the role of infections in the emergence of non – communicable diseases (ncds): compelling needs...

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

INTRAUTERINE INFECTIONS AND FOETAL IMPRINTING BAKERS HYPOTHESIS I.Foetal malnutrition and stress(infection) II.Foetal programming, Immune programming III.Intrauterine growth retardation(low birth weight) A.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. B.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. C.MALARIA SCHISTOMIASIS IN MOTHER MAKES TH 2 RESPONSE TH 1 RESPONSE IN CHILDHOOD.

CLASSIFICATIONS OF INFECTIONS INTRACELLULAR AND EXTRACELLULAR 1.BACTERIA 2.VIRUSES 3.CHLAMYDIA 4.PARASITES 5.PRIONS

Cell mediated INNATE SYSTEM WORKS WITH ADAPTIVE IMMUNE SYSTEM

MECHANISMS TOXINS ENDOTOXIN MIMICRY Rheumatic fever/ Rheumatic disease INDUCE AUTOIMMUNE TYPE I - IV PRION/CALCIFICATION HOST/IMMUNE PARASITE/INFECTION INTERACTION AGGRESSINS IMMUNO SUPPRESSION ONCOGENE CO-CARCINOGEN SUPPRESSION OF AUTOIMMUNITY (Plasmodium knowelsi on NZB mice) CELLULAR DIFFERENTIATION (Ad 36 virus Adipocyte) PERSISTENCE/ TRANSFORMATION CHRONIC INFLAMMATION MODULATION OF TH1/TH2/T(REG) BALANCE CYTOKINE CHEMOKINES GENE PRESSURE (MALARIA) 1.Sickle gene 2.Thalasemia 3.G6PD HYPERSENSITIVITY (TYPE I V)

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

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

FAT CELL IN ENERGY HOMEOSTASIS, INFLAMATION, IMMUNITY 1.RESISTIN 2.LEPTIN 3.ADIPONECTIN INSULIN RESISTANCE 4.VISFATIN 5.APELIN 6.TUMOUR NECROSIS FACTOR (TNF) 7.RETINOL BINDING PROTEIN 8.MONOCYTE CHEMOTACTIC PROTEIN1 (MCP-1) 9.PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) 10.INTERLEUKIN 6 ABDOMINAL FAT CELL IS ACTIVE

PATHOGENS RESPONSIBLE FOR OBESITY PATHOGEN (REFERENCE) ANIMAL MODEL POSSIBLE MECHANISM(S) *Human adenovirus (11,15,16) Chickens, mice, nonhuman primates Up-regulation of preadipocyte differentiation Human adenovirus(33)ChickensUnknown SMAM-1 adenovirus (8,9)ChickensUnknown Borna-disease virus (10,50,51)RatsHypothalamic damage Chlamydia pneumoniae(68) No animal model, associated with weight gain in humans Unknown Scrapie agent (76-79)Mice Hypothalamic-pituitaryadrenal axis damage Canine Distemper virus (5)Mice Hypothalamic damage, reduced hypothalamic leptin receptor expression Rous-Associated virus-7 (6,7)ChickensReduced thyroid hormone levels * Human pathogens, and/or associated with human obesity.

Adenovirus Ad-36: Up-regulation of fat cell differentiation, reduced leptin secretion. Borna-disease virus (BDV) Hypothalamic damage Hypothalamus Scrapie agent Hypothalamic- pituitaryadrenal axis damage GLUT-1 Alterations Rous virus-7 RAV-7: Reduced thyroid hormone levels Adipose tissue Chlamydia pneumonia Immunomodulators (?) ADIPOGENIC PATHOGENS AND THE POTENTIAL MECHANISMS LEADING TO OBESITY 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

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

Metabolic adaptation of C57Bl/6J and SWR/J mice to infection with H. polygyrus. A) Body weights of nave mice compared to those infected with H. polygyrus for 21 days, Mean SEM, N=58 in each group; B) Average food intake per 24 hours in nave vs. 21 day H. polygyrus infected mice, Mean SEM, N=58 mice per group, *p=0.001; C) A comparison of energy expenditure in nave 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 nave vs. H. polygyrus infected SWR/J mice over 24 hours, arrows indicate dark cycle period, N=4 mice per group.

