Early Inflammation Dysregulates Neuronal Circuit Formation In Vivo via Upregulation of IL-1β

Neuroimmune interaction during development is strongly implicated in the pathogenesis of neurodevelopmental disorders, but the mechanisms that cause neuronal circuit dysregulation are not well understood. We performed in vivo imaging of the developing retinotectal system in the larval zebrafish to characterize the effects of immune system activation on refinement of an archetypal sensory processing circuit. Acute inflammatory insult induced hyperdynamic remodeling of developing retinal axons in larval fish and increased axon arbor elaboration over days. Using calcium imaging in GCaMP6s transgenic fish, we showed that these morphologic changes were accompanied by a shift toward decreased visual acuity in tectal cells. This finding was supported by poorer performance in a visually guided behavioral task. We further found that the pro-inflammatory cytokine, interleukin-1β (IL-1β), is upregulated by the inflammatory insult, and that downregulation of IL-1β abrogated the effects of inflammation on axonal dynamics and growth. Moreover, baseline branching of the retinal ganglion cell arbors in IL-1β morphant animals was significantly different from that in control larvae, and their performance in a predation assay was impaired, indicating a role for this cytokine in normal neuronal development. This work establishes a simple and powerful non-mammalian model of developmental immune activation and demonstrates a role for IL-1β in mediating the pathologic effects of inflammation on neuronal circuit development.SIGNIFICANCE STATEMENT Maternal immune activation can increase the risk of neurodevelopmental disorders in offspring; however, the mechanisms involved are not fully understood. Using a non-mammalian vertebrate model of developmental immune activation, we show that even brief activation of inflammatory pathways has immediate and long-term effects on the arborization of axons, and that these morphologic changes have functional and behavioral consequences. Finally, we show that the pro-inflammatory cytokine IL-1β plays an essential role in both the effects of inflammation on circuit formation and normal axonal development. Our data add to a growing body of evidence supporting epidemiological studies linking immune activation to neurodevelopmental disorders, and help shed light on the molecular and cellular processes that contribute to the etiology of these disorders.     

Bidirectionally adjustable TIPS reduction by parallel stent and stent-graft deployment

Excessive shunting through transjugular intrahepatic portosystemic shunts (TIPS) can cause life-threatening hepatic encephalopathy and insufficiency. Intentional reduction of flow may be effective but difficult to control. The present report describes refinements of the parallel stent/stent-graft technique of flow reduction that is adjustable in either direction. Six patients underwent TIPS reduction with varying stent positioning and a variety of commercial products. Flow was adjusted by iterative balloon dilatation of the stent and stent-graft, resulting in a mean gradient increase of 8 mm Hg. All cases were technically successful, but 1-year survival was seen in only the patient who underwent liver transplantation.     

Effects of formulation variables and post-compression curing on drug release from a new sustained-release matrix material: polyvinylacetate-povidone.

A new commercially available sustained-release matrix material, Kollidon SR, composed of polyvinylacetate and povidone, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound, diphenhydramine HCl. Kollidon SR was found to provide a sustained-release effect for the model compound, with certain formulation and processing variables playing an important role in controlling its release kinetics. Formulation variables affecting the release include the level of the polymeric material in the matrix, excipient level, as well as the nature of the excipients (water soluble vs. water insoluble). Increasing the ratio of a water-insoluble excipient, Emcompress, to Kollidon SR enhanced drug release. The incorporation of a water-soluble excipient, lactose, accelerated its release rate in a more pronounced manner. Stability studies conducted at 40 degrees C/75% RH revealed a slow-down in dissolution rate for the drug-Kollidon SR formulation, as a result of polyvinylacetate relaxation. Further studies demonstrated that a post-compression curing step effectively stabilized the release pattern of formulations containing > or = 47% Kollidon SR. The release mechanism of Kollidon-drug and drug-Kollidon-Emcompress formulations appears to be diffusion controlled, while that of the drug-Kollidon-lactose formulation appears to be controlled predominantly by diffusion along with erosion.     

Long Term Trends and Racial/Ethnic Disparities in the Prevalence of Obesity

Obesity is an epidemic associated with higher rates of hypertension, diabetes, and cardiovascular diseases. However, significant racial disparities in the prevalence of obesity have been reported. To evaluate racial disparities and trends in the prevalence of obesity and obesity-related diseases. A population-based retrospective cohort study utilized data from the 1985 to 2011 California Behavioral Risk Factor Survey. Trends in obesity prevalence were stratified by age, sex, race/ethnicity, and socioeconomic factors. Multivariate logistic regression models evaluated independent predictors of obesity. The prevalence of obesity in significantly increased from 1985 to 2011 (8.6 vs. 22.8 %, p < 0.001). This increase was seen among men and women, and among all race/ethnic, age, and socioeconomic groups. Hypertension and diabetes also increased during this time period (hypertension 20.7–35.9 %; diabetes 4.2–11.2 %). Obesity prevalence was highest in blacks and Hispanics, and lowest in Asians (blacks 33.3 %; Hispanics 28.8 %; Asians 9.0 %; p < 0.001). Obesity prevalence was associated with lower education level, lower income, and unemployment status. After adjustments for age, sex, co morbidities, and surrogates of socioeconomic status, the increased risk of obesity in blacks and Hispanics persisted (blacks OR 1.51; Hispanics OR 1.18), whereas Asians were less likely to be obese (OR 0.37). While the overall prevalence of obesity increased from 1985 to 2011, significant racial/ethnic disparities in obesity have developed, with the highest prevalence seen in blacks and Hispanics, and the lowest seen in Asians.