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Rationale: Raised serum C-Reactive Protein (CRP) 14 days after a COPD exacerbation predicts a second exacerbation, presumably due to persistent inflammation or bacterial infection. We examined if a further exacerbation could be prevented by re-treating incompletely resolved COPD exacerbations using Ciprofloxacin. Methods: This multi-centre randomized double-blind placebo-controlled study assessed retreatment with twice daily oral ciprofloxacin 500mg vs placebo for 7 days in patients whose symptoms and/or CRP had not normalised ( Results: Of 826 COPD patients screened at 4 centres, 144 eligible participants with incomplete recovery at day 12-16 post exacerbation were randomised to ciprofloxacin (n=72) or placebo (n=72). Patients had baseline mean age 69.0, 63.2% male, FEV1 49.5% predicted and CAT score 20.5. Median time to the next exacerbation was 32.5 days (IQR 13-50) in the placebo arm and 34 days (IQR 17-62) in the treatment arm. After pre-specified adjustments for previous exacerbations and site there were no significant differences between the groups (p=0.76) (fig 1). No significant differences were seen in CAT, SGRQ or lung function between treatment groups. Conclusion: In patients with incomplete recovery after a treated COPD exacerbation, an additional course of ciprofloxacin provided no additional benefit relative to placebo.

Background: Axial inflammation is a key feature in axial SpA (axSpA). There is lack of data relative to the persistence of BME in the same anatomical quadrant (Q, 8 in total for both SIJ together), regardless of the overall presence of BME. Objectives: This study aims to investigate particular patterns of distribution of SIJ-BME across quadrants over time, their persistence over time, and their impact on clinical and structural outcomes. Methods: Patients from the DESIR cohort (early axSpA according to the rheumatologist) with MRI-SIJ available at baseline, 2 and 5 years were included. Each image was scored by 3 trained central readers blinded to chronological order. BME was considered positive if detected in ≥1/6 slices in each of the 8 quadrants, according to each individual reader. Four different patterns of BME over time were defined (no BME, sporadic pattern, fluctuating BME and persistent BME) considering all 8 quadrants (Figure). The effect of BME patterns on 5-year structural (mNY, mSASSS, ≥5 erosions and/or fatty lesions in MRI-SIJ) and clinical outcomes (BASFI, BASMI and ASQoL) was evaluated using multilevel generalised estimating equations (GEE) models (taking the individual reader data into account) and linear regression (using the agreement of ≥ 2 out of 3), as appropriate. All models were adjusted for relevant confounders including treatment (Table). Results: In total, 136 patients were included (age 34 (SD 9) years, 50% male, and 63% HLA-B27 positive). ‘No BME’ was seen in 63 patients (46%), the ‘sporadic pattern’ in 34 patients (25%), the ‘fluctuating pattern’ was seen in 21 patients (15%) and the ‘persistent BME pattern’ was seen in 18 patients (13%). Compared to the ‘no BME’ pattern (reference), the ‘sporadic’ [OR (95% CI): 2.1 (1.0;4.5)], ‘fluctuating’ [OR: 5.6 (2.2;14.4)] and ‘persistent’ [OR: 7.5 (2.8;19.6)] patterns were associated with higher likelihood to be mNY positive at 5-years, suggesting a gradient between cumulative inflammation and damage. Similar findings were observed for mNY as a continuous outcome variable and for ≥5 erosions and/or fatty lesions on spinal MRI as outcomes, but not for mSASSS (Table). There was no association between the BME patterns and the clinical outcomes. Conclusion: Only 13% of the patients showed persistent inflammation in the same Q over a 5-year period and in 15% inflammation was fluctuating across different Qs. More structural damage was found in patients with increasing cumulative levels of local inflammation in the quadrant. Even when BME (temporarily) disappears there is an important effect on structural outcomes, and that effect t is independent of treatment. Disclosure of Interests: Santiago Rodrigues-Manica Grant/research support from: Novartis, MSD, Speakers bureau: Novartis, Alexandre Sepriano: None declared, Sofia Ramiro Grant/research support from: MSD, Consultant for: AbbVie, Lilly, MSD, Novartis, Pfizer, Sanofi, Speakers bureau: AbbVie, Lilly, MSD, Novartis, Pfizer, Sanofi, Robert B.M. Landewe: None declared, Pascal Claudepierre Consultant for: Honoraria from Novartis as steering committe of this survey, Anna Molto: None declared, maxime dougados Grant/research support from: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Miranda van Lunteren: None declared, Desiree van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, Union Chimique Belge

While intrauterine fluid (IUF) is observed as mucous in healthy mares during estrus, the presence of IUF during diestrus is an indicator of endometritis. Mating induces endometrial inflammation in healthy mares, called mating-induced endometritis, that disappears within 1–2 days after mating. On the other hand, it is also known that IUF remaining beyond 12 hr after mating can cause persistent inflammation, bacterial growth, and decreased fertility. This study aimed to investigate the relationship between the presence of IUF and cervical bacteria before and after mating. Mares were classified into three groups based on the degree of IUF: Grade 1 (G1), neither IUF nor echogenic lines at the inner lining of the uterus; Grade 2 (G2), small amount of IUF (

