Elevated Pro-inflammatory Markers Research Articles

Throat spray formulated with virucidal pharmaceutical excipients as an effective early prophylactic or treatment strategy against pharyngitis post-exposure to SARS-CoV-2

Our study aimed to develop a virucidal throat spray using bioactive compounds and excipients, focusing on the preparation of Curcumin (CUR) in a self-nano emulsifying drug delivery system (SNEDDS). Two molecular docking studies against SARS-CoV-2 targets guided the selection of proper oil, surfactant, co-surfactant, and natural bioactive that would maximize the antiviral activity of the throat spray. Two self-nanoemulsifying formulas that were diluted with different vehicles to prepare eight CUR-loaded SNESNS (self-nanoemulsifying self-nanosuspension) formulas. In vitro characterization studies and in vitro anti-SARS-CoV-2 effect revealed that the optimal formula, consisted of 20 % Anise oil, 70 % Tween 80, 10 % PEG 400, and 0.1 %w/w CUR, diluted with DEAE-Dx. Preclinical toxicity tests on male rats confirmed the safety of a mild throat spray dose (5 µg/mL CUR). In a rat model of acute pharyngitis induced by ammonia, post-treatment with the optimal formula of CUR loaded SNESNS for one week significantly reduced elevated proinflammatory markers (TNF-α, IL6, MCP1, and IL8). In conclusion, our CUR-loaded SNESNS formula, at 5 µg/mL concentration, shows promising effect as a prophylactic throat spray against SARS-CoV-2 and as a treatment for pharyngitis.

FRI464 Subacute Thyroiditis Related To COVID-19 Vaccines- A Case Series

Abstract Disclosure: H. Mejia: None. S.A. Gillis Funderburk: None. S.R. Thomas: None. Background: Subacute thyroiditis (SAT) has been reported following SARS-COV-2 viral infection, as well as in recipients of the mRNA vaccines for SARS-COV-2. Patients present with palpitations, tremors and weight loss as well as low grade fevers and a tender thyroid. It is a self-limited condition that typically follows a triphasic course that may include thyrotoxicosis, hypothyroidism and return to normal thyroid function. Clinical features and sonographic findings can provide a specific diagnosis, and a radioactive iodine uptake study is often not required. Report: In 2021, 123 patients were referred to our outpatient service for evaluation of thyrotoxicosis. Among them, we identified 9 women without history of thyroid disease who presented with clinical findings of SAT with thyrotoxicosis. Patients with history of thyroid dysfunction and thyroid nodules were excluded. The symptoms began between 4-27 days after the first or second dose of either the Pfizer Bio-NTech or the Moderna COVID-19 mRNA vaccine. All tested negative for TSI and had no nodules on ultrasound. 2 patients had thyroid uptake scans which confirmed thyroiditis. All 9 patients improved with symptomatic treatment and thyroid functions normalized with time. Discussion: Since the mRNA vaccines for SARS-COV-2 became nationally available, several adverse reactions have been reported including SAT. The mechanism for post-vaccination SAT or thyroid dysfunction remains unknown. Transmembrane protease serine-2 (TMPRSS-2) and ACE-2 receptors allow the SARS-CoV-2 to enter human cells. ACE-2 and TMPRSS-2 are expressed in thyroid follicular cells, and their expression is higher than in lung cells, especially in women. These situations may explain why SARS-CoV-2 causes SAT in women more frequently. Inactive virus vaccines contain many proteins belonging to the pathogen virus and similar antigenic parts. The increased affinity of the SARS-CoV-2 towards the thyroid suggests that inactive vaccine may also affect the thyroid tissue. In the past, SAT has been reported after an inactive virus vaccine- seasonal influenza vaccine, H1N1 vaccine and hepatitis B vaccine. In addition, the COVID-19 vaccine contains aluminum hydroxide as an adjuvant. Autoimmune inflammatory syndrome induced by adjuvants (ASIA syndrome) was previously reported following various vaccines. A recent article describes a patient with COVID-19 vaccine related ASIA syndrome and SAT. In some cases, elevated proinflammatory markers and cytokines after receiving the vaccine may play a major role, as it can stimulate a significant response from our immune system. Hence, SAT should be included as a possible side effect of receiving these vaccines. Conclusion: Our case series highlights a possible relationship between the COVID-19 mRNA vaccines and subacute thyroiditis which has been previously underreported or not recognized by healthcare providers. Presentation: Friday, June 16, 2023

Multiplexed trackable intratumor microdosing of the investigational STING agonist TAK-676 alone and in combination in the native tumor microenvironment of patients with head and neck cancer: A phase 0 trial.

