Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The Aids Clinical Trials Group 175 Team.

OBJECTIVE: To prospectively examine differences in baseline characteristics and study outcomes between HIV-infected women and men during a clinical trial of nucleoside analogue therapy. METHODS: ACTG 175 randomized HIV-infected patients with CD4+ counts between 200 and 500 cells/mm3 to one of four nucleoside analogue regimens: zidovudine (ZDV), didanosine (ddI), ZDV + ddI, or ZDV + zalcitabine (ddC). Differences in time to first dose modification, voluntary withdrawal, development of toxicity and symptomatology, and AIDS progression were compared by gender. RESULTS: The study included 438 women and 2029 men. Baseline values of HIV RNA plasma concentrations were significantly lower for women (0.3 log10) than men in a subset of patients in whom assays were taken and this difference persisted after adjustment for CD4+ count. Women reported reducing dosage and discontinue ddI-containing regimens more frequently than men did; adjustment for weight did not completely explain this difference. Women were at lower risk than men for progression to a study endpoint (19% of women versus 24% of men; p <.0001). Among those antiretroviral-naive study subjects receiving ZDV, men were four times more likely to progress to a study endpoint than women. CONCLUSIONS: Differences in pretreatment characteristics and on study experiences were demonstrated between women and men enrolled in this clinical trial. The suggestion of a gender difference in response to ZDV monotherapy by antiretroviral-naive study subjects and the lower baseline values for HIV RNA in women compared with those in men provides evidence for gender differences in the relationship between virus replication, CD4+ decline, and responses to nucleoside analogue therapy.

Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214.

The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

Chiral alpha-substituted carbonyls and alcohols from the S(N)2' displacement of cuprates on chiral carbonates: An alternative to the alkylation of chiral enolates

A highly stereoselective sequence of reactions, based on the anti-selective S(N)2' addition of cuprates to allylic carbonates, transforms alkynes or alkenyl halides into carbonyls having alpha-chiral centers. The method, which uses menthone as a chiral auxiliary, is a useful alternative to the alkylation of chiral enolates with the added advantage of allowing for the "alkylation" of sec- and tert-alkyl and aryl groups.

Effects of negative life events on immune suppression in children and youth infected with human immunodeficiency virus type 1.

OBJECTIVES: To evaluate the association of negative stressful life events experienced over 12 months and the risk of moderate to severe immune suppression among children and youth infected with human immunodeficiency virus type 1 (HIV-1). METHODS: Longitudinal study of 618 HIV-1-infected children, baseline ages 1 to 20 years (mean age: 6.4 years), who completed 52 weeks of participation in the Pediatric Late Outcomes Study (Pediatric AIDS Clinical Trials Group Protocol 219). Severity of immune suppression was indicated by the Centers for Disease Control and Prevention Pediatric HIV Disease Classification System, based on CD4 percentages. The total number of negative life events-categorized as none, 1, or >1 life event reported as having occurred in the previous 12 months (previous 6 months for children <3 years of age)-was the predictor variable. Multiple logistic regressions were estimated to assess the relationship of negative life events and immune suppression at outcome, controlling for baseline measures of immune suppression, continuous CD4%, negative life events, age, race/ethnicity, gender, primary caretaker, education level of caretaker, and acquired immunodeficiency syndrome status. RESULTS: At week 52, 379 subjects (61% of total study population) had moderate to severe immune suppression. Of 275 children with normal immune function at baseline, 68 (24.7%) subsequently developed moderate to severe suppression levels by week 52 of follow-up. Of 343 children with immune suppression at baseline, 32 (9.2%) had recovered to normal CD4% levels by week 52. More than 1 negative life event was associated with an increased risk (prevalence) of immune suppression (odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.44,5.31), controlling for baseline CD4%, total life events, and other covariates. Children without immune suppression at baseline who experienced >1 negative life event had an increased incidence of immune suppression (OR: 2.93; 95% CI: 1.34,6.39), controlling for baseline covariates. CONCLUSIONS: Results indicate that negative stressful life events increase the risk of children with HIV-1 infection having impaired immune function. Further research is needed to identify potential mechanisms of the relationship between stressful life events and impaired immune function. These mechanisms include psychoneuroendocrinologic response and difficulties in adherence to therapy after exposure of a child to major negative life events.

Benzophenones of Garcinia pseudoguttifera (Clusiaceae).

