New problems of a new health system: the creation of a national public policy of rare diseases care in Brazil (1990s-2010s). / Nuevos problemas de un nuevo sistema de salud: la creación de una política pública nacional de atención de enfermedades raras en Brasil (1990-2014).

This study discusses actors and institution movements leading to the disclosure in 2014 of Resolution 199 by the Brazilian Ministry of Health, which establishes the National Policy for the Comprehensive Care of Persons with Rare Diseases. Taking as sources the mainstream newspapers, drafts law, and secondary literature on the subject, we begin our analysis in the early 1990s when the first patient associations were created in Brazil - mainly for claiming more funds for research on genetic diseases - and arrive at the late 2010s when negotiations for a national policy are taking place in the National Congress. Resolution 199 is part of an ongoing process and the path towards its disclosure and the complications that followed have given us elements to discuss contemporary aspects of the Brazilian public health. Based on the references of the history of the present time and the social studies of science, we argue that two aspects have been fundamental to creating a national policy: framing different illnesses within the terminology "rare diseases" and the construction of a public perception about the right of health which is guaranteed by the 1988 Brazilian Constitution.

En este trabajo se analizan los movimientos de actores e instituciones que llevaron a la promulgación, en 2014, de la Resolución 199 del Ministerio de Salud de Brasil, que establece la Política Nacional de Atención Integral a las Personas con Enfermedades Raras. Tomando como fuentes los principales periódicos, proyectos de ley y bibliografía secundaria sobre el tema, comenzamos nuestro análisis a principios de la década de 1990 con la creación de las primeras asociaciones de pacientes en Brasil, para reclamar fundamentalmente más fondos para la investigación de enfermedades genéticas, y llegamos a fines de la década de 2010 con las negociaciones para una política nacional. La Resolución 199 es parte de un proceso en curso, en el que el camino hacia la promulgación y las complicaciones posteriores nos dan elementos para discutir aspectos actuales de la salud pública brasileña. Sobre la base de la historia del tiempo presente y los estudios sociales de la ciencia, argumentamos que hay dos aspectos que han sido fundamentales para crear una política nacional: enmarcar diferentes enfermedades en la terminología "enfermedades raras" y la construcción de una percepción pública sobre el derecho a la salud, que se garantiza en la Constitución brasileña de 1988.

Nuevos problemas de un nuevo sistema de salud: la creación de una política pública nacional de atención de enfermedades raras en Brasil (1990-2014) / New problems of a new health system: the creation of a national public policy of rare diseases care in Brazil (1990s-2010s)

RESUMEN En este trabajo se analizan los movimientos de actores e instituciones que llevaron a la promulgación, en 2014, de la Resolución 199 del Ministerio de Salud de Brasil, que establece la Política Nacional de Atención Integral a las Personas con Enfermedades Raras. Tomando como fuentes los principales periódicos, proyectos de ley y bibliografía secundaria sobre el tema, comenzamos nuestro análisis a principios de la década de 1990 con la creación de las primeras asociaciones de pacientes en Brasil, para reclamar fundamentalmente más fondos para la investigación de enfermedades genéticas, y llegamos a fines de la década de 2010 con las negociaciones para una política nacional. La Resolución 199 es parte de un proceso en curso, en el que el camino hacia la promulgación y las complicaciones posteriores nos dan elementos para discutir aspectos actuales de la salud pública brasileña. Sobre la base de la historia del tiempo presente y los estudios sociales de la ciencia, argumentamos que hay dos aspectos que han sido fundamentales para crear una política nacional: enmarcar diferentes enfermedades en la terminología "enfermedades raras" y la construcción de una percepción pública sobre el derecho a la salud, que se garantiza en la Constitución brasileña de 1988.