2579 Background: TAK-676 is a novel synthetic STING agonist developed to induce an inflammatory state through release of interferon (IFN), production of proinflammatory chemokines and cytokines, and activation of innate and adaptive immune cells in the tumor microenvironment (TME). To gain early mechanistic insights on the effects of TAK-676 in the native TME alone and in combination with standard-of-care chemotherapies, we completed a Phase 0 intratumoral microdosing trial in head and neck squamous cell carcinoma patients using the Comparative In Vivo Oncology (CIVO) platform. CIVO enables direct evaluation of biomarker response in trackable, distinct regions of drug exposure upon resection. These studies were designed to identify rational combinations that could be evaluated in future clinical trials with therapeutic intent. Methods: This IRB-approved study was conducted at four centers within the United States. Fifteen subjects provided Informed Consent and enrolled in the trial. Microdoses (≤1/100th systemic dose) of TAK-676, carboplatin, 5-FU, paclitaxel, and combinations thereof, were simultaneously injected via CIVO to eligible patients presenting with a surface-accessible primary or metastatic lesion ≥ 2 cm and planned surgical resection of the target lesion at 24 (n=8) or 72–96 (n=7) hours. Injection sites were identified via co-injection of fluorescent tracking markers (CIVO GLO). Multiplexed ISH, IHC, and spatial molecular profiling via GeoMx and CosMx were used to resolve molecular responses at each injection site. Patients were monitored for adverse events (AEs) for 28 days following injection. Results: TAK-676 exposure was associated with increased IFN signaling in all samples analyzed at the 24-hour cohort. This was accompanied by increased expression of pro-inflammatory cytokines and chemokines, “M1-like” macrophages, NK cells, and CD8+ T cells. Spatial profiling with GeoMx and CosMx revealed an IFN signature and elevated pro-inflammatory markers across multiple cell types throughout the TME. In addition, exposure to TAK-676 plus chemotherapy resulted in localized enhancement of apoptosis vs. chemotherapy alone across multiple tumors. The responses observed at 24 hours were transient and not detected in the 72–96-hour cohort. No AEs related to injection procedure or contents were reported. Conclusions: Intratumor microdosing via CIVO of TAK-676 alone and in combination with chemotherapy was shown to promote an early pro-inflammatory response, providing evidence of an on-target mechanism of action. The absence of effect at the late timepoints could be due to pharmacokinetics of drug exposure or compensatory signaling within the TME. In this Phase 0 clinical trial we safely demonstrated precise, mechanistic effects of TAK-676 on the native TME of intact human tumors. Clinical trial information: NCT04541108 .

Clinical characteristics and outcome of COVID-19 patients with Parkinson's disease: a hospital-based case-control study in Shanghai, China.

Clinical manifestations of Parkinson's disease (PD) after Corona Virus Disease 2019 (COVID-19) infection are poorly investigated. We aimed to explore the clinical features and outcomes of hospitalized PD patients with COVID-19. A total of 48 PD patients and 96 age-and sex-matched non-PD patients were included. Demographics, clinical characteristics and outcomes were compared between two groups. PD patients with COVID-19 were elderly (76.69 ± 9.21 years) with advanced stage (H-Y stage 3-5 as 65.3%). They had less clinical symptoms (nasal obstruction, etc.), more proportions of severe/critical COVID-19 clinical classification (22.9 vs. 1.0%, p < 0.001), receiving oxygen (29.2 vs. 11.5%, p = 0.011), antibiotics (39.6 vs. 21.9%, p = 0.031) therapies, as well as longer hospitalization duration (11.39 vs. 8.32, p = 0.001) and higher mortality (8.3% vs. 1.0%, p = 0.001) relative to those without PD. Laboratory results showed that the PD group had higher white blood cell counts (6.29 vs. 5.16*109, p = 0.001), neutrophil-to-lymphocyte ratio (3.14 vs. 2.11, p < 0.001) and C-reactive protein level (12.34 vs. 3.19, p < 0.001). PD patients with COVID-19 have insidious clinical manifestation, elevated proinflammatory markers and are prone to the development of severe/critical condition, contributing to a relatively poor prognosis. Early identification and active treatment of COVID-19 are pivotal to advanced PD patients during the pandemic.

