Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-ß, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.

Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response.

central nervous system (CNS) inflammation triggers activation of the integrated stress response (ISR). We previously reported that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation. However, the exact mechanisms through which this occurs remain unknown. Here, we investigated whether the ISR modulator Sephin1 in combination with the oligodendrocyte differentiation enhancing reagent bazedoxifene (BZA) is able to accelerate remyelination under inflammation, and the underlying mechanisms mediating this pathway. We find that the combined treatment of Sephin1 and BZA is sufficient to accelerate early-stage remyelination in mice with ectopic IFN-γ expression in the CNS. IFN-γ, which is a critical inflammatory cytokine in multiple sclerosis (MS), inhibits oligodendrocyte precursor cell (OPC) differentiation in culture and triggers a mild ISR. Mechanistically, we further show that BZA promotes OPC differentiation in the presence of IFN-γ, while Sephin1 enhances the IFN-γ-induced ISR by reducing protein synthesis and increasing RNA stress granule formation in differentiating oligodendrocytes. Finally, pharmacological suppression of the ISR blocks stress granule formation in vitro and partially lessens the beneficial effect of Sephin1 on disease progression in a mouse model of MS, experimental autoimmune encephalitis (EAE). Overall, our findings uncover distinct mechanisms of action of BZA and Sephin1 on oligodendrocyte lineage cells under inflammatory stress, suggesting that a combination therapy may effectively promote restoring neuronal function in MS patients.

A systematic approach for successful PCSK9 inhibitor prescribing in clinical practice.

BACKGROUND: Despite patient and provider interest, the use of PCSK9i therapy remains limited in clinical practice. High annual listed prices have created intense payer scrutiny and frequent health plan denials, with national approval rates in the range of 30% to 40%. OBJECTIVE: Our goal was to validate the strategies for increasing PCSK9i approval rates and to present a framework for successful PCSK9i prescribing in clinical practice. METHODS: In Sept 2015, a systematic team-based approach was developed and implemented at our institution. The approach centered on a preventive team of 3 senior staff cardiologists, 1 nurse practitioner, 1 physician assistant, 1 care coordinator, 1 pharmacist, and 1 pharmacy technician. The team was responsible for gathering and compiling the required documents to support an approval, as well as collaborating with the in-house pharmacy to complete PA and appeals processes. RESULTS: In the total study population, 141 (71.9%) were approved for PCSK9i therapy at first submission and 55 (28.1%) were rejected. Of those initially rejected, 48 (85.7%) appealed and all 48 who appealed (100.0%) were ultimately approved. The final coverage decision was 189 (96.4%) approved and 7 (3.6%) rejected. CONCLUSION: Our study highlights the presence of modifiable barriers in the PCSK9i approval process. Given the crucial role of health care teams in overcoming these modifiable barriers, we developed a simple stepwise algorithm for navigating the PCSK9i approval process. Our algorithm can help relieve busy providers of heavy administrative burdens and facilitate greater accuracy, standardization, and efficiency in documentation.

Inferior vena cava thrombosis as a cause of haemolysis in a patient on ECMO.

Haemolysis, thrombosis and haemorrhage are well-documented complications of extracorporeal membrane oxygenation. This case report outlines an unusual case of haemolysis, thought secondary to a large mobile thrombus in the inferior vena cava.