Penetrating assaults in children: often non-fatal near-miss events with opportunities for prevention in the UK.

INTRODUCTION: Media reports portray a growing problem of gun and stab assaults amongst UK children. Recent legislative changes aim to increase integration between services and protect children better. Child victims of gun or stab assaults are at increased risk of reinjury and are therefore vital targets for interventions shown to be effective at preventing violent injury. There is currently a paucity of data with which to inform public debate, guide policy and develop prevention strategies. We therefore aimed to provide contemporary data on the epidemiology and clinical outcomes for intentional gun and stab injuries in children, using a large UK city as a model environment and also to ascertain whether interventions to prevent violent injury are currently in routine use in a sample of UK urban paediatric EDs. METHODS: A retrospective case series analysis was performed of children (<16 years) attending Emergency Departments (EDs) in a typical major UK city with high levels of deprivation. In addition, we undertook a qualitative survey of a sample of UK urban paediatric EDs regarding their use of violent injury prevention strategies in children. RESULTS: Contrary to media reports and data from London, rates of gun and stab assault remained unchanged through the study (2003-2008). Although tragic fatal injury can occur, the majority of injuries were minor, with most children not requiring admission. Of those admitted, a minority needed surgery (mainly wound debridement and closure). Socioeconomically deprived, adolescent boys appear to be particularly at risk, with attacks at weekends and in public spaces beyond home and school being more common. Interventions to prevent violent reinjury are not currently employed in paediatric EDs in the 15 most populated urban areas of the UK. CONCLUSIONS: Patient safety literature emphasises the need to identify near miss events. Media reports of tragic child deaths due to gunshot and stabbing are actually accompanied by large numbers of minor wounds that we should see as near miss events. Measures shown to reduce reinjury in these high-risk groups could now be pursued in the UK for patient safety and child protection purposes.

Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: a systematic review and meta-analysis.

OBJECTIVES: Intrathoracic liver herniation (ILH) is being used to estimate prognosis and hence guide antenatal interventions in fetal congenital diaphragmatic hernia (CDH). However, the literature regarding its utility in this role is conflicting. This review systematically examines the currently available evidence of ILH use in fetal CDH. METHODS: MEDLINE and EMBASE databases were searched for the terms ((congenital diaphragmatic hernia) OR CDH) AND liver. Inclusion criteria were human case series of fetuses diagnosed with CDH using either ultrasound or magnetic resonance imaging. Included studies were required to have reported the antenatal liver position and the outcome (survival or not). Case reports, reviews and eventration series were excluded. Studies reporting similar cases from the same center over an overlapping time period were considered duplicates; only the larger of the studies were therefore included. Absolute totals were extracted and sums calculated. Fisher's exact test (FET) was used to compare survival rates in different groups. RESULTS: The original search retrieved 338 studies. Applying inclusion/exclusion criteria and removing duplicates left 21 case series in 20 studies. Retrieved studies differed in the definitions of liver herniation, survival and treatment modality. In total, there were 407 fetuses in the liver-up (herniated) and 303 in the liver-down (not herniated) groups. Survival rates were 45.4% and 73.9%, respectively. The difference was statistically significant (FET = 56.4, P < 0.005). Sensitivity analysis for cases that had only conventional postnatal treatment was still significant (FET = 52.8, P < 0.005). CONCLUSIONS: Liver herniation is associated with poorer prognosis in fetal CDH. Grading liver herniation or using it as part of a panel of markers may enhance the value of liver herniation as a prognostic test in fetal CDH.

Airway smooth muscle: an architect of the lung?

This review examines the rationale for increased study of the prenatal development of airway smooth muscle (ASM). With a critical role in asthma and airway remodelling, ASM has been extensively investigated. Nevertheless, there is a paucity of studies looking at prenatal ASM development and function. A working party report from the National Heart Lung and Blood Institute identified this issue and has recommended further investigation. The impetus for this call stems not only from an appreciation that childhood and adulthood disease may have their origins in fetal life, but also because recent studies indicate that prenatal ASM regulates lung development (via its phasic contractility and growth factor production). Moreover, recognition that phasic ASM contractility is the prenatal norm has raised interest in the idea that postnatal reactive airways disease may likewise be a periodic oscillatory phenomenon. Finally, bronchial thermoplasty represents an exciting new therapy for refractory asthma. However, the mechanism for its effects is unclear. Recent studies show that prenatal ASM contractility is governed by a hierarchy of pacemakers within proximal airways. If such a pacemaker arrangement persists postnatally, it is possible that bronchial thermoplasty achieves its distal airway effects via ablation of controlling proximal pacemaker centres. Hence, study of prenatal ASM may allow us not only to develop ways to stimulate prenatal lung growth, but also to understand and develop new therapies for reactive airways disease.