Cognitive Frailty is Associated With Elevated Proinflammatory Markers and a Higher Risk of Mortality

BackgroundCognitive impairment and physical frailty are common among older adults and associated with a higher likelihood of adverse health outcomes. These two conditions frequently coexist in the same individual as cognitive frailty, yet few studies have examined the impact of such comorbidity on clinical outcomes or underlying biological mechanisms. MethodsA total of 1,340 older adults (age ≥60 years old) from the Bambui Cohort Study of Ageing, with a total follow-up of 10 years, were included in this study. Frailty was defined by the accumulation of deficit framework and cognitive impairment based on scores on the MMSE less than 22. In addition, serum IL-6 levels were measured by cytometric bead array assay. ResultsIndividuals classified with cognitive frailty had significantly higher serum IL-6 levels compared to the robust, cognitively unimpaired group. Those with cognitive frailty (aOR = 1.97 [1.18–3.27] and prefrailty and cognitive impairment (aOR = 1.83 [1.24–2.69]) had the highest mortality risk over 10 years of follow-up. Higher IL-6 levels were also independently associated with a higher mortality rate (aOR = 1.37 [1.23–1.54]). ConclusionOur study shows that cognitive Frailty indicates a vulnerability state and of increasing mortality risk. Our findings also suggested that proinflammatory abnormalities can be viewed as a central phenomenon underlying common age-related problems (e.g., cognitive impairment and Frailty) and outcomes (e.g., mortality).

Inflammatory markers, brain-derived neurotrophic factor, and the symptomatic course of adolescent bipolar disorder: A prospective repeated-measures study

BackgroundNumerous studies have found elevated pro-inflammatory markers and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD, or longitudinally in any BD age group. Methods79 adolescents, ages 13–19 years, were enrolled, including 43 symptomatic adolescents with BD and 36 age-matched healthy controls (HC). Blood samples were collected from all participants at intake, and repeatedly from BD participants at pre-specified intervals over the course of two years. Serum was assayed for levels of pro-inflammatory markers (c-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor alpha [TNF-α]), BDNF and the anti-inflammatory marker, IL-10. Week-by-week severity of mood symptoms was assessed using semi-structured interviews. ResultsAdolescents with BD provided an average of 4.6 blood samples, on average every 5.0 months. During the most severe symptomatic interval (i.e., highest sum of mood symptom scores) among BD adolescents, levels of CRP (p = 0.01) and pro- to anti-inflammatory ratios (CRP/IL-10; p < 0.001 and IL-6/IL-10; p = 0.046) were significantly greater, and IL-10 levels (p = 0.004) were significantly lower, vs. HC. There were no differences between BD and HC in IL-6, TNF-α or BDNF. Within BD participants, higher BDNF (p = 0.01) and IL-10 levels (p = 0.001) significantly predicted greater burden of mood symptoms over the subsequent epoch. Moreover, higher CRP levels (p = 0.009) at intake predicted greater time to recovery from the index symptomatic episode. ConclusionsIn the first repeated-measures study on this topic in adolescents with BD, we found evidence that CRP, an inexpensive and ubiquitous blood test, may be useful in predicting the prospective course of BD symptoms. Future larger studies are warranted.

2.2 INFLAMMATORY MARKERS, BRAIN-DERIVED NEUROTROPHIC FACTOR, AND THE SYMPTOMATIC COURSE OF ADOLESCENT BIPOLAR DISORDER: A PROSPECTIVE REPEATED-MEASURES STUDY

Numerous studies have found elevated proinflammatory markers (PIMs) and reduced brain-derived neurotrophic factor (BDNF) during symptomatic episodes of bipolar disorder (BD) in adults. There is a paucity of research examining these markers in youth with BD or longitudinally in any BD age group.

