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Title: MULTIPLE SCLEROSIS RESEARCH IN LATIN AMERICA is it p0.05 significant


1
MULTIPLE SCLEROSIS RESEARCH IN LATIN
AMERICAis it (plt0.05) significant ?
  • VICTOR M. RIVERA, M.D.
  • Professor of Neurology
  • Baylor College of Medicine
  • Houston, Texas

2
CURRENT STUDIES IN LATINAMERICA
  • Buenos Aires, Argentina
  • CMSC PRECEPTORSHIP
  • June 9 11, 2004

3
significance
  • Meaningful ? Grammatical
  • Important ? Connotations
  • Place of Emphasis?
  • OR
  • ? Statistical analysis term

4
LACTRIMS (lecture)
  • MISSION,
  • VISION and the
  • PASSION of
  • LACTRIMS

5
LACTRIMS
  • LACTRIMS Represents 21 countries
  • Languages Spanish
  • Portuguese
  • English
  • Final directives are provided by a
  • Multinational Assembly (gt300 registered
    neurologist members) represented by 2 Delegates
    per country..
  • Executive Committee
  • Scientific Committee
  • Steering Committee
  • Working Groups

6
LACTRIMS
  • HISTORY
  • GEO-SOCIAL POLITICS
  • THE FOUNDATION
  • THE FUTURE

7
HISTORY
  • EARLY STUDIES IN LATIN AMERICA EVOLUTION OF
    THE UNDERSTANDING OF MS IN THE CONTINENT

8
Early Observations - BRAZIL
  • Marques, A Esclerosis en Placas Jornal de
    Pernambuco, Junho, 1923 (Tesis Doctoral)
  • first documented report on MS in Latin America
  • General Description of the understanding of the
    disease at that time

9
Early Observations - BRAZIL
  • Vampre, Prado, Austregésilo, Costa-Rodriguez
  • Descriptions of cases, clinical
    diagnostic techniques
    (examination), treatment (1925, 1926,
    1936, 1939)

10
Early Observations - URUGUAY
  • Saron,
  • JAMA, 1924
    General description of the
    clinical manifestations of the disease



11
Early Observations - ARGENTINA
  • Camaller, Sacón, Negri
  • Prensa Médica Argentina, 1931, 1933
  • Pseudoencephalitic onset, hemiplegic form and
    discussion of atypical manifestations

12
Early Observations - ARGENTINA
  • Between 1934 1965
  • 26 local publications
  • Differential Diagnosis
  • Associated Disorders
  • Treatments Attempts
  • Biochemical Essays

13
Early Observations - PERU
  • Lastre
  • Rev Med Per, 1935
  • Description of four cases detected and diagnosed
    in Lima

14
No articles or works published between 1935
1945
15
Early Observations - MEXICO
  • Ramos Murguía (Neurosurgeon)
  • Rev Med Mex, 1946
  • 19 Cases ( 2.5 admissions) ( ! ) Central
    Military Hospital
  • 1946 Sylvia Lawry founds the NMSS in New York

16
Early Observations - CHILE
  • Arce
  • Bol Hosp Viha , 1949
  • One Case.

17
Influential landmark report(21 years later)
  • Alter M, Olivares L
  • Multiple Sclerosis in Mexico. Arch Neurol 1970
    23 451459
  • Prevalence 1.6 / 100,000 one of the lowest in
    the world

18
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19
Published General Reviews
  • Between 1965 1990 (25 years)
  • CUBA 3
  • MEXICO 1
  • JAMAICA 1

20
Significant paper
  • LACK OF IDENTIFICATION OF MS IN NON-MIXED
    AMERICAN INDIANS
  • First Published Observation Corona,
    Rodriguez, Otero, Stopp.. Multiple Sclerosis in
    Mexico Neurología 1996
  • MEXICO

21
Genetics and MS
  • MS is a polygenic disease associated to Class I
    and Class II HLA antigens
  • Most common candidates for MS are groups with
  • HLA A3, B7,DR2/DQW1 haplotypes

22
Genetics and MS
  • Facts
  • HLA A3,B7,DR2/DQW1
  • VERY PROMINENT IN NORTHERN AND CENTRAL EUROPEAN
    population groups (CAUCASIANS or CAUCASOIDS)

23
Genetics and MS
  • Facts
  • HLA A3,B7,DR2/DQW1
  • RARE IN EAST ASIANS (Mongoloid), BLACK AFRICANS
    AUSTRALIANS..

