ROLE OF ARYL HYDROCARBON RECEPTOR IN CHRONIC INFLAMMATORY DISEASES

Aryl Hydrocarbon Receptor (AhR) is a ligand-actviated receptor known as the dioxin receptor. Environmental pollutants called dioxin-like toxicants are found in food, cigarette smoke, automobile exhaust and air. Therefore, they could chronically amplify the pathology of numerous chronic inflammatory diseases. AhR is a well known target of these environmental chemicals that disrupt endocrine signaling. By the year 2020, the number of people older than 60 years is expected to top 1 billion. The burden of treating chronic disease is significant both in dollars spent and in lost productivity. The need to identify risk factors for chronic diseases must be evaluated along with diet and lifestyle factors that will promote healthy aging. The studies presented in this dissertation tested the hypothesis that habitual exposure to dioxin-like contaminants contributes to chronic inflammatory disease states through activation of AhR pathway. Due to their lipophilicity, dioxin like toxicants (like PCB 77) accumulated in mice\u27 visceral adipose tissue and induced adipocytes maturation and ectopic fat deposition. Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCB 77) can cause endothelial cells activation and inflammation by inducing pro-inflammatory signaling pathways. In our studies, PCB 77 had cumulative effects in Angiotensin II - induced Abdominal Aortic Aneurysm (AAA) by exacerbating inflammation in and around the aortic wall. More, PCB 77 increased mortality in mice that developed AAA. In order to appreciate the AhR involvement in inflammation we used a mouse model of Inflammatory Bowel Disease(IBD). Mice that had a reduced Ahr Receptor expression developed a less severe colitis and had a decreased general inflammatory status. These data provide evidence that exposure to environmental toxicants could augment inflammation and contribute to the social burden of obesity and obesity related chronic inflammatory diseases

NOVEL MECHANISMS IN INFLAMMATORY BOWEL DISEASE

Inflammatory Bowel Diseases, Crohn\u27s Disease and Ulcerative colitis, are idiopathic chronic conditions with multifactorial determinants. In general, terms, intestinal inflammation results from abnormal host-microbe interactions. Alterations in homeostasis involve host genetic factors, environmental cues and unique luminal microbial niches. We have examined the coordinated expressions of several molecular targets relevant to the mucosal immune system and identified signature biomarkers of IBD. Qualitative and quantitative changes in the composition of microbiota can be related to unique immuno-phenotypes. This in turn can have more systemic effects that involve energy metabolism. Adiponectin, an adipose tissue derived adipokine, can restore cellular ATP levels and fulfills innate immune functions. We have concluded that IBD might represent a state of adiponectin resistance relating to chronic inflammation and obesity status. Lastly we hypothesized that activation of xenobiotic pathway (AHR-aryl hydrocarbon receptor) can further modulate host immune and metabolic responses, and thus contribute to IBD phenotypes. We found that IBD is associated with robust mucosal, aryl hydrocarbon receptor pathway and related to proinflammatory cytokine secretion. We conclude that IBD heterogeneity is reflected through distinct immunophenotypes. Furthermore, environmental cues that involve the AhR receptor and adipose tissue derived adiponectin are important regulators of the inflammatory process in IBD

Autoimmune Enteropathy with a CD8\u3csup\u3e+\u3c/sup\u3e CD7\u3csup\u3e-\u3c/sup\u3e T-cell Small Bowel Intraepithelial Lymphocytosis: Case Report and Literature Review

Background Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, are uncertain. We present a unique case of AIE associated with a CD8+CD7- lymphocytosis and review the literature to characterize the histologic and immunologic abnormalities, and the autoantibodies and autoimmune conditions associated with AIE. Case Presentation We present a case of immune mediated enteropathy distinguished by the CD8+CD7- intra-epithelial and lamina propria lymphocytosis. Twenty-nine cases of AIE have been reported. The majority of patients had auto-antibodies (typically anti-enterocyte), preferential small bowel involvement, and predominately CD3+ CD4+ infiltrates. Common therapies included steroids or immuno-suppressive agents and clinical response with associated with histologic improvement. Conclusions AIE is most often characterized (1) IgG subclass anti-epithelial cell antibodies, (2) preferential small bowel involvement, and (3) CD3+ alphabeta TCR+ infiltrates; there is insufficient evidence to conclude CD4+ T-cells are solely responsible in all cases of AIE