Circulating HMGB1 is elevated in veterans with Gulf War Illness and triggers the persistent pro-inflammatory microglia phenotype in male C57Bl/6J mice

Gulf War Illness (GWI) is a chronic, multi-symptom peripheral and CNS condition with persistent microglial dysregulation, but the mechanisms driving the continuous neuroimmune pathology are poorly understood. The alarmin HMGB1 is an autocrine and paracrine pro-inflammatory signal, but the role of circulating HMGB1 in persistent neuroinflammation and GWI remains largely unknown. Using the LPS model of the persistent microglial pro-inflammatory response, male C57Bl/6J mice injected with LPS (5 mg/kg IP) exhibited persistent changes in microglia morphology and elevated pro-inflammatory markers in the hippocampus, cortex, and midbrain 7 days after LPS injection, while the peripheral immune response had resolved. Ex vivo serum analysis revealed an augmented pro-inflammatory response to LPS when microglia cells were cultured with the 7-day LPS serum, indicating the presence of bioactive circulating factors that prime the microglial pro-inflammatory response. Elevated circulating HMGB1 levels were identified in the mouse serum 7 days after LPS administration and in the serum of veterans with GWI. Tail vein injection of rHMGB1 in male C57Bl/6 J mice elevated TNFα mRNA levels in the liver, hippocampus, and cortex, demonstrating HMGB1-induced peripheral and CNS effects. Microglia isolated at 7 days after LPS injection revealed a unique transcriptional profile of 17 genes when compared to the acute 3 H LPS response, 6 of which were also upregulated in the midbrain by rHMGB1, highlighting a distinct signature of the persistent pro-inflammatory microglia phenotype. These findings indicate that circulating HMGB1 is elevated in GWI, regulates the microglial neuroimmune response, and drives chronic neuroinflammation that persists long after the initial instigating peripheral stimulus.

COVID-19 and Coronary Heart Disease

Coronary heart disease (CHD) is the leading cause of mortality worldwide. One of the main contributions of mortality and morbidity in CHD patients is acute myocardial infarction (AMI), which is the result of abrupt occlusion of an epicardial coronary artery due to a sudden rupture of atherosclerotic plaque, causing myocardial ischemia. In the initial stage of myocardial ischemia, lack of oxygen and nutrient supply results in biochemical and metabolic changes within the myocardium. Depletion of oxygen switches the aerobic cellular metabolism to anaerobic metabolism and impairs the oxidative phosphorylation pathway eventually leading to cardiomyocyte death. Several studies suggest an interlink between COVID-19 and ischemic heart disease. An increased ACE2 receptor expression in the myocardium may partly contribute to the myocardial injuries that are observed in patients affected by SARS-CoV-2. Furthermore, pre-existing cardiovascular disease, in conjunction with an aggravated inflammatory response which causes an up-regulation in pro-inflammatory cytokines. Moreover, patients with atherosclerosis are observed to be more prone to ischemic attacks when affected by COVID-19, due to hypercoagulation in the blood as well as elevated pro-inflammatory markers.

Poor Prognostic Factors in Sickle Cell Disease Patients Infected with Covid-19 – Review of Literatures

Sickle cell disease (SCD) is the co-inheritance of HbS with other abnormal haemoglobin. COVID-19 is a severe acute respiratory distress syndrome caused by coronavirus 2 infections. The immunosuppression and chronic inflammatory states in patients with SCD predispose them to severe form of COVID-19. The few case studies on sickle cell disease patients infected with COVID-19 mostly discuss the pattern of clinical presentations and laboratory changes in patients with SCD infected with COVID-19. This review of literature assesses the prognostic indicators in sickle cell disease patients infected with COVID 19 in three major case series. Some presenting symptoms and signs, presence of comorbidities and certain laboratory parameters were compared with poor outcome of patients. Poor clinical outcomes of patients in this review included: 1. Duration of admission of ≥10 days, 2. A week or more of intensive care unit admission, 3. Death of patient despite intervention while on admission, and 4. Deterioration in the presenting comorbid clinical condition. The presenting symptoms and signs, presence of comorbidities and certain laboratory parameters associated with these poor clinical outcomes were considered as poor prognostic factors. The presence of comorbidities, markedly elevated pro-inflammatory markers such as leukocytosis, IL-6, C-reactive proteins, marked elevated D-Dimer and high serum creatinine are poor prognostic factors in sickle cell disease patients with COVID-19 infection.