24
Genetics, MS and LA
  • NATIVE AMERICAN INHABITANTS
    (Amerindians)
  • Have ancestral Mongoloid genes
  • Peopling of the Americas 17,000 years ago, from
    Siberia by way of the Bering land bridgemelting
    glaciers 12 15,000 years ago, Ainu of Sakhalin
    Islands, north of Japan.by canoes all the way
    down the Pacific littoral to Chiles Monte
    Verde..by steps for centuries. Polynesians to
    Chiles Easter Islands during the XII century ???

25
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27
Genetics, MS and LA
  • DNA studies have shown a rare genetic mutation in
    the chromosome of a son of a very ancestral
    American (or Asiatic ?) man 90 of male South
    American Indians and 50 of male North American
    tribesman share now that genetic marknot present
    in any other male population !
  • HLA DR6 is common in Japanese and Mexican
    Mestizos

28
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30
Significant paper
  • SOUTH ATLANTIC PROJECT
  • Multicentric Study in Prevalence Cohort.
    Observations in Ethnic prevalence. Impact in
    Afro-Brazilians (1995 1998). Rev Neurol Arg
    2000
  • Papais-Alvarenga, Alves-Leon, Miranda Santos,
    Tilbery, Andrade, Poser
  • BRAZIL

31
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32
Genetics and MS in LA
  • AFRICAN AMERICANS
    Mostly represented by Mulattos and
    probably more complex genetically than even the
    Mestizo cohort..
  • Africans
  • Appear in the continent during the XVIII and XIX
    centuries and start to have a population impact
    in North America (except Mexico), Caribbean
    Islands, Central America, top geographic portion
    of South America and Brazil. Not so much in Chile
    and Argentina and small in Uruguay and Paraguay.

33
Genetics and MS in LA
  • BLACK AMERICA ( Africa in America )
  • Another Genetic Phenomenon
  • Caribe Indians and other indigenous groups in
    other parts of America become extinguished in the
    XVIII century (part due to decimation, part due
    to epidemics of diseases brought by the
    Europeans).
  • Africans are brought by the thousands for labor
    in mines, agriculture and house holds.

34
African Americans
  • 40 less MS than caucasians North/South gradient
    ?
  • Doubtful
  • Cuban, Colombian, Brazilian observations do not
    identify geographic gradient
  • Rather, these observations suggest local genetic
    influences
  • Almost half of patient in Rio de Janeiro are Afro
    Brazilian (Papais, Moreira, Tilbery Liem et al)

35
Significant event
  • I SIMPOSIO INTERNACIONAL DE ESCLEROSIS MULTIPLE
  • Baylor International MS Center
  • HOUSTON, 1999
  • U.S.A., Spain and Latin America
  • 130 neurologists
  • 11 countries
  • Historically the First MS Event held in Spanish
    and Portuguese BIRTH OF LACTRIMS CONCEPT Rev
    Neurol 2000, 31 (5) 469 -478

36
Geo SocialP O L I T I C S
  • have to be factual, objective, unbiased and
    educational

37
USA POPULATION BORN ABROAD
  • 1960
  • ITALY 1,257,000
  • GERMANY 990,000
  • CANADA 953,000
  • UK 833,000
  • POLLAND 748,000
  • 2000
  • MEXICO 7,841,000 ?
  • CHINA 1,391,000
  • PHILIPPINES 1,222,000
  • INDIA 1,007,000
  • CUBA 952,000 ?

38
ARE TERMS TOO (unnecessarily) ETHNIC ?
  • HISPANICS ?
  • Preferred by Democrats and Mexican-Americans..
  • (U.S. Census, 1975, Grace Flores-Hugues) Excludes
    Brazilians, African Americans, many Caribbeans..
  • LATINOS ? (Ital, Fr, Sp, Port, Ru)
  • Preferred by Republicans
  • LATIN AMERICANS ? Term derived during the
    Mexican war against the Napoleon III forces
    (1862, cinco de Mayo), this invasion was planned
    in part to contra rest the United States
    Americanism influence in the region

