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By PROF. G. C. ONYEMELUKWE (MON )

THE ROLE OF INFECTIONS IN THE EMERGENCE OF NON – COMMUNICABLE DISEASES (NCDs): Compelling needs for novel strategies . By PROF. G. C. ONYEMELUKWE (MON ) FORMER CHAIRMAN FEDERAL MINISTRY OF HEALTH EXPERT COMMITTEE ON NCDs. NON COMMUNICABLE DISEASES AND RISK FACTORS.

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By PROF. G. C. ONYEMELUKWE (MON )

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  1. THE ROLE OF INFECTIONS IN THE EMERGENCE OF NON – COMMUNICABLE DISEASES (NCDs): Compelling needs for novel strategies. By PROF. G. C. ONYEMELUKWE (MON) FORMER CHAIRMAN FEDERAL MINISTRY OF HEALTH EXPERT COMMITTEE ON NCDs

  2. NON COMMUNICABLE DISEASES AND RISK FACTORS

  3. INTRAUTERINE INFECTIONS AND FOETAL IMPRINTING BAKER’S HYPOTHESIS Foetal malnutrition and stress(infection) Foetal programming, Immune programming Intrauterine growth retardation(low birth weight) INSULIN RESISTANCE, NIDDM, HYPERTENSION, STROKE, CORONARY HEART DISEASE IN ADULT LIFE. UTI, TOXOPLASMA, RUBELLA, CMV, HERPES. FORRESTAL T. HISTORIC EARLY LIFE ORIGINS OF HYPERTENSION IN AFRICA. J. Nutr.2004:134:211-6. PSYCHOLOGICAL; SCHIZOPHRENIA - CYTOKINE INDUCED PROBLEM DURING FOETAL NEURODEVELOPMENT BY RUBELLA, INFLUENZA, TOXOPLASMOSIS BROWN. A. PRENATAL INFECTIONS AS RISK FOR SCHIZOPHRENIA. SCHIZOPHRENIA BULL 2006;32(2); 200-202.DOGRA S. V. INTRAUTERINE GROWTH. MALARIA SCHISTOMIASIS IN MOTHER MAKES TH2 RESPONSE ˃ TH1 RESPONSE IN CHILDHOOD.

  4. CLASSIFICATIONS OF INFECTIONS INTRACELLULAR AND EXTRACELLULAR BACTERIA VIRUSES CHLAMYDIA PARASITES PRIONS

  5. INNATE SYSTEM WORKS WITH ADAPTIVE IMMUNE SYSTEM Cell mediated

  6. MECHANISMS MIMICRY Rheumatic fever/ Rheumatic disease INDUCE AUTOIMMUNE TYPE I - IV TOXINS ENDOTOXIN PRION/CALCIFICATION GENE PRESSURE (MALARIA) Sickle gene Thalasemia G6PD AGGRESSINS HOST/IMMUNE – PARASITE/INFECTION INTERACTION CYTOKINE CHEMOKINES IMMUNO SUPPRESSION ONCOGENE ±CO-CARCINOGEN PERSISTENCE/ TRANSFORMATION CHRONIC INFLAMMATION HYPERSENSITIVITY (TYPE I – V) SUPPRESSION OF AUTOIMMUNITY (Plasmodium knowelsi on NZB mice) MODULATION OF TH1/TH2/T(REG) BALANCE CELLULAR DIFFERENTIATION (Ad – 36 virus – Adipocyte)

  7. INFECTIONS AND STRESS HEART DISEASE ARTHRITIS IL-6 ANXIETY DEPRESSION CHRONIC CRIME/VIOLENCE STRESS STRESS PSYCHONEUROIMMUNOLOGY STRESS INDUCED MEMORY DYSFUNCTION NEUROENDOCRINEIMMUNE AXIS INFECTIONS

  8. A OBESITY OF INFECTIOUS ORIGIN Nikhil V. Dhurandhar, PhD; Richard L. Atkinson,MD; AftabAhmed,PhD. GGH JOURNAL.COM 2004:20(3)

  9. FAT CELL IN ENERGY HOMEOSTASIS, INFLAMATION, IMMUNITY RESISTIN LEPTIN ADIPONECTIN INSULIN RESISTANCE VISFATIN APELIN TUMOUR NECROSIS FACTOR (TNF) RETINOL BINDING PROTEIN MONOCYTE CHEMOTACTIC PROTEIN1 (MCP-1) PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) INTERLEUKIN 6 ABDOMINAL FAT CELL IS ACTIVE

