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Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs) and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP) that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant.

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AIM: The aim of this study was to determine whether amniotic fluid levels of annexin A2, a phospholipid-binding protein that is abundant in amnion and regulates fibrin homeostasis, are associated with histological chorioamnionitis, preterm premature rupture of the membranes, and subsequent preterm delivery. MATERIALS AND METHODS: Amniotic fluid was obtained from 55 pregnant women with preterm labor and/or preterm premature rupture of the membranes before 32weeks of gestation, and amniotic fluid levels of annexin A2 were measured with a sandwich enzyme-linked immunosorbent assay. RESULTS: Amniotic fluid levels of annexin A2 in patients with histological chorioamnionitis was higher than that in the remainder (P=0.053), whereas amniotic fluid levels of annexin A2 in patients with preterm premature rupture of the membranes was significantly higher than that in the remainder (P=0.002). Amniotic levels of annexin A2 was a fair test (area under receiver-operator characteristic curve=0.679), and amniotic fluid levels of annexin A2>878.2ng/mL had a sensitivity of 68.8%, a specificity of 65.2%, a positive predictive value of 73.3%, and a negative predictive value of 60.0% for predicting delivery within 2weeks after amniotic fluid sampling. Furthermore, the combined use of amniotic fluid cut-off levels of 878.2ng/mL for annexin A2 and 13.3ng/mL for interleukin-8 improved the specificity (91.3%) and the positive predictive value (89.5%). CONCLUSIONS: We identified amniotic fluid levels of annexin A2, especially in combination with amniotic fluid levels of interleukin-8, as a novel predictive marker for preterm delivery.

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The prevalence and incidence of food protein-induced enterocolitis syndrome (FPIES) are clearly not known; its onset before first feeding at birth especially has been rarely reported. A female newborn was referred to our institution due to blood-stained diarrhea before her first feeding at birth. Examination of the stool with Wright-Giemsa staining on day 6 revealed numerous fecal eosinophils, including Charcot-Leyden crystals. Lymphocyte stimulation test (LST) against cow's milk protein also showed positive values on day 12. The hematochezia resolved immediately after starting intravenous nutrition. She was fed with breast milk and extensively hydrolyzed formula and discharged from hospital on day 49. FPIES was diagnosed based on these symptoms and data. Our case was thought to have acquired allergic enterocolitis after sensitization in her fetal period, which caused severe FPIES triggered by the first intake of cow's milk soon after birth. The patient with FPIES presents atypical clinical findings, which is likely to cause misdiagnosis and delay of appropriate treatment. Heightened awareness and increased attention may be necessary to diagnose FPIES, even soon after birth. Evaluating fecal eosinophils and LST, which may be difficult to perform in every clinical hospital, is thought to be useful for the detection of FPIES without oral food challenge.

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Innate antimicrobial peptides are considered to play an important role in host defense against microbial invasion. They are expressed in a wide variety of organisms. In the case of human beings, defensins and the cathelicidin LL-37 appear to be the major microbicidal peptides. With respect to human neonates, only few investigations have been performed in this context, revealing the presence of alpha-defensins and LL-37 in neutrophils and vernix caseosa. In addition, beta-defensins are present in tracheal aspirates and breast milk, whereas LL-37 has been detected in the skin of the newborn baby. During recent years, immunomodulatory activities such as chemotaxis have emerged as important functions of antimicrobial peptides. Thus, these innate effectors may work synergistically to provide a first line of defense against infection, as well as to promote interactions between the innate and adaptive immunity in newborn infants.

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Antimicrobial peptides/proteins are widespread in nature and play a critical role in host defense. To investigate whether these components contribute to surface protection of newborns at birth, we have characterized antimicrobial polypeptides in vernix caseosa (vernix) and amniotic fluid (AF). Concentrated peptide/protein extracts were obtained from 11 samples of vernix and six samples of AF and analyzed for antimicrobial activity using an inhibition zone assay. Proteins/peptides in all vernix extracts exhibited strong antibacterial activity against Bacillus megaterium (strain Bm11), in addition to antifungal activity against Candida albicans, whereas AF-derived proteins/peptides showed only the former activity. Fractions obtained after separation by reverse-phase HPLC exhibited antibacterial activity, with the most pronounced activity in a fraction containing alpha-defensins (HNP1-3). The presence of HNP1-3 was proved by dot blot analysis and confirmed by mass spectrometry. Lysozyme and ubiquitin were identified by sequence analysis in two fractions with antibacterial activity. Fractions of vernix and AF were also positive for LL-37 with dot blot and Western blot analyses, and one fraction apparently contained an extended form of LL-37. Interestingly, psoriasin, a calcium-binding protein that is up-regulated in psoriatic skin and was found recently to exhibit antimicrobial activity, was characterized in the vernix extract. The presence of all of these antimicrobial polypeptides in vernix suggests that they are important for surface defense and may have an active biologic role against microbial invasion at birth.

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