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Showing 641–660 of 2058 publications.
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Carroll, Luke; Karton, Amir; Radom, Leo; Davies, Michael J.; Pattison, David I.Hypochlorous acid (HOCl) is a highly reactive, toxic species generated by neutrophils via the action of myeloperoxidase in order to destroy invading pathogens. However, when HOCl is produced inappropriately, it can damage host tissue and proteins and plays a role in the initiation and progression of disease. Carnosine, a peptide of ?-alanine and histidine, has been shown to react rapidly with HOCl yielding monochloramines and can undergo intramolecular transchlorination. The current study examines the kinetics and pH dependence of the reactions of carnosine and novel structural derivatives with HOCl and the occurrence of intra- and intermolecular transchlorination processes. We demonstrate that the transchlorination reactions of carnosine are pH dependent, with intramolecular transfer favored at higher pH. Carcinine, having a structure identical to carnosine though lacking the carboxylic acid group of the histidine residue, reacts with HOCl and forms monochloramines though intramolecular transfer reactions are not observed, and this is supported by computational modeling. Novel analogues with one (carnosine+1) and two (carnosine+2) methylene groups in the alkyl chain of the ?-alanine react with HOCl to yield monochloramines that undergo transchlorinations to yield a mixture of mono- and dichloramines. The latter are stable over 24 h. The ability of carnosine and derivatives to react rapidly with HOCl to give long-lived, poorly reactive, species may prevent damage to proteins and other targets at sites of inflammation. 2019 American Chemical Society.
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OSullivan, John F.; Neylon, Antoinette M.; Fahy, Eoin Francis; Yang, Pengyi; McGorrian, Catherine M.; Blake, Gavin J.Aims MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of multiple phases of atherothrombosis, and some reports have suggested altered levels in coronary artery in-stent restenosis (ISR). We recently demonstrated that miR-93-5 p was able to discriminate between patients with stable coronary artery disease (CAD) and those with no CAD, after adjusting for traditional risk factors (RFs). Thus, we wanted to determine if circulating miRNAs could predict coronary ISR. Objective To determine if circulating miRNAs have diagnostic capability for determining ISR in a cohort of matched patients with and without ISR. Approach and results To determine if miRNA plasma levels are elevated in coronary ISR, we conducted a study comprising 78 patients (39 with no ISR and 39 with ISR) and measured plasma miRNAs in each. We then determined the predictive ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) RFs, and stent length and diameter, to discriminate between ISR and no ISR. After correction for multiple testing, two miRNAs - miR425-5p and miR-93-5 p - were differential between patients with ISR and patients without ISR. Only miR-93-5 p remained a strong independent predictor of ISR after correction for FHS RFs (OR 6.30, p=0.008) and FHS RFs plus stent length and diameter (OR 4.80, p=0.02) and improved discriminatory power for ISR over FHS RFs alone in receiver operator characteristic curve analysis. Conclusion This novel finding that miR-93-5 p independently predicts ISR extends our recent observation that miR-93-5 p predicted CAD after adjustment for traditional CAD RFs. These data suggest further potential diagnostic utility. Author(s) (or their employer(s)) 2019.
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Parker, Helen M.; Cohn, Jeffrey S.; OConnor, Helen T.; Garg, Manohar Lal; Caterson, Ian Douglas; George, Jacob A.; Johnson, Nathan A.Being overweight increases the risk of the development of metabolic conditions such as non-alcoholic fatty liver disease (NAFLD), which is itself an independent predictor of cardiovascular disease. Omega-3 polyunsaturated fatty acid (PUFA) supplementation is recommended for prevention of chronic disease, and is thought to reduce raised liver fat, yet there have been few randomized controlled trials with accurate measurement of liver fat. We assessed the effect of 12 weeks of supplementation with omega-3 PUFA from fish oil versus placebo on quantified liver fat, liver tests, and body composition including visceral adipose tissue (VAT) in a double-blind randomized controlled trial. Fifty apparently healthy overweight men (BMI 25.0-29.9 kg/m2; waist > 94 cm) were randomly allocated to consume fish oil (total daily dose: 1728 mg marine triglycerides, of which 588 mg EPA and 412 mg DHA, combined with 200 mg antioxidant, coenzyme Q10) or placebo (olive oil capsules) daily for 12 weeks. Liver fat was assessed using proton magnetic resonance spectroscopy. All outcomes were assessed at baseline and following 6 and 12 weeks of supplementation. Baseline liver fat was 4.6 0.5% (range: 0.6 to 18.2%); 16 (32%) participants met the criteria for NAFLD (>5.5% liver fat). Repeated measures ANOVA revealed no significant time or group time effect for fish oil versus placebo for liver fat, liver enzymes, anthropometry, or body composition including VAT (p > 0.05 for all), with similar finding for sub-analysis of participants with NAFLD. Omega-3 PUFA did not appear to be an effective agent for reducing liver fat in overweight men. The factors determining the health benefits of omega-3 PUFA supplementation on an individual level need to be clarified. 2019 by the authors. Licensee MDPI, Basel, Switzerland.
