From septicemia to sepsis 3.0 – from Ignaz Semmelweis to Louis Pasteur

Sepsis remains a contemporary threat, and its frequency remains high amongst an aging population. Its definition has been regularly revisited, but the impact of the translational research studying it remains very modest compared to the results seen after the introduction of hygiene and the use of antibiotics. In the past, the main forms of sepsis were hospital gangrene (also known as nosocomial fever or putrid fever) that affected the wounded, and puerperal fever that affected women shortly after delivery. In 1858, Armand Trousseau stated that these two pathologies were identical. Lucrezia Borgia, who died in 1519, is undoubtedly the most famous woman to die from puerperal fever. The notion of sepsis as a real epidemic was deplored. For decades doctors remained deaf to the recommendations of their clairvoyant colleagues who advocated for the use of hygienic measures. It was as early as 1795 that Alexander Gordon (UK) and later in 1843, Oliver Holmes (USA), called for the use of hygienic practices. In 1847, Ignaz Semmelweis, a Hungarian physician, provided an irrefutable demonstration of the importance of hygiene in the prevention of contamination by the hands of the practitioners. But Ignaz Semmelweis' life was a tragedy, his fight against the medical nomenklatura was a tragedy, and his death was a tragedy! Nowadays, Ignaz Semmelweis is receiving the honor that he deserves, but never received during his life. Carl Mayrhofer, Victor Feltz, and Léon Coze were the first to associate the presence of bacteria with sepsis. These observations were confirmed by Louis Pasteur who, thanks to his prestige, had a great influence on how to undertake measures to prevent infections. He inspired Joseph Lister who reduced mortality associated with surgery, particularly amputation, by utilizing antiseptic methods.     

Poetry, physiology, and puerperal fever: understanding the young Oliver Wendell Holmes

The 19th-century American physician Oliver Wendell Holmes (1809-1894) is known, internationally, more for his literary output than for his contributions to medical science. Yet a single paper he wrote in 1843--"The Contagiousness of Puerperal Fever"--has made him a hero in the eyes of many (especially in the United States) of the struggle against that scourge. Why that one article, written when Holmes was still in his thirties, should--even in its expanded 1855 version--so routinely be referred to as a "classic of medical literature", and why its author should have been raised on such a high pedestal that some grant him a position beside Ignác Semmelweis, are complicated questions. This present paper is an attempt to begin assessing what it is that makes someone a medical hero by looking at three different aspects of Holmes's early career. He was even as a young man a poet and a physiologist/anatomist as well as the author of this important essay. Whether and how those three features of Holmes's many-sides public persona are connected is discussed as a prelude to considering whether his work on puerperal fever legitimates his status as a medical hero.     

Hempelian and Kuhnian approaches in the philosophy of medicine: the Semmelweis case

Semmelweis's investigations of puerperal fever are some of the most interesting in the history of medicine. This paper considers analysis of the Semmelweis case. It argues that this analysis is inadequate and needs to be supplemented by some Kuhnian ideas. Kuhn's notion of paradigm needs to be modified to apply to medicine in order to take account of the classification schemes involved in medical theorising. However with a suitable modification it provides an explanation of Semmelweis's failure which is argued to be superior to some of the external reasons often given. Despite this success in applying Kuhn's ideas to medicine, it is argued that these ideas must be further modified to take account of the fact that medicine is not a natural science but primarily a practice designed to prevent and cure diseases.     

Genetic determination of the O antigens of Salmonella groups B (4,5,12) and C1(6,7)

M?kel?, P. Helena (University of Helsinki, Helsinki, Finland). Genetic determination of the O antigens of Salmonella groups B (4,5,12) and C(1) (6,7). J. Bacteriol. 91:1115-1125. 1966.-The genetic determination of the O antigens of Salmonella was studied by Hfr or F' crosses between strains of groups B (antigens 4,5,12) and C(1) (antigens 6,7). The main genetic determinants of the specificities 4 of group B and 7 of group C(1) behaved as alleles of one locus, called O or O-4/7. This is probably identical with O-4/9, responsible for the serological difference between groups B and D, and with the "rough" locus rouB. At least parts of the antigens 12 of group B and 6(2) of group C are determined at the same locus. The gene O-5 is closely linked to O-4/7, both mapping in the approximately 2 minutes distance between his and metG in the order his - O-4/7 - O-5 - metG. In crosses of group B donors with group C(1) recipients, a serologically new type, called semirough (SR), appeared in most recombinants that had inherited the O-4 allele of the group B donor. These SR forms are serologically intermediate between smooth and rough forms, showing poor stability in saline but possessing the specificities 4 and 12 and (some of them) 5. On the basis of previous biochemical studies, the hypothesis has been put forward that the side chains of their lipopolysaccharide are much shorter than normal group B side chains, probably containing only one repeating unit per side chain. A gene SR-4 responsible for the elongation of group B side chains beyond the first repeating unit was mapped between gal and try, group B and D bacteria being Sr-4(+), and group C being SR-4(-).     

