Immune activation represents an adaptive reaction triggered by both noxious exogenous (microbes) and endogenous [high mobility group box-1 protein (HMGB1), S100 calcium binding proteins] inducers of inflammation. Cell stress or necrosis lead the release of HMGB1 and S100 proteins in the extracellular compartment where they act as damage-associated molecular pattern molecules (or alarmins) by engaging the receptor for advanced glycation end-products (RAGE). Although the biology of RAGE is dictated by the accumulation of damage-associated molecular pattern molecules at sites of tissue injury, the role of RAGE in mediating antenatal fetal injury remains unknown. First, we studied the relationships at birth between the intensity of human fetal inflammation and sRAGE (an endogenous RAGE antagonist), HMGB1, and S100␤ protein. We found significantly lower sRAGE in human fetuses that mounted robust inflammatory responses. HMGB1 levels correlated significantly with levels of interleukin-6 and S100␤ in fetal circulation. We then evaluated the levels and areas of tissue expression of RAGE, HMGB1, and S100␤ in specific organs of mouse fetuses on E16. Using an animal model of endotoxin-induced fetal damage and preterm birth, we determined that inflammation induces a significant change in expression of RAGE and HMGB1, but not S100␤, at sites of tissue damage. Our findings indicate that RAGE and Conventional wisdom holds that the primary causes of the high neonatal morbidity and mortality attendant preterm birth are complications of immature organ systems.1-4 However, a growing body of investigation suggests that the poor outcome observed in many preterm children is not entirely dependent on their gestational age at birth. 2,5,6 After correcting for gestational age, several risk factors remain significantly associated with an increased risk of cerebral palsy, such as intra-amniotic infection, histological chorioamnionitis, prolonged rupture of the membranes, and hypoxemic fetal growth re-

PURPOSE OF THE REVIEW: Particularities of the fetal immune response to infection cause a heightened inflammatory state that acts synergistically with microbial insult to induce damage. Proteomics offers the opportunity for detecting fetuses at risk of sepsis and neurological injury. RECENT FINDINGS: Molecular tools (16S-rRNA) demonstrate the diversity of microbial agents of intra-amniotic infection exceeds what is suspected clinically or is documented by cultures. The resulting inflammatory process has the potential to damage the fetus in utero. Stepwise algorithms [mass restricted (MR) score] have been developed to extract proteomic profiles characteristic of amniotic fluid (AF) inflammation. The MR score includes 4 proteomic biomarkers: defensin-2, defensin-1, S100A12 and S100A8 proteins. Other AF biomarkers relevant for preterm birth are S100A9 and insulin-like-growth-factor-binding protein 1 (IGFBP-1). S100A12, ligand for the receptor of advanced glycation end-products (RAGE), has the strongest association with histological chorioamnionitis and funisitis. Presence of S100A12 and S100A8 in AF is predictive of early-onset neonatal sepsis and poor neuro-developmental outcome. SUMMARY: Presence of AF proteomic biomarkers of inflammation is associated with increased inflammatory status of the fetus at birth. Future challenges are finding biomarkers that provide insight into molecular mechanisms of chronic fetal and neonatal cellular damage and identify candidates for early neuro-protection strategies.

We found that the LigaSure was as safe as standard vessel ligation for thyroidectomy, with the benefit of reduced operating time. A future prospective study has been designed.

Fetal membranes are a rich source of sRAGE. Elevated maternal serum and amniotic fluid sRAGE and esRAGE, paralleled by increased RAGE expression in the amniochorion, suggest activation of this system in sPE.

Background High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6. Methods We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin. Results AF HMGB1 levels are not gestational age regulated but increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments. Conclusions Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated HMGB1 levels may have an impact on the newborn beyond the time of birth.