Randomised controlled trial of nebulised gentamicin in children with bronchiectasis.

AIM: Following trials of inhaled antibiotics in adults, this study investigates the efficacy of nebulised gentamicin to improve respiratory function in children with bronchiectasis. METHODS: This is a randomised, double-blind, placebo-controlled, crossover trial of 12-week nebulised placebo/gentamicin, 6-week washout, 12-week gentamicin/placebo. Participants were children (5-15 years) with bronchiectasis, chronic infection (any pathogen), and able to perform spirometry from a hospital bronchiectasis clinic. Primary outcomes were change in forced expiratory volume in 1 s (FEV1 ) and hospitalisation days. Secondary outcomes included sputum bacterial density, sputum inflammatory markers, additional antibiotics and symptom severity. Analyses were on an intention-to-treat basis. RESULTS: Fifteen children (mean 11.7-years-old) completed the study. There was no significant change in mean FEV1 (56%/55%, P = 0.38) or annual rate of hospital admissions (1.1/0, P = 0.12) between gentamicin and placebo, respectively. However, Haemophilus influenzae sputum growth (27% vs. 80%, P = 0.002) and bacterial density (2.4 log10 cfu/mL lower P < 0.001) improved with gentamicin. Sputum inflammatory markers interleukin-1ß (P < 0.001), interleukin-8 (P < 0.001) and tumour necrosis factor-α (P = 0.003) were lower with gentamicin. Poor recruitment limited study power and treatment adherence was challenging for this cohort. CONCLUSIONS: In this crossover study of nebulised gentamicin in children with bronchiectasis, there was a reduction in sputum bacterial density and inflammation. However, there were no major improvements in clinical outcomes and adherence was a challenge.

Associations between neonatal hypoglycaemia and brain volumes, cortical thickness and white matter microstructure in mid-childhood: An MRI study.

Neonatal hypoglycaemia is a common metabolic disorder that may cause brain damage, most visible in parieto-occipital regions on MRI in the acute phase. However, the long term effects of neonatal hypoglycaemia on the brain are not well understood. We investigated the association between neonatal hypoglycaemia and brain volumes, cortical thickness and white matter microstructure at 9-10 years. Children born at risk of neonatal hypoglycaemia at ≥ 36 weeks' gestation who took part in a prospective cohort study underwent brain MRI at 9-10 years. Neonatal hypoglycaemia was defined as at least one hypoglycaemic episode (at least one consecutive blood glucose concentration < 2.6 mmol/L) or interstitial episode (at least 10 min of interstitial glucose concentrations < 2.6 mmol/L). Brain volumes and cortical thickness were computed using Freesurfer. White matter microstructure was assessed using tract-based spatial statistics. Children who had (n = 75) and had not (n = 26) experienced neonatal hypoglycaemia had similar combined parietal and occipital lobe volumes and no differences in white matter microstructure at nine years of age. However, those who had experienced neonatal hypoglycaemia had smaller caudate volumes (mean difference: -557 mm3, 95% confidence interval (CI), -933 to -182, p = 0.004) and smaller thalamus (-0.03%, 95%CI, -0.06 to 0.00; p = 0.05) and subcortical grey matter (-0.10%, 95%CI -0.20 to 0.00, p = 0.05) volumes as percentage of total brain volume, and thinner occipital lobe cortex (-0.05 mm, 95%CI -0.10 to 0.00, p = 0.05) than those who had not. The finding of smaller caudate volumes after neonatal hypoglycaemia was consistent across analyses of pre-specified severity groups, clinically detected hypoglycaemic episodes, and severity and frequency of hypoglycaemic events. Neonatal hypoglycaemia is associated with smaller deep grey matter brain regions and thinner occipital lobe cortex but not altered white matter microstructure in mid-childhood.

Could automated analysis of chest X-rays detect early bronchiectasis in children?

