Altered inflammasome activation in neonatal encephalopathy persists in childhood.

Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1ß, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)- and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1ß and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1ß gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention.

Primary External Ventricular Drains in the Management of Open Myelomeningocele Repairs in the Neonatal Setting in Ireland

Aim The aim of this study is to outline the role of primary external ventricular drains (EVD) in the management of open myelomeningoceles in the neonatal setting in Ireland. Methods Retrospective cohort study involving all infants who underwent open myelomeningocele repair in a teritary centre in Ireland between January 2009 and April 2016. Medical charts and laboratory data was reviewed on all infants meeting the inclusion criteria. Results One hundred and forty-three neonates underwent open myelomeningocele repair in the 6.5 year period. EVD were inserted at the time of primary wound closure in 19 cases (13%). EVD were used to aid in wound closure and as a primary method of cerebrospinal fluid (CSF) diversion. They remained in place for a median of 8 days, ranging from 1-22 days. All EVD, apart from one, in our series were replaced by a ventricular-peritoneal (VP) shunt at some stage. Conclusion EVD were used in 13% of cases of open myelomeningocele repairs from Jan 2009-Apr 2016 as a primary measure to aid in management. Compared to the cohort in whom an EVD was not inserted at the time of surgery, there was a decrease in the rate of infections. However, there was an increased rate of wound dehiscence/leak and a later need for VP shunt insertion.

Four-oil intravenous lipid emulsion effect on plasma fatty acid composition, inflammatory markers and clinical outcomes in acutely ill patients: A randomised control trial (Foil fact).

BACKGROUND AND AIMS: Data in critically ill patients on the effect of intravenous lipid emulsions (LEs), containing omega-3 polyunsaturated fatty acids (PUFAs), in parenteral nutrition (PN) are scarce and conflicting. This study compared the effects of a four-oil LE (30% soybean oil, 30% medium-chain triglycerides, 25% olive oil and 15% fish oil (FO)) (SMOFlipid®) to those of a 100% soybean oil-based LE in critically ill adult intensive care unit (ICU) patients. METHODS: In this double-blind, randomised study, patients (n = 75) predicted to need PN for more than 5 days were randomised to receive either a four-oil LE (Study Group (SG)) or a 100% soybean oil LE (Control Group (CG)). Isocaloric, isonitrogenous PN was administered continuously for 5 days. FO was provided at a dose of 0.09-0.22 g/kg body weight. Measurements included biochemical parameters and sequential organ failure assessment (SOFA) score daily and plasma total phospholipid fatty acids (FAs) and cytokine levels on days 1, 3, 6. Days on mechanical ventilation, length of stay and mortality were also recorded. ANOVA was used to compare response variables between the two groups over the time and Pearson correlation was used to measure relationships between continuous variables. RESULTS: 68 patients completed the study (n = 35 SG, n = 33 CG), with male predominance (66% SG, 56% CG). Average age was 60.8 ± 13.9 years (SG) versus 55.7 ± 14.8 (CG) (p = 0.143). The majority were surgical admissions (85% SG versus 91% CG) followed by medical. Plasma phospholipid oleic acid (p = 0.022) and alpha-linolenic acid (p<0.0005) increased in both groups. In the SG, plasma phospholipid EPA and DHA increased (both p<0.001), whereas the omega-6:omega-3 PUFA (n-6:n-3 PUFA) ratio decreased (p < 0.001). Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin decreased in both treatment groups. Considering only the change from day 1 to day 6 there was a bigger decrease in AST, ALT and bilirubin levels in the SG. Concentrations of TNF-α decreased from day 1 to day 6 in the SG, whereas they increased in the CG, but the change was not statistically significant (p = 0.112). A significant negative correlation was found between EPA provision on day 3 and the SOFA score (r = -0.4047, p = 0.018). Days on mechanical ventilation (1.24 ± 0.83 days in SG versus 0.88 ± 1.63 days in CG, p = 0.385) and ICU LOS (9.5 ± 7.09 days in SG versus 10.7 ± 7.6 days in CG, p = 0.490) were not different between groups. CONCLUSION: PN containing a four-oil LE increased plasma EPA and DHA, decreased n-6:n-3 PUFA ratio, and was safe and well tolerated. The negative relationship between day 3 EPA and SOFA score seems promising, but EPA intake and effects may have been diluted by enteral nutrition which was started in more than half of patients on day 4. There was no significant difference in terms of other biochemical measurements, SOFA score, length of ICU stay and mortality. More research is needed in this patient population, particularly regarding dose, duration and timing of FO and the effects on clinical outcomes.