ABSTRACT This study discusses actors and institution movements leading to the disclosure in 2014 of Resolution 199 by the Brazilian Ministry of Health, which establishes the National Policy for the Comprehensive Care of Persons with Rare Diseases. Taking as sources the mainstream newspapers, drafts law, and secondary literature on the subject, we begin our analysis in the early 1990s when the first patient associations were created in Brazil - mainly for claiming more funds for research on genetic diseases - and arrive at the late 2010s when negotiations for a national policy are taking place in the National Congress. Resolution 199 is part of an ongoing process and the path towards its disclosure and the complications that followed have given us elements to discuss contemporary aspects of the Brazilian public health. Based on the references of the history of the present time and the social studies of science, we argue that two aspects have been fundamental to creating a national policy: framing different illnesses within the terminology "rare diseases" and the construction of a public perception about the right of health which is guaranteed by the 1988 Brazilian Constitution.

How diseases became "genetic" / Como as doenças se tornaram "genéticas"

Abstract This article examines the origins of the term "genetic disease." In the late 19 and early 20th century, an earlier idea that diseases that occur in families reflect a vague familiar "predisposition" was replaced by the view that such diseases have specific causes, while Mendelian genetics provided then clues to the patterns of their transmission. The genetictisation of inborn pathologies took a decisive turn with the redefinition, in 1959, of Down syndrome as a chromosomal anomaly, then the development of tests for the diagnosis of other hereditary pathologies. At that time, geneticists distinguished "hereditary" diseases that run in families, from "genetic" conditions that are the result of new mutations during the production of egg and sperm cells. In the latter case, the inborn impairment is produced by an anomaly in the genetic material of the cell, but is not hereditary, because it is not transmitted from one or both parents. In the late 20th and early 21st century, new genomic technologies blurred the distinction between hereditary and genetic impairments, extended the concept of genetic disease, and modified the experience of people living with such a disease.

Resumo O presente artigo tem o objetivo de examinar as origens do termo "doença genética. No final do século XIX e início do XX, a vaga ideia que a doença manifesta entre familiares refletia uma "predisposição" familiar, foi substituída pela visão que essas doenças possuem causas específicas, enquanto a genética mendeliana forneceu as pistas para os padrões de transmissão da doença. A genética das patologias congênitas deu uma guinada decisiva, em 1959, com a redefinição da Síndrome de Down como uma anomalia cromossômica e, depois, com o desenvolvimento de testes para o diagnóstico de outras patologias hereditárias. Naquela época, os geneticistas distinguiam doenças "hereditárias" como aquelas que acometiam os elementos de uma família, de condições "genéticas" que são o resultado de novas mutações ocorridas durante a produção dos óvulos e espermatozoides. Neste último caso, a deficiência inata é causada por uma anomalia do material genético da célula, porque não é transmitida por qualquer um ou ambos os pais. No final do século XX e início do XXI, as novas tecnologias genômicas obscureceram a distinção entre deficiências hereditária e a genética, estenderam o conceito da doença genética e modificaram a experiência das pessoas que vivem com esse tipo de doença.

Emilio Zola y la influencia de la Medicina en su obra La Fortuna de los Rougon-Macquart / The influence of medicine in Emile Zola's "Fortune of the Rougon-Macquart"

Emile Zola is one of the greatest writers in universal literature. In his important series of novels called "The Fortune of the Rougon-Macquart", Zola shows a surprising medical knowledge even though he did not have a formal medical education. We highlight not only his outstanding literary talent, but also the scientific relevance of the tremendous contribution to the medical field that can be extracted from his work. In this series, which describe the history of five generations within a large family suffering from neuropsychiatric and general pathologies, Zola emphasizes the hereditary component of several diseases. These observations probably place him as the first novelist who made an explicit emphasis on the power of inheritance in human behavior. He also mentions for the first time several medical aspects that were seldom addressed in the scientific literature of the time, demonstrating the genius of the writer, his outstanding power of observation and the rigorous preparation with which he wrote his work.