CANCER AND INFECTIONS TOTAL INFECTION-ATTRIBUTABLE CANCERS WORLDWIDE AgentCancer# cases% all Ca. H. PyloriStomach592,0005.5 Lymphoma11,500 HPVCervix492,8005.2 Anogenital53,880 Oropharynx14,500 HBV, HCVLiver535,0004.9 EBVNasopharynx78,1001.0 Hodgkin L.28,600 Burkitt L.6,700 HIV/HHV8Kaposi sarcoma66,2000.9 Non-Hod. L.36,100 Schistosomes Bladder 10,6000.1 HTLV-1ATL3,3000.03 Liver flukesBile duct2,5000.02 Total1,932,80017.8 B

I-A Ca in Developing and Developed Countries Developed CountriesDeveloping Countries SiteAgent# cases% all Ca# cases% all Ca. LiverHBV,HCV48,0001.0475,0008.2 Flukes02,500 CervixHPV83,4001.7409,4007.0 StomachH. pylori192,0003.8400,0006.9 KaposiHHV83,7000.162,5001.1 NHLHIV/EBV9,3000.226,8000.7 EBV (BL)1006,600 H.pylori5,6005,900 HTLV-15502,790 AnogenitalHPV22,4500.431,4300.5 Nasopharyn x EBV6,5000.171,6001.2 OropharynxHPV5,6000.18,8000.2 Hodgkin L.EBV11,5000.217,1000.3 BladderSchistos00.010,6000.2 Total389,0007.71,527,00026.3

COULD INFECTIONS CAUSE PROSTRATE CANCER? IS A VIRUS INVOLVED? 1.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? 1.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.

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

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

STRATEGIES FOR HPV VACCINATION Prevent Infection Mediate Regression Eliminate Residual Disease

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.

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

EBV is associated with multiple cancers Burkitts lymphoma Post transplant lymphomas Hodgkins lymphoma Nasopharyngeal carcinoma Gastric cancer

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.

EBV associated cancers PTLD EBNAs1-3, LMPs1-2b Hodgkins EBNA1, LMP1,2A Burkitts EBNA1 only Other B cells Nave B cell Germinal Center Memory B cell

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

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

STAGES IN DEVELOPMENT OF CANCER 1.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-Hippel Lindau syndrome e. NF1 and NF2 genes in neurofi bromatosis f. APC and DCC genes in familial adenomatous polyposis

HUMAN ONCOGENIC DNA VIRUSES TAXONOMIC GROUPINGEXAMPLESTUMOR TYPES AdenoviridaeAdenovirus types 9, 12, 18, 31Various solid tumors in rodents HepadnaviridaeHBVHepatocellular carcinoma HerpesviridaeEBVBurkitts lymphoma Nasopharyngeal carcinoma B-cell lymphoma Hodgkins lymphoma KSHV (HHV-8)Kaposis sarcoma Primary eff usion lymphoma Multicentric Castlemans disease PapillomaviridaeHPV types 6, 11, 16, 18, 31, 45Oral, cervical, and anal cancer Merkel cell polyomavirusMerkel cell carcinoma PolyomaviridaeBK virus, JC virusSolid tumors in rodents PoxviridaeMCVVarious solid tumors HBV: Hepatitis B virus, EBV: Epstein-Barr virus, KSHV: Kaposis sarcoma-associated herpesvirus, HHV: Human herpes virus, HPV:Human papillomavirus, MCV: Molluscum contagiosum virus

HUMAN ONCOGENIC RNA VIRUSES. Taxonomic grouping ExamplesTumor types RetroviridaeHTLV type 1 Adult T-cell leukemia FlaviviridaeHepatitis C virusHepatocellular carcinoma HTLV: Human T-cell leukemia virus.