Persistent systemic monocyte and neutrophil activation in neonatal encephalopathy.

AIM: Circulating immune cell activation is associated with worse outcome in adult and animal models of brain injury. Our aim was to profile the systemic inflammatory response over the first week of life in infants at risk of neonatal encephalopathy and correlate early neutrophil and monocyte endotoxin and activation responses with outcome. METHODS: Prospective observational study in a tertiary referral university hospital including 22 infants requiring resuscitation at birth who had serial (five time points) neutrophil and monocyte CD11b (marker of cell adhesion) (intracellular Reactive oxygen intermediates) ROI (cell activation), and Toll-like receptor (endotoxin recognition) before and after endotoxin stimulation ex vivo compared to neonatal controls. RESULTS: All neonates requiring resuscitation at delivery (n = 122 samples) had higher neutrophil and monocyte CD11b and TLR-4 expressions compared with adults and neonatal controls. Neonates with abnormal neuroimaging and/or severe neonatal encephalopathy had increased CD11b, ROI and TLR-4. Increased PMN TLR-4 expression was associated with increased mortality in infants with neonatal encephalopathy (NE). CONCLUSION: Innate immune dysregulation in the first week of life is associated with severity of outcome in neonatal brain injury in this cohort and may be amenable to immunomodulation.

ICRP publication 121: radiological protection in paediatric diagnostic and interventional radiology.

Paediatric patients have a higher average risk of developing cancer compared with adults receiving the same dose. The longer life expectancy in children allows more time for any harmful effects of radiation to manifest, and developing organs and tissues are more sensitive to the effects of radiation. This publication aims to provide guiding principles of radiological protection for referring clinicians and clinical staff performing diagnostic imaging and interventional procedures for paediatric patients. It begins with a brief description of the basic concepts of radiological protection, followed by the general aspects of radiological protection, including principles of justification and optimisation. Guidelines and suggestions for radiological protection in specific modalities - radiography and fluoroscopy, interventional radiology, and computed tomography - are subsequently covered in depth. The report concludes with a summary and recommendations. The importance of rigorous justification of radiological procedures is emphasised for every procedure involving ionising radiation, and the use of imaging modalities that are non-ionising should always be considered. The basic aim of optimisation of radiological protection is to adjust imaging parameters and institute protective measures such that the required image is obtained with the lowest possible dose of radiation, and that net benefit is maximised to maintain sufficient quality for diagnostic interpretation. Special consideration should be given to the availability of dose reduction measures when purchasing new imaging equipment for paediatric use. One of the unique aspects of paediatric imaging is with regards to the wide range in patient size (and weight), therefore requiring special attention to optimisation and modification of equipment, technique, and imaging parameters. Examples of good radiographic and fluoroscopic technique include attention to patient positioning, field size and adequate collimation, use of protective shielding, optimisation of exposure factors, use of pulsed fluoroscopy, limiting fluoroscopy time, etc. Major paediatric interventional procedures should be performed by experienced paediatric interventional operators, and a second, specific level of training in radiological protection is desirable (in some countries, this is mandatory). For computed tomography, dose reduction should be optimised by the adjustment of scan parameters (such as mA, kVp, and pitch) according to patient weight or age, region scanned, and study indication (e.g. images with greater noise should be accepted if they are of sufficient diagnostic quality). Other strategies include restricting multiphase examination protocols, avoiding overlapping of scan regions, and only scanning the area in question. Up-to-date dose reduction technology such as tube current modulation, organ-based dose modulation, auto kV technology, and iterative reconstruction should be utilised when appropriate. It is anticipated that this publication will assist institutions in encouraging the standardisation of procedures, and that it may help increase awareness and ultimately improve practices for the benefit of patients.

Ultrasonically detectable cerebellar haemorrhage in preterm infants.

