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Background Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke. Methods Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO. Results Infarct sizes on day 7 after tMCAO decreased about 35% after delayed and about 60% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis. Conclusions Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome—even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke.

Background Angiogenesis is crucial in neuroprotection of secondary thalamic injury after cortical infarction. The p75 neurotrophin receptor (p75NTR) plays a key role in activating angiogenesis. However, the effects of p75NTR on angiogenesis in the thalamus after cortical infarction are largely unknown. Herein we investigate whether p75NTR facilitates angiogenesis to attenuate secondary thalamic damage via activating hypoxia‐inducible factor 1α (HIF‐1α)/vascular endothelial growth factor (VEGF) pathway mediated by Von Hippel–Lindau (VHL) after distal middle cerebral artery occlusion (dMCAO). Methods The male rat model of dMCAO was established. The effects of p75NTR on the angiogenesis was evaluated using RNA‐sequencing, immunohistochemistry, western blot, quantitative real‐time polymerase chain reaction, magnetic resonance imaging, behavior tests, viral and pharmacological interventions. Results We found that the p75NTR and vessel density were decreased in ipsilateral thalamus after dMCAO. The p75NTR‐VHL interaction was reduced, which promoted the ubiquitination degradation of HIF‐1α and reduced VEGF expression after dMCAO. Notably, p75NTR overexpression restrained the ubiquitination degradation of HIF‐1α by inhibiting VHL‐HIF‐1α interaction, further promoted angiogenesis, increased cerebral blood flow of ipsilateral thalamus and improved neurological function after dMCAO. Conclusion For the first time, we highlighted that the enhancement of p75NTR‐VHL interaction promoted angiogenesis in attenuating secondary thalamic damage after dMCAO. The expression of p75NTR and the interaction of p75NTR‐VHL were decreased in the ipsilateral VPN after dMCAO, which in turn, increased the VHL‐HIF‐1α interaction, promoted the degradation of HIF‐1α via ubiquitin proteasome pathway, downregulated the expression of VEGF and inhibited angiogenesis, ultimately leading to secondary thalamic damage. Instead, neuronal‐targeted p75NTR overexpression enhanced the interaction of p75NTR‐VHL and upregulated the expression of HIF‐1α and VEGF in the ipsilateral VPN through inhibiting HIF‐1α ubiquitination degradation mediated by VHL, which facilitates angiogenesis and increases CBF, consequently alleviating secondary thalamic damage after dMCAO.

•Left atrial appendage occlusion reduces risk of ischemic stroke and thromboembolism.•Patients with kidney impairment also benefit from left atrial appendage occlusion.•Kidney impairment does not increase harm risk from left atrial appendage occlusion.•Advanced chronic kidney disease patients were underrepresented in this substudy. Optimal anticoagulation in patients with chronic kidney disease and atrial fibrillation is unclear. Effect of left atrial appendage occlusion may differ in these patients. We conducted a secondary analysis of the Left Atrial Appendage Occlusion Study (LAAOS III) to investigate LAAOS III randomized 4,811 participants with atrial fibrillation undergoing cardiac surgery. Baseline serum creatinine measurement was available for 4,768 participants (99.9%). We estimated the Glomerular Filtration Rate (eGFR) using the 2021 Chronic Kidney Disease -Epidemiology Collaboration equation. We investigated the effect of left atrial appendage occlusion using Cox-proportional hazards model with baseline kidney function as continuous and categorical variables. Among 4,768 participants, 67.5% were men and the median age was 71.2 years. Occluding the left atrial appendage demonstrated similar effects after adjusting for eGFR; occlusion was associated with significant reduced risk of stroke compared to no occlusion (HR0.67, 95% CI 0.53-0.85, P = .001). There was no difference in all-cause mortality (HR0.99, 95% CI 0.88-1.12, P = .88), cardiovascular deaths (HR0.93, 95% CI 0.80-1.09, P = .36), hospitalizations for heart failure (HR1.13, 95% CI 0.91-1.39, P = 0.27), major bleeding (HR0.92, 95% CI 0.78-1.10, P = .37), and myocardial infarction (HR0.86, 95% CI 0.59-1.27, P = .45). The P-value for interaction for eGFR was not significant for any outcome. The effects of surgical left atrial appendage occlusion in participants with impaired kidney function was consistent with findings from LAAOS III. Left atrial appendage occlusion was associated with reduced stroke without increased risk of serious adverse events. LAAOS III ClinicalTrials.gov number: NCT01516151. https://clinicaltrials.gov/study/NCT01561651. [Display omitted]

Motor impairment is the most common and widely recognised clinical outcome after stroke. Current clinical practice in stroke rehabilitation focuses mainly on physical therapy, with no pharmacological intervention approved to facilitate functional recovery. Several studies have documented positive effects of growth hormone (GH) on cognitive function after stroke, but surprisingly, the effects on motor function remain unclear. In this study, photothrombotic occlusion targeting the motor and sensory cortex was induced in adult male mice. Two days post-stroke, mice were administered with recombinant human GH or saline, continuing for 28 days, followed by evaluation of motor function. Three days after initiation of the treatment, bromodeoxyuridine was administered for subsequent assessment of cell proliferation. Known neurorestorative processes within the peri-infarct area were evaluated by histological and biochemical analyses at 30 days post-stroke. This study demonstrated that GH treatment improves motor function after stroke by 50%–60%, as assessed using the cylinder and grid walk tests. Furthermore, the observed functional improvements occurred in parallel with a reduction in brain tissue loss, as well as increased cell proliferation, neurogenesis, increased synaptic plasticity and angiogenesis within the peri-infarct area. These findings provide new evidence about the potential therapeutic effects of GH in stroke recovery.