  10. PATHOGENS RESPONSIBLE FOR OBESITY * Human pathogens, and/or associated with human obesity.

  11. ADIPOGENIC PATHOGENS AND THE POTENTIAL MECHANISMS LEADING TO OBESITY Borna-disease virus (BDV) Hypothalamic damage Canine distemper virus (CDV) 1. Reduced catecholamine Levels 2. Hypothalamic damage 3. Reduced expression of hypothalamic leptin receptor 4. Down-regulation of Melanin- concentrating hormone precursor mRNA Hypothalamus Scrapie agent Hypothalamic-pituitaryadrenal axis damage GLUT-1 Alterations Adipose tissue Rous virus-7 RAV-7: Reduced thyroid hormone levels Adenovirus Ad-36: Up-regulation of fat cell differentiation, reduced leptin secretion. Chlamydia pneumonia Immunomodulators (?)

  12. METABOLIC SYNDROME AND ALTERED GUT MICROBIOTA IN MICE LACKING TOLL-LIKE RECEPTORS Matam Vijay-Kumar, Jesse D. Aitken, Frederic A. Carvalho, Tyler C. Cullender, Simon Mwangi, Shanthi Srinivasan, Shanthi V. Sitaraman, Rob Knight, Ruth E. Ley, Andrew T. Gewirtz.Sci 2010, Apr;328 (9): 5975,228-231 DOI: 10.1126/sci.1179721 TLR-5 DEFICIENT MICE cannot recognize PAMP(pathogen associated molecular pattern of bacteria

  13. Metabolic adaptation of C57Bl/6J and SWR/J mice to infection with H. polygyrus. A) Body weights of naïve mice compared to those infected with H. polygyrus for 21 days, Mean ± SEM, N=5–8 in each group; B) Average food intake per 24 hours in naïve vs. 21 day H. polygyrus infected mice, Mean ± SEM, N=5–8 mice per group, *p=0.001; C) A comparison of energy expenditure in naïve vs. H. polygyrus infected SWR/J mice over 24 hours measured by indirect calorimetry, arrows indicate dark cycle period, N=4 mice per group; D) Total ambulatory activity in naïve vs. H. polygyrus infected SWR/J mice over 24 hours, arrows indicate dark cycle period, N=4 mice per group.

  14. CANCER AND INFECTIONS B TOTAL INFECTION-ATTRIBUTABLE CANCERS WORLDWIDE

  15. I-A Ca in Developing and Developed Countries

  16. COULD INFECTIONS CAUSE PROSTRATE CANCER? IS A VIRUS INVOLVED? Robert Schlaberg in 2006 found a virus called Xenotropic murine-like retrovirus, or XMRV, in the cell samples from prostate cancer patients. RNaseL gene, XMRV is one of the retroviruses. IS A PARASITE INVOLVED? Parasites called Trichomonas vaginalis (T. vaginalis) Casey, G et al.(2002),32 (4), 581-583 doi:10.1038/ng1021; Urisman, A et al.(2006) RNASEL Variant PLoS; Pathogens, 2 (3) doi:10.1371 Stark, J. et al.(2009),JNCI .doi:10.1093.

  17. PRINCIPLES OF ONCOLOGY • Uncontrolled proliferation induces apoptosis Noxa, Puma p53 Noxa, Puma BclxL, Mcl1 Bak,Bax BclxL,Mc1 Cyt C caspases Mule Bak/Bax

  18. NATURAL HISTORY OF CERVICAL HPV INFECTIONS Atypia/ASCUS/ CIN1-2/LSIL CIN2-3/CIS/HSIL

  19. STRATEGIES FOR HPV VACCINATION Eliminate Residual Disease Prevent Infection Mediate Regression

  20. HBV and HCV in the etiology of Hepatocellular Carcinoma • Prevalence of HCC is correlated with endemic chronic infection with HBV and HCV • Chronic HBV and HCV infections result in cirrhosis in ~ 15% of subjects in 25-30 years, with HCC arising in ~1% of subjects with cirrhosis. • Non-viral cirrhosis is also a risk factor for HCC. HCC only arises in the context of cirrhosis.

