100 años de la visita del Dr. Hideyo Noguchi al Perú y su contribución al estudio de la Enfermedad de Carrión / 100 years after visit of Dr. Hideyo Noguchi to Peru and his contribution to the study of Carrion's disease

RESUMEN Se conoce poco sobre la visita al Perú en abril de 1920, hace 100 años, del Dr. Hideyo Noguchi y su contribución al estudio de la Enfermedad de Carrión o bartonelosis humana. Tal vez por ser una enfermedad casi exclusiva del Perú, aunque se han reportado casos en menor número en Ecuador y Colombia, sin tener repercusión internacional. Aun cuando su visita fue muy comentada por los diarios de la época, el tiempo han difuminado las actividades de la visita, cuyo objetivo era combatir un brote epidémico de fiebre amarilla en Paita. Permaneció tres semanas en Piura y una cuarta semana en Lima. Es en Lima que se enteró de la Enfermedad de Carrión y la controversia de que era una o eran dos enfermedades distintas (fiebre de La Oroya y verruga peruana). Un lustro después realizó numerosas investigaciones experimentales en New York contribuyendo a resolver la controversia.

ABSTRACT Little is known about the visit to Peru in april 1920, 100 years ago, of Dr. Hideyo Noguchi and his contribution to the study of Carrion's disease or human bartonellosis. Perhaps because it is an almost exclusive disease in Peru, although cases have been reported in smaller numbers in Ecuador and Colombia, they have not had much international impact. Even though his visit was much commented by the newspapers of those years, time has blurred the activities of the visit, whose objective was to fight an outbreak of yellow fever in Paita. He spent three weeks in Piura and one week in Lima. It is in Lima that he learned of Carrion's disease and the controversy as to whether La Oroya fever and peruvian wart were two distinct diseases or diferent phases of one disease. After five years he carried out numerous experimental investigations in New York contributing to the resolution of the controversy.

Prioritisation of potential drug targets against Bartonella bacilliformis by an integrative in-silico approach

BACKGROUND Carrion's disease (CD) is a neglected biphasic illness caused by Bartonella bacilliformis, a Gram-negative bacteria found in the Andean valleys. The spread of resistant strains underlines the need for novel antimicrobials against B. bacilliformis and related bacterial pathogens. OBJECTIVE The main aim of this study was to integrate genomic-scale data to shortlist a set of proteins that could serve as attractive targets for new antimicrobial discovery to combat B. bacilliformis. METHODS We performed a multidimensional genomic scale analysis of potential and relevant targets which includes structural druggability, metabolic analysis and essentiality criteria to select proteins with attractive features for drug discovery. FINDINGS We shortlisted seventeen relevant proteins to develop new drugs against the causative agent of Carrion's disease. Particularly, the protein products of fabI, folA, aroA, trmFO, uppP and murE genes, meet an important number of desirable features that make them attractive targets for new drug development. This data compendium is freely available as a web server (http://target.sbg.qb.fcen.uba.ar/). MAIN CONCLUSION This work represents an effort to reduce the costs in the first phases of B. bacilliformis drug discovery.

One hundred years after the expedition by Harvard University to Peru to investigate Carrion's disease. Lessons for science / Cien años de la expedición de Harvard a Perú para investigar la enfermedad de Carrión. Lecciones para la ciencia

Abstract In 1913, around 100 years ago, the Harvard University sent an expedition to Peru, led by Richard Strong, to investigate Carrion's disease. This paper provides a critical review of the scientific research carried out in this expedition. Richard Strong was a physician who performed unethical human experimentation in the Philippines and China. In Peru, Strong conducted experiments on humans to inoculate wart secretions to a psychiatric patient, which led him to replicate the Peruvian wart in this individual, although he could not replicate Oroya fever. Based on this experiment, and without taking into account epidemiological and clinical evidence, the Harvard expedition erroneously concluded that Oroya fever and Peruvian wart were two different diseases. A retrospective review of the scientific work conducted by the expedition in Peru allows drawing the following lessons for science: a) disapproving unethical human experimentation conducted by the expedition; b) to determine the cause of infectious diseases, it is necessary to obtain the best scientific, experimental and observational evidence, and c) to acknowledge that, despite the poor infrastructure, researchers in developing countries are able to produce high-quality scientific knowledge that may surpass the knowledge generated by researchers in developed countries.

