The effects of PEGylation on LNP based mRNA delivery to the eye

als.fakia shared this article with you from Inoreader The effects of PEGylation on LNP based mRNA delivery to the eye Via PLOS ONE Alerts: New Articles by Renee C. Ryals, Siddharth Patel, Chris Acosta, Madison McKinney, Mark E. Pennesi, Gaurav Sahay Gene therapy is now an effective approach to treat many forms of retinal degeneration. Delivery agents that are cell-specific, allow for multiple dosing regimens, and have low immunogenicity are needed to expand the utility of gene therapy for the retina. We generated eight novel lipid nanoparticles (LNPs) ranging in size from 50 nm to 150 nm by changing the PEG content from 5% to 0.5%, respectively. Subretinal injections of LNP-mRNA encoding luciferase revealed that 0.5% PEG content within nanoparticles elicits the highest expression. Similar injections of LNP delivered cre mRNA into Ai9 mice revealed cell-specific protein expression in the retinal pigment epithelium (RPE), confirmed by fundus photography and immunohistochemistry of whole globe cross-sections. To investigate mechanisms of LNP delivery to the eye, we injected mCherry mRNA using the subretinal approach in apoE-/- and Mertk-/- mice. RPE transfection was observed in both mouse models suggesting that LNP intracellular delivery is not solely dependent on apolipoprotein adsorption or phagocytosis. To investigate LNP penetration, particles were delivered to the vitreous chamber via an intravitreal injection. The 0.5% PEG particles mediated the highest luciferase activity and expression was observed in the Müller glia, the optic nerve head and the trabecular meshwork, but failed to reach the RPE. Overall, particles containing less PEG (~150 nm in size) mediated the highest expression in the eye. Thus far, these particles successfully transfect RPE, Müller cells, the optic nerve head and the trabecular meshwork based on route of administration which can expand the utility of LNP-mediated gene therapies for the eye. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Neutrophil extracellular trap components and myocardial recovery in post-ischemic acute heart failure

als.fakia shared this article with you from Inoreader Neutrophil extracellular trap components and myocardial recovery in post-ischemic acute heart failure Via PLOS ONE Alerts: New Articles by Miriam Sjåstad Langseth, Geir Øystein Andersen, Trygve Husebye, Harald Arnesen, Manuela Zucknick, Svein Solheim, Jan Eritsland, Ingebjørg Seljeflot, Trine Baur Opstad, Ragnhild Helseth Objective The role of neutrophil extracellular traps (NETs) in acute heart failure is unknown. We recently showed that interleukin 8, a putative NETs stimulator, was associated with myocardial recovery in acute heart failure complicating ST-elevation myocardial infarction (STEMI). In this exploratory post-hoc study, we aimed to investigate the role of NETs components in relation to myocardial function and interleukin 8 in STEMI patients with symptomatic acute heart failure. Methods In 61 STEMI patients developing acute heart failure within 48 hours of successful revascularization, wall motion score index (WMSI), global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography at baseline and on day 5. Blood drawn at baseline and days 1, 2 and 5 was used to quantify double-stranded DNA (dsDNA), myeloperoxidase-DNA complexes (MPO-DNA) and citrullinated histone 3 (CitH3). The area under the curve (AUC) of each NETs marker and int erleukin 8 was approximated for the first 5 days. Results dsDNAAUC and MPO-DNAAUC correlated significantly with change in WMSI from baseline to day 5 (rs = 0.28 for both, p≤0.05), whereas NETs AUCs did not correlate with changes in GLS and LVEF. dsDNAAUC was significantly correlated with interleukin 8AUC (r = 0.40, p = 0.003). However, mixed model regression could not identify a significant effect of the NETs components on myocardial function parameters. Conclusions In this cohort with acute heart failure complicating STEMI, NETs components were partly correlated with myocardial function and interleukin 8 levels, yet no causal relationship between NETs components and myocardial recovery could be established. Clinical trial registration ClinicalTrials.gov, identifier: NCT00324766. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Image-guided percutaneous sclerotherapy of venous malformations of the head and neck: Clinical and MR-based volumetric mid-term outcome

