61. Projects e mapeamento cromossómico da doença de MachadoJoseph (Search for a genetic markerand gene mapping of machado-joseph disease), Principal Investigator Jorge http://gaia.ibmc.up.pt/groups/unigene/html/body_projects.html

Some of the more relevant (financed) research projects in the last 5 years Programa STRIDE, STRDA/C/SAU/300/92 – (Mar 93 - Feb 95) Busca de um marcador genético e mapeamento cromossómico da doença de Machado-Joseph (Search for a genetic marker and gene mapping of Machado-Joseph disease) Principal Investigator: Jorge Sequeiros J.Sequeiros, P.Coutinho, I.Silveira, P.Maciel, C.Gaspar, A.Sousa, J.Guimarães, J.M.Leal Loureiro Exclusion of linkage to 12q of MJD. Confirmation of and refinement of linkage of MJD to 14q. Establishment of phenotype-genotype correlation in MJD (age at onset and subtype). Definition of the distributions of normal and expanded alleles in MJD . Meiotic and mitotic instability of the MJD mutation . Genetic heterogeneity of dominant ataxias and their frequency in different populations. Definition of the existence of two different haplotypes in the Azores (Flores and São Miguel) , and their distributions in Portugal and other countries. Some of these were pursued under projects PECS/P/SAU/50/95 and, particularly, under PRAXIS/P/SAU/84/96 Comissão de Fomento e Investigação em Cuidados de Saúde, 95/92 - (Apr 93 - Jun 94)

62. Huntington And Other Neurodegenerative Disorders of our group has been the molecular pathomechanism of Huntington's disease andrelated polyglutamine disorders, such as machadojoseph disease and several http://www.molgen.mpg.de/~agwanker/

Disorders Projects Huntington and other Neurodegenerative Disorders Protein Interaction Networks The main focus of our group has been the molecular pathomechanism of Huntington's disease and related polyglutamine disorders, such as Machado-Joseph disease and several other spinocerebellar ataxias. A characteristic feature of these illnesses is the formation of insoluble protein aggregates in neuronal cells. Aggregates are formed due to an elongated glutamine repeat and are deposited in the nucleus and the cytoplasm of neurons in various regions of the brain. We try to understand the conditions that lead to aggregation and to find ways of inhibiting it, in order to prevent cell death (Wanker, 2000a,b). Recently we performed a high-throughput drug screening to find small molecules that prevent polyglutamine aggregation in HD. Our activities concerning Huntington's disease have led us to investigate a broader range of illness related proteins. We have identified and characterised the Huntingtin interacting proteins HIP1 and SH3GL3, and are now using them to establish larger protein-protein interaction networks involved in HD. In our systematic approach, we are employing an automated yeast two-hybrid system, as well as affinity chromatography and mass spectrometry. Work on protein interaction networks in Parkinson's, Alzheimer's and prion diseases is under way. Wanker, E. E. (2000a). Protein aggregation and pathogenesis of Huntington's disease: mechanisms and correlations, Biol Chem

63. Introduction Molecular and Metabolic Characterization of machadojoseph disease. RS Liu,BW Soong, YK Chu, LS Chu, SM Yu, KL Chou, and SH Yeh. Introduction. http://www.npcc.gov.tw/pet-5year/Clinical/mole.htm

Molecular and Metabolic Characterization of Machado-Joseph Disease R.S. Liu, B.W. Soong, Y.K. Chu, L.S. Chu, S.M. Yu, K.L. Chou, and S.H. Yeh Introduction Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar atrophy characterized pathologically by degeneration of the spinocerebellar tracts, dentate nuclei, pontine and vestibular nuclei, extrapyramidal structures, and neuronal loss in motor cranial nerves, anterior horn cells and the posterior root ganglion. MJD gene is an expansion of a trinucleotide CAG repeat that lies at the 3'terminal of the coding region. This study aims to investigate the metabolic abnormalities of the MJD patients identified by the presence of expanded CAG repeats in the MJD gene. Methods and Materials Eight MJD patients (3 males, 5 females; average duration of illness: 9.6 7.8 years) and 10 normal control subjects were studied with positron emission tomography (PET) using [F-18] fluorodeoxyglucose (FDG). Regional uptake ratios of FDG were calculated from the radioactivity of the cerebellar hemispheres, cerebellar vermis, brain stem, and the temporal, parietal and occipital cortices, divided by the activity of the thalamus. Results The results showed that uptake ratios of MJD patients were significantly lower than that in control subjects in the occipital cortex, cerebellar hemispheres, vermis, and brain stem. Furthermore, the FDG uptake ratios in the occipital cortex was found to be inversely correlated with the duration of illness, but not with the age of onset of illness.