Non-cystic fibrosis bronchiectasis is increasingly described in the paediatric population. While diagnosis is by high-resolution chest computed tomography (CT), chest X-rays (CXRs) remain a first-line investigation. CXRs are currently insensitive in their detection of bronchiectasis. We aim to determine if quantitative digital analysis allows CT features of bronchiectasis to be detected in contemporaneously taken CXRs. Regions of radiologically (A) normal, (B) severe bronchiectasis, (C) mild airway dilation and (D) other parenchymal abnormalities were identified in CT and mapped to corresponding CXR. An artificial neural network (ANN) algorithm was used to characterise regions of classes A, B, C and D. The algorithm was then tested in 13 subjects and compared to CT scan features. Structural changes in CT were reflected in CXR, including mild airway dilation. The areas under the receiver operator curve for ANN feature detection were 0.74 (class A), 0.71 (class B), 0.76 (class C) and 0.86 (class D). CXR analysis identified CT measures of abnormality with a better correlation than standard radiological scoring at the 99% confidence level.Conclusion: Regional abnormalities can be detected by digital analysis of CXR, which may provide a low-cost and readily available tool to indicate the need for diagnostic CT and for ongoing disease monitoring. What is Known: • Bronchiectasis is a severe chronic respiratory disorder increasingly recognised in paediatric populations. • Diagnostic computed tomography imaging is often requested only after several chest X-ray investigations. What is New: • We show that a digital analysis of chest X-ray could provide more accurate identification of bronchiectasis features.

Prospective community programme versus parent-driven care to prevent respiratory morbidity in children following hospitalisation with severe bronchiolitis or pneumonia.

BACKGROUND: Hospitalisation with severe lower respiratory tract infection (LRTI) in early childhood is associated with ongoing respiratory symptoms and possible later development of bronchiectasis. We aimed to reduce this intermediate respiratory morbidity with a community intervention programme at time of discharge. METHODS: This randomised, controlled, single-blind trial enrolled children aged <2 years hospitalised for severe LRTI to 'intervention' or 'control'. Intervention was three monthly community clinics treating wet cough with prolonged antibiotics referring non-responders. All other health issues were addressed, and health resilience behaviours were encouraged, with referrals for housing or smoking concerns. Controls followed the usual pathway of parent-initiated healthcare access. After 24 months, all children were assessed by a paediatrician blinded to randomisation for primary outcomes of wet cough, abnormal examination (crackles or clubbing) or chest X-ray Brasfield score ≤22. FINDINGS: 400 children (203 intervention, 197 control) were enrolled in 2011-2012; mean age 6.9 months, 230 boys, 87% Maori/Pasifika ethnicity and 83% from the most deprived quintile. Final assessment of 321/400 (80.3%) showed no differences in presence of wet cough (33.9% intervention, 36.5% controls, relative risk (RR) 0.93, 95% CI 0.69 to 1.25), abnormal examination (21.7% intervention, 23.9% controls, RR 0.92, 95% CI 0.61 to 1.38) or Brasfield score ≤22 (32.4% intervention, 37.9% control, RR 0.85, 95% CI 0.63 to 1.17). Twelve (all intervention) were diagnosed with bronchiectasis within this timeframe. INTERPRETATION: We have identified children at high risk of ongoing respiratory disease following hospital admission with severe LRTI in whom this intervention programme did not change outcomes over 2 years. TRIAL REGISTRATION NUMBER: ACTRN12610001095055.

IL-14 and IL-16 are expressed in the thyroid of patients with either Graves' disease or Hashimoto's thyroiditis.

