The effect of maternal position on placental blood flow and fetoplacental oxygenation in late gestation fetal growth restriction: a magnetic resonance imaging study

Fetal growth restriction (FGR) and maternal supine going-to-sleep position are both risk factors for late stillbirth. This study aimed to use magnetic resonance imaging (MRI) to quantify the effect of maternal supine position on maternal-placental and fetoplacental blood flow, placental oxygen transfer and fetal oxygenation in FGR and healthy pregnancies. Twelve women with FGR and 27 women with healthy pregnancies at 34–38 weeks’ gestation underwent MRI in both left lateral and supine positions. Phase-contrast MRI and a functional MRI technique (DECIDE) were used to measure blood flow in the maternal internal iliac arteries (IIAs) and umbilical vein (UV), placental oxygen transfer (placental flux), fetal oxygen saturation (FO2), and fetal oxygen delivery (delivery flux). The presence of FGR, compared to healthy pregnancies, was associated with a 7.8% lower FO2 (P = 0.02), reduced placental flux, and reduced delivery flux. Maternal supine positioning caused a 3.8% reduction in FO2 (P = 0.001), and significant reductions in total IIA flow, placental flux, UV flow and delivery flux compared to maternal left lateral position. The effect of maternal supine position on fetal oxygen delivery was independent of FGR pregnancy, meaning that supine positioning has an additive effect of reducing fetal oxygenation further in women with FGR, compared to women with appropriately grown for age pregnancies. Meanwhile, the effect of maternal supine positioning on placental oxygen transfer was not independent of the effect of FGR. Therefore, growth-restricted fetuses, which are chronically hypoxaemic, experience a relatively greater decline in oxygen transfer when mothers lie supine in late gestation compared to appropriately growing fetuses. (Figure presented.). Key points: Fetal growth restriction (FGR) is the most common risk factor associated with stillbirth, and early recognition and timely delivery is vital to reduce this risk. Maternal supine going-to-sleep position is found to increase the risk of late stillbirth but when combined with having a FGR pregnancy, maternal supine position leads to 15 times greater odds of stillbirth compared to supine sleeping with appropriately grown for age (AGA) pregnancies. Using MRI, this study quantifies the chronic hypoxaemia experienced by growth-restricted fetuses due to 13.5% lower placental oxygen transfer and 26% lower fetal oxygen delivery compared to AGA fetuses. With maternal supine positioning, there is a 23% reduction in maternal-placental blood flow and a further 14% reduction in fetal oxygen delivery for both FGR and AGA pregnancies, but this effect is proportionally greater for growth-restricted fetuses. This knowledge emphasises the importance of avoiding supine positioning in late pregnancy, particularly for vulnerable FGR pregnancies

Partial Depletion of Natural CD4+CD25+ Regulatory T Cells with Anti-CD25 Antibody Does Not Alter the Course of Acute Influenza A Virus Infection

Foxp3+ CD4+ regulatory T cells represent a T cell subset with well-characterized immunosuppressive effects during immune homeostasis and chronic infections, and there is emerging evidence to suggest these cells temper pulmonary inflammation in response to acute viral infection. Recent studies have demonstrated treatment with PC61 CD25-depleting antibody potentiates inflammation in a murine model of RSV infection, while paradoxically delaying recruitment of CD8+ T cells to the site of inflammation. The present study therefore sought to examine the role of these cells in a murine model of acute influenza A virus infection through the administration of PC61 CD25-depleting antibody. PC61 antibody is able to partially deplete CD25+Foxp3+ regulatory T cells to a comparable degree as seen within previous work examining RSV, however this does not alter influenza A-virus induced mortality, weight loss, viral clearance and cellularity within the lung. Collectively, these data demonstrate that partial depletion of CD4+CD25+ regulatory T cells with PC61 antibody does not alter the course of influenza A virus infection

Six weeks of home enteral nutrition versus standard care after esophagectomy or total gastrectomy for cancer: study protocol for a randomized controlled trial

Background: Each year approximately 3000 patients in the United Kingdom undergo surgery for esophagogastric cancer. Jejunostomy feeding tubes, placed at the time of surgery for early postoperative nutrition, have been shown to have a positive impact on clinical outcomes in the short term. Whether feeding out of hospital is of benefit is unknown. Local experience has identified that between 15 and 20% of patients required ‘rescue’ jejunostomy feeding for nutritional problems and weight loss while at home. This weight loss and poor nutrition may contribute to the detrimental effect on the overall quality of life (QoL) reported in these patients. Methods/Design: This randomized pilot and feasibility study will provide preliminary information on the routine use of jejunostomy feeding after hospital discharge in terms of clinical benefits and QoL. Sixty participants undergoing esophagectomy or total gastrectomy will be randomized to receive either a planned program of six weeks of home jejunostomy feeding after discharge from hospital (intervention) or treatment-as-usual (control). The intention of this study is to inform a multi-centre randomized controlled trial. The primary outcome measures will be recruitment and retention rates at six weeks and six months. Secondary outcome measures will include disease specific and general QoL measures, nutritional parameters, total and oral nutritional intake, hospital readmission rates, and estimates of healthcare costs. Up to 20 participants will also be enrolled in a qualitative sub-study that will explore participants’ and carers’ experiences of home tube feeding. The results will be disseminated by presentation at surgical, gastroenterological and dietetic meetings and publication in appropriate peer review journals. A patient-friendly lay summary will be made available on the University of Leicester and the University Hospitals of Leicester NHS Trust websites. The study has full ethical and institutional approval and started recruitment in July 2012. Trial registration: UKClinical Research Network ID #12447 (Main study); UKCRN ID#13361 (Qualitative sub study); ClinicalTrials.gov #NCT01870817 (First registered 28 May 2013

