Macrophages Educated with Exosomes from Primed Mesenchymal Stem Cells Treat Acute Radiation Syndrome by Promoting Hematopoietic Recovery.

In the setting of radiation-induced trauma, exposure to high levels of radiation can cause an acute radiation syndrome (ARS) causing bone marrow (BM) failure, leading to life-threatening infections, anemia, and thrombocytopenia. We have previously shown that human macrophages educated with human mesenchymal stem cells (MSCs) by coculture can significantly enhance survival of mice exposed to lethal irradiation. In this study, we investigated whether exosomes isolated from MSCs could replace direct coculture with MSCs to generate exosome educated macrophages (EEMs). Functionally unique phenotypes were observed by educating macrophages with exosomes from MSCs (EEMs) primed with bacterial lipopolysaccharide (LPS) at different concentrations (LPS-low EEMs or LPS-high EEMs). LPS-high EEMs were significantly more effective than uneducated macrophages, MSCs, EEMs, or LPS-low EEMs in extending survival after lethal ARS in vivo. Moreover, LPS-high EEMs significantly reduced clinical signs of radiation injury and restored hematopoietic tissue in the BM and spleen as determined by complete blood counts and histology. LPS-high EEMs showed significant increases in gene expression of STAT3, secretion of cytokines like IL-10 and IL-15, and production of growth factors like FLT-3L. LPS-EEMs also showed increased phagocytic activity, which may aid with tissue remodeling. LPS-high EEMs have the potential to be an effective cellular therapy for the management of ARS.

Mean of Daily Versus Single Week Recall-Based Pain Quality Assessments in Neuropathic Pain Trials: Implications for Assay Sensitivity.

Patients with neuropathic pain often present with variable pain and nonpainful sensory qualities that could serve as outcomes in randomized clinical trials (RCTs). This study aimed to investigate the within-participant variability in the severity of these sensory qualities and whether the means of 7 daily pain quality assessments provide better assay sensitivity (ie, more sensitivity to treatment effects) than single-week recall-based assessments. This secondary analysis used data from an RCT of transcutaneous electrical nerve stimulation for chemotherapy-induced peripheral neuropathy (N = 142). Participants rated the severity of painful and nonpainful sensory qualities using 0 to 10 numeric rating scales daily for 1 week (24-hour recall) and 1 time at the end of each week (week recall) at trial baseline and endpoint (after 6 weeks of treatment). For pain quality assay sensitivity analyses, the 2 types of measures were used to 1) define the study sample (ie, how many participants met minimum baseline pain quality severity) and 2) calculate the observed effect sizes (ie, between-group differences in mean pain qualities) using analysis of covariances. The projected sample sizes required to detect the observed effect sizes in future clinical trials for hot/burning pain and cramping were substantially smaller using the daily mean outcome compared with week recall (ie, hot/burning pain: 153 vs 388, cramping: 121 vs 349), and only marginally larger for sharp/shooting pain (22 participants) with the daily mean outcome. Compared with single-week recall-based assessments of pain qualities, the mean of daily assessments may improve RCT assay sensitivity when used to define entry criteria and assess outcomes. PERSPECTIVES: This study suggests that means of daily pain quality assessments may improve assay sensitivity when used to define entry criteria and assess outcomes in clinical trials. This work may inform design of future clinical trials evaluating the intensity of different pain qualities.

Cannabinoid Therapy: Attitudes and Experiences of People With Chronic Pain.