39
A M E R I C A N S
  • Term formerly adjudicated to all people that
    lived in the American continent, from Alaska to
    the Tierra de Fuego (Patagonia)
  • In December 23, 1823, John Quincy Adams
    promulgated the MONROE DOCTRINE America for
    the Americans to prevent the European powers to
    continue their influence in the continent. The
    Monroe Doctrine received absolute solidarity from
    all the LIBERATORS of the Americas that were
    fighting Spain for independence

40
A M E R I C A N S
  • By 1825 most countries in the continent have
    become independent, making reality the Monroe
    Doctrine (America for the Americans), however,
    24 years later (1847) United States invaded
    Mexico (against protests from Quincy Adams
    himself and Abraham Lincoln) and took 40 of its
    territory.
  • Since the last part of the XIX century the term
    American became practically synonymous (IF NOT
    EXCLUSSIVE) of a person from United States of
    North America

41
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42
N O T E S
  • From LOS ANGELES, CAL., welcome to
    Mexifornia I am an immigrant in a land of
    immigrants and the place where I live every day
    looks more like me
  • Chicanos in CALIFORNIA, ARIZONA, NEW MEXICO,
    TEXAS,ILLINOIS, GEORGIA, ALASKA
  • From EL PASO, TEXAS we are Tejanos.. Tex-Mex
    culture
  • From NOGALES, ARIZONA we did not come to
    United States United States came to us
  • Cuban-Americans and Central Americans in Florida
  • Puerto Ricans in NY

43
USA Populations and Ethnic Shifts
  • 2000 282 million
  • HISPANIC 13
  • NON-HISPANIC 69
  • 2050 420 million
  • HISPANIC 24
  • NON-HISPANIC 50
  • Caucasian non-hispanic

44
How long current racial and ethnic categories
will remain relevant?
  • and, ARE THEY really MEANINGFUL FOR Latin
    American MS ?
  • There may be phenotypic and genotypic
    differences affecting clinical characteristics
    and therapeutic responses
  • Increasing MS prevalence in Latin America will
    reflect in ? group prevalence in USA
  • Genetic dissemination appears to increment the
    presence of MS

45
LACTRIMS
  • THE FOUNDATION

46
LATIN AMERICAN COMMITTEE FOR TREATMENT AND
RESEARCH IN MS
  • L A C T R I M S
  • Preliminary meetings Houston, Basel,
    Philadelphia
  • Founded in 1999 (PanAmerican Congress, Cartagena
    de Indias, Colombia)
  • Congresses
  • I Buenos Aires 2000
  • II Monterrey 2002

47
First XXI Century Review
  • Rivera VM, Cabrera JA
  • Avance de la Esclerosis Múltiple en Latinoamérica
  • (INCREASING PREVALENCE IN LATIN AMERICA)
  • MEDICO Interamericano 2000,Vol 19 No. 10, 458 -
    465 (96 references)

48
Prof. Posers observations
  • SINCE THE INCEPTION OF THE CONCEPT ON INDEXED
    JOURNALS, gt 40,000 MS RELATED ARTICLES HAD BEEN
    PUBLISHED UNTIL NOVEMBER 2003.
  • THE SHARPEST INCREASE OCCURRING WITHIN THE LAST
    10 YEARS..

49
Main Topics of Original Papers 1990 2000
  • MEDLINE LILACS
  • Data Base Publications
  • PREVALENCE (EPIDEMIOLOGY) 26
  • CUBA 7 JAMAICA/HAITI 2
  • BRAZIL 5 COLOMBIA
    1
  • ARGENTINA 4 PERU
    1
  • MEXICO 3
  • URUGUAY 3

50
INFORMATIVE PAPER (1990S)
  • Example
  • Calegaro D, Goldbaum M, Morais L, Tilbery CP,
    Moreira MA, Gabbai AA, Scaff M.
  • THE PREVALENCE OF MULTIPLE SCLEROSIS IN THE CITY
    OF SÃO PAULO, BRAZIL, 1997.
  • Acta Neurol Scand 2001 104 208 213
  • Describes increase prevalence in São Paulo from
    1990 (5/100,000) to 1997 (15/100,000) attributed
    to more detailed recording methods and
    improvement in diagnosis and treatment.