Resumen Hace poco se cumplieron 100 años de la expedición de la Universidad de Harvard a Perú, liderada por Richard Strong, para investigar la enfermedad de Carrion. El presente estudio realizó una revisión crítica de la investigación científica de dicha expedición. Richard Strong era un médico con antecedentes relacionados con la realización de experimentaciones humanas antiéticas en Filipinas y China. En Perú, Strong realizó experimentación humana al inocular secreciones de verruga en un paciente psiquiátrico, logrando reproducir en este la verruga peruana, pero no la fiebre de la Oroya; con base en este experimento, y sin considerar la evidencia epidemiológica y clínica, la expedición de Harvard concluyó erróneamente que la fiebre de la Oroya y la verruga peruana eran dos enfermedades diferentes. Una visión retrospectiva de la labor científica de la expedición de Harvard en Perú lleva a extraer las siguientes lecciones para la ciencia: a) se debe condenar la antiética experimentación humana realizada por la expedición de Harvard; b) es necesario obtener la mejor evidencia científica, experimental y observacional en la causalidad de las enfermedades infecciosas, y c) es necesario reconocer que en países subdesarrollados se puede generar conocimiento científico de alta calidad y que, pese a la escasa infraestructura, puede ser mejor al de los países desarrollados.

Daniel Alcides Carrión: la teoría unicista / Daniel Alcides Carrión: Unicist theory

La enfermedad de Carrión presenta clásicamente dos fases clínicas: la fiebre de la Oroya y la verruga peruana. La teoría unicista reconoce que ambas formas clínicas pertenecen a la misma enfermedad, la obtención de este conocimiento representó un duro desafío para la ciencia peruana y mundial. A través de un histórico experimento en 1885, Daniel Alcides Carrión obtuvo la evidencia clínica-experimental que sentó las bases de la teoría unicista; el científico diseñó esta teoría solo hasta las horas finales de su experimento, por lo cual su hallazgo es considerado un acto de serendipia. La demostración bacteriológica de la teoría la realizaría Hideyo Noguchi en 1926; Carrión brindó además evidencia de la transmisibilidad de esta infección y debido a este aporte científico se convirtió en el símbolo de la medicina peruana.

Carrion's disease typically presents two clinical phases: Oroya fever and Peruvian wart. Unicist theory recognizes that both clinical forms belong to the same disease. Obtaining this knowledge represented a challenge for both the Peruvian and the world science. In 1885, through a historical experiment, Daniel Alcides Carrión obtained the clinical-experimental evidence that work as the foundations of this theory. Carrion did not design this theory but only in the final hours of his experiment; therefore his finding is considered as an act of serendipity. Bacteriological demonstration of the theory was made in 1926 by Hideyo Noguchi. Carrion also provided evidence showing the transmission of this infection. Due to its scientific contribution Carrión became the symbol of the Peruvian medicine.

Experiencias en la prevención y control de la enfermedad de Carrión en el Perú / Experiences in the prevention and control of Carrión's disease in Peru

La enfermedad de Carrión, enfermedad emblemática de la medicina peruana, ha sido descrita en la sierra de Ecuador, Colombia y valles interandinos del Perú. En la década de 1990, el fenómeno de El Niño fue asociado con incremento significativo del riesgo de enfermedad en Ancash, Cajamarca y Cusco. Justamente en Cusco en 1998 se produjo una importante epidemia de la fase aguda en diversas provincias andinas y la zona selvática. Posteriormente entre 2001 y 2005 la enfermedad se ha expandido o reactivado en diversas regiones como Ancash, Cajamarca, Amazonas, Piura, Cusco, La Libertad, Puno, Ayacucho. El 2004 se presentó un rebrote importante de la enfermedad en todo el Perú, reportándose más de 11 164 casos, por ello se aplicaron diversas estrategias de control basados en estudios de susceptibilidad de vectores, disminuyendo en forma significativa el número de casos.

Carrion’s disease, the iconic disease in Peruvian medicine has been found in the mountains of Ecuador, Colombia and the Andean valleys of Peru. In the 1990s, the phenomenon of El Niño was associated with significantly increased risk of disease in Ancash, Cajamarca and Cusco. In Cusco in 1998 there was an acute phase epidemic in various Andean provinces and the jungle area. Between 2001 and 2005 the disease has spread or reactivated in different regions such as Ancash, Cajamarca, Amazonas, Piura, Cusco, La Libertad, Puno, and Ayacucho. In 2004 a major outbreak of the disease in all of Peru was presented, reporting more than 11 164 cases, and therefore diverse strategies based vector susceptibility studies was applied, lowering significantly the number of cases.

