-cell counts of 534 and 499 cells/mm(3), respectively. Only 8.1% of subjects had CD4(+)-T-cell counts below 200 cells/mm(3), and 25% had viral loads that were below the threshold of detection (<400 copies/ml). Detailed analyses of these data indicate that there were no differences in cytokines detected in HIV-seropositive and HIV-seronegative adolescents, and there was no apparent relationship between the cytokine measurements and the viral load or CD4(+)-T-cell categorization, the parameters selected as markers of HIV-associated disease status. These adolescents, including the HIV-seropositive subjects, were relatively healthy, and the HIV-infected subjects were at an early stage in the course of their HIV-associated disease. On the basis of our data, we conclude that, early in the course of HIV-associated disease in adolescents, there are no detectable shifts from TH1 to TH2 cytokine production.     

The association between human papillomavirus deoxyribonucleic acid status and the results of cytologic rescreening tests in young, sexually active women.

We examined the utility of cytologic rescreening tests in women who had positive test results for human papillomavirus deoxyribonucleic acid but who were diagnosed as having benign conditions at cytologic testing. One hundred twenty-five Papanicolaou smears from women who were screened for human papillomavirus deoxyribonucleic acid were sent routinely to a private laboratory for diagnoses. These slides were then reviewed independently by two pathologists who were blinded to the human papillomavirus deoxyribonucleic acid results. The effects of cytologic rescreening in cases of both positive and negative human papillomavirus deoxyribonucleic acid were assessed by calculating z scores. Cervical intraepithelial neoplasia was diagnosed in 40% by pathologist A and in 20% by pathologist B of the human papillomavirus-positive subjects compared with none diagnosed by the private cytology laboratory (z = 3.09, p less than 0.005 and z = 1.98, p less than 0.05, respectively). No significant differences were found in the human papillomavirus-negative group. We conclude that cytologic rescreening in human papillomavirus deoxyribonucleic acid-positive women who were initially diagnosed as having benign cytologic results will yield a significant proportion of cases of cervical intraepithelial neoplasia.     

Anesthetic potency of dezocine and its interaction with morphine in rats

A new partial agonist-antagonist analgesic drug, dezocine, was evaluated in rats for its anesthetic potency using a MAC-reduction model. Respiratory effects as shown by changes in PaCO2 were also analyzed. A reduction of approximately 50% in cyclopropane MAC was found with doses of 6 mg/kg or more. This is the largest reduction for any drug of this class. PaCO2 levels increased up to 52 mm Hg with doses of dezocine up to 2 mg/kg. No evidence of reversal of respiratory depression or of further respiratory depression was found with increasing dosages. Combining dezocine with morphine resulted in a further reduction in cyclopropane MAC without a significant change in PaCO2. This suggests that dezocine acts primarily on the same receptor (mu) as morphine and that this receptor activity is further modulated by effects of dezocine on a second opioid receptor.     

Human papillomavirus infections in women with HIV disease: prevalence, risk, and management

Among the most common coinfections and comorbidities associated with the immunosuppression induced by HIV are human papillomavirus (HPV) and its associated diseases: external genital warts, low- and high-grade squamous intraepithelial lesions, and genital squamous cell cancers. Studies have consistently shown that HPV infections in HIV-seropositive women are detected more frequently, are more persistent, and are more difficult to treat than are those in HIV-seronegative women. This article reviews the prevalence, risk, and management of HPV associated infections in HIV-seropositive women.     

American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors

The American Cancer Society (ACS) has developed guidelines for the use of the prophylactic human papillomavirus (HPV) vaccine for the prevention of cervical intraepithelial neoplasia and cervical cancer. These recommendations are based on a formal review of the available evidence. They address the use of prophylactic HPV vaccines, including who should be vaccinated and at what age, as well as a summary of policy and implementation issues. Implications for screening are also discussed.     

Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females.