Traumatic brain injury (TBI) is one of the leading causes of disability and mortality of people at all ages. Biochemical, cellular and physiological events that occur during primary injury lead to a delayed and long-term secondary damage that can last from hours to years. Secondary brain injury causes tissue damage in the central nervous system and a subsequent strong and rapid inflammatory response that may lead to persistent inflammation. However, this inflammatory response is not limited to the brain. Inflammatory mediators are transferred from damaged brain tissue to the bloodstream and produce a systemic inflammatory response in peripheral organs, including the cardiovascular, pulmonary, gastrointestinal, renal and endocrine systems. Complications of TBI are associated with its multiple and systemic effects that should be considered in the treatment of TBI patients. Therefore, in this review, an attempt was made to examine the systemic effects of TBI in detail. It is hoped that this review will identify the mechanisms of injury and complications of TBI, and open a window for promising treatment in TBI complications.

Objectives:To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research.Design:Literature search us

Recently significant advances have been made to understand the pathophysiological mechanisms of neurodegenerative disorders to provide real therapeutic benefits. There is evidence that persistent inflammation and oxidative stress are the crucial factors of ongoing cell damage in neurodegenerative complex etiology. The variety of reactive oxygen and nitrogen species are the cause of both axonal and neuronal destruction, which is pathological hallmark of neurodegeneration. Therefore, the reduction of oxidative stress is currently one of the main neuroprotective strategies. The World Health Organization (WHO) estimates that, by 2040, neurodegenerative diseases will be the main cause of death in industrialized countries ahead of the cancers. The redox therapeutic approch can target: degnerative component, inflammatory/autoimmune component and neurodegenerative component. Redox therapy should not be applied uniformly, and must be develop to target specific mechanisms. This review focus on the main antitoxidative therapies that are used in many countries as a supplements or even as a standart treatment. Aditionally, clinical synmptoms of most common neurodegenerative disordes and centralnervous system structures involved in oxidative/nitrosative stress are showed.

Bioresorbable vascular scaffolds (BVS) have emerged as an interesting alternative since the presence of the prosthesis in the coronary artery is transient. This technology enables to restore the normal vasomotor tone and allows positive remodeling, simultaneously reducing the trigger for persistent inflammation and facilitating further interventions by percutaneous or surgical means. Absorb BVS ® is the first generation everolimus-eluting poly-L-lactide (PLLA) bioresorbable scaffold. In recent meta-analyses Absorb BVS ® was definitely proved to be safe and effective device in the treatment of symptomatic coronary artery disease. This was recently confirmed by FDA advisory panel of experts who recommended approval of the device based on an analysis of its risks and rewards. Nevertheless, still there are some concerns regarding stent thrombosis, and the real vessel functionality restoration at long-term observation. Worth mentioning is the fact that apart from stable coronary disease Absorb BVS ® is used successfully in a series of off-label clinical settings such as acute coronary syndromes including STEMI, in-stent restenosis, coronary bifurcations, left main stenting or chronic total occlusions. Moreover, new bioresorbable scaffolds are under development with DEsolve ® and DREAM 2G ® , which are the most advanced.

Stevens-Johnson syndrome (SJS) is an acute blistering disease of the skin and mucous membranes. Acute SJS leads to the acute inflammation of the ocular surface and chronic conjunctivitis. If not properly treated, it causes chronic cicatricial conjunctivitis and cicatricial lid margin abnormalities. Persistent inflammation and ulceration of the ocular surface with cicatricial complications of the lids leads to chronic ocular sequelae, ocular surface damage, and corneal scarring. The destruction of the glands that secrete the tear film leads to a severe form of dry eye that makes the management of chronic SJS difficult. The option that is routinely used for corneal visual rehabilitation, keratoplasty, is best avoided in such cases. We describe the management strategies that are most effective during the acute and chronic stages of SJS. Although treatments for acute SJS involve immunosuppressive and immunomodulatory therapies, amniotic membrane transplantation is also useful. The options for visual rehabilitation in patients with chronic SJS are undergoing radical change. We describe the existing literature regarding the management of SJS and highlight recent advances in the management of this disorder.

Objectives To better understand the effect of TNF-α inhibitors (TNFi) on new bone formation in ankylosing spondylitis (AS) patients. Methods We systematically searched the articles in EMBASE and PubMed. Results Fifteen articles were enrolled. In all the 9 TNFi-treated cohorts, the vertebral corners with inflammatory lesions at baseline were at higher risk to develop new syndesmophytes than those without inflammatory lesions, although a few syndesmophytes also developed at the vertebral corners without inflammatory lesions at baseline. The advanced inflammatory lesions including fat deposition on baseline MRI showed a higher risk for syndesmophyte formation than the acute inflammatory lesions. Because the number of analyzed vertebral corners were too small, it might not be true that new syndesmophytes developed more frequently at the corners with inflammatory lesions completely resolved than those with persistent inflammation after TNFi treatment. Four studies with 2-year follow-up revealed null effect of TNFi on radiographic progression compared with historical controls with lower disease activity, and 3 studies with ≥ 4-year follow-up proved inhibitory effect of TNFi on new bone formation in AS patients. Patients with a delay of > 10 years in starting TNFi therapy were more likely to experience radiographic progression as compared to those who started earlier. Conclusions In TNFi treated AS patients, baseline inflammation is linked with syndesmophyte development. An earlier initiation of TNFi therapy may slow the radiographic progression in AS, and TNFi may lose its benefit of retarding new bone formation at advanced stage of AS especially after the focal fat infiltration or syndesmophyte formation.

