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Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. Impact: This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts.Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use.Methods to personalize medicine and technologies feasible for bedside clinical use are described.

Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. IMPACT: This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts. Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use. Methods to personalize medicine and technologies feasible for bedside clinical use are described.

ObjectivesAs quality of care in the delivery room has major impact on outcome of preterm infants, multiple guidelines have been established in recent years. There is, however, little evidence on how to proceed during postdelivery room care, the time of transfer and admission to the neonatal intensive care unit (NICU). The aim of this study was to identify processes taking place during this period with potential impact on outcome.Study designProspective observational study.SettingSingle-centre German tertiary NICU.Patients40 inborn preterm infants undergoing postdelivery room care.Main outcomePrevalence of prolonged duration of postdelivery room care, disconnections from the ventilator and positioning of preterm infants.ResultsTotal duration of postdelivery room care and NICU admission procedures were shorter in infants transferred in a transport incubator compared with using a NICU care station from birth. Extremely low birth weight (ELBW) infants spend 8% of the time in prone position in contrast to 39% in non-ELBW. Total duration of disconnection from the ventilator was 50 s and was ten times longer in infants who had nasal CPAP compared with infants intratracheally intubated. Infants with nCPAP had longer duration of disconnection from the ventilator if body weight was >1000 g or if they were transferred in a transport incubator.ConclusionsMultiple parameters like birth weight or type of transport affect neonatal care during the postdelivery room period. Prospective studies are needed to identify and optimise parameters within this period that affect long-term outcome.

Isolation precautions required for neonatal intensive care units are part of a bundle with the aim to prevent transmission, colonization, and infection with multidrug-resistant gram-negative pathogens as neonates face an increased risk of mortality and morbidity in case of infection. The following short report describes a transmission of 3MDRGN Klebsiella pneumoniae on a neonatal intensive care unit in a university hospital in Germany. This transmission occurred even though intensified infection control measures were in place, which impressively shows the importance of surveillance, outbreak management, and awareness of contributing factors regarding outbreak situations.

Background: Bilateral perisylvian polymicrogyria (BPP) is a well-recognized malformation of cortical development commonly associated with epilepsy, cognitive impairment, and oromotor apraxia. Reports have suggested the association of BPP with arthrogryposis multiplex congenita. We sought to investigate the clinical, electrophysiological, and neuroradiological features of this combined syndrome to determine if there are unique features that distinguish BPP with arthrogryposis from BPP alone. Methods: Cases of BPP with congenital arthrogryposis were identified from a large research database of individuals with polymicrogyria. Clinical features (including oromotor function, seizures, and joint contractures), MR brain imaging, and results of neuromuscular testing were reviewed. Results: Ten cases of BPP with congenital arthrogryposis were identified. Most cases had some degree of oromotor apraxia. Only a few had seizures, but a majority of cases were still young children. Electrophysiological studies provided evidence for lower motor neuron or peripheral nervous system involvement. On brain imaging, bilateral polymicrogyria (PMG) centered along the Sylvian fissures was seen, with variable extension frontally or parietally; no other cortical malformations were present. We did not identify obvious neuroimaging features that distinguish this syndrome from that of BPP without arthrogryposis. Conclusions: The clinical and neuroimaging features of the syndrome of BPP with congenital arthrogryposis appear similar to those seen in cases of isolated BPP without joint contractures, but electrophysiological studies often demonstrate coexistent lower motor neuron or peripheral nervous system pathology. These findings suggest that BPP with arthrogryposis may have a genetic etiology with effects at two levels of the neuraxis.

Objective To assess whether breastmilk feeding is associated with a reduced risk of bronchopulmonary dysplasia (BPD). Secondary outcome measures analyzed were retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC). Study design In an ongoing multicenter cohort study, the data of 1433 very low birth weight infants born before 32 weeks of gestation and discharged in 2013 were analyzed. We compared growth and neonatal complications of infants who received breastmilk exclusively (N = 223) with those who received formula feedings exclusively (N = 239). Logistic regression models were estimated for BPD, ROP, and NEC using nutrition as an independent variable. The Firth logistic regression model and Lasso were used for sensitivity analyses. Results Exclusively breastmilk-fed infants gained less weight compared with formula-fed infants. SDS for weight decreased between birth and discharge (median (Q1-Q3): formula −0.9 (−1.4 to [−0.5]) vs breastmilk −1.1 (−1.7 to [−0.6])). Exclusive formula feeding of very low birth weight infants was associated with increased risks of BPD (OR 2.6) as well as NEC (OR 12.6) and ROP (OR 1.80) after controlling for known risk factors. Conclusions Exclusive breastmilk feeding was associated with lower growth rates and a reduced risk of BPD as well as NEC and ROP.

The aim of this prospective observational study was to compare a bedside test with the reference laboratory method in routine postnatal glucose monitoring. Term newborns with increased risk or clinical signs of hypoglycemia were screened with a bedside test. In case of a glucose value below 2.25 mmol/L, a second blood sample was taken and a duplicate glucose measurement done in the laboratory using a bedside test (Accutrend sensor) and the reference laboratory method (hexokinase method) at the same time and from the same sample. From 110 term newborns, 122 blood samples were obtained for duplicate measurements (median 1.69 mmol/L, SD 0.45 mmol/L). Of these 122, Accutrend correctly identified 97% as being

The mammalian endopeptidase furin is a type 1 integral membrane protein that is predominantly localized to the TGN and is degraded in lysosomes with a t1/2 = 2–4 h. Whereas the localization of furin to the TGN is largely mediated by sorting signals in the cytosolic tail of the protein, we show here that targeting of furin to lysosomes is a function of the luminal domain of the protein. Inhibition of lysosomal degradation results in the accumulation of high molecular weight aggregates of furin; aggregation is also dependent on the luminal domain of furin. Temperature and pharmacologic manipulations suggest that furin aggregation occurs in the TGN and thus precedes delivery to lysosomes. These findings are consistent with a model in which furin becomes progressively aggregated in the TGN, an event that leads to its transport to lysosomes. Our observations indicate that changes in the aggregation state of luminal domains can be potent determinants of biosynthetic targeting to lysosomes and suggest the possible existence of quality control mechanisms for disposal of aggregated proteins in compartments of the secretory pathway other than the endoplasmic reticulum.

Introduction: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. Methods: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. Results: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. Discussion: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care. © 2012 Härtel et al. OA gold

The high affinity IgE receptor (Fc epsilon RI) is a tetrameric hetero-oligomer composed of an alpha chain, a beta chain, and two disulfide-linked gamma chains. The beta chain contains four transmembrane (TM) segments and long cytoplasmic domains that are thought to play an important role in intracellular signaling. We now report the structural characterization and the sequence of the complete human beta gene and cDNA. The gene spans approximately 10 kilobases and contains seven exons. There is a single transcription initiation site preceded by a TATA box. The first exon codes for the 5'-untranslated region and a portion of the N-terminal cytoplasmic tail. TM-1 is encoded in exons 2 and 3, TM-2 in exons 3 and 4, TM-3 in exon 5, and TM-4 in exon 6. The seventh and final exon encodes the end of the C-terminal cytoplasmic tail and the 3'-untranslated sequence. The human beta gene appears to be a single copy gene. Two corresponding transcripts, detected as a doublet around 3.9 kilobases, are present in cells of mast cell and basophil lineage from different individuals, but not in the other hematopoietic cells tested here. The human beta protein is homologous to rodent beta. The consensus amino acid sequences of human, mouse, and rat beta show 69% identical residues. Analysis of the surface expression of transfected receptors indicates that human alpha gamma and alpha beta gamma complexes are expressed with comparable efficiency. Human beta interacts with human alpha more efficiently than does rat beta, and both rat and mouse beta interact with their corresponding alpha more efficiently than does human beta, demonstrating a species specificity of the alpha/beta interaction.

The high affinity IgE receptor, Fc epsilon RI, is one of the key molecules involved in allergic reactions. It is a tetrameric complex (alpha beta gamma 2). The gamma chains from Fc epsilon RI are also subunits of other Fc receptors. We have isolated, characterized, and sequenced the gene for the human gamma chain of Fc epsilon RI. It consists of five exons and spans 4 kilobases. The leader sequence is encoded by two exons, the second of which also contains the short extracellular domain, the hydrophobic transmembrane region, and the beginning of the cytoplasmic tail. Three short exons encode the remaining of the polypeptide and the 3'-untranslated flanking sequence. The transcription initiation sites have been mapped. Comparison between the gene structures of the gamma chain of the Fc receptor and of the zeta chain of the T-cell receptor indicates that these genes have evolved from a common ancestor by duplication and that they define a new gene family. In addition to being localized on the same chromosome, both genes show an analogous organization of their exons. A high level of homology is found in three of their respective exons, and the splice sites between them are identical. Furthermore, gamma and zeta chains are essential for surface expression of their respective receptors. Therefore, gamma chains of Fc receptors and zeta chains of T-cell receptors may also define a new family of functionally related polypeptides. Expression studies in COS cells show that the human gamma chain alone is sufficient to achieve expression of the human alpha chain on the cell surface, whereas both beta and gamma chains are required for the surface expression of the rodent alpha chain.

Bacteria in human milk are predominantly apathogenic, but potential pathogens have been found in about 1 out of 5 human milk samples.1,2 To protect prematures, many neonatologists advocate human milk to be regularly screened for bacteria and, in case of contamination, to be heat-treated or even discarded 3-6However, heat treatment of human milk causes significant damage to immunoglobulins, enzymes, growth factors and live cells that are known to protect gainst a wide range of diseases.7-9 On the other hand, the potential of heating human milk to prevent infection has never been shown.3

Neonatal jaundice is a common finding in neonates and has considerable impact on healthcare costs (1)(2)(3). Bilirubin at higher concentrations may cause kernicterus, a severe and often debilitating disease (4). Thus, jaundice may require phototherapy or even exchange transfusion to reduce plasma bilirubin concentrations (5). A decision-making process predominantly based on plasma bilirubin concentration is required in clinically jaundiced infants. Therefore, measurement of total bilirubin is one of the most frequently performed laboratory tests in newborns. For monitoring hyperbilirubinemia in the newborn, methods are desirable that provide fast but reliable results from very small volumes of whole blood, enabling bilirubin measurements at the point of care. We evaluated a new method that uses a blood gas analyzer with multiple-wavelength photometry to determine total bilirubin concentrations in whole blood from jaundiced and nonjaundiced neonates and compared the results with a standard clinical chemistry procedure for total bilirubin measurement in plasma. Samples were collected between April and June 2000 in a 40-bed nursery situated within the obstetrics department of the University Hospital. A total of 142 blood samples from 79 neonates (ages, 0–22 days) were investigated. Blood samples were obtained by heel prick and collected simultaneously into heparin-containing 55-μL capillaries (Radiometer Medical) and heparin-containing 200-μL microtubes (Sarstedt) used routinely for clinical chemistry determinations in our nursery. Oral informed consent was obtained from the parents. The sample in the 55-μL capillary was measured immediately on an ABL 735 blood gas analyzer (Radiometer Medical) for pH, P co2, and P o2 …