Study on the Role of Inflammatory Markers and Type D Personality on Symptom Profiles and Severity in Patients with Major Depressive Disorder

The high rates of chronicity and recurrences account for the limited efficacy of current antidepressants, conceived based on the current neurobiological hypotheses, in reaching the full clinical and functional remission of major depressed (MDD) patients. We aimed to analyze the role of pro-inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6), respectively, and type D personality (TDP) on the depressive symptoms measured by the 17-item Hamilton Depression Rating Scale (HAM-D). The processed data are part of a prospective 8-weeks follow-up study conducted in 50 subjects with MDD referred to ‘Eduard Pamfil’ Psychiatric Clinic Timisoara. The presence of elevated pro-inflammatory markers in MDD patients with TDP has been significantly associated with higher somatic anxiety (p = 0.005) and somatic symptoms-general (p = 0.016) mean rank scores compared to their counterparts without significant inflammation. The combination of increased CRP and IL-6 levels were significantly correlated with higher impaired insight (p = 0.026) mean rank scores, additionally. The presence of a significant level of IL-6 has shown a significant effect of size (p = 0.023) on the severity of major depression at baseline. On the contrary, type D personality has not influenced the severity of depressive symptoms (p &gt; 0.05). Inflammatory markers significantly impact the clinical profiles and symptoms severity of MDD patients.

Association Between Systemic Inflammation And Skeletal Muscle Mass Following Exercise In Breast Cancer Survivors

INTRODUCTION: Reductions in skeletal muscle mass contribute to reduced physical function and poorer prognosis among breast cancer survivors (BCS). Elevated pro-inflammatory markers stimulate catabolic pathways in skeletal muscle, and have been associated with muscle loss in overweight individuals and older adults. This evidence suggests that elevated pro-inflammatory markers such as IL-6, TNF-alpha , and C-reactive protein (CRP) may explain subsequent muscle loss in BCS. While we previously found exercise reduces inflammation and increases skeletal muscle mass in overweight or obese BCS, an associative investigation is warranted. PURPOSE: The purpose of this secondary analysis was to determine whether associations between post-exercise inflammatory markers and skeletal muscle mass exist among overweight/obese BCS. METHODS: Sedentary, overweight/obese BCS (BMI ≥ 25 kg/m2; Stages I-III) were randomized to exercise (EX; n=50) and control (CON; n=50) groups. EX participated in a supervised 16-week moderate-vigorous intensity aerobic and resistance exercise intervention. CON was asked to maintain current levels of activity. Appendicular Skeletal Muscle Index (ASMI), calculated as ∑extremity lean mass (kg)/ height (m2), was obtained from a whole-body scan using Dual Energy X-Ray Absorptiometry. CRP, IL-6, and TNF-∝ were measured using enzyme-linked immunosorbent assays from fasting blood samples. Pearson’s correlations assessed associations between post-exercise ASMI and inflammatory biomarkers. RESULTS: On average, BCS were 53.5±10.4 years old, postmenopausal (60%), and Hispanic (55%) with a BMI of 33.5±5.5 kg/m2. Post-intervention, EX experienced an increase in ASMI (8.3%; p=0.001), and reductions in CRP (-47.8%; p=0.001) IL-6 (-73.6%; p=0.001) and TNF-∝ (-25.1%; p=0.001). No significant changes were seen in CON (p>0.01). There were significant correlations between ASMI and IL-6 (r=-0.78; p=0.02), CRP (r=-0.91; p=0.01), and TNF-alpha (r=-0.82; p=0.03). CONCLUSIONS: This secondary analysis provides preliminarily evidence to support the relation between changes in skeletal muscle mass and inflammation among BCS, and supports the implementation of exercise to maintain muscle mass during survivorship.

Tocilizumab in patients with severe COVID-19: A single-center observational analysis.

