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Background: Erythropoietin (Epo) was originally defined as a hematopoietic growth factor, but also has potent tissue-protective properties. The cytokine-modulating actions of Epo have received scant attention. We hypothesized that Epo significantly influences the in vitro cytokine production in both neonates and adults. Methods: The effects of Epo were investigated using a standardized in vitro whole blood assay. Production of various cytokines was assessed by means of intracellular cytokine detection (IL-2, -6, -8, IFN-γ and TNF-α) in preterm infants, term neonates and adults. Furthermore, synthesis of IL-4, -5 and -10 in adults was investigated via cytometric bead array. Results: Epo significantly inhibits the production of various cytokines in preterm infants, term neonates and adults. In CD3+ lymphocytes, Epo predominantly decreases the number of IL-2-positive cells in all age groups. Similarly, in CD14+ cells, Epo significantly diminishes the number of IL-6- and TNF-α-producing cells. Furthermore, Epo significantly inhibits the synthesis of IL-4, IL-5 and IL-10 in adults. Conclusion: rhEpo has significant inhibitory potential on the production of various cytokines by leukocytes in preterm and term infants as well as in adults. The described effect likely contributes to the tissue protective properties of Epo. [ABSTRACT FROM AUTHOR]

Aim: To further evaluate the underlying mechanism of a formerly demonstrated immature anti-inflammatory response in neonates ( 1 ). Methods: Interleukin (IL)-10 production was measured by enzyme-linked immunosorbent-assay (ELISA) after anti-CD3/anti-CD28 costimulation of neonatal and adult T cells. IL-10 receptor expression on T lymphocytes, B lymphocytes and monocytes were analysed by flow cytometry in neonates and adult controls. Results: After anti-CD3/anti-CD28 costimulation, IL-10 production of neonatal T lymphocytes was profoundly reduced (median 247 pg/mL vs. 1062 pg/mL, p < 0.0001). IL-10 receptor expression was diminished on neonatal T lymphocytes compared to adults (3% vs. 39.5% IL-10 receptor positive lymphocytes; p < 0.0001). On neonatal B lymphocytes and monocytes the IL-10 receptor expression was comparable to adult controls. Conclusion: The strongly reduced IL-10 receptor expression on the main immune regulative T lymphocytes in conjunction with a significantly impaired synthesis of IL-10 may play a crucial role in the formerly demonstrated deficient anti-inflammatory immune response in neonates. [ABSTRACT FROM AUTHOR]

The novel immunosuppressant Sanglifehrin A (SFA) is an immunophilin-binding metabolite with a yet unidentified mechanism of action. Several reports demonstrated the effects of SFA on proliferation and cytokine production of purified T cells with in part different results. However, less is known about the impact of SFA on the regulation of innate immune responses. We used a whole blood assay to investigate the impact of SFA on monocyte responses and T-lymphocyte activity/proliferation upon lipopolysaccharide (LPS) stimulation and anti-CD3/anti-CD28 costimulation, respectively. SFA was found to inhibit interleukin (IL)-2 protein expression of T lymphocytes. Whereas IL-2 mRNA expression was significantly reduced after 4 h of costimulation, the mRNA expression of IL-4 and IL-6 but not tumour necrosis factor (TNF)-α was inhibited by SFA both after 4 and 24 h of costimulation. The production of IL-2 and IL-6 protein in T lymphocytes was even strongly affected by SFA than the mRNA expression of the respective cytokine. Unlike other immunophilin-binding immunosuppressants, SFA also inhibited LPS-induced IL-6 and TNF-α mRNA and protein expression. At the single cell level, SFA was demonstrated to block the intracellular production of IL-6 in CD14+ monocytes but not the expression of other proinflammatory cytokines such as IL-8 and TNF-α. On the basis of these data, we propose that SFA may have a significant effect on the initiation and direction of immune responses. Considering the pleiotropic role of bioactive IL-6 production at the interface of innate and acquired immunity in a variety of disease conditions, it was found that these novel aspects of the unique immunosuppressive action could strongly impact on future clinical application of SFA. [ABSTRACT FROM AUTHOR]