OBJECTIVE: Clinical trials of cannabinoids for chronic pain have mixed and often inconclusive results. In contrast, many prospective observational studies show the analgesic effects of cannabinoids. This survey study aimed to examine the experiences/attitudes of individuals with chronic pain who are currently taking, have previously taken, or never taken cannabinoids for chronic pain to inform future research. METHODS: This study is based on a cross-sectional, web-based survey of individuals with self-reported chronic pain. Participants were invited to participate through an email that was distributed to the listservs of patient advocacy groups and foundations that engage individuals with chronic pain. RESULTS: Of the 969 respondents, 444 (46%) respondents reported currently taking, 213 (22%) previously taken, and 312 (32%) never taken cannabinoids for pain. Participants reported using cannabinoids to treat a wide variety of chronic pain conditions. Those currently taking cannabinoids (vs previously) more frequently reported: (1) large improvements from cannabinoids in all pain types, including particularly difficult-to-treat chronic overlapping pain conditions (eg, pelvic pain), (2) improvements in comorbid symptoms (eg, sleep), and (3) lower interference from side effects. Those currently taking cannabinoids reported more frequent and satisfactory communication with clinicians regarding cannabinoid use. Those never taken cannabinoids reported a lack of suggestion/approval of a clinician (40%), illegality (25%), and lack of FDA regulation (19%) as reasons for never trying cannabinoids. CONCLUSION: These findings underscore the importance of conducting high-quality clinical trials that include diverse pain populations and clinically relevant outcomes that if successful, could support FDA approval of cannabinoid products. Clinicians could then prescribe and monitor these treatments similarly to other chronic pain medications.

Peripheral edema: A common and persistent health problem for older Americans.

Peripheral edema (i.e., lower limb swelling) can cause pain, weakness, and limited range of motion. However, few studies have examined its prevalence in the U.S. or its association with demographics, comorbidities, activity, or mobility. This study used data from the Health and Retirement Study, a nationally representative longitudinal survey of U.S. adults (age 51+/ N = 19,988 for 2016), to evaluate time trends and correlates of peripheral edema using weighted descriptive statistics and logistic regressions, respectively. Peripheral edema was assessed with the question "Have you had… // Persistent swelling in your feet or ankles?" The weighted prevalence of edema among older U.S. adults was 19% to 20% between 2000 and 2016. Peripheral edema was associated with older age, female sex, non-white race, low wealth, obesity, diabetes, hypertension, pain, low activity levels, and mobility limitations (odds ratios ranging from 1.2-5.6; p-values ≤0.001). This study provides the first estimates of national prevalence and correlates of peripheral edema among older Americans. Peripheral edema is common and strongly associated with comorbidities, pain, low activity levels, and mobility limitations, and disproportionately affects poorer and minority groups. Peripheral edema should be a focus of future research in order to develop novel and cost-effective interventions.

Corneal Mesenchymal Stromal Cells Are Directly Antiangiogenic via PEDF and sFLT-1.

Purpose: To evaluate the angiogenic properties of corneal derived mesenchymal stromal cells (Co-MSC). Methods: Co-MSCs were extracted from human cadaver, and wild-type (C57BL/6J) and SERPINF1-/- mice corneas. The MSC secretome was collected in a serum-free medium. Human umbilical vein endothelial cell (HUVEC) tube formation and fibrin gel bead assay (FIBA) sprout formation were used to assess the angiogenic properties of Co-MSC secretome. Complete corneal epithelial debridement was used to induce corneal neovascularization in wild-type mice. Co-MSCs embedded in fibrin gel was applied over the debrided cornea to evaluate the angiogenic effects of Co-MSCs in vivo. Immunoprecipitation was used to remove soluble fms-like tyrosine kinase-1 (sFLT-1) and pigment epithelium-derived factor (PEDF, SERPINF1 gene) from the Co-MSC secretome. Results: Co-MSC secretome significantly inhibited HUVECs tube and sprout formation. Co-MSCs from different donors consistently contained high levels of antiangiogenic factors including sFLT-1 and PEDF; and low levels of the angiogenic factor VEGF-A. In vivo, application of Co-MSCs to mouse corneas after injury prevented the development of corneal neovascularization. Removing PEDF or sFLT-1 from the secretome significantly diminished the antiangiogenic effects of Co-MSCs. Co-MSCs isolated from SERPINF1-/- mice had significantly reduced antiangiogenic effects compared to SERPINF1+/+ (wild-type) Co-MSCs. Conclusions: These results illustrate the direct antiangiogenic properties of Co-MSCs, the importance of sFLT-1 and PEDF, and their potential clinical application for preventing pathologic corneal neovascularization.