Patients with coronavirus disease 2019 (COVID‐19) may develop severe respiratory distress, thought to be mediated by cytokine release. Elevated proinflammatory markers have been associated with disease severity. Tocilizumab, an interleukin‐6 receptor antagonist, may be beneficial for severe COVID‐19, when cytokine storm is suspected. This is a retrospective single‐center analysis of the records of patients diagnosed with COVID‐19 who received tocilizumab. Outcomes, including clinical improvement, mortality and changes in oxygen‐support at 24, 48, and 72 hours, and 7, 14, and 28 days post‐tocilizumab, are reported. Patients were evaluated by baseline pre‐tocilizumab oxygenation status and changes in proinflammatory markers within 7 days post‐tocilizumab are reported. Sixty‐six patients received tocilizumab at a mean dose of 724 mg (7.4 mg/kg), 3.7 days from admission. At baseline, 53% of patients were on ventilation support and all had elevated proinflammatory markers, including c‐reactive protein (CRP). Common comorbidities were diabetes mellitus (43%) and hypertension (74%). Most patients received concomitant glucocorticoids and hydroxychloroquine. Seven days after tocilizumab, ten patients (15.2%) had clinical improvement in their oxygenation status, and there was a 95% decrease in CRP. Within 14 days of treatment, 29% of patients had clinical improvement, 20% had minimal or no improvement, 17% worsened, 27% died, and 7% were transferred to an outside hospital. Ultimately, 42% of all patients that received tocilizumab expired and 49% were discharged. This study found limited clinical improvement in patients that received tocilizumab in the setting of severe COVID‐19. Clinical trials are ongoing to further evaluate tocilizumab's benefit in this patient population.

Pulmonary Toxicity and Inflammatory Response of E-Cigarette Vape Cartridges Containing Medium-Chain Triglycerides Oil and Vitamin E Acetate: Implications in the Pathogenesis of EVALI.

Recently, there has been an outbreak of a condition named e-cigarette or vaping products-associated lung injury (EVALI). The primary components of vaping products include tetrahydrocannabinol (THC), vitamin E acetate (VEA) and medium-chain triglycerides (MCT), may be responsible for acute lung toxicity. Currently, little information is available on the physiological and biological effects of exposure to these products. We hypothesized that these CBD/counterfeit vape cartridges and their constituents (VEA and MCT) induce pulmonary toxicity, mediated by oxidative damage and inflammatory responses, leading to acute lung injury. We studied the potential mechanisms of CBD/counterfeit vape cartridge aerosol induced inflammatory response by evaluating the generation of reactive oxygen species by MCT, VEA, and cartridges and their effects on the inflammatory state of pulmonary epithelium and immune cells both in vitro and in vivo. Cells exposed to these aerosols generated reactive oxygen species, caused cytotoxicity, induced epithelial barrier dysfunction, and elicited an inflammatory response. Using a murine model, the parameters of acute toxicity to aerosol inhalation were assessed. Infiltration of neutrophils and lymphocytes was accompanied by significant increases in IL-6, eotaxin, and G-CSF in the bronchoalveolar lavage fluid (BALF). In mouse BALF, eicosanoid inflammatory mediators, leukotrienes, were significantly increased. Plasma from e-cig users also showed increased levels of hydroxyeicosatetraenoic acid (HETEs) and various eicosanoids. Exposure to CBD/counterfeit vape cartridge aerosols showed the most significant effects and toxicity compared to MCT and VEA. In addition, we determined SARS-CoV-2 related proteins and found no impact associated with aerosol exposures from these tested cartridges. Overall, this study demonstrates acute exposure to specific CBD/counterfeit vape cartridges induces in vitro cytotoxicity, barrier dysfunction, and inflammation and in vivo mouse exposure induces acute inflammation with elevated proinflammatory markers in the pathogenesis of EVALI.

Unmetabolized folic acid is associated with TNF-α, IL-1β and IL-12 concentrations in a population exposed to mandatory food fortification with folic acid: a cross-sectional population-based study in Sao Paulo, Brazil.

The study assessed associations between inflammatory markers, as cytokines, adhesion molecules and unmetabolized folic acid (UMFA) among a population exposed to mandatory fortification. Data were collected from a cross-sectional population-based survey (n = 302) conducted in São Paulo City, Brazil. UMFA was assayed by a modified affinity-HPLC method with electrochemical detection to measure the different forms of the folate in plasma. We used a commercial test kit to analyze cytokines and adhesion molecules. Multiple logistic regressions were applied to investigate the association between inflammatory markers and UMFA. Multiple models were adjusted for sex, age, self-reported skin color, BMI and smoking status. The prevalence of detectable UMFA in this population was high (81.2%), with median concentration of 1.67nmol/L. The odds ratios (95% CIs) for having higher immunological markers levels among individuals in the highest tertile of UMFA were 0.44 (0.24; 0.81) for TNF-α, 0.92 (0.49; 1.75) for CRP, 1.32 (0.70; 2.48) for ICAM, 0.99 (0.54; 1.81) for VCAM, 0.45 (0.25; 0.83) for IL-1β, 0.74 (0.40; 1.38) for IL-6, 1.34 (0.73; 2.44) for IL-8, 0.65 (0.36; 1.18) for IL-10 and 0.49 (0.27; 0.89) for IL-12. UMFA concentrations were inversely associated with elevated proinflammatory markers (TNF-α, IL-1β and IL-12). These results signalize a link between folate metabolism and the inflammatory status of adults in an apparently folate-replete population.