The aim of the study was to characterize thein vitroeffect of non-steroidal anti-inflammatory drugs (NSAIDs) on the production of pro-inflammatory cytokines in a human whole blood assay. Whole blood samples were pre-incubated with acetylsalicylic acid, indomethacin, selective cyclooxygenase (COX)-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or prostaglandin E2 (PGE2) before stimulation with lipopolysaccharide (LPS). Pro-inflammatory and anti-inflammatory cytokines were determined directly at the cell level with the help of flow cytometry and/or in the plasma supernatant with the help of ELISA. High doses of acetylsalicylic acid were needed to inhibit pro-inflammatory cytokine production. In contrast, low-to-moderate doses induced a modestly enhanced production of pro-inflammatory cytokines. Moreover, indomethacin was demonstrated to increase the expression of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in a dose-dependent fashion. Upon addition of PGE2, however, LPS-induced IL-6 and TNF-α production was suppressed regardless of indomethacin presence. Interestingly, selective COX-2 inhibition (NS-398), but not selective COX-1 inhibition (SC-560), exerted a stimulatory effect on the expression of pro-inflammatory cytokines. These data emphasize that the immunomodulating effects of NSAIDs in whole blood are dose-dependent. Furthermore, the induction of pro-inflammatory cytokine expression by NSAIDs is potentially mediated by COX-2 inhibition. Although NSAIDs are successfully used in clinical practice for their net anti-inflammatory properties, our observations may contribute to the understanding of side effects induced by NSAIDs and selective COX-2 inhibitors. [ABSTRACT FROM AUTHOR]

In this study we explored the hassles and uplifts (i.e. negative and positive emotional events) experienced by registered nurses, nursing assistants and personal carers working with people with cognitive impairment in community and residential healthcare settings in Brisbane, Queensland, Australia. The primary aim of the research was to explore what aspects of caring for cognitively impaired clients hassles nurses, what helps to relieve these hassles, what aspects of this work nurses find rewarding and what detracts from those rewards, as well as the intensity with which each of these aspects were felt. A questionnaire developed to explore hassles and uplifts at work was administered and 57 responses obtained. Results indicated that caring for the cognitively impaired client provides many uplifts for nurses and few hassles. However, the hassles that occurred were of high importance. This paper will be of interest to managers, nurses and carers in settings where there are people with cognitive impairment as well as scholars, who may find that assessing emotional hassles and uplifts provides additional insights into other areas of nursing. [ABSTRACT FROM AUTHOR]

Background and Objectives Inflammatory cytokines in platelet concentrates (PC) may cause side-effects such as febrile non-haemolytic transfusion reactions. The maximum white blood cell (WBC) content tolerable to avoid the accumulation of cytokines, and whether these cytokines originate from degranulating leucocytes or de novo synthesis during storage, had not been investigated prior to this study. Material and Methods We investigated the secretion of interleukin (IL)-1β, IL-2, IL-6, IL-8, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and quantified the appropriate expression of corresponding mRNA in PC with regard to different levels of WBC contamination and storage times. In addition we tested the viability of WBCs during PC storage (by staining with 7-aminoactinomycin D) and their ability to perform de novo cytokine synthesis (by using superantigen stimulation). Results We detected a statistically significant increase of IL-1β, IL-6, IL-8 and TNF-α in PC with ≥ 108 WBCs. Quantitative reverse transcription–polymerase chain reaction (RT–PCR) showed increasing mRNA expression of the respective cytokines depending on the number of WBC present. On day 5 of storage, WBC viability was > 80% and the leucocytes were still able to produce cytokines de novo . Conclusions These data show clear evidence for de novo synthesis of cytokines in PC. The cytokine pattern supports the hypothesis that activated monocytes are responsible for this cytokine synthesis. PC with a WBC contamination of ≥ 108 contain inflammatory mediators in clinically relevant concentrations. [ABSTRACT FROM AUTHOR]

Studies the cerebral magnetic resonance imaging of a 14-year old boy with hypertensive encephalopathy and pharyngitis. Observance of acute onset of neurological symptoms including consciousness, seizures and hemiplegia; Causes of cerebral vascular vasodilatation.