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Papa, Anne Laure; Jiang, Amanda R.; Korin, Netanel; Chen, Michelle B.; Langan, Erin T.; Waterhouse, Anna; Nash, Emma; Caroff, Jildaz; Graveline, Amanda R.; Vernet, Andyna; Mammoto, Akiko; Mammoto, Tadanori; Jain, Abhishek; Kamm, Roger D.; Gounis, Matthew J.; Ingber, Donald E.Platelets are crucial for normal hemostasis; however, their hyperactivation also contributes to many potentially lethal pathologies including myocardial infarction, stroke, and cancer. We hypothesized that modified platelets lacking their aggregation and activation capacity could act as reversible inhibitors of platelet activation cascades. Here, we describe the development of detergent-extracted human modified platelets (platelet decoys) that retained platelet binding functions but were incapable of functional activation and aggregation. Platelet decoys inhibited aggregation and adhesion of platelets on thrombogenic surfaces in vitro, which could be immediately reversed by the addition of normal platelets; in vivo in a rabbit model, pretreatment with platelet decoys inhibited arterial injury-induced thromboembolism. Decoys also interfered with platelet-mediated human breast cancer cell aggregation, and their presence decreased cancer cell arrest and extravasation in a microfluidic human microvasculature on a chip. In a mouse model of metastasis, simultaneous injection of the platelet decoys with tumor cells inhibited metastatic tumor growth. Thus, our results suggest that platelet decoys might represent an effective strategy for obtaining antithrombotic and antimetastatic effects. American Association for the Advancement of Science 2019.
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Cartland, Si; Genner, Scott W.; Martez, Gonzalo J.; Robertson, Stacy; Kockx, Maae; Lin, Ruby CY; OSullivan, John F.; Koay, Yen Chin; Cholan, Pradeep Manuneedhi; Kebede, Melkam A.; Murphy, Andrew James; Masters, Seth L.; Bennett, Martin Richard; Jessup, Wendy; Kritharides, Leonard; Geczy, Carolyn L.; Patel, Sanjay; Kavurma, Mary M.Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s)of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.; Pathophysiology; Molecular Mechanism of Behavior; Diabetology; Immunology; Immune Response 2019 The Authors; 2019 The Authors
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Mackie, Grace; Gao, Lingzi; Yau, Stephen; Leslie, Daniel C.; Waterhouse, AnnaImmobilized liquid (IL) surface coatings are an emerging technology that provide to materials the ability to repel complex biological fluids and hold promise in medical applications to prevent biological fouling, especially in the context of preventing medical device-induced thrombosis, fibrosis, and biofilm formation. However, little is known about the biological interactions of the IL with proteins and cells, and an increased understanding is critical for optimal device application, function, and successful clinical translation. Here, we review existing clinical and biological knowledge of the liquids used in these surface coatings, recent developments in understanding the biological interactions of IL coatings, and future directions and challenges for the clinical translation of this new class of IL surface coatings. 2018
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Schilter, Heidi; Findlay, Alison D.; Perryman, Lara A.; Yow, Tin Thing; Moses, Joshua; Zahoor, Amna; Turner, Craig I.; Deodhar, Mandar; Foot, Jonathan S.; Zhou, Wenbin; Gre?o, Angelique; Joshi, Amar; Rayner, Benjamin Saul; Townsend, Sarah; Buson, Alberto A.; Jarolimek, WolfgangFibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ?-amino group of lysine or hydroxylysine on collagen side-chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS-5153A, a novel mechanism based, fast-acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS-5153A dose-dependently reduced LOXL2-mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet-induced, PXS-5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS-5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis. 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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Barraclough, Jennifer Y.; Skilton, Michael R.; Garden, Frances L.; Toelle, Brett G.; Marks, Guy B.; Celermajer, David S.Introduction: Carotid Intima Media Thickness (CIMT) is a marker of subclinical atherosclerosis, associated with cardiovascular risk in adults. Telomere length (TL) is a marker of cellular ageing. We sought to determine whether telomere length in early childhood and/or at 14-years is associated with CIMT in adolescence, in a community-based cohort study. Methods: 118 children had TL measured at mean age 3.6-years and 165 children had TL and CIMT, measured at 14-years, from the community-based Childhood Asthma Prevention Study. Results: TL in early childhood was significantly inversely associated with CIMT at 14 years, p = 0.04. TL in teenage life was also significantly inversely associated with CIMT at 14 years, p = 0.03. This latter association was no longer significant, however, after adjusting for early life TL. Conclusion: TL measured in early childhood and adolescence is significantly associated with CIMT at 14-years, suggesting that telomere length is a biological marker or even early determinant of late cardiovascular risk. 2018 Elsevier B.V.
