Oncogenic Virus

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Oncogenic Virus

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ONCOGENIC VIRUS basics: 

ONCOGENIC VIRUS basics Dr.T.V.Rao MD 1 Dr.T.V.Rao MD 10/7/2012

Distinguishing Characteristics of Viruses : 

Distinguishing Characteristics of Viruses Obligate intracellular parasites Extreme genetic simplicity Contain DNA or RNA Replication involves disassembly and reassembly Replicate by "one-step growth” 2 Dr.T.V.Rao MD 10/7/2012

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Viruses enter the body of the host in a variety of ways, for example... 3 Dr.T.V.Rao MD 10/7/2012

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Routes of entry: sexual Inhalation inoculation Blood organ t/plant ingestion Congenital / vertical 10/7/2012 Dr.T.V.Rao MD 4

WHO Estimates: 

WHO Estimates Worldwide, the WHO International Agency for Research on Cancer estimated that in 2002, 20% of human cancers were caused by infection, of which 10–15% are caused by one of seven different viruses. The importance of this is that some of these cancers might be easily prevented through vaccination 5 Dr.T.V.Rao MD 10/7/2012

What is Cancer: 

What is Cancer Cancer results from alterations in critical regulatory genes that control cell proliferation, differentiation, and survival. Studies of tumor viruses revealed that specific genes (called oncogenes) are capable of inducing cell transformation, thereby providing the first insights into the molecular basis of cancer . Dr.T.V.Rao MD 6 10/7/2012

How virus causes Cancers:: 

How virus causes Cancers: The viral agents causing cancer in eukaryotic animals by integrating in host genome *A virus associated with malignancies in natural host, experimental animals or cell cultures. *viruses which modified proto-oncogene, obligatory host specific, with the ability immortalization, possess genes which stimulate growth and cause cancer. Dr.T.V.Rao MD 7 10/7/2012

Early History: 

Early History The theory that cancer could be caused by a virus began with the experiments of Oluf Bang and Vilhelm Ellerman in 1908 who first show that avian erythroblastosis (a form of chicken leukemia) could be transmitted by cell-free extracts. This was subsequently confirmed for solid tumors in chickens in 1910-1911 by Peyton Rous. 8 Dr.T.V.Rao MD 10/7/2012

Research History: 

Research History In 1908, Ellerman & Bang first discovered virus, producing leukemia in chicken. In 1911 Peyton Rous 1 st shows the presence of filterable sarcoma material that induce the CANCER. 10/7/2012 Dr.T.V.Rao MD 9

Relationship of viruses with malignancy : 

Relationship of viruses with malignancy Ellerman & Bang (1908) – leukemia in fowls Rous (1911) – fowl sarcoma Shope isolated Rabbit fibroma virus (1932), papilloma virus (1933) Bittner (1936) –Breast Ca in mice 10 Dr.T.V.Rao MD 10/7/2012

Oncovirus: 

Oncovirus An oncovirus is a virus that can cause cancer. This term originated from studies of acutely-transforming retroviruses in the 1950–60s, often called oncornaviruses to denote their RNA virus origin. It now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus". 11 Dr.T.V.Rao MD 10/7/2012

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by transforming cells cancer When a virus infects a cell, it expresses proteins that cause the cell to proliferate and/or block apoptosis Cancer is multi-factorial: Oncogenic viruses are very common, only a small % of people infected actually get cancer 10/7/2012 Dr.T.V.Rao MD 12

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Major viral cancers Copyright John Valentine DMD 1999 Cancer of the cervix Cancer of the liver Certain leukemia's & lymphomas Kaposi’s sarcoma Viruses are involved in about 15% of human cancers : 10/7/2012 Dr.T.V.Rao MD 13

Classification : 

Classification 10/7/2012 Dr.T.V.Rao MD 14

Major human Oncogenic Viruses: 

15 Major human Oncogenic Viruses DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposi’s Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C

Oncogenic viruses may be RNA or DNA: 

Oncogenic viruses may be RNA or DNA 20% of human cancers believed to be of viral origin These include: Cervical cancer Burkitt’s lymphoma Hepatocarcinoma Kaposi’s sarcoma Virus is not only factor 16 Dr.T.V.Rao MD 10/7/2012

