Luciano Polonelli

1. Luciano Polonelli This speaker has no conflict of interest to report regarding this talk Department of Medicine and Surgery, University of Parma, Italy The history of Medical Mycology within the ISHAM web site 20th Congress of the International Society for Human and Animal Mycology Amsterdam, The Netherlands 30 June - 4 July, 2018

2. AtharvaVeda 2000 - 1000 A.C. The first record of fungal infections is found in the fourth collection (Samhita) of Hindu scriptures (Atharva Veda), regarding the mycetoma of the foot, metamorphically referred to “padavalmika” (foot-ant-hill). Ainsworth G.C. Introduction to the History of Medical and Veterinary Mycology. Cambridge University Press, Cambridge, 1976 Ajello L. Italian contribution to the history of general and medical mycology. Med. Mycol., 1998; 1: 1-11

3. Hippocrates (~460-370 A.C.), the Greek physician, is considered to be the father of Medicine and in his writings discussed candidiasis in the form presently recognized as “trush”. ~ 400 A.C. Ainsworth G.C. Introduction to the History of Medical and Veterinary Mycology. Cambridge University Press, Cambridge, 1976 Ajello L. Italian contribution to the history of general and medical mycology. Med. Mycol., 1998; 1: 1-11

4. G. Della Porta 1558 The first observation of fungal spores must be attributed to Giambattista della Porta (1538-1615), thematician and naturalist of Naples who published “Phytognomonica” (1558), in which he described the collecting of “seeds” from a wide variety of fungi. Ainsworth G.C. Introduction to the History of Medical and Veterinary Mycology. Cambridge University Press, Cambridge, 1976 Ajello L. Italian contribution to the history of general and medical mycology. Med. Mycol., 1998; 1: 1-11

5. R. Hooke M. Malpighi 1665 The first depiction of a variety of microorganisms, including fungi, is to be attributed to the anatomist Marcello Malpighi (1628-1694), a Professor of the University of Bologna (1666-1691), Anthon van Leeuwenhoek (1632-1723), a draper, amateur scientist and maker of microscopes in Delft, and Robert Hooke (1635-1703), an English astronomer, inventor and physicist, who also described micoorganisms in his “Micrographia” (1665). Ainsworth G.C. Introduction to the History of Medical and Veterinary Mycology. Cambridge University Press, Cambridge, 1976 Ajello L. Italian contribution to the history og general and medical mycology. Med. Mycol., 1998; 1: 1-11

6. P. A. Micheli 1729 Pietro Antonio Micheli (1679-1737) , Professor in Pisa and Prefect of the Botanical Garden in Florence, proved that fungi produced spores that germinated and gave rise to colonies of the same species. The results of his fundamental observations were published in his seminal contribution to botany and mycology “Nova Plantarum Genera” (1729) in which he described 900 different fungi.Pietro Antonio Micheli has to be considered the father of Mycology with its birth date set in 1729. Ainsworth G.C. Introduction to the History of Medical and Veterinary Mycology. Cambridge University Press, Cambridge, 1976 Lazzari G. Storia della Micologia Italiana, Arte Grafiche Saturnia, Trento, 1973 Micheli P.A. Nova Plantarum Genera Juxta Tourneforti Methodum Disposta, Firenze, 1729 Ajello L. Italian contribution to the history of general and medical mycology. Med. Mycol., 1998; 1: 1-11

7. A. Bassi 1835 Agostino Bassi (1773-1856) a civil servant and self-thaugt scientist of Lodi, published the results of his fundamental study of a disease of silkworm, the larva of the mulberry moth (Bombyx mori),that was destroying the flourishing silk industry in Italy and France (1835). Bassi also stated that not only animal, but also human diseases were caused by other living organisms (1844). Bassi is recognized as the first to have discovered the mycotic nature of an animal disease and, as such, is properly considered to be the father of Medical Mycology. Bassi A. Del Mal del Segno Calcinaccio o Moscardino. Malattia che Affligge i Bachi da Seta e sul Modo di Liberarne le Bagattaje anche le più Infestate. Parte Prima-Teoria, Parte Seconda-Pratica. Lodi Tipografia Orcesi, 1835-1836 Ferron P. , Fargues J., Riba G. Fungi as microbial insecticides against pests. In: Arora D.K., Ajello L., Mukerji K.G. (eds). Handbook of Applied Mycology, Vol. 2: Humans, Animals, and Insects, pp. 665-706. Marcel Dekker, Inc. New York, 1991. Ajello L. Italian contribution to the history of general and medical mycology. Med. Mycol., 1998; 1: 1-11