Fox-Fordyce disease (FFD) is a rare chronic disorder characterised by persistent inflammation because of the obstruction of apocrine sweat glands, which is a key factor of pathogenesis. The treatment of FFD is known to be difficult, and the modalities of treatment have not yet been widely studied. We report the successful treatment of a case of bilateral areolar FFD by a combination of surgical excision and 1550-nm fractionated erbium glass laser in an 18-year-old woman. The patient presented with a bilateral areolar eruption of multiple, severely pruritic, 3-4 mm skin- to grey-coloured folliculocentric dome-shaped papules. The initial treatment plan was for bilateral surgical excision of the larger and more highly elevated papules via circumferential dermal excision, which was intended to maintain the areolar contour and minimise distortion. A 1550-nm fractional erbium glass laser was then used to control the remnant lesions. The patient was recurrence-free at 14 months after the final laser treatment, and she was fully satisfied with the treatment results.

Macrophages are key players in wound healing- along with mediating the acute inflammatory response, macrophages activate cutaneous epithelial cells and promote tissue repair. Diabetes complications, including diabetic chronic wounds, are accompanied by persistent inflammation and macrophage malfunction. Several studies indicate that hyperglycemia induces various alterations that affect macrophage function in wound healing including epigenetic changes, imbalance between pro- and anti-inflammatory modulators, and insensitivity to proliferative stimuli. In this review, we briefly summarize recent studies regarding those alterations and their implications on skin well-being in diabetes.

Small genetically-determined differences in transcription (eQTLs) are implicated in complex disease but the mechanisms by which small changes in gene expression impact complex disease are unknown. Here we show that a persistent small increase in expression of the innate sensor NOD1 precipitates large cancer-promoting changes in cell state. A ~1.2-1.4 fold increase in NOD1 protein concentration by loss of miR-15b/16 regulation sensitizes cells to ligand-induced inflammation, with an additional slight increase leading to ligand-independent NOD1 activation that is linked to poor prognosis in gastric cancer. Our data show that tight expression regulation of NOD1 prevents this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and oncogene expression and reveal the impact of a single small quantitative change in cell state on cancer.One Sentence SummaryA small change in NOD1 expression has a large cancer-promoting impact on cell state.

Introduction:The recently published 2018 ESPEN Guidelines on Clinical Nutrition in the Intensive Care Unit [1] represents a valuable revision of the 2006 Enteral Nutrition Guidelines [2] and the 2009 Parenteral Nutrition Guidelines [3] published earlier by this European group. The guidelines committee members have done an excellent job in putting thismanuscript together, providing directives that are clear, concise, brief, and most importantly, transparent. They included only studies published since 2000 for use in their meta-analyses, commenting that this time of transition heralded a new era in the literature involving higher quality randomized control trials (RCTs) and methodologic innovations such as trial registry. Not mentioned (but felt by many within the nutrition community) was the sense that this particular time was a tipping point, following the publication of Van den Berghe’s seminal paper on intensive insulin therapy [4]. Studies published in nutrition prior to this date were felt to reflect an older more antiquated style of management that was less effective. These authors utilized the persistent inflammation catabolism syndrome (PICS) system where four parameters (the patient, intervention, controls, and outcomes) are clearly described, which in turn direct the questions that the guideline committee members were to address. Quality of evidence was assessed by GRADE methodology, and a cut-off date of August 2017 for data entry from the literature was clearly identified. Not all of the recommendations were based on RCTs. The authors are to be commended in that they provided recommendations based on Level 4 low-quality evidence, in areas where RCTs were not available, clearly taking advantage of the group of experts on the committee to provide practical guidance for clinicians where there was a paucity of literature to support evidence-based practices.

The aim of the study was to evaluate the inflammatory reaction in children with pseudocroup and compare it with other laryngological diseases according to the available literature data. The study group included 51 children hospitalized because of pseudocroup. The measurements of the acute phase proteins (APP), such as C-reactive protein (CRP), alpha-1-antitrypsin (AT), alpha-1-antichymotrypsin (ACT), alpha-1-acid glycoprotein (AGP), ceruloplasmin (Cp), transferrin (Tf), alpha-2-macroglobulin (A2M), and haptoglobin (Hp) were obtained at 3 time points. The glycosylation profiles of AGP, ACT, and Tf were completed. An increased AGP level was observed in girls. The AGP glycosylation revealed the advantage of the W0 variant over the W1 variant. W1 and W2 were decreased in boys. W3 emerged in boys. The Tf concentration and T4 variant were lower compared to the control group. The A2M level was lower after treatment. The Hp and AT levels were decreased a few weeks later. The ACT glycosylation revealed a decrease of the A4 variant in boys. In conclusion, the inflammatory reaction during pseudocroup was of low intensity. The APP glycosylation suggested a chronic process. In a follow-up investigation, no normalization of the parameters was noted, but signs of persistent inflammation were observed.