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Tanyanskiy, Dmitry A.; Jarzebska, Natalia; Birkenfeld, Andreas L.; OSullivan, John F.; Rodionov, Roman NikolaevichThe prevalence and incidence of metabolic syndrome is reaching pandemic proportions worldwide, thus warranting an intensive search for novel preventive and treatment strategies. Recent studies have identified a number of soluble factors secreted by adipocytes and myocytes (adipo-/myokines), which link sedentary life style, abdominal obesity, and impairments in carbohydrate and lipid metabolism. In this review, we discuss the metabolic roles of the recently discovered myokine ?-aminoisobutyric acid (BAIBA), which is produced by skeletal muscle during physical activity. In addition to physical activity, the circulating levels of BAIBA are controlled by the mitochondrial enzyme alanine: glyoxylate aminotransferase 2 (AGXT2), which is primarily expressed in the liver and kidneys. Recent studies have shown that BAIBA can protect from diet-induced obesity in animal models. It induces transition of white adipose tissue to a beige phenotype, which induces fatty acids oxidation and increases insulin sensitivity. While the exact mechanisms of BAIBA-induced metabolic effects are still not well understood, we discuss some of the proposed pathways. The reviewed data provide new insights into the connection between physical activity and energy metabolism and suggest that BAIBA might be a potential novel drug for treatment of the metabolic syndrome and its cardiovascular complications. 2019 by the authors. Licensee MDPI, Basel, Switzerland.
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Nash, Megan; McGrath, Jordan P.; Cartland, Si; Patel, Sanjay; Kavurma, Mary M.Current treatment of ischaemic vascular diseases such as coronary and peripheral artery disease includes angioplasty and bypass grafting, as well as lipid lowering therapies and control of other cardiovascular risk factors. Numerous members of the tumour necrosis factor superfamily (TNFSF) have recently shown emerging roles in both the protection and progression of such diseases. Understanding the role TNFSF members play in ischaemic vascular disease may provide insight into the development of novel therapeutics to prevent or treat diseases relating to atherosclerosis and ischaemia. This review summarizes the most recent findings relating to TNFSF members and the mechanisms that precede ischaemic vascular disease progression, particularly endothelial dysfunction, chronic inflammation, and atherosclerotic plaque development. This review also explores recent translational research on the role of TNFSF therapies in cardiovascular disease. Published on behalf of the European Society of Cardiology. All rights reserved. The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
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Solon-Biet, Samantha M.; Cogger, Victoria Carroll; Pulpitel, Tamara Jayne; Wahl, Devin; Clark, Ximonie; Bagley, Elena E.; Gregoriou, Gabrielle C.; Senior, Alistair M.; Wang, Qiaoping; Brandon, Amanda E.; Perks, Ruth; OSullivan, John F.; Koay, Yen Chin; Bell-Anderson, Kim S.; Kebede, Melkam A.; Yau, Belinda; Atkinson, Clare; Svineng, Gunbjg; Dodgson, Tim; Wali, Jibran A.; Piper, Matthew DW; Juricic, Paula; Partridge, Linda Donald; Rose, Adam J.; Raubenheimer, David R.; Cooney, Gregory J.; Le Couteur, David G.; Simpson, Stephen JamesElevated branched-chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA per se or hepatic mammalian target of rapamycin activation, but instead are due to a shift in the relative quantity of dietary BCAAs and other amino acids, notably tryptophan and threonine. Increasing the ratio of BCAAs to these amino acids results in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high-BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but instead are a consequence of hyperphagia driven by amino acid imbalance. 2019, The Author(s), under exclusive licence to Springer Nature Limited.
