Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg 2+ in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n ¼ 14), congenital alveolar dysplasia (n ¼ 2), and other lethal lung hypoplasias (n ¼ 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n ¼ 8 and n ¼ 2, respectively) or FGF10 (n ¼ 2 and n ¼ 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping $2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Procalcitonin (PCT) and C reactive protein (CRP) concentrations in umbilical cord blood of 197 neonates were measured to evaluate their value as markers of infection. Sixteen of the neonates were infected. The sensitivity, specificity, and negative and positive predictive values were respectively 87.5%, 98.7%, 87.5%, and 98.7% for PCT and 50%, 97%, 67%, and 94% for CRP. Serum PCT in cord blood seems to be a useful and early marker of antenatal infection.M aternofetal bacterial infection is one of the most common causes of neonatal morbidity and mortality. Early diagnosis and treatment are vital to improve outcome. In the absence of reliable infection markers during the first hours of life, paediatricians often start early antibiotic treatment in newborn infants with risk factors for infection, exposing a considerable number of patients to unnecessary treatment. Procalcitonin (PCT) has been implicated as a sensitive and specific marker of bacterial infection. 2However, it is well established that PCT concentrations in the neonate show a physiological increase during the first two days of life, which complicates the interpretation of results during this period. 3 The aim of this study was to evaluate the diagnostic value of PCT measured in umbilical cord blood before this physiological increase as an early and specific marker of neonatal bacterial sepsis. STUDY DESIGN PatientsWe conducted a prospective study from November 2003 to April 2004 in all children born with a suspected maternofetal infection. Three groups were defined according to clinical, biological, and bacterial criteria: infected, colonised, and noninfected non-colonised. Infected neonates had clinical and postnatal biological signs of sepsis, and a positive central (blood or cerebrospinal fluid) or peripheral bacteriological sample. Colonised neonates had a positive gastric sample, without any clinical or biological sign of sepsis. Non-infected non-colonised neonates had no sign of infection and a negative gastric sample. We also studied a group of newborns without any risk factors, which constituted a control group. MeasurementsWe measured PCT concentration in umbilical cord blood samples using an immuno-chromatographic semiquantitative test (PCT-Q; Brahms, Hennigsdorf, Germany) and C reactive protein (CRP) concentration using an immunoreactive quantitative method. We also measured PCT in maternal blood to evaluate its relevance in the diagnosis of chorioamnionitis. Judgment criteriaThe first judgment criterion was the sensitivity, specificity, and positive and negative predictive values, and positive and negative likelihood ratios of PCT, as assessed by a comparison of PCT concentrations in infected neonates with those in the groups of colonised and non-infected non-colonised neonates. The second criterion involved a comparison of PCT and CRP as predictive markers of neonatal infection. RESULTSA total of 197 newborn infants (167 with suspected maternofetal infection and 30 in the control group) were included in the study; 161 were full term and 36...

Emerging resistance to antibiotics shows no signs of decline. At the same time, few new antibacterials are being discovered. There is a worldwide recognition regarding the danger of this situation. The urgency of the situation and the conviction that practices should change led the Société de Réanimation de Langue Française (SRLF) and the Société Française d'Anesthésie et de Réanimation (SFAR) to set up a panel of experts from various disciplines. These experts met for the first time at the end of 2012 and have since met regularly to issue the following 67 recommendations, according to the rigorous GRADE methodology. Five fields were explored: i) the link between the resistance of bacteria and the use of antibiotics in intensive care; ii) which microbiological data and how to use them to reduce antibiotic consumption; iii) how should antibiotic therapy be chosen to limit consumption of antibiotics; iv) how can antibiotic administration be optimized; v) review and duration of antibiotic treatments. In each institution, the appropriation of these recommendations should arouse multidisciplinary discussions resulting in better knowledge of local epidemiology, rate of antibiotic use, and finally protocols for improving the stewardship of antibiotics. These efforts should contribute to limit the emergence of resistant bacteria.

This article describes a study of procalcitonin (PCT) measured in cord blood as a discriminating marker of early-onset neonatal infection. This was a monocenter retrospective study with prospective collection of data including all babies born during the study period. Those presenting infection risk factors had PCT measurement. Three groups were defined: certainly infected, probably infected, and non-infected. A total of 12,485 newborns were included, 2151 had PCT measurement, and 26 were infected. Receiver operating curves of PCT determined 0.6 ng/ml as the best cut-off, with an area under the curve of 0.96 (CI 95% 0.95-0.98). Sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratios were 0.92 (range, 0.75-0.98), 0.97 (0.96-0.98), 0.28 (0.20-0.36), 0.99 (0.99-0.99), 32 (24-41) and 0.08 (0.02-0.3), respectively. Post-test probabilities were 28% (23-33) if the test was positive, and less than 0.001% (0-1.10(-5)) if the test was negative. Gestational age between 28 and 32 weeks (OR 4.4; range, 1.2-16.2) and pH at birth < 7.10 (OR 2.9; 1.1-7.4) were other independent factors of increasing PCT (p < 0.05). PCT measured in umbilical cord blood is reliable to detect early infected and non-infected newborns.