CONTEXT: Low-grade squamous intraepithelial lesions (LSILs) have been described as a benign cytological consequence of active human papillomavirus (HPV) replication. Several studies have reported that certain behavioral and biological risks exist for LSIL, suggesting that HPV alone is not sufficient for the development of LSIL. However, because most of these studies have been cross-sectional, it is not known whether behavioral and biological risks are simply risks for HPV infection itself. OBJECTIVE: To prospectively examine risks of incident HPV infection in HPV-negative females and of incident LSIL development in females with HPV infection. DESIGN: Prospective cohort study conducted between 1990-2000, with a median follow-up of 50 months. SETTING AND PARTICIPANTS: Females aged 13 to 21 years who attended 2 family planning clinics in the San Francisco bay area; 496 had prevalent HPV infection and 105 were HPV-negative. MAIN OUTCOME MEASURE: Incident development of HPV infection and LSIL, analyzed by various demographic, behavioral, and clinical risk factors. RESULTS: Fifty-four incident HPV infections occurred in the 105 females who were HPV-negative at study entry (median duration of follow-up for those who remained HPV-negative was 26 months). Multivariable analysis showed that risks of HPV included sexual behavior (relative hazard [RH], 10.10; 95% confidence interval [CI], 3.24-31.50 per new partner per month), history of herpes simplex virus (RH, 3.54; 95% CI, 1.37-9.10), and history of vulvar warts (RH, 2.73; 95% CI, 1.27-5.87). Current use of oral contraceptives had a significantly protective effect (RH, 0.49; 95% CI, 0.28-0.86). Among the 496 individuals who were HPV-positive at baseline or in follow-up, there were 109 incident cases of LSIL during the follow-up interval, with a median follow-up time of 60 months for those who never developed LSIL. Human papillomavirus infection was the most significant risk factor for development of LSIL. The multivariable model showed the following risks for LSIL: HPV infection for less than 1 year (RH, 7.40; 95% CI, 4.74-11.57); HPV infection for 1 to 2 years (RH, 10.27; 95% CI, 5.64-18.69); HPV infection for 2 to 3 years (RH, 6.11; 95% CI, 1.86-20.06); and daily cigarette smoking (RH, 1.67; 95% CI, 1.12-2.48). CONCLUSION: Our results indicate distinct risks for HPV and LSIL. In addition, most women with HPV infection in our study did not develop LSIL within a median follow-up period of 60 months. These findings underscore the hypothesis that certain biological risks thought to be associated with LSIL are, in fact, risks for acquisition of HPV. Cigarette smoking was a risk specific to LSIL, supporting the role of tobacco in neoplastic development.     

Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women

Background

Vaccines are now available for the prevention of HPV-16/18-related cervical infections and pre-cancers, primarily targeting adolescent girls. Since the risk of HPV exposure potentially persists throughout a woman's sexual life, vaccine-derived immunity should be long-term. The current study, HPV-024 (NCT00546078, http://clinicaltrials.gov), assessed the immune memory in North American women who received three doses of HPV-16/18 AS04-adjuvanted vaccine 7 years earlier in HPV-001 (NCT00689741).

Methods

Women vaccinated in HPV-001 received a 4th-dose of the HPV-16/18 vaccine (024-4DV group, N = 65). Post 4th-dose immune responses were compared with post 1st-dose immune responses in cross-vaccination controls (024-3DV group, N = 50). Reactogenicity was compared between the 4th-dose and the 1st-dose administration.

Results

Pre 4th-dose, 100% of subjects in the 024-4DV group remained seropositive for anti-HPV-16/18 antibodies (ELISA). Compared to pre 4th-dose, GMTs for anti-HPV-16 and anti-HPV-18 antibodies were respectively 9.3-fold and 8.7-fold higher at day 7, and 22.7-fold and 17.2-fold higher at month 1. Compared to post 1st-dose, GMTs for anti-HPV-16 and anti-HPV-18 were respectively 80.5-fold and 205.4-fold higher at day 7, and 11.8-fold and 20.5-fold higher at month 1. Furthermore, 68.2% and 77.3% of women had HPV-16/18 specific memory B-cells, respectively, pre 4th-dose, rising to 100% one month post 4th-dose vaccination. The 4th-dose was generally well tolerated.

Conclusion

A 4th-dose of HPV-16/18 AS04-adjuvanted vaccine triggered a rapid and strong anamnestic response in previously vaccinated women, demonstrating vaccine-induced immune memory.     

Comparison of pH-adjusted lidocaine solutions for epidural anesthesia

One hundred forty-eight adult patients having epidural anesthesia for cesarean section, postpartum tubal ligation, lower extremity orthopedic procedures, or lithotriptic therapy were assigned to five groups. Group 1 patients were given a commercially prepared 1.5% lidocaine solution with 1:200,000 epinephrine plus 1 ml of normal saline per 10 ml of lidocaine; the solution pH was 4.6. Group 2 patients were given commercially prepared 1.5% lidocaine solution plus 1:200,000 epinephrine, with 1 mEq (1 ml) NaHCO3 per 10 ml of lidocaine; the solution pH was 7.15. Group 3 patients received the commercial solution of 1.5% lidocaine with 1:200,000 epinephrine; the solution pH was 4.55. Group 4 patients were given a mixture of 18 ml of 2% lidocaine with 30 ml of 1.5% lidocaine, both commercially packaged with 1:200,000 epinephrine, plus 1 mEq (1 ml) of NaHCO3 added per 10 ml of solution; the solution pH was 7.2. Group 5 patients received 1.5% plain lidocaine to which epinephrine was added to a final concentration of 1:200,000; the solution pH was 6.35. Times of onset of analgesia (time between the completion of the anesthetic injection and loss of scratch sensation at the right hip (L-2 dermatome] and of surgical anesthesia (time between completion of injection and loss of discomfort following tetanic stimulation produced by a nerve stimulator applied to skin on the right hip) were significantly more rapid in the groups that received the pH-adjusted solutions (groups 4 and 2). Group 4 had the fastest mean onset time, 1.92 +/- 0.17 min, followed by group 2, 3.31 +/- 0.23 min.(ABSTRACT TRUNCATED AT 250 WORDS)