Risk of Myocardial Infarction in Inflammatory Bowel Disease: A Population-based National Study.

Chronic inflammation is linked to increased cardiovascular risk. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and elevated pro-inflammatory markers. The association between IBD and myocardial infarction (MI) is not well understood. We sought to elucidate this risk using a large database. We reviewed data from a large commercial database (Explorys, IBM Watson) that aggregates electronic medical records from 26 nationwide health care systems. Using systemized nomenclature of medicine-clinical terms, we identified adult patients (20 to 65 years) with a diagnosis of IBD-ulcerative colitis (UC) or Crohn's disease (CD)-who had active records between August 2013 and August 2018. We then examined the risk of MI in patients with or without IBD. Out of 29,090,220 patients, 131,680 (0.45%) had UC, and 158,750 (0.55%) had CD. Prevalence of MI was higher in patients with UC and CD versus non-IBD patients (UC 6.7% vs CD 8.8% vs non-IBD 3.3%, odds ratio [OR] for UC 2.09 [2.04 -2.13], and CD 2.79 [2.74-2.85]. The odds of MI in IBD patients overall were highest in younger patients and decreased with age (age 30-34 years: OR 12.05 [11.16-13.01], age 65+ years: OR 2.08 [2.04-2.11]). After adjusting for age, race, sex, and traditional cardiovascular risk factor, IBD conferred greater odds of MI (adjusted odds ratio [aOR] 1.25 [1.24-1.27]). In this large cohort, IBD is associated with significantly increased MI compared with non-IBD patients. The relative risk of MI was highest in younger patients and decreased with age. These findings emphasize the need for aggressive risk factor reduction in IBD.

P200 TRENDS IN THE INCIDENCE AND OUTCOMES OF ATRIAL FIBRILLATION IN HOSPITALIZED PATIENTS OF INFLAMMATORY BOWEL DISEASE: NATIONWIDE ANALYSIS 2002–2014

Inflammation plays a role in the development of atrial fibrillation (AF). Thus, inflammatory bowel disease (IBD) may increase the risk of AF. Elevated Proinflammatory markers such as interleukin (IL)-6 in IBD have been closely associated with AF. We analyzed the National Inpatient Sample (NIS) database for all subjects with discharge diagnosis of IBD (Ulcerative Colitis & Crohn’s disease) with or without AF as primary or secondary diagnosis via ICD 9 codes during the period from 2002–2014. All analyses were performed with the use of SAS (version 9.4) From 2002–2014 there were total 21950 discharges of Ulcerative Colitis (UC) patients with AF and 24726 discharges of Crohn’s Disease (CD) patients with AF, constituting 9% & 5.7% discharges respectively. Most of the patients with AF were Caucasians (90% in UC & 91.5% in CD), with age above 65 (81% in UC & 74% in CD), males in UC (51.4%) and females in CD (53%). The odds of discharge to skilled nursing facility and in-hospital mortality was more with AF in IBD. There was a rising incidence of AF in IBD (6.8% of UC discharges & 3.9% of CD discharges in 2002 to 11.4% of UC & 7.6% of CD discharges in 2014) as well as median length of stay and the median cost of care. The In-hospital mortality remained stable over this period in patients of AF with IBD. Obesity, Renal failure, Hypothyroidism, HTN, CAD, CHF, Valvular disorders, PVD and chronic pulmonary disease were the significant predictors of AF in IBD on Multivariate regression analysis. This is the first analysis that assesses the national disease burden and outcomes of AF in IBD. The incidence of AF in IBD is rising particularly in UC. There is significant burden of AF in IBD, which is associated with significant morbidity and increased cost of care. The treatment strategies for AF risk reduction in IBD should be explored further.

Elevated Proinflammatory Markers in 22q11.2 Deletion Syndrome Are Associated With Psychosis and Cognitive Deficits.