64. Medicalseek - Search Engine For The Healthcare Industry International Joseph Disease Foundation Offers education, medical referrals, updates,and support to all individuals interested in machado-joseph disease. http://www.medicalseek.net/Conditions_and_Diseases_Genetic_Disorders_Machado_Jos

CATEGORIES ADD A LINK ADVERTISE CONTACT US ... Genetic Disorders Machado-Joseph Conditions and Diseases:Genetic Disorders:Machado-Joseph International Joseph Disease Foundation Offers education, medical referrals, up-dates, and support to all individuals interested in Machado-Joseph Disease. ijdf.net Machado-Joseph Disease Fact Sheet Developed by the National Institute of Neurological Disorders and Stroke (NINDS). ninds.nih.gov/health_and_medical/pubs/m... Machado-Joseph Information A definition of joseph disease with a look at the symptoms, diagnosis, how it is inherited and research. lusaweb.com/machado.htm MJD Fact Sheet In depth look at machado-joseph disease with some resources for further reading. glawen.freeyellow.com/joseph3.htm MJD: Getting Help Information about machado-joseph disease, genetic counselling, access to medical care and improving life quality. uac.pt/paginas/gain/doenca_i.html Pediatric Database In depth look at this machado-joseph disease, starting with a definition, epidemiology, pathogenesis, clinical features, investigation and management. icondata.com/health/pedbase/files/MACHA...

65. Spinocerebellar Degeneration machadojoseph disease Search PUBMED for machado-joseph disease All ReviewTherapy Diagnosis; machado-joseph disease OMIM. Olivopontocerebellar http://www.ohsu.edu/cliniweb/C10/C10.228.140.252.253.871.html

Spinocerebellar Degeneration Back to previous level Ataxia Telangiectasia Search PUBMED for Ataxia Telangiectasia: All Review Therapy Diagnosis ... What is Ataxia-Telangiectasia: Johns Hopkins U. Cerebellar Dyssynergia Search PUBMED for Cerebellar Dyssynergia: All Review Therapy Diagnosis Friedreich's Ataxia Search PUBMED for Friedreich's Ataxia: All Review Therapy Diagnosis Machado-Joseph Disease Search PUBMED for Machado-Joseph Disease: All Review Therapy Diagnosis ... Machado-Joseph Disease: OMIM Olivopontocerebellar Atrophy Search PUBMED for Olivopontocerebellar Atrophy: All Review Therapy Diagnosis

66. Listings Of The World Health Conditions And Diseases Genetic Joseph Disease Foundation Post Review Offers education, medical referrals, updates,and support to all individuals interested in machado-joseph disease. http://listingsworld.com/Health/Conditions_and_Diseases/Genetic_Disorders/Machad

67. Genetic Testing For Ataxia Diseases The name eventually changed to machadojoseph disease (MJD), recognizing the twoPortuguese-American families who were living on opposite US coasts when first http://www.swmed.edu/home_pages/news/machado.htm

Genetic testing for ataxia diseases now possible for people at risk Contact: Emily Martinez e-mail: emart2@mednet.swmed.edu DALLAS November 16, 1995 Genetic testing is now possible for individuals who are at risk for certain degenerative neurological diseases known as ataxias, says a researcher at UT Southwestern Medical Center at Dallas. Today's issue of the New England Journal of Medicine features an editorial by Dr. Roger Rosenberg in which he writes that "recent progress in deciphering the molecular basis of the ataxias has been extraordinary." An ataxia is a type of disease that results in loss of coordination in muscle movements. Rosenberg, professor of neurology and holder of the Abe (Brunky), Morris and William Zale Distinguished Chair in Neurology, was one of two physicians in 1975 who discovered a rare and fatal neurological disorder, which they called the Joseph family disease. The name eventually changed to Machado-Joseph disease (MJD), recognizing the two Portuguese-American families who were living on opposite U.S. coasts when first diagnosed with the illness. It is classified as an ataxia and causes degeneration of the cerebellum, resulting in a gradual loss of coordination, involuntary movement in muscles and spasticity. Rosenberg has devoted a great deal of research time in the past 20 years to determining the mutant gene products that cause ataxias and classifying patients according to genotype.