Viruses Associated With The Development Of Human Neoplasia: 

Viruses Associated With The Development Of Human Neoplasia VIRUSES NEOPLASMS DNA VIRUSES Human papilloma virus Cervical Ca, warts, ano- genital carcinoma Herpes simplex virus II Cervical carcinoma Epstein-Barr virus NPCa, African Burkitt’s Human Herpes virus 8 Kaposi’s sarcoma Hepatitis B virus Hepatocellular Ca Herpes simplex virus 6 Certain B cell (HBLV) lymphomas 17 Dr.T.V.Rao MD 10/7/2012

Viruses Associated With The Development Of Human Neoplasia: 

VIRUSES NEOPLASMS RNA VIRUSES Human T-cell leukemia virus I Some T-cell leukemia, Lymphoma Human T-cell leukemia virus II Some cases of hairy cell leukemia Human immunodeficiency virus Lymphoma; Kaposi’s Promote sarcoma Viruses Associated With The Development Of Human Neoplasia 18 Dr.T.V.Rao MD 10/7/2012

RNA viruses : 

RNA viruses Some RNA viruses have also been associated such as the hepatitis virus as well as human T-lymphotropic virus (HTLV-1). 19 Dr.T.V.Rao MD 10/7/2012

• Oncogenic viruses Oncogenesis is the result of genetic changes that alter the expression or function of proteins that play critical roles in the control of cell growth and division • Oncogenic viruses cause cancer by inducing changes that affect cell growth and division 20 Dr.T.V.Rao MD 10/7/2012

Oncogenic Retroviruses: 

Oncogenic R etroviruses More than 40 different highly oncogenic retroviruses have been isolated from a variety of animals, including chickens, turkeys, mice, rats, cats, and monkeys. All of these viruses, like RSV, contain at least one oncogene In some cases, different viruses contain the same oncogenes, but more than two dozen distinct oncogenes have been identified among this group of viruses Dr.T.V.Rao MD 21 10/7/2012

Changes in cell that are at the roots of cancer: 

22 Changes in cell that are at the roots of cancer Genetic and epigenetic alterations: Mutations Deletions Recombination's Transpositions Epigenetic alterations (DNA methylation, imprinting) Acquisition of viral genetic material

Changes in cell that are at the roots of cancer: 

23 Changes in cell that are at the roots of cancer Genetic and epigenetic alterations: Mutations Deletions Recombination's Transpositions Epigenetic alterations (DNA methylation, imprinting) Acquisition of viral genetic material Various combinations of these lead to the development of cancers - some viruses contribute single hits while others contribute multiple hits.

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24 Integrations that cause activation or inactivation of oncogenes or tumor suppressors (e.g. RNA viruses) Expression of genes that alter key signal transduction pathways - this is our focus Chronic activation of inflammatory responses How do Viruses contribute to cancer?

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TRANSFORMATION 10/7/2012 Dr.T.V.Rao MD 25

Viruses causing human malignancies : 

Viruses causing human malignancies Hepatitis B & C viruses: Hepatocellular Cancer. E-B virus: Nasopharyngeal Ca, Burkitt’s lymphoma HPV 16 & 18: Ca Cx HTLV: Adulât T cell leukemia HHV 8: Kaposi’s sarcoma 26 Dr.T.V.Rao MD 10/7/2012

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10/7/2012 Dr.T.V.Rao MD 27

Retroviruses: : 

Retrovirus es: 1.Avian leukosis viruses 2.Murine leukosis viruses 3.Murine mammary tumor virus 4.Leukosis-sarcoma viruses 5.Human T cell leukemia virus Dr.T.V.Rao MD 28 10/7/2012

Retroviridae: 

Retroviridae Any virus capable of inducing tumors. The RNA tumor viruses (family Retroviridae), which are well defined and rather homogeneous, or the DNA viruses, which contain a number of viruses capable of inducing Dr.T.V.Rao MD 29 10/7/2012

Cancer: 