Summary Background Neonatal sepsis is a common and lifethreatening disorder, particularly among preterm infants. Early initiation of antibiotic therapy is frequently delayed because the first clinical signs of sepsis are non-specific and there are no reliable early laboratory indicators. We investigated the time course of expression and the prognostic power of the early inflammatory mediators interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), and circulating intercellular adhesion molecule-1 (cICAM-1) before clinical diagnosis of sepsis. Methods In a prospective multicentre study, we monitored 182 very-low-birthweight infants in six intensive-care units for occurrence of sepsis. During routine or clinically indicated blood sampling, an additional sample was collected for measurement of IL-1ra, IL-6, cICAM-1, and C-reactive protein (CRP). Infants were grouped into those with proven sepsis, no infection, or unclassified. The mean study duration was 34 days. Whenever sepsis occurred, a study period of 10 days was defined: day 0 was the day of clinical diagnosis of sepsis; days −4 to −1 were the 4 days before diagnosis; days +1 to +5 were the 5 days after. We compared the concentrations of the immune mediators during the 10-day study period with group-specific baseline values from before day −4. Findings 101 infants were included in the analysis: 21 with proven sepsis, 20 with no infection, and 60 unclassified. We excluded 57 because of incomplete datasets and 24 who had early-onset sepsis. IL-1ra and IL-6 increased significantly 2 days before diagnosis of sepsis; maximum median increases within the study period were 15-fold for IL-1ra and 12-fold for IL-6. The diagnostic sensitivities of IL-1ra, IL-6, and CRP concentrations on day 0 of diagnosis were 93%, 86%, and 43%, respectively; corresponding values on day −1 were 64%, 57%, and 18%. The specificities of IL-1ra, IL-6, and CRP concentrations were 92%, 83%, and 93%. cICAM-1 had a specificity of only 64%. Interpretation IL-1ra and IL-6 are superior to cICAM-1 and CRP as predictors of sepsis 1 or more days before clinical diagnosis. Ad-hoc measurement of these cytokines could allow earlier initiation of antibiotic therapy with corresponding improvement in outcome in very-low-birthweight infants with sepsis.

The high-affinity receptor for IgE (Fc epsilon RI) on mast cells and basophils is a tetrameric complex, alpha beta gamma 2. Here we summarize the latest developments on the structure and function of this receptor. By genetic transfer, we have engineered a cell line secreting substantial amounts of a peptide containing exclusively the extracellular domain of the alpha-subunit. This domain by itself is sufficient to mediate high-affinity binding of IgE. Glycosylation and the presence of the other subunits are not necessary for the binding function. The gamma-subunit of Fc epsilon RI is part of other receptors such as Fc gamma RIII and the T cell receptor, and therefore is likely to play an important although still undefined functional role. A detailed knowledge of how the receptor interacts with IgE and induces cellular degranulation may lead to the design of new therapeutic approaches to allergic diseases. The potential strategies are discussed.

Mastcells and basophils express on their cell surface a receptor with high affinity for IgE (FceRI). Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators (like histamine) responsible for the symptoms seen in allergic reactions. Understanding the structure and function of this receptor could lead to the development of new therapeutic approaches which would directly interfere with IgE-mediated mastcell activation. FceRI consists of a tetramer of one α, one β and two γ subunits. Our group has already published the cloning of the α and γ subunits (J. Kochan et al., Nucleic Acids Res. 16: 3584-94, 1988 / H. Kuster et al., J. Biol. Chem. 265: 6448-52, 1990). Here we report the cloning of the gene and of the cDNA for the β subunit and the expression of the complete human receptor in COS-7 cells. The β subunit is a peptide of 244 aminoacids which crosses the plasma membrane 4 limes, both termini being inside the cell. It is encoded by 7 exons spanning over 8 kilobases. Previously transient expression of the rodent receptor showed that all three subunits are required in order to achieve cell surface expression of the receptor. In contrast for human FceRI the α and γ subunit alone are sufficient, the β subunit seems not necessary.

Granulocyte and natural killer (NK) cell Fc receptors for immunoglobulin G (CD16) differ in only a few amino acids, yet have phosphatidylinositol glycan (PIG) or polypeptide membrane anchors, respectively. Mutagenesis shows that anchoring is regulated by a serine residue near the PIG anchor attachment site in the extracellular domain. The NK cell isoform was not expressed on the surface of COS cells unless cotransfected with a subunit that was expressed in NK cells and that was identical to the gamma subunit of the high affinity IgE Fc receptor (Fc epsilon RI). However, the CD16 sequence and not expression of the gamma subunit is dominant in regulating PIG reanchoring.

Over the last few years considerable progress has been made in the field of the high affinity receptor for immunoglobulin E (FceRI). The recent achievements were made possible by the rapid development of the techniques of molecular genetics. The cloning of complementary DNA for the rat a (Kinet et al 1987) (Shimizu et al 1988), the rat p (Kinet et al 1988), and the rat γ subunits (Blank et al 1989) of the receptor unveiled the respective DNA and amino-acid sequences of the subunits which became the basis for a new model of the receptor.