[The Emergence of Genetic Prenatal Diagnosis from Environmental Research : On a Methodological Shift in Prevention Around 1970]. / Wie aus Umweltforschung die genetische Pränataldiagnostik entstand : Über eine Methodenverschiebung in der Vorsorge um 1970.

The history of genetic prenatal diagnosis has so far been analyzed as a part of the history of human genetics and its reorientation as a clinical and laboratory-based scientific discipline in the second half of the 20th century. Based on new source material, we show in this paper that the interest in prenatal diagnosis also arose within the context of research on mutagenicity (the capacity to induce mutations) that was concerned with environmental dangers to human health. Our analysis of the debates around the establishment of the German Research Foundation's (DFG) research program "Prenatal Diagnosis of Genetic Defects" reveals that amniocentesis was introduced in Western Germany by a group of scientists working on the dangers for the human organism caused by radiation, pharmaceuticals, and other substances and consumer goods. We argue that, in a period of growing environmental concern, the support of prenatal diagnosis aimed to close a perceived gap in the prevention of environmental mutagenicity, i. e. genetic anomalies induced by environmental factors. The expected financing of prenatal diagnosis by health insurance in the course of the reform of abortion rights was used as another argument for the new technology's introduction as a "defensive measure". Only in a second step did changes in research structures, but most importantly experience from gynecological practice lead to a reframing of the technology as a tool for the diagnosis and prevention of mostly genetic or spontaneously occurring anomalies. Eventually, prenatal diagnosis, as it became routinely used in Western Germany from the early 1980s onward, had little to do with "environmental" questions. This case study of the early history of genetic prenatal diagnosis analyzes the still poorly researched relationship between research in human genetics, environmental research and medical practice. Furthermore, we aim to shed new light on a shift in perspective in prevention around 1970 that has so far been described in different contexts.

The 11p15.5 chromosomal region: When did the instability occur?

The disturbances of the 11p15.5 chromosomal region are associated with Beckwith-Wiedemann syndrome, Russell-Silver syndrome, Wilms tumor, IMAGe syndrome, and idiopathic hemihyperplasia. The aim of this research was to examine the hypothesis that 11p15.5 initially became unstable in the European population about 200 years ago. The medical literature from 1557 onwards, especially treatises on teratology, body asymmetry, and books of normal and pathologic anatomy, was searched for any mentioning of lateral body asymmetry, macroglossia and other possible visually detectable symptoms associated with the above-mentioned syndromes. The results indicate that lateral body asymmetry was not described before the first half of the 19th century, it was mentioned in the 1820s, and the first description of a true case was published in 1850. All first cases of hemihyperplasia were reported in continental Europe. Historical data suggest that the 11p15.5 chromosomal region became unstable in the first half of the 19th century. Our preliminary hypothesis is that de novo mutation occurred in continental Europe. Additional genetic research is needed to investigate the development of 11p15.5 instability during this period.

The forty years of medical genetics in China.

Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy, Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a well-constructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection, along with strong support at the national industry level.

[The advent of a newborn specialty: 19th century pediatrics]. / Naissance de la pédiatrie au 19e siècle.

Pediatrics began under the most unfavorable conditions that are difficult to imagine nowadays. Children at the start of the 19th century were considered as negligible. The death rate was tremendous, increased by the work of children in factories as soon as 6 years of age in textile industries. In upper classes, infants were fed by a wet nurse, far from their parents and death rate was high as well. The emergence of pediatrics was the result of work carried out in adult medicine in the first half of the 19th century: clinical anatomic method, knowledge of contagious diseases even before the discovery of bacteria, birth of bacteriology. During the whole century, infectious diseases contributed in a large part to children mortality, as that of adults, by cholera, typhus, variola, diphtheria, measles and tuberculosis. Progresses noted during the 2nd part of the century resulted from beginning of hygiene, antisepsis, nutrition improvement, taking consideration of children as human being asking for protection. In contrast, therapeutics as serotherapy, vaccinations at the break of the 20th century played a secondary role.

