B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo

Highly regulated activation of B cells is required for the production of specific antibodies necessary to provide protection from pathogen infection. This process is initiated by specific recognition of antigen through the B cell receptor (BCR), leading to early intracellular signaling followed by the late recruitment of T cell help. In this study we demonstrate that specific BCR uptake of CD1d-restricted antigens represents an effective means of enhancing invariant natural killer T (iNKT)-dependent B cell responses in vivo. This mechanism is effective over a wide range of antigen affinities but depends on exceeding a tightly regulated avidity threshold necessary for BCR-mediated internalization and CD1d-dependent presentation of particulate antigenic lipid. Subsequently, iNKT cells provide the help required for stimulating B cell proliferation and differentiation. iNKT-stimulated B cells develop within extrafollicular foci and mediate the production of high titers of specific IgM and early class-switched antibodies. Thus, we have demonstrated that in response to particulate antigenic lipids iNKT cells are recruited for the assistance of B cell activation, resulting in the enhancement of specific antibody responses. We propose that such a mechanism may operate to potentiate adaptive immune responses against pathogens in vivo.     

Long-term outcome and its predictors among patients with ST-segment elevation myocardial infarction complicated by shock: insights from the GUSTO-I trial.

OBJECTIVES: This study sought to assess long-term outcome and determine its predictors among 30-day survivors of cardiogenic shock. BACKGROUND: Patients with cardiogenic shock have high in-hospital and 30-day mortality, but there are little data about those who survive beyond 30 days. METHODS: We analyzed baseline, in-hospital, and survival data from patients in the U.S. with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock enrolled in the GUSTO (Global Utilization of Streptokinase and Tissue-Type Plasminogen Activator for Occluded Coronary Arteries)-I trial and compared them with patients in the same trial who did not have shock. RESULTS: Of 22,883 patients enrolled in the U.S., shock occurred in 1,891 (8.3%); 953 (50.4%) survived 30 days and 527 (27.8%) survived 11 years. Of 20,992 U.S. patients without shock, 20,360 (96.9%) survived 30 days and 14,131 (67.3%) survived 11 years. After the first year, 2% to 4% of patients died each year regardless of whether they had cardiogenic shock. Using Cox proportional hazards models, we were able to predict long-term mortality in all U.S. GUSTO-I 30-day survivors from their baseline demographics and in-hospital complications. The strongest predictors were diabetes mellitus, cardiogenic shock, hypertension, previous myocardial infarction, current smoking, anterior infarct, higher Killip class, higher heart rate, and older age; patients >75 years were at highest risk. Percutaneous revascularization during the index hospitalization was associated with a reduced risk of death. CONCLUSIONS: Among patients with cardiogenic shock who survive 30 days after STEMI, annual mortality rates of 2% to 4% approximate those of patients without shock.     

The effectiveness of personalized smoking cessation strategies for callers to a Quitline service

Aim To assess the effectiveness of a program of computer‐generated tailored advice for callers to a telephone helpline, and to assess whether it enhanced a series of callback telephone counselling sessions in aiding smoking cessation. Design Randomized controlled trial comparing: (1) untailored self‐help materials; (2) computer‐generated tailored advice only, and (3) computer‐generated tailored advice plus callback telephone counselling. Assessment surveys were conducted at baseline, 3, 6 and 12 months. Setting Victoria, Australia. Participants A total of 1578 smokers who called the Quitline service and agreed to participate. Measurements Smoking status at follow‐up; duration of cessation, if quit; use of nicotine replacement therapy; and extent of participation in the callback service. Findings At the 3‐month follow‐up, significantly more (χ²(2) = 16.9; P < 0.001) participants in the computer‐generated tailored advice plus telephone counselling condition were not smoking (21%) than in either the computer‐generated advice only (12%) or the control condition (12%). Proportions reporting not smoking at the 12‐month follow‐up were 26%, 23% and 22%, respectively (NS) for point prevalence, and for 9 months sustained abstinence; 8.2, 6.0, and 5.0 (NS). In the telephone counselling group, those receiving callbacks were more likely than those who did not to have sustained abstinence at 12 months (10.2 compared with 4.0, P < 0.05). Logistic regression on 3‐month data showed significant independent effects on cessation of telephone counselling and use of NRT, but not of computer‐generated tailored advice. Conclusion Computer‐generated tailored advice did not enhance telephone counselling, nor have any independent effect on cessation. This may be due to poor timing of the computer‐generated tailored advice and poor integration of the two modes of advice.     

