Sex differences in the regulation of brain IL-1ß in response to chronic stress.

Elevations in brain interleukin-1 beta (IL-1ß) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1ß production during times of stress are glucocorticoids and catecholamines. These hormones work in opposition to one another to inhibit (via glucocorticoid receptors) or stimulate (via beta-adrenergic receptors: ß-AR) IL-1ß production. While chronic stress often heightens both corticosterone and catecholamine levels, it remains unknown as to how chronic stress may affect the "yin-yang" balance between adrenergic stimulation and glucocorticoid suppression of brain IL-1ß. To investigate this further, male and female rats underwent 4 days of stress exposure or served as non-stressed controls. On day 5, animals were administered propranolol (ß-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1ß mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1ß expression in non-stressed controls but significantly reduced IL-1ß in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1ß in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1ß mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1ß in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1ß indicating the increase in brain IL-1ß following metyrapone treatment was due to increase ß-AR activation. Additional studies revealed that metyrapone significantly increases norepinephrine turnover in the hypothalamus and medial prefrontal cortex in male rats and that microglia appear to be the cell type contributing to the production of IL-1ß. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1ß by the norepinephrine-ß-AR pathway, while stress had no effect in the regulation of brain IL-1ß in female rats.

Ribosomal stress and Tp53-mediated neuronal apoptosis in response to capsid protein of the Zika virus.

We report here that in rat and human neuroprogenitor cells as well as rat embryonic cortical neurons Zika virus (ZIKV) infection leads to ribosomal stress that is characterized by structural disruption of the nucleolus. The anti-nucleolar effects were most pronounced in postmitotic neurons. Moreover, in the latter system, nucleolar presence of ZIKV capsid protein (ZIKV-C) was associated with ribosomal stress and apoptosis. Deletion of 22 C-terminal residues of ZIKV-C prevented nucleolar localization, ribosomal stress and apoptosis. Consistent with a casual relationship between ZIKV-C-induced ribosomal stress and apoptosis, ZIKV-C-overexpressing neurons were protected by loss-of-function manipulations targeting the ribosomal stress effector Tp53 or knockdown of the ribosomal stress mediator RPL11. Finally, capsid protein of Dengue virus, but not West Nile virus, induced ribosomal stress and apoptosis. Thus, anti-nucleolar and pro-apoptotic effects of protein C are flavivirus-species specific. In the case of ZIKV, capsid protein-mediated ribosomal stress may contribute to neuronal death, neurodevelopmental disruption and microcephaly.

Cost-effectiveness of antiplatelet therapy to prolong primary patency of hemodialysis graft.

INTRODUCTION: The Dialysis Access Consortium (DAC) study group previously reported that treatment with extended-release dipyridamole plus aspirin (DASA) resulted in a significant but clinically modest improvement in primary unassisted arteriovenous graft (AVG) patency. Utilizing DAC published data, the objective of this study is to evaluate the cost effectiveness of antiplatelet interventions aimed at preventing loss of primary AVG patency in hemodialysis (HD) patients. METHODS: We performed a cost-utility analysis, using a decision analysis tree model with a 12-month time horizon and a third party payer perspective. Interventions included DASA with and without concurrent aspirin, aspirin alone, and no prophylaxis. The modeled population was defined as adult (≥ 18 years of age) end-stage renal disease (ESRD) patients who had undergone placement of a new AVG in the United States. The outcomes were costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratios, and net monetary benefit. Probabilities were based upon published studies performed by the DAC Study Group while costs of medications and procedures were drawn from public sources. Utilities of health states were derived from published reports and the Short Form 6D (SF-6D) instrument. RESULTS: Aspirin alone is the most cost effective strategy for AVG pharmacologic prophylaxis, as compared to no prophylaxis or DASA with or without concurrent aspirin. The results are robust on multiple scenario analyses using both deterministic and Monte Carlo probabilistic sensitivity analyses. Accounting for both costs and QALY, using aspirin alone to prevent AVG thrombosis can potentially reduce healthcare costs by $24,679,412 per year compared to no aspirin use, at a willingness-to-pay of $50,000/ QALY. CONCLUSIONS: Aspirin monotherapy compared favorably to other strategies based on cost per QALY. Our findings support the use of aspirin prophylaxis in HD patients with a new AVG who do not have a contraindication to aspirin.