Chronic visceral pain is a frequent and disabling condition. Despite high prevalence and impact, chronic visceral pain is not represented in ICD-10 in a systematic manner. Chronic secondary visceral pain is chronic pain secondary to an underlying condition originating from internal organs of the head or neck region or of the thoracic, abdominal, or pelvic regions. It can be caused by persistent inflammation, by vascular mechanisms or by mechanical factors. The pain intensity is not necessarily fully correlated with the disease process, and the chronic visceral pain may persist beyond successful treatment of the underlying cause. This article describes how a new classification of chronic secondary visceral pain is intended to facilitate the diagnostic process and to enable the collection of accurate epidemiological data. Furthermore, it is hoped that the new classification will improve the tailoring of patient-centered pain treatment of chronic secondary visceral pain and stimulate research. Chronic secondary visceral pain should be distinguished from chronic primary visceral pain states that are considered diseases in their own right.

BACKGROUND: Chronic inflammation and immune dysfunction occur in human immunodeficiency virus (HIV)-infection despite stable antiretroviral therapy (ART). Red blood cell distribution width (RDW) has been shown to correlate with markers of inflammation in non-HIV conditions. The study objective was to determine associations between RDW with cellular markers of immune activation and immune dysfunction including soluble inflammatory mediators in ART treated HIV infection. METHODS: We performed a cross-sectional analysis of the Hawaii Aging with HIV-Cardiovascular study. RDW was defined as one standard deviation of RBC size divided by mean corpuscular volume multiplied by 100%. Correlations were analyzed between RDW, soluble inflammatory biomarkers and T cell activation (CD38 + HLA-DR+), senescence (CD28-CD57+), and immune exhaustion (PD-1, TIGIT, TIM-3 expression). RESULTS: Of 158 participants analyzed, median age was 50 years, duration of ART 12.6 years, virally suppressed 84.4%, and CD4 count 503 cells/mm3. Significant positive correlations were identified between RDW and soluble biomarkers including sICAM, IL-8, IL-6, SAA, TNF-α, sE-selection, fibrinogen, D-dimer, CRP, CD4/CD8 ratio, and frequency of multiple CD8 T-cell populations such as CD38 + HLA-DR + T-cells, single TIGIT+, and dual expressing of TIGIT + PD1+, TIGIT + TIM3+, and TIM3 + PD1+ CD8+ T-cell subsets (p < .05). Frequencies of CD38 + HLA-DR + CD8+ T-cells and TIGIT + CD8+ T-cells remained significant adjusting for baseline variables (p < .01). CONCLUSION: Our study revealed correlations between RDW with systemic inflammatory biomarkers and CD8+ T-cell populations related to immune activation and exhaustion in HIV-infected individuals on ART. Further studies are warranted to determine the utility of RDW as a marker of immune dysregulation in HIV.

Inflammation-resolution is an active process that is governed in part by specialized pro-resolving mediators (SPMs) such as lipoxins, resolvins, protectins, and maresins. SPMs, which are endogenously biosynthesized, quell inflammation and repair tissue damage in a manner that does not compromise host defense. Importantly, failed inflammation-resolution is an important driving force in the progression of several prevalent diseases including atherosclerosis. Atherosclerosis is a leading cause of death worldwide and uncovering mechanisms that underpin defective inflammation-resolution and whether SPMs themselves can revert the progression of the disease are of utmost clinical interest. Because atherosclerosis is a disease in which low-grade persistent inflammation results in tissue injury, SPMs have garnered immense interest as a potential treatment strategy. This mini review will highlight recent work that describes mechanisms associated with defective inflammation-resolution in atherosclerosis, as well as the protective actions of SPMs and their potential use as a therapeutic.

IntroductionSubclinical inflammation, detected by MRI, in patients with arthralgia is predictive for development of inflammatory arthritis (IA). However, within patients that develop IA, the course of inflammation at the joint level during this transition is unknown. This longitudinal study assessed progression of inflammation at the joint level.Methods350 joints (unilateral metacarpophalangeals (MCPs), wrist, metatarsophalangeal (MTP) joints) of 35 patients presenting with clinically suspect arthralgia (CSA) that progressed to IA were studied at presentation with CSA and subsequently when clinical synovitis was first identified at joint examination (median time interval 17 weeks). At both time points, subclinical inflammation (bone marrow oedema, synovitis, tenosynovitis) was evaluated with MRI and joint examination was performed.ResultsAt presentation with CSA, 71 joints showed subclinical inflammation. During progression to IA, 20% of these joints had resolution of inflammation, 60% had persistent inflammation and 20% progressed to clinical synovitis. Of all joints that had developed clinical synovitis (n = 45), no prior subclinical inflammation was detected in 69%. Similar results were observed for anticitrullinated protein antibodies (ACPA)-positive and ACPA-negative patients.ConclusionsThis longitudinal study demonstrated moderate correlations between joints with subclinical inflammation and joints that developed clinical synovitis. These data imply that IA development is a more systemic rather than a locally outgrowing process.