High-sensitivity cardiac troponin assays (hs-cTn) aid in diagnosis of myocardial infarction (MI). These assays have lower specificity for non-ST Elevation MI (NSTEMI) in patients with renal disease. Our objective was to determine an optimized cutoff for patients with renal disease. We conducted an a priori secondary analysis of a prospective FDA study in adults with suspected MI presenting to 29 academic urban EDs between 4/2015 and 4/2016. Blood was drawn 0, 1, 2–3, and 6–9 h after ED arrival. We recorded cTn and estimated glomerular filtrate rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation. The primary endpoint was NSTEMI (Third Universal Definition of MI), adjudicated by physicians blinded to hs-cTn results. We generated an adjusted hscTn rule-in cutoff to increase specificity. 2505 subjects were enrolled; 234 were excluded. Patients were mostly male (55.7%) and white (57.2%), median age was 56 years 472 patients [20.8%] had an eGFR <60 mL/min/1.73 m2. In patients with eGFR <15 mL/min/1.73 m2, a baseline rule-in cutoff of 120 ng/L led to a specificity of 85.0% and Positive Predictive Value (PPV) of 62.5% with 774 patients requiring further observation. Increasing the cutoff to 600 ng/L increased specificity and PPV overall and in every eGFR subgroup (specificity and PPV 93.3% and 78.9%, respectively for eGFR <15 mL/min/1.73m2), while increasing the number (79) of patients requiring observation. An eGFR-adjusted baseline rule-in threshold for the Siemens Atellica hs-cTnI improves specificity with identical sensitivity. Further study in a prospective cohort with higher rates of renal disease is warranted. •High sensitivity troponin specificity is lower in patients with renal disease.•Increasing troponin baseline Rule-in cutoff maintains sensitivity.•Increasing baseline cutoff increases specificity and positive predictive value.•Increasing baseline cutoff requires observing more patients.

The present study aimed to estimate posttraumatic stress symptoms (PTSS) and posttraumatic growth (PTG) among heart disease survivors and examine whether PTG moderates the association between PTSS and mental health. Data from 82 myocardial infarction and acute coronary artery bypass graft survivors (aged 46–82) was obtained at admission to a cardiac rehabilitation unit. Mental status was assessed by the PTSD Inventory, Posttraumatic Growth Inventory (PTGI), Mental Health Inventory and Health Related Quality of Life (HRQOL). 17.1 % of the participants suffered significantly from PTSS and most of the study sample (71.2 %) reported PTG. PTSS were positively associated with PTG and psychological distress and negatively with well-being and HRQOL. PTG moderated the association between PTSS and most mental health outcomes. We conclude that posttraumatic growth may attenuate the negative effect of posttraumatic stress symptoms on mental health.

SummaryBackground Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44–77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2–6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 – 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 − 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7–19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541.

Aims. We have shown that growth hormone (GH) treatment poststroke increases neuroplasticity in peri-infarct areas and the hippocampus, improving motor and cognitive outcomes. We aimed to explore the mechanisms of GH treatment by investigating how GH modulates pathways known to induce neuroplasticity, focusing on association between brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the peri-infarct area, hippocampus, and thalamus. Methods. Recombinant human growth hormone (r-hGH) or saline was delivered (0.25 μl/hr, 0.04 mg/day) to mice for 28 days, commencing 48 hours after photothrombotic stroke. Protein levels of pro-BDNF, total-mTOR, phosphorylated-mTOR, total-p70S6K, and phosporylated-p70S6K within the peri-infarct area, hippocampus, and thalamus were evaluated by western blotting at 30 days poststroke. Results. r-hGH treatment significantly increased pro-BDNF in peri-infarct area, hippocampus, and thalamus (p<0.01). r-hGH treatment significantly increased expression levels of total-mTOR in the peri-infarct area and thalamus (p<0.05). r-hGH treatment significantly increased expression of total-p70S6K in the hippocampus (p<0.05). Conclusion. r-hGH increases pro-BDNF within the peri-infarct area and regions that are known to experience secondary neurodegeneration after stroke. Upregulation of total-mTOR protein expression in the peri-infarct and thalamus suggests that this might be a pathway that is involved in the neurorestorative effects previously reported in these animals and warrants further investigation. These findings suggest region-specific mechanisms of action of GH treatment and provide further understanding for how GH treatment promotes neurorestorative effects after stroke.

The aim of the present study was to focus on the relative contributions of personality, psychological health and cognitive coping to post-traumatic growth in patients with recent myocardial infarction (MI). The sample consisted of 139 patients who had experienced a first-time acute MI between 3 and 12 months before data assessment. Multivariate relationships were tested by means of Structural Equation Modeling. The results showed that besides the contribution of personality and psychological health, a significant amount of variance in growth was explained by the cognitive coping strategies people used to handle their MI. As cognitive coping strategies are generally assumed to be mechanisms that are subject to potential influence and change, this provides us with important targets for intervention.

Purpose of Review Cardiac Rehabilitation (CR) was originally designed to return patients to their prior level of functioning after myocardial infarction (MI). Research has since revealed the mortality benefit of CR, and CR has been given a class 1A recommendation by the American Heart Association/American College of Cardiology (AHA/ACC). In this review, we shift our focus back to function and highlight the most recent research on the functional benefits of CR in a broad range of cardiac diseases and conditions. Recent Findings Currently, CR is indicated for patients with coronary artery disease (CAD), heart failure with reduced ejection fraction (HFrEF), peripheral arterial disease (PAD), transcatheter aortic valve replacement (TAVR), left ventricular assist devices (LVADs), and cardiac transplant. Among patients with those conditions, CR has been shown to improve exercise capacity, cognition, mental health, and overall quality of life. Summary As survival of cardiac diseases increases, CR emerges as an increasingly important tool to lend quality to patients’ lives and therefore give meaning to survival.