Infantile myofibromatosis of the craniovertebral junction.

Infantile myofibromatosis (IM) is a rare pathological entity characterized by solitary or multiple nodular skin, soft tissues or bony lesions. Craniovertebral (CV) junction lesions are rare. We report the successful management of a solitary IM involving the posterior elements of the CV junction in a 6-month-old child.

Oesophageal atresia with cleft lip and palate: a marker for associated lethal anomalies?

An adverse association between oesophageal atresia (OA) and cleft lip-palate (3% incidence) has been reported. The present study analyses outcomes of this rare association at a UK paediatric surgical centre. Hospital charts of newborns diagnosed with OA were reviewed. Demographics, associated anomalies and prognostic classification (after Spitz 1994) were recorded. Mortality rates and causes of death were examined in OA babies with cleft lip-palate. Of 152 patients treated for OA, five babies (3%) had cleft lip-palate. All of these newborns had common variant OA-TEF and were Spitz group II category. Deaths occurred in 3 of 5 patients (60%) in the OA-cleft group compared to only 8 of 147 patients (5%) without clefts (p < 0.005; Fisher's exact test). OA-cleft non-survivors succumbed to tetralogy of Fallot (n = 2) and trisomy 18 (n = 1; treatment withdrawn). Both survivors with cleft lip-palate had features of the VACTERL sequence: one baby also had Goldenhaar syndrome, the other aortic coarctation. These children now attend mainstream school. Although high-quality survival is possible in OA with cleft lip-palate, this rare phenotype is associated with a substantially decreased survival. Rather than causing death directly, the combination of OA and cleft lip-palate appears to be a marker for further lethal anomalies.

How useful is the lung-to-head ratio in predicting outcome in the fetus with congenital diaphragmatic hernia? A systematic review and meta-analysis.

OBJECTIVE: Fetal surgery to improve lung growth comprises tracheal occlusion in selected 'high-risk' fetuses with congenital diaphragmatic hernia (CDH). Sonographically measured fetal lung-to-head ratio (LHR) is utilized to recruit candidates for fetal surgery. This study provides a meta-analysis of the evidence regarding the prognostic use of lung-to-head ratio measurements in fetal CDH. METHODS: MEDLINE, SCOPUS and ISI PROCEEDINGS databases were searched for MeSH terms: lung, head, hernia and ratio. References in retrieved studies were also searched. Studies were categorized as follows: Phase I studies measured normal fetal LHR; Phase II studies compared fetal LHR in CDH survivors and non-survivors (if LHR informed therapy decisions or LHR was not measured during the window for intervention (< 32 weeks' gestation), studies were excluded); Phase III studies used LHR to guide selection for fetal surgery (non-randomized trials were excluded); Phase IV studies measured CDH survival before and after LHR application in clinical practice. RESULTS: The one Phase I study showed that LHR varied substantially with gestation and technique. No complete studies met the selection criteria for Phase II: meta-analysis of subgroups revealed similar LHR in CDH survivors and non-survivors. A single Phase III study revealed no benefit for LHR-directed fetal surgery. No Phase IV studies were identified. CONCLUSION: The prognostic use of LHR in fetal CDH entered clinical practice prior to publication of robust normal data and is not supported by current evidence. Application of a structured approach to any 'new' prognostic test could improve its validity and clinical application.

Novel 'phage display antibodies identify distinct heparan sulfate domains in developing mammalian lung.