Abraham Flexner and medical education

The Flexner Report had its roots in the recognition in the mid-19th century that medical knowledge is not something fixed but something that grows and evolves. This new view of medical knowledge led to a recasting of the goal of medical education as that of instilling the proper techniques of acquiring and evaluating information rather than merely inculcating facts through rote memorization. Abraham Flexner, a brilliant educator, had the background to understand and popularize the meaning of this new view of education, and he took the unprecedented step of relating the developments in medical education to the ideas of John Dewey and the progressive education movement. Although the Flexner Report is typically viewed as a historical document--due to an understandable tendency to refer only to the second half of the report, where Flexner provides his famous critiques of the medical schools that existed at the time--this article argues that the Flexner Report is actually a living educational document of as much significance to medical educators today as in Flexner's time. The article analyzes Flexner's discussion of medical education and shows that his message--the importance of academic excellence, professional leadership, proper financial support, and service and altruism--is timeless, as applicable to the proper education of physicians today and tomorrow as in the past.     

Lewis W. Hackett and the early years of the International Health Board's Yellow Fever Program in Brazil, 1917-1924

Lewis W. Hackett joined the staff of the International Health Board (IHB) in 1914. He was sent to Brazil in 1916, where his original responsibility was hookworm control, but he was gradually and inevitably drawn into combating other diseases. Hackett had a strong influence on public health in Brazil. In 1922 he instituted grass-roots (local) health units and programs. The next year, he negotiated with the federal government a cooperative yellow fever control program, which was described in the IHB's 1923 annual report as the "new and final campaign against yellow fever" in Brazil. Eleven offices were established in northern Brazil, where it was expected that yellow fever would quickly be eradicated. Just as the new program got underway Hackett was reassigned to Italy, where he remained until the beginning of World War II. Nonetheless, Hackett had done a classic job of developing the IHB program in Brazil, moving carefully but authoritatively from the initial focus on hookworm, to the development of a more comprehensive public health program, and then to the strategic thrust toward yellow fever.     

Could a neurological disease be a part of Mozart's pathography?

As expected, since we recently celebrated the 250th anniversary of birth of Wolfgang Amadeus Mozart, there has been again a renewal of interest in his short but intensive life, as well as in the true reason of his untimely dead. Mozart lived and died in time when the medical knowledge was based mostly on subjective observations, without the established basics of standardized medical terminology and methodology. This leaves a great space for hypothesizing about his health problems, as well as about the cause of his death. The medical academic community attributed to Mozart approximately 150 different medical diagnoses. There is much speculation on the possible causes of Mozart's death: uremia, infection, rheumatic fever, trichinellosis, etc. Recently some authors have raised the question about a possible concomitant neurological disease. According to available records, Mozart has shown some elements of cyclotimic disorder, epilepsy and Gilles de la Tourette syndrome. Furthermore, the finding of a temporal fracture on (allegedly) Mozart's skull, gives a way to speculations about the possibility of a chronic subdural hematoma and its compressive effect on the temporal lobe. Despite numerous theories on Mozart's pathography that also include a concomitant neurological disorder, the medical and history records about Mozart's health status indicate that he probably had suffered from an infective illness, followed most likely by the reactivation of rheumatic fever, which was followed by strong immunologic reaction in the last days of his life. Taking all the above into consideration, it is reasonably to conclude that Mozart's neurological disturbances were caused by the intensity of the infective disease, and not primarily by a neurological disease.     

Built for speed,not for comfort. Darwinian theory and human culture

Darwin believed that his theory of evolution would stand or fall on its ability to account for human behavior. No species could be an exception to his theory without imperiling the whole edifice. The ideas in the Descent of Man were widely discussed by his contemporaries although they were far from being the only evolutionary theories current in the late nineteenth century. Darwin's specific evolutionary ideas and those of his main followers had very little impact on the social sciences as they emerged as separate disciplines in the early Twentieth Century. Not until the late twentieth century were concerted, sophisticated efforts made to apply Darwinian theory to human behavior. Why such a long delay? We argue that Darwin's theory was rather modern in respects that conflicted with Victorian sensibilities and that he and his few close followers failed to influence any of the social sciences. The late Twentieth Century work takes up almost exactly where James Baldwin left off at the turn of the century.     