OBJECTIVES: Cytokines have an important role in orchestrating the pathophysiology in autoimmune thyroid disease. The aim of the current study was to analyse the expression of interleukin (IL)-14 and IL-16 in the thyroid tissue of patients with Graves' disease (GD), Hashimoto's thyroiditis (HT) or multinodular goitre (MNG) and in that of normal individuals, in patients' intrathyroidal CD4(+) and CD8(+) T cells, and in patient and normal cultured thyroid follicular cells. METHODS: The expression of IL-14 and IL-16 mRNA and protein was investigated using reverse transcription-polymerase chain reaction (RT-PCR) amplification, and Western blotting and ELISAs, respectively. RESULTS: IL-14 mRNA expression was detected in thyroid tissue from 8/9 GD, 3/4 HT and 3/13 MNG patients and 1/6 normal individuals, and IL-16 mRNA expression in thyroid tissue from 9/9 GD, 4/4 HT and 9/13 MNG patients and 4/6 normal individuals. IL-14 mRNA expression was detected in intrathyroidal CD4(+) and CD8(+) T cells from 2/2 GD and 2/2 HT patients, while IL-16 mRNA was detected in samples from 1/2 HT patients but not in those from either patient with GD. IL-14 and IL-16 mRNA expression was found in thyroid follicular cells derived from 2/2 patient with GD and 1/1 normal individual. IL-14 protein was detected in thyroid tissue from 6/6 GD, 1/1 HT and 0/6 MNG patients and 0/6 normal individuals, and IL-16 protein in thyroid tissue from 6/6 GD, 1/1 HT and 1/6 MNG patients and 0/6 normal individuals. Expression of IL-14 protein was stimulated in thyroid follicular cells derived from two patients with GD and one normal individual by peripheral blood mononuclear cell (PBMC)-conditioned medium. Treatment of thyrocytes from two patients with GD and one normal individual with PBMC-conditioned medium and tumour necrosis factor (TNF)-α stimulated IL-16 protein expression. In normal thyrocytes, IL-16 protein synthesis was induced also by IL-1ß, IL-17A, IL-4 and transforming growth factor (TGF)-ß. CONCLUSIONS: The data provide evidence that the intrathyroidal production of IL-14 and IL-16 is associated with the pathogenesis of autoimmune thyroid disease. Thyroid follicular cells display the ability to express IL-14 and IL-16 mRNA and can be stimulated to express IL-16 protein, by a panel of cytokines, and IL-14 protein, by as yet unidentified factors.

Radiographic skeletal survey for non-accidental injury: systematic review and development of a national New Zealand protocol.

INTRODUCTION: Clinically occult fractures from non-accidental injury (NAI) are best detected on radiographic skeletal survey. However, there are regional variations regarding the views included in such surveys. We undertook a systematic review of the evidence supporting skeletal survey protocols to design a protocol that could be implemented across New Zealand. METHODS: In June 2013, we searched Medline, Google Scholar, the Cochrane database, UpToDate and relevant reference lists for English-language publications on skeletal survey in NAI from 1946. We included publications that contained a protocol or reported evidence supporting including, or excluding, specific views in a skeletal survey. All included publications were critically appraised. Based on this systematic review, a draft protocol was developed and presented to an Australian and New Zealand Society for Paediatric Radiology NAI symposium in October 2013. Feedback from the symposium and later discussions was incorporated into the final protocol. RESULTS: We identified 2 guidelines for skeletal survey, 13 other protocols and 15 articles providing evidence for inclusion of specific images in a skeletal survey. The guidelines scored poorly on critical appraisal of several aspects of their methods. We found no studies that validate any of the protocols or compare their performance. Evidence supporting inclusion in a skeletal survey is limited to ribs, spine, pelvis, hands and feet, and long bone views. Our final protocol is a standardised, two-tiered protocol consisting of between 17 and 22 views. CONCLUSION: A standardised protocol for radiographic skeletal survey protocol has been developed in New Zealand. We present it here for consideration by others.

Ultrasound in pediatric peripheral nerve injuries: can this affect our surgical decision making? A preliminary report.