NUTRITION AND INFECTION SPIRAL OF MALNUTRITION AND INFECTION INADEQUATE DIETARY INTAKE APPETITE LOSS NUTRIENT LOSS MALABSORPTION ALTERED METABOLISM WEIGHT LOSS GROWTH FATTERING LOWERED IMMUNITY MUCOSAL DAMAGE DISEASE: INCIDENCE DURATION SEVERITY Onyemelukwe GC, 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.) AFLATOXINS FROM FUNGI ASPERGILLUS FLAVUS HYPERMETABOLISM IL-1,IL-6,TNF, FEVER PROTEIN LOOSING ENTEROPATHY C

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

CARDIOVASCULAR - ATHEROSCLEROSIS D

ATHEROSCLEROSIS IS ASSOCIATED WITH MULTIPLE PATHOGENIC MECHANISMS IN HIV-INFECTED ANTIRETROVIRAL-NAVE 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. 1.HIV- infected patients have a greater burden of sub-clinical and clinical atherosclerotic disease compared to the general population. 2.A complex pathogenesis drives atherogenesis in HIV infection. Thus, whereas inflammation could be responsible for this process in ART- nave individuals. 3.ABCA-1, an ATP-binding transporter cassette protein involved in cholesterol efflux, which is inhibited by Nef, is up-regulated in ART- treated individuals.

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.

INFLUENZA AND CARDIOVASCULAR DISEASE Mohammad Madjid, MD; Ibrahim Aboshady, MD; Imran Awan, MD; Silvio Litovsky, MD; S.Ward Casscells, MD. Tex Heart Inst J 2004; 31:4-13 We appraise the relationship between influenza and coronary heart disease, on the basis of Bradford Hills 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.

INFECTIOUS AGENTS IMPLICATED IN ATHEROSCLEROSIS Chlamydia pneumoniae Cytomegalovirus Herpes simplex viruses 1 and 2 (HSV-1, HSV-2) Helicobacter pylori Mycoplasma pneumoniae Porphyromonas gingivalis Enterovirus species Salmonella typhi Streptococcus sanguis Coxsackie B virus Adenovirus species Mycoplasma gallisepticum Mareks disease virus Measles virus Epstein-Barr virus Human immunodeficiency virus Mycoplasma fermentans Coxiella burnetti Actinobacillus actinomycetemcomitans Bacteroides forsythus Hepatitis A virus Prevotella intermedia Influenza virus

EFFECTS OF INFLUENZA ON THE COAGULATION SYSTEM TargetEffectStudy Platelet aggregation50-53IncreasedIn vivo human and animal Platelet count50,54,55DiminishedIn vivo and in vitro human AT III56DiminishedIn vivo human Clotting time57IncreasedIn vivo human DIC prevalence58IncreasedIn vivo human PT61ProlongedIn vivo human PTT61ProlongedIn vivo human Fibrinogen62DecreasedIn vitro human Factor V61DiminishedIn vivo human Factor VIII61DiminishedIn vivo human FDPs56,61,63Markedly IncreasedIn vivo and in vitro human Fibrin monomers63PositiveIn vitro human Soluble fibrin61IncreasedIn vivo human Staphylococcal clumping test61 AbnormalIn vivo human

PlasminogenDecreasedIn vivo human 1-Antitrypsin ReducedIn vivo human 2-Macroglobulin5 ReducedIn vivo human Plasmin inhibitor complexes Produced, then consumed In vivo human Secondary fibrinolysis56InitiationIn vivo human Tissue factor64,65IncreasedIn vivo human Factor VII64ActivationIn vivo human Factor X64ActivationIn vivo human TFPI66 Exhausts the inhibitory effect In vivo human MonocytesActivate the procoagulantIn vivo human 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

HILLS CRITERIA FOR CAUSALITY Strength of association Consistency Temporal sequence Coherence Biologic plausibility Biologic gradient (dose-response relationship) Specificity Experimental evidence Analogy