22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder whose phenotype includes high rates of a schizophrenia-like psychotic disorder and immune system abnormalities. Thus, 22q11.2DS is an ideal model for studying the relationship between psychosis and inflammation. The aim of the present study was to identify inflammatory markers that may play a role in the pathophysiologic pathways associated with psychosis and cognitive deficits in 22q11.2DS. Forty-nine individuals with 22q11.2DS (13 with psychotic disorders according to DSM-IV criteria and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric and cognitive assessments at an outpatient clinic. Blood samples from all participants were analyzed for C-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNFα), and IL-1 receptor antagonist levels. The study was conducted between August 2014 and September 2015. The 22q11.2DS participants had elevated levels of CRP (P = .004), IL-6 (P = .001), TNFα (P < .001), and IL-10 (P = .028) compared with controls. Furthermore, the psychotic 22q11.2DS participants had higher levels of IL-6 (P < .001) and IL-6/IL-10 ratio (used as an indicator for proinflammatory activation, P < .001) compared with the nonpsychotic 22q11.2DS individuals and controls. IL-6 levels and the IL-6/IL-10 ratio correlated with the severity of the cognitive deficits in the 22q11.2DS participants. Our preliminary findings indicate an involvement of inflammatory processes in the pathophysiology of psychosis and cognitive deficits in 22q11.2DS and are in line with the accumulating evidence for the role of neuroinflammation in nonsyndromic schizophrenia.

Early life stress induces immune priming in kidneys of adult male rats.

Early life stress (ELS) in humans is associated with elevated proinflammatory markers. We hypothesized that ELS induces activation of the immune response in a rat model of ELS, maternal separation (MatSep), in adulthood. MatSep involves separating pups from the dam from postnatal day 2 to postnatal day 14 for 3 h/day. Control rats are nonseparated littermates. We determined circulating and renal immune cell numbers, renal immune cell activation markers, renal cytokine levels, and the renal inflammatory gene expression response to low-dose lipopolysaccharide (LPS) in male MatSep and control rats. We observed that MatSep did not change the percentage of gated events for circulating CD3+, CD4+, CD8+, and CD4+/Foxp3+ cells or absolute numbers of mononuclear and T cells in the circulation and kidneys; however, MatSep led to an increase in activation of renal neutrophils as well as CD44+ cells. Renal toll-like receptor 4 (TLR4) and interleukin 1 beta (IL-1β) was significantly increased in MatSep rats, specifically in the outer and inner medulla and distal nephron, respectively. Evaluation of renal inflammatory genes showed that in response to a low-dose LPS challenge (2 mg/kg iv) a total of 20 genes were significantly altered in kidneys from MatSep rats (17 genes were upregulated and 3 were downregulated), as opposed to no significant differences in gene expression in control vs. control + LPS groups. Taken together, these findings indicate that MatSep induces priming of the immune response in the kidney.

Peptide-based vaccination against OPN integrin binding sites does not improve cardio-metabolic disease in mice

Obesity causes insulin resistance via a chronic low-grade inflammation. This inflammation is characterized by elevated pro-inflammatory markers and macrophage accumulation in the adipose tissue (AT). AT inflammation is a key factor causing insulin resistance and thus type 2 diabetes, both linked to atherosclerotic cardiovascular disease. Osteopontin (OPN), a well-known inflammatory cytokine, is involved in obesity-linked complications including AT inflammation, insulin resistance, atherosclerosis and CVD. During inflammation, OPN is proteolytically cleaved by matrix metalloproteinases or thrombin leading to increased OPN activity. Therefore, OPN provides a new interesting target for immunological prevention and treatment of obesity-associated diseases. The aim of our study was to evaluate peptide-based vaccines against integrin binding sites of OPN and to examine whether these active immunotherapies are functional in reducing metabolic tissue inflammation, insulin resistance, and atherosclerosis in a cardio-metabolic (Ldlr−/− mice) and a diet-induced obesity model (WT mice). However, atherosclerosis, insulin resistance and AT inflammation were not diminished after treatment with OPN-derived peptides in murine models. Lack of efficacy was based on a failure to induce antibodies capable to bind epitopes in the context of functional OPN protein. In conclusion, our data point to unexpected challenges in the immunotherapeutic targeting of adhesive motives, such as RGD containing sequences, on endogenous proteins.