68. The Multiracial Activist - Guest Commentary: Melungeon Health Issues By Nancy Sp machadojoseph disease was discovered in the United States in 1972. The nameof this group is The Friends of machado-joseph disease Nucleus . http://www.multiracial.com/readers/sparks2.html

"Stand up and Sound off!!" Melungeon Health Issues by Nancy Sparks Morrison April/May 2001 I am not a doctor. I can neither diagnose nor prescribe. I am a lay person, who because of my own personal health problems, has done extensive research on some Mediterranean illnesses which seem to run throughout my Melungeon connected families. The information that I am providing here is to be used for educational purposes only. It should not be used for diagnostic or treatment purposes. Here is an overview of the five major medical problems that some Melungeon descendants inherit. MEDITERRANEAN DISEASES WHICH MAY AFFECT MELUNGEON DESCENDANTS SYNDROME is a relapsing, multi-system inflammatory disease in which there are oral/genital ulcers. There may be inflammation of the eyes, joints, blood vessels, central nervous system and gastrointestinal tract involvement. Attacks last about a week to a month and reoccur spontaneously. Onset is usually between 20-30 years of age with symptoms ocurring up to several years after the onset. Twice as many men as women are affected. There is a genetic predisposition with autoimmune mechanism and viral infection which may all play a part. Related disorders are Reiters Syndrome, Stevens Johnson Syndrome, and Ulcerative Colitis. Also, visit the

69. The Sackler Faculty Of Medicine - Natan Gadoth The Israeli Pocket of machadojoseph diseaseGenotipic-Phenotipic correlation.An open trial of Septrin in machado-joseph disease. http://www.tau.ac.il/medicine/Med_school/Neurology/USR/gadothn.htm

The Sackler Faculty of Medicine Natan Gadoth, Professor Address: Department of Neurology Sackler School of Medicine Tel Aviv University Ramat Aviv, Tel Aviv 69978, ISRAEL Tel: Fax: E-mail: gadoth@post.tau.ac.il Research interests: Evoked responses, Neural regeneration, Epilepsy, Dyslexia, Neurogenetics, Neurogenic metabolic and deficiency disorders, disorders of the autonomic nervous system. Research Projects: Late evoked responses in Epilepsy ( Y. Henkin -Ph.D. Thesis). Electrophysiologic and morphologic evaluation of the regenerative response in the rabbit's optic nerve.( A.Solomon -Ph.D.Thesis). Cognitive evoked responses in children with learning disabilities. ( H. Puter -Ph.D. Thesis). Dichotic listening in bilingual children with learning disabilities. ( R. Fayans - MSc Thesis). The vestibular system in professional divers.( Z. Sharoni -MSc Thesis). The Israeli Pocket of Machado-Joseph disease:Genotipic-Phenotipic correlation. An open trial of Septrin in Machado-Joseph disease. Gabapentin in complex partial epilepsy. A multicenter study. The neurology of Vit. B12 deficiency (with Prof. U. Zeligson of the Department of Hematology).

70. Machado-joseph-disease Treatment machadojoseph-disease treatment. This article submitted by thorsten schulteon 2/4/97. Author's Email thorsten.schulte@rz.ruhr-uni-bochum.de Hallo, http://neuro-www.mgh.harvard.edu/neurowebforum/MovementDisordersArticles/2.4.971

Machado-joseph-disease treatment This article submitted by thorsten schulte on 2/4/97. Author's Email: thorsten.schulte@rz.ruhr-uni-bochum.de Hallo, I´m a german medical student and have been working in a clinical trial on the effect of sulfamethoxazole and trimethorin (Bactrim) on neurologic dysfunction in patients with Joseph´s disease, for one year now. Has anybody (patient or M.D.)any experience with this form of therapy ? Maybe we could discuss our results. Next Article Previous Article Return to Topic Menu Here is a list of responses that have been posted to this article... You now have TWO OPTIONS: Post a new Article or post a Response to this Article Click here to post a new Article! If you would like to post a Response to this article, fill out this form completely... Do not use slashes ("/") or colons (":") or other "special" characters in your Article title! Also, please be sure to make your Response Title something descriptive...NOT the same title as the original article.. Response Title: Author: Author Email: Response Text: Original Article: (Don't change this field!)