During virally-suppressed chronic human immunodeficiency virus (HIV) infection, persistent inflammation contributes to the development of cardiovascular disease, a major comorbidity in people living with HIV. Monocytes play a key role in atherosclerotic plaque development, inflammation, and stability, but their contribution to the CVD under viral suppression in people living with HIV remains unknown. Here, we investigated the transcriptomes of classical (CD14 ++ CD16 - ) blood monocytes from 92 women with and without chronic HIV infection and subclinical cardiovascular disease (sCVD), defined as the presence of focal carotid artery plaque, from the Women's Interagency HIV Study (WIHS). Differential gene expression, based on four two-way comparisons among participant groups (HIV-sCVD-, HIV+sCVD-, HIV-sCVD+, and HIV+sCVD+, 23 subjects each), identified large pro-inflammatory gene signatures for both sCVD and virally-suppressed HIV. These findings were further corroborated by Ingenuity Pathway Analysis. We found that classical monocytes persistently express common CVD-related markers of inflammation, including IL6, IL1β, and IL12B; overlapping with many transcripts identified in sCVD+ participants. In comorbid disease (HIV+sCVD+), those reporting statin use showed dramatically reduced pro-coagulant tissue factor (F3) and tissue factor pathway inhibitor (TFPI and TFPI2) gene expression to a level comparable with healthy participants. Cytokine expression profiles associated with the tissue factor pathway were also modified in participants on statins, suggesting that statins may benefit women with chronic HIV infection by limiting pro-coagulation and inflammation pathways in classical monocytes.

This article describes a case of large persistent posttreatment apical periodontitis associated with 2 maxillary incisors, which was successfully managed by periradicular surgery. Histobacteriologic analysis revealed that the lesion was a granuloma that contained in its body a very large actinomycoticlike colony surrounded by accumulations of polymorphonuclear leukocytes and showing no direct communication with the root canal systems from both teeth. One incisor had no evidence of persistent intraradicular infection, whereas the other exhibited some residual dentinal tubule infection in the apical canal, which may have not significantly contributed to persistent inflammation given the organization and agglomeration of inflammatory cells around the large extraradicular bacterial colony. Findings showed that the main cause of persistent disease was the extraradicular infection in the form of a large bacterial floc, apparently independent of an intraradicular infection and as such only solved by surgery.

Background Obesity is an established risk and progression factor for several intrinsic subtypes of breast cancer, including basal-like breast cancer (BLBC). Increased local and systemic levels of pro-inflammatory mediators, which typically accompany obesity, can independently influence tumor growth. Currently, it is unclear whether weight loss can reverse the enhancing effects of obesity on breast tumorigenesis. We hypothesize that chronic obesity results in epigenetic reprogramming, which may mediate residual inflammation, and lead to persistent mammary tumor growth despite moderate weight loss. Methods Female C57BL/6 mice (n=51) were administered a control (10% kcal from fat) or diet-induced obesity (DIO; 60% kcal from fat) regimen. After 17 weeks, DIO mice either continued on DIO diet or were switched to control diet to stimulate gradual weight loss, subsequently designated as Formerly Obese (FOb). Mice were orthotopically injected with Wnt-1 mammary tumor cells (a model of BLBC) at week 25, and monitored for an additional 9 weeks, then killed and their tumors excised, measured and stored for subsequent analysis. In an ongoing tumor study, we will randomize mice to the control or DIO regimen, switching half the DIO mice to the control diet after 15 weeks, resulting in normal weight, obese, and FOb mice. Within each of these groups, the mice will be further randomized to +/- supplementation with Sulindac, a non-steroidal anti-inflammatory drug (NSAID), starting at the time of the diet switch. After 10 weeks of +/- Sulindac supplementation, mice will receive orthotopic injections of a mesenchymal derivative of an MMTV-Wnt-1 transgenic tumor, the M-Wnt cell line, and will continue on diet and treatment until euthanization. Results In our initial study, body weight, adiposity, and serum levels of leptin and insulin were similar in FOb and control mice, but serum levels of IL-6 were similar in FOb and DIO mice, and significantly higher than controls. Moreover, tumor burden, the mammary gland expression of key inflammatory genes, and the prevalence of hypermethylated inflammation-related genes in DNA from mammary tissue were comparable in DIO and FOb mice and significantly higher than in control mice, and there was high concordance with DNA methylation profiles in breast DNA from obese versus normoweight women participating in the UNC Normal Breast Study. Conclusions Our preclinical findings suggest that modest weight loss may not be sufficient to reverse the effects of chronic obesity on epigenetic reprogramming and inflammatory signals that are associated with obesity-related mammary tumor progression. Moreover, we have identified several genes with concordant obesity-related hypermethylation in humans and mice; which were unchanged in FOb mice. Thus combining weight loss regimens with epigenetic or inflammatory modulators may be an effective strategy for breaking the obesity-breast cancer link. We are currently assessing whether combining moderate weight loss with anti-inflammatory interventions (Sulindac or omega-3 fatty acids), or reprograming metabolism with a bariatric surgical intervention, is more effective than moderate weight loss alone at offsetting the persistent enhancing effects of chronic obesity on BLBC. Citation Format: Rossi EL, Bowers LW, Khatib SA, Doerstling SS, Hursting SD. Pre-clinical findings on obesity reversal and breast cancer progression: Targeting persistent inflammation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-22.