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

PRION DISEASES E Kajander E (2006). "Nanobacteria--propagating calcifying nanoparticles". Lett Appl Microbiol 42 (6): 549-52. www.nanobac.org Nanobacteria cause kidney stones and arterial classifications

F AUTOIMMUNE DISEASES AND ALLERGIES

STRACHAN DV BMJ, 1989 HYGIENE HYPOTHESIS

HYGIENE HYPOTHESIS I.Worm Therapy. Worm therapy has been or is being studied in humans as a treatment for several immunological diseases including Crohn's disease, Ulcerative Colitis, Multiple Sclerosis, Eczema or atopic dermatitis and allergies. Autoimmune liver disease has also been demonstrated to be modulated by active helminth infections. II.The Hygiene Hypothesis & Worm therapy. a. Extra-cellular antigens primarily trigger the TH2 response, as observed with allergies, while intracellular antigens trigger a TH1 response. The Hygiene Hypothesis states that there is a regulatory action between the two types of response. b. The Old Friends Hypothesis modifies the Hygiene Hypothesis, proposing that T regulator cells (T regs) only become mature and completely effective if they are stimulated by repeated exposure to microorganisms and parasites that are relatively benign and which have coexisted with humans throughout our evolutionary history. III.Which worms are used in therapy? Only Necator Americanus meet all these requirements, although Trichuris Suis Ova only, so it is more expensive at therapeutic doses. The main difference between N. americanus and T. suis is residency time, because T. suis has a lifespan of only 2-3 weeks in humans, while N. americanus has an average life span of 5 years.

DC= DENDRITIC CELLS; APC=ANTIGEN PRESENTING CELLS;

DENDRITIC CELLS PRESENTATION OF ANTIGENS LEAD TO FORMATION OF Treg and TISSUE GROWTH FACTOR (TGF-b)

CHILDREN IN WESTERN COUNTRIES VERSUS CHILDREN IN AFRICAN COUNTRIES

IL-25 elicits a multi-potent progenitor cell population that promotes Th2 cytokine responses Steven A. Saenz1, Mark C. Siracusa1, Jacqueline G. Perrigoue1, Sean P. Spencer1, Joseph F. Urban Jr.2, Joel E. Tocker3, Alison L. Budelsky3, Melanie A. Kleinschek4, Robert A. Kastelein4, Taku Kambayashi5, Avinash Bhandoola5, and David Artis. Nature. 2010 April 29; 464(7293): 13621366. doi:10.1038/nature08901.

PARASITES AND ALLERGIC DISEASES

VACCINATION with Human Hookworm Vaccine "Necator americanus Aspartic Protease-1 M74 Generates Neutralizing Antibodies and a Potent Immune Response in BALB/c Mice. Amar R. Jariwala, George Washington University; Xi Chen, George Washington University; Mark S. Pearson, James Cook University; Brian Keegan, Baylor College of Medicine; Jill B. Brelsford, George Washington University; Medical Immunology Commons; 4-22-2013

INFANT GUT MICROBIOTA AND THE HYGIENE HYPOTHESIS OF ALLERGIC DISEASE: IMPACT OF HOUSEHOLD PETS AND SIBLINGS ON MICROBIOTA COMPOSITION AND DIVERSITY Meghan B Azad 1, Theodore Konya 2, Heather Maughan 3, David S Guttman 3, Catherine J Field 4, Malcolm R Sears 5, Allan B Becker 67, James A Scott 2, Anita L Kozyrskyj 17* and CHILD Study Investigators 7. Allergy, Asthma & Clinical Immunology 2013, 9:15 doi:10.1186/1710-1492-9-15 1 2 3 4 5 67 2 17 7

Model for the possible influence of pets and siblings on infant gut microbiota and subsequent development of atopic disease. Household pets (D, dogs; C, cats) and siblings increase infant exposure to environmental microbes, promoting enrichment for distinct combinations of organisms within the gut microbiota; overall richness and diversity are also impacted. Despite favoring different microbiota profiles, the net effect of both pets and siblings is to promote healthy immune system development and protect against atopic disease. Further research is required to characterize the underlying biological mechanisms. Azad et al. Allergy, Asthma & Clinical Immunology 2013 9:15 doi:10.1186/1710- 1492-9-15