Heparan sulfate proteoglycans (HSPGs) are essential to respiratory morphogenesis in species as diverse as Drosophila and mice; they play a role in the regulation of numerous HS-binding growth factors, e.g. fibroblast growth factors. Moreover, an HS analogue, heparin, modulates lung growth in vitro. However, it has been difficult to assess the roles of specific HS structures in lung development due to technical barriers to their spatial localisation. Lungs from Sprague-Dawley rats were harvested between E15.5 and E19.5 and immediately fixed in 4 % (w/v) paraformaldehyde (in 0.1 M phosphate-buffered saline (PBS), pH 7.4). Lungs were washed in PBS, cryoprotected with 20% (w/v) sucrose (in PBS), gelatin embedded [7.5% (w/v) gelatin, 15% (w/v) sucrose in PBS], before being covered in Cryo-M-Bed (Bright, Huntingdon, UK) and snap frozen at -40 degrees C. Cryosections were cut at 8 microm and stained with the HSPG core protein specific antibody 3G10 and a HS 'phage display antibody, EW4G2V. 3G10 and EW4G2V immunohistochemistry highlighted the presence of specific HS structures in lungs at all gestational ages examined. 3G10 strongly labelled airway basement membranes and the surrounding mesenchyme and showed weak staining of airway epithelial cells. EW4G2V, however, was far more selective, labelling the airway basement membranes only. Mesenchymal and epithelial cells did not appear to possess the HS epitope recognised by EW4G2V at these gestational ages. Novel 'phage display antibodies allow the spatial distribution of tissue HS to be analysed, and demonstrate in situ that distinct cellular compartments of a tissue possess different HS structures, possibly on the same proteoglycan core protein. These probes offer a new opportunity to determine the role of HS in the pathogenesis of congenital defects such as congenital diaphragmatic hernia (CDH), where lung development is aberrant, and the resulting pulmonary hypoplasia and hypertension are a primary cause of mortality.

Peristalsis of airway smooth muscle is developmentally regulated and uncoupled from hypoplastic lung growth.

Prenatal airway smooth muscle (ASM) peristalsis appears coupled to lung growth. Moreover, ASM progenitors produce fibroblast growth factor-10 (FGF-10) for lung morphogenesis. Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia, FGF-10 deficiency, and postnatal ASM dysfunction. We hypothesized ASM dysfunction emerges in tandem with, and may contribute toward, the primordial lung hypoplasia that precedes experimental CDH. Spatial origin and frequency of ASM peristaltic waves were measured in normal and hypoplastic rat lungs cultured from day 13.5 of gestation (lung hypoplasia was generated by nitrofen dosing of pregnant dams). Longitudinal lung growth was assayed by bud counts and tracing photomicrographs of cultures. Coupling of lung growth and peristalsis was tested by stimulation studies using serum, FGF-10, or nicotine and inhibition studies with nifedipine or U0126 (MEK1/2 inhibitor). In normal lung, ASM peristalsis is developmentally regulated: proximal ASM becomes quiescent (while retaining capacity for cholinergic-stimulated peristalsis). However, in hypoplastic lung, spontaneous proximal ASM activity persists. FGF-10 corrects this aberrant ASM activity in tandem with improved growth. Stimulation and inhibition studies showed that, unlike normal lung, changes in growth or peristalsis are not consistently accompanied by parallel modulation of the other. ASM peristalsis undergoes FGF-10-regulated spatiotemporal development coupled to lung growth: this process is disrupted early in lung hypoplasia. ASM dysfunction emerges in tandem with and may therefore contribute toward lung hypoplasia in CDH.

Abnormal lung development precedes oligohydramnios in a transgenic murine model of renal dysgenesis.

PURPOSE: Renal development regulates prenatal lung growth by maintaining fetal urine output and liquor volume. However, shared signaling pathways underpinning renal and lung morphogenesis indicate that lung hypoplasia in the presence of renal dysgenesis may not result from oligohydramnios alone. We used a transgenic model of renal agenesis/anuria to test whether lung hypoplasia precedes any possible influence of oligohydramnios. MATERIALS AND METHODS: E12 lung primordia from normal and gamma1III4 deficient murine embryos (fetal anuria and renal agenesis-dysgenesis) were cultured for 72 hours. Morphological lung development was measured at 24, 48 and 78 hours by bud counting and tracings of lung epithelial contour using image analysis software and photomicrographs. Genotyping was performed by a separate blinded investigator. RESULTS: E12 homozygous mutant lungs branched but had significant decreases in bud count, epithelial area and perimeter compared to heterozygous or WT controls. These changes presented prior to oligohydramnios and persisted in isolation from the developing renal tract throughout the 72-hour culture period. CONCLUSIONS: Lethal lung hypoplasia seen at term in this model is present from the earliest stages of development, persists in vitro and, therefore, it is not consequent on renal dysfunction. These data implies that 1) fetal interventions for severe prenatal uropathies may have variable success for protecting future lung function and 2) patients with fetal uropathies may warrant greater scrutiny of prenatal lung growth and long-term postnatal lung function.

Sex and congenital diaphragmatic hernia.