Systemic or local thrombolysis in high-risk pulmonary embolism

Background and Aim: High-risk pulmonary embolism (PE) represents an important health problem in emergency cardiology, being associated with a high rate of mortality. The aim of this study is to assess the efficacy and safety of pulmonary intra-arterial thrombolysis with streptokinase compared to systemic thrombolysis. Methods and Results: In our study, 28 patients with acute high risk PE were treated by intra-arterial thrombolysis with clinical success rate of 96.4%, while in the group with systemic thrombolysis (24 patients) the rate of clinical success was significantly lower (70.8%). Also, pressure gradient between right ventricle (RV) and right atrial (RA) (PRV-RA) decreased significantly in patients treated by pulmonary intra-arterial thrombolysis instead of systemic thrombolysis. Mortality during the hospitalization was 0% in the group with local thrombolysis and 29.2% in the other group, with a significant statistical difference. Major bleeding complications appeared in 14.3% of the patients with local thrombolysis and in 20.8% of the ones treated by systemic thrombolysis, without statistical significance. Moreover, the proportion of minor bleeding was comparable in the two groups of patients. There was no intracranial bleeding. Disseminated intravascular coagulation occurred in 1 patient with systemic thrombolysis. Conclusions: The rate of clinical success and the regression of RV overload were significantly higher in patients treated by pulmonary intra-arterial thrombolysis. The results regarding the efficiency of the pulmonary intra-arterial thrombolysis in high-risk PE are encouraging, the mortality in these patients being significantly lower than the one for systemic administration of the thrombolytic agent.

Linear and nonlinear parameters of heart rate variability in ischemic stroke patients

Introduction Cardiovascular system presents cortical modulation. Post-stroke outcome can be highly influenced by autonomic nervous system disruption. Heart rate variability (HRV) analysis is a simple non-invasive method to assess sympatho-vagal balance. Objectives The purpose of this study was to investigate cardiac autonomic activity in ischemic stroke patients and to asses HRV nonlinear parameters beside linear ones. Methods We analyzed HRV parameters in 15 right and 15 left middle cerebral artery ischemic stroke patients, in rest condition and during challenge (standing and deep breathing). Data were compared with 15 age- and sex-matched healthy controls. Results There was an asymmetric response after autonomic stimulation tests depending on the cortical lateralization in ischemic stroke patients. In resting state, left hemisphere stroke patients presented enhanced parasympathetic control of the heart rate (higher values for RMSSD, pNN50 and HF in normalized units). Right hemisphere ischemic stroke patients displayed a reduced cardiac parasympathetic modulation during deep breathing test. Beside time and frequency domain, using short-term ECG monitoring, cardiac parasympathetic modulation can also be assessed by nonlinear parameter SD1, that presented strong positive correlation with time and frequency domain parameters RMSSD, pNN50, HFnu, while DFA α1 index presented negative correlation with the same indices and positive correlation with the LFnu and LF/HF ratio, indicating a positive association with the sympatho-vagal balance. Conclusions Cardiac monitoring in clinical routine using HRV analysis in order to identify autonomic imbalance may highlight cardiac dysfunctions, thus helping preventing potential cardiovascular complications, especially in right hemisphere ischemic stroke patients with sympathetic hyperactivation

Monotonicity of quantum ground state energies: Bosonic atoms and stars

The N-dependence of the non-relativistic bosonic ground state energy is studied for quantum N-body systems with either Coulomb or Newton interactions. The Coulomb systems are "bosonic atoms," with their nucleus fixed, and the Newton systems are "bosonic stars". In either case there exists some third order polynomial in N such that the ratio of the ground state energy to the respective polynomial grows monotonically in N. Some applications of these new monotonicity results are discussed

Antimatter and Matter Production in Heavy Ion Collisions at CERN (The NEWMASS Experiment NA52)

Besides the dedicated search for strangelets NA52 measures light (anti)particle and (anti)nuclei production over a wide range of rapidity. Compared to previous runs the statistics has been increased in the 1998 run by more than one order of magnitude for negatively charged objects at different spectrometer rigidities. Together with previous data taking at a rigidity of -20 GeV/c we obtained 10^6 antiprotons 10^3 antideuterons and two antihelium3 without centrality requirements. We measured nuclei and antinuclei (p,d,antiprotons, antideuterons) near midrapidity covering an impact parameter range of b=2-12 fm. Our results strongly indicate that nuclei and antinuclei are mainly produced via the coalescence mechanism. However the centrality dependence of the antibaryon to baryon ratios show that antibaryons are diminished due to annihilation and breakup reactions in the hadron dense environment. The volume of the particle source extracted from coalescence models agrees with results from pion interferometry for an expanding source. The chemical and thermal freeze-out of nuclei and antinuclei appear to coincide with each other and with the thermal freeze-out of hadrons.Comment: 12 pages, 8 figures, to appear in the proceedings of the conference on 'Fundamental Issues in Elementary Matter' Bad Honnef, Germany, Sept. 25-29, 200