als.fakia shared this article with you from Inoreader Image-guided percutaneous sclerotherapy of venous malformations of the head and neck: Clinical and MR-based volumetric mid-term outcome Via PLOS ONE Alerts: New Articles by Dominik F. Vollherbst, Philipp Gebhart, Steffen Kargus, Astrid Burger, Reinald Kühle, Patrick Günther, Jürgen Hoffmann, Martin Bendszus, Markus A. Möhlenbruch Objective To report the clinical and MRI-based volumetric mid-term outcome after image guided percutaneous sclerotherapy (PS) of venous malformations (VM) of the head and neck. Methods A retrospective analysis of a prospectively maintained database was performed, including patients with VM of the head and neck who were treated with PS. Only patients with available pre- and post-interventional MRI were included into this study. Clinical outcome, which was subjectively assessed by the patients, their parents (for paediatric patients) and/or the physicians, was categorized as worse, unchanged, minor or major improvement. Radiological outcome, determined by MRI-based volumetric measurements, was categorized as worse (>10% increase), unchanged (≤10% increase to Results Twenty-seven patients were treated in 51 treatment sessions. After a mean follow-up of 31 months, clinical outcome was worse for 7.4%, unchanged for 3.7% of the patients, while there was minor and maj or improvement for 7.4% and 81.5%, respectively. In the volumetric imaging analysis 7.4% of the VMs were worse and 14.8% were unchanged. Minor improvement was observed in 22.2%, intermediate improvement in 44.4% and major improvement in 11.1%. The rate of permanent complications was 3.7%. Conclusion PS can be an effective therapy to treat the symptoms of patients with VMs of the head and neck and to downsize the VMs. MRI-based volumetry can be used to objectively follow the change in size of the VMs after PS. Relief of symptoms frequently does not require substantial volume reduction. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Consideration of body mass index (BMI) in the association between hand grip strength and hypertension: Korean Longitudinal Study of Ageing (KLoSA)

als.fakia shared this article with you from Inoreader Consideration of body mass index (BMI) in the association between hand grip strength and hypertension: Korean Longitudinal Study of Ageing (KLoSA) Via PLOS ONE Alerts: New Articles by Doukyoung Chon, Jaeyong Shin, Jae-Hyun Kim Objective The purpose of this study was to investigate the association between grip strength and hypertension in the Korean population aged 65 years or older. Furthermore, individual differences in BMI were taken into account to examine whether grip strength or a relative grip strength predicted hypertension better. Methods Data from the Korean Longitudinal Study of Ageing from 2006 to 2016 were assessed, and a total of 3,383 participants were analyzed in our study (Male: 1,527, Female: 1,856). Using the generalized estimating equation model, the association between grip strength and hypertension, assessed by the response to the question 'have you ever been diagnosed with hypertension from your doctor?', over the follow-up period was analyzed. The relative grip strength, calculated by dividing the mean grip strength by BMI, was also analyzed in association of hypertension. Results Both grip strength and relative grip strength were significantly associated with hy pertension in our sample. However, the results were more significant in the total sample when relative grip strength was used. In terms of grip strength, as the High group as reference: Low (Odds Ratio (OR): 1.238, 95% Confidence Interval (CI): 1.096, 1.397), Middle Low (OR: 1.104, 95% CI: 0.990, 1.231), and Middle high (OR: 1.024, 95% CI: 0.934, 1.122). In the analysis using relative grip strength, as High group as reference: Low (OR: 1.393, 95% CI: 1.234, 1.573), Middle low (OR: 1.232, 95% CI: 1.104, 1.374), and Middle high (OR:1.104, 95% CI: 1.009, 1.209). Furthermore, the lower QIC measure in the model with relative grip strength (QIC: 25,251) compared with the one using grip strength (QIC: 25,266) indicated a better model fit in the former. Conclusions The results of the current study strengthen the previous findings in regards to hand grip strength and health. Furthermore, the results of our study shines light on the necessity of considering individual differences in BM I, when using a physical measure as a study variable. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Metabolomics profiles associated with diabetic retinopathy in type 2 diabetes patients