Fifty years of newborn screening.

Newborn screening has evolved fast following recent advances in diagnosis and treatment of disease, particularly the development of multiplex testing and applications of molecular testing. Formal evidence of benefit from newborn screening has been largely lacking, due to the rarity of individual disorders. There are wide international differences in the choice of disorders screened, and ethical issues in both screening and not screening are apparent. More evidence is needed about benefit and harm of screening for specific disorders and renewed discussion about the basic aims of newborn screening must be undertaken.

Como la vara de Moisés: la herencia patológica como argumento para la vigilancia médica del matrimonio consanguíneo en México, 1870-1900 / Like Moses' staff: pathological inheritance as an argument for medical vigilance of consanguine marriage in Mexico, 1870-1900

Se da cuenta de las discusiones que se dieron principalmente en la medicina legal mexicana acerca de la prudencia de las regulaciones sobre el matrimonio consanguíneo que fueron decretadas en los códigos civiles para el Distrito Federal de 1871 y 1884. Se muestra que el ánimo de las mismas llevó a que sus autores pugnaran por la necesidad de la vigilancia médica de las uniones entre parientes en virtud de un ánimo profiláctico sostenido en una visión nihilista de la herencia patológica. Se concluye en proponer una lectura filosófica que abandona los antiguos campos de lo 'externo' y lo 'interno'.

This paper analyzes the discussions in the field of legal medicine in Mexico about the prudence of regulations concerning intermarriage that were decreed in the civil codes for the Federal District of 1871 and 1884. It shows that the heated debate forced the authors of the regulations to struggle for the need for medical vigilance of marriages between relatives, as a preventive measure sustained in a nihilistic vision of the pathological inheritance. The paper concludes by proposing a philosophical analysis that abandons the old fields of the "external" and the "internal".

Warts and the kings of Parthia: an ancient representation of hereditary Neurofibromatosis depicted in coins.

Parthian coins depict a nodule on the face of many of their kings over succeeding generations. Loosely described as a wart in the literature, the nature of these lesions has been the subject of speculation. The accepted view is that they were unlikely to be simply a cosmetic or symbolic feature. Evidence suggests that they may represent the cutaneous tumors of Neurofibromatosis. The hereditary nature and physical appearance of these round nodules are consistent with this diagnosis. Although final proof may be lacking, these prominent facial features are worthy of discussion even though the matter may not be settled with certainty.

Zebrafish in hematology: sushi or science?

After a decade of the "modern era" of zebrafish hematology research, what have been their major contributions to hematology and what challenges does the model face? This review argues that, in hematology, zebrafish have demonstrated their suitability, are proving their utility, have supplied timely and novel discoveries, and are poised for further significant contributions. It presents an overview of the anatomy, physiology, and genetics of zebrafish hematopoiesis underpinning their use in hematology research. Whereas reverse genetic techniques enable functional studies of particular genes of interest, forward genetics remains zebrafish's particular strength. Mutants with diverse and interesting hematopoietic defects are emerging from multiple genetic screens. Some mutants model hereditary blood diseases, occasionally leading to disease genes first; others provide insights into developmental hematology. Models of malignant hematologic disorders provide tools for drug-target and pharmaceutics discovery. Numerous transgenic zebrafish with fluorescently marked blood cells enable live-cell imaging of inflammatory responses and host-pathogen interactions previously inaccessible to direct observation in vivo, revealing unexpected aspects of leukocyte behavior. Zebrafish disease models almost uniquely provide a basis for efficient whole animal chemical library screens for new therapeutics. Despite some limitations and challenges, their successes and discovery potential mean that zebrafish are here to stay in hematology research.

Genetic and other diseases in the pottery of Tumaco-La Tolita culture in Colombia-Ecuador.

