Diet during pregnancy and infancy, and risk of allergic or autoimmune disease: a systematic review and meta-analysis

Background: There is uncertainty about the influence of diet during pregnancy and infancy on a child’s immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. Methods and findings: Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68–0.90; I2 = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20–64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53–0.90; I2 = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10–47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow’s milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures—including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake—influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy. Conclusions: Our findings support a relationship between maternal diet and risk of immune-mediated diseases in the child. Maternal probiotic and fish oil supplementation may reduce risk of eczema and allergic sensitisation to food, respectively

Urine tests for Down's syndrome screening

Background Down's syndrome occurs when a person has three copies of chromosome 21, or the specific area of chromosome 21 implicated in causing Down's syndrome, rather than two. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life. The risk of a Down's syndrome affected pregnancy increases with advancing maternal age. Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. Objectives To estimate and compare the accuracy of first and second trimester urine markers for the detection of Down's syndrome. Search methods We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), EMBASE (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2011, Issue 7), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (archived 2007), Health Services Research Projects in Progress database (25 August 2011). We studied reference lists and published review articles. Selection criteria Studies evaluating tests of maternal urine in women up to 24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. Data collection and analysis We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC (receiver operating characteristic) meta-analytical methods to analyse test performance and compare test accuracy. We performed analysis of studies allowing direct comparison between tests. We investigated the impact of maternal age on test performance in subgroup analyses. Main results We included 19 studies involving 18,013 pregnancies (including 527 with Down's syndrome). Studies were generally of high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Twenty-four test combinations were evaluated formed from combinations of the following seven different markers with and without maternal age: AFP (alpha-fetoprotein), ITA (invasive trophoblast antigen), ß-core fragment, free ßhCG (beta human chorionic gonadotrophin), total hCG, oestriol, gonadotropin peptide and various marker ratios. The strategies evaluated included three double tests and seven single tests in combination with maternal age, and one triple test, two double tests and 11 single tests without maternal age. Twelve of the 19 studies only evaluated the performance of a single test strategy while the remaining seven evaluated at least two test strategies. Two marker combinations were evaluated in more than four studies; second trimester ß-core fragment (six studies), and second trimester ß-core fragment with maternal age (five studies). In direct test comparisons, for a 5% false positive rate (FPR), the diagnostic accuracy of the double marker second trimester ß-core fragment and oestriol with maternal age test combination was significantly better (ratio of diagnostic odds ratio (RDOR): 2.2 (95% confidence interval (CI) 1.1 to 4.5), P = 0.02) (summary sensitivity of 73% (CI 57 to 85) at a cut-point of 5% FPR) than that of the single marker test strategy of second trimester ß-core fragment and maternal age (summary sensitivity of 56% (CI 45 to 66) at a cut-point of 5% FPR), but was not significantly better (RDOR: 1.5 (0.8 to 2.8), P = 0.21) than that of the second trimester ß-core fragment to oestriol ratio and maternal age test strategy (summary sensitivity of 71% (CI 51 to 86) at a cut-point of 5% FPR). Authors' conclusions Tests involving second trimester ß-core fragment and oestriol with maternal age are significantly more sensitive than the single marker second trimester ß-core fragment and maternal age, however, there were few studies. There is a paucity of evidence available to support the use of urine testing for Down's syndrome screening in clinical practice where alternatives are available

Inactivation of the Pta-AckA Pathway Causes Cell Death in \u3ci\u3eStaphylococcus aureus\u3c/i\u3e

During growth under conditions of glucose and oxygen excess, Staphylococcus aureus predominantly accumulates acetate in the culture medium, suggesting that the phosphotransacetylase-acetate kinase (Pta-AckA) pathway plays a crucial role in bacterial fitness. Previous studies demonstrated that these conditions also induce the S. aureus CidR regulon involved in the control of cell death. Interestingly, the CidR regulon is comprised of only two operons, both encoding pyruvate catabolic enzymes, suggesting an intimate relationship between pyruvate metabolism and cell death. To examine this relationship, we introduced ackA and pta mutations in S. aureus and tested their effects on bacterial growth, carbon and energy metabolism, cid expression, and cell death. Inactivation of the Pta-AckA pathway showed a drastic inhibitory effect on growth and caused accumulation of dead cells in both pta and ackA mutants. Surprisingly, inactivation of the Pta-AckA pathway did not lead to a decrease in the energy status of bacteria, as the intracellular concentrations of ATP, NAD+, and NADH were higher in the mutants. However, inactivation of this pathway increased the rate of glucose consumption, led to a metabolic block at the pyruvate node, and enhanced carbon flux through both glycolysis and the tricarboxylic acid (TCA) cycle. Intriguingly, disruption of the Pta-AckA pathway also induced the CidR regulon, suggesting that activation of alternative pyruvate catabolic pathways could be an important survival strategy for the mutants. Collectively, the results of this study demonstrate the indispensable role of the Pta-AckA pathway in S. aureus for maintaining energy and metabolic homeostasis during overflow metabolism