als.fakia shared this article with you from Inoreader Metabolomics profiles associated with diabetic retinopathy in type 2 diabetes patients Via PLOS ONE Alerts: New Articles by Jun Ho Yun, Jeong-Min Kim, Hyun Jeong Jeon, Taekeun Oh, Hyung Jin Choi, Bong-Jo Kim Diabetic retinopathy (DR) is a common complication of diabetes, and it is the consequence of microvascular retinal changes due to high glucose levels over a long time. Metabolomics profiling is a rapidly evolving method used to identify the metabolites in biological fluids and investigate disease progression. In this study, we used a targeted metabolomics approach to quantify the serum metabolites in type 2 diabetes (T2D) patients. Diabetes patients were divided into three groups based on the status of their complications: non-DR (NDR, n = 143), non-proliferative DR (NPDR, n = 123), and proliferative DR (PDR, n = 51) groups. Multiple logistic regression analysis and multiple testing corrections were performed to identify the significant differences in the metabolomics profiles of the different analysis groups. The concentrations of 62 metabolites of the NDR versus DR group, 53 metabolites of the NDR versus NPDR group, and 30 metabolites of the NDR versus PDR group were found to be si gnificantly different. Finally, sixteen metabolites were selected as specific metabolites common to NPDR and PDR. Among them, three metabolites including total DMA, tryptophan, and kynurenine were potential makers of DR progression in T2D patients. Additionally, several metabolites such as carnitines, several amino acids, and phosphatidylcholines also showed a marker potential. The metabolite signatures identified in this study will provide insight into the mechanisms underlying DR development and progression in T2D patients in future studies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Reduced activity, reactivity and functionality of the sympathetic nervous system in fibromyalgia: An electrodermal study

als.fakia shared this article with you from Inoreader Reduced activity, reactivity and functionality of the sympathetic nervous system in fibromyalgia: An electrodermal study Via PLOS ONE Alerts: New Articles by Gustavo A. Reyes del Paso, Pablo de la Coba Alterations in autonomic activity are well established in fibromyalgia syndrome (FMS). Previous studies found reduced parasympathetic activity and sympathetic reactivity to physical and stress manipulations. However, sympathetic activity at rest has not been well studied in FMS. Sweating is exclusively controlled by sympathetic mechanisms. In this study, skin conductance (SC), as an indirect measure of sweating, was analyzed in 45 women with FMS and 38 healthy women. Tonic SC levels were recorded during a 4-minute rest period, and a breathing maneuver consisting of deep breathing with posterior breath holding was used to evoke SC responses. Associations of tonic SC with state anxiety and body temperature, measured in the hand, were explored to determine sweat functionality. The results showed reduced tonic SC levels, with a less marked decrease in SC during the recording period, and blunted SC reactivity to the breathing manipulation in FMS patients relative to healthy participants. Positive associations of SC with state anxiety and body temperature were observed in healthy participants, but these associations were absent in FMS patients. These results indicate alterations of sweating in FMS, suggesting reduced tonic and reactivity sympathetic influences. Furthermore, the absence of associations between SC levels and state anxiety and body temperature in the patient sample suggested a loss of functionality of the autonomic nervous system in FMS. Diminished autonomic regulation in FMS would reduce the ability to cope with environmental demands, thus favoring increases in stress and pain levels. Finally, the observed reduction in sweating is in accordance with evidence of small nerve fiber neuropathy in FMS. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comparable human reconstitution following Cesium-137 versus X-ray irradiation preconditioning in immunodeficient NOG mice