Osler and the Jewish people

In his writings and actions, Sir William Osler betrayed no evidence of anti-Semitism. In his era, this trait was unusual. Two of his articles, "Letter from Berlin" and "Israel and medicine," dealt directly with his thoughts on the Jewish people. In both he spoke out against anti-Semitism. Osler had friendships with Jewish colleagues--an example is the great regard in which he held US pediatrician Dr. Abraham Jacobi. Osler was not a saint, and he had his "rough side," but in his relationships with Jewish colleagues his example remains relevant.     

Toxicity of the blue-green alga Oscillatoria agardhii to the mosquito Aedes aegypti and the shrimp Artemia salina

The cyanobacterium Oscillatoria agardhii 27, which does not produce mammalian neuro- or hepatotoxins, was highly toxic to the larval stages of the yellow fever mosquito Aedes aegypti: its 24-h LC₅₀ values against fourth-and second-instar larvae of A. aegypti were 8.7 and 6.1 g live cells/ml, respectively. The toxin was water-soluble and was partially purified but the chemical nature of the toxic compound(s) is still unknown. Aqueous solutions were also toxic to the newborn larvae of the brine shrimp, Artemia salina, used for the bioassay. The toxic activity of these solutions decreased markedly on heating to 90°C for 15 min.J. Kiviranta is with the Department of Pharmacy, P.O. Box 15, FIN-00014 University of Helsinki, Helsinki, Finland; A. Abdel-Hameed is usually with the Department of Microbiology, Faculty of Pharmacy, Cairo University, Kasr-El-Aini Street, Cairo, Egypt, but is presently with the Department of Applied Chemistry and Microbiology, P.O. Box 27, Viikki, Building B, FIN-00014 University of Helsinki, Helsinki, Finland.     

A tribute to Thomas Roosevelt Punnett, Jr. (1926-2008)

We honor here Thomas (Tom) Roosevelt Punnett, Jr. (May 25, 1926–July 4, 2008), who was a pioneer of Biology, particularly of biochemistry of plants and algae, having specialized in photosynthesis under Robert Emerson of the University of Illinois at Urbana-Champaign. He did exciting work on regulation and control of various metabolic reactions. He was an innovator and raconteur par excellence, and he prized critical thinking. His enthusiasm for basic science questions was matched by his grasp of their “real-world” implications. His last project was a patent for anaerobic sewage treatment that he hoped would lead to solution of waste disposal and energy creation world wide, including the clean-up of Lake Erie, where he had sailed as a boy. On the personal side, he had a strong sense of morality and a great wit and humor.     

Focus: Zoonotic Disease: A Severe Case of Falciparum Malaria, 10 Years After Malaria Eradication: A Case Report

Malaria is a major mosquito-borne public health problem especially in tropical countries. The authors report a malaria infection in a 31-year-old man who had returned from East Africa with developed fever and rigor. Because of his thrombocytopenia, decreased hemoglobin, elevated liver enzymes, and splenomegaly, and because of failure to question about recent travel history, he was initially referred to the hematological hospital and medical staff suspected a hematological problem, so he was investigated for bone marrow aspirate and biopsy. As he progressively deteriorated, and after retaking history, his relatives eventually came to mention their travel to Africa. Blood samples were sent to detect malarial parasites, but the results were negative. When an internist was consulted, the patient was drowsy with low oxygen saturation (SpO2), so he was intubated and put on continuous positive airway pressure (CPAP). The internist suggested empirical anti-malarial treatment, which improved the clinical and hematological conditions of the patient. However, the repeated thin blood film showed falciparum malaria ring-shaped trophozoites. The patient persisted with the same treatment for 1 week until his condition improved gradually and completely stabilized, and then he was discharged. Presentation of this case of malaria is crucial to outpatient clinics’ proper referral of cases, as is encouraging the physician to think of malaria as a cause of fever and rigor even in countries with eradicated malaria and to insist on mentioning travel history. It is also imperative, in the case of sustaining fever with further deterioration of the patient after proper antibiotic use, to start empirical anti-malarial treatment immediately.     

