Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system

<p>Abstract</p> <p>Background</p> <p>Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with a number of severe and prevalent neurodevelopmental disorders, including autism spectrum disorder, schizophrenia and Down syndrome. Although several studies have shown that cytokines have potent effects on neural function, their role in neural development is still poorly understood. In this study, we investigated the link between abnormal cytokine levels and neural development using the <it>Xenopus laevis </it>tadpole visual system, a model frequently used to examine the anatomical and functional development of neural circuits.</p> <p>Results</p> <p>Using a test for a visually guided behavior that requires normal visual system development, we examined the long-term effects of prolonged developmental exposure to three pro-inflammatory cytokines with known neural functions: interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. We found that all cytokines affected the development of normal visually guided behavior. Neuroanatomical imaging of the visual projection showed that none of the cytokines caused any gross abnormalities in the anatomical organization of this projection, suggesting that they may be acting at the level of neuronal microcircuits. We further tested the effects of TNF-α on the electrophysiological properties of the retinotectal circuit and found that long-term developmental exposure to TNF-α resulted in enhanced spontaneous excitatory synaptic transmission in tectal neurons, increased AMPA/NMDA ratios of retinotectal synapses, and a decrease in the number of immature synapses containing only NMDA receptors, consistent with premature maturation and stabilization of these synapses. Local interconnectivity within the tectum also appeared to remain widespread, as shown by increased recurrent polysynaptic activity, and was similar to what is seen in more immature, less refined tectal circuits. TNF-α treatment also enhanced the overall growth of tectal cell dendrites. Finally, we found that TNF-α-reared tadpoles had increased susceptibility to pentylenetetrazol-induced seizures.</p> <p>Conclusions</p> <p>Taken together our data are consistent with a model in which TNF-α causes premature stabilization of developing synapses within the tectum, therefore preventing normal refinement and synapse elimination that occurs during development, leading to increased local connectivity and epilepsy. This experimental model also provides an integrative approach to understanding the effects of cytokines on the development of neural circuits and may provide novel insights into the etiology underlying some neurodevelopmental disorders.</p

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n = 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m2/day (n = 5) or 14 g/m2/day (n = 55) on days −6 to −4, and Flu (30 mg/m2/day) on days −6 to −2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <<1um, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term "secular" dimming, which may be caused by independent processes, or probe different regimes of a single process

Development of Multisensory Convergence in the Xenopus Optic Tectum

The adult Xenopus optic tectum receives and integrates visual and nonvisual sensory information. Nonvisual inputs include mechanosensory inputs from the lateral line, auditory, somatosensory, and vestibular systems. While much is known about the development of visual inputs in this species, almost nothing is known about the development of mechanosensory inputs to the tectum. In this study, we investigated mechanosensory inputs to the tectum during critical developmental stages (stages 42–49) in which the retinotectal map is being established. Tract-tracing studies using lipophilic dyes revealed a large projection between the hindbrain and the tectum as early as stage 42; this projection carries information from the Vth, VIIth, and VIIIth nerves. By directly stimulating hindbrain and visual inputs using an isolated whole-brain preparation, we found that all tectal cells studied received both visual and hindbrain input during these early developmental stages. Pharmacological data indicated that the hindbrain-tectal projection is glutamatergic and that there are no direct inhibitory hindbrain-tectal ascending projections. We found that unlike visual inputs, hindbrain inputs do not show a decrease in paired-pulse facilitation over this developmental period. Interestingly, over this developmental period, hindbrain inputs show a transient increase followed by a significant decrease in the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA)/N-methyl-d-aspartate (NMDA) ratio and show no change in quantal size, both in contrast to visual inputs. Our data support a model by which fibers are added to the hindbrain-tectal projection across development. Nascent fibers form new synapses with tectal neurons and primarily activate NMDA receptors. At a time when retinal ganglion cells and their tectal synapses mature, hindbrain-tectal synapses are still undergoing a period of rapid synaptogenesis. This study supports the idea that immature tectal cells receive converging visual and mechanosensory information and indicates that the Xenopus tectum might be an ideal preparation to study the early development of potential multisensory interactions at the cellular level