Cervical shedding of human T cell lymphotropic virus type I is associated with cervicitis

Human T cell lymphotropic virus type I (HTLV-I) is sexually transmitted. The purpose of this study was to determine the prevalence and risk factors for cervical shedding of HTLV-I DNA among Peruvian sex workers. HTLV tax DNA was detected in cervical specimens from 43 (68%) of 63 HTLV-I-infected sex workers and in samples obtained during 113 (52%) of 216 clinic visits between 1993 and 1997. Detection of HTLV DNA was associated with the presence of > or =30 polymorphonuclear cells (PMNs) within cervical mucus per 100x microscopic field (odds ratio [OR], 4.3, 95% confidence interval [CI], 1.8-10.1) and with the presence of cervical secretions (OR, 2.0; 95% CI 1.2-3.4). Hormonal contraceptive use (OR 1.7; 95% CI, 0.8-3.6) and concomitant cervical infection by Chlamydia trachomatis (OR, 1.5; 95% CI, 0.3-4.3) or Neisseria gonorrhoeae (OR, 1.1; 95% CI, 0.6-3.7) were not significantly associated with HTLV-I shedding. Our results suggest that cervicitis may increase cervical HTLV-I shedding and the sexual transmission of this virus.     

Employment During Pregnancy and Obstetric Intervention Without Medical Reason: Labor Induction and Cesarean Delivery

BackgroundRising rates of labor induction and cesarean delivery, especially when used without a medical reason, have generated concern among clinicians, women, and policymakers. Whether employment status affects pregnant women's childbirth-related care is not known. We estimated the relationship between prenatal employment and obstetric procedures, distinguishing whether women reported that the induction or cesarean was performed for medical reasons.MethodsUsing data from a nationally representative sample of women who gave birth in U.S. hospitals (n = 1,573), we used propensity score matching to reduce potential bias from nonrandom selection into employment. Outcomes were cesarean delivery and labor induction, with and without a self-reported medical reason. Exposure was prenatal employment status (full-time employment, not employed). We conducted separate analyses for unmatched and matched cohorts using multivariable regression models.FindingsThere were no differences in labor induction based on employment status. In unmatched analyses, employed women had higher odds of cesarean delivery overall (adjusted odds ratio [AOR], 1.45; p = .046) and cesarean delivery without medical reason (AOR, 1.94; p = .024). Adding an interaction term between employment and college education revealed no effects on cesarean delivery without medical reason. There were no differences in cesarean delivery by employment status in the propensity score–matched analysis.ConclusionsFull-time prenatal employment is associated with higher odds of cesarean delivery, but this association was not explained by socioeconomic status and no longer existed after accounting for sociodemographic differences by matching women employed full time with similar women not employed during pregnancy.     

Impact of single immunosuppressive drug withdrawal on lymphocyte immunoreactivity

Background

Chronic rejection is a major cause of graft loss in kidney transplant recipients. Nonadherence to drug therapy is a well-recognized cause of chronic rejection leading to long-term graft dysfunction and failure for transplant recipients. Immunosuppressive medications with short half-lives that require frequent dosing, such as tacrolimus, complicate transplant regimens and may increase noncompliance. Regimens could be simplified using drugs with long half-lives requiring once-daily administration, such as sirolimus. The impact of missing doses of single agents has not been studied extensively. Erratic compliance or temporary discontinuation of immunosuppressive drugs may have significant implications for chronic rejection.

Methods

Our study evaluated the impact of single drug withdrawal of commonly used immunosuppressive agents (sirolimus and tacrolimus) on lymphocyte responses. We analyzed lymphocyte proliferation, cytokine secretion, and adenosine triphosphate generation using a crossover study design with normal healthy patients. Lymphocyte proliferation was assessed using 5-bromo-2-deoxyuridine incorporation, and T cell function was analyzed by examining adenosine triphosphate generation.

Results

Our results indicate that sirolimus exerts prolonged suppression of lymphocyte proliferation and decreased interleukin 17A that lasts up to 48 h after drug withdrawal. In comparison, tacrolimus did not have a similar effect on lymphocyte proliferation or interleukin 17A secretion.

Conclusion

Future analysis of sirolimus in diverse transplantation populations merits investigation.