71. Spinocerebelläre Ataxie Typ 3 (SCA3, Machado-Joseph-Disease, MJD) Translate this page Spinocerebelläre Ataxie Typ 3 (SCA3, machado-joseph-disease, MJD). Klinik.Die Spinocerebelläre Ataxie Typ 3 präsentiert sich klinisch http://www.pedgen.med.uni-muenchen.de/medgen/patinfo/diagnostik/sca3.html

Klinik Genetik Molekulargenetische Diagnostik Indikation: Material: 5-10 ml EDTA-Blut Methodik: Dauer: 1-2 Wochen

72. Flies Are Us SCA3/machadojoseph's disease. Machado/Joseph machado.htm. machado-josephdisease - http//www.icondata.com/health/pedbase/files/MACHADO-.HTM. http://www.molbio.princeton.edu/courses/mb427/2001/projects/03/links.html

Drosophila Resources The WWW Virtual Library: Drosophila - http://ceolas.org/fly/ The Interactive Fly - http://sdb.bio.purdue.edu/fly/aimain/1aahome.htm FlyBase - A Database of the Drosophila Genome - http://flybase.bio.indiana.edu:82/ Flyview - http://pbio07.uni-muenster.de/ http://www.nih.gov/ Berkeley Drosophila Genome Project - http://www.fruitfly.org/ Page of links - http://www.carlitos.ch/b2000/links.html The Fly Lab - http://www.biologylab.awlonline.com/FlyLab/ FlyBrain - http://flybrain.uni-freiburg.de/ Alzheimer’s Disease Alzheimer’s Research Forum - http://www.alzforum.org/ American Health Assistance Foundation - http://www.ahaf.org/ Alzheimer’s Disease Research Center in St. Louis - http://www.biostat.wustl.edu/alzheimer/ Alzheimer’s Disease Cooperative Study - http://antimony.ucsd.edu/ Alzheimer’s Association - http://www.alz.org/ Parkinson’s Disease American’s Parkinson’s Disease Association - http://www.apdaparkinson.org/ Michael J. Fox Foundation for Parkinson’s Research - http://www.michaeljfox.org/ National Parkinson’s Foundation - http://www.parkinson.org/

73. Medical Dictionary Online : MEDICAL TERMINOLOGY -M- PAGE Machado Joseph disease Type I Machado Joseph disease Type II Machado Joseph diseaseType III Machado Joseph disease Type IV machadojoseph Azorean disease http://www.online-medical-dictionary.org/medical-dictionary/m-medical-terms-3.ht

Medical Dictionary Online a free online medical dictionary search engine for definitions of medical terminology, pharmaceutical drugs, healthcare equipment, health conditions, medical devices, specialty terms and medical abbreviations. A B C D ... Link to the Medical Dictionary Online

74. M.G.L - Chapter 111, Section 6D. system diseases in persons of Portuguese ancestry variously known as Machado'sdisease, Joseph's disease, Azorean disease, machadojoseph's disease or spino http://www.state.ma.us/legis/laws/mgl/111-6D.htm

GENERAL LAWS OF MASSACHUSETTS PART I. ADMINISTRATION OF THE GOVERNMENT. TITLE XVI. PUBLIC HEALTH. CHAPTER 111. PUBLIC HEALTH. Chapter 111: Section 6D. Advisory committee for genetically handicapped persons; investigation and study; rules and regulations. Section 6D. There is hereby established within the department an advisory committee for genetically handicapped persons, hereinafter referred to as the committee. The committee shall be composed of six members to be appointed by the commissioner, one of whom shall be a geneticist, two of whom shall be medical specialists, at least one of whom shall be a neurologist involved in the medical treatment of individuals afflicted with inherited neurological degenerative diseases in persons of Portuguese ancestry, and three of whom shall be members of the general public. Each member shall hold office for a term of four years and until his successor is appointed and qualified. The members of the committee shall serve without compensation but shall be reimbursed for actual expenses incurred in carrying out their official duties. The department shall, with the advice and recommendations of the committee, make an investigation and study into heredo-familial neuronal degenerative diseases including, but not limited to, autosomal dominant motor system diseases in persons of Portuguese ancestry variously known as Machado's Disease, Joseph's Disease, Azorean Disease, Machado-Joseph's Disease or spino-nigro-dentatal degeneration, Huntington's Chorea, Friedreich's Ataxia and similar disorders. Said investigation and study shall be conducted for the purposes of establishing and administering a program for the medical care, treatment and counseling of genetically handicapped persons afflicted with the said medical problems.

