Tyro3, Axl and Mertk are members of the TAM family of tyrosine kinase receptors. TAMs are activated by two structurally homologous ligands GAS6 and PROS1. TAM receptors and ligands are widely distributed and often co-expressed in the same cells allowing diverse functions across many systems including the immune, reproductive, vascular, and the developing and adult nervous systems. This review will focus specifically on TAM signaling in the nervous system, highlighting the essential roles they play in maintaining cell survival and homeostasis, cellular functions such as phagocytosis, immunity and tissue repair. Dysfunctional TAM signaling can cause complications in development, disruptions in homeostasis which can rouse autoimmunity, neuroinflammation and neurodegeneration. The development of therapeutics modulating TAM activities in the nervous system has great prospects, however, foremost we need a complete understanding of TAM signaling pathways.
Background and purposeImpaired upper extremity (UE) motor function is a common disability after ischemic stroke. Exposure to extremely low frequency and low intensity electromagnetic fields (ELF-EMF) in a frequency-specific manner (Electromagnetic Network Targeting Field therapy; ENTF therapy) is a non-invasive method available to a wide range of patients that may enhance neuroplasticity, potentially facilitating motor recovery. This study seeks to quantify the benefit of the ENTF therapy on UE motor function in a subacute ischemic stroke population.MethodsIn a randomized, sham-controlled, double-blind trial, ischemic stroke patients in the subacute phase with moderately to severely impaired UE function were randomly allocated to active or sham treatment with a novel, non-invasive, brain computer interface-based, extremely low frequency and low intensity ENTF therapy (1–100 Hz, < 1 G). Participants received 40 min of active ENTF or sham treatment 5 days/week for 8 weeks; ~three out of the five treatments were accompanied by 10 min of concurrent physical/occupational therapy. Primary efficacy outcome was improvement on the Fugl-Meyer Assessment – Upper Extremity (FMA-UE) from baseline to end of treatment (8 weeks).ResultsIn the per protocol set (13 ENTF and 8 sham participants), mean age was 54.7 years (±15.0), 19% were female, baseline FMA-UE score was 23.7 (±11.0), and median time from stroke onset to first stimulation was 11 days (interquartile range (IQR) 8–15). Greater improvement on the FMA-UE from baseline to week 4 was seen with ENTF compared to sham stimulation, 23.2 ± 14.1 vs. 9.6 ± 9.0, p = 0.007; baseline to week 8 improvement was 31.5 ± 10.7 vs. 23.1 ± 14.1. Similar favorable effects at week 8 were observed for other UE and global disability assessments, including the Action Research Arm Test (Pinch, 13.4 ± 5.6 vs. 5.3 ± 6.5, p = 0.008), Box and Blocks Test (affected hand, 22.5 ± 12.4 vs. 8.5 ± 8.6, p < 0.0001), and modified Rankin Scale (−2.5 ± 0.7 vs. −1.3 ± 0.7, p = 0.0005). No treatment-related adverse events were reported.ConclusionsENTF stimulation in subacute ischemic stroke patients was associated with improved UE motor function and reduced overall disability, and results support its safe use in the indicated population. These results should be confirmed in larger multicenter studies.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04039178, identifier: NCT04039178.
Background: Novel recovery interventions may be particularly beneficial started 3-10d poststroke, when patients become eligible for intensive inpatient rehabilitation and biologic neuroplasticity is at its peak. To design recovery clinical trials in this population, it is important to characterize the evolution of global disability through 3mo of conventional care. Methods: Among all ischemic stroke (IS) and intracranial hemorrhage (ICH) patients enrolled in an NIH multicenter acute treatment trial (FAST-MAG), we analyzed disability course among patients discharged to acute inpatient rehabilitation facilities (IRFs) 2-9 days poststroke. Results: Among 1426 IS and ICH patients, 255 (17.9%) were discharged to IRFs, including 12.8% within 2-9d and 5.1% beyond 9d. Among IS patients, rate of 2-9d discharge to IRFs was 13.0% (135/1041), age 71.1 (±12.4), 42% female, NIHSS on first hospital arrival 10.3 (±6.8), and global disability on day 4 mRS=3 in 15.9% and mRS=4 in 43.8%. Among ICH patients, rate of 2-9d discharge to IRFs was 12.2% (47/385), age 62.4 (±11.7), 32.9% female, NIHSS on first hospital arrival 11.5 (±5.7), and global disability on day 4 mRS=3 in 12.2% and mRS=4 in 45.1%. Among Day 4 mRS 3-4 patients, mRS improvement by 90d among ICH and IS patients was 83.0% vs 72.6%, p = 0.17. Mean mRS change for ICH and IS was -1.5 (±1.1) vs -1.3 (±1.4) (Figure). Final 90D mRS among ICH and IS patients was mean 2.2 (±1.1) vs 2.4 (±1.5). Conclusion: In this broad acute stroke patient cohort, 1 in 8 patients were transferred to inpatient rehabilitation within 2-9d days poststroke. Intracranial hemorrhage patients had nominally greater improvement on the mRS by 90d than ischemic stroke patients. This course delineation provides a roadmap for future rehabilitation intervention studies.