BACKGROUND AND PURPOSE: Human studies note sex reversal syndromes and sex difference(s) in the incidence of congenital diaphragmatic hernia (CDH). Epidemiology surveys record a higher incidence of CDH in females, whilst other reports cite a higher frequency in males. Nitrofen, a teratogen, produces experimental CDH. This agent is speculated to interfere with retinoid acid-steroid signalling pathways and may also be linked with sexual differentiation. This study was designed therefore to test the hypothesis that nitrofen may influence sexual phenotype and frequency of CDH. METHODS: Time mated Sprague Dawley rats were dosed with nitrofen at day 9.5 to generate predominantly left sided CDH. Fetuses were delivered by caesarean section on days 20 or 21 of gestation (term=day 22). External genitalia were examined to define external genital phenotype. The abdominal cavity was opened and the genito-urinary system carefully examined. The internal genital organs were assigned a phenotype and findings correlated with external appearances. The diaphragm of each fetus was studied for the absence or presence of CDH and the laterality of defect recorded. Controls (non nitrofen fed) were used for all comparative analysis. RESULTS: Control (n=600) and nitrofen exposed offspring (n=504) had equal frequencies of males and females. CDH occurred with similar incidence in male and female nitrofen treated pups. In all nitrofen exposed fetuses and normal controls, internal and external genitalia concorded without evidence of significant genital tract malformations or intersex states. CONCLUSIONS: Prenatal nitrofen exposure is not associated with significant gender differences (or prenatal loss) in the risk of CDH. Genital tract malformations do not appear to accompany CDH in the nitrofen model.

Recent advances in congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a common birth defect which continues to challenge paediatric surgeons and intensivists. Affecting approximately 1:2500 births, a baby with CDH is born every 24-36 hours in the UK.

Emergent embolisation to control severe haematuria in Wilms' tumour.

Wilms' tumour commonly presents with an abdominal mass and gross haematuria. Here, we present the novel application of paediatric renal arterial embolisation to control life-threatening haematuria in Wilms' tumour.

Challenging embryological theories on congenital diaphragmatic hernia: future therapeutic implications for paediatric surgery.

Lung hypoplasia is central to the poor prognosis of babies with congenital diaphragmatic hernia (CDH). Prolapse of abdominal organs through a diaphragmatic defect has traditionally been thought to impair lung growth by compression. The precise developmental biology of CDH remains unresolved. Refractory to fetal correction, lung hypoplasia in CDH may instead originate during embryogenesis and before visceral herniation. Resolving these conflicting hypotheses may lead to reappraisal of current clinical strategies. Genetic studies in murine models and the fruitfly, Drosophila melanogaster are elucidating the control of normal respiratory organogenesis. Branchless and breathless are Drosophila mutants lacking fibroblast growth factor (FGF) and its cognate receptor (FGFR), respectively. Sugarless and sulphateless mutants lack enzymes essential for heparan sulphate (HS) biosynthesis. Phenotypically, all these mutants share abrogated airway branching. Mammalian organ culture and transgenic models confirm the essential interaction of FGFs and HS during airway ramification. Embryonic airway development (branching morphogenesis) occurs in a defined spatiotemporal sequence. Unlike the surgically-created lamb model, the nitrofen rat model permits investigation of embryonic lung growth in CDH. Microdissecting embryonic lung primordia from the nitrofen CDH model and normal controls, we demonstrated that disruption of stereotyped airway branching correlates with and precedes subsequent CDH formation. To examine disturbed branching morphogenesis longitudinally, we characterised a system that preserves lung hypoplasia in organ culture. We tested FGFs and heparin (an HS analogue) as potential therapies on normal and hypoplastic lungs. Observing striking differences in morphological response to FGFs between normal and hypoplastic lung primordia, we postulated abnormalities of FGF/HS signalling in the embryonic CDH lung. Evaluating this hypothesis further, we examined effects of an HS-independent growth factor (epidermal growth factor, EGF) on hypoplastic lung development. Visible differences in morphological response indicate an intrinsic abnormality of hypoplastic lung primordia that may involve shared targets of FGFs and EGE. These studies indicate that lung hypoplasia precedes diaphragmatic hernia and may involve disturbances of mitogenic signalling pathways fundamental to embryonic lung development. What does this imply for human CDH? Fetal surgery may be 'too little, too late' to correct an established lung embryopathy. In utero growth factor therapy may permit antenatal lung rescue. Prevention of the birth defect by preconceptual prophylaxis may represent the ultimate solution.

Does the developing liver inhibit early lung growth in congenital diaphragmatic hernia?

