Background: Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiplebreath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. Objectives: To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco-abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. Methods: Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. Results: Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume ) than boys (mean (95% CI girls-boys): -1.2 (-2.1 to 20.3) for FEV 0.5 Z score; FEF 25-75 : -1.2 (-2.2 to 20.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. Conclusions: These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.

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The generation and homeostasis of bone tissue throughout development and maturity is controlled by the carefully balanced processes of bone formation and resorption. Disruption of this balance can give rise to a broad range of skeletal pathologies. Lethal osteosclerotic bone dysplasia (or, Raine syndrome) is an autosomal recessive disorder characterized by generalized osteosclerosis with periosteal bone formation and a distinctive facial phenotype. Affected individuals survive only days or weeks. We have identified and defined a chromosome 7 uniparental isodisomy and a 7p telomeric microdeletion in an affected subject. The extent of the deleted region at the 7p telomere was established by genotyping microsatellite markers across the telomeric region. The region is delimited by marker D7S2563 and contains five transcriptional units. Sequence analysis of FAM20C, located within the deleted region, in six additional affected subjects revealed four homozygous mutations and two compound heterozygotes. The identified mutations include four nonsynonymous base changes, all affecting evolutionarily conserved residues, and four splice-site changes that are predicted to have a detrimental effect on splicing. FAM20C is a member of the FAM20 family of secreted proteins, and its mouse orthologue (DMP4) has demonstrated calcium-binding properties; we also show by in situ hybridization its expression profile in mineralizing tissues during development. This study defines the causative role of FAM20C in this lethal osteosclerotic disorder and its crucial role in normal bone development.

Delayed cord clamping of 45 s is feasible and safe in preterm infants below 33 weeks of gestation. It is possible to perform the procedure at caesarean section deliveries and it should be performed whenever possible. It reduces the need for packed red cell transfusions during the first 6 weeks of life.

Background: Previous studies have suggested that preterm birth with or without subsequent chronic lung disease is associated with reduced functional residual capacity (FRC) and increased ventilation inhomogeneity in the neonatal period. We aimed to establish whether such findings are associated with the degree of prematurity, neonatal respiratory illness and disproportionate somatic growth. Methods: Multiple breath washout measurements using an ultrasonic flowmeter were obtained from 219 infants on 306 test occasions during the first few months of life, at three neonatal units in the UK and Australia. Tests were performed during unsedated sleep in clinically stable infants (assigned to four exclusive diagnostic categories: term controls, preterm controls, respiratory distress syndrome and chronic lung disease). The determinants of neonatal lung function were assessed using multivariable, multilevel modelling. Results: After adjustment for age and body proportions, the factors gestation, intrauterine growth restriction and days of supplemental oxygen were all significantly associated with a reduced FRC. In contrast, increased ventilation inhomogeneity (elevated lung clearance index) was only significantly associated with duration of supplemental oxygen. After adjusting for continuous variables, diagnostic category made no further contribution to the models. Despite using identical techniques, unexpected inter-centre differences occurred, associated with the equipment used; these did not alter the negative association of preterm delivery and disease severity with lung function outcomes. Conclusion: Reduction in FRC is independently associated with prematurity, intrauterine growth restriction and severity of neonatal lung disease. Determinants of lung function shortly after birth are highly complex in different disease groups.Abnormal lung development in preterm infants caused by intrauterine and early postnatal factors 1 is characterised by impaired alveolarisation and dysmorphic vasculogenesis.2 These features are the pathological hallmarks of chronic lung disease of infancy (CLD, frequently referred to as bronchopulmonary dysplasia). Despite increasing survival of extremely preterm infants, the incidence of CLD remains high.3 While infants are generally categorised as having CLD or not based on the need for mechanical ventilation and/or supplemental oxygen (O 2 ) at 36 weeks postmenstrual age (PMA), the reality is that a continuum of disease severity is observed. [4][5][6][7] Accurate and non-invasive bedside techniques that evaluate the functional consequences of these structural changes are urgently required. Measurements of lung volume are relevant for assessing lung growth and development and for interpreting volume dependent lung function parameters. Functional residual capacity (FRC), the resting lung volume at end expiration, is the only ''static'' lung volume that can be readily assessed in non-cooperative infants and very young children. As summarised recently, 9 FRC is initially low in CLD but...

Dependence on published equations for interpreting FEFV data in infants may lead to misinterpretation of lung function status, which could impact adversely both in the research setting and on clinical management. Use of a contemporary control group or establishment of equipment-specific reference data is essential for meaningful interpretation of infant lung function data.

During the last 30 years, there has been an unexplained trend toward declining values for plethysmographic assessments of lung volume at functional residual capacity (FRC) in infants. The aim of this study was to compare data collected from healthy infants using contemporary equipment with published reference data and to explore reasons for discrepancies. Lung volumes were measured in 32 healthy infants (age, 4-93 weeks; weight, 3.9-12.4 kg) using a new, commercially available infant plethysmograph. Mean (SD) FRC was 19.6 (3.4) ml/kg (within subject coefficient of variation 3.4 [2.3%]), which was on average 7.0 [3.5] ml/kg and 2.3 [1.2] SD (Z) scores lower than the recently collated reference data from an American Thoracic Society task force. A total of 66% of these healthy infants had a FRC that was below the predicted normal range. Comparison of equipment, software, and protocols with those from previous reports revealed the importance of minimization of dead space and of adequate subtraction of all compressible occluded volume when calculating FRC in infants. These findings emphasize the need to establish reference data for lung function tests in infants that are appropriate for the equipment and protocols in current use.

Summary. This is the second paper in a review series that will summarize available data and discuss the potential role of lung function testing in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses the expansive subject of measurements of lung volume using plethysmography and gas dilution/ washout techniques. Following orientation of the reader to the subject area, we focus our comments on areas of inquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically, and recommendations are provided to guide future investigation in this field. Measurements of lung volume are important both for assessing growth and development of lungs in health and disease, and for interpreting volume-dependent lung function parameters such as respiratory compliance, resistance, forced expiratory flows, and indices of gas-mixing efficiency. Acute neonatal lung disease is characterized by severely reduced functional residual capacity (FRC), with treatments aimed at securing optimal lung recruitment. While FRC may remain reduced in established chronic lung disease of infancy, more commonly it becomes normalized or even elevated due to hyperinflation, with or without gas-trapping, secondary to airway obstruction. Ideally, accurate and reliable bedside measurements of FRC would be feasible from birth, throughout all phases of postnatal care (including assisted ventilation), and during subsequent long-term follow-up. Although lung volume measurements in extremely preterm infants were described in a research environment, resolution of several issues is required before such investigations can be translated into routine clinical monitoring. Pediatr