  21. Hepatitis viruses are very diverse • Hepatitis C virus (HCV) is a positive strand RNA Flavivirus. HCV core induces signalling pathways E2 interferes with interferon signalling

  22. EBV is associated with multiple cancers • Burkitt’s lymphoma • Post transplant lymphomas • Hodgkin’s lymphoma • Nasopharyngeal carcinoma • Gastric cancer

  23. EBV is associated with multiple cancers • EBV infection occurs in > 90% of the population; cancer is very rare. • Most EBV associated cancers are associated with immunosuppression- transplantation (drugs); HIV; malaria; • EBV causes cancer in both B cells, where the virus is latent and productive, and in epithelial cells that do not support viral latency.

  24. EBV associated cancers PTLD EBNAs1-3, LMPs1-2b Other B cells Naïve B cell Hodgkin’s EBNA1, LMP1,2A Germinal Center Burkitt’s EBNA1 only Memory B cell

  25. EBV associated cancers Nasopharyngeal Carcinoma EBNA1, LMP1, 2a Epithelial cell Plasma cells Memory B cell

  26. HHV-8 (KSHV) and Cancer •Kaposi’s sarcoma - spindle cell (endothelial origin) • Pulmonary Effusion Lymphoma • MulticentricCastleman’s Disease - B cell (non- cancer) Viral genome encodes homologues for cellular genes that block innate and adaptive immunity, block apoptosis, induce proliferation.

  27. STAGES IN DEVELOPMENT OF CANCER Protooncogenes(c-onc genes) are the cellular counterparts of v-onc genes. Their functions are cellular growth and development. The activation of c-onc genes with mutation leads to uncontrolled cell growth. a. Growth factors b. Growth factor receptors c. Signal transducers d. Transcription factors 2. Antioncogenes (tumor suppressor genes). When these genes lose their suppressive effects, unpreventable growth occurs. a. Retinoblastoma gene (Rb) b. p53 c. Wilms tumor gene (WTI) d. VHL gene in Von-HippelLindausyndrome e. NF1 and NF2 genes in neurofibromatosis f. APC and DCC genes in familial adenomatouspolyposis

  28. HUMAN ONCOGENIC DNA VIRUSES HBV: Hepatitis B virus, EBV: Epstein-Barr virus, KSHV: Kaposi’s sarcoma-associated herpesvirus, HHV: Human herpes virus, HPV:Humanpapillomavirus, MCV:Molluscumcontagiosum virus

  29. HUMAN ONCOGENIC RNA VIRUSES. HTLV: Human T-cell leukemia virus.

  30. NUTRITION AND INFECTION SPIRAL OF MALNUTRITION AND INFECTION C HYPERMETABOLISM IL-1,IL-6,TNF, FEVER INADEQUATE DIETARY INTAKE WEIGHT LOSS GROWTH FATTERING LOWERED IMMUNITY MUCOSAL DAMAGE APPETITE LOSS NUTRIENT LOSS MALABSORPTION ALTERED METABOLISM PROTEIN LOOSING ENTEROPATHY DISEASE: INCIDENCE DURATION SEVERITY AFLATOXINS FROM FUNGI – ASPERGILLUS FLAVUS OnyemelukweGC, Ogoina D, Ibiam G E, GH Ogbadu. Aflatoxins in body fluids and food of Nigerian children with protein- energy malnutrition. Afri. J. of Food, Agriculture, Nutrition and development, 12: (5 )2012 , ISSN 1684 5374 (KWASHIOKOR,MARASMUS,STUNTING.)

  31. UNDERNUTRITION INFECTION • DECREASED IMMUNE FUNCTION • INNATE • ACQUIRED IMPAIRED ABSORPTION . ALTERED GUT LUMEN . MUCOSAL INJURY

  32. CARDIOVASCULAR - ATHEROSCLEROSIS D

  33. ATHEROSCLEROSIS IS ASSOCIATED WITH MULTIPLE PATHOGENIC MECHANISMS IN HIV-INFECTED ANTIRETROVIRAL-NAÏVE OR TREATED INDIVIDUALS. Piconi, Stefania;Parisotto, Serena; Rizzardini, Guiliano; Passerini, Simone; Meraviglia, Paola; Schiavini, Monica; Niero, Fosca; Biasin, Mara; Bonfanti, Paolo; Ricci, Elena Delfina; Trabattoni, Daria; Clerici, Mario. AIDS 2013,27:381-389. HIV- infected patients have a greater burden of sub-clinical and clinical atherosclerotic disease compared to the general population. A complex pathogenesis drives atherogenesis in HIV infection. Thus, whereas inflammation could be responsible for this process in ART-naïve individuals. ABCA-1, an ATP-binding transporter cassette protein involved in cholesterol efflux, which is inhibited by Nef, is up-regulated in ART-treated individuals.