Simultaneous tromboembolic events in a patient with heterozygous MTHFR mutation

Background: Hyperhomocysteinemia is a well recognised risk factor for arterial and venous thrombosis. The most common form results from methylenetetrahydrofolate reductase (MTHFR) gene mutations leading to decreased enzymatic activity.Case report: We present the case of a 34 year-old woman with a sudden onset of left hemiparesis and aphasia accompanied by retrosternal pain. She is diagnosed with acute posteroinferolateral myocardial infarction and stroke. Homocysteine level was determined and it was moderately elevated. The coronary angiogram revealed partially recanalised embolic occlusion of posterior left ventricular branch and posterior interventricular artery. A conservative treatment management is adopted. She remained haemodynamically stable, with complete resolution of neurological symptoms and evolution to subacute myocardial infarction.Conclusions: The particularity of our case is represented by symultaneous thromboembolic events causing myocardial infarction and ischemic stroke in a patient with a history of recurrent pregnancy loss, which was previously diagnosed with MTHFR gene mutation. Moderate hyperhomocysteinemia, also found in our patient, is recognised as an ethiopathogenic factor of thrombophilia. The right diagnosis and therapeutic approach could be the key to improved prognosis in this category of patients. MTHFR gene mutation causing hyperhomocysteinemia should be suspected in patients with thromboembolic events, especially when occuring repeatedly or at young age

Molecular Signaling and Dysfunction of the Human Reactive Enteric Glial Cell Phenotype: Implications for GI Infection, IBD, POI, Neurological, Motility, and GI Disorders

BACKGROUND: Clinical observations or animal studies implicate enteric glial cells in motility disorders, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal (GI) infections, postoperative ileus, and slow transit constipation. Mechanisms underlying glial responses to inflammation in human GI tract are not understood. Our goal was to identify the "reactive human enteric glial cell (rhEGC) phenotype" induced by inflammation, and probe its functional relevance. METHODS: Human enteric glial cells in culture from 15 GI-surgical specimens were used to study gene expression, Ca, and purinergic signaling by Ca/fluo-4 imaging and mechanosensitivity. A nanostring panel of 107 genes was designed as a read out of inflammation, transcription, purinergic signaling, vesicular transport protein, channel, antioxidant, and other pathways. A 24-hour treatment with lipopolysaccharide (200 μg/mL) and interferon-γ (10 μg/mL) was used to induce inflammation and study molecular signaling, flow-dependent Ca responses from 3 mL/min to 10 mL/min, adenosine triphosphate (ATP) release, and ATP responses. RESULTS: Treatment induced a "rhEGC phenotype" and caused up-regulation in messenger RNA transcripts of 58% of 107 genes analyzed. Regulated genes included inflammatory genes (54%/IP10; IFN-γ; CxCl2; CCL3; CCL2; C3; s100B; IL-1β; IL-2R; TNF-α; IL-4; IL-6; IL-8; IL-10; IL-12A; IL-17A; IL-22; and IL-33), purine-genes (52%/AdoR2A; AdoR2B; P2RY1; P2RY2; P2RY6; P2RX3; P2RX7; AMPD3; ENTPD2; ENTPD3; and NADSYN1), channels (40%/Panx1; CHRNA7; TRPV1; and TRPA1), vesicular transporters (SYT1, SYT2, SNAP25, and SYP), transcription factors (relA/relB, SOCS3, STAT3, GATA_3, and FOXP3), growth factors (IGFBP5 and GMCSF), antioxidant genes (SOD2 and HMOX1), and enzymes (NOS2; TPH2; and CASP3) (P < 0.0001). Treatment disrupted Ca signaling, ATP, and mechanical/flow-dependent Ca responses in human enteric glial cells. ATP release increased 5-fold and s100B decreased 33%. CONCLUSIONS: The "rhEGC phenotype" is identified by a complex cascade of pro-inflammatory pathways leading to alterations of important molecular and functional signaling pathways (Ca, purinergic, and mechanosensory) that could disrupt GI motility. Inflammation induced a "purinergic switch" from ATP to adenosine diphosphate/adenosine/uridine triphosphate signaling. Findings have implications for GI infection, inflammatory bowel disease, postoperative ileus, motility, and GI disorders