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Aim: Left vocal cord paralysis (LVCP) is variably reported post ligation of patent ductus arteriosus (PDA). Our objective was to determine the incidence of LVCP and identify predictive factors and associated morbidities in preterm infants post PDA ligation., Methods: This is a retrospective cohort study of infants less than 29 weeks gestational age from 2006 to 2014 who underwent PDA ligation. Infants with laryngeal symptoms underwent flexible fibreoptic nasopharyngolaryngoscopy to evaluate vocal cord function. We compared short- and long-term morbidities among infants with and without symptomatic LVCP., Results: A total of 35 infants underwent PDA ligation in the study period, of which 11 infants (31%) developed symptomatic LVCP. Dysphonia was the presenting symptom in all neonates with LVCP and stridor was present in 46% (5/11) of them. The median (interquartile range) gestation (25 weeks (24-27) vs. 25 weeks (23-28)), birthweight (810 g (550-1180) vs. 825 g (550-1220)) and age at surgery (19 days (9-27) vs. 20 (5-69)) were similar in infants with and without LVCP, respectively. Infants with LVCP took significantly longer to reach suck feeds (128 vs. 90 days, P = <0.001), stayed longer in hospital (119 vs. 95 days, P = 0.01) and were more likely to go home on oxygen (73 vs. 27%; P = 0.024). Neurodevelopmental outcomes were similar in the two groups., Conclusions: LVCP was noted in 31% of infants post PDA ligation and was associated with prolonged hospital stay, a longer time to reach suck feeds and a need for home oxygen. No predictive factors for development of LVCP were identified., (© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Vein of Galen aneurysmal malformation (VGAM) is a rare congenital vascular malformation. We report a case of VGAM being associated with presence of bilateral hydrocephalus, gross cardiomegaly and is unique in two ways. Firstly, clinical presentation was associated with a large discrete cystic swelling along right side of the neck, which has not previously been reported. Secondly, this was a missed diagnosis of VGAM due to omission of colour Doppler study while performing diagnostic fetal cranial ultrasound just prior to delivery, following referral for assessment on a previously identified abnormality., Competing Interests: None., (© 2016 Australasian Society for Ultrasound in Medicine.)

Cells expressing both the regulatory T cell (Treg)-inducing transcription factor Foxp3 and the Th17 transcription factor RORγt have been identified (biTregs). It is unclear whether RORγt(+)Foxp3(+) biTregs belong to the Th17-specific Treg17 cells, represent intermediates during Treg/Th17 transdifferentiation, or constitute a distinct cell lineage. Because the role of biTregs in inflammatory renal disease is also unknown, we studied these cells in the nephrotoxic nephritis (NTN) model of acute crescentic GN. Induction of NTN resulted in rapid renal and systemic expansion of biTregs. Notably, analyses of the biTreg expression profile revealed production of both anti-inflammatory (IL-10, IL-35) and proinflammatory (IL-17) cytokines. Additionally, biTregs expressed a signature of surface molecules and transcription factors distinct from those of Th17 cells and conventional Tregs (cTregs), and biTregs were identified in Treg17-deficient mice. Finally, fate reporter and cell transfer studies confirmed that biTregs are not Treg/Th17 transdifferentiating cells. Therapeutic transfer of biTregs suppressed the development of nephritis to an extent similar to that observed with transferred cTregs, but in vitro studies indicated different mechanisms of immunosuppression for biTregs and cTregs. Intriguingely, as predicted from their cytokine profile, endogenous biTregs displayed additional proinflammatory functions in NTN that were abrogated by cell-specific deletion of RORγt. In summary, we provide evidence that RORγt(+)Foxp3(+) biTregs are a novel and independent bifunctional regulatory T cell lineage distinct from cTregs, Treg17 cells, and Th17 cells. Furthermore, biTregs appear to contribute to crescentic GN and hence may be novel therapeutic targets., (Copyright © 2016 by the American Society of Nephrology.)

Systemic lupus erythematosus (SLE) is a complex and potentially fatal autoimmune disorder. Although Th17 cells are thought to be central mediators of SLE, mechanisms underlying their counter regulation remain largely unknown. To help define this, we studied the function of the newly defined Stat3-dependent Th17-specific regulatory T cells (Treg17). Treg-specific deletion of Stat3 was achieved by generating Foxp3(Cre) × Stat3(fl/fl) mice and SLE was induced by intraperitoneal injection of pristane. Lack of Treg17 cells in these mice caused selectively enhanced peritoneal Th17 inflammation. Importantly, Treg17 deficiency also resulted in aggravated pulmonary vasculitis with increased percentages of Th17 cells and significantly higher mortality. Similarly, 4 and 9 months after pristane injection, analysis of renal and systemic immunity showed overshooting Th17 responses in the absence of Treg17 cells, associated with the aggravation of lupus nephritis. Expression of the Th17 characteristic trafficking receptor CCR6 was strikingly reduced on Tregs of Foxp3(Cre) × Stat3(fl/fl) mice, resulting in impaired renal Treg infiltration. Thus, Stat3-induced Treg17 cells are novel antiinflammatory mediators of SLE. One mechanism enabling Treg17 cells to target pathogenic Th17 responses is shared expression of the chemokine receptor CCR6., (Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Rα, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6(-/-) mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing., (Copyright © 2015 by the American Society of Nephrology.)