Cancer Cancer arises from a combination of dominant gain of function mutations in proto- oncogenes and recessive loss of function mutations in tumor suppressor genes 30 Dr.T.V.Rao MD 10/7/2012

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Understanding Cancer CANCER Cancer is an overgrowth of cells bearing cumulative genetic injuries that confer growth advantage over the normal cells [ Nowell’s Law ] Cancer cells can be characterized as antisocial, fairly autonomous units that appear to be indifferent to the constraints and regulatory signals imposed on normal cells [ Robbin’s ] 31 Dr.T.V.Rao MD 10/7/2012

CANCER CELLS AND NORMAL CELLS : 

CANCER CELLS AND NORMAL CELLS CANCER CELLS NORMAL CELLS Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Oncogene expression is rare Intermittent or co-ordinated growth factor secretion Presence of tumor suppressor genes Normal cell Few mitoses Frequent mitoses Nucleus Blood vessel Abnormal heterogeneous cells 32 Dr.T.V.Rao MD 10/7/2012

CHARACTERISTICS OF CANCER Clonality: 

CHARACTERISTICS OF CANCER Clonality Cancer is a genetic disease at the cellular level. Genetic mutations play a critical role in pathogenesis of cancer. Consequences of genetic instability: Phenotypic heterogeneity Tumor progression Proto-oncogenes and oncogenes Dominant and recessive mutations 33 Dr.T.V.Rao MD 10/7/2012

Cancer Genetics: 

Cancer Genetics Tumors arise as clones from a single cell. At the cellular level, cancer is a genetic disease. The development of the malignant clone is due to mutations in DNA due to: Random replication errors Exposure to carcinogens Faulty DNA repair process 34 Dr.T.V.Rao MD 10/7/2012

Cancer Genes: 

Cancer Genes Proto-oncogenes – normally promote normal cell growth; mutations convert them to oncogenes. Tumor suppressor genes – normally restrain cell growth; loss of function results in unregulated growth. Mutator or DNA repair genes – when faulty, result in an accumulated rate of mutations. 35 Dr.T.V.Rao MD 10/7/2012

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ONCOGENE FAMILY + oncogenes Oncogenes promote cell proliferation dominant & highly conserved types : viral oncogenes [ v-oncs ] cellular oncogenes [ c-oncs ] Proto-oncogene  “Mutation”  Oncogene Mouse fibroblast cell line NIH 3T3 can take up foreign D Mouse fibroblast cell line NIH 3T3 can take up foreign DNA, incorporate them into their genome and express them •DNA extracted from human tumour cells can transform NIH 3T3 •Such transforming genes have been shown to be identical with cellular oncogenes 14NA, incorporate them into their genome and express them •DNA extracted from human tumour cells can transform NIH 3T3 •Such transforming genes have been shown to be identical with cellular oncogenes 14 36 Dr.T.V.Rao MD 10/7/2012

Viral Carcinogenesis: 

Viral Carcinogenesis Viral carcinogens are classified into RNA and DNA viruses. Most RNA oncogenic viruses belong to the family of retroviruses that contain reverse transcriptase mediates transfer of viral RNA into virus specific DNA. 37 Dr.T.V.Rao MD 10/7/2012

Statistical Prevalence in Different Worlds: 

Statistical Prevalence in D ifferent Worlds 10/7/2012 Dr.T.V.Rao MD 38

DNA Tumor Viruses In Human Cancer : 

39 DNA Tumor Viruses In Human Cancer Adenoviruses Highly oncogenic in animals Only part of virus integrated Always the same part Early functions E1A region: 2 T antigens E1B region: 1 T antigen E1A and E1B = Oncogenes Dr.T.V.Rao MD 10/7/2012

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40 Two Major Classes of Tumor Viruses DNA Tumor Viruses DNA viral genome Host RNA polymerase Viral mRNA Viral protein DNA-dependent DNA polymerase (Host or viral) Dr.T.V.Rao MD 10/7/2012

