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Nuffield Department of Women's & Reproductive Health sits within the Medical Sciences Division of the University of Oxford. The department encompasses multi-disciplinary research across four overarching themes; Cancer, Global Health, Maternal & Fetal Health and Reproductive Medicine & Genetics
Conditional requirement for accessory cells in the response of T cells to Con A.
The response to Concanavalin A (Con A) of unseparated lymph node cells and of T cells isolated from them has been studied over a mitogen dose range of 0.2 microgram to 16 micrograms/ml. Accessory cell depleted T cells respond only to high doses of Con A and then only weakly. The magnitude (proliferative activity) of the response as well as the sensitivity to the mitogen can be modified by accessory cells (AC), lymphokines and by chemical modification of cell surface glycoproteins. Accessory cell function can be inhibited by antibodies directed against cell surface molecules on accessory cells (Ia) or on T cells (L3T4). Changes in the mitogen sensitivity of the response are not necessarily associated with changes in the magnitude of the response. The mitogen sensitivity can be decreased with anti-Ia antibody and can be increased by treatment with IL-l and/or interferon gamma (IFN-). We postulate that the increase in sensitivity to Con A is a function of the density of cell surface molecules with which T and AC cells interact. The magnitude of the response is primarily determined by the frequency of AC in culture; it decreases as the number of AC is reduced and increases as AC are added to the cultures. Mitogen sensitivity is a new tool for the analysis of nonspecific T cell activation. Our data bring the accessory cell requirement for mitogen activation of T cells into a new perspective: AC--or factors produced by them--are essential when low (1-2 micrograms/ml Con A) doses are used and are less or not at all necessary when high doses (6-10 micrograms/ml) of mitogen are applied.
Enhancement of cytotoxic activity of natural killer cells by interleukin 2, and antagonism between interleukin 2 and adenosine cyclic monophosphate.
Two cytokines, interferon (IFN) and interleukin 2 (IL-2), activate murine natural killer (NK) cells in vitro. Together both factors synergize considerably. Antibody against IFN eliminates the response of NK cells to IFN as well as to IL-2, whereas antibody against IL-2 blocks the effect of IL-2 but not of IFN. These findings as well as previous observations imply that both factors act on the same cell but have different roles. We suggest that IFN induces NK cell activation and IL-2 enhances this effect. Further studies revealed that besides inducing cytotoxicity in NK cells IFN induces the production of prostaglandin E (PGE) which inhibits NK cell activation. We propose therefore that IFN has a dual effect on NK cells: it induces NK cells to become cytotoxic and initiates a negative feedback by increasing the production of PGE. IL-2, which synergizes with IFN in the activation of NK cells, ceases to do so when the negative feedback (PGE-mediated) is blocked with indomethacin. We infer that IL-2 enhances NK cell activity by interfering with the negative feedback rather than by aiding NK cell activation.
IL 1 requirement for B cell activation revealed by use of adult serum.
Fetal calf serum is an essential component of the culture medium developed by Mishell and Dutton for the immunization of murine spleen cells in vitro. Serum from adult donors (mouse, human, rabbit) does not support antibody synthesis in this system. This "deficiency" of adult serum can be overcome with IL 1. Adult serum in the presence of IL 1 is as effective in stimulating a B cell response against xenogeneic red cells as fetal calf serum. We attribute the capacity of fetal calf serum to support an immune response in the absence of exogenous IL 1 to serum factors that cause macrophages to release IL 1 endogenously. Our findings strengthen the notion that IL 1 plays an essential role in the process of B cell activation and suggests that the use of fetal calf serum should be avoided in studies concerned with the function of interleukin 1.
Suppression and enhancement of the T cell-dependent production of antibody to SRBC in vitro by bacterial lipopolysaccharide.
LPS induced the production of antibody to sheep red blood cells (SRBC) in cultures of spleen cells from normal and T cell-depleted mice, and addition of SRBC to the cultures enchanced this T cell-independent response very little. By contrast, the T cell-dependent production of antibody to SRBC in vitro was suppressed when lipopolysaccharide (LPS) was added at the time when the spleen cells were cultured. Later addition of LPS to spleen cell cultures caused enhancement of antibody production, but only when LPS had not been added before. Addition of T cells that had been primed with SRBC in vivo did not reverse the LPS-induced suppression of antibody production. The data are interpreted to mean that either B cells are rendered incapable of receiving T cell signals in the presence of LPS or that LPS interferes with the appropriate association of cellular components which cooperate in the immune response to SRBC.
Standardization and quality control of the introduction of a noninvasive cardiac output monitor for pregnancy measurements in a low- and middle-income country.
INTRODUCTION: There is increasing awareness of the role of the maternal cardiovascular system in complicated pregnancies. Despite the high disease burden, noninvasive cardiac output monitors have not been used extensively in low- and middle-income countries. The aim of this study was to evaluate the quality control of the use of the ultrasonic cardiac output monitor (USCOM) 1A® in a LMIC. MATERIAL AND METHODS: This was a quality assessment study of the introduction of the USCOM 1A® to measure maternal hemodynamic indices. Inter-observer agreement was assessed across all four study sites by intraclass correlation coefficient. Quality control was assessed using pre-defined acceptability criteria, rated by 2 independent scorers. RESULTS: On average, nurses or midwives needed to obtain 30.4 (range 24-36) Doppler waveform recordings to be deemed competent to undertake USCOM 1A® measurements. There was very good inter-observer agreement across all 4 sites (intraclass correlation coefficient 0.86-0.93, all p
The efficacy of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction: the STRIDER RCT
BackgroundSevere early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes.MethodsThe STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age.ResultsBetween 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95).ConclusionSildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction.Trial registrationThis trial is registered as ISRCTN39133303.FundingThis award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.