75. Machado Joseph Disease - Information And Support Resources Machado Joseph disease Overview, Screening, Testing, Information and SupportResources. , Jewish Genetic diseases Boards. Machado Joseph disease. http://www.mazornet.com/genetics/machado.asp

Jewish Genetic Diseases A Mazornet Guide VISIT MazorNet's other Jewish Guides The MazorNet-Jewish Celebrations Kosher Restaurant Guide The MazorNet- Jewish Celebrations Vendor Directory ( ... Photographers, Kosher Caterers, Bridal Gowns, and Much More) Important Information Home Page Genetic Counseling and Screening Genetic Screening Laboratories - A Directory A Brief Key to Basic Genetic ... s Select Disorder Bloom's Syndrome Breast and Ovarian Cancers Breast Cancers - Prevention and Resources Canavan Disease ... Ulcerative Colitis Recommended Reeading Genetic Diversity Among Jews - Diseases and Markers at the DNA Level Provides an authoritative, up-to-date account of the impact of molecular genetics on our understanding of genetic diseases prevalent among Jews. Jewish Genetic Disorders : A Layman's Guide Guide to genetic disorders that tend to affect the Jewish population more than the non-Jewish, including a short history of the Jews and basic facts concerning genetics and genetic disorders. Interactive Jewish Genetic Diseases Boards Machado Joseph Disease Origins of Machado Joseph Disease and the Jewish Connection What is the Machado Joseph Disease?

76. Health In The XXI Century: A Vision Of The European Youth Machado Joseph disease. Machado Joseph disease (Text produced by the researcher).Researcher Professor Jorge Sequeiros. Paramyloidoisis Machado Joseph disease. http://www.ucv.mct.pt/healthXXI/topics.asp?lang=en&accao=ibmc2_en

77. International Joseph Disease Foundation by Sheri Rogers Bashor. Personal Thoughts. A question that continuesto arise in my mind is the origin of MJD (Machado Joseph disease). http://www.shasta.com/bastiana/sephardic.html

What's MJD? MJD Research Founding of IJDF IJDF Memorials ... E-Mail Us MJD and the Sephardic Connection by Sheri Rogers Bashor Personal Thoughts A question that continues to arise in my mind is the origin of MJD (Machado Joseph Disease). A disease that once was thought to be contained in my own family and thought of as our "family secret" is now known as a "common ataxia" through out the world. In twenty-five short years a disease that was hidden for over "500 or more years" has now sparked the interest of medical professionals world wide. I am not, nor do I claim to be a medical professional but I would like to present some facts that I believe have a definite connection between a genetic disease (which has been in my family for centuries) and many Sephardic Jews. Machado Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder. In layman terms a genetic neurological disease or stated simply an inherited disease of the central nervous system. It was first thought that this disease originated in the Azores Islands. If your parent has or had the disease you have a 50/50 chance of getting the disease. This disease does not skip generations nor is it a respecter of persons. This disease progresses year after year, the affected person becomes wheel chair bound, their body becomes stiff, they must depend on others for their primary care, and they are unable to communicate or be understood. The intellect is usually intact which means "one is trapped in a body that does not work; a virtual prison." My father had this disease (he died at 39 yrs. of age), as did his father, generation, after generation. My sister now has this disease.

