Panum's next step was to modify the basic test solution and examine the reactivity of each modification in the same experimental setup. He made nine experiments, as outlined below 2, 3. A dog was given 24 ml of non-modified stock solution prepared as described above.
It reacted with typical symptoms and signs and died after six hours. Autopsy findings were as described above. It elicited the same complex of symptoms as seen in experiment 1. The dog survived and recovered over the next nine days. A major volume of the stock solution was evaporated to dryness, and the residue was extracted with absolute alcohol. The alcoholic extract was evaporated to dryness, re-suspended in distilled water, and infused into the dog used in experiments 2 and 3.
The dog became drowsy, but showed no signs of toxicity.
This experiment was a repetition of experiment 3, but with a new dog, which reacted with typical symptoms and signs. It survived and recovered over the next days. This experiment was a repetition of experiment 2, using the same dog as in experiment 5. It reacted with no signs of toxicity.
Panum had observed that an albumen-like substance was precipitated upon prolonged boiling of the stock solution. In order to test if this substance was toxic he performed the following experiment: After filtration, the residue on the filter was triturated, re-suspended in distilled water, and infused into a new dog.
It reacted with typical symptoms and signs, and recovered gradually over the next eight days. In order to test if toxicity was due to the albumen-like substance itself or to soluble toxins adsorbed to its surface he extracted the filtrated residue first with absolute alcohol, then with cold, and finally with boiling water.
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The residue was then treated in the same manner as in experiment 7 and infused into the surviving dog used in experiment 7. This time the dog showed no signs of toxicity. Finally, a major volume of the original test solution was evaporated to dryness, and the residue was extracted, first with absolute alcohol, and thereafter with cold and boiling distilled water.
The watery extract was filtered and infused into a new dog, which reacted with typical symptoms and signs. It survived the first time, but was sacrificed afterwards. Based on these experiments Panum concluded that "putrid poison" was a solid, non-volatile substance, which was soluble in water, but not in alcohol.
It was not decomposed by prolonged boiling or evaporation even to completely dry residue. The albuminoidal contents of putrefying solutions were not poisonous per se, but "putrid poison" could adsorb to their surface. In its intensity of action it was comparable only to snake venom, curare, and plant alkaloids 2.
As noted by Panum, his stock solutions contained rod shaped bacteria "vibrios" before filtration. It can therefore be taken for granted that they also contained endotoxin. Autopsy findings indicate that "putrid poison", like endotoxin, gives rise to organ inflammation and signs of disseminated intravascular coagulation. Of particular importance is the observed resistance to long-term boiling and the delay in onset of symptoms, which are particularly distinctive features of endotoxin 4.
It is also notable that none of the observations in the nine experiments contradict the hypothesis that "putrid poison" could be endotoxin.
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Panum reused dogs for several of the experiments 3, 4, 6, 8. This could have biased his "negative" results severely, because endotoxin may induce tolerance 4. By pure luck, he avoided this problem, because the order of experiments implied that the reused dogs had either not been exposed to endotoxin in the foregoing experiment the dog in experiment 3 , or the test solution used in the actual experiment would not contain endotoxin experiments 4, 6, 8.
For the moment, Panum's work attracted little attention from the international scientific community, presumably because it was published in Danish. In a short extract of his article was translated into German, apparently without his knowledge 3, 9, This served as an inspiration for other investigators, but did not provide many details.
Panum himself planned to publish a more detailed German translation; however, the war between Denmark and Germany in interrupted his plans, and he was forced to leave Kiel. Later the same year he was appointed professor of physiology at Copenhagen University, and apparently he did not work with "putrid poison" for the next ten years. Others went on with studies of "putrid poison", in part inspired by Panum 3, 9. His results gave rise to some criticism, however, this was mainly due to misunderstandings, which could be attributed to the lack of access to details in his original publication 3.
At length several of his observations were confirmed by others. Thus Hemmer in his studies confirmed that "putrid poison" is insoluble in alcohol, but soluble in water and resistant to boiling Rosenberger also confirmed the heat stability of "putrid poison" The nature of "putrid poison" puzzled Panum's mind.
He was faced with two possibilities, which both seemed improbable: It could be a chemical substance, or it could be microorganisms, in particular vibrios, which he had frequently detected in the putrefying fluids. In his first publication he rejected both possibilities, the former because of the characteristic delay in onset of symptoms, which was inconsistent with any known chemical substance, the latter because toxicity was not abolished by prolonged boiling.
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So he left the question open 2. In the clinical role of bacteria was very poorly understood, and the miasma theory was still the prevailing explanatory model of infectious diseases. Over the next two decades the germ theory came into evidence, primarily supported by Pasteur's works on fermentation and Lister's work on the effect of antiseptic treatment of wounds In the early s several investigators demonstrated streptococci in pus from infected patients and claimed that they played a causative role in disease. Among them was the young Danish bacteriologist Carl Julius Salomonsen, who performed his first clinical studies on pyaemia in Copenhagen at the end of Although bacteria had come in focus, their role in disease was still a very controversial issue.
This prompted Panum to reconsider his experiments, and in he re-published his observations on "putrid poison" in Virchow's Archive 3. Compared with his first publication, he had modified his views considerably in favour of a microbial origin of "putrid poison", although he was still sceptical and warned against any hasty conclusions. Remarkably, he no longer considered a chemical or microbial origin as mutually exclusive in explaining the nature of "putrid poison".
In his own words: "Maybe this poison is produced through the life process of bacteria, or to be more explicit probably through the small rods named Bacterium termo Cohn , and it seems to be produced in a way analogous to ergotine" author's translation 3. In the time of Panum Bacterium termo was a designation of small rod-shaped organisms "vibrios". We cannot say with certainty that they were Gram-negative Gram staining was only invented in 11 , but in all probability they were.
So Panum came very close to the truth about the nature of "putrid poison", although he seems to have regarded it a secretory product i.
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Panum had a remarkably clear idea about the clinical significance of his discoveries. In principle, he envisaged both antimicrobial chemotherapy and anti-endotoxin therapies of sepsis, as may be seen from the following paragraphs of his paper author's translation : "If it would turn out through investigations If one succeeded with that Panum's introduced his ideas decades before Ehrlich, Fleming and Domagk, through their ground-breaking discoveries in the first half of the 20th century, made antimicrobial chemotherapy a clinical reality During the s anti-endotoxin antibodies were tested as a supplement to antibiotics in the treatment of septicaemia, but results were equivocal and on the whole disappointing Nevertheless the basic idea of immunomodulatory therapy is still clinically relevant, and at length this part of Panum's vision may also come true.
Contrasting with the situation in , Panum's publication immediately aroused great scientific attention, and Pasteur had it translated into French 9, In addition to his considerations on the management of septicaemia, the article also contains a footnote in which Panum hypothesized that leukocytes might play a role in killing bacteria, which had invaded the bloodstream 3. When Panum took up the appointment as professor of physiology at the University of Copenhagen, he insisted on having built a new physiological institute. It was inaugurated in , and provided excellent facilities for experimental laboratory medicine.
He became the tutor of a whole generation of brilliant young scientists, and thereby had an enormous impact on the development of laboratory sciences in Denmark. Among his pupils were the physiologist Christian Bohr , the zymologist Emil Christian Hansen , and the medical microbiologist Carl Julius Salomonsen 9, Unfortunately, Siemian appeared to have suffered a broken ankle after getting walloped by Myles Garrett. That left the Jets with their third-stringer, Luke Falk, at quarterback. Statistically, Falk seemingly did all right, going for for yards. But Bill Belichick and Co.
Defensively, the Jets showed plenty of problems, despite limiting the Browns to a somewhat modest 23 points. Gregg Williams: "That's your opinion…what did the Giants do? The Jets also committed 12 penalties for 89 yards in the loss to Cleveland. Jamal Adams committed a roughing the passer penalty on a third-down incompletion that led to a Browns field goal in the first quarter, and he was penalized on back-to-back plays — once for encroachment, once for offside — in the fourth quarter.
The Jets took two false start penalties, a delay of game penalty, and they were called for a defensive holding penalty, which was declined. Way down. After losing to facing the Patriots in Week 3, the Jets have a gift from the heavens with a Week 4 bye.
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They have a good shot of being when they head to Jacksonville in Week 8. And then, in Week 9, the most magical of matchups will take place: Jets at Dolphins. The battle for AFC inferiority promises to be one for the ages. Facts show that such has rarely been the case, that the AFC East has more or less been comparable to move every other division over the past 20 years, and that the Patriots have had as difficult a road to the playoffs as any other team.