The strongest risk factors for BPD are prematurity and low birth weight 19-25. Almost 80% of infants who are born at 22-24 weeks of gestation are diagnosed with BPD 26 , whereas only 20% of infants born at 28 weeks of gestation develop BPD. Among infants with BPD, 95% are VLBW 27. Other perinatal risk factors include intrauterine growth restriction (IUGR) 13 , male sex 13,20,23 and, inconsistently, chorioamnionitis 28 , race or ethnicity 13,20,23 , and smoking 29,30. Genetic risk factors may also contribute to the development of BPD, as indicated by twin studies 31,32 , and there is an ongoing search for genetic markers for BPD 33-37. Early respiratory patterns of premature infants provide insight into risk factors for BPD. An early study suggested that peak inspiratory ventilator pressure and requirement for assisted ventilation on day 4 of life are early predictors of BPD 38. Subsequent studies found that three patterns of lung disease generally emerge in the first 2 weeks of life 39-45 (FIG. 2). In the first pattern, infants have fairly minimal lung disease and progressively recover. In the second pattern, early persistent pulmonary deterioration (EPPD), substantial and prolonged respiratory support is required from birth. In the third pattern, an initial improvement in lung disease in the first week of life is followed by a respiratory decompensation termed pulmonary deterioration, which often requires mechanical ventilation and an increase in supplemental oxygen. Risk factors that may be associated with pulmonary deterioration include late surfactant deficiency 46 , sepsis, increased levels of inflammatory proteins (such as RANTES) 47 and patent ductus arteriosus 40,43. Almost 50% of infants with pulmonary deterioration and almost 70% of infants with EPPD develop BPD 48. The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network developed an online, publicly available risk estimator (https:// neonatal.rti.org/index.cfm) that accurately estimates the risk of developing BPD by postnatal day 49. Investigators identified risk factors for BPD, and the competing outcome of death, among gestational age, birth weight, ethnicity and sex, ventilatory support (ranging from no support (breathing room air without positive airway pressure) to high frequency ventilation) and fraction of inspired oxygen (FiO 2), on postnatal days 1, 3, 7, 14, 21 and 28 in 3,636 infants born at 23-30 weeks of gestation. The BPD prediction tool is internally and externally validated. The models predict the correct level of BPD or the occurrence of death in >80% of cases and have the highest area under the curve (AUC) among current BPD risk predictors 50. This tool is used to provide counselling to families and to quantify risk for determining patient inclusion in early phase therapeutic trials. Interestingly, systemic inflammation occurs early in the neonatal period and precedes clinical symptoms in infants with BPD 51. This finding suggests that a therapeutic window of opportunity exists during the early p...

Definition of the diseaseAtaxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.EpidemiologyThe world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.Clinical descriptionA-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.EtiologyA-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.DiagnosisThe diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.Differential diagnosisThere are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.Antenatal diagnosisAntenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.Genetic counselingGenetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.Management and prognosisTreatment of the neurologic problems associated wit...

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-Type II epithelial cells are essential for lung development and remodeling, as they are precursors for type I cells and can produce vascular mitogens. Although type II cell proliferation takes place after hyperoxia, it is unclear why alveolar remodeling occurs normally in adults whereas it is permanently disrupted in newborns. Using a line of transgenic mice whose type II cells could be identified by their expression of enhanced green fluorescent protein and endogenous expression of surfactant proteins, we investigated the age-dependent effects of hyperoxia on type II cell proliferation and alveolar repair. In adult mice, type II cell proliferation was low during room air and hyperoxia exposure but increased during recovery in room air and then declined to control levels by day 7. Eight weeks later, type II cell number and alveolar compliance were indistinguishable from those in room air controls. In newborn mice, type II cell proliferation markedly increased between birth and postnatal day 7 before declining by postnatal day 14. Exposure to hyperoxia between postnatal days 1 and 4 inhibited type II cell proliferation, which resumed during recovery and was aberrantly elevated on postnatal day 14. Eight weeks later, recovered mice had 70% fewer type II cells and 30% increased lung compliance compared with control animals. Recovered mice also had higher levels of T1␣, a protein expressed by type I cells, with minimal changes detected in genes expressed by vascular cells. These data suggest that perinatal hyperoxia adversely affects alveolar development by disrupting the proper timing of type II cell proliferation and differentiation into type I cells. alveoli; cell proliferation; differentiation; enhanced green fluorescent protein; proliferating cell nuclear antigen THE ALVEOLUS IS COMPOSED OF two epithelial cell types that can be identified by their distinct morphology and expression of unique genes. Type I cells are thin, flat cells that cover pulmonary vascular endothelial cells and comprise 95% of the alveolar surface (56). These cells are important for gas exchange, regulation of alveolar fluid levels, and stretch-induced modulation of surfactant secretion. Type I cells can be identified by their expression of T1␣ (also known as RTI 40 ), aquaporin-5, caveolin-1, or the cyclin-dependent kinase inhibitor p15 (41,42). Type II cells, on the other hand, are large,