BackgroundEarly-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2Akita mouse model.MethodsIns2Akita mice at 24 weeks of age received intravitreal injections of CD140b-positive ASCs (1000 cells/1 μL) or 20× conditioned media from cytokine-primed ASCs (ASC-CM, 1 μL). Age-matched wildtype mice that received saline served as controls. Visual function experiments and histological analyses were performed 3 weeks post intravitreal injection. Biochemical and molecular analyses assessed the ASC-CM composition and its biological effects.ResultsThree weeks post-injection, Ins2Akita mice that received ASCs had ameliorated decreased b-wave amplitudes and vascular leakage but failed to improve visual acuity, whereas Ins2Akita mice that received ASC-CM demonstrated amelioration of all aforementioned visual deficits. The ASC-CM group demonstrated partial amelioration of retinal GFAP immunoreactivity and DR-related gene expression but the ASC group did not. While Ins2Akita mice that received ASCs exhibited occasional (1 in 8) hemorrhagic retinas, mice that received ASC-CM had no adverse complications. In vitro, ASC-CM protected against TNFα-induced retinal endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrated several anti-inflammatory proteins including TSG-6 being highly expressed in cytokine-primed ASC-CM.ConclusionsASCs or their secreted factors mitigate retinal complications of diabetes in the Ins2Akita model. Further investigation is warranted to determine whether ASCs or their secreted factors are safe and effective therapeutic modalities long-term as current locally delivered therapies fail to effectively mitigate the progression of early-stage DR. Nonetheless, our study sheds new light on the therapeutic mechanisms of adult stem cells, with implications for assessing relative risks/benefits of experimental regenerative therapies for vision loss.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1059-y) contains supplementary material, which is available to authorized users.

While numerous studies and patient experiences have demonstrated the efficacy of spinal cord stimulation as a treatment for chronic neuropathic pain, the exact mechanism underlying this therapy is still uncertain. Recent studies highlighting the importance of microglial cells in chronic pain and characterizing microglial activation transcriptomes have created a focus on microglia in pain research. Our group has investigated the modulation of gene expression in neurons and glial cells after spinal cord stimulation (SCS), specifically focusing on transcriptomic changes induced by varying SCS stimulation parameters. Previous work showed that, in rodents subjected to the spared nerve injury (SNI) model of neuropathic pain, a differential target multiplexed programming (DTMP) approach provided significantly better relief of pain-like behavior compared to high rate (HRP) and low rate programming (LRP). While these studies demonstrated the importance of transcriptomic changes in SCS mechanism of action, they did not specifically address the role of SCS in microglial activation. The data presented herein utilizes microglia-specific activation transcriptomes to further understand how an SNI model of chronic pain and subsequent continuous SCS treatment with either DTMP, HRP, or LRP affects microglial activation. Genes for each activation transcriptome were identified within our dataset and gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations indicated that DTMP yields the highest significant correlations to expression levels found in the healthy animals across all microglial activation transcriptomes. In contrast, HRP or LRP yielded weak or very weak correlations for these transcriptomes. This work demonstrates that chronic pain and subsequent SCS treatments can modulate microglial activation transcriptomes, supporting previous research on microglia in chronic pain. Furthermore, this study provides evidence that DTMP is more effective than HRP and LRP at modulating microglial transcriptomes, offering potential insight into the therapeutic efficacy of DTMP.

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Stilbenoids are bioactive polyphenols, and resveratrol (trans-3,5,4′-trihydroxystilbene) is a representative stilbenoid that reportedly exerts cardioprotective actions. As resveratrol exhibits low oral bioavailability, we turned our attention to other stilbenoid compounds with a history of medicinal use and/or improved bioavailability. We determined the effects of gnetol (trans-3,5,2′,6′-tetrahydroxystilbene) and pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene) on cardiac hypertrophy. In vitro, gnetol and pterostilbene prevented endothelin-1-induced indicators of cardiomyocyte hypertrophy including cell enlargement and protein synthesis. Gnetol and pterostilbene stimulated AMP-activated protein kinase (AMPK), and inhibition of AMPK, using compound C or shRNA knockdown, abolished these anti-hypertrophic effects. In contrast, resveratrol, gnetol, nor pterostilbene reduced blood pressure or hypertrophy in the spontaneously hypertensive heart failure (SHHF) rat. In fact, AMPK levels were similar between Sprague-Dawley and SHHF rats whether treated by stilbenoids or not. These data suggest that the anti-hypertrophic actions of resveratrol (and other stilbenoids?) do not extend to the SHHF rat, which models heart failure superimposed on hypertension. Notably, SHHF rat hearts exhibited prolonged isovolumic relaxation time (an indicator of diastolic dysfunction), and this was improved by stilbenoid treatment. In conclusion, stilbenoid-based treatment as a viable strategy to prevent pathological cardiac hypertrophy, a major risk factor for heart failure, may be context-dependent and requires further study.

Background: The treatment of sacral fractures has evolved since its first description in 1982. Several techniques for sacral augmentation have been developed since 2001, and the rate of improvement is rapid with over 50% reduction in pain achieved prior to post-procedure discharge of the patient. Pain reduction occurs primarily within the first 3 months and is sustained at 12 months; however, the long-term outcomes have not previously been studied. Objectives: We aim to evaluate the long-term efficacy of sacroplasty versus non-surgical management (NSM) in treating sacral insufficiency fractures (SIFs), including the effect on pain relief, opioid and other analgesic use, patient satisfaction, and complication rates. Additionally, we aim to review the most current sacroplasty literature. Study Design: A 10-year prospective, observational cohort study of patients with SIFs treated with sacral augmentation. Setting: A single-center interventional pain management private practice. Methods: Two-hundred and forty-four patients with SIFs were treated with sacroplasty (210 patients) or NSM (34 patients) beginning in January 2004 and then followed for 10 years. The patients’ gender, age, pre-procedure pain duration, analgesic use, pain level, and satisfaction were recorded at baseline and at post-procedure follow-up intervals of 2, 4, 12, 24, 52 weeks, and 2 years. The experimental group was then contacted at 10 years. Post-procedure complications before discharge and at each follow-up were also evaluated. Results: Both NSM and sacroplasty resulted in statistically significant drops in visual analog scale (VAS) scores from pre-treatment to 2-year follow-up (P < 0.001). When measured from followup to follow-up, the NSM group’s only significant decrease in the mean VAS score was between pre-treatment and 2 weeks (P = 0.002). The experimental group had significant decreases over the periods pre-op through post-op (P < 0.001), post-op through 2 weeks (P < 0.001), 12 weeks through 24 weeks (P = 0.014), and 24 weeks through one year (P = 0.002). The experimental cohort experienced statistically significant drops in the mean VAS scores between follow-ups for a longer period of time. Opioid and non-opioid analgesic use was markedly decreased preoperatively to postoperatively and was sustained at the 10-year follow-up. Limitations: Patients were placed into the control group, NSM, if they did not meet inclusion criteria for sacroplasty. However, the baseline characteristics of the sacroplasty versus NSM group were not statistically different. Additionally, the control group was only followed through 2 years and was not contacted at the 10-year follow-up. Conclusions: Our results and those reported in previous studies establish that sacroplasty allows for decreased use of medications and results in pain relief, greater patient mobility, and improved patient satisfaction. In addition to the published body of literature, our results show strong evidence in support of sacroplasty as a safe and efficacious treatment of SIFs. Key words: Sacroplasty, sacral fracture, fracture, osteoporosis, insufficiency, radiology