Four biogenetically related benzophenones have been isolated from the Fijian Garcinia pseudoguttifera. They are: 6-hydroxy-2,4-dimethoxy-3,5-bis(3-methyl-2-butenyl)benzophenone (myrtiaphenone-A); 2,2-dimethyl-8-benzoyl-7-hydroxy-5-methoxy-6-(3-methyl-2-butenyl)benzopy ran (myrtiaphenone-B); 2,6-dihydroxy-4-methoxy-3,5-bis(3-methyl-2-butenyl)benzophenone (vismiaphenone-C) and a new benzophenone, 2,2-dimethyl-8-benzoyl-3,7-dihydroxy-5-methoxy- 6-(3-methyl-2-butenyl)-3,4-dihydrobenzopyran (pseudoguttiaphenone-A). Pseudoguttiaphenone-A could be biogenetically derived from vismiaphenone-C. The major component of G. pseudoguttifera was identified as eupha-8,24-dien-3 beta-ol.

Comparison of gynecologic history and laboratory results in HIV-positive women with CD4+ lymphocyte counts between 200 and 500 cells/microl and below 100 cells/microl.

OBJECTIVE: To assess rates of sexual activity, contraceptive use, genital infections and dysplasia, and other gynecologic symptoms among well-characterized populations of HIV-seropositive women enrolled in two Adult AIDS Clinical Trials Group (AACTG) randomized studies. METHODS: Gynecologic data were collected using standardized interview and examination forms from women enrolled in two protocols: ACTG 175, an antiretroviral trial (CD4+ lymphocyte counts 200-500 cells/microl) and ACTG 196, a Mycobacterium avium complex prophylaxis trial (CD4+ counts < or =100 cells/microl). RESULTS: Women enrolled in the two studies were similar in age, race, weight, and history of illicit or injection drug use, but women in ACTG 196 (n = 67) had lower median CD4+ counts (median, 35 cells/microl; range, 0-135 cells/microl versus median, 356 cells/microl; range, 131-620 cells/microl; p < .0005), were less likely to be antiretroviral naive (6% versus 38%; p < .0005), and were more likely to have a Karnofsky score <80 (28% versus 5%; p < .0001) than women in ACTG 175 (n = 185) at baseline. Recent changes in menstrual cycle were not different between groups. Women enrolled in ACTG 196 were less likely to be sexually active (40% versus 61%; p < .005), but both groups reported high levels of contraceptive use. Papanicolaou smear results in ACTG 196 and ACTG 175 respectively, were: normal, 38% and 50%, atypia, 24% and 39%, low-grade squamous intraepithelial lesions (SIL), 27% and 10%, and high-grade SIL, 11% and 0.7% (p < .001). CONCLUSIONS: Gynecologic complications are common among HIV-seropositive women with CD4+ lymphocyte counts < 500 cells/microl and are more common and severe among those with more advanced immunosuppression.

The Noble-Mengert-Fish operation-revisited: a composite approach for persistent rectovaginal fistulas and complex perineal defects.

OBJECTIVE: Our aims were to evaluate the full-thickness anterior rectal wall advancement flap in the treatment of primary and recurrent or persistent rectovaginal fistulas, evaluate the surgical exposure for composite repair of site-specific perineal defects, and categorize clinical manifestations of site-specific perineal defects caused by obstetric injury. STUDY DESIGN: This is a prospective study of all patients with fecal incontinence from rectovaginal septal defects and complex perineal obstetric injuries treated by the Noble-Mengert-Fish operation. RESULTS: Thirty-four patients were classified into groups on the basis of site-specific perineal defects. Anatomic success was 94.2%. Functional success was excellent in 76.5%, good in 14.7%, fair in 5.9%, and poor in 2.9%. CONCLUSION: The Noble-Mengert-Fish operation is effective for primary and recurrent or persistent rectovaginal fistulas. The circumanal surgical exposure permits concomitant repair of all perineal defects.

Anti-HIV coumarins from Calophyllum seed oil.

The seeds of Calophyllum cerasiferum Vesque (Family-Clusiaceae), and Calophyllum inophyllum Linn. (Family-Clusiaceae) contain several known coumarins, among which were the potent HIV reverse transcriptase inhibitors costatolide and inophyllum P. Calophyllum cerasiferum contained (-)-calanolide B as its major coumarin constituent in significant amount and thus constitute a renewable source of this compound.

Effect of therapeutic immunization with recombinant gp160 HIV-1 vaccine on HIV-1 proviral DNA and plasma RNA: relationship to cellular immune responses.

Therapeutic vaccination has been proposed as a strategy to augment immune mechanisms to control viral replication and slow clinical progression of HIV infection to disease. Following recombinant gp160 (r-gp160) immunization in three clinical trials, plasma HIV-1 RNA and cellular proviral DNA were assessed by quantitative polymerase chain reaction (PCR) in 76 HIV-seropositive subjects with CD4+ T cell counts > or = 300/mm3. Immunization increased HIV-specific cellular immune responses (e.g., cytotoxic T lymphocyte [CTL] activities, lymphocyte proliferative responses); however, there were no significant effects of immunization or cellular immune responses on measures of plasma RNA or cellular DNA viral load.