Electron microscopy of tick-borne fever agent in bovine and ovine phagocytizing leukocytes

Tuomi, Jaakko (University of Helsinki, Helsinki, Finland), and C.-H. von Bonsdorff. Electron microscopy of tick-borne fever agent in bovine and ovine phagocytizing leukocytes. J. Bacteriol. 92:1478-1492. 1966.-Two strains of tick-borne fever agent, one more virulent to cattle and the other more virulent to sheep, were studied in thin sections of leukocyte concentrates of an affected calf and sheep, respectively. The calf was partially immune from previous infections. To obtain leukocyte concentrate, erythrocytes were lysed by ammonium chloride solution. Glutaraldehyde fixation and osmium tetroxide postfixation were used. Agent particles were detected in neutrophil and eosinophil granulocytes (occasionally also in monocytes) inside cytoplasmic vacuoles. The preparation from the sheep revealed that the tick-borne fever agent has a life cycle; it appeared as large particles, intermediate forms, and small particles. In the preparation from the calf, only large particles were observed, probably as a result of partial immunity. Large particles had a cell wall, plasma membrane, cytoplasm with ribosome-like granules, and nucleoid. They were often elongated, bearing closer resemblance to rickettsiae than to psittacosis-lymphogranuloma-trachoma (PLT) agents. The arrangement of large particles in vacuoles was variable and provided an explanation for the different forms of light microscopic tick-borne fever bodies. The intermediate forms and small particles resembled those of PLT organisms. Release of particles occurred by rupture of inclusions. In the calf also extrusion of whole inclusions was observed. This phenomenon was thought to reflect increased resistance of the cells. The large particle was considered to be the usual infective form of the agent. A middle-ground position of the agent between the genus Rickettsia and the PLT group is suggested.     

David Hubel and Torsten Wiesel

While attending medical school at McGill, David Hubel developed an interest in the nervous system during the summers he spent at the Montreal Neurological Institute. After heading to the United States in 1954 for a Neurology year at Johns Hopkins, he was drafted by the army and was assigned to the Neuropsychiatry Division at the Walter Reed Hospital, where he began his career in research and did his first recordings from the visual cortex of sleeping and awake cats. In 1958, he moved to the lab of Stephen Kuffler at Johns Hopkins, where he began a long and fruitful collaboration with Torsten Wiesel. Born in Sweden, Torsten Wiesel began his scientific career at the Karolinska Institute, where he received his medical degree in 1954. After spending a year in Carl Gustaf Bernhard's laboratory doing basic neurophysiological research, he moved to the United States to be a postdoctoral fellow with Stephen Kuffler. It was at Johns Hopkins where he met David Hubel in 1958, and they began working together on exploring the receptive field properties of neurons in the visual cortex. Their collaboration continued until the late seventies. Hubel and Wiesel's work provided fundamental insight into information processing in the visual system and laid the foundation for the field of visual neuroscience. They have had many achievements, including--but not limited to--the discovery of orientation selectivity in visual cortex neurons and the characterization of the columnar organization of visual cortex through their discovery of orientation columns and ocular-dominance columns. Their work earned them the Nobel Prize for Physiology or Medicine in 1981, which they shared with Roger Sperry.     

Tschermak: a non-discoverer of mendelism. II. A critique

An examination of Tschermak's two papers of 1900 not only reinforces our conclusion cited in our first paper on Tschermak that he was not a rediscoverer of Mendelism, but also he did not understand Mendel when he had read it. His concept of dominance differed from that of Mendel, and his use of his own concept is inconsistent and contradictory. His discussion of his backcross data indicated that he had no idea of the nature of Mendelian ratios. Nowhere did he develop the ideas of segregation and independent assortment.     

Scientific research at the Laboratoire Arago (Banyuls, France) in the twentieth Century: Edouard Chatton, the "master", and André Lwoff, the "pupil"

Edouard Chatton (1883–1947) began his scientific career in the Pasteur Institute, where he made several important discoveries regarding pathogenic protists (trypanosomids, Plasmodium, toxoplasms, Leishmania). In 1908 he married a "Banyulencque", Marie Herre; from 1920, he focused his research on marine protists. He finished his career as Professor at the Sorbonne (Paris) and director of the Laboratoire Arago in Banyuls-sur-mer, where he died in 1947. André Lwoff (1902–1994) lived several scientific lives in addition to his artistic and family life. But it is the study of protists that filled his first life after he encountered the exceptional Master who was Chatton. Lwoff's father was a psychiatrist and his mother an artist sculptor. He became a Doctor of Medicine in 1927 and then a Doctor of Sciences in 1932, his thesis dealing with biochemical aspects of protozoa nutrition. He met Chatton in 1921 and – until Chatton's death – their meetings, first in Roscoff and then in Banyuls-sur-mer, were numerous and their collaboration very close. Their monograph on apostome ciliates was one of the peaks of this collaboration. In 1938, Lwoff was made director of the Microbial Physiology Department at the Pasteur Institute in Paris, where he began a new life devoted to bacteria, and then to viruses, before pursuing his career as director of the Cancer Research Institute in Villejuif (France). Lwoff was awarded the Nobel Prize in Physiology or Medicine in 1965. He died in Banyuls in 1994. "Master" and "pupil" had in common perseverance in their scientific work, conception and observation, a critical sense and rigor but also a great artistic sensibility that painting and drawing in the exceptional surroundings of Banyuls-sur-mer had fulfilled. Electronic Publication     