It has been hypothesised that the liver induces lung hypoplasia in congenital diaphragmatic hernia (CDH) by non-compressive intrathoracic growth rather than traditional mass herniation. Utilising a co-culture system, we tested the capacity of liver cells to inhibit lung growth by contact rather than compression. Heart, liver, and lungs were microdissected from normal rat embryos (n > 20 from at least three litters) on day 13.5 of gestation. Monolayer cultures of enzymatically dispersed livers and hearts were established at the same cell density. Lung primordia were cultured in direct contact with hepatic cells or partitioned from them by a permeable polytetrafluoroethylene membrane. This permits the contributions of diffusable factors and cell contact to be distinguished. Lungs were similarly cultured in direct contact with or partitioned from cardiac cells. Lungs cultured in isolation served as further controls. Daily inspection permitted assessment of in-vitro lung growth. Growth of lungs in direct contact with hepatic cells was equivalent to that of lungs partitioned from liver cells. Lungs in direct contact with cardiac cells and lungs partitioned from cardiac cells were also not inhibited compared to lungs cultured in isolation. Early lung development is thus not inhibited by humoral or contact-mediated interactions with embryonic liver cells. Lung hypoplasia in CDH is therefore unlikely to originate from contact inhibition with the developing liver. An intrinsic pulmonary defect may better explain hypoplastic lung development in CDH.

Heparin and in-vitro experimental lung hypoplasia.

Pulmonary hypoplasia (PH) is a leading contributor to the lethality of congenital diaphragmatic hernia (CDH). Studies now suggest that PH arises prior to visceral herniation. Growth factors (GF) are pivotal to this embryonic lung growth. With striking in-vitro effects on lung morphogenesis, GF are under investigation as therapies for PH. Heparin modulates the kinetics of heparan-sulphate binding ligands that drive lung development. We hypothesised that heparin may rescue PH by favourable alteration of endogenous pulmonary GF activity. Normal and hypoplastic lung primordia were microdissected on day 13.5 of gestation and cultured for up to 78 h in plain media with and without heparin. In-vitro morphological development was studied by serial measurements of terminal bud count, lung area, and lung perimeter. Nitrofen-exposed lungs cultured with heparin showed no significant improvements in terminal bud count, lung area, and lung perimeter at 30, 54, and 78 h compared to untreated hypoplastic lungs maintained in vitro. In normal lungs heparin demonstrated no sustained significant morphological effects compared to untreated control lungs. In this study, heparin did not stimulate branching morphogenesis of normal or hypoplastic lungs in our organ culture system. Known at higher concentrations to inhibit smooth-muscle proliferation, heparin may ameliorate pulmonary vascular hypermuscularisation with the prospect of benefiting CDH infants on extracorporeal membrane oxygenation. Future studies will address the impact of exogenous GF on hypoplastic lung development in organ culture.

In vitro effects of growth factors on lung hypoplasia in a model of congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Pulmonary hypoplasia, a leading contributor to the lethality of congenital diaphragmatic hernia (CDH), precedes diaphragmatic malformation in the nitrofen model and persists to allow experimental manipulations in organ culture. Fibroblast growth factors (FGFs) are crucial to early lung development. Acidic FGF (FGF-1) binds to all FGF receptors and enhances in vitro branching morphogenesis. Basic FGF (FGF-2) is localized to developing airway epithelium, basement membrane, and extracellular matrix. Heparin (HEP) modulates FGF kinetics and inhibits smooth muscle proliferation in lung primordia. The aim of this study was to examine the morphological effects of fibroblast growth factors and heparin on lung hypoplasia in an organ culture model. METHODS: Sprague-Dawley rats were fed nitrofen on day 9.5 of pregnancy to induce lung hypoplasia and CDH in newborns. Control rats received olive oil. Normal and hypoplastic lung primordia were microdissected on day 13.5 of gestation and cultured up to 78 hours in plain media with or without FGF-1 or FGF-2, with or without HEP. In vitro morphological development was studied by serial measurements of terminal bud count, lung area, and lung perimeter. RESULTS: Over 120 fetal lung specimens were studied (n > or = 4 per group). Significant increases in area, perimeter, and bud count were seen in normal lungs cultured with FGF-1 plus HEP compared with control media (P < .05). In the nitrofen lungs, FGF1 plus HEP yielded reductions in all parameters compared with those in control media (P < .05), whereas FGF-2 produced significant expansion in lung area but marked reductions in bud count and lung perimeter divided by square root of area (P < .05). Heparin did not produce substantial or sustained alteration of morphology in normal or hypoplastic lungs. CONCLUSIONS: These observations may indicate an intrinsic abnormality of FGF processing in the hypoplastic nitrofen lung before diaphragmatic malformation. Heparin did not rescue abnormal lung development. Mechanisms underlying the differential effects of these agents now need to be explored to target fetal lung growth and improve the dismal prognosis of human CDH.