51
Main Topics of Original Papers 1990 - 2000
  • MEDLINE LILACS
  • Data Base Publications
  • GENETICS 3
  • BRAZIL 2
  • COLOMBIA 1
  • BIOCHEMISTRY AND CSF
  • URUGUAY 1

52
ORIGINAL PAPERS FROM THE N.I.N.N., (Public
Health), MEXICO
  • Tarrats R, Ordoñez G, Rios C, Sotelo J.
    VARICELLA, EPHEMERAL BREASTFEEDING AND ECZEMA AS
    RISK FACTORS FOR MS IN MEXICANS. Acta Neurol
    Scand 108, 2002
  • VZV infection antecedent, most significant risk
    factor in Mexicans
  • Ordoñez G, Pineda B, García-Navarrete R, Sotelo
    J. BRIEF PRESENCE OF VZV VIRAL DNA IN
    MONONUCLEAR CELLS DURING RELAPSES OF MS. Arch
    Neurol 61, 2004
  • ? VZV infection ethiopathogenesis of MS or
    epiphenomenon

53
ORIGINAL PAPERS FROM THE N.I.N.N., (Public
Health), MEXICO
  • Leon C, Violante A, Arriada N, Santana HR, Corona
    T EL INTERFERON-beta 1a EN EL TRATAMIENTO DE LA
    EM (RR). Rev Neurol 31, 2003
  • First description of INF therapy in a Mexican
    population
  • Corona T, Leon T, Ostrosky-Zeichner L. SEVERE
    ANAPHYLASIS WITH RECOMBINANT INTERFERON
    INTERFERON BETA. Neurology 1999
  • Corona T, Ruiz L Letter to the Editor. Pearls
    and pitfalls
  • Acevedo AR, Nava C, Arriada N, Violante A, Corona
    T. CARDIOVASCULAR DYSFUNCTION IN MS. Acta
    Neurol Scand 100, 1999

54
Significant paper from the N.I.N.N. (Public
Health), Mexico
  • Gonzalez O, Sotelo J. IS THE FREQUENCY OF
    MULTIPLE SCLEROSIS INCREASING IN MEXICO? J
    Neurol Neurosurg Psychiatry, 1995

55
Significant paper
  • Alvarado de la Barrera, Zúñiga Ramos, et al HLA
    Class II genotypes in Mexican Mestizos with
    familial and no familial MS Neurology 55, 2000
  • Mexican Mestizos with MS share HLA-DR2 and DR3
    similar to European populations at high risk

56
Important Genetic Studies
  • C O L O M B I A
  • National Prevalence Studies are not available
  • Medellín (JL Sánchez et al, 1998) .. more
    frequent HLA DQ alpha 1.1, 1.2 allele 3
    significantly less frequent (lt0.05) similar to
    Caucasians residing in non-tropical areas..
  • 85 Caucasians, 10 mestizos, 5 Afro-Colombians
  • NO CASES IN LOCAL INDIANS

57
MS still not identified in non-mixed American
Indians Surveys by Rivera and Cabrera,
  • MEXICO 10 Indian (7 total pop. does not
    speak Spanish) Náhuatl,huastecos, otomíes,
    purépechas (central México), tarahumaras,
    tepehuanes, pimas, mazahuas, guarijios (north).
    No information on mayas,tzentales,mixtecos,lacando
    nes (south)
  • GUATEMALA (gt80 Indian) Maya quiché
  • COLOMBIA Kogis
  • BRAZIL Guatos, ipicas, guaraníes (Rio
    Paraguay/Paraná),xingús, yanomanis (central
    Brazil), kaigang (south), tembers, timbiras,
    kaapor (east), kalungas
  • PERU Aymaras (Titicaca lake)
  • ( Rivera VM, Cabrera JA. MEDICO Interamericano.
    October 2000)
  • CANADA Algonkians ( Rivera VM, Cabrera JA.
    Aborigenals with MS.Letter to theEditor,
  • NEUROLOGY
    2001)

58
Significant Study
  • First epidemiological INCIDENCE studies in Latin
    America
  • Cristiano E and collaborators,
  • ARGENTINA 2002 - 2003

59
John F. Kurtzke, M.D. 7509 Salem Road Falls
Church, VA 22043-3240 U.S.A. Nov 2002
60
Socioeconomic Search Paper
  • Lana-Peixoto MA
  • STUDIES ON MS THE GROSS DOSMETIC PRODUCT PER
    CAPITA (GDPpc) OF A COUNTRY AS AN INDEX OF
    RESEARCH PRODUCTIVITY (publications 1991-2000),
    BCTRIMS 2003, São Paulo, Brazil
  • USA first with 35 of the worlds total
    publications Italy second (11), UK (10),
    Canada (6)

