Outcomes of endovascular thrombectomy for ischaemic stroke among nonagenarians with and without pre-existing dependency.

BACKGROUND: Our aim was to compare the outcomes of treatment with endovascular thrombectomy for pre-stroke dependent versus pre-stroke independent among the very elderly ≥90 years. METHODS: A retrospective cohort study was performed on 106 patients ≥90 years who underwent endovascular thrombectomy for ischaemic stroke in Western Australia between June 2016 and September 2021. Patient, stroke and procedural details along with inpatient progress and outcome at 90 days were recorded. Patients were divided into Group A (pre-stroke modified Rankin Scale 0-2) and Group B (pre-stroke modified Rankin Scale >2). Primary outcome measure was functional status at 90 days post-stroke, with favourable clinical outcome defined as a 90-day mRS category equal to the patients' respective pre-stroke mRS category. Secondary outcome measures include successful reperfusion, symptomatic intracranial haemorrhage, hospital length-of-stay, change in accommodation to an aged care facility, and mortality during admission, at 90 days and one year. RESULTS: 61 patients were allocated to Group A and 45 to Group B. There was none with pre-stroke mRS 5. Group B had more pre-existing cognitive impairment, aged care facility residents, higher median age and lower Alberta Stroke Program Early CT Score. For primary outcome measure, 38 % of patients in Group A and 49 % in Group B achieved a favourable clinical outcome. The difference was not significant (p=0.3408). For secondary outcome measures, Group B had a significantly higher 90-day mortality rate at 47 % versus 24 % in Group A (p=0.03). All other secondary outcome measures were similar between the two groups. These include the rate of successful reperfusion and symptomatic intracranial haemorrhage, hospital length-of-stay, new transition into an aged care facility, inpatient mortality rate and 1-year mortality rate. CONCLUSION: When treated with endovascular thrombectomy for ischaemic stroke, nonagenarians with pre-existing dependency achieved a rate of favourable functional outcome comparable with their independent peers, although they also had higher 90-day mortality rate.

STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production.

Neutrophils are key effector cells of the innate immune system. Calcium-dependent signaling pathways initiated by store-operated calcium entry (SOCE) are known to regulate neutrophil activation; however, the precise mechanism of this process remains unclear. STIM1 and STIM2 are calcium-sensing molecules that link calcium depletion of the endoplasmic reticulum with opening of plasma membrane calcium channels. Although a role for STIM1 in neutrophil SOCE and activation has been established, the function of STIM2 is unknown. Here we use mice with conditional ablation of Stim1 and/or Stim2 to investigate the role of STIM2 in neutrophil activation. We demonstrate that loss of STIM2 results in decreased SOCE, particularly at lower doses of agonists. Reactive oxygen species (ROS) production, degranulation, and phagocytosis are normal in the absence of STIM2, suggesting STIM1 is the dominant calcium sensor required for classical short-term neutrophil responses. However, neutrophil cytokine production required STIM2, but not STIM1, at least in part as a result of redox regulation of cytokine gene expression. In vivo loss of STIM2 results in lower cytokine levels and protection from mortality in a mouse model of systemic inflammatory response syndrome. These data, combined with previous studies focusing on STIM1, define distinct but cooperative functions for STIM1 and STIM2 in modulating neutrophil bactericidal and cytokine responses.

A monocyte-keratinocyte-derived co-culture assay accurately identifies efficacies of BET inhibitors as therapeutic candidates for psoriasiform dermatitis.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins perform key roles in epigenetic control of gene expression that is involved in inflammatory conditions, including psoriasiform dermatitis (PsD). Predicting which (of many potential available BET inhibitors) will be effective in vivo is challenging. OBJECTIVE: We determine if a novel in vitro assay that includes two critical cell types involved in human psoriasis can predict the therapeutic potential of specific BET inhibitors in vivo. METHODS: An in vitro model consisting of U-937 and HaCaT cell co-culture was created to screen small molecule BET antagonists for inhibition of cutaneous inflammatory genes. Efficacious BET inhibitors were tested in a mouse imiquimod (IMQ)-induced PsD model. RESULTS: In the co-culture system, HaCaT cells exhibited a marked increase in the secretion of a characteristic set of proinflammatory and Th17-associated cytokines. Of the ten commercially-available small molecules targeting BET proteins assayed, most compounds exhibited inhibitory functions at 1 µM against inflammatory activation, but responded variably at lower concentrations. OTX015, a typical representative for most of the compounds, barely inhibited the inflammatory reactions at 0.1 µM. By contrast, ABBV075 was effective in concentrations as low as 0.01 µM. While oral administration OTX015 in IMQ-treated mice reduced disease severity, ABBV075 equally decreased the symptoms and molecular and cellular severity markers at one-tenth of the minimal dosing required for OTX015. CONCLUSION: In vitro screening system combined with an in vivo animal model, can serve as a convenient pre-clinical screening tool for the selection of BET inhibitors (and possibly other drugs) that may have clinical potential in psoriasis therapy.