8. J.L. Schoenlein R. Remak D. Gruby 1839 On the basis of Bassi’s epochal work, independently of each other, Johann Lucas Schonlein (1793-1864)and Robert Remak(1815-1865),both of Germany, and David Gruby(1810-1878)of France, studied favus, a widespread, virulent scalp and skin disease that afflicted the children and adults of Europe (1839). They found, for the first time, that a human disease was caused by a mould that today is named Trychophyton schoenleinii(Lebert 1845) Langeron and Milochevitch, 1930. Erste zeichnerische darstellung des Favuspilzesmaus Schònlein j.L.: Zur Pathogenie der Impetigines. Arch. Nat. Physiol. Wiss. Med. 1939. P. 82. Tafel 3, Abb. 5 Ainsworth G.C. Introduction to the History of Medical and Veterinary Mycology. Cambridge University Press, Cambridge, 1976 Gemeinhardt H. 150 years of medical mycology. Z. Gesamte Hig., 1990; 36: 191-194 Ziegler-Bòhme H., Gemeinhardt H. 150 years medical mycology since Johann Lucas Schònlein. Deramtol. Monatsschr., 1990; 10: 623-631 Ajello L. Italian contribution to the history of general and medical mycology. Med. Mycol., 1998; 1: 1-11

9. B. Langenbeck 1839 Bernhard (von) Langenbeck (1810-1887), a young lecturer of the University of Gottingen, published the first description of the fungus Oidium albicans(Candida albicans) as a parasite on oesophageal mucosa of a patient who died of typhoid fever (1839). Langenbeck B. Auffindung von Pilzen auf der Schleimhaut der Speiseròhre einer Typhusleiche. Neue Notizen aus dem Gebiete der Natur-und Heilkkunde, 1839; 12: 146-147 Knoke M, Bernhardt H. The first description of an oesophagel candidosis by Bernhard von langenbeck 1n 1839. Mycoses, 2006; 49: 283-287 N. Notiz. Geb.Nat. Heilk 12 (1839) 145-147

10. Rose and Rudolf Virchow 1865 Rudolf Virchow, a German pathologist, anthropologist and politician, in his comment to Schònlein’s discovery reported “…mould diseases may be summarized within the term mykosen…” (1865). Verlag von August Hirschwald, Berlin, 1865

11. O. Busse 1894-1895 At an evening lecture of the Greifswald Medical Society (1894),a Jewish German dermatologist, Abraham Buschke (1868-1943) from the Hospital of Surgery, gave a talk on a peculiar disease caused by “coccidia” which was followed by a talk of the pathologist Otto Busse (1867-1922) whose subsequent publications are the first descriptions of cryptococcosis, although Cryptococcus neoformans was named after Francesco Sanfelice’s studies (1895). A. Buschke F. Sanfelice Knoke M., Schwesinger G. One hundred years ago: the history of cryptococcosis in Greifswald. Medical mycology in the nineteenth century. Mycoses, 1994; 37: 229-233

12. T.C. Gilchrist 1894 The American physician Thomas Caspar Gilchrist (1862-1927), reported on a case of “pseudo-lupus vulgaris” related to Blastomyces(Van Tieghem 1876) at the American Dermatological Society in Washington D.C. (1894) and then published an extensive description of this case and the fungus was named Blastomyces dermatitidis(Gilchrist et Stokes 1898). Gilchrist T.C. A case of blastomycetic dermatitis in man. Johns Hopkins Hosp. Rep., 1896; 1: 269-283 Gilchrist T.C., Stokes W.R. A case of pseudo-lupus vulgaris caused by a Blastomyces. J. Exp. Med., 1898; 3: 53-83 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