Persistent inflammation and oxidative stress are the main mechanisms that increase the risks of cardiovascular disease-related morbidity and mortality in systemic lupus erythematosus (SLE). As a natural antioxidant, lycopene can alleviate oxidative stress and suppress inflammation. We hypothesized that lycopene could have the potential to reduce mortality in SLE.Thirty-seven participants with SLE from the NHANES III were divided into two groups (higher level group and lower level group) by rank method according to serum lycopene. These participants were followed-up from the date of interview (1988-1994) to 31 December 2006 for mortality. Mortality rate and survival function were compared between the two SLE groups.The mortality rate was significantly lower in the higher level group (5.3%) than that in the lower level group (33.3%). There was a significant survival difference between the higher level group and the lower level group (Log rank p = 0.0436). In addition, cardiovascular disease-related mortality was dramatically lower in the higher level group than that in the lower level group.These findings from nationally representative samples indicate that higher serum lycopene has the protective effect on mortality in SLE. Further studies with large sample size are needed to confirm these primary results.

In the work presented here, a novel mathematical model was developed to explore the bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory cytokines in acute inflammation. The dynamic model consists of five delay differential equations 5D for two main pro-inflammatory cytokines (TNF-α and IL-6) and two hormones of the HPA axis (ACTH and cortisol) and LPS endotoxin. The model is an attempt to increase the understanding of the role of primary hormones and cytokines in this complex relationship by demonstrating the influence of different organs and hormones in the regulation of the inflammatory response. The model captures the main qualitative features of cytokine and hormone dynamics when a toxic challenge is introduced. Moreover, in this work a new simple delayed model of the HPA axis is introduced which supports the understanding of the ultradian rhythm of HPA hormones both in normal and infection conditions. Through simulations using the model, the role of key inflammatory cytokines and cortisol in transition from acute to persistent inflammation through stability analysis is investigated. Also, by employing a Markov chain Monte Carlo (MCMC) method, parameter uncertainty and the effects of parameter variations on each other are analyzed. This model confirms the important role of the HPA axis in acute and prolonged inflammation and can be a useful tool in further investigation of the role of stress on the immune response to infectious diseases.

The goal of treating chronic inflammatory diseases must be to inhibit persistent inflammation and restore tissue function. To achieve this we need to improve our understanding of the pathways that drive inflammation as well as those that bring about its resolution. In particular, resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of injury or infection and restore homeostasis. Indeed, it may be argued that dysfunctional resolution may underpin the aetiology of some chronic inflammatory disease and that a novel goal in treating such diseases is to develop drugs based on the mode of endogenous pro-resolution factors in order to drive on-going inflammation down a pro-resolution pathway. And while we are improving our understanding of the resolution of acute and chronic inflammation, much remains to be discovered. Here we will discuss the key endogenous checkpoints necessary for mounting an effective yet limited inflammatory response and the crucial biochemical pathways necessary to prevent its persistence and trigger its resolution. In doing so, we will provide an update on what is known about resolution of acute inflammation, in particular its link with adaptive immunity.

Elite controllers naturally suppress HIV viraemia below the level of detection using standard methods, but demonstrate persistent inflammation and low-level viraemia that is detectable via ultrasensitive assays. These factors may contribute to an increased risk of non-AIDS-related morbidity and mortality among elite controllers. Data suggest that cardiovascular disease may be of particular concern in elite controllers, as evidenced by an increased burden of subclinical cardiovascular disease upon radiographic screening and an elevated rate of hospitalisations for cardiovascular disease as compared to non-controllers who are treated with antiretroviral therapy (ART). Widespread use of ART among non-controllers has led to significant declines in morbidity and mortality, but guidelines are generally silent on the role of ART in the care of elite controllers. Multiple small studies have demonstrated that laboratory markers of inflammation, immune activation and HIV burden improve after initiation of ART in elite controllers. Clinicians must consider these potential benefits of ART when deciding whether to initiate treatment in asymptomatic elite controllers.

Background We have recently found that 3 repeated doses (12×106 each) of c‐kitPOS cardiac progenitor cells (CPCs) were markedly more effective than a single dose of 12×106 cells in alleviating postinfarction left ventricular dysfunction and remodeling. However, since the single‐dose group received only one third of the total number of CPCs given to the multiple‐dose group, it is unknown whether the superior therapeutic efficacy was caused by repeated treatments per se or by administration of a higher total number of CPCs. This issue has major clinical implications because multiple cell injections in patients pose significant challenges, which would be obviated by using 1 large injection. Accordingly, we determined whether the beneficial effects of 3 repeated CPC doses can be recapitulated by 1 large dose containing the same total number of cells. Methods and Results Rats with a 30‐day‐old myocardial infarction received 3 echo‐guided intraventricular infusions, 35 days apart, of vehicle‐vehicle‐vehicle, 36×106 CPCs‐vehicle‐vehicle, or 3 equal doses of 12×106 CPCs. Infusion of a single, large dose of CPCs (36×106 cells) produced an initial improvement in left ventricular function, but no further improvement was observed after the second and third infusions (both vehicle). In contrast, each of the 3 doses of CPCs (12×106) caused a progressive improvement in left ventricular function, the cumulative magnitude of which was greater than with a single dose. Unlike the single dose, repeated doses reduced collagen content and immune cell infiltration. Conclusions Three repeated doses of CPCs are superior to 1 dose even though the total number of cells infused is the same, possibly because of greater antifibrotic and anti‐inflammatory actions.