61
Socioeconomic Search Paper
  • (Lana-Peixoto, BCTRIMS 2003)
  • Higher GDPpc was not necessarily related to MS
    scientific production USA first in GDPpc and
    first in of publications Switzerland second in
    GDP, 18th in production Norway third in GDP,
    16th in production. 25 countries responsible for
    99.6 of the world publications (including
    Brazil, Turkey and Mexico, but the former Br and
    Tur- despite lower GDPs fared better that
    Switzerland and Norway).

62
XIX Congreso Brasileiro de Neurologia
  • SALVADOR, BAHIA, 2000
  • 48 abstracts pertaining to MS or
    related topics
  • Epidemiology, MR, Case Reports, NMO, MS in
    children, Psychological and Social Issues,
    Interferon Therapy, Cognition and QOL

63
XXVI Academia Mexicana de Neurología
  • PUEBLA, PUEBLA, 2002
  • 4 MS abstracts
  • (from a total of 77 papers on general
    neurology)
  • Case Reports 2
  • Epidemiology 1
  • Electrophysiology 1

64
54th Annual Meeting American Academy of
Neurology
  • DENVER, COL., 2002
  • 1 Scientific Paper
  • ( From a LACTRIMS member, ARGENTINA )
  • Correale J, Bassani Molinas JC.
  • Temporal Variations of Adhesion Molecules and
    Matrix Metalloproteinases (MMP) during the course
    of MS.

65
55th Annual MeetingAmerican Academy of Neurology
  • HONOLULU, HAWAii, 2003
  • 3 abstracts
  • Basic Research 1 (Argentina)
  • Cognitive Dysfunction 1 (Argentina)
  • Therapy of NMO in Children 1 (Argentina)

66
56th Annual Meeting American Academy of Neurology
  • SAN FRANCISCO, 2004
  • 2 abstracts
  • Basic research 1 (Argentina) Correale J, Filol
    MP. Humoral Immunity and Eosinophilic Activation
    in NMO
  • Therapy 1 (Argentina) Tenebaum SN, Segura MJ.
    Modifying Therapies in Early-Onset MS

67
Consortium of MS Centers
  • DALLAS/FORT WORTH, TEXAS, 2001
  • 3 abstracts
  • Epidemiology 2 (Caribe New Mexico, USA)
  • Social Issues 1 (USA)
  • ( LACTRIMS members )

68
Consortium of MS Centers
  • CHICAGO, ILL., 2002
  • 8 abstracts
  • Epidemiology 2 (Canada Cuba)
  • Social Issues 2 (Brazil ABEM)
  • Psychol. 1 (Brazil ABEM)
  • QOL 1 (Brazil ABEM)
  • PT 1 (Brazil
    ABEM)
  • Therapeutics 1 (USA )

69
Consortium of MS Centers
  • SAN DIEGO, CAL., 2003
  • 2 abstracts
  • Immunology 1 (Argentina)
  • LACTRIMS II Award
  • Clinical Cases 1 (Cuba)

70
ECTRIMS 2001 ACTRIMS/ECTRIMS
2002
  • DUBLIN 2001 7 abstracts (Brazil)
  • BALTIMORE 2002 7 abstracts (Brazil)
  • Epidemiology, Genetics, Clinical Aspects.

71
LACTRIMS meetings
  • BUENOS AIRES I 48 Abstracts
  • 2000 Rev Neurol Arg
  • MONTERREY II 73 Abstracts
  • 2002 Rev Neurol (Sp)
  • (indexed)




72
LACTRIMS meetings
  • IGUAçU Falls , Brazil LACTRIMS
    III
  • August 25 28, 2004
  • (Borders between Brazil, Argentina, Paraguay)

73
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74
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75
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76
TEXT BOOKS
  • ESCLEROSIS MULTIPLE (Manejo Integral)

    Asociación Médica Mexicana para el Estudio de la
    Esclerosis Múltiple (AMMEEM)
  • Editorial Prado México, 2002
  • ESCLEROSIS MULTIPLE. UNA MIRADA IBEROAMERICANA
    Camilo Arriagada, Jorge Nogales-Gaete, Editores
    Arrynog Ediciones Santiago,
    Chile, 2002
  • SPONSORED BY LACTRIMS

