Summary Cherubism is caused by mutations in SH3BP2. Studies of cherubism mice showed that TNF-α-dependent autoinflammation is a major cause for the disorder, but failed to explain why human cherubism lesions are restricted to jaws and regress after puberty. We demonstrate that the inflammation in cherubism mice is MYD88-dependent and is rescued in the absence of TLR2 and TLR4. However, germ-free cherubism mice also develop inflammation. Mutant macrophages are hyper-responsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) that activate TLRs, resulting in TNF-α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-α production. Finally, SYK depletion in macrophages prevents the inflammation. These data suggest that the presence of a large amount of TLR ligands, presumably oral bacteria and DAMPs during jawbone remodeling, may cause the jaw-specific development of human cherubism lesions. Reduced levels of DAMPs after stabilization of jaw remodeling may contribute to the age-dependent regression.

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BACKGROUND: Near Infrared Spectroscopy (NIRS) combined with the method of partial jugular venous occlusion (JVO) has been introduced to measure cerebral venous saturation (CVSO2) at the bedside. As yet, the method has not been validated in the newborn brain. We aimed to validate the JVO procedure in a newborn lamb model using cerebral venous oxygen saturation in withdrawn superior sagittal sinus blood as the 'gold standard'.METHOD: Seven newborn lambs were anaesthetised and ventilated using 10 -40% inspired oxygen to generate a range of oxygen saturations from normoxia (SPO2 Ͼ 95%) and hypoxia (SPO2 Ͻ 95%). Unilateral JVO was performed by compressing the jugular vein for 20s. NIRS (Hamamatsu NIRO-500) measurements of cerebral oxyhaemoglobin (delta HbO) and total haemoglobin (delta HbT) concentrations were used to calculate CVSO2 (CVSO2 ϭ (delta HbO / delta HbT) x100%). Blood samples drawn from the superior sagittal sinus were analysed for oxgyen saturation (SSSO2; Radiometer Hemoximeter) as the 'gold standard' for comparison with CVSO2.RESULTS: Median (range) SSSO2 was 45.5% (4.3-76.6%). Median (range) CVSO2 measured by NIRS was 49.8% (10.6 -88.5%) with significant correlation between the two measurements (rϭ0.7, pϽ0.0001). The mean difference (SD) between SSSO2 and CVSO2 was 5.1% (13.7%). Median percentage change in cerebral blood volume (CBV, calculated using delta HbT) induced by JVO during hypoxia was significantly less than what was induced during normoxia (14.7% and 23.3% respectively, pϽ0.001). When only occlusions inducing change of CBV Ͼ10% were included, mean difference (SD) betweeen SSSO2 and CVSO2 reduced to 2.7% (9.3%) with further improved correlation (rϭ0.9).CONCLUSION: The accuracy of NIRS with JVO in estimating CVSO2 varies according to the changes in cerebral venous blood volume induced by JVO. This critical aspect of the JVO technique needs to be taken into consideration in developing an accurate measurement in human infants. CEREBRAL OXYGEN DELIVERY AND CONSUMPTION INCREASE WITH POSTNATAL AGE IN PRETERM INFANTS ON INOTROPES RITCHIE CENTRE FOR BABY HEALTH RE-SEARCH, MONASH UNIVERSITY , 2 NEWBORN SERVICES, MONASH MEDICAL CENTRE (AUS-TRIA)BACKGROUND: The effect of inotropic medication on cerebral oxygen metabolism of preterm infants remains unknown. We recently validated the method of Near Infrared Spectroscopy (NIRS) combined with partial jugular venous occlusion to measure cerebral venous saturation (CVSO2) in the newborn lamb brain (separate abstract). Using NIRS, we studied normotensive infants (NT) and infants who were on inotropes (INO, dopamine) for hypotension, and compared their cerebral oxygen delivery (CDO2) and consumption (CMRO2) in the first few days of life.METHOD: Nineteen infants in the NT group and ten infants in the INO group, born at median (range) gestational age of 26 (24 -30) weeks, were studied at median (range) postnatal age (PNA) of 17 (2.4 -77) hours. Using NIRS (Hamamatsu NIRO-500), cerebral blood flow (CBF) and CVSO2 were measured to compute CDO2 (CDO2 ϭ CBF x cereb...