Microwave-assisted hydrolysis and extraction of tricyclic antidepressants from human hair

The objective of this research was to develop, optimize, and validate a modern, rapid method of preparation of human hair samples, using microwave irradiation, for analysis of eight tricyclic antidepressants (TCADs): nordoxepin, nortriptyline, imipramine, amitriptyline, doxepin, desipramine, clomipramine, and norclomipramine. It was based on simultaneous alkaline hair microwave-assisted hydrolysis and microwave-assisted extraction (MAH–MAE). Extracts were analyzed by high-performance liquid chromatography with diode-array detection (HPLC–DAD). A mixture of n-hexane and isoamyl alcohol (99:1, v/v) was used as extraction solvent and the process was performed at 60°C. Application of 1.0 mol L−1 NaOH and microwave irradiation for 40 min were found to be optimum for hair samples. Limits of detection ranged from 0.3 to 1.2 μg g−1 and LOQ from 0.9 to 4.0 μg g−1 for the different drugs. This enabled us to quantify them in hair samples within average therapeutic concentration ranges

2019 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations : summary from the basic life support; advanced life support; pediatric life support; neonatal life support; education, implementation, and teams; and first aid task forces

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Partial Regulatory T Cell Depletion Prior to Acute Feline Immunodeficiency Virus Infection Does Not Alter Disease Pathogenesis

Feline immunodeficiency virus (FIV) infection in cats follows a disease course similar to HIV-1, including a short acute phase characterized by high viremia, and a prolonged asymptomatic phase characterized by low viremia and generalized immune dysfunction. CD4+CD25hiFoxP3+ immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modulating virus-specific and inflammatory immune responses. Additionally, the immunosuppressive capacity of feline Treg cells has been shown to be increased during FIV infection. We have previously shown that transient in vivo Treg cell depletion during asymptomatic FIV infection reveals FIV-specific immune responses suppressed by Treg cells. In this study, we sought to determine the immunological influence of Treg cells during acute FIV infection. We asked whether Treg cell depletion prior to infection with the highly pathogenic molecular clone FIV-C36 in cats could alter FIV pathogenesis. We report here that partial Treg cell depletion prior to FIV infection does not significantly change provirus, viremia, or CD4+ T cell levels in blood and lymphoid tissues during the acute phase of disease. The effects of anti-CD25 mAb treatment are truncated in cats acutely infected with FIV-C36 as compared to chronically infected cats or FIV-naïve cats, as Treg cell levels were heightened in all treatment groups included in the study within two weeks post-FIV infection. Our findings suggest that the influence of Treg cell suppression during FIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection

IL-10 from CD4+CD25−Foxp3−CD127− Adaptive Regulatory T Cells Modulates Parasite Clearance and Pathology during Malaria Infection

The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-β are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown. Here we have examined the role of natural and adaptive regulatory T cells in the control of malaria infection and find that classical CD4+CD25hi (and Foxp3+) regulatory T cells do not significantly influence the outcome of infections with the lethal (17XL) strain of Plasmodium yoelii (PyL). In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25−, Foxp3−, and CD127− and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance. In summary, we have identified a population of induced Foxp3− regulatory (Tr1) T cells, characterised by production of IL-10 and down regulation of IL-7Rα, that modulates the inflammatory response to malaria

IL-33-mediated protection against experimental cerebral malaria is linked to induction of Type 2 innate lymphoid cells, M2 macrophages and regulatory T cells

Author Summary Cerebral malaria (CM) caused by the parasite Plasmodium sp . is a fatal disease, especially in children. Currently there is no effective treatment. We report here our investigation on the role of a recently discovered cytokine IL-33, in treating experimental cerebral malaria (ECM) in the susceptible C57BL/6 mice. IL-33 protects the mice against ECM. The protection is accompanied by a reduction of Th1 response and the enhancement of type 2 cytokine response. We also found that IL-33 mediates its protective effect by inducing a population of type 2 innate lymphoid cells (ILC2), which then polarize macrophages to alternatively-activated phenotypes (M2). M2 in turn expand regulatory T cells (Tregs) which suppress the deleterious Th1 response. Our report therefore reveals hitherto unrecognised mechanisms of the regulation of ECM and provide a novel function of IL-33

Malaria Infections Do Not Compromise Vaccine-Induced Immunity against Tuberculosis in Mice

BACKGROUND: Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis. PRINCIPAL FINDINGS: Here we show that the anti-tuberculosis protective immunity induced by four different tuberculosis vaccines was not impacted by a concurrent infection with Plasmodium yoelii NL, a nonlethal form of murine malaria. After an aerogenic challenge with virulent M. tuberculosis, the lung bacterial burdens of vaccinated animals were not statistically different in malaria infected and malaria naïve mice. Multi-parameter flow cytometric analysis showed that the frequency and the median fluorescence intensities (MFI) for specific multifunctional T (MFT) cells expressing IFN-γ, TNF-α, and/or IL-2 were suppressed by the presence of malaria parasites at 2 weeks following the malaria infection but was not affected after parasite clearance at 7 and 10 weeks post-challenge with P. yoelii NL. CONCLUSIONS: Our data indicate that the effectiveness of novel TB vaccines in protecting against tuberculosis was unaffected by a primary malaria co-infection in a mouse model of pulmonary tuberculosis. While the activities of specific MFT cell subsets were reduced at elevated levels of malaria parasitemia, the T cell suppression was short-lived. Our findings have important relevance in developing strategies for the deployment of new TB vaccines in malaria endemic areas