Background Many stroke recovery interventions are most beneficial when started 2-14d post-stroke, a time when patients become eligible for inpatient rehabilitation facilities (IRF) and neuroplasticity is often at its peak. Clinical trials focused on recovery need to expand the time from this plasticity to later outcome timepoints. Methods The disability course of patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) enrolled in Field Administration of Stroke Therapy Magnesium (FAST-MAG) Trial with moderate-severe disability (modified Rankin Scale [mRS] 3–5) on post-stroke day4 who were discharged to IRF 2-14d post-stroke were analyzed. Results Among 1422 patients, 446 (31.4%) were discharged to IRFs, including 23.6% within 2-14d and 7.8% beyond 14d. Patients with mRS 3–5 on day4 discharged to IRFs between 2-14d accounted for 21.7% (226/1041) of AIS patients and 28.9% (110/381) of ICH patients, (p < 0.001). Among these AIS patients, age was 69.8 (± 12.7), initial NIHSS median 8 (IQR 4–12), and day4 mRS = 3 in 16.4%, mRS = 4 in 50.0%, and mRS = 5 in 33.6%. Among these ICH patients, age was 62.4 (± 11.7), initial NIHSS median 9 (IQR 5–13), day 4 mRS = 3 in 9.4%, mRS = 4 in 45.3%, and mRS = 5 in 45.3% (p < 0.01 for AIS vs ICH). Between day4 to day90, mRS improved ≥ 1 levels in 72.6% of AIS patients vs 77.3% of ICH patients, p = 0.3. For AIS, mRS improved from mean 4.17 (± 0.7) to 2.84 (± 1.5); for ICH, mRS improved from mean 4.35 (± 0.7) to 2.75 (± 1.3). Patients discharged to IRF beyond day14 had less improvement on day90 mRS compared with patients discharged between 2-14d. Conclusions In this acute stroke cohort, nearly 1 in 4 patients with moderate-severe disability on post-stroke day4 were transferred to IRF within 2-14d post-stroke. ICH patients had nominally greater mean improvement on mRS day90 than AIS patients. This course delineation provides a roadmap for future rehabilitation intervention studies.
Background: Many stroke recovery interventions are most beneficial when started 2-14d post-stroke, a time when patients become eligible for inpatient rehabilitation facilities (IRF) and neuroplasticity is often at its peak. Clinical trials focused on recovery need to expand the time from this plasticity to later outcome timepoints. Methods: The disability course of patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) enrolled in Field Administration of Stroke Therapy Magnesium (FAST-MAG) Trial with moderate-severe disability (modified Rankin Scale [mRS] 3-5) on post-stroke day4 who were discharged to IRF 2-14d post-stroke were analyzed. Results: Among 1422 patients, 446 (31.4%) were discharged to IRFs, including 23.6% within 2-14d and 7.8% beyond 14d. Patients with mRS 3-5 on day4 discharged to IRFs between 2-14d accounted for 21.7% (226/1041) of AIS patients and 28.9% (110/381) of ICH patients, (p<0.001). Among these AIS patients, age was 69.8 (±12.7), initial NIHSS median 8 (IQR 4-12), and day4 mRS=3 in 16.4%, mRS=4 in 50.0%, and mRS=5 in 33.6%. Among these ICH patients, age was 62.4 (±11.7), initial NIHSS median 9 (IQR 5-13), day 4 mRS=3 in 9.4%, mRS=4 in 45.3%, and mRS=5 in 45.3% (p<0.01 for AIS vs ICH). Between day4 to day90, mRS improved ≥ 1 levels in 72.6% of AIS patients vs 77.3% of ICH patients, p=0.3. For AIS, mRS improved from mean 4.17 (±0.7) to 2.84 (±1.5); for ICH, mRS improved from mean 4.35 (±0.7) to 2.75 (±1.3). Patients discharged to IRF beyond day14 had less improvement on day90 mRS compared with patients discharged between 2-14d. Conclusions: In this acute stroke cohort, nearly 1 in 4 patients with moderate-severe disability on post-stroke day4 were transferred to IRF within 2-14d post-stroke. ICH patients had nominally greater mean improvement on mRS day90 than AIS patients. This course delineation provides a roadmap for future rehabilitation intervention studies.
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