OBJECTIVE: To determine the frequency and pattern of cerebellar haemorrhage (CBH) on routine cranial ultrasound (cUS) imaging in infants of ≤32 weeks gestation, and to investigate how extremely preterm infants with CBH differ from those with severe intraventricular haemorrhage (IVH). METHODS: 672 infants of ≤32 weeks gestation were prospectively examined for CBH on serial cUS imaging. In a separate case--control analysis, the clinical features, ultrasound findings and outcome of preterm infants with CBH were compared to those of infants with isolated severe IVH (grade III-IV). RESULTS: Nine cases of CBH were identified among 53 infants with severe IVH. The incidence of CBH in infants of ≤32 weeks gestation was 1.3%. Five infants had bilateral CBH involving both hemispheres, three had unilateral left sided CBH and one had a right hemispheric lesion. Infants with CBH were male, significantly more preterm (24.4 vs 27.0 weeks) and of lower birth weight (692 g vs 979 g). Vaginal births predominated in the CBH group (89% vs 50%). The median time to identification of haemorrhage for both groups was 3 days. Mortality in the CBH group was 100% (9/9) compared to 43% (19/44) in the severe IVH group. CONCLUSIONS: Extensive CBH in preterm infants is rare and devastating. It appears to be confined to very preterm, extremely low birthweight infants and may have a male predominance. The co-existence of severe IVH and extensive CBH on routine cot-side cUS in the early neonatal period is an ominous finding.

Cumulative radiation exposure in children with cystic fibrosis.

This retrospective study calculated the cumulative radiation dose for children with cystic fibrosis (CF) attending a tertiary CF centre. Information on 77 children with a mean age of 9.5 years, a follow up time of 658 person years and 1757 studies including 1485 chest radiographs, 215 abdominal radiographs and 57 computed tomography (CT) scans, of which 51 were thoracic CT scans, were analysed. The average cumulative radiation dose was 6.2 (0.04-25) mSv per CF patient. Cumulative radiation dose increased with increasing age and number of CT scans and was greater in children who presented with meconium ileus. No correlation was identified between cumulative radiation dose and either lung function or patient microbiology cultures. Radiation carries a risk of malignancy and children are particularly susceptible. Every effort must be made to avoid unnecessary radiation exposure in these patients whose life expectancy is increasing.

Congenital diaphragmatic hernia: neonatal outcomes following referral to a paediatric surgical centre.

Congenital diaphragmatic hernia (CDH) is a rare malformation observed in approximately 1 in 3000 live births. Estimates of postnatal survival range from 50 to 70% despite advances in neonatal care. Antenatal diagnosis is associated with termination of pregnancy in 25-50% pregnancy internationally which may not be reflective of the Irish population. We aimed to evaluate the mortality of infants with CDH who survived to admission in a tertiary referral paediatric hospital between 1996 and 2007. The Hospital In-Patient Enquiry system was used to determine the number of neonatal referrals for CDH to OLHSC between 1996 and 2007. Mortality, sex distribution, length of patient stay and the number of cases per year were examined. 141 neonates with CDH were over 12 years with approximately 12 referrals per annum of which 82 (58%) were male and 59 (42%) female. The average length of stay in the hospital was 33 (range 0-364) days. Overall 71% of the patients survived to discharge. In the first epoch (1996-2001) survival was 63% compared with 78% in the later epoch (2002-7). The overall survival for neonates with CDH presenting to OLCHC during the 12 year-period was 71% although this improved to 78% in recent epoch. Further study of associated congenital anomalies, number of terminations of pregnancy, complexity of the diaphragmatic defect and degree of pulmonary hypertension are required to compare this population with other international centres.

RetCam image analysis of optic disc morphology in premature infants and its relation to ischaemic brain injury.

AIMS: To assess optic disc characteristics in premature infants with and without ischaemic brain injury and to evaluate the role of optic disc morphology in dating the injury. METHODS: RetCam fundal images, cranial ultrasounds and magnetic resonance imaging (MRI) of 109 premature infants were analysed. The study cohort was divided into subgroups depending on the presence or absence of periventricular leucomalacia (PVL) and intraventricular haemorrhage (IVH). The control group consisted of infants with normal neuroimaging at term and 2 years of age. Using the image analysis software of the RetCam, optic disc diameter (ODD), optic disc area (ODA), and optic cup area (OCA) were measured at 33-34 weeks gestational age. As serial cranial ultrasonography had been performed, it was possible to date the brain injury in those infants with periventricular white matter (PVWM) damage. RESULTS: Although there was a trend towards reducing ODD, ODA, and OCA with increasing severity of IVH, only the IVH 4 group differed significantly from the controls for these parameters (p = 0.002, p = 0.02, and p = 0.04, respectively). 44.4% of infants with grade 4 IVH had small discs. Only one patient had a large cup in a normal sized disc; this patient had IVH 4. In patients with PVWM damage, the median time of insult was 27 weeks in those with small discs and 28 weeks in those with normal discs. This difference was not significant (p = 0.23). CONCLUSIONS: Premature infants with IVH 4 have an increased incidence of optic nerve hypoplasia. We found no association between disc morphology and timing of brain injury.

Elective Caesarean section is associated with a reduction in developmental dysplasia of the hip in term breech infants.

We wished to establish whether delivery by Caesarean section influenced the incidence of developmental dysplasia of the hip in term breech infants compared with those delivered vaginally. We used maternal charts, singleton term breech presentation, mode of delivery and incidence of developmental dysplasia of the hip for births between January 1997 and October 2002. During the study period 46 089 infants were born. We analysed a total of 941 breech infants of whom 756 were delivered by Caesarean section (515 pre-labour, 241 intrapartum) and 185 vaginally. The incidence of developmental dysplasia of the hip according to the mode of delivery was 19 of 515 (3.69%) following pre-labour Caesarean section, 16 of 241 (6.64%) for intrapartum Caesarean section and 15 of 185 (8.11%) after vaginal delivery. There was a lower incidence of developmental dysplasia of the hip among those infants delivered by elective Caesarean section compared with those delivered vaginally (p < 0.02). These results demonstrate a significantly lower incidence of developmental dysplasia of the hip in term singleton breech births delivered by elective, pre-labour Caesarean section and suggest that labour and delivery influence hip stability in predisposed infants.

Auditing hip ultrasound screening of infants at increased risk of developmental dysplasia of the hip.

BACKGROUND: Clinical examination, while useful, has been shown to be insufficient as the sole screening method in infants. Ultrasound examination at 8 weeks in high risk infants is an integral part of the screening process in some units. AIMS: To show the efficiency of hip sonography in detection of developmental dysplasia of the hips in those without clinically dislocated hips. METHODS: All infants born at the National Maternity Hospital between January 1994 and December 2001 were included. All those with clinically dislocated hips were treated by a Pavlik harness and referred for follow up to a paediatric orthopaedic surgeon. An 8 week hip ultrasound scan was performed for those infants with stable hips on examination but who met the following criteria: (1) a first degree relative with congenital dislocation of hips; (2) breech presentation at birth; and (3) a persistent "click" at birth in an otherwise stable hip. RESULTS: During the period of study a total of 52 893 infants were born in the National Maternity Hospital. Based on the criteria above, 5485 hip ultrasound scans were performed. Of those scanned, 18 (0.33%) were found to have dislocated hips and 153 (2.78%) to have dysplasic hips. The 18 infants with dislocation were treated with Pavlik harness; the remaining 153 were followed up by serial ultrasound examinations but did not require active intervention. CONCLUSIONS: Among the population of infants at increased risk of developmental dysplasia of the hip, the hip screening programme identified 18 cases among 5485 infants; a rate of 3.2 per 1000. Hip sonography is therefore worthwhile.

Alveolar rhabdomyosarcoma presenting with symmetrical bony and renal metastases in infancy.

Alveolar Rhabdomyosarcoma is a small round cell tumour in which may be radiologically and histologically difficult to differentiate from other small round cell tumours such as lymphoma, neuroblastoma and Ewing's tumours. We report a case in infancy of disseminated alveolar rhabdomyosarcoma with symmetrical renal and bony metastases.

Effects of nicotine and stress on startle amplitude and sensory gating depend on rat strain and sex.

We recently reported that 14 days of nicotine administration (12 mg/kg/day) reduced acoustic startle reflex amplitude and impaired prepulse inhibition (PPI) of startle in male and female Long-Evans rats. These findings contrasted with reports of nicotine-induced enhancement of startle and PPI in Sprague-Dawley (a different strain) male rats. The present experiment administered 0, 6, or 12 mg/kg/day nicotine via osmotic minipump for 14 days to 120 Sprague-Dawley rats (male and female) and to 120 Long-Evans rats (male and female) and examined ASR and PPI. Half of the subjects also were stressed by immobilization once each day to examine nicotine-stress interactions. Nicotine enhanced ASR and PPI responses of Sprague-Dawley rats but impaired these responses in Long-Evans rats, regardless of sex. Effects of stress were complex and depended on strain, sex, and drug dose. These findings indicate that effects of nicotine on measures of reactivity (ASR) and sensory gating (PPI) depend on genotype and that nicotine stress interactions depend on genotype, sex, and nicotine dosage.

Ischio-vertebral dysplasia: a distinct entity.