13. R. Wernicke A. Posadas 1896 Alejandro Posadas (1870-1902), then a student of Medicine in Buenos Aires, at the experimental pathology laboratory led by Roberto Wernicke (1852-1922), met a patient mistakenly diagnosed with mycosis fungoides. Posadas noted microscopically an organism that resembled a protozoan, belonging to the group referred to coccidia and the organism was named Coccidioides immitis. The fungal nature of the organism remained unrecognized until a filamentous mould, believed for several years to have been a contaminant, was shown by inoculation of laboratory animals to change its morphological structure into one resembling a protozoan thus providing proof of the diphasic nature of C. immitis(1896). Lobo J. Contribução ao estudo das blastomycoses. Tese de livre-docência à cadeira de Dermatologia e Sifilografia na Faculdade Medica de Recife, Brazil, 1933 Pappagianis D. Coccidoides immitis. In. Ajello L., Hay R.J., eds. Medical Mycology, Vol. 4, Topley & Wilson’s Microbiology and Microbial Infections. London: Arnold, 1988: 357-371 San-Blas G. from magic to science: a journey throughout Latin American medical mycology. Med. Mycol., 2000; 1:1-8

14. E. F. Smith BB. R. Schenck L. Hektoen 1898-1901 Benjamin R. Schenck (1872-1920) reported the case of a patient, at the Surgical Clinic of the Johns Hopkins Hospital in Baltimore, with an infection of the right arm originating from the index finger, with the infection extending up the radial side following the lymph system (1896).He isolated an “organism, not resembling bacteria” able to reproduce experimental infections in a dog and mice. Erwin F. Smith described the mycelial form of the fungus, lately named Sporothrix schenckii by Ludvig Hektoen and C. F. Perkins (1901). Schenck B.R. On refractory subcutaneous abscesses caused by a fungus possibly related to the sporotricha. Johns Hopkins Hosp. Bull., 1898; 9: 286-290 Hektoen L., Perkins C.F. Refractory subcutaneous abscesses by Sprothrix schenckii, a new pathogenic fungus. J. Exp. Med., 1900; 5: 77-89 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

15. S. T. Darling H. Da Rocha-Lima 1906-1913 The American Samuel T. Darling (1872-1925)working as pathologist in Panama, observed many small oval to round unicellular bodies, often within alveolar epithelial cells, while examining autopsy smears of the lungs, spleen and bone marrow of a patient from Martinique who was suspected of having pulmonary miliary tuberculosis (1906). He believed, erroneously, that the clear refractive nonstaining rim was a capsule and thought that the organism was similar to the parasite Leishmania donovanii. Although Darling named the microorganism Histoplasma capsulatum(Darling 1906), it was the Brazilian Henrique da Rocha-Lima (1879-1956) who concluded that it was a fungus (1913). Darling S.T. A protozoon general infection producing pseudotubercles in the lungs and focal necroses in the liver, spleen and limphnodes. J. Am. Med. Assoc., 1906; 46: 1283-1285 da Rocha–Lima H. Beitrag zur kenntnis der Blastomykoses Lymphangitis epizootica und Histoplasmosia. Zentralbl. Bakteriol., 1913; 67: 233-249 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

16. A. Lutz A. Splendore F. P. De Almeida 1908-1930 The Brazilian Adolfo Lutz (1855-1940) described oropharyngeal lesions produced by a fungus that reproduced by multiple budding and grew as a filamentous microorganism at room temperature. Consequently, he noted its dimorphic nature, although he did not name the microorganism. Alfonso Splendore (1871-1953), an Italian scientist working in Sào Paulo, deeply studied the fungus and named it Zymonema brasiliense(1909-1912). The disease was confused with blastomycosis or coccidioidomycosis until the brazilian physician Floriano Paulo de Almeida (1898-1977) characterized the mycosis and its agent, naming it Paracoccidioides brasiliensis(1930). Wanke B., Londero a.T. Paracoccidioides brasiliensis. In. Ajello L. Hay R.J., eds. Medical Mycology, Vol. 4, Topley & Wilson’s Microbiology and Microbial Infections. London: Arnold, 1988: 395-407 San-Blas G., San-Blas F. Immune and chemical responses to paracoccidioidomycosis. In: Jacobs P.H., Nall L., eds: Fungal Disease, Biology, Immunology, and Diagnosis. New York: Marcel Dekker Inc., 1997: 219-235 San-Blas G. from magic to science: a journey throughout Latin American medical mycology. Med. Mycol., 2000; 1:1-8

17. 1910 R. J. Sabouraud The French dermatologist Raymond Jacques Adrien Sabouraud (1864-1938) published the celebrated treatise “Les teignes” in which were studied in depth the infections caused by dermatophytes (1910). Sabouraud R. Les teignes (Las tineas), 1910; Masson et Cie, Paris