G. MENTAL DISEASES- DEPRESSION AND VIRAL INFECTIONS Shalini, Malhotra; Nirmaljit, Kaur; P. Kumar; M.S. Bhatia; Charu, Hans. Delhi psychiatry journal vol. 15 no.1 1.Human immunodeficiency virus 2.Hepatitis C virus 3.Epstein-Barr Virus 4.Herpes simplex virus 5.Influenza virus 6.Hepatitis B virus 7.Hepatitis A virus 8.BORNA DISEASE VIRUS 9.Human T-cell Lymphotropic virus (HTLV). markers of inflammation (C-reactive protein, interleukin 1 and 6) were positively correlated with depression.43. Cytokines seem to trigger a quick onset of what is called sickness behavior-meaning malaise and fatigue, as well as a delayed onset of depressed. etanercept (a TNFtumor necrosis factor-blocker) reduced depressive symptoms in people with psoriasis.

MECHANISM OF ACTION OF MICROBIAL PATHOGENS IN DEPRESSION A. Chronic infection with any of these viruses can lead to raised interferon-alpha levels (interferon-alpha is secreted by cells of the immune system as it tries to control the virus), and it is now known that interferon-alpha can significantly affect the serotonin system. B Coxsackie virus B, which have a particular affinity for, and disruptive action on, the hypothalamus. C. Raising glutamate and quinolinic acid levels in the brain (high glutamate levels are linked to depression). The excess glutamate/quinolinic acid in this case comes from the activated microglia cells (microglia are specialized macrophages permanently resident in the brain). D. Depression can sometimes be caused by low levels of the adrenal hormone cortisol. Viruses like enterovirus often chronically infect the adrenal glands. E. Chronic fatigue syndrome, the working memory and long-term recall is often severely disrupted.

LIST OF NON COMMUNICABLE DISEASES (NCDs) AND THEIR KNOWN OR PROBABLE INECTIOUS RISK FACTORS CARDIOVASCULAR H

RESEARCHES IN CARDIOVASCULAR DISEASES 1.RHEUMATIC FEVER/ RHEUMATIC HEART DISEASE- Grp A, B, C streptococcal pharynigitis and skin infections Ogunbi et al (lagos) J. Epid. Comm. Health 1978 march 3(1) 68-71 2. Endomyocardial fibrosis(EMF) and loa loa induced eosinophilia. Others trichinella spiralis,ascaris, hookworm, toxoplasmosis Andy JJ et al (Calabar, Ife) Acta tropica 1998; 69 127-140 Urhogide A, Falase A (Ibadan) Afri J Med Med Sci 1987, 16 133

3. PERIPARTUM CARDIAC FAILURE (PPCF) Zaria syndrome- salt lake, Hot bath, volume overload,pre HT, ? Viral myocarditis Davidson N, Parry E Q J Med N S 1976, 47 431-461, Adesanya c et al Trop. Geog Med 1989, 41 (3) 190-196, Ford l, Abdullahi et al Q J Med 1998 91 93-103 Danbauchi SS Trop Doc 2002,32 24-27 4. OTHERS DUE TO MYOCARDITIS from toxoplasmosis, coxsackie B virus and chlamydia. Falase A (Ibadan) Heart vessels Supp 1985 1, 232-35, Cenac A et al(Niger) Med Trop(Mars) 2000,60,2, 137-40 5.ECLAMPSIA AND INFECTION Ekwempu CC(Zaria) Tropical doctor 1980 174-78 Ekwempu CC Int J Gynae Obstect 1980, 18 4, 300-2