78. MACHADO JOSEPH DISEASE MACHADO JOSEPH disease. This article submitted by EDUARDO NEVES on 8/13/98.Email Address FAMILIANEVES@MAIL.TELEPAC.PT I HAVE MACHADO http://neuro-www.mgh.harvard.edu/forum/CerebellarAtaxiaF/8.13.9811.46AMMACHADOJO

MACHADO JOSEPH DISEASE This article submitted by EDUARDO NEVES on 8/13/98. Email Address: FAMILIANEVES@MAIL.TELEPAC.PT I HAVE MACHADO JOSEPH DISEASE AND I READ AN ABSTRACT IN THE JOURNAL NEUROPATHOLOGY EXP NEUROL OF LAST MAY PP426-428 ABOUT THE PROMISSING POTENTIAL OF IGF-I IN TREATING DEGENERACTIVE DISEASES OF THE CNS. I' WOULD APPRECIATTE VERY MUCH IN LISTENINGS YOUR OPINIONS. THANK YOU. Next Article Previous Article Return to Neurological Disorder Topic Menu Here is a list of responses that have been posted regarding this article... Machado Joseph (8/18/98) 2:05 AM If you want to post a completely new article on any topic you like, click here. If you would like to post a direct response to this article, fill out this form completely... Response Title: Name: Email: Remember that your Name and Email Address are optional...you don't have to enter them! You can remain completely anonymous if you like by leaving these fields empty. Response Text: Click HERE to return to the main Neurology WebForum Homepage.

79. MACHADO JOSEPH DISEASE MACHADO JOSEPH diseaseMJD SYMPTOMS OF MACHADO JOSEPH disease *weakness in thearms and legs *spasticity *staggering, lurching gait,easily mistaken for http://members.tripod.com/~ebs_2/info/mjd.html

Get Five DVDs for $.49 each. Join now. Tell me when this page is updated MACHADO JOSEPH DISEASE-MJD SYMPTOMS OF MACHADO JOSEPH DISEASE *weakness in the arms and legs *spasticity *staggering, lurching gait,easily mistaken for drunkenness *difficulty with speech and swallowing *involuntary eye movements *double vision *frequent urination Symptoms most commonly begin between the ages of 15 and 40, but may appear earlier or much later in life. Progression may be fast or slow, and life expectancy ranges from 10-30 years after the disease begins. Neurologists have classified MJD into three types, depending on age at onset and characteristic symptoms. HOW IS MACHADO-JOSEPH DISEASE INHERITED? Machado Joseph Disease is an autosomal dominant disorder. This means that each child of an affected parent has a 50 percent chance of inheriting the defective gene. MJD does not skip generations, but people at risk who escape the disease will not pass it on to their children or future generations. As with any inherited disorder, MJD is not contagious and cannot be "caught" by people who are not at risk. Prepared by Office of Scientific and Health Reports National Institute of Neurological and Communicative Disorders and Stroke Bethesda, Maryland 20892

80. IJDF By RoseMarie Silva Chronological History of The IJDF and Machado Joseph disease In 1972, physiciansin Massachusetts examined a Machado family for its neurological problem. http://irmas.freeyellow.com/page3.html

Chronological History of The IJDF and Machado- Joseph Disease With the advent of a new disease entity, Joseph family members, friends and professionals joined together in 1977 to form the International Joseph Diseases Foundation, a non-profit corporation. Members of the new Board of Directors and physicians were aware of Machado disease and other existing disorders affecting persons of Portuguese ancestry. It was decided to make the word disease plural in the new foundations name to encompass these other neurological diseases. In 1979, scientists working with the Joseph family established, through clinical and pathological studies, that Joseph disease could be expressed in three different ways, with varying symptoms and ages of onset of the disease. Medical researchers have documented the three types of the disease in scientific articles. Due to this variation, Joseph Disease has been referred to as a mysterious disease. During the year, 1980, research teams concluded that both Machado and Joseph disease could be clinically expressed as Type 31. Because Machado and Joseph disease are considered to be one and the same, about the year 1981, medical researchers began referring to the disorder as Machado-Joseph disease or MJD: Machado for the first family described and Joseph for the largest family affected. With the publication of medical articles written by teams of scientist researching both Machado and Joseph disease in the United States, Canada and Portugal, other physicians from within the United States and from other countries realized that some of their patients were also expressing symptoms of the disease. In 1980, it was medically established that the disease can affect persons of other ethnic backgrounds, not just those of Portuguese descent. Due to increased knowledge and worldwide education, Machado-Joseph disease has been documented on five continents. Countries where patients have been reported in medical articles include Japan, China, India, Brazil, the Azores Islands, Spain, Canada, Australia, Taiwan, Italy, and the United States (and possibly other countries from which we have not heard.)

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