Microdeletion 1p35.2: a recognizable facial phenotype with developmental delay.

We describe two patients with microdeletion 1p35.2, intrauterine growth retardation, small stature, hypermetropia, hearing impairment and developmental delay. Both patients have long, myopathic facies, with fine eyebrows, small mouths and micrognathia. We postulate a role for the histone deacetylase HDAC1 in the facial phenotype and suggest that deletion of KPNA6 may prevent transmission of the 1p35.2 deletion from affected girls to any offspring through impaired zygotic genome activation.

Selective modulation of monocyte and neutrophil responses with activated protein C in preterm infants.

BACKGROUND: Inflammation is associated with many disorders of preterm infants including periventricular leukomalacia, chronic lung disease, and necrotizing enterocolitis. Activated protein c (APC) has shown positive immunomodulatory effects. OBJECTIVES: We aimed to study neutrophil and monocyte function in response to lipopolysaccharide (LPS) and APC stimulation ex vivo in preterm infants <32 weeks gestation over the first week of life compared to neonatal and adult controls. METHODS: Peripheral blood was taken on day 1, 3, and 7 and stimulated with LPS in the absence or presence of APC. Expression of toll-like receptor 4 (TLR4) and CD11b and reactive oxygen intermediate (ROI) release from neutrophils and monocytes was examined by flow cytometry. RESULTS: LPS induced neutrophil ROI in adults and preterm infants and was significantly reduced by APC. Baseline and LPS-induced monocyte ROI production in preterm neonates was increased compared to adult and term controls. Neutrophil TLR4 baseline expression was higher in term controls compared to preterm infants. CONCLUSION: Increased systemic ROI release in preterm infants may mediate tissue damage, ROI was reduced by APC. However, due to the high risk of hemorrhage further examination of APC mutant forms with anti-inflammatory but decreased anticoagulant properties is merited.

Protein C Pathway in Paediatric and Neonatal Sepsis.

Protein C plays a major role in the physiological regulation of coagulation pathways through inactivation of factor Va, factor VIIIa, and plasminogen activator inhibitor. Protein C is involved in the control of inflammation during sepsis, by inhibiting release of pro-inflammatory cytokines, thereby controlling neutrophil, and monocyte effects on injured tissue. Recombinant human activated protein C (rhAPC) reduced mortality in adult sepsis in earlier studies but had no significant benefit in more recent trials. Protein C levels are reduced during paediatric and neonatal sepsis, which may play a major role in the development of disseminated intravascular thrombosis, purpura fulminans, and multiorgan dysfunction. The role of protein C in paediatric sepsis requires further clinical and immunological evaluation to define the patient subgroups who may benefit from this therapy. Newer versions of rhAPC are under development with less risk of haemorrhage potentially broadening the scope of this intervention.

Emerging Role of the NLRP3 Inflammasome and Interleukin-1ß in Neonates.

Infection and persistent inflammation have a prominent role in the pathogenesis of brain injury and cerebral palsy, as well as other conditions associated with prematurity such as bronchopulmonary dysplasia. The NLRP3 inflammasome-interleukin (IL)-1ß pathway has been extensively studied in adults and pre-clinical models, improving our understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders. IL-1 blockade has transformed the course and outcome of conditions such as chronic infantile neurological, cutaneous, articular (CINCA/NOMID) syndrome. Inflammasome activation and upregulation has recently been implicated in neonatal brain and lung inflammatory disease and may be a novel therapeutic target.