The people of Tumaco-La Tolita culture inhabited the borders of present-day Colombia and Ecuador. Already extinct by the time of the Spaniards arrival, they left a huge collection of pottery artifacts depicting everyday life; among these, disease representations were frequently crafted. In this article, we present the results of the personal examination of the largest collections of Tumaco-La Tolita pottery in Colombia and Ecuador; cases of Down syndrome, achondroplasia, mucopolysaccharidosis I H, mucopolysaccharidosis IV, a tumor of the face and a benign tumor in an old woman were found. We believe these to be among the earliest artistic representations of disease.

[Molecular paleopathology: a novel perspective for biomedical history]. / La paleopatologia moleceolare: il futuro per indagare il passato.

Molecular paleopathology is an emerging field that is devoted to the detection, indentification and characterization of the molecular signatures in past diseases. When studied with modern molecular techniques, ancient human remains may yield direct informations on the diseases of ancient populations as well as the history of human diseases. Data concerning specific diseases of infectious, neoplastic and genetic origin can be obtained by molecular investigations of skeletal and mummified human remains. In particular, ancient DNA extracted from bone tissue, teeth and mummified soft tissue can be deeply analyzed by using PCR-based molecular techniques. Additionally, DNA of ancient pathogens, including bacteria, viruses and parasites, can be isolated from human remains and molecular diagnosis of infectious diseases can be made. Thus, molecular data, complemented by morphological and biochemical analyses, could help to reconstruct the epidemiology of past diseases and epidemics.

Population history and its impact on medical genetics in Quebec.

Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).

["Euthanasia" operation by Nazis on patients with psychiatric or hereditary diseases, and Bishop von Galen of Münster].

In so-called "euthanasia" operations, Nazis murdered patients with psychiatric or hereditary diseases in large numbers. Psychiatric patients in Germany were sent to six institutions, where they were deprived of their lives in gas chambers. In his sermon delivered on 3rd August, 1941, at St Lambert's Church in Münster, Bishop von Galen of Münster intensely condemned this cruel operation in public. Quoting the fifth commandment, "Thou shall not kill", he said it was sinful to kill innocent people on account of their unproductiveness. By the influence of this brave sermon, Hitler had to order the closure of the institutions, though the "euthanasia" operation itself was secretly continued.

Genetic disease in the 1960s: a structural revolution.

From about 1955 to about 1975, an explosion of new institutions, disciplines, databases, interventions, practices, techniques, and ideas turned technically driven human genetics from a medical backwater to an exotic and appealing medical research frontier. In the early 1960s, health care professionals were attracted to the new insights of cytogenetics, including the chromosomal explanation of Down syndrome and of other congenital defects and abnormalities of sexual development. The discovery of a connection between myeloid leukemia and chromosomal abnormalities in leukemic cells made human cytogenetics suddenly relevant to cancer research and diagnosis. Successful dietary treatment of phenylketonuria brought genetic disease into the domain of public health and provoked legislative programs with sweeping long-term consequences. Meanwhile, those promoting the importance of genetic disease to medical education began to elaborate the idea that disease was literally becoming more genetic, as a consequence of techno-historical change. In this article, I present an overview of these remarkable events and a framework for understanding how and why they occurred. I emphasize the important roles of family members, religious isolates, legislators, pediatricians, and others who were not trained in genetic science, but who became advocates, at many levels, of genetic medicine. And I suggest that the idea, so important to the Human Genome Project, that "all disease is genetic disease" was structurally realized and institutionalized long before technologies for mapping the genome were available.

Hereditary pancreatitis. Historical perspectives.

Clinically, hereditary pancreatitis was not distinguishable from any other cause of pancreatitis. But astute clinical observations demonstrated an evolution toward chronic pancreatitis that could develop into carcinoma in some patients. A chromosomal abnormality was identified on chromosome 7q35, and then three separate genetic abnormalities were identified. It is now understood that a defect in trypsinogen is at the basis of the anomaly, and further developments should help identify new therapeutic approaches.