New means to assess neonatal inflammatory brain injury

Preterm infants are especially vulnerable to infection-induced white matter injury, associated with cerebral palsy, cognitive and psychomotor impairment, and other adverse neurological outcomes. The etiology of such lesions is complex and multifactorial. Furthermore, timing and length of exposure to infection also influence neurodevelopmental outcomes. Different mechanisms have been posited to mediate the observed brain injury including microglial activation followed by subsequent release of pro-inflammatory species, glutamate-induced excitotoxicity, and vulnerability of developing oligodendrocytes to cerebral insults. The prevalence of such neurological impairments requires an urgent need for early detection and effective neuroprotective strategies. Accordingly, noninvasive methods of monitoring disease progression and therapy effectiveness are essential. While diagnostic tools using biomarkers from bodily fluids may provide useful information regarding potential risks of developing neurological diseases, the use of magnetic resonance imaging/spectroscopy has emerged as a promising candidate for such purpose. Various pharmacological agents have demonstrated protective effects in the immature brain in animal models; however, few studies have progressed to clinical trials with promising results

Environmental factors and disturbances of brain development

Foetal and neonatal brain is under the influence of environmental factors from maternal and extra-maternal origin. Based on the available data, these environmental factors can be classified into three arbitrary groups: (i) factors and maternal status with a demonstrated deleterious effect on the foetal brain (i.e. ethanol, cocaine, some drugs including anticonvulsants, some viral infections, maternal diabetes, untreated maternal phenylketonuria); (ii) factors highly suspected to interfere with foetal brain development (i.e. lead and other heavy metals, some drugs like benzodiazepines, nicotine); (iii) factors which have been shown to be safe for the developing brain in the available studies (i.e. low to moderate doses of caffeine, methadone). However, most of these studies do not address the potential risk of environmental factors on minimal to moderate cognitive and behavioural disturbances. Finally, the impact of the neonatal environment on brain development in very pre-term infants is probably underestimated

[Pneumonia due to adenovirus type 7: a case report in a healthy infant].

International audienceA 15-month-old boy treated with amoxicillin and clavulanic acid therapy for 8 days was admitted for persistent gastroenteritis and fever. He received ceftriaxone for pneumonia modified on day 4 for cefotaxime and josamycin due to extension of alveolar lesions. On day 7, persistent fever and worsened respiratory distress led to addition of rifampicin. The child was then admitted to an intensive care unit. A hemophagocytic syndrome was suspected based on clinical signs and laboratory findings and confirmed by cytological examination of bone marrow. Adenovirus type 7 was identified by polymerase chain reaction and culture of bronchoalveolar fluid. Prognosis was good within 3 weeks. B and T immunologic evaluations were normal 5 months after the infection. This case of severe adenovirus pneumonia was associated with hemophagocytic syndrome in a child without identified primary immunodeficiency. Adenovirus type 3 and 7 are most frequently responsible for severe or fatal respiratory infections

Mast cells are essential intermediaries in regulatory T-cell tolerance

Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4(+)CD25(+)Foxp3(+) regulatory T (T-Reg)-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T-Reg cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9 - a mast cell growth and activation factor - are produced by activated T-Reg cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T-Reg cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T-Reg - IL-9-mast cell relationship within tolerant allografts

Melatonin Reduces Inflammation and Cell Death in White Matter in the Mid-Gestation Fetal Sheep Following Umbilical Cord Occlusion

The premature infant is at increased risk of cerebral white matter injury. Melatonin is neuroprotective in adult models of focal cerebral ischemia and attenuates ibotenate-induced white matter cysts in neonatal mice. Clinically, melatonin has been used to treat sleep disorders in children without major side effects. The aim of this study was to investigate the protective and anti-inflammatory effects of melatonin in the immature brain following intrauterine asphyxia. Fetal sheep at 90 d of gestation were subjected to umbilical cord occlusion. Melatonin (20 mg/kg, n = 9) or vehicle (n = 10) was administered IV to the fetus, starting 10 min after the start of reperfusion and continued for 6 h. Melatonin treatment resulted in a slower recovery of fetal blood pressure following umbilical cord occlusion, but without changes in fetal heart rate, acid base status or mortality. The production of 8-isoprostanes following umbilical cord occlusion was attenuated and there was a reduction in the number of activated microglia cells and TUNEL-positive cells in melatonin treated fetuses, suggesting a protective effect of melatonin. In conclusion, this study shows that melatonin attenuates cell death in the fetal brain in association with a reduced inflammatory response in the blood and the brain following intrauterine asphyxia in mid-gestation fetal sheep

IL-9/IL-9 receptor signaling selectively protects cortical neurons against developmental apoptosis.

In mammals, programmed cell death (PCD) is a central event during brain development. Trophic factors have been shown to prevent PCD in postmitotic neurons. Similarly, cytokines have neurotrophic effects involving regulation of neuronal survival. Nevertheless, neuronal PCD is only partially understood and host determinants are incompletely defined. The present study provides evidence that the cytokine interleukin-9 (IL-9) and its receptor specifically control PCD of neurons in the murine newborn neocortex. IL-9 antiapoptotic action appeared to be time-restricted to early postnatal stages as both ligand and receptor transcripts were mostly expressed in neocortex between postnatal days 0 and 10. This period corresponds to the physiological peak of apoptosis for postmitotic neurons in mouse neocortex. In vivo studies showed that IL-9/IL-9 receptor pathway inhibits apoptosis in the newborn neocortex. Furthermore, in vitro studies demonstrated that IL-9 and its receptor are mainly expressed in neurons. IL-9 effects were mediated by the activation of the JAK/STAT (janus kinase/signal transducer and activator of transcription) pathway, whereas nuclear factor-kappaB (NF-kappaB) or Erk pathways were not involved in mediating IL-9-induced inhibition of cell death. Finally, IL-9 reduced the expression of the mitochondrial pro-apoptotic factor Bax whereas Bcl-2 level was not significantly affected. Together, these data suggest that IL-9/IL-9 receptor signaling pathway represents a novel endogenous antiapoptotic mechanism for cortical neurons by controlling JAK/STAT and Bax levels