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Korgaonkar, Mayuresh S.; Erlinger, May; Breukelaar, Isabella A.; Boyce, Philip M.; Hazell, Philip L.; Antees, Cassandra; Foster, Sheryl L.; Grieve, Stuart M.; Gomes, Lavier J.; Williams, Leanne M.; Harris, Anthony W.F.; Malhi, Gin S.Background: Mechanistically based neural markers, such as amygdala reactivity, offer one approach to addressing the challenges of differentiating bipolar and unipolar depressive disorders independently from mood state and acute symptoms. Although emotion-elicited amygdala reactivity has been found to distinguish patients with bipolar depression from patients with unipolar depression, it remains unknown whether this distinction is traitlike and present in the absence of an acutely depressed mood. We addressed this gap by investigating patients with bipolar disorder (BP) and unipolar major depressive disorder (MDD) in remission. Methods: Supraliminal and subliminal processing of faces exhibiting threat, sad, happy, and neutral emotions during functional magnetic resonance imaging was completed by 73 participants (23 BP patients and 25 MDD patients matched for age and gender, number of depressive episodes and severity; 25 age- and gender-matched healthy control subjects). We compared groups for activation and connectivity for the amygdala. Results: BP patients had lower left amygdala activation than MDD patients during supraliminal and subliminal threat, sad, and neutral emotion processing and for subliminal happy faces. BP patients also exhibited lower amygdala connectivity to the insula and hippocampus for threat and to medial orbitofrontal cortex for happy supraliminal and subliminal processing. BP patients also demonstrated greater amygdala-insula connectivity for sad supraliminal and subliminal face processing. Both patient groups were distinct from control subjects across several measures for activation and connectivity. Conclusions: Independent of valence or level of emotional awareness, amygdala activation and connectivity during facial emotion processing can distinguish BP patients and MDD patients. These findings provide evidence that this neural substrate could be a potential trait marker to differentiate these two disorders largely independent of illness state. 2018 Society of Biological Psychiatry
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Soni, Apurv V.; Karna, Sunil; Fahey, Nisha; Sanghai, Saket R.; Patel, Harshil Anurag; Raithatha, Shyamsundar J.; Thanvi, Sunil S.; Nimbalkar, Somashekhar Marutirao; Freedman, Ben Ben; Allison, Jeroan J.; McManus, David D.Background: Early detection of Atrial Fibrillation (AF) is a public health priority across the globe because AF-related strokes are preventable. Despite an ongoing stroke epidemic in India, a public health strategy for AF screening and treatment is missing because the epidemiology of AF in India remains poorly defined. Methods: This population-based study used mobile technology to derive age and sex-stratified AF prevalence by screening 7 participants in each of six age and sex strata (age 4055, 5665, 65+, and male and female) from 50 villages (2100 participants). A health worker from each village used a handheld digital electrocardiogram (iECG) device (Kardia) to screen for AF on 3 separate days, and administered a questionnaire. All abnormal (AF or unclassified) iECGs were reviewed by the Indian cardiologist and AF determination confirmed by a US-based cardiac electrophysiologist. Results: Of the 2100 individuals enrolled, iECGs were collected from 2074 participants (98.8%) and 1947 (92.7%) participants responded to the questionnaire. AF was identified in 33 participants (1.6%), two-thirds on the first iECG. AF prevalence was higher among males (2.3% vs 1.0%, p = 0.03) and in older people (0.6%, 0.9%, 2.1%, 5.6%; p < 0.01). Conclusions: The prevalence of AF observed in our population-based sample is comparable to rates found in studies from North America and Western Europe and increases similarly with age. AF screening using village health workers in rural India is feasible and presents an opportunity for a strategy to address the stroke epidemic in India through primary prevention. 2018 Elsevier B.V.