Aim: Preterm infants with respiratory distress syndrome (RDS) requiring surfactant treatment are often retrieved mechanically ventilated to the receiving hospital. INSURE (INtubate, SURfactant, Extubate) technique is not routinely performed by Newborn and Pediatric Emergency Transport Services NSW (NETS) during retrieval. This study aims to evaluate the likelihood of using INSURE technique during retrieval. We attempted to study the clinical characteristics of preterm infants with RDS who were favourably extubated (FE) shortly after admission to the receiving hospital., Methods: Retrospective study of preterm infants, gestational age (GA) > 28 weeks with RDS requiring retrieval by NETS., Results: Two hundred twenty-three infants, median GA of 33 weeks (range 29-36), median birthweight 2200 g (1000-4080) were examined. A percentage of 49.7 received CPAP, and 50.3% required MV. Eighteen (16%) infants were FE (<6 h) at receiving hospital. FiO2 on stabilisation (FiO2 (st)) by NETS correlated with FiO2 on admission to receiving hospital (r = 0.863). A percentage of 81 of ventilated infants received premedications including morphine. No significant differences were noted for GA, stabilisation ventilator settings, surfactant dose (mean 155 mg/kg) and mode of transport between FE and non-FE groups. FiO2 (st) post-surfactant treatment was significantly lower in FE compared with non-FE group (mean 0.28 vs. 0.41 respectively). The area under the curve from receiver operating characteristic based on FiO2 (st) was 0.646 (P = 0.050), the sensitivity and specificity of FiO2 (st) cut-off points (between 0.25 and 0.30) was low., Conclusion: FiO2 on stabilisation post-surfactant treatment has a weak predictive value and may not be adequate to be used as sole criteria to extubate to CPAP prior to transport. FiO2 at stabilisation should be included as an eligibility criteria for a randomised trial of INSURE during retrieval, but other clinical assessments are needed., (© 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Introduction: The objective was to evaluate the respiratory management of neonates of 23 to 26 weeks' gestation transported after birth outside a tertiary center. Another objective was to collect data regarding survival, intraventricular hemorrhage (IVH), and chronic lung disease., Methods: This was a retrospective study of transports from a statewide dedicated neonatal and pediatric transport service over a 3-year period. Data were collected from the local databases. Neonates with and without transcutaneous carbon dioxide (TcCO2) monitoring were compared. Outcomes were compared with the inborn group from the same period., Results: A total of 43 mechanically ventilated neonates were included. Significant hypocarbia and/or hypercarbia were seen in 49%. Hyperoxia was noted in 46.5%. Despite the moderate correlation between PCO2 and TcCO2 readings, no clinical benefit was seen with TcCO2 monitoring. Survival was 65.1%. Rates of IVH were 60% for any IVH and 27.5% for severe IVH. IVH was more common in the study cohort., Conclusions: Neonates born at 23 to 26 weeks' gestation outside tertiary centers have high rates of mortality and morbidity. The avoidance of hypocarbia, hypercarbia, and hyperoxia is challenging in the transport environment. Transcutaneous monitoring is an imperfect tool for following PCO2 levels., (Copyright © 2014 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

A pathogenic role for Th17 cells in inflammatory renal disease is well established. The mechanisms underlying their counter-regulation are, however, largely unknown. Recently, Th17 lineage-specific regulatory T cells (Treg17) that depend on activation of the transcription factor Stat3 were identified. We studied the function of Treg17 in the nephrotoxic nephritis (NTN) model of crescentic GN. The absence of Treg17 cells in Foxp3(Cre)×Stat3(fl/fl) mice resulted in the aggravation of NTN and skewing of renal and systemic immune responses toward Th17. Detailed analysis of Stat3-deficient Tregs revealed that the survival, activation, proliferation, and suppressive function of these cells remained intact. However, Tregs from Foxp3(Cre)×Stat3(fl/fl) mice lacked surface expression of the chemokine receptor CCR6, which resulted in impaired renal trafficking. Furthermore, aggravation of NTN was reversible in the absence of Th17 responses, as shown in CD4(Cre)×Stat3(fl/fl) mice lacking both Treg17 and Th17 cells, suggesting that Th17 cells are indeed the major target of Treg17 cells. Notably, immunohistochemistry revealed CCR6-bearing Treg17 cells in kidney biopsy specimens of patients with GN. CCR6 expression on human Treg17 cells also appears dependent on STAT3, as shown by analysis of Tregs from patients with dominant-negative STAT3 mutations. Our data indicate the presence and involvement of Stat3/STAT3-dependent Treg17 cells that specifically target Th17 cells in murine and human crescentic GN, and suggest the kidney-specific action of these Treg17 cells is regulated by CCR6-directed migration into areas of Th17 inflammation., (Copyright © 2014 by the American Society of Nephrology.)

IL-10-secreting regulatory B cells have been postulated as negative mediators of inflammation. However, their impact on immune-mediated diseases requires further investigation. We recently found that IL-10-secreting B cells infiltrate the kidney during crescentic glomerulonephritis (GN). We therefore studied the function of B-cell-derived IL-10 in light of the potential risks associated with increasingly used B-cell depleting therapies. Lack of IL-10 production by B cells, however, did not influence acute or adaptively mediated progressive renal injury in terms of renal function and histological damage in the nephrotoxic nephritis model of GN. Renal leukocyte infiltration and cytokine expression were similar apart from increased macrophages in mice lacking B-cell-derived IL-10. Systemic immune responses as assessed by cytokine production, leukocyte composition, proliferation, and activation were indistinguishable, while production and renal deposition of Ag-specific IgG were mildly impaired in the absence of B-cell-produced IL-10. Importantly, detailed analysis of systemic and renal regulatory T cells did not show any differences between nephritic mice bearing IL-10-deficient B cells and WT controls. Finally, studies in reporter mice revealed that B cells are only a minor source of systemic IL-10. In summary, our data reveal that endogenous B-cell-derived IL-10 does not play a major role in the nephrotoxic nephritis model of crescentic GN., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)