als.fakia shared this article with you from Inoreader Comparable human reconstitution following Cesium-137 versus X-ray irradiation preconditioning in immunodeficient NOG mice Via PLOS ONE Alerts: New Articles by Anna Halling Folkmar Andersen, Stine Sofie Frank Nielsen, Rikke Olesen, Jakob Le Fèvre Harslund, Ole Schmeltz Søgaard, Lars Østergaard, Paul W. Denton, Martin Tolstrup Humanized mouse models are used extensively in research involving human pathogens and diseases. However, most of these models require preconditioning. Radio-active sources have been used routinely for this purpose but safety issues have motivated researchers to transition to chemical or X-ray based preconditioning. In this study, we directly compare 350 kV X-ray and Cs-137 low-dose precondition of NOG mice before human stem cell transplantation. Based on flow cytometry data, we found that engraftment of human cells into the mouse bone marrow was similar between radiation sources. Likewise, human engraftment in the peripheral blood was comparable between Cs-137 and three different X-ray doses with equal chimerization kinetics. In primary lymphoid organs such as the thymus and lymph nodes, and spleen, liver and lung, human-to-mouse chimerization was also comparable between irradiation sources. Development of different CD4 and CD8 T cells as well as these cells' maturation stages, i.e . from naïve to effector and memory subsets were generally analogous. Based on our results, we conclude that there are no discernable differences between the two sources in the low-dose spectrum investigated. However, while we encourage the transition to X-ray-based sources, we recommend all research groups to consider technical specifications and dose-finding studies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Development of the life change adaptation scale for family caregivers of individuals with acquired brain injury

als.fakia shared this article with you from Inoreader Development of the life change adaptation scale for family caregivers of individuals with acquired brain injury Via PLOS ONE Alerts: New Articles by Yuka Shindo, Etsuko Tadaka Aim Life changes due to the sudden onset of acquired brain injury (ABI) are drastic personal and social changes that require adaptation and are also an important indicator of the quality of life of family caregivers. However, there are no instruments for evaluating life change adaptation among family caregivers of individuals with acquired brain injury. This study aimed to develop the Life Change Adaptation Scale (LCAS) for family caregivers of individuals with ABI and examine its reliability and validity. Methods A cross-sectional study was conducted using a self-reported questionnaire. A total of 1622 family caregivers of individuals with ABI who belonged to 82 associations for families of individuals with ABI were selected as eligible participants. The construct validity was evaluated using a confirmatory factor analysis. Internal consistency was calculated using Cronbach's alpha. The K6 was also administered to assess the criterion-related validity of the LCAS. Re sults In total, 339 valid responses were received. The confirmatory factor analysis identified eight items from two domains, "Changes in the appraisal of caregiving resources" and "Changes in the health belief as a caregiver" (goodness of fit index = 0.963, adjusted goodness of fit index = 0.926, comparative fit index = 0.986, root mean square error of approximation  = 0.043.) Cronbach's alpha was 0.84. The LCAS was negatively correlated with the K6 (r = -0.504; P Conclusions The LCAS is a brief, easy-to-administer instrument that is reliable and valid for family caregivers of individuals with ABI. This study contributes to the assessment and identification by family caregivers of individuals with ABI who require aid in adapting to life changes. Further research should be undertaken to verify the predictive value in a longitudinal study and to attempt to apply the LCAS to assess a broader range of subjects in a wider range of settings. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Adult-onset temporal lobe epilepsy suspicious for autoimmune pathogenesis: Autoantibody prevalence and clinical correlates

als.fakia shared this article with you from Inoreader Adult-onset temporal lobe epilepsy suspicious for autoimmune pathogenesis: Autoantibody prevalence and clinical correlates Via PLOS ONE Alerts: New Articles by Julia C. Kuehn, Carolin Meschede, Christoph Helmstaedter, Rainer Surges, Randi von Wrede, Elke Hattingen, Hartmut Vatter, Christian E. Elger, Susanne Schoch, Albert J. Becker, Julika Pitsch Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. In this context, certain autoantibodies (autoABs) were often associated with limbic encephalitis (LE). Here, we aimed to gain insights into (a) the distribution of 'neurological' autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or 'onconeuronal' ABs or anti-glutamate acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs. Blood sera/cerebrospinal fluid (CSF) of TAOS patients (n = 800) and healthy donors (n = 27) were analyzed for neuroABs and screened for other autoABs by indirect immunofluorescence on hippocampal/cerebellar sections and immunoblots of whole brain and synaptosome lysates. Serological results were correlated with clin ico-neuropsychological features. 13% of TAOS patients (n = 105) were neuroAB+, with anti-GAD65 and anti-N-methyl-D-aspartate receptors (NMDAR) as most frequent autoABs in this group. In our screening tests 25% of neuroAB- patients (n = 199) were positive (screening+), whereas all control samples were negative (n = 27). Intriguingly, key clinico-neuropsychological characteristics including magnetic resonance imaging (MRI) findings, epileptiform electroencephalographic (EEG) activity, and inflammatory cellular infiltrates in CSF were shared to a greater extent by neuroAB+ with neuroAB-/screening+ patients than with neuroAB-/screening- patients. Serological testing in a large consecutive TAOS patient series revealed seropositivity for anti-GAD65 autoABs as the most frequent neuroAB. Intriguingly, neuroAB+ individuals were virtually indistinguishable from neuroAB-/screening + patients in several major clinical features. In contrast, neuroAB-/screening- TAOS patients differed in many parameters. These data support the potential presence of so far unrecognized autoABs in patients with TAOS. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine

als.fakia shared this article with you from Inoreader Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine Via PLOS ONE Alerts: New Articles by Bernadette M. M. Zwaans, Heinz E. Nicolai, Michael B. Chancellor, Laura E. Lamb Radiation for pelvic cancers can result in severe bladder damage and radiation cystitis (RC), which is characterized by chronic inflammation, fibrosis, and vascular damage. RC development is poorly understood because bladder biopsies are difficult to obtain. The goal of this study is to gain understanding of molecular changes that drive radiation-induced cystitis in cancer survivors using urine samples from prostate cancer survivors with history of radiation therapy. 94 urine samples were collected from prostate cancer survivors with (n = 85) and without (n = 9) history of radiation therapy. 15 patients with radiation history were officially diagnosed with radiation cystitis. Levels of 47 different proteins were measured using Multiplex Luminex. Comparisons were made between non-irradiated and irradiated samples, and within irradiated samples based on radiation cystitis diagnosis, symptom scores or hematuria. Statistical analysis was performed using Welch's t-test. In prostate canc er survivors with history of radiation therapy, elevated levels of PAI 1, TIMP1, TIMP2, HGF and VEGF-A were detected in patients that received a radiation cystitis diagnosis. These proteins were also increased in patients suffering from hematuria or high symptom scores. No inflammatory proteins were detected in the urine, except in patients with gross hematuria and end stage radiation cystitis. Active fibrosis and vascular distress is detectable in the urine through elevated levels of associated proteins. Inflammation is only detected in urine of patients with end-stage radiation cystitis disease. These results suggest that fibrosis and vascular damage drive the development of radiation cystitis and could lead to the development of more targeted treatments. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Mesenchymal stem cells promote metastasis through activation of an ABL-MMP9 signaling axis in lung cancer cells

als.fakia shared this article with you from Inoreader Mesenchymal stem cells promote metastasis through activation of an ABL-MMP9 signaling axis in lung cancer cells Via PLOS ONE Alerts: New Articles by Jing Jin Gu, Jacob Hoj, Clay Rouse, Ann Marie Pendergast Mesenchymal stem cells (MSCs) are recruited and activated by solid tumors and play a role in tumor progression and metastasis. Here we show that MSCs promote metastasis in a panel of non-small cell lung cancer (NSCLC) cells. MSCs elicit transcriptional alterations in lung cancer cells leading to increased expression of factors implicated in the epithelial-to-mesenchymal transition (EMT) and secreted proteins including matrix metalloproteinase-9 (MMP9). MSCs enhance secretion of enzymatically active MMP9 in a panel of lung adenocarcinoma cells. High expression of MMP9 is linked to low survival rates in lung adenocarcinoma patients. Notably, we found that ABL tyrosine kinases are activated in MSC-primed lung cancer cells and functional ABL kinases are required for MSC-induced MMP9 expression, secretion and proteolytic activity. Importantly, ABL kinases are required for MSC-induced NSCLC metastasis. These data reveal an actionable target for inhibiting MSC-induced metastatic acti vity of lung adenocarcinoma cells through disruption of an ABL kinase-MMP9 signaling axis activated in MSC-primed lung cancer cells. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.