Sergei Winogradsky: a founder of modern microbiology and the first microbial ecologist

Sergei Winogradsky, was born in Russia in 1856 and was to become a founder of modern microbiology. After his Master's degree work on the nutrition and growth physiology of the yeast Mycoderma vini at the University of St. Petersburg, he joined the laboratory of Anton DeBary in Strassburg. There he carried out his studies on the sulfur-oxidizing bacterium Beggiatoa which resulted in his formulation of the theory of chemolithotrophy. He then joined the Swiss Polytechnic Institute in Zurich where he did his monumental work on bacterial nitrification. He isolated the first pure cultures of the nitrifying bacteria and confirmed that they carried out the separate steps of the conversion of ammonia to nitrite and of nitrite to nitrate. This led directly to the concept of the cycles of sulfur and nitrogen in Nature. He returned to Russia and there was the first to isolate a free-living dinitrogen-fixing bacterium. In the flush of success, he retired from science and spent 15?years on his familial estate in the Ukraine. The Russian revolution forced him to flee Russia. He joined the Pasteur Institute in Paris where he spent his remaining 24?years initiating and developing the field of microbial ecology. He died in 1953.     

George I. Finch and his pioneering use of oxygen for climbing at extreme altitudes.

George Ingle Finch (1888-1970) was the first person to prove the great value of supplementary oxygen for climbing at extreme altitudes. He did this during the 1922 Everest expedition when he and his companion, Geoffrey Bruce, reached an altitude of 8,320 m, higher than any human had climbed before. Finch was well qualified to develop the oxygen equipment because he was an eminent physical chemist. Many of the features of the 1922 design are still used in modern oxygen equipment. Finch also demonstrated an extraordinary tolerance to severe acute hypoxia in a low-pressure chamber experiment. Remarkably, despite Finch's desire to participate in the first three Everest expeditions in 1921-1924, he was only allowed to be a member of one. His rejection from the 1921 expedition was based on medical reports that were apparently politically biased. Then, following his record ascent in 1922, he was refused participation in the 1924 expedition for complex reasons related to his Australian origin, his forthright and unconventional views, and the fact that some people in the climbing establishment in Britain saw Finch as an undesirable outsider.     

Darwin,Wallace, and Huxley,and Vestiges of the Natural History of Creation

Conclusion Publication of the Vestiges and the rather primitive theory of evolution it expounded thus played a significant role in the careers of Darwin and Wallace. In addition, in spite of his poor opinion of the Vestiges, it presented Huxley with a convenient topic for critical discussion and the opportunity to focus more attention on the subject of evolution. The dynamic interactions among these leading figures of nineteenth-century natural science helped spur the development of more sophisticated models of evolution.Darwin had a proper appreciation of Chambers's contribution to evolutionary thought, although he fully recognized the shortcomings of this work. He understood the importance of allowing fresh ideas about organic change to be ventilated. However, he was primarily concerned with his own theory and viewed all developments in evolutionary biology from this perspective. If he did not give full consideration to Chambers and his book early on, it was due mainly to his feeling that the concepts in the Vestiges were very different from his own; he was therefore reluctant to embrace them as the forerunners of his own theory. As a scholar, he was also troubled by the scientific errors in the book. However, the record demonstrates that he attempted to make amends for any oversight on his part. His generous letter to Chambers's daughter, and his gracious treatment of Chambers during the brief time the latter lived in London, are ample proof of that.The attacks of Huxley, Sedgwick, and other prominent natural historians and geologists at the time, the problems inherent in Chambers's evolutionary theory, and the publication of the Origin, are the major reasons why the Vestiges became a neglected work. Nevertheless, Chambers's contribution will always stand out because, together with those of other late eighteenth- and early nineteenth-century predecessors of Darwin, it laid the foundations of modern evolutionary thought and, more importantly, helped prepare the scientific community for the more fully developed ideas of Darwin and Wallace.