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41 RNA Tumor Viruses Viral RNA genome Reverse transcriptase (Virus-encoded) Viral DNA genome (integrated) DNA-dependent RNA polymerase ( Host RNA pol II) Viral genomic RNA Splicing (Host splicing enzymes) messenger RNA viral protein Virus Important: Use HOST RNA polymerase to make its genome An enzyme that normally makes mRNA IMPORTANT Dr.T.V.Rao MD 10/7/2012

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42 Adenovirus Human virus but only causes cancer in non-human cells SV40 Mesothelioma HPV Cervical Cancer Squamous cell anal carcinoma Penile cancer Oral cancers Small DNA tumor viruses

DNA Tumor Viruses In Human Cancer : 

43 DNA Tumor Viruses In Human Cancer Papilloma Viruses urogenital cancer wart malignant squamous cell carcinoma Papilloma viruses are found in 91% of women with cervical cancer Squamous cell carcinoma: Larynx Esophagus All histologically similar Lung 10% of human cancers may be HPV-linked

DNA Tumor Viruses In Human Cancer : 

44 DNA Tumor Viruses In Human Cancer Herpes Viruses Considerable evidence for role in human cancer Some very tumorigenic in animals Viral DNA found in small proportion of tumor cells: “hit and run” Epstein-Barr Virus Burkitt’s Lymphoma Nasopharyngeal cancer Infectious mononucleosis Transforms human B-lymphocytes in vitro Dr.T.V.Rao MD 10/7/2012

DNA Tumor Viruses In Human Cancer Hepatitis B continued : 

45 DNA Tumor Viruses In Human Cancer Hepatitis B continued Epidemiology: Strong correlation between HBV and hepatocellular carcinoma China: 500,000 - 1 million new cases of hepatocellular carcinoma per year Taiwan: Relative risk of getting HCC is 217 x risk of non-carriers Dr.T.V.Rao MD 10/7/2012

DNA Tumor Viruses In Human Cancer : 

46 DNA Tumor Viruses In Human Cancer Papilloma Viruses 51 types identified - most common are types 6 and 11 most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers) Dr.T.V.Rao MD 10/7/2012

Human Papillomavirus (HPV) : 

Human Papillomavirus (HPV) Human Papillomavirus (HPV) is a double-stranded DNA virus of the family Papovaviridae. It infects only epithelial cells in humans such as skin and mucus membranes. It can affect the lower genital tract including the vulva, vagina, urethra, penis, anal canal and perianal skin 10/7/2012 Dr.T.V.Rao MD 47

DNA viruses Human Papilloma virus : 

DNA viruses Human Papilloma virus ( HPV), a DNA virus, causes transformation in cells through interfering with tumor suppressor proteins such as p53. Interfering with the action of p53 allows a cell infected with the virus to move into a different stage of the cell cycle, enabling the virus genome to be replicated. Forcing the cell into the S phase of the cell cycle could cause the cell to become transformed types of HPV increase the risk of, e.g., cervical cancer. 48 Dr.T.V.Rao MD 10/7/2012

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10/7/2012 Dr.T.V.Rao MD 49

Epstein Barr virus : 

50 Epstein Barr virus Pathologies in immuno- competent individuals Infectious mononucleosis Burkitt’s Lymphoma Hodgkin’s lymphoma Nasopharyngeal carcinoma Pathologies in immuno- compromised individuals Post-transplant lymphoproliferative diseases (PTLD) Hodgkin’s lymphoma A variety of non-Hodgkin’s lymphoblastic malignancies

Epstein-Barr virus (Human herpes virus 4): 

Epstein-Barr virus (Human herpes virus 4) EBV is the herpes virus that is most strongly associated with cancer.  It infects primarily lymphocytes and epithelial cells. In lymphocytes, the infection is usually non-productive, while virus is shed (productive infection) from infected epithelial cells. 51 Dr.T.V.Rao MD 10/7/2012

Burkitt's lymphoma: 

Burkitt's lymphoma Burkitt's lymphoma in the tropics, where it is more common in malaria-endemic regions Nasopharyngeal cancer, particularly in China and SE Asia, where certain diets may act as co-carcinogens B cell lymphomas in immune suppressed individuals (such as in organ transplantation or HIV) Hodgkin's lymphoma in which it has been detected in a high percentage of cases (about 40% of affected patients) X-linked lymphoproliferative Disease (Duncan's syndrome) 52 Dr.T.V.Rao MD 10/7/2012