18. 1915 The American physician Jean V. Cooke described the first immunological studies in Medical Mycology (1915).He detected precipitin, but not complement-fixing or agglutinating antibodies, in the serum of a patient affected by coccidioidomycosis, by using an antigenic extract (the “precipitinogen”) of dried cultures of Coccidioides immitis. The serological reaction was specific, since the precipitin antibodies did not react with Blastomyces dermatitidis antigens and suggested to be a potential diagnostic tool. Cooke J.V. Immunity tests in coccidioidal granuloma. Arch. Intern. Med., 1915; 15 :479-486 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

19. 1919 The American physician William D. Bowman was the first to describe the X-ray diagnostic potential in five patients afflicted with coccidioidomycosis while he was at the Los Angeles Country Hospital (1919). Bowman W.B. Coccidioidal granuloma. Am. J. Roentgenol., 1919; 6: 547-555 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

20. Formula gm/litro peptone 10.0 glucosio 40.0 agar 15.0 pH 5.6 ± 0.2 Agar Sabouraud 1928 Robert S. Hodges, at the University of Alabama, defined a medium for the identification of dermatophytes on the basis of the studies performed by Fred D. Weidman e Dorothy Spring at the University of Pennsylvania(1928). In its final formulation, this medium was named Sabouraud and is the routine medium used to grow fungi in clinical laboratories. Hodges R. S. Cultures of ringworm fungi on Sabouraud’s proof medium and on medium prepared with American Peptones and sugars. Arch. Dermatol. Syphilol., 1928; 18. 852-856 Weidman F.D., Spring D. Comparison of ringworm culture ingredients: II and III. Arch. Dermatol Syphilol., 1928; 18.829-851 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

21. Emmons C. W. Isolation of Histoplasma capsulatum from soil. Public Health Rep. (Washington), 1949; 64: 892-896 Zeidberg L.D., Ajello L., Dillon A., Runyon L.C. Isolation of Histoplasma capsulatum from soil. A. J. Pulic. Health. 1952; 42. 930-935 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272 Stewart R.A., Meyer K.F. Isolation of Coccidioides immitis (Stiles) from the soil. Proc. Soc. Exp. Biol. Med., 1932; 29:937-938 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272 1932-1955 R. A. Stewart and K. F. Meyer described the first isolation of Coccidioides immitis from the soil collected near the dormitories of a ranch close to Delano, Kern Country, California (1932), justifying the infection known as “valley fever” which was still of unknown origin. Chester W. Emmons isolated Histoplasma capsulatum from soil samples (1949) and observed that Cryptococcus neoformans was present in pigeon feces (1955) while L. D. Zeidberg, L. Ajello, A. Dillon and L. C. Runyon observed that Histoplasma capsulatum was particularly recurrent in case of soil contamination by feces from chickens and bats (1952) , thus establishingthe concept of fungal epidemiology. K. F. Meyer L. Ajello

22. C. Emmons 1934 Chester W. Emmons (1900-1985), of the National Institute of Health in Bethesda, studying the development of conidiophores and conidia by using Henrici’s modified slide culture, proposed to retain the generic names Trichophyton, Microsporum and Epidermophyton and declared that the genera Achorion and Endodermophyton were unnecessary (1934). Emmons C.W. Dermatophytes: natural grouping based on form of the spores and accessory organs. Arch. Dermatol. Syphilol. (Chicago), 1934; 30: 337-362 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

23. Aflatoxin B1 1939 The American bacteriologistArthur T. Henrici (1889-1943), at the University of Minneapolis,reported for the first time that Aspergillus fumigatus produced a hemolyticand a pyrogenic toxin (1939).The importance of his discovery was recognized during the well known ‘‘turkey X disease’’ in England in the early 1960s. The turkeys, swine, poultry, and cattle affected with severe systemic disease had consumedfoodstuffs contaminated with a metabolite of Aspergillus flavus, Aflatoxin,introducing to the hera of mycotoxicoses. Henrici A.T. An endotoxin from Aspergillus fumigatus. J. Immunol., 1939; 36: 319-338 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