Aging is a complex process that results from a combination of environmental, genetic, and epigenetic factors. A chronic pro-inflammatory status is a pervasive feature of aging. This chronic low-grade inflammation occurring in the absence of overt infection has been defined as “inflammaging” and represents a significant risk factor for morbidity and mortality in the elderly. The low-grade inflammation persists even after reversing pro-inflammatory stimuli such as LDL cholesterol and the renin–angiotensin system (RAS). Recently, several possible sources of chronic low-grade inflammation observed during aging and age-related diseases have been proposed. Cell senescence and dysregulation of innate immunity is one such mechanism by which persistent prolonged inflammation occurs even after the initial stimulus has been removed. Additionally, the coagulation factor that activates inflammatory signaling beyond its role in the coagulation system has been identified. This signal could be a new source of chronic inflammation and cell senescence. Here, we summarized the factors and cellular pathways/processes that are known to regulate low-grade persistent inflammation in aging and age-related disease.

In sepsis-3, in contrast with sepsis-1, the definition “systemic inflammatory response” has been replaced with “dysregulated host response”, and “systemic inflammatory response syndrome” (SIRS) has been replaced with “sequential organ failure assessment” (SOFA). Although the definition of sepsis has changed, the debate regarding its nature is ongoing. What are the fundamental processes controlling sepsis-induced inflammation, immunosuppression, or organ failure? In this review, we discuss the heterogeneity of sepsis-3 and address the central role of inflammation in the pathogenesis of sepsis. An unbalanced pro- and anti-inflammatory response, inflammatory resolution disorder, and persistent inflammation play important roles in the acute and/or chronic phases of sepsis. Moreover, powerful links exist between inflammation and other host responses (such as the neuroendocrine response, coagulation, and immunosuppression). We suggest that a comprehensive evaluation of the role of the inflammatory response will improve our understanding of the heterogeneity of sepsis.

Innate, inflammatory responses towards persistent Opisthorchis viverrini (OV) infection are likely to contribute to the development of cholangiocarcinoma (CCA), a liver cancer that is rare in the West but prevalent in Greater Mekong Subregion countries in Southeast Asia. Infection results in the infiltration of innate immune cells into the bile ducts and subsequent activation of inflammatory immune responses that fail to clear OV but instead may damage local tissues within the bile ducts. Not all patients infected with OV develop CCA, and so tumourigenesis may be dependent on multiple factors including the magnitude of the inflammatory response that is activated in infected individuals. The purpose of this review is to summarize how innate immune responses may promote tumourigenesis following OV infection and if such responses can be used to predict CCA onset in OV-infected individuals. It also hypothesizes on the role that Helicobacterspp., which are associated with liver fluke infections, may play in activation of the innate the immune system to promote tissue damage and persistent inflammation leading to CCA.

Microbial exposures early in life modulate our susceptibility to depression via effects on the composition of the microbiota and the development of the immune system. Modern urban lifestyles reduce these exposures resulting in altered microbiota and defective regulation of inflammatory responses. These changes are reflected in the increasing prevalence of chronic inflammatory disorders and of persistently raised biomarkers of inflammation among those living in modern urban societies, compared with those living a hunter-gatherer or subsistence agriculture-based lifestyle. Moreover, the microbiota regulates metabolism, so a distorted microbiota can promote obesity and the associated inflammation. Similarly, the microbiota regulates the size of the inflammatory response to psychosocial stressors. Thus, there are multiple links between childhood exposures to microbes and the later presence of persistent inflammation that contributes to the risk of depression. Here, we evaluate the evidence for the impact of childhood microbial exposures on subsequent vulnerability to stress-related psychiatric disorders.

Fabry disease can cause various neurological manifestations. We describe the case of a Japanese woman with Fabry disease who presented with ischemic stroke, aseptic meningitis, and psychiatric symptoms. The patient had a mutation in intron 4 of her α-galactosidase A gene, which was not detected in her family. This case suggests that Fabry disease should be considered in young patients who exhibit central nervous system symptoms such as ischemic stroke, even if there is no family history of the condition. The episodes of aseptic meningitis and stroke experienced by our patient suggest that persistent inflammation might be the mechanism underlying Fabry disease.