Aim: Retinopathy of prematurity (ROP) is a major morbidity in preterm infants causing visual impairment including blindness. Prevention and timely treatment are critical. We investigated the potential role of red blood cell (RBC) transfusions as risk factor for ROP development., Methods: Retrospective cohort study of data from 68 tertiary level neonatal intensive care units in Germany. Preterm infants born at 22 + 0 to 28 + 6 weeks of gestation between January 2009 and December 2021 were enrolled., Results: We included n = 12 565 infants. Prevalence of any ROP was 49.2% with most infants being diagnosed with stage 1 (21.5%) and 2 disease (17.2%). ROP stage 3 was present in 10.2%, stage 4 in 0.3%, and ROP requiring treatment in 6.6%. Infants with ROP had significantly more frequently a history of RBC transfusions. Adjusting for confounders, RBC transfusions were associated with increased odds of ROP (OR 1.4, p < 0.001), ROP progression (OR 2.1, p < 0.01) and ROP requiring treatment (OR 3.6, p < 0.001). Restrictive transfusion approaches correlated with decreased (OR 0.7, p < 0.001), liberal regimes with increased odds (OR 1.2, p = 0.001)., Conclusion: The present study confirmed an association of RBC transfusions and ROP. Our findings emphasise the need for anaemia prevention and critical re-evaluation of transfusion practices in preterm infants., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: We explored whether subnormal forced expiratory volume within 1 s (FEV 1 ) at 5-9 years of age was lower in children born preterm who received less invasive surfactant administration (LISA) rather than surfactant via an endotracheal tube., Methods: The multi-centre, randomised Nonintubated Surfactant Application trial enrolled 211 preterm infants born at 23-26 weeks of gestation from 13 level III neonatal intensive care units from April 2009 to March 2012. They received surfactant via LISA (n = 107) or after conventional endotracheal intubation (n = 104). The follow-up assessments were carried out by a single team blinded to the group assignments. The main outcome was FEV 1  < 80% of predicted values., Results: Spirometry was successful in 102/121 children. The other children died or were lost to follow-up. Median FEV 1 was 93% (interquartile range 80%-113%) of predicted values in the LISA group and 86% (interquartile range 77-102%) in the control group (p = 0.685). Rates of FEV 1  < 80% were 11/57 (19%) and 15/45 (33%), respectively, which was an absolute risk reduction of 14% (95% confidence interval -3.1% to 31.2%, p = 0.235). There were no differences in other outcome measures., Conclusion: The proportion of children aged 5-9 years with subnormal FEV 1 was not significantly different between the groups., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: In animal studies, aminoglycosides induced ductus arteriosus relaxation in a dose-dependent fashion. We tested the hypothesis that antibiotic treatment of preterm infants with aminoglycosides is associated with higher rates of surgical patent ductus arteriosus (PDA) closure., Methods: Preterm infants (birthweight <1000 grams or gestational age <29 weeks) enrolled in 62 German neonatal intensive care units (NICUs) were analysed. NICUs were stratified according to the use of aminoglycosides as first-line antibiotics., Results: Baseline data were not different when NICUs using aminoglycosides (n = 9965 infants) were compared to NICUs using other antibiotics (n = 1948 infants). Rates of surgical PDA closure were 5.9% for NICUs using aminoglycosides; 6.2% for units using gentamicin; and 5.0% for NICUs using tobramycin compared to 4.1% in NICUs using other antibiotics (P < .001, P < .001 and P = .140, respectively, Fisher's exact test). Indomethacin and ibuprofen use was more common in NICUs using aminoglycosides (41% vs 33%, P < .001, Fisher's exact test). Gentamicin trough levels were higher in NICUs with surgical closure rates above the mean (median 2.0 µg/mL, inter-quartile range 0.8-4.0 µg/mL vs 1.2 µg/mL, IQR 0.8-1.7, P < .001, Mann-Whitney U test)., Conclusion: First-line antibiotic treatment of preterm infants with aminoglycosides was associated with higher rates of surgical PDA closure., (© 2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: To determine the regional cerebral tissue oxygenation saturation (rcSO 2 ) in a group of infants requiring less invasive surfactant administration (LISA) as compared to infants with continuous positive airway pressure (CPAP) only., Methods: In preterm infants with a gestational age 26 0/7-31 6/7 weeks, we conducted an observational study using near-infrared spectroscopy (NIRS) in the first 120 hours of life., Results: We analysed the data of 22 infants who never received surfactant (CPAP), 22 infants had LISA and CPAP (LISA) and 6 infants received surfactant