Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes.

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.

Same yet different - how lymph node heterogeneity affects immune responses.

Lymph nodes are secondary lymphoid organs in which immune responses of the adaptive immune system are initiated and regulated. Distributed throughout the body and embedded in the lymphatic system, local lymph nodes are continuously informed about the state of the organs owing to a constant drainage of lymph. The tissue-derived lymph carries products of cell metabolism, proteins, carbohydrates, lipids, pathogens and circulating immune cells. Notably, there is a growing body of evidence that individual lymph nodes differ from each other in their capacity to generate immune responses. Here, we review the structure and function of the lymphatic system and then focus on the factors that lead to functional heterogeneity among different lymph nodes. We will discuss how lymph node heterogeneity impacts on cellular and humoral immune responses and the implications for vaccination, tumour development and tumour control by immunotherapy.

Women's Perspectives on Smoking During Pregnancy and Factors Influencing Their Willingness to Quit Smoking in Pregnancy: A Study From the United Kingdom.

Objective This was a prospective questionnaire-based survey conducted in the Barnsley District of the United Kingdom among antenatal women smoking during pregnancy. The aim of the study was to assess the awareness of women regarding the risks with smoking during pregnancy, study their smoking behavior, their willingness to quit smoking during pregnancy, and the factors that could influence their intention to quit smoking. Methods A cohort of antenatal women smoking during pregnancy was surveyed prior to their contact with the maternity Stop Smoking Services. A well-structured, pre-tested, and validated questionnaire was used to assess their awareness regarding risks with smoking during pregnancy and their willingness to quit smoking during pregnancy. Descriptive statistics were used to analyze the results. Binomial logistic regression (univariate and multivariate) was used to identify the factors influencing the women's willingness to quit smoking during pregnancy. Results Among 66 women surveyed, 52 (79%) were multigravida and 14 (21%) were primigravida, with a mean age of 27.4 ± 5.7 years. Most women (68%) were in the first trimester of their pregnancy. Nearly two-thirds of women (64%) had low educational attainment, 53% were unemployed, 68% lived with family members who smoked, and 35% had mental health problems. One-third (33%) of women had an unsuccessful attempt at quitting smoking in the past. Around 44% of women had a low level of nicotine dependence, while 56% had a moderate level of nicotine dependence. More than three-fourths of women (77%) were aware that smoking during pregnancy is harmful for their baby, though most could not report the specific adverse effects. Nearly half of the women (51.5%) were willing to quit smoking during pregnancy with the rationality of having a healthy baby. On multivariate logistic regression analysis, awareness of the women that smoking during pregnancy has ill effects on the baby (adjusted odds ratio (aOR): 46.459, confidence interval (CI): 5.356-402.961, p value <0.001) was found to be the strongest predictor of willingness to quit smoking during pregnancy. Other determinants found to be significantly associated with willingness to quit smoking during pregnancy were unsuccessful quit attempts in the past (aOR: 0.048, CI: 0.007-0.309, p value 0.001) and the absence of any mental health concerns (aOR: 6.097, CI: 1.105-33.647, p value 0.038). Conclusion There is considerable room for raising awareness about the risks of smoking during pregnancy and providing effective smoking cessation and relapse prevention interventions in pregnancy. Obstetricians and midwives should actively participate in providing risk-focused information to pregnant women on smoking during pregnancy and support them in smoking cessation. Various factors such as employment status, nicotine dependence, previous failed attempts at quitting smoking, mental health issues, and awareness levels significantly influence the willingness to quit smoking during pregnancy. Hence, there is an imperative need to identify and address the barriers that could affect a woman's intention to quit smoking during pregnancy.

A rare case of intestinal malrotation in pregnancy resulting in hemicolectomy postnatally.

INTRODUCTION: Small and large bowel obstruction secondary to volvulus on the background of intestinal malrotation is a very rare occurrence, especially in pregnancy. This can be associated with significant feto-maternal morbidity and mortality. CASE REPORT: We report a case of a pregnant lady who developed symptoms of subacute intestinal obstruction during the 2nd trimester of pregnancy and was subsequently dia-gnosed with intestinal malrotation on imaging. Though she had symptoms of abdominal pain and constipation persisting for 9 long weeks during pregnancy, there was no evidence of definite intestinal obstruction or volvulus on her abdominal magnetic resonance imaging. She underwent a caesarean section at 34 weeks of pregnancy due to worsening abdominal pain. Postnatally, she was dia-gnosed with midgut volvulus on a computer tomography scan, leading to obstruction of both small and large bowels and needed an emergency laparotomy and right hemicolectomy. CONCLUSION: The case highlights the importance of timely dia-gnosis and prompt management of intestinal obstruction in pregnancy with a multidisciplinary team approach.

H2O2 mediated FLIP and XIAP down-regulation involves increased ITCH expression and ERK-Akt crosstalk in imatinib resistant Chronic Myeloid Leukemia cell line K562.

Regulation of anti-apoptotic protein FLICE-like inhibitory protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) remains a crucial step in the cell fate determination and thus targeting these anti-apoptotic proteins could be a viable strategy for the treatment of cancer. However the regulation of FLIP and XIAP is not very well established till date. Here we have shown that ROS decreased XIAP and FLIP by activation of ubiquitin-proteasomal pathway in imatinib resistant K562 cells. Activation of the components of MAPK pathway, ERK and JNK, played a crucial role in XIAP and FLIP degradation because ectopic expression or knock down of ERK and JNK changed the pattern of ROS mediated down-regulation of these two proteins. We have also found that JNK and ERK differentially regulates FLIP and XIAP, respectively. Moreover, our data suggests that activated ERK decreased Akt phosphorylation and thus its binding to and stabilization of XIAP. On the other hand, JNK activation increased E3 ubiquitin ligase ITCH expression and its binding to FLIP which leads to its degradation. Thus, we have, for the first time elucidated that ROS mediated ERK-Akt crosstalk regulates XIAP. We have also shown for the first time that ROS regulates ITCH expression which controls FLIP degradation.

Manipulation of Inflammasome: A Promising Approach Towards Immunotherapy of Lung Cancer.

Chronic inflammation has emerged as a key player at different stages of cancer development. A prominent signaling pathway for acute and chronic inflammation is the activation of the caspase-1 inflammasomes. These are complexes that assemble on activation of certain nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs), AIM2-like receptors (ALRs), or pyrin due to activation via PAMPs or DAMPs. Of these, five complexes-NLRP1, NLRP3, NLRC4, Pyrin, and AIM2 are of importance in the context of cancer for their activities in modulating immune responses, cell proliferation, and apoptosis. Inflammasomes have emerged as clinically relevant in multiple forms of cancer making them highly promising targets for cancer therapy. As lungs are a tissue niche that is prone to inflammation owing to its exposure to external substances, inflammasomes play a vital role in the development and pathogenesis of lung cancer. Therefore, manipulation of inflammasome by various immunomodulatory means could prove a full-proof strategy for the treatment of lung cancer. Here, in this review, we tried to explore the various strategies to target the inflammasomes for the treatment of lung cancer.

Day care versus inpatient management of nausea and vomiting of pregnancy: cost utility analysis of a randomised controlled trial.

OBJECTIVE: To assess the comparative cost effectiveness of day care over inpatient management of nausea and vomiting of pregnancy (NVP). STUDY DESIGN: A cost utility analysis was performed using a decision analytical model in which a Markov model was constructed. The Markov model was primarily populated with data from a recently published randomised controlled trial. Which included pregnant women presenting to Cork University Maternity Hospital, a tertiary referral maternity hospital, seeking treatment for NVP. Costs and outcomes were estimated from the perspective of the Irish health service (HSE) and patients. A probabilistic sensitivity analysis, using a Monte Carlo simulation, was also performed. A Bayesian Value of Information analysis was used to estimate the value of collecting additional information. RESULTS: When both the healthcare provider and patient's perspective was considered, day care management of NVP remained less costly (mean €985; 95% C.I. 705-1456 vs. €3837 (2124-8466)) and more effective (9.42; 4.19-12.25 vs. 9.49; 4.32-12.39 quality adjusted life years) compared with inpatient management. The Cost Effectiveness Acceptability Curve indicates the probability that day care management is 70% more cost effective compared to inpatient management at a ceiling ratio of €45,000 per QALY, indicating little decision uncertainty. The Bayesian Value of Information analysis indicates there is value in collecting further information; the Expected Value of Perfect Information (EVPI) is estimated to be €5.4 million. CONCLUSION: Day care management of NVP is cost effective compared to inpatient management.

Day care compared with inpatient management of nausea and vomiting of pregnancy: a randomized controlled trial.

OBJECTIVE: To examine day care treatment of nausea and vomiting of pregnancy compared with the traditional inpatient management of this condition. METHODS: We conducted an open-label, single-center, randomized controlled trial to examine the differences between day care and inpatient management of pregnant women with nausea and vomiting of pregnancy. Primary outcome was total number of inpatient nights related to nausea and vomiting of pregnancy. RESULTS: Ninety-eight women were randomized to initial day care management (n=42) or inpatient management (n=56). Results are calculated from the time of randomization until resolution of nausea and vomiting of pregnancy. Women randomized to inpatient care experienced a median (interquartile range) of 2 (1-4) inpatient days compared with 0 (0-2) inpatient days for women randomized to day care (P<.001). Women randomized to initial treatment as an inpatient had significantly more median total number of inpatient admissions (one [1-2] compared with zero [0-1] admissions; P<.001) compared with women randomized to day care. No significant differences were observed in day care visits (median [interquartile range] one [1-4] compared with two [1-4]; P=.30). Women randomized to inpatient care were as satisfied with their care as those randomized to day care (median [interquartile range]: 67 [57-69] compared with 63 [58-71] Client Satisfaction Questionnaire score; P=.7). CONCLUSION: Day care treatment of nausea and vomiting of pregnancy reduced hospital inpatient stay and was acceptable to patients. CLINICAL TRIAL REGISTRATION: ISRCTN Register, http://www.isrctn.org, ISRCTN05023126. LEVEL OF EVIDENCE: : I.

Illegal drug use, smoking and alcohol consumption in a low-risk Irish primigravid population.

To evaluate the prevalence of illegal drug use, smoking and alcohol consumption in Irish primigravidas, we interviewed 1011 women at their booking visit. A total of 23.5% (235) of women had used illegal drugs prior to their first pregnancy, 28.9% were ex-smokers and 27.9% were still smoking during pregnancy. A total of 53.9% admitted to drinking alcohol during pregnancy. Smokers are 2.8 times more likely to have used drugs in the past than non-smokers. Level of alcohol consumption appears to be a significant predictor of drug use.

The incidence and impact of increased body mass index on maternal and fetal morbidity in the low-risk primigravid population.

OBJECTIVE: To determine the incidence and impact of increased body mass index (BMI) on maternal and fetal morbidity in the low-risk primigravid population. METHODS: This was a prospective study with retrospective analysis of delivery outcome data. All low-risk primigravida who met the inclusion criteria during the recruitment period were approached. BMI was calculated using the formula weight/height squared. The participants were divided into five categories: 'underweight' (BMI <20 kg/m2), 'normal' (BMI 20.01-25 kg/m2), 'overweight' (BMI 25.01-30 kg/m2), 'obese' (BMI 30.01-40 kg/m2), and 'morbidly obese' (BMI >40 kg/m2). Maternal outcomes evaluated included gestation at delivery, onset of labor (spontaneous/induced/elective cesarean section), length of labor, use of oxytocin and epidural, mode of delivery, and estimated blood loss. Perinatal outcome measures included infant birth weight (kg) and centile, gestational age, ponderal index, Apgar score <7 at 5 minutes, cord pH <7.1, presence of meconium grade 3 at delivery, degree of resuscitation required, admission to neonatal intensive care unit (NICU), and duration of stay. RESULTS: One thousand and eleven women participated in the study. Complete outcome data were available for 833 women (82%). A significant difference was identified in gestation at delivery between the subgroups (p < 0.004). A significant positive correlation was identified between cesarean section rates with increasing BMI, even when gestation was controlled for (p = 0.004). Similarly, women in the normal BMI group remained significantly less likely to have an infant requiring NICU admission than obese women (2.2% vs. 8.6%; p = 0.011). CONCLUSION: High BMI is associated with longer gestations, higher operative delivery rates, and an increased rate of neonatal intensive care admission