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Cai, Huan; Chuang, Christine Y.; Vanichkitrungruang, Siriluck; Hawkins, Clare L.; Davies, Michael J.The extracellular matrix (ECM) influences the structure and function of the arterial wall and modulates the behavior of vascular cells through ECM-cell interactions. Alterations to the ECM have been implicated in multiple pathological processes, including atherosclerosis which is characterized by low-grade chronic inflammation and the infiltration and proliferation of smooth muscle cells during disease development. Considerable evidence has been presented for a role for inflammation-derived oxidation in atherogenesis, with enzymatically-active myeloperoxidase (MPO), elevated levels of 3-chlorotyrosine (a biomarker of MPO-catalyzed damage) and oxidized ECM materials detected in advanced human atherosclerotic lesions. Whether oxidant-modified ECM contributes to the altered behavior of smooth muscle cells is however unclear. This study therefore investigated the effects of hypochlorous acid (HOCl), a major MPO-derived oxidant, on the structure of the native ECM synthesized by human coronary artery smooth muscle cells (HCAMSCs) and whether modified ECM proteins affected HCASMC adhesion, proliferation and gene expression. Exposure of native HCASMC-derived ECM to reagent HOCl or a MPO-Cl - -H <inf>2</inf> O <inf>2</inf> system resulted in extensive ECM modifications as evidenced by the loss of antibody recognition of epitopes on type IV collagen, laminin, versican and fibronectin. Oxidation of HCASMC ECM markedly reduced HCASMC adhesion to matrix components, but facilitated subsequent proliferation in vitro. Multiple genes were upregulated in HCASMCs in response to HOCl-modified HCASMC-ECM including interleukin-6 (IL-6), fibronectin (FN1) and matrix-metalloproteinases (MMPs). These data reveal a mechanism through which inflammation-induced ECM-modification may contribute to the behavioral switching of HCASMCs, a key process in plaque formation during the development of atherosclerosis. 2019 Elsevier Inc.
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Reyes, Leila; Hawkins, Clare L.; Rayner, Benjamin SaulOxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury, which is in part due to the release of the enzyme myeloperoxidase (MPO) from activated infiltrating leukocytes, and the subsequent production of the oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). Although exposure of various cell types to either oxidant is known to cause cellular dysfunction within a variety of pathological settings, the precise role of HOCl and HOSCN in the initiation of tissue damage evident following cardiac I/R injury remains unclear. In this study, we have employed the use of the cardiac myoblast cell line H9c2 as a model for cardiac myocytes and demonstrate that exposure to either oxidant elicits a dose-dependent increase in cytosolic calcium accumulation, depletion of the cellular thiol pool, reduction of glutathione (GSH) levels and loss of mitochondrial inner trans-membrane potential, concomitant with increased necrotic cell death. H9c2 cell recovery from the initial oxidant exposure involves the initiation of cell survival signalling pathways centred around Nrf2-antioxidant response element (ARE) and activator protein 1 (AP-1) activation, with cell survival accompanied by restoration of mitochondrial function following exposure to HOSCN, but not HOCl. These data highlight the cellular responses elicited by HOCl and HOSCN in cardiac myocytes furthering our understanding of the pathogenesis of oxidant injury following cardiac I/R injury. 2019 Elsevier Inc.
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Morganti-Kossmann, Maria Cristina; Semple, Bridgette D.; Hellewell, Sarah Claire; Bye, Nicole; Ziebell, Jenna M.This review recounts the definitions and research evidence supporting the multifaceted roles of neuroinflammation in the injured brain following trauma. We summarise the literature fluctuating from the protective and detrimental properties that cytokines, leukocytes and glial cells play in the acute and chronic stages of TBI, including the intrinsic factors that influence cytokine responses and microglial functions relative to genetics, sex, and age. We elaborate on the pros and cons that cytokines, chemokines, and microglia play in brain repair, specifically neurogenesis, and how such conflicting roles may be harnessed therapeutically to sustain the survival of new neurons. With a brief review of the clinical and experimental findings demonstrating early and chronic inflammation impacts on outcomes, we focus on the clinical conditions that may be amplified by neuroinflammation, ranging from acute seizures to chronic epilepsy, neuroendocrine dysfunction, dementia, depression, post-traumatic stress disorder and chronic traumatic encephalopathy. Finally, we provide an overview of the therapeutic agents that have been tested to reduce inflammation-driven secondary pathological cascades and speculate the future promise of alternative drugs. 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
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Fullard, Karen J.; Maller, Jerome Joseph; Welton, Thomas; Lyon, Matthew; Gordon, Evian; Koslow, Stephen H.; Grieve, Stuart M.Occipital bending (OB) describes asymmetry of the occipital lobes where one lobe wraps across the midline, and has been associated with the presence of mood disorders. We evaluated the relationship between OB and major depressive disorder (MDD) in a large population of subjects from the International Study to Predict Optimized Treatment in Depression. MDD patients (n = 231) and healthy controls (n = 68) underwent MRI and neuropsychiatric evaluation, including response or remission to antidepressant medication at baseline and at 8 weeks. Cortical thickness, ventricular volumes and regional grey matter volumes were measured. OB was visually assessed and OB angle measured using a semi-automated method. Correlations with MDD diagnosis, MRI measures and clinical features were tested. Results demonstrated a greater proportion of rightwards OB in MDD compared to control subjects (p = 0.02). There was no difference in the total prevalence of OB (combined left and rightward bending) between MDD and controls. MDD subjects with right OB had greater cortical thickness in three medial occipital regions (cuneus, lingual gyrus and calcarine sulcus) on the left. Lateral ventricular size was 20% lower bilaterally in right OB MDD subjects compared to non-OB MDD subjects. OB was not associated with severity (HDRS-17). Our data suggest the presence of a strong link between greater rightward occipital bending and MDD. Rightward-OB is associated with greater left medial occipital cortical thickness, and with reduced lateral ventricular size. The cause for greater rightward bending in MDD patients is unclear, however our data suggest a developmental aetiology. 2019
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Brieger, David B.; Connell, Cia; Freedman, Ben Ben[No abstract available]
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Barraclough, Jennifer Y.; Garden, Frances L.; Toelle, Brett G.; Marks, Guy B.; Baur, Louise Alison; Ayer, Julian Ganesh J.; Celermajer, David S.Objective: To assess the influence of the trajectory of weight gain from birth to adolescence on cardiovascular and metabolic risk. We studied childhood body mass index (BMI) trajectories from birth to age 14 years and cardiometabolic risk factors at age 14 years. Study design: In total, 410 children with weight and height measurements were assessed from birth throughout childhood, from the Childhood Asthma Prevention Study, a prospective community-based cohort. BMI trajectory groups were determined by latent basis growth mixture models. Of these subjects, 190 had detailed cardiometabolic risk factors assessed at age 14 years. Results: Three BMI trajectory groups were identified; normal BMI, early rising excess BMI from 2 years, and late rising excess BMI from 5 years. Differences were found between normal and excess BMI in children at 14 years of age. In addition, children with an early rising BMI trajectory had statistically significantly higher central adiposity and a more atherogenic lipoprotein profile at age 14 years than children with a late rising BMI trajectory (P <.05). No differences between BMI trajectory groups in vascular structure or function was identified at age 14 years. Conclusions: Earlier onset of an elevated BMI trajectory persisting from birth to age 14 years results in an unfavorable cardiometabolic risk profile at age 14 years, including central adiposity and more atherogenic lipoproteins, independent of achieved BMI. 2018 Elsevier Inc.
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Yuan, Jun; Tan, Joanne Tsui Ming; Rajamani, Kushwin; Solly, Emma L.; King, Emily J.; Lecce, Laura; Simpson, Philippa J.L.; Lam, Yuen Ting; Jenkins, Alicia J.; Bursill, C. A.; Keech, Anthony C.; Ng, Martin K.C.Fenofibrate, a peroxisome proliferator-activated receptor ? (PPAR?) agonist, reduces lower limb amputations in patients with type 2 diabetes. The mechanism is, however, unknown. In this study, we demonstrate that fenofibrate markedly attenuates diabetes-related impairment of ischemia-mediated angiogenesis. In a murine model of hindlimb ischemia, daily oral fenofibrate treatment restored diabetes-impaired blood flow recovery, foot movement, hindlimb capillary density, vessel diameter, and vascular endothelial growth factor signaling to nondiabetic levels in both wild-type and PPAR?knockout mice, indicating that these fenofibrate effects are largely PPAR? independent. In vitro, fenofibric acid (FFA) rescued high glucose-induced (25 mmol/L) impairment of endothelial cell migration, tubulogenesis, and survival in a PPAR?-independent manner. Interestingly, fenofibrate in vivo and FFA in vitro reversed high glucose-induced expression of thioredoxin-interacting protein (TXNIP), an exquisitely glucose-inducible gene previously identified as a critical mediator of diabetesrelated impairment in neovascularization. Conversely, adenoviral overexpression of TXNIP abrogated the restorative effects of FFA on high glucose-impaired endothelial cell function in vitro, indicating that the effects of FFA are mediated by TXNIP. We conclude that fenofibrate rescues diabetic impairment in ischemia- mediated angiogenesis, in large part, by PPAR?independent regulation of TXNIP. These findings may therefore explain the reduction in amputations seen in patients with diabetes treated with fenofibrate. 2019 American Diabetes Association Inc.. All rights reserved.