Predictors of survival in HIV-infected persons with 50 or fewer CD4 cells/mm3.

The objective of this study was to identify prognostic factors for survival in patients with pretreatment CD4 < or =50 cells/mm3 treated with nucleoside analogs, and to develop and validate a mortality risk model based on these factors. The design of the study consisted of retrospective analysis of AIDS Clinical Trials Group (ACTG) protocols 116a, 116b/117, 155, and 118. The setting was the multicenter AIDS Clinical Trials Group. The patients were HIV-infected with pretreatment CD4 < or =50 cells/mm3 and various degrees of prior zidovudine (ZDV) use. Double-blind, three-arm randomized control trials ACTG 116a and ACTG 116b/117 compared ZDV with didanosine (ddI). ACTG 155 compared ZDV with zalcitabine or combination therapy. Our validation study, ACTG 118, compared the effects of three different doses of ddI on survival. The main outcome measures were survival and mortality. The three studies combined enrolled 699 patients with entry CD4 T-lymphocyte counts of < or =50 cells/mm3. Forty percent of patients died during follow-up, with a median survival of 19.7 months. Multivariate analysis showed shorter survival at p < 0.0001 with lower CD4 count (relative hazard [RH] = 0.98) and lower hemoglobin level (RH = 0.81). Other factors included older age (RH = 1.03), male gender (RH = 1.70), Hispanic ethnicity (RH = 1.68), and symptomatic disease stage (RH = 2.06). Our predictive mortality risk model differentiated well patients with differing risks of mortality. When the risk model was applied to ACTG 118, the validation data set, the identified prognostic factors could distinguish patients with varying risks of death (p < 0.001, stratified log-rank test). These results demonstrate that CD4 T-lymphocytes counts < or =50 cells/mm3 should not be considered a precursor of imminent death; considerable variability in survival exists in severely immunocompromised patients. Our identification of prognostic indicators for survival can aid clinicians and patients in management of their disease and researchers in design of future clinical trials.

Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1.

F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60-minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half-life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 +/- 9.62 micrograms/ml. The disposition of the drug was linear for the doses studied. Simulations were performed to design future studies aimed at investigating the efficacy of the antibody. This study concluded that F105 can be administered as a bolus dose every 21 days.

A randomized, placebo-controlled study of the immunogenicity of human immunodeficiency virus (HIV) rgp160 vaccine in HIV-infected subjects with > or = 400/mm3 CD4 T lymphocytes (AIDS Clinical Trials Group Protocol 137).

Immune responses provoked by human immunodeficiency virus (HIV) infection ultimately are insufficient to control the disease and do not include strong lymphocyte-proliferative responses to HIV antigens or antibodies to many viral epitopes. A randomized double-blind, placebo-controlled trial evaluated the immunogenicity of recombinant HIV envelope vaccine (rgp160) in HIV-infected subjects with > or = 400/mm3 CD4 T cells. Controls received hepatitis B vaccine. Of subjects receiving rgp160, 98% developed lymphocyte-proliferative responses to the immunogen, 33% to a different envelope protein, and 56% and 60% to p24 and p66, respectively. All doses of vaccine (20, 80, 320, 1280 microgram) induced new responses. New antibodies to epitopes on rgp160 developed only in recipients of higher doses of rgp160. CD4 T cell percentages declined less rapidly in recipients of rgp160 than in controls. Vaccination of HIV-infected subjects with rgp160 results in cellular and humoral immune responses to HIV that infection itself had not stimulated.

Standardization of absolute CD4+ lymphocyte counts across laboratories: an evaluation of the Ortho CytoronAbsolute flow cytometry system on normal donors.

The Ortho CytoronAbsolute is a flow cytometer designed to provide direct absolute counts of lymphocytes and their subsets from a single instrument. This study was designed to determine the performance of four geographically separated CytoronAbsolute instruments using 24-h-old, shipped, whole blood samples and to compare the results obtained on the CytoronAbsolute to those obtained using combinations of hematology instruments and other flow cytometers. The absolute count feature of the CytoronAbsolutes located at the four sites were cross calibrated and gave across-site coefficients of variation (CVs) of <4.0% for absolute count and 8.2% for absolute lymphocyte count. The calibration was stable for at least 2 months. Absolute lymphocyte counts and lymphocyte percentage immunophenotypes were determined on blood from 50 healthy human immunodeficiency virus (HIV)-seronegative donors. There were no significant site-to-site differences (each P > .05) in CD3+/CD4+ absolute lymphocyte counts determined on the CytoronAbsolute. In contrast, there was a significant site-to-site difference (P < .001) between sites 2 and 3 and sites 3 and 4 in the absolute CD3+/CD4+ lymphocyte counts determined via the conventional method of combining a flow cytometry-derived percentage with a hematology instrument-derived lymphocyte count. There was no significant difference (P = .388) in CD3+/CD4+ lymphocyte percent determinations between the CytoronAbsolute and the FACScan or Profile II flow cytometers used in this study. These results demonstrate that different operators can cross calibrate CytoronAbsolutes for absolute CD3+/CD4+ lymphocyte subset determinations, even over large geographic distances.

