Purified protein derivatives of tuberculin--past, present, and future.

The tuberculin skin test, which involves monitoring the immune reaction to an injection of purified protein derivative (PPD), has been the most widely used method for detecting infection with Mycobacterium tuberculosis since its development in 1930s. Until recently, the molecular composition of PPD was unknown. This thwarted the discovery of improved skin testing reagents and drastically hindered efforts to define the mechanism of action. Proteomic evaluation of PPD combined with a detailed analysis in the guinea pig model of tuberculosis led to further definition of the molecular composition of PPD. This communication reviews the history and current status of PPD, in addition to describing candidate next-generation PPD reagents, based on the use of an individual protein or protein cocktails.

Tuberculin immunotherapy: its history and lessons to be learned.

The use of tuberculin for the therapy of tuberculosis was attempted more than 100 years ago and abandoned because of its adverse reactions. In this historical review we point out that some of the intensive efforts to avoid the reactions were based on the best scientific rationale available at that time. Balancing the dosage and intervals of tuberculin delivery with clinical and laboratory monitoring of patients achieved a limited success, with implications, toward current research in the field. The role of economical and social aspects at that time is also a lesson to be learned toward current approaches to tuberculosis control.

The treatment of tuberculosis in Ferrara (Italy) in the 19th century.

The present work is a review of the remedies in use in Ferrara against tuberculosis in the 1800s. The work started from the discovery of accounts describing methods and remedies. These remedies were also in use world wide. Of particular interest is the work by Antonio Campana, a famous professor of Pharmaceutical Chemistry and Botany in Ferrara, who wrote a pharmacopoeia which had several editions between 1797 and 1841. The Farmacopea Ferrarese was addressed to the apothecaries of Ferrara. Nevertheless, due to its great reputation it had an international distribution. It provided us with an exhaustive view about the medical field in Ferrara in the early 1800s. The remedies adopted in the city in the second half of the century were in line with those present abroad. The work was also supported by the discovery of statistical accounts of the Sant'Anna hospital from 1871. The manuscript written by Alessandro Bennati enabled elucidation of the methods used to treat tuberculosis in the second half of the century. Bennati's work is an historical document completed by the work of the physician Cesare Minerbi.

Hughlings Jackson's suggestion for the treatment of epilepsy.

John Hughlings Jackson articulated a neurologic method of systematically evaluating the anatomy, physiology, and pathology of every patient with neurologic disease. He used this mode of analysis to develop a theory of the physiology of epilepsy. We examined an example of his method in a newly discovered, unpublished manuscript containing his suggestions for the treatment of epilepsy based on his physiologic ideas. He had his private papers destroyed at the time of his death, but the Rockefeller Library of the University College London Institute of Neurology, Queen Square, contains a collection of his papers probably saved from destruction by his collaborator James Taylor. Among these articles is an 1899 memorandum, labeled "For Private Circulation" and entitled "A Suggestion for the Treatment of Epilepsy." In it, Hughlings Jackson claimed that focal discharging lesions cause both focal and generalized epilepsy, and that the cells in the lesion discharge their energy more easily than normal tissue. Citing microscopic evidence that such lesions are congested and inflamed, and that tuberculin destroys such tissue in the lung, he reasoned that destroying these unstable neurons with tuberculin would improve epilepsy. In this private manuscript, Hughlings Jackson uses an unusually detailed analysis of the pathology, anatomy, and physiology of epilepsy to predict a scientific approach to its treatment.

[Constant Charles Delprat, editor-in-chief of the Dutch Journal of Medicine 1889-1896]. / Constant Charles Delprat, 'redacteur-gérant' van het Tijdschrift 1889-1896.

Constant Charles Delprat (1854-1934) was a general practitioner and for many years a central figure in the Vereeniging Nederlandsch Tijdschrift voor Geneeskunde (Dutch Journal of Medicine Society). He was particularly interested in bacteriology and travelled to Berlin in 1890 to obtain tuberculin, which was said to cure tuberculosis patients, but he returned empty handed. He reported this experience in the Journal. One of his other interests was medical history. Today, he is mainly remembered for writing the history of the first 50 years of the Journal and of the Dutch medical periodicals prior to 1857, the year that the Dutch Journal of Medicine was first published.

Robert Koch tenía razón. Hacia una nueva interpretación de la terapia con tuberculina / Robert Koch was right. Towards a new interpretation of tuberculin therapy

Con motivo del centenario de la concesión del premio Nobel a Robert Koch, se vuelve a considerar un fracaso el tratamiento de la tuberculosis con tuberculina anunciado en Berlín, en 1890. Sin embargo, hoy en día hay información suficiente para suponer que esta terapia fue ampliamente utilizada hasta la segunda mitad del siglo xx, por lo que se debería estudiar su contribución en el declive de la mortalidad por tuberculosis experimentado en este período. Además, la terapia con tuberculina ha inspirado al menos dos nuevas inmunoterapias, aunque buscando precisamente el efecto contrario: la supresión del fenómeno de Koch. Así, la inoculación de Mycobacterium vaccae polariza la respuesta inmunitaria hacia el tipo Th1; y la inoculación de RUTI evita la inmunodepresión local después de una quimioterapia de corta duración, sin inducir toxicidad. Por esta razón, es necesaria una relectura de la contribución de Robert Koch a la terapia contra la tuberculosis, y un justo reconocimiento de su labor (AU)