BACKGROUND AND PURPOSE: MR imaging–pathologic studies have reported that paramagnetic rims on 7T susceptibility-based MR imaging identify, in vivo, the subset of MS lesions with compartmentalized inflammation at the lesion edge and associated remyelination failure. Here, we assessed the reliability of detecting these rims on high-resolution 3T phase images. MATERIALS AND METHODS: High-resolution T2* and phase MR imaging was collected in 20 patients with MS at 3T (3D segmented EPI, 0.65 mm3) and 7T (2D gradient-echo, 0.2 × 0.2 × 1 mm) MR imaging. In each case, 5 discrete chronic (nonenhancing) MS lesions were selected on T2 FLAIR images for rim evaluation. Five raters experienced in MS imaging contributed to the rim assessment, of whom 3 worked independently on 3T data, and 2, on 7T data. Consensus agreement was reached for both 3T and 7T rim evaluations. Discrepancies between 3T and 7T were discussed, and consensus was reached. RESULTS: Phase rims were seen in 34 lesions at 7T and in 36 lesions at 3T by consensus. Inter- and intrarater reliability were “substantial/good” both at 3T and 7T analysis (Cohen κ, >0.71). Based on consensus agreement, the reliability of rim visualization at 3T versus 7T was 0.78 (κ) with a pair-wise agreement of 90%. More lesions were judged to be false-positive or false-negative at 3T than at 7T. CONCLUSIONS: Nearly all 7T paramagnetic rims can also be seen at 3T. Imaging at 3T opens the possibility of implementing paramagnetic rims as an outcome measure in multicenter, MR imaging–based clinical trials aimed at treating perilesional persistent inflammation and its potential effects on remyelination.

PURPOSE: Hospital-associated deconditioning due to a combination of illness and inactivity is a serious problem for elderly adults. Here we investigate whether persistence in inflammatory status affects changes in physical function during short-term hospitalization.METHODS: This was a prospective observational study in elderly medical patients at a geriatric department. Measurements were obtained at admission and one week after admission and included de Morton Mobility Index (DEMMI) test, 30-second chair stand test (30-s CST), 4-m gait speed (4-m GST) test, handgrip strength, activity levels determined with ActivPALs, and concentrations of circulating C-reactive protein (CRP) from blood samples. Only patients with inflammation (C-reactive protein levels ≥10mg·L(-1)) at admission were included in this study. They were divided into those with continued inflammation (CI: CRP remained ≥10mg·L(-1)) and those that became non-inflammatory (BN: CRP decreased to RESULTS: On admission 214 patients (67% female) with a median (IQR) age of 86 (81-91) years were categorized as inflammatory. There were no baseline differences in physical function between CI (n=138, 67% female) and BN (n=76, 68% female). DEMMI-score increased similarly in both groups (PCONCLUSION: Hospitalized geriatric patients admitted with inflammation showed only moderate improvement of general mobility during hospital stay, regardless of changes in their inflammatory status. However, handgrip strength increased only in those patients who became non-inflammatory during hospitalization.

Tissue regeneration following acute or persistent inflammation can manifest a spectrum of phenotypes ranging from the adaptive to the pathologic. Heterotopic Ossification (HO), the endochondral formation of bone within soft-tissue structures following severe injury serves as a prominent example of pathologic differentiation; and remains a persistent clinical issue incurring significant patient morbidity and expense to adequately diagnose and treat. The pathogenesis of HO provides an intriguing opportunity to better characterize the cellular and cell-signaling contributors to aberrant differentiation. Indeed, recent work has continued to resolve the unique cellular lineages, and causative pathways responsible for ectopic bone development yielding promising avenues for the development of novel therapeutic strategies shown to be successful in analogous animal models of HO development. This review details advances in the understanding of HO in the context of inciting inflammation, and explains how these advances inform the current standards of diagnosis and treatment.

The high potency and tolerability of the currently available antiretroviral drugs has modified HIV-1 infection from a life-threatening disease to a chronic illness. Nevertheless, some issues still remain open to optimize the management of HIV-1 infected patients in term of maintenance of virological suppression over time, identifying patients that could benefit from simplification therapy, and reducing co-mordibities driven by chronic inflammation. The availability of robust and affordable virological and immunological markers can help in solving these issues by providing information on the burden of HIV-1 reservoir in all the anatomical compartments in which the virus replicates as well as on persistent inflammation, immune activation and senescence despite successful virological suppression. In this light, this review is aimed at providing new insights (arising from a two-day Italian expert meeting hold in Rome in March 2016) in evaluation and monitoring of HIV-1 infection from a virological, immunological and clinical perspective. Particular attention has been focused on role of novel parameters (such as total HIV-1 DNA, residual viremia, and immunological markers) in optimizing treatment strategies, enhancing medical adherence, and individualizing monitoring.

This week’s articles describe how the immune system in some children is better able to cope with dengue virus infection; how targeting a specific population of monocytes may relieve persistent inflammation associated with HIV infection; and how targeting the vascular niche may suppress fibrosis around lung and liver engraftments.

Patients in the intensive care unit (ICU) who develop chronic critical illness significantly stress the clinical capacity and financial resources of healthcare systems. Although vast improvements have been made in critical care management, outcomes for this ICU subset remain poor. A hallmark for patients who progress to chronic critical illness is the development of persistent inflammation and immunosuppression. The risk factors associated with the development of chronic critical illness include increased age, medical comorbidities, severe injury, septic shock, and malnutrition. Interestingly, each of these clinical states bears strikingly similar immune defects, often resulting in the activation of a persistent inflammatory state. Strategies aimed at the prevention or early recognition of this state of immune compromise may help improve outcomes for these individuals and minimize the number who progress to chronic critical illness. This review explores the current knowledge regarding the immune defects associated with the development of persistent inflammation, the ways in which it can manifest clinically, attempted therapeutic interventions to date, and future insights into improving outcomes for this patient population.