24. Griseofulvin J. Gentles 1939-1964 A. E. Oxford purified in Scotland a metabolite of Penicillium janczewskii(P. griseofulvum)(1939) and James C. Gentles demonstrated its activity as “Griseofulvin” against experimental infections caused by Trichophyton mentagrophytesfollowing oral administration in guinea pigs (1958). This finding was forerunner of the intense search for antifungal agents such as Nystatin by H. L. Hazen and R. Brown (1950), Amphotericin B by W. Gold, H. A. Stout, J. F. Pagano and R. Donovick (1955) and 5-fluorocytosine by D. Tassel and M. A. Madoff (1964) during the following years. Oxford A.E., Raistrick H., Simonart P. Studies in the biochemistry of microorganism 60. Griseofulvin, a metabolic product of Penicillium griseofulvum. Dierk. Bichem J., 1939; 33: 240-248 Gentles J.C. Experimental ringworm in guinea pigs: oral trteatment with griseofulvin. Nature (London), 1958; 182: 476-477 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

25. W. Kaplan A. Coons Gomori G. A new histochemical test for glycogen and mucin. A. J. Clin. Pathol., 1946, 10: 177-179 Grocott R. C. A stain for fungi in tissue and smears using Gomori’s methenamine–silver nitrate technique. Am J. Clin. Pathol., 1955; 25: 975-979 Huppert M.D., Oliver D.J., Sun S.H. combined methenamine silver and ematoxylin and eosin stain for fungi in tissues. J. Clin. Microbiol., 1978; 8:598-803 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272 Coons A., Kaplan M.H. Localization of antigen in tisuue cells. II. Improvement in a method for the detection of antigen by means of fluorescent antibody. J. Exp. Med., 1950; 91:1-13 1946-1950 The Hungarian GyörgyGomori (1946) notably implemented the diagnostic sensitivity of histological examinations by developing a specific staining method, successively modified by R. C. Grocott, (1955) and, then, by M. D. Huppert, D. J. Oliver e S. H. Sun (1978), allowing the observation of the tissue reactions against fungi in association with hematoxylin and eosin. Albert Coons and William Kaplan developed (1950) a specific histochemical technique for detecting fungal antigens in tissues by using fluorescein-labeled antibodies.

26. 1948 Lynferd J. Wickerham and Kermit A. Burton demonstrated the potential of assimilation tests in the classification of yeasts (1948). The test led to the development of commercial kits during the 1970’s. Wickerham L.J., Burton K.A. Carbon assimilation tests for the classification of yeasts. J. Bacteriol., 1948; 56:363-371 Land D.G., Vinton E.C., Adcock G.B., Hopkins J.M. Improved auxenographic method for yeast assimilation: a comparison with other approaches. J. Clin Microbiol., 1975; 2: 206-227 Robert G.D., Wang H.S., Hollick G.E. Evaluation of the API 20C microtube system for the identification of clinically important yeasts. J. Cli. Microbiol., 1976; 3:302-305 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

27. NIH 1949-1958 Leo Pine and C. L. Peacok (1954) at the National Institute of Health in Bethesda,carried out studies onHistoplasma capsulatumresulting in the development of a three-amino-acid medium for yeast conversion and confirming the previous findings of S. B. Salvin (1949) that sulfhydryl groups affected by temperature determined the growth form of H. capsulatum. Pine L., Peacock C.L. Studies on the growth of Histolasma capsulatum. IV. Factors influencing conversion of the mycelial phase to the yeast phase. J. Bacteriol., 1958; 75: 167-174 Salvin S. B. Cysteine and related compounds in the growth of the yeast-like phase of Histoplasma capsulatum. J. Infect. Dis., 1949; 84: 275-283 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

28. Edouard Drouhet 1950 Edouard Droueht (1919-2000) at the Pasteur Institute in Paris, demonstrated the role of the polysaccharide glucuronoxylomannan as virulence factor in Cryptococcus neoformas (Torulopsis neoformans) and identified that as the cause of the immunological paralysis during cryptococcosis. Drouhet E, Segretain G, Aubert JP. Capsular polyoside of a pathogenic fungus Torulopsis neoformans; relation to virulence. Ann Inst Pasteur (Paris). 1950; 79: 891-900