via endotracheal tube (ETT). Four infants had both surfactant application modes including six LISA applications. In total, there were 32 successful LISA applications but 44 attempts; 13/44 (30%) of LISA attempts resulted in a 20% decrease of rcSO 2 . During the first 120 hours of life, rcSO 2 values of CPAP were similar to those of infants in the LISA group, that is median rcSO 2 values 90% vs 85%, respectively (P = .126). Episodes with rcSO 2 values <65% were 0.4% in the CPAP group as compared to 4.8% in the LISA group (P < .001)., Conclusion: Our observational data indicate that rcSO 2 values of infants in the LISA group were similar to the CPAP group., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: Providing less invasive surfactant administration (LISA) to spontaneously breathing preterm infants has been reported to reduce mechanical ventilation and bronchopulmonary dysplasia (BPD) in randomised controlled trials. This large cohort study compared these outcome measures between LISA-treated infants and controls., Methods: Infants receiving LISA, who were born before 32 gestational weeks and enrolled in the German Neonatal Network, were matched to control infants by gestational age, umbilical cord pH, Apgar-score at 5 min, small for gestational age status, antenatal treatment with steroids, gender and highest supplemental oxygen during the first 12 h of life. Outcome data were compared with chi-square and Mann-Whitney U-tests and adjusted for multiple comparisons., Results: Between 2009 and 2012, 1103 infants were treated with LISA at 37 centres. LISA infants had lower rates of mechanical ventilation (41% versus 62%, p < 0.001), postnatal dexamethasone treatment (2.5% versus 7%, p < 0.001), BPD (12% versus 18%, p = 0.001) and BPD or death (14% versus 21%, p < 0.001) than the controls., Conclusion: Surfactant treatment of spontaneously breathing infants was associated with lower rates of mechanical ventilation and BPD. Additional large-scale randomised controlled trials are needed to assess the possible long-term benefits of LISA., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: To determine levels of antimicrobial polypeptides (AMP) in cord blood of term and preterm neonates and to investigate influencing factors., Methods: In a single-centre study, n = 139 preterm infants and n = 36 term infants were included. AMP levels were analysed in supernatants of whole cord blood cultures with a standardised concentration of 5 × 10(6) white blood cells/mL via enzyme-linked immunosorbent assay (ELISA)., Results: Lactoferrin, human neutrophil peptides (HNP) 1-3 and bacterial permeability-increasing protein (BPI) expression in cord blood of preterm infants were influenced by the cause of preterm delivery, that is increased levels in infants with clinical amniotic infection. AMP levels also weakly correlated with white blood cell and neutrophil count at birth. In the whole cohort, no association between gestational age or birthweight with AMP levels was found. In the subgroup of infants without clinical amniotic infection (n = 77 preterm infants, n = 36 healthy term infants), we noted a weak correlation between gestational age and lactoferrin, calprotectin and HNP1-3 levels. In addition to that, we observed higher levels of lactoferrin and HNP1-3 in large-for-gestational-age infants., Conclusion: Our study confirms that several factors influence cord blood AMP levels which underlines the difficulties of using AMP levels as biomarkers of immunological response., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: ATP-binding cassette member A 3 (ABCA3) plays a critical role for the transport of surfactant phospholipids into the lamellar bodies of type II alveolar epithelial cells. Term infants carrying the E292V missense mutation of the gene encoding ABCA3 are likely to develop respiratory distress syndrome, and the mutation has also been linked to interstitial lung disease in paediatric patients. The aim of this study was to investigate the association of the E292V genotype with pulmonary morbidity in a large cohort of very-low-birth-weight (VLBW) infants., Methods: We performed a genetic association study with a prospective, population-based multi-centre cohort of 3177 VLBW infants born in 16 German study centres between 2003 and 2009 (German Neonatal Network). The ABCA3 genotype was determined by restriction fragment length polymorphism-PCR in genomic DNA samples derived from buccal swabs., Results: In a large cohort of 3177 VLBW infants, 11 individuals were found to be heterozygote for the E292V mutation (0.34%). After stratification according to ABCA3 genotype, no differences were noted for clinical characteristics, necessary treatments and neonatal pulmonary outcomes., Conclusions: Within the size limits of our study cohort, the ABCA3 