Cesarean section to reduce perinatal transmission of human immunodeficiency virus. A metaanalysis.

OBJECTIVE: Individual epidemiologic investigations into the association between type of delivery and perinatal HIV transmission have been suggestive but inconclusive. Metaanalysis was used in an attempt to establish if there is, at present, adequate evidence concerning the effectiveness of cesarean section in reducing vertical HIV transmission rates. METHODS: The MEDLINE data retrieval system and other sources were used to identify studies containing data on the relationship between type of delivery and vertical HIV transmission. No randomized control trials were located. Six cohort studies identified were included in the metaanalysis. Crude and, in the only study in which these were available, adjusted data were extracted and pooled. RESULTS: The overall weighted risk of perinatal HIV infection was 20.2% and 14.0% after vaginal and cesarean delivery, respectively. Pooling data of all studies showed a statistically significant difference of HIV perinatal transmission rates between cesarean and vaginal delivery (odds ratio 0.65; 95% CI, 0.43 to 0.99; P = 0.044) (Random effects model: DerSimonian and Laird method). Approximately 16 (95% CI, 76 to 9) HIV-infected women must deliver by cesarean in order to prevent 1 case of HIV perinatal infection. CONCLUSIONS: Results of this study show that performing elective cesarean section in HIV-infected women is potentially an effective procedure. However, the nonexperimental nature of the available studies leads us to conclude that randomized control trials are indicated before setting specific guidelines for mode of delivery in HIV-infected women.

Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762).

The Philadelphia (Ph1) chromosome, or its molecular counterpart, the BCR-ABL fusion gene, is a rare but important prognostic indicator in childhood acute lymphoblastic leukemia (ALL), but its impact on adult ALL has not been well ascertained. A prospective study of the BCR-ABL fusion gene was begun on patients entered on clinical trials conducted by the Cancer and Leukemia Group B (CALGB). All patients received intensive, multiagent chemotherapy that included daunorubicin. Over 2 years, 56 patients were studied for molecular evidence of a BCR-ABL gene using Southern blot and pulsed-field gel hybridization analysis. Results were compared with cytogenetic detection of a Ph1 chromosome, and clinical features were compared for the BCR-ABL-positive and -negative groups. Molecular methods detected the BCR-ABL gene in 30% of cases compared with cytogenetic detection of the Ph1 chromosome in only 23%. The majority of cases (76%) showed the p190 gene subtype similar to pediatric ALL; the BCR-ABL-positive cases displayed a more homogeneous immunophenotype than the BCR-ABL-negative cases and were predominantly CALLA positive (86%) and B-cell surface antigen positive (82%). The rate of achieving complete remission was similar in the BCR-ABL-positive and -negative groups (71% and 77%, respectively, P = .72). There were more early relapses in the BCR-ABL-positive group, resulting in a shorter remission duration that was especially marked in the CALLA-positive and B-cell antigen-positive populations. These preliminary data suggest that the impact of the BCR-ABL gene on clinical outcome in ALL may be on maintenance of complete remission (CR) rather than achievement of CR when aggressive, multiagent chemotherapy is used. This study identifies the BCR-ABL gene as an important factor in adult ALL and demonstrates the utility of molecular methods for its accurate diagnosis.

Assessment of drug abuser treatment needs in Rhode Island.

BACKGROUND: Rhode Island's Division of Substance Abuse asked us to assess the State's drug treatment needs and make recommendations regarding its treatment system for the next three years. METHODS: We used a statewide telephone drug use survey of 5,176 households supplemented by drug-related hospital discharges, Division of Drug Control statistics, and interviews with providers, state officials, and out-of-state experts. Drug abuse was measured with items from the Diagnostic Interview Schedule. Abusers were asked if they were receiving or wanted to receive treatment. RESULTS: Survey responses, used to estimate the unmet need for drug treatment, indicated a need to triple drug treatment services. Regression models using survey data indicated that the treatment network was overly centralized in the Providence area. Interviews with state officials, clinicians, and out-of-state experts provided material for recommendations on reimbursement policy, treatment mix, quality assurance, and cost containment. CONCLUSIONS: The RI Department of Health's certificate-of-need program adopted our overall recommendation for tripling the drug treatment system as its guideline in evaluating proposals for new treatment facilities. With State funding of a new adolescent center and expansion of outpatient slots in the private sector, this recommendation has now been fully implemented.