BACKGROUND: Kyphoscoliosis is a complication of some bone dysplasias, including cleidocranial dysplasia. OBJECTIVES: We report a distinct disorder with defective ossification of the ischial rami, severe kyphoscoliosis and normal clavicles. Early recognition of this syndrome allows prevention of complications. MATERIALS AND METHODS: All patient cases (aged 1 day to 33 years) were selected according to the above criteria, with special attention to radiological findings, family history and follow-up (5-30 years). RESULTS: In all eight patients, we observed the following: (a) Severe thoracic scoliosis of early onset and rapid progression, leading to rotatory dislocation. Spinal cord compression occurred in four cases with respiratory problems related to chest deformity. (b) Bilateral and symmetrical incomplete ossification of the ischial rami. (c) Peculiar facies with retrognathia. (d) Normal clavicles. Three patients were from the same family (grandmother, mother and daughter). CONCLUSION: Ischio-vertebral dysplasia seems to represent a true entity, with radiological and genetic findings that make it distinct from cleidocranial dysostosis. The association of kyphoscoliosis and these pelvic abnormalities is specific for this condition. Neurological and respiratory complications can be avoided if the condition is recognised early and early treatment is instituted.

High attenuation gyri CT in postasphyxial encephalopathy.

Two term infants suffering severe asphyxial events were found to have diffusely high attenuation of the cortical gyri on CT scanning within 12 days. The findings are consistent with haemorrhagic necrosis or microcalcification. This feature has rarely been described in the literature. The evolution of the CT appearance, the possible neuropathological findings and the relationship with hypoxic-ischaemic encephalopathy are discussed.

Effects of ddC and AZT on locomotion and acoustic startle. I: Acute effects in female rats.

Several synthetic nucleoside analogues, including AZT(RETROVIR), ddC (HIVID), ddI (VIDEX), and d4T (ZERIT), are currently being used in the treatment of HIV infection. Unfortunately, in clinical use the appearance of severe and sometimes debilitating peripheral neuropathy and pain has been associated with the long-term use of several of these drugs (i.e., ddC, ddI and d4T), although not with AZT. To date, standard pre-clinical animal toxicity studies have failed to reveal any adverse neurologic effects of these compounds. However, previously reported preliminary findings suggest that ddC may alter several neuro-behavioral parameters (including locomotor activity, acoustic startle responding, and aggression) in rats and mice following presentation in the animals' drinking water for 7 days. The current series of experiments examined effects of acutely administered ddC and AZT on spontaneous locomotor activity and acoustic startle responses (with and without pre-pulse) in female Sprague-Dawley rats. Following intragastric administration, ddC reduced locomotion at all but the highest dose, whereas AZT had no significant effect on locomotor activity. Acutely administered ddC had no effect on ASR, whereas AZT increased ASR at the highest stimulus intensity. These data support the use of behavioral testing in the development of the antiviral nucleoside analogues, as behavioral testing may be more effective in identifying the neurologically active agents than is standard toxicity testing.

The echogenic thalamus in hypoxic ischaemic encephalopathy.

This paper reports 16 term infants in whom an echogenic thalamus was identified on cranial ultrasonography. Fourteen of the patients suffered severe birth asphyxia. The prognostic significance of this finding and the underlying pathogenesis is assessed.

Isolated single umbilical artery--the case for routine renal screening.

To determine the incidence of silent renal anomalies in infants with isolated single umbilical artery (SUA), all infants with SUA and without other obvious congenital anomalies, identified over a six year period, were screened using renal ultrasonography. Over 35,000 placentas were examined. An isolated single umbilical artery was identified in 112 (0.32%). Nineteen infants had abnormal renal imaging. Eight of 112 (7.1%) had significant persisting abnormalities. Vesicoureteric reflux was found in five infants (4.5%). It is recommended that renal ultrasonography be performed for all infants with isolated SUA.

Radiographic screening at four months of infants at risk for congenital hip dislocation.

We report on a radiographic screening programme at four months of age for infants who were clinically normal at neonatal examination but were considered to be 'at risk' for congenital dislocation of the hip because of their family history, breech presentation, or a persistent click. From a total population of 13,662 live births over a two-year period, 357 (2.6%) infants at risk were identified. Of these 46 had abnormal radiographs (six subluxations, 40 acetabular dysplasia). In 12 infants treatment resulted in a normal hip; 34 required no treatment but were followed up until their radiographs were normal and walking had begun. Of the 311 infants with normal radiographs, 256 (82%) were examined after 15 months of age; none had any detectable abnormality. We suggest that radiography of the hip at four months is a valuable adjunct to neonatal screening for infants at increased risk of congenital dislocation of the hip.