29. J. E. Bennett 1950-1973 The association ofsevere fungal infections with antibiotics and steroid therapies, drug addiction, and leukemia or lymphoma, especially Hodgkin’s disease, was first documented by the American pathologist Lorenz Zimmerman (1920-2013) who reported three cases of Candida and Aspergillus endocarditis, ‘‘apparently stimulated’’ by the constant administration of penicillin (1950). JohnE. Bennett, of the National Institute of Health in Bethesda, observed the first case of induction of resistance in a patient affected by cryptococcosis and treated with 5-Fluorocytosine (1973). Zimmerman L.E. Candida and Aspergillus endocarditis. Arch. Pathol., 1950; 50:591-605 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

30. 1953 The prefoundation of the International Society for Human and Animal Mycology (ISHAM) started with an informal meeting in a small romantic restaurant “Giardino dei poeti” in the picturesque part of Rome overlooking the river Tevere, called Trastevere. A dozen of enthusiastic mycologists, most European, including Raymond Vanbreseughem (Antwerp, Belgium), Geoffrey Ainsworth (London, UK), Gabriel Segretain, Edouard Drouhet and Francois Mariat (Paris, France), Jacomina Lodder (Delft, Holland), Heiti Paldrolck (Stockholm, Sweden), Heinz Seeliger (Wùrzburg, Germany), Juan Mackinnon (Montevideo, Uruguay) were invited by Piero Redaelli and Raffaele Ciferri (Italy) to a very intimate meeting and their names are signed in the menu. After delicious pasta and excellent boleti (illustrated by free-hand drawing of a talented mycologist), the idea of a New Society for the study and development of Human and Animal Mycology was advanced by the passionate mycologists present at the dinner. E. Drouhet. The birth of ISHAM: 1953, Rome, Italy. Mycopathol., 1997, 139: 63-70

31. 1953 The birth of ISHAM was precisely in Rome, Italy, in September (1953) at the 6th International Congress of Microbiology after the last war. Selam Waksman, Nobel Prize on the Actinomycetes, source of the first antifungal antibiotic, lectured at the Conference. E. Drouhet. The birth of ISHAM: 1953, Rome, Italy. Mycopathol., 1997, 139: 63-70

32. 1954 A year later, in july (1954),in Paris, at Pasteur Institute, during the 8th International Congress of Botany, ISHAM was officially founded. On the foundation document of ISHAM can be recognized the signatures of some of the prefounders of the first meeting in Rome, as Piero Redaelli (Italy) who became President, Raymond Vanbreuseghem (Belgium), General Secretary, Geoffrey Ainsworth (UK), Gabriel Segretain (France), Chester W. Emmons (USA) and Pablo Negroni (Argentina), Vice Presidents, as well as other charter members as Raffaele Ciferri (Italy), Pedro Lavalle (Mexico) and Gerard A. De Vries (Holland). E. Drouhet. The birth of ISHAM: 1953, Rome, Italy. Mycopathol., 1997, 139: 63-70

33. 1959 Milton H. Huppert e Edmund L. Keeney performed the first experiments devoted to the study of active immunization against Trichophyton mentagrophytes, thus introducing the concept of antifungal vaccinology in man and animals (1959). Keeney E.L. Huppert M. Immunization against superficial fungus infection. I. Studies on experimental animals. J. Invest. Dermatol., 1959; 32: 7-13 Huppert M., Keeney E.L. Immunization against superficial fungus infection. II. Studies on human volunteer subjects. J. Invest. Dermatol., 1959; 32: 15-19

34. A. Stenderup 1966 Roger Storck in the United States and Axel Stenderup andLeth A. Bak in Denmark studied the nucleotide composition of DNA from filamentous fungi and yeasts. They found that the mean base composition, most frequently expressed as the percent guanine plus cytosine content, varied among the species studied and that this kind of analysis appeared to have taxonomic and phylogenetic significance, introducing to the field of molecular mycology (1968). Storck R. Nucleotide composition of nucleic acids of fungi. II. Deoxyribonucleic acids. J. Bacteriol., 1966; 91: 227-230 Stenderup A., Bak A. L. Deoxyribonucleic acid base composition of some species within the genus Candida. J. Gen. Microbiol. 1968; 52:231-236. Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

35. J. W. Murphy 1974-1978 Juneann W. Murphy, Jay A. Gregory e Howard W. Larsh developed their first murine model to study the mechanism of pathogenicityin cryptococcosis(1974).T-lymphocyte-mediated mechanisms appeared to be the primary means of host defense in this disease as well as against other mycoses as histoplasmosis (1977),coccidioidomycosis (1977) and candