Cognitive deficits develop 1month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge.

Traumatic brain injury (TBI) elicits immediate neuroinflammatory events that contribute to acute cognitive, motor, and affective disturbance. Despite resolution of these acute complications, significant neuropsychiatric and cognitive issues can develop and progress after TBI. We and others have provided novel evidence that these complications are potentiated by repeated injuries, immune challenges and stressors. A key component to this may be increased sensitization or priming of glia after TBI. Therefore, our objectives were to determine the degree to which cognitive deterioration occurred after diffuse TBI (moderate midline fluid percussion injury) and ascertain if glial reactivity induced by an acute immune challenge potentiated cognitive decline 30 days post injury (dpi). In post-recovery assessments, hippocampal-dependent learning and memory recall were normal 7 dpi, but anterograde learning was impaired by 30 dpi. Examination of mRNA and morphological profiles of glia 30 dpi indicated a low but persistent level of inflammation with elevated expression of GFAP and IL-1ß in astrocytes and MHCII and IL-1ß in microglia. Moreover, an acute immune challenge 30 dpi robustly interrupted memory consolidation specifically in TBI mice. These deficits were associated with exaggerated microglia-mediated inflammation with amplified (IL-1ß, CCL2, TNFα) and prolonged (TNFα) cytokine/chemokine expression, and a marked reactive morphological profile of microglia in the CA3 of the hippocampus. Collectively, these data indicate that microglia remain sensitized 30 dpi after moderate TBI and a secondary inflammatory challenge elicits robust microglial reactivity that augments cognitive decline. STATEMENT OF SIGNIFICANCE: Traumatic brain injury (TBI) is a major risk factor in development of neuropsychiatric problems long after injury, negatively affecting quality of life. Mounting evidence indicates that inflammatory processes worsen with time after a brain injury and are likely mediated by glia. Here, we show that primed microglia and astrocytes developed in mice 1 month following moderate diffuse TBI, coinciding with cognitive deficits that were not initially evident after injury. Additionally, TBI-induced glial priming may adversely affect the ability of glia to appropriately respond to immune challenges, which occur regularly across the lifespan. Indeed, we show that an acute immune challenge augmented microglial reactivity and cognitive deficits. This idea may provide new avenues of clinical assessments and treatments following TBI.

Zoonosis: Update on Existing and Emerging Vector-Borne Illnesses in the USA.

PURPOSE OF REVIEW: This review describes mosquito- and tick-borne diseases found in the Western Hemisphere. It focuses on emerging diseases and recent geographic shifts in the presence of disease vectors. RECENT FINDINGS: Mosquito and tick vectors have become more widespread as environmental conditions have become more favorable. Zika recently has emerged as a concern for fetal anomalies. West Nile Virus has become widespread. Lyme disease and other tick-borne diseases are more prevalent in areas previously inhospitable to these ticks. SUMMARY: Healthcare providers must consider the possibility of mosquito- and tick-borne diseases in broader geographic areas and council patients traveling to endemic areas on precautions against these diseases. Treatment for suspected cases of serious tick-borne illnesses should not be delayed pending culture results.

Ex vivo stimulation of whole blood as a means to determine glucocorticoid sensitivity.

PURPOSE: Glucocorticoids are commonly prescribed to treat a number of diseases including the majority of inflammatory diseases. Despite considerable interpersonal variability in response to glucocorticoids, an insensitivity rate of about 30%, and the risk of adverse side effects of glucocorticoid therapy, currently no assay is performed to determine sensitivity. PATIENTS AND METHODS: Here we propose a whole blood ex vivo stimulation assay to interrogate known glucocorticoid receptor (GR) up- and downregulated genes to indicate glucocorticoid sensitivity. We have chosen to employ real-time PCR in order to provide a relatively fast and inexpensive assay. RESULTS: We show that the GR-regulated genes, GILZ and FKBP51, are upregulated in whole blood by treatment with dexamethasone and that LPS-induction of cytokines (IL-6 and TNFα) are repressed by dexamethasone in a dose responsive manner. There is considerable interpersonal variability in the maximum induction of these genes but little variation in the EC(50) and IC(50) concentrations. The regulation of the GR-induced genes differs throughout the day whereas the suppression of LPS-induced cytokines is not as sensitive to time of day. CONCLUSION: In all, this assay would provide a method to determine glucocorticoid receptor responsiveness in whole blood.