The immediate or innate immune response is the first line of defense against diverse microbial pathogens and requires the expression of recently discovered toll-like receptors (TLRs). TLR4 serves as a specific receptor for lipopolysaccharide (LPS) and is localized on the surface of a subset of mammalian cells. Although innate immunity is a necessary host defense against microbial pathogens, the consequences of its activation in the CNS can be deleterious, as we show here in a developing neural model. We examined the major non-neuronal cell types in the CNS for expression of TLR4 and found that microglia expressed high levels, whereas astrocytes and oligodendrocytes expressed none. Consistent with TLR4 expression solely in microglia, we show that microglia are the only CNS glial cells that bind fluorescently tagged lipopolysaccharide. Lipopolysaccharide led to extensive oligodendrocyte death in culture only under conditions in which microglia were present. To determine whether TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte death in mixed glial cultures, we studied cultures generated from mice bearing a loss-of-function mutation in the tlr4 gene. Lipopolysaccharide failed to induce oligodendrocyte death in such cultures, in contrast to the death induced in cultures from wild-type mice. Finally, stereotactic intracerebral injection of lipopolysaccharide into the developing pericallosal white matter of immature rodents resulted in loss of oligodendrocytes and hypomyelination and periventricular cysts. Our data provide a general mechanistic link between (1) lipopolysaccharide and similar microbial molecular motifs and (2) injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis.
In this report we examine the biological and molecular basis of the control of sympathetic neuron differentiation and survival by NGF and neurotrophin-3 (NT-3). NT-3 is as efficient as NGF in mediating neuritogenesis and expression of growth-associated genes in NGF-dependent sympathetic neurons, but it is 20–40fold less efficient in supporting their survival. Both NT-3 and NGF induce similar sustained, long-term activation of TrkA, while NGF is 10-fold more efficient than NT-3 in mediating acute, short-term TrkA activity. At similar acute levels of TrkA activation, NT-3 still mediates neuronal survival two- to threefold less well than NGF. However, a mutant NT-3 that activates TrkC, but not TrkA, is unable to support sympathetic neuron survival or neuritogenesis, indicating that NT3–mediated TrkA activation is necessary for both of these responses. On the basis of these data, we suggest that NGF and NT-3 differentially regulate the TrkA receptor both with regard to activation time course and downstream targets, leading to selective regulation of neuritogenesis and survival. Such differential responsiveness to two ligands acting through the same Trk receptor has important implications for neurotrophin function throughout the nervous system.
We have asked whether p75 NTR may play a role in neuronal apoptosis by producing transgenic mice that express the p75 NTR intracellular domain within peripheral and central neurons. These animals showed profound reductions in numbers of sympathetic and peripheral sensory neurons as well as cell loss in the neocortex, where there is normally little or no p75 NTR expression. Developmental loss of facial motor neurons was not observed, but induced expression of the p75 NTR intracellular domain within adult animals led to increased motor neuron death after axotomy. Biochemical analyses suggest that these effects were not attributable to a p75 NTR -dependent reduction in trk activation but instead indicate that the p75 NTR intracellular domain may act as a constitutive activator of signaling cascades that regulate apoptosis in both peripheral and central neurons.
Oligodendrocytes (OLs) are the primary targets in the autoimmune disease multiple sclerosis (MS). Cell receptors belonging to the tumor necrosis factor receptor (TNF-R) superfamily, such as TNF receptors and fas, are implicated in signaling the injury response of OLs. The p75 neurotrophin receptor (p75(NTR)), another member of the TNF-R superfamily, has been reported to mediate nerve growth factor (NGF)-induced apoptosis in some neural systems. To address the potential relationship between p75(NTR) signaling and OL injury, we assayed adult human OLs cultured under several different conditions for p75(NTR) and tyrosine kinase receptor trkA expression, for NGF-mediated apoptosis, and for NGF-mediated jun kinase (JNK) or nuclear factor (NF) kappaB activation. In the current study, we have found expression of p75(NTR) on cultured adult CNS-derived human OLs but not on other glial cells. TrkA was not detected on these OLs in any of the culture conditions tested. Treatment of the OLs with varying concentrations of NGF over a range of time periods resulted in no significant increase in numbers of terminal transferase (TdT)-mediated d-uridine triphosphate (UTP)-biotin nick-end labeling positive OLs, whereas significant cell death was observed using TNF-alpha. Furthermore, unlike TNF-alpha treatment, NGF treatment did not significantly activate JNK, although both TNF-alpha and NGF induced nuclear translocation of NF-kappaB. These findings contrast with the recent report of NGF-mediated apoptosis in the OLs of neonatal rats matured in vitro, which express p75(NTR) but not trkA (), and suggest that, at least in humans, p75(NTR) signaling may mediate responses other than apoptosis of OLs.
OBJECTIVE: To assess whether the videolaryngoscope (VL) is superior to the classic laryngoscope (CL) in acquiring skill in neonatal endotracheal intubation (ETI) and, once acquired with the VL, whether the skill is transferable to the CL. METHODS:This randomized controlled trial, in a level 3 Canadian hospital, recruited junior pediatric residents who performed ETI in the NICU. The primary outcome was success rate of ETI. Secondary outcomes were time to successful intubation, number of bradycardia episodes andlowest oxygen saturation during procedure, occurrence of mucosal trauma, reason for ETI failure, and recognition of problems related to ETI bysupervisor andresident. RESULTS:In phase 1, 34 pediatric residents performed 213 ETIs by using either VL or CL. Intervention groups were comparable at baseline. The success rate was higher (75.2% vs 63.4%, P = .03), and time to successful intubation was longer, inVL group (57 vs 47 seconds, P = .008). In phase 2, 23 residents performed 55 ETIs using CL. The success rate of residents inVL group performing ETI by using the CL was 63% (compared with 75% in phase 1, P = .16). CONCLUSIONS:When learning ETI, the success rate is improved with the VL. Time to successful intubation is longer, but the difference is not clinically significant. When switched to the CL, residents' success rate slightly decreased, but not significantly. This suggests that residents retain a certain level of ETI skill when switched to the CL. The VL is a promising tool for teaching neonatal ETI.
Objective To determine if the discrete myocardial diastolic dysfunction documented previously in the recipient twin during the early stages of twin-twin transfusion syndrome (TTTS) has any repercussion on flow velocities through the ductus venosus (DV) and to investigate if this could allow early differentiation between TTTS and selective intrauterine growth restriction (IUGR). Methods
The p75 neurotrophin receptor (p75NTR) has been linked to activation of the NF-B transcriptional complex in oligodendrocytes, Schwann cells, and PCNA cells. In this report, tumor necrosis factor (TNF)-and neurotrophin-mediated NF (nuclear factor)-B activation were compared in several cell lines. All cell types showed TNF-mediated activation of NF-B, but direct neurotrophin-dependent activation of NF-B was never observed under normal growth conditions. In PCNA cells, a modest nerve growth factor (NGF)-dependent induction of NF-B was detected but only after cells were subjected to severe stress. Although NGF binding did not directly activate NF-B under normal conditions, NGF consistently altered TNF-dependent NF-B activation in each cell type examined, and extended exposure to NGF and TNF always increased NF-B activation over that achieved with TNF alone. The increase in NF-B activity mediated by NGF correlated with reduced levels of IB␣; NGF added alone had no effect on IB␣ levels, but when added with TNF, NGF treatment significantly reduced IB␣ levels. We propose that modulation of cytokine receptor signaling is a significant physiological function of the p75 neurotrophin receptor and that previous reports of direct NF-B activation through p75NTR reflect this modulatory activity.
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