BACKGROUND: The treatment of closed fractures with associated peripheral nerve palsy is controversial. Traditionally, the nerve palsy is managed with watchful waiting and subsequent neurophysiological studies if no improvement is seen within 4 months. This may not be necessary if nerve integrity can be imaged acutely with ultrasound scan. We present a case series of pediatric patients with closed upper limb injuries and associated peripheral nerve palsy who underwent ultrasound scanning to assess nerve integrity. METHODS: A retrospective review of patients attending Starship Children's Hospital between May 2008 and April 2010 with closed upper limb injuries and associated peripheral nerve palsy was undertaken. Those patients up to and including the age of 14 years (skeletally immature) with complete clinical records available were included. RESULTS: Complete clinical records were available for 24 patients who fit the inclusion criteria for the period of May 2008 to April 2010. Fifteen patients were managed expectantly and showed signs of spontaneous nerve recovery at a mean of 4 weeks. One patient proceeded to theater for early exploration where an intact but kinked nerve was found. Eight patients underwent ultrasound examination of their nerves; on the basis of the ultrasound findings, 3 proceeded to theater for nerve repair or neurolysis and 5 were managed expectantly with first signs of nerve recovery seen at a mean of 12 weeks for the surgical group, and 13.2 weeks for the nonsurgical group. CONCLUSIONS: Ultrasound examination of peripheral nerves provides pathomorphologic information that can aid our clinical decision-making process and identify those patients who would benefit from early surgical intervention. In our case series, ultrasound findings correlated with intraoperative findings and clinical recovery. LEVEL OF EVIDENCE: Level III evidence retrospective comparative study.

Screw placement after pinning of slipped capital femoral epiphysis: a postoperative CT scan study.

BACKGROUND: Unrecognized pin penetration in the treatment of slipped capital femoral epiphysis has serious long-term sequelae. The purpose of this study was to use postoperative computerized tomographic (CT) scans to determine the true position of the screw tip when compared with standard radiograph views. METHODS: Twenty-four patients with 33 slipped capital femoral epiphyses were included in the study. Intraoperative or postoperative radiographs [anteroposterior (AP) and frog lateral] were compared with postoperative CT scans (coronal and axial) to determine (1) distance of the screw tip from the subchondral bone of the femoral head, (2) the number of screw threads across the physis, and (3) the 3-dimensional placement of the screw tip in the femoral head. RESULTS: The positions of 38 screws in 33 hips were assessed. Screw position within specific quadrants of the femoral head was more anterior and superior than appreciated on radiographs. AP radiographs overestimated the distance between the screw tip and the subchondral bone, the average distance being 5.5 mm on AP radiographs and 3.4 mm on coronal CT (P<0.0001). Bland-Altman analysis confirmed 95% limits of agreement of -5.6 to 1.5 mm, indicating that screws could be up to 5.6 mm closer to the subchondral bone than estimated by the AP radiograph. Closer agreement was found between the frog lateral radiograph and the axial CT views, with the distance from the subchondral bone averaging 4.7 mm on frog lateral radiographs and 4.1 mm on axial CT (P<0.01). Bland-Altman analysis showed 95% limits of agreement between the 2 measures of -3.5 to 2.3 mm, suggesting that some screws were up to 3.5 mm closer to the subchondral bone. Three more anteriorly placed screws seemed to penetrate subchondral bone on CT, findings not shown on standard radiographs. CONCLUSIONS: Frog lateral radiographs of the hip provide a more accurate estimation of screw placement than AP radiographs. Screws closer than 4 mm to the subchondral bone on frog lateral radiographs or 6 mm on AP radiographs may penetrate subchondral bone.

Function-blocking autoantibodies to the melanin-concentrating hormone receptor in vitiligo patients.

Vitiligo is a common depigmenting skin disorder resulting from the loss of melanocytes in the cutaneous epidermis. Although the cause of the disease remains obscure, autoimmune mechanisms are thought to be involved. Recently, melanin-concentrating hormone receptor (MCHR)-binding autoantibodies have been identified in vitiligo patients. In the present study, we aimed to determine if MCHR autoantibodies could also affect receptor function either by direct activation or by blocking its response to melanin-concentrating hormone. The results indicated that 10/18 (56%) vitiligo patient IgG samples inhibited the function of MCHR expressed in a Chinese hamster ovary cell line. In contrast, neither control (n=20) nor SLE patient (n=10) IgG samples blocked receptor function. Compared with healthy controls, MCHR function-blocking autoantibodies were found at a significantly increased frequency in the vitiligo patient group (P=0.0004). No MCHR-activating autoantibodies were detected in any of the vitiligo patient, SLE patient or control IgG samples that were analysed. In addition, vitiligo patient IgGs were tested for MCHR autoantibodies that could mediate antibody-dependent cell-mediated cytotoxicity via the receptor. However, this could only be demonstrated in two vitiligo patient sera. Overall, this work has provided additional evidence that MCHR is a B-cell autoantigen in vitiligo and has demonstrated the existence of MCHR function-blocking autoantibodies further to the receptor-binding autoantibodies previously reported.

Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease.

Experimental evidence from animal models has provided a framework for our current understanding of autoimmune disease pathogenesis and supports the importance of genetic predisposition, molecular mimicry, and immune dysregulation. However, only recently has evidence emerged to support the role of immune dysregulation in human organ-specific autoimmune disease. In the current study of the "late" manifestation of autoimmune thyroid disease (AITD) in a cohort of human immunodeficiency virus (HIV)-positive patients following highly active antiretroviral therapy (HAART), we discuss how immune dysregulation and factors associated with the immunopathology of HIV infection fit the current understanding of autoimmunity and provide a plausible basis for our clinical observations. De novo diagnoses of thyroid disease were identified between 1996 and 2002 in 7 HIV treatment centers (5/7 centers completed the study). Patients were diagnosed as clinical case entities and not discovered through thyroid function test screening. Paired plasma specimens were used to demonstrate sequential rise in thyroid antibodies. Seventeen patients were diagnosed with AITD (median age, 38 yr; 65% were of black African or black Caribbean ethnicity; and 82% were female). The median duration of immune reconstitution was 17 months. Graves disease (GD) was diagnosed in 15 of 17 patients. One patient developed hashithyrotoxicosis with atypically raised C-reactive protein, and another developed hypothyroidism. One GD patient had associated secondary hypoadrenalism. The estimated combined prevalence of GD for 4 treatment centers for female patients was 7/234 and for males was 2/1289. The denominator numbers were matched controls, from 4 centers able to provide data, who commenced HAART during the same time (January 1996 to July 2002) and who did not develop clinical AITD. The mean baseline pre-HAART CD4 count was 67 cells/mL, and the mean increase from nadir to AITD presentation was 355 cells/mL. AITD patients were more likely than controls (95% confidence interval, chi-square test) to be severely compromised at baseline (as defined by a CD4 count < 200 cells/mL or the presence of an acquired immunodeficiency syndrome [AIDS]-defining diagnosis), and to experience greater CD4 increments following HAART. AITD may be a late manifestation of immune reconstitution in HIV-positive patients taking HAART, and immune dysregulation may be an important factor.

Detection and localization of chemokine gene expression in autoimmune thyroid disease.

OBJECTIVE: Autoimmune thyroid disease (Hashimoto's thyroiditis and Graves' disease) is characterized by lymphocytic infiltration of the thyroid gland. Chemokines are cytokines with chemoattractant properties for a range of immune effector cells and might therefore play a significant role in the initiation and maintenance of the autoimmune process. The aim of this study was to analyse chemokine gene expression in autoimmune thyroid tissue and in cultured thyroid follicular cells (TFC). DESIGN AND PATIENTS: Immunocytochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR) amplification were used to analyse the expression of monocyte chemoattractant protein (MCP)-1, RANTES (regulated upon activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, interferon (IFN)-gamma-inducible protein (IP)-10 and monokine induced by IFN-gamma (Mig) in thyroid tissue from patients with Hashimoto's thyroiditis (n = 4), Graves' disease (n = 6) and nonautoimmune multinodular goitre (n = 4). Chemokine gene expression was also examined in cultured TFC by RT-PCR. RESULTS: Expression of MCP-1, RANTES, MIP-1 alpha, MIP-1 beta, IP-10 and Mig was demonstrated in all Hashimoto's and most Graves' thyroid specimens but very little expression was detected in the nonautoimmune goitre samples. In thyroid tissue from Graves' disease patients, positive staining for chemokines was largely restricted to the lymphocytic cell infiltrate. Within thyroid tissue from Hashimoto's patients, there was evidence for the expression of all chemokines by thyroid follicular cells, suggesting a role for local chemokine synthesis by the glandular epithelial cells in the recruitment of inflammatory cells into the gland in autoimmunity. The present work also showed that expression all the chemokine genes analysed could be induced in cultured thyroid cells by IFN-gamma and interleukin (IL)-1 alpha. Expression of all the chemokines examined was not stimulated by TSH. CONCLUSION: We postulate that TFC may play a role in the pathogenesis of autoimmune thyroid disease as they are able to express the chemokines MIP-1 alpha, MIP-1 beta, MCP-1, RANTES, IP-10 and Mig that would promote the infiltration of immune cells into the thyroid gland.