Infectious mononucleosis: 

Infectious mononucleosis EBV also causes infectious mononucleosis, otherwise known as glandular fever. This is a self-resolving infection of B-lymphocytes which proliferate benignly. Often infection goes unnoticed (it is sub-clinical) and about half of the population in western countries has been infected by the time they reach 20 years of age. Why this virus causes a benign disease in some populations but malignant disease in others is unknown 53 Dr.T.V.Rao MD 10/7/2012

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54 Kaposi’s Sarcoma Herpes Virus - HHV-8 Hematologic malignancies Primary effusion lymphoma Multicentric Castleman's disease (MCD) – a rare lymphoproliferative disorder (AIDS) MCD-related immunoblastic/plasmablastic lymphoma Various atypical lymphoproliferative disorders Kaposi’s sarcoma

Human Herpes Virus 8 (HHV-8, Kaposi's Sarcoma Herpes Virus): 

Human Herpes Virus 8 (HHV-8, Kaposi's Sarcoma Herpes Virus) HHV-8 infects lymphocytes and epithelial/endothelial cells and is the causative agent of Kaposi's sarcoma. It has also been associated with hematologic malignancies, including primary effusion lymphoma, Multicentric Castleman's (also Castelman's) disease (MCD), MCD-related immunoblastic/plasmablastic lymphoma and various atypical lymphoproliferative disorders 55 Dr.T.V.Rao MD 10/7/2012

Kaposi's sarcoma-associated herpesvirus: 

Kaposi's sarcoma-associated herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is associated with Kaposi’s sarcoma, a type of skin cancer. Epstein-Barr virus (EBV or HHV-4) is associated with four types of cancers Merkel cell polyomavirus – a polyoma virus – is associated with the development of Merkel cell cancer 56 Dr.T.V.Rao MD 10/7/2012

RNA oncogenic viruses: 

RNA oncogenic viruses Retroviridae Human T cell leukemia viruses (HTLV-1 and HTLV-2) Causes Adult T – cell leukemia Lymphoma Feline leukemia virus (FeLV) Contagious Causes leukemia and lymphoma in cats Related to presence of reverse transcriptase Some contain promoters that turn on other oncogenes 10/7/2012 Dr.T.V.Rao MD 57

RNA Tumor Viruses: 

58 RNA Tumor Viruses Groups of Retroviruses Oncovirinae Tumor viruses and similar Lentiviruses Long latent period Progressive chronic disease Visna HIV Spumavirinae important important

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VIRAL AGENTS: DNA viruses Human Papillomavirus [HPV types 16, 18, 31, 33 & 35] Interruption of the E1/E2 ORF E2 is not expressed Over-expression of E6 & E7 59 Dr.T.V.Rao MD 10/7/2012

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VIRAL AGENTS: DNA viruses Epstein-Barr Virus [EBV] in Burkitt’s, B-cell & Hodgkin’s lymphomas + NP ca tropism: CD21+ cells [e.g., B cells, epithelial cells] mechanism: viral entry  episomal existence  latency  (+) LMP-1, EBNA-1, EBNA-2  immortalization Hepatitis B virus [HBV] induction of chronic hepatocyte injury  (+) HBx HBx activates protein kinase c for transformation 60 Dr.T.V.Rao MD 10/7/2012

Hepatitis B: 

Hepatitis B DNA virus with RNA intermediate In tumors virus is integrated with little gene expression Believed to be from chronic liver damage/loss and replacement causing increased mutations (similar to SOS response?) 61 Dr.T.V.Rao MD 10/7/2012

DNA Tumor Viruses In Human Cancer : 

62 DNA Tumor Viruses In Human Cancer Hepatitis B Virus DNA genome RNA polymerase II RNA Provirus Reverse transcriptase DNA genome Host enzyme Viral enzyme

HEPADNAVIRIDAE HEPATITIS B VIRUS  : 