NEUROLOGY/ PSYCHIATRY

1. Tropical spastic paraparesis and HTLV1 Roman GC et al Neurology 1985,35, 1158 2. Epidemic seasonal ataxia and viral (arbovirus) encephalitis Adamolekun B et al Met Brain Dis 1997, 12, 251 3. Post malaria cerebellar ataxia Osuntokun BO Afr J Med Med Sci 1983, sept 3-4, 165-172 4. Typhoid and Fregoli syndrome(rare persecutory delusion) Stanley et al (Jos), Nig J Med 2002,4, no 1,jan-march 33-34 5. Typhoid and neuropsychiatric manifestation Osuntokun et al Arch 1972 Neurol 27 July 7-13 RESEARCHES IN NEUROLOGICAL IN AFRICA

AUTOIMMUNE/ ENDOCRINE NOTE: EFFECT OF MALARIA PLASMODIUM BERGHEI IN REDUCED INCIDENCE OF AUTOIMMUNE DISEASES. B. M. GREENWOOD; VOLLER. A. SUPPRESSION OF AUTOIMMUNE DISEASE IN NEW ZEALAND MICE ASSOCIATED WITH INFECTION IN MALARIA II. NZB MICE. CLIN.EXP. 1970; IMMUNOL. 71(6) 805-815

GASTROINTESTINAL DISEASES

1. LIVER CIRRHOSIS, HBV AND SCHISTOSOMIASIS FAKUNLE Y, ET AL (ZARIA) 2. HBV, HCV,HDV(DELTA VIRUS) OJO S ET AL EAST AFRI MED J,1995,72,II,719-21 3. HELICOBACTER PYLORI AND PEPTIC ULCER HOLCOMBE C ET AL (MAIDUGURI) TRANS R SOC TROP MED HYG 1994 88,569 4. MALARIA AND TROPICAL SPLENOMEGALY SYNDROME Fakunle Y, Greenwood B, 1976 Trans R Soc Trop Med Hyg 70 346-51 Fakunle Y, Greenwood B,1977 Clin exp Immunol 28, 153- 6 RESEARCHES IN GIT DISEASES

RENAL DISEASES

SOME RESEARCHES ON RENAL DISEASES 1. QUARTAN MALARIAL NEPHROPATHY Hendricks RG, Adeniyi A (Ibadan) Kidney Int 1979, 16,64 2. SCABIES AND NEPHRITIS INCLUDING NEPHROTIC SYNDROME Whittle HC et al Trans R Soc Trop Med Hyg 1973 67, 349-363 Abdulrahman m,b 1984 J Inf Mar 8, 100-9 Aikionbare H et al 1984 Nig J Paed 11,2,59-62 3. VIRAL HEPATITIS AND IMMUNE COMPLEX GLOMERULONEPHRITIS, LEPROSY, YERSINIA ENTEROCOLITICA(BY RENNER.A) ETC.

RESPIRATORY DISEASES

RESEARCHES IN RESPIRATORY DISEASES 1. Asthma and air borne fungi (Aspergillus fumigatus), house dust mite (dermatophagoides farinae/pterysinnus) Lawande R, Onyemelukwe GC (Zaria) Ann allergy 1984 52(1) 47 Onyemelukwe GC (Zaria) et al Ann Allergy 1986 Feb 56(2), 167-70 2. Asthma and hookworm Salako LA N.Eng J Med 1970,283,264 3. Asthma and strongyloides Nwokolo CU, BMJ,1973, 1, 153

VICIOUS CYCLE HYPOTHESIS IN COPD

CANCERS AND OTHER DISEASES

1.Mutation of tumor suppressor gene in codon 249 by aflatoxin in PLCC. Ndububa et al Afri J Med Sci 2001 30, 125- 127 2. Schistosomiasis and bladder cancers Bedwani R et al(Egypt) Bri J Cancer 1998, 77,1186-9 3. Aflatoxin B1B2 G1 G2(Aspergillus flavus) and PLCC Ndububa et al Afri J.Med Sci 2001 30, 125- 127 Onyemelukwe et al Toxicol Letters,1982,56,2, 167-70 RESEARCHES IN CANCER

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