Demonstration of immunoglobulin G, A, and E autoantibodies to the human thyrotropin receptor using flow cytometry.

Human TSH receptor (TSHR) autoantibodies with biological activity result in thyroid dysfunction, but antibodies that simply bind do not. We have applied flow cytometry to the measurements of IgG, IgA, and IgE immunoreactivity to the TSHR in patients with Graves' disease (GD) and thyroid eye disease (TED) and in normal controls. CHO cells stably expressing the extracellular domain of the TSHR with a glycophosphatidylinositol anchor were produced and found to express approximately 4 times as many receptors, but of similar affinity, as JP09 in TSH binding studies. Substantial increases in median fluorescence and peak channel fluorescence were obtained by flow cytometry using TSHR monoclonal antibodies on the glycophosphatidylinositol cells. IgG autoantibodies were demonstrated in 55 of 65 untreated GD patients, 3 of 25 normal subjects, and 4 of 8 atypical TED sera (negative for TSHR autoantibodies with biological activity) by flow cytometry and correlated poorly with thyroid-stimulating antibodies. IgA antibodies were present in 1 of 12 normal, 1 of 7 treated GD with TED, and 3 of 8 atypical TED sera. IgE binding was observed in 1 of 12 normal, 2 of 8 treated GD without TED, 1 of 6 treated GD with TED, and 0 of 8 atypical TED sera. In conclusion, we have demonstrated autoantibodies that bind directly to the TSHR in the majority of GD patients and in 50% of patients with atypical TED and a small number of normal controls lacking TSHR antibodies that affect function. Although predominantly IgG lambda, TSHR autoantibodies of the IgA and IgE isotypes are also detectable.

Mutations of the PDS gene, encoding pendrin, are associated with protein mislocalization and loss of iodide efflux: implications for thyroid dysfunction in Pendred syndrome.

Pendred syndrome (PDS) is an autosomal recessive disorder characterized by deafness and goiter. Phenotypic heterogeneity is observed in affected individuals, and thyroid dysfunction is particularly variable. The syndrome is caused by mutations in the PDS (SLC26A4) gene, encoding an anion transporter pendrin, which localizes to the apical membrane of thyroid follicular cells. PDS is thought to enable efflux iodide into the follicle lumen. More than 50 diseases causing mutations of PDS have been reported. Here we have investigated the effect of nine PDS missense mutations on pendrin localization and iodide transport with the view to understanding their functional impact. As demonstrated by transient expression of green fluorescent protein-tagged pendrin mutant constructs in mammalian cell lines, appropriate trafficking to the plasma membrane was observed for only two mutants. The remaining PDS mutants appear to be retained within the endoplasmic reticulum following transfection. Iodide efflux assays were performed using human embryonic kidney 293 cells transfected with mutant pendrin and cotransfected with sodium iodide transporter to provide a mechanism of iodide uptake. The results indicated loss of pendrin iodide transport for all mislocalizing mutations. However, PDS mutants are associated with variable thyroid dysfunction in affected subjects. We concluded that additional genetic and/or environmental factors influence the thyroid activity in Pendred syndrome.