Cytokines and T-Lymphocute count in patients in the acute and chronic phases of Bartonella bacilliformis infection in an endemic area in peru: a pilot study / Citoquinas y recuento de Linfocitos T en pacientes en fase aguda y crónica de infección por Bartonella bacilliformis, en una área endémica del Perú: estudio piloto

Human Bartonellosis has an acute phase characterized by fever and hemolytic anemia, and a chronic phase with bacillary angiomatosis-like lesions. This cross-sectional pilot study evaluated the immunology patterns using pre- and post-treatment samples in patients with Human Bartonellosis. Patients between five and 60 years of age, from endemic areas in Peru, in the acute or chronic phases were included. In patients in the acute phase of Bartonellosis a state of immune peripheral tolerance should be established for persistence of the infection. Our findings were that elevation of the anti-inflammatory cytokine IL-10 and numeric abnormalities of CD4+ and CD8+ T-Lymphocyte counts correlated significantly with an unfavorable immune state. During the chronic phase, the elevated levels of IFN-γ and IL-4 observed in our series correlated with previous findings of endothelial invasion of B. henselae in animal models.

La Bartonelosis Humana, tiene una fase aguda caracterizada por fiebre y anemia hemolítica, así como una fase crónica con lesiones semejantes a angiomatosis bacilar. En un estudio transversal piloto los patrones inmunológicos en pacientes con Bartonelosis Humana fueron estudiados mediante muestras pre y post tratamiento. Pacientes entre 5 y 60 años en fase aguda y crónica fueron incluidos en área endémica del Perú. En aquellos pacientes con fase aguda, una fase de tolerancia inmunológica periférica es necesaria para la persistencia de la infección. Los hallazgos de significativa elevación de citoquina anti-inflamatoria (IL-10) y anormalidades numéricas en el recuentos de Linfocitos T CD4+ y CD8+ correlacionan con un estado inmune que favorece la infección. Durante la fase crónica, elevados niveles de INF-γ y IL-4 observados en la serie de pacientes correlacionan con previos hallazgos en modelos animales que favorecen la invasión del endotelio por B. henselae.

Immunological response in cases of complicated and uncomplicated bartonellosis during pregnancy

Bartonellosis (Carrion's Disease) during pregnancy is associated with high rates of maternal and perinatal mortality. We report the immunological patterns in two cases of human bartonellosis during pregnancy. One patient had an uncomplicated course while the second patient developed life threatening anasarca and cardiac tamponade. The patient with a complicated course had a Th1 response with a higher elevation of IL-10. This elevation has been associated with poor outcome pregnancies during bacterial infections.

Bartonelosis (Enfermedad de Carrión) durante el embarazo esta asociado a una alta tasa de mortalidad maternal y perinatal. Reportamos el perfil inmunológico de dos casos de Bartonelosis humana en el embarazo. Una paciente tuvo un curso sin complicaciones, mientras la segunda presento complicaciones severas de anasarca y tamponamiento cardiaco. La paciente con curso complicado tuvo un patrón de repuesta Th1, con una elevación de IL-10, que se ha asociado a mal pronóstico en infecciones durante embarazo.

Cromoblastomicose em pacientes com hanseniase / Chromoblastomycosis in leprosy patients

Um paciente procedente da Amazônia do Brasil, seringueiro, portador de uma branqueada de haseníase, tratado com sulfonas, tendo sequelas lesões disfróficas das extremidades e manchas hipocrômicas, com pertubações da sensibilidade, apresentou no hipocôndrio esquerdo uma lesão verrucosa extensa, com evolução de mais de 10 anos, rebeldes aos tratamentos feitos. Foram feitas biopsias para esclarecimento histopatologico da doença, tendo-se concluido trata-se de dermatite verrucosa cromomicótica, com presença dos fungos bem caracterizados pelas colorações de rotina, histoquíomicas. A cultura do material obtido da lesão em meio ágar-Sabouraud deu crescimento a colônia gigante com as caracteristicas típicas do genêro Philophora: hifasseptadas e conidioforos com morfologia de taca. O tratamento, na falta de 5-fluorocitosina, foi feito com infiltrações de anfotericina B, associada a iodureto de sódio, endovenosamente, estando a lesão em plena regressão. Os exames histopatológicos das lesões discrômicas mostraram apenas infiltrado linfoplasmocitário e ausência de bacilos álcool-ácido resistentes íntegros (AU).