  34. 1. CHRONIC HEPATITIS C VIRUS INFECTION IS ASSOCIATED WITH EARLY ATHEROSCLEROSIS. Mostafa et al Gut June 28, 2010. 2. Bacterial persistence in phagocyte cells by Dr. Emil Kozarov in Columbia University: J. Atherosclerosis Thrombosis Bacillus Enterobacter hormaechei chronic infection. Periodontal bacteria in carotid artery. 3. Autoimmunity to heat shock proteins(HSP 60) from bacteria with autoantibodies in the lesion. Zhu et al 2001. Am.Coll.Cardiol.Florida 850. 4. Individual pathogens CMV, Hepatitis A, Herpes simplex 1 (HSV1), Herpes simplex 2 (HSV2), C.pneumoniae, Helicobacter pylori. 5. Pathogen burden. Zhu J. et al; Am. J. Cardiol.2000, 85: 140-146 of multiple infections with intracellular organisms in (4 )above asociated with elevated C-reactive proteins.

  35. INFLUENZA AND CARDIOVASCULAR DISEASE Mohammad Madjid, MD; Ibrahim Aboshady, MD; ImranAwan, MD; SilvioLitovsky, MD; S.WardCasscells, MD. Tex Heart Inst J 2004; 31:4-13 We appraise the relationship between influenza and coronary heart disease, on the basis of Bradford Hill’s criteria of causality. We show that our proposed relationship meets the following criteria: strength of association, consistency, temporal sequence, coherence, biologic plausibility, experimental evidence, and analogy.

  36. INFECTIOUS AGENTS IMPLICATED IN ATHEROSCLEROSIS Chlamydia pneumoniae Cytomegalovirus Herpes simplex viruses 1 and 2 (HSV-1, HSV-2) Helicobacter pylori Mycoplasma pneumoniae Porphyromonasgingivalis Enterovirus species Salmonella typhi Streptococcus sanguis Coxsackie B virus Adenovirus species Mycoplasmagallisepticum Marek’s disease virus Measles virus Epstein-Barr virus Human immunodeficiency virus Mycoplasmafermentans Coxiellaburnetti Actinobacillusactinomycetemcomitans Bacteroidesforsythus Hepatitis A virus Prevotellaintermedia Influenza virus

  37. EFFECTS OF INFLUENZA ON THE COAGULATION SYSTEM

  38. Endothelial cell damage57 A. Release of phosphatidyl serine B. Lysis a. Exposure of the prothrombotic extracellular matrix to the vascular lumen b. Alteration of the procoagulant-anticoagulant balance

  39. HILL’S CRITERIA FOR CAUSALITY Strength of association Consistency Temporal sequence Coherence Biologic plausibility Biologic gradient (dose-response relationship) Specificity Experimental evidence Analogy

  40. RECOMMENDATIONS FOR IMPROVING INFLUENZA CONTROL IN CARDIOVASCULAR PATIENTS • Motivate doctors and patients by increasing recognition of the heart-protective effect of flu shots • Update cardiology practice guidelines to include flu shots • Examine the feasibility of financial incentives to doctors and patients to improve adherence to existing guidelines • Determine which virus strains trigger cardiovascular events • Strengthen educational efforts to persuade pediatricians, internists, gynecologists, and family practitioners to improve vaccination rate of household contacts of patients with heart disease • Intensify research on the mechanism of the effect of the virus on the vascular system • Design new clinical trials to determine high-risk groups that may benefit from influenza prevention in terms of cardiovascular prevention

  41. PRION DISEASES E Nanobacteria cause kidney stones and arterial classifications KajanderE (2006). "Nanobacteria--propagating calcifying nanoparticles". LettApplMicrobiol42 (6): 549-52. www.nanobac.org

  42. F AUTOIMMUNE DISEASES AND ALLERGIES

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