HEPADNAVIRIDAE HEPATITIS B VIRUS Hepatitis B virus is very different from the other DNA tumor viruses. Indeed, even though it is a DNA virus, it is much more similar to the oncornaviruses (RNA tumor viruses) in its mode of replication. The DNA is transcribed into RNA not only for the manufacture of viral proteins but for genome replication. Genomic RNA is transcribed back into genomic DNA. This is called reverse transcription. The latter is not typical of most DNA tumor viruses but reverse transcription is a very important factor in the life cycles of RNA-tumor viruses 63 Dr.T.V.Rao MD 10/7/2012

HCC is one of the most common tumors worldwide: 

HCC is one of the most common tumors worldwide Dr.T.V.Rao MD 64 10/7/2012

Hepatocellular carcinoma: 

Hepatocellular carcinoma Hepatocellular carcinoma (HCC, also called malignant hepatoma ) is a primary malignancy (cancer) of the liver. Most cases of HCC are secondary to either a viral hepatitide infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis).In countries where hepatitis is not endemic, most malignant cancers in the liver are not primary HCC but metastasis (spread) of cancer from elsewhere in the body, e.g., the colon. Dr.T.V.Rao MD 65 10/7/2012

RNA Tumor Viruses: 

66 RNA Tumor Viruses Human T cell lymphotropic virus -2 (HTLV-2) Hairy cell leukemia Retroviruses known to cause human cancer Human T cell lymphotropic virus -1 (HTLV-1) Adult T cell leukemia, Sezary T-cell leukemia Africa, Caribbean, Some Japanese Islands HIV ? Dr.T.V.Rao MD 10/7/2012

Proto-oncogenes: 

67 Proto-oncogenes Heterozygote Homozygote Allele 1 Allele 2 Allele 1 Allele 2 Normal Mutant Mutant Mutant Function gained Function gained Dominant mutations Binds under special circumstances Mutant always binds Mutant always binds Mutant always binds Always binds Always binds Dr.T.V.Rao MD 10/7/2012

Anti-Oncogenes: 

68 Anti-Oncogenes Rb Gene Mutant Rb Mutant Rb Rb Rb Rb protein Binds and controls cell cycle No binding - Growth continues Mutant Rb Recessive mutations Function lost Mutation growth Heterozygote Homozygote Dr.T.V.Rao MD 10/7/2012

Anti-Oncogenes: 

69 Anti-Oncogenes Retinoblastoma gene has normal regulatory function in many cells Involved in Retinoblastoma Lung carcinomas Breast carcinomas

RNA Tumor Viruses: 

70 RNA Tumor Viruses What do oncogenes encode? Proteins that are involved in growth control and differentiation Growth factors Growth factor receptors Signal transduction proteins Transcription factors

Anti-Oncogenes: 

71 Anti-Oncogenes Retinoblastoma gene has normal regulatory function in many cells Involved in Retinoblastoma Lung carcinomas Breast carcinomas Dr.T.V.Rao MD 10/7/2012

Anti-Oncogenes: 

72 Anti-Oncogenes Rb Gene Rb Rb protein Rb Stops replication Rb Adenovirus E1A Cell cycle continues Retinoblastoma 105kD Dr.T.V.Rao MD 10/7/2012

Anti-Oncogenes: 

73 Anti-Oncogenes P53 Inactivated by deletion point mutation In a series of colorectal cancers all showed: Allele 1: partial or complete deletion Allele 2: Point mutation

Anti-Oncogenes: 

74 Anti-Oncogenes p53 P53 gene P53 gene P53 gene P53 P53 DNA Stops replication Hepatitis C P53 replication replication Papilloma proteolysis P53 Papilloma Dr.T.V.Rao MD 10/7/2012

For more articles of Interest on Infectious Diseases visit me….: 

For more articles of Interest on Infectious Diseases visit me…. 10/7/2012 Dr.T.V.Rao MD 75

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Programme Created by Dr.T.V.Rao MD for Medical and Health care Professionals in the Developing World Email doctortvrao@gmail.com 10/7/2012 Dr.T.V.Rao MD 76