77
Established MS Research Laboratories in Latin
America
  • INSTITUTO FLENI, BUENOS AIRES
  • HOSPITAL UNIVERSITARIO CLEMENTINO FRAGA FILHO,
    RIO DE JANEIRO
  • NATIONAL INSTITUTE OF NEUROLOGY NEUROSURGERY
    MANUEL VELASCO SUAREZ,
    MEXICO
  • INSTITUTO DE NEUROLOGIA ANTIOQUIA, MEDELLIN
  • CIREN, HAVANA
  • INSTITUTO de NEUROLOGIA del HOSPITAL DE CLINICAS,
    MONTEVIDEO AND MANY OTHERS

78
NATIONAL CONSENSUS ON TREATMENT
  • ARGENTINA
  • BRAZIL
  • COSTA RICA
  • GUATEMALA
  • MEXICO
  • URUGUAY
  • VENEZUELA

79
PRELIMINARY CONCLUSIONS(Factors influencing
Research)
  • INCREASING PREVALENCE OF MS IN LATIN AMERICA
  • INCREASING PUBLIC AWARENES OF THE DISEASE
  • MODERNIZATION OF NEUROLOGICAL EDUCATION
  • AVAILABILITY OF DMTS (A,B,C,R,)
  • RESULTS more interest in MS more studies

80
TENDENCIES in Latin American MS Research
  • EMPHASIS IN EPIDEMIOLOGICAL OBSERVATIONS (Most
    of them regional, institutional and limited in
    technical design)
  • EMPHASIS IN CASE REPORTS (Although these are
    becoming less fashionable and more inclined
    towards regional clinical characterizations of
    the disease)
  • INCREASING STUDIES IN QOL, COGNITIVE
    PSYCOSOCIAL ISSUES and GENETICS

81
LACTRIMS
  • THE FUTURE

82
THE FUTURE
  • BASIC RESEARCH
  • Available in just a few centers in Latin
    America
    Probable Contributing Factors
  • Lack of training
  • Lack of Education
  • Lack of Official Support --? results NO MONEY
    () NO RESEARCHERS NO RESEARCH


83
THE FUTURE
  • GENETIC CHARACTERIZATION
  • ADEQUATE EPIDEMIOLOGICAL STUDIES
    Including not only Prevalence but
    also Incidence Studies
  • PARTICIPATION IN MULTICENTER CONTROLLED Phase II,
    III and IV STUDIES
  • MR TECHNIQUES OF RELEVANCE

84
GENETIC CHARACTERIZATIONS
  • Caucasians
  • Native Americans (Amerindians)
  • Mestizos
  • African Americans
  • Mulattos
  • All possible combinations
  • Studies are important because genetic
    differences may influence clinical behavior and
    response to therapy i.e. DR2 and GA
    Betainterferon1-a and AMs AMs have more
    aggressive disease the Asian Optic Spinal Form
    of MS, etc.

85
GENETIC CHARACTERIZATIONS
  • LATIN AMERICAN MESTIZOS
  • (admixture between Caucasians and Amerindians)
  • REPRESENT A GROUP OF RECENT APPEARANCE (lt500
    years). The European genetic contribution
    PROBABLY HAS INCREASED THE RISK OF DEVELOPING MS
  • HLA Colombian Studies (gtfrequency of HLA alleles
    DQA-alpha 1.1,1.2 and ltfrequency allele 3),
    similar to Caucasian populations residing in
    non-tropical areas (Sanchez JL et al, 1998)

86
MS RESEARCH IN LATIN AMERICA(Final Thoughts)
  • ORIENTED MOSTLY TO CLINICAL ASPECTS AND
    EPIDEMIOLOGY. LACK OF TRAINING, EDUCATION AND
    OFFICIAL AND/OR INSTITUTIONAL SUPPORT TEND TO
    LIMIT POSSIBILITIES OF BASIC RESEARCH IN THE
    REGION. HOWEVER THE NUMBER OF MS- RELATED WORKS
    PRESENTED AT LOCAL, NATIONAL AND INTERNATIONAL
    EVENTS HAS NOTABLY INCREASED IN NUMBER AND
    QUALITY
  • Thank you for your significant work ! VICTOR M.
    RIVERA, M.D.
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