At the centenary of Robert Koch's Nobel Prize award, tuberculosis treatment with tuberculin, which was announced in Berlin in 1890, is still considered a failure. Nevertheless, there is now sufficient information supporting the idea that tuberculin therapy was widely used until the second half of the twentieth century; thus, the impact of this treatment should be studied and related to the decrease in tuberculosis-related mortality recorded in that period. Moreover, tuberculin therapy has inspired at least two new immunotherapies; these, however, were directed toward precisely the opposite effect: suppression of the Koch phenomenon. Thus, inoculation of Mycobacterium vaccae polarizes the immune response towards the Th1 type; and inoculation of RUTI avoids local immunodepression after short-term chemotherapy without inducing toxicity. For this reason, Robert Koch's work on antituberculosis therapy should be reread and proper recognition given to his contribution in this field (AU)

Robert Koch and the white death: from tuberculosis to tuberculin.

The German medical bacteriologist Robert Koch is commonly considered one of the founding fathers of medical bacteriology. His investigations into the aetiology of tuberculosis uncovered the pathogen of this condition, the tubercle bacillus today known as Mycobacterium tuberculosis, in 1882. This work can be seen as a cornerstone of contemporary medical bacteriology, its technologies and methods. It has often been asked how such successful research connected to the tuberculin episode of 1890/91, when Koch produced a medicine for that disease, which spectacularly failed when applied in practice. The analysis concentrates on the path of mostly experimental investigations which Koch followed between 1882 and 1890. From Koch's laboratory notes it becomes clear that tuberculin therapy did in fact work in Koch's laboratory, even though it failed to do so almost anywhere else. The clue to this contradictory picture lies in the peculiar nature of Koch's understanding of tuberculosis as a disease e.g. his reliance an animal experiments, which essentially differed from what many of his contemporaries held as essentials of that condition.

The opsonic rejuvenation of tuberculin as portrayed in Bernard Shaw's Doctor's Dilemma.

In 1906, at a late evening tea party in Sir Almroth Wright's laboratory when the pathologist was working on his opsonic index as a guide to the therapeutic use of tuberculin, Bernard Shaw instigated a discussion on patient selection in the face of limited resources. In converting the various responses into a play Shaw turned the choice between a rogue artist and an honest doctor into a moral dilemma, and then thickened the plot by involving the artist's beguiling wife innocently in the decision. He added a blackly comedic denouement to answer a public challenge that he could not write a convincing death scene. With his penchant for irrepressible exaggeration, his doctors are amiable but inordinately opinionated, each convinced that he alone holds the secret of healing. The senior physician escapes censure and even measured praise is bestowed on the panel doctor who accepts a full-time public post. This article summarises the play and how it came to be written.

Robert Koch: Nobel laureate and controversial figure in tuberculin research.

Tuberculosis has been a major cause of death for centuries. Likewise, anthrax has posed a deadly threat to both farm animals and humans and today poses a threat as a weapon of biological warfare. Cholera, which wreaked havoc in the East and threatened to enter Europe, also posed a deadly threat. The causes of these diseases remained mysteries for centuries. Nobel laureate Robert Koch (1843-1910), often called the founder of medical bacteriology, is credited with discovering the tubercle bacillus, Mycobacterium tuberculosis; with demonstrating for the first time in history the life cycle of the anthrax bacillus under controlled in vitro conditions; and with identifying Vibrio cholorae as the cause of cholera. In later life, he also was at the center of several controversies. This article provides a brief summary of Koch's exploration into bacteriology and, especially, his experience with tuberculosis and the controversies that developed in the latter part of his life, as well as his childhood and early adult years and the development of his now well-known "postulates."

Koch's dilemma revisited.

Robert Koch's description of the etiologic agent of tuberculosis on 24 March 1882 made him the hero of tuberculosis research overnight. In 1890, at the 10th International Congress of Medicine in Berlin, he claimed that he had discovered a remedy for the disease. This announcement was received with great excitement by both the medical community and the public. Medical trials performed in the subsequent months failed, however, to reveal a protective effect of Koch's remedy. In contrast, the diagnostic potential of tuberculin is still used and valued nowadays. This short article discusses Koch's reasons for fighting for the success of his remedy.

Money and microbes: Robert Koch, tuberculin and the Foundation of the Institute for Infectious Diseases in Berlin in 1891.

Starting from an assessment of how far Robert Koch's bacteriology had developed in the late 1880s this paper attempts to analyse different aspects of the process that led to the foundation of the Berlin Institute for Infectious Diseases in 1891. With the development of his supposed cure against tuberculosis, tuberculin, Koch attempted to give his research a new direction, earn a fortune with the profits and become more independent of Prussian government officials who, up to that point, had had a major influence on his career. In the period following the presentation of the cure in autumn 1890, however, it became clear that tuberculin's value in treatment was at most dubious. Thus, the failure of tuberculin meant that Koch had to drop his own plans and accommodate those of the Prussian Ministry of Culture. As a result he assumed directorship of the newly founded Institute for Infectious Diseases in Berlin. Even though this was definitely a prestigious position it reaffirmed Koch's dependency on Prussian government officials and was by no means the kind of institution he had aimed for at the outset.