missense mutation E292V had no remarkable effect on pulmonary outcome in VLBW infants. Present results do not rule out the possibility that E292V phenotype is associated with minor difference in the morbidity., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Background: It was the aim of this study to evaluate the effects of the well-known immunosuppressive drugs ciclosporin A (CsA), tacrolimus and sirolimus on the intracytoplasmic cytokine expression of neonatal immune cells., Methods: Immunosuppressive drugs were added to whole blood cultures of neonatal cord blood samples (n = 17) and peripheral blood samples of adults (n = 17) in vitro prior to stimulation of lymphocytes with phorbol 12-myristate 13-acetate (PMA)/ionomycin or monocytes., Results: Upon exposure to ciclosporin A (500 ng/mL) or tacrolimus (25 ng/mL) the number of cytokine expressing T cells was almost completely blocked in neonatal T cells while sirolimus (10 ng/mL) only inhibited intracytoplasmatic tumour necrosis factor alpha (TNF-alpha) expression (mean% positive cells; 4.0 +/- 2.1% vs. 1.09 +/- 0.6%, p = 0.003), but mildly stimulated the intracellular expression of interleukin (IL)-2 (24.4 +/- 6.5% vs. 28.1 +/- 7.1%, p = 0.041). In cord blood lymphocytes, the inhibitory effect of ciclosporin A and tacrolimus was dose-dependent (e.g. IL-2: control, 12.3 +/- 5.33%, ciclosporin A 5 ng/mL, 10.1 +/- 5.5%; 50 ng/mL, 7.1 +/- 4.7%; 500 ng/mL, 1.2 +/- 0.3%; tacrolimus 0.25 ng/mL, 9.3 +/- 4.9%; 2.5 ng/mL, 6.1 +/- 3.3%; 25 ng/mL, 1.0 +/- 0.6%), while the function of adult lymphocytes was only impaired at high doses of both compounds. In contrast, the number of cytokine expressing monocytes was not influenced by ciclosporin A and tacrolimus except for a minor decrease of TNF-alpha producing neonatal monocytes after addition of tacrolimus (17.9% vs. 13.9%, p = 0.031). Interestingly, sirolimus was shown to inhibit intracellular IL-6 production in adults (63.1 +/- 12.7% vs. 52.0 +/- 16.0%, p = 0.005), but in neonatal monocytes intracellular IL-6 expression was stimulated (53.5 +/- 22.0% vs. 64.7 +/- 19.1%, p = 0.041)., Conclusions: The potent dose-dependent inhibitory effect of ciclosporin A and tacrolimus in cord blood lymphocytes provides the basis for further studies on functional immaturity of the neonatal immune system and for future strategies to optimize umbilical cord blood transplantion. Sirolimus was demonstrated to have a distinct effect on neonatal immune cells as shown by increased expression of IL-2 in lymphocytes and IL-6 in monocytes, while only lymphocytic TNF-alpha expression was inhibited.

Context: In recent years, tremendous effort has been carried out to study the genetic basis of susceptibility to development, progression and severity of complex diseases and response to therapy. The ultimate goal of these investigations is to find new tools for prevention and treatment of these complex diseases, such as sepsis in very-low-birth-weight (VLBW) infants. VLBW cohorts have a restricted clinical risk profile for the development of sepsis including immaturity of immune functions and antenatal/perinatal risk factors but also a significant event rate of sepsis within a short period of observational time. Therefore, prospective VLBW cohorts are advantageous for the investigation of candidate genetic risk factors of sepsis compared to adult cohorts. Furthermore, environmental factors are much better documented and highly controlled for VLBW infants in a standardized NICU setting compared to adult cohorts which are influenced by a variety of environmental risk factors, e.g. habits and comorbidities., Objective: The aim of this review is to discuss the value and limitations of genetic association studies in VLBW infant cohorts exemplifying recent findings for genetic susceptibility to neonatal sepsis., Data Source: Published Medline articles reporting on studies of associations between genetic polymorphisms, neonatal sepsis and septic shock in VLBW infants., Conclusions: Up-to-date, the classical approach to investigate the genetic component of susceptibility to sepsis in VLBW infants by means of twin and concordance studies has not been implemented yet. Regarding the interpretation of data from current genetic association studies, one should be aware of significant differences in cohort size, study design and definition of cases, controls and clinical end points. Furthermore, the contribution of genetic variants to susceptibility to sepsis may be specifically influenced by the immaturity of the immune response in VLBW infants, the selectivity of responsiveness to certain pathogens and the genotopyic/phenotypic variability of pathogens. We provide implications for the conduct and evaluation of future association studies with particular reference to methodological quality standards.