Reductionist and system approaches to study the role of infection in preterm labor and delivery

A substantial number of patients with preterm labor and delivery do not show clinical signs of infection, however, it is the subclinical form which is the main causative factor and often results in premature delivery. The hitherto commonly applied methods of inflammation detection are based either on potentially hazardous amniocentesis or still insufficient inflammation-related protein measurement in the serum or other biological fluids

Adenovirus DNA in Guthrie cards from children who develop acute lymphoblastic leukaemia (ALL)

Aims: The aim of this thesis was to increase understanding of how molecular processes influence the development and risk assessment of childhood leukemia. Studies I and II investigates whether a specific virus infection in utero could be involved in a “first hit” in leukemogenesis. Studies III and IV examine whether alterations in protein expression from cell cycle regulating genes may predict a relapse in children with myeloid malignancies undergoing hematopoietic stem cell transplantation (HSCT). Background: Genetic alterations, analyzed at time of diagnosis in children who develop leukemia, have been traced back to neonatal dried blood spots (DBS). This suggests that the majority of chromosome translocations occur in utero during fetal hematopoiesis, generating a “first hit”. A “second hit” is then required to generate a leukemic clone. Today, experiments in vitro, animal models, and clinical observations have revealed that several viruses are oncogenic and capable of initiating a genetic alteration. Smith M postulated the theory that an in utero infection might be the “first hit”, causing genetic aberrations that could later lead to the development of the leukemic clone, which is supported by the early age of onset and space-time clustering data, based on time, place of birth, and diagnosis. Leukemia develops as a result of hematopoietic or lymphoid tissue with uncontrolled cell division. Normally cell division is controlled by the cell cycle, the network of which is complex with numerous regulating proteins both up and down stream, but also containing several feedback loops. The important regulators of this process are tumor suppressor genes, essential for normal cell proliferation and differentiation as well as for controlling DNA integrity. Errors in these genes or their protein expression affect the ability of the cell to check for DNA damage, thus tumors may occur. Proteins from these genes could serve as prognostic markers and predict relapse. Methods: In studies I and II we investigated neonatal DBS by PCR for the presence of adenovirus DNA (243 samples) and the three newly discovered polyomaviruses (50 samples) from children who later developed leukemia but also from controls (486 and 100 samples respectively). In studies III and IV we explored the expression of one (p53) respectively four (p53, p21, p16 and PTEN) cell cycle regulating proteins in bone marrow at diagnosis as well as pre and post HSCT in myeloid malignancies in children. We retrospectively collected clinical data and bone marrow samples from 33 children diagnosed with chronic myeloid malignancies (MDS, JMML and CML), 34 children diagnosed with AML as well as 55 controls. The samples were prepared by tissue micro array (TMA) as well as immunohistochemistry and examined for protein expression in a light microscope. Results: In study I we detected adenovirus DNA in only two patients who later developed leukemia, but in none of the controls. In study II all the samples were negative for KIPyV, WUPyV and MCPyV DNA in both patients and controls. In study III we found an overexpression of p53 protein at diagnosis that significantly predicted relapse after HSCT in children with rare chronic myeloid malignancies. In study IV a significantly higher p53 expression was found in the relapse compared to the non-relapse group at six months post HSCT in children with AML, suggesting that p53 may be used as prognostic markers for predicting a relapse. In addition, the calculated cut off level for p53 at diagnosis (study III) and at six months (study IV) post HSCT was approximately 20%, which indicates that a p53 expression over 20% may predict relapse in children with myeloid malignancies. Conclusion: Although we did not find an association between adenoviruses or the three newly discovered polyomaviruses and the development of childhood leukemia, a virus could still be involved in this process; the virus may have escaped detection, other new viruses could be involved or a virus could precipitate the “second hit”. We suggest that evaluation of p53 protein expression may be used as a supplement to regular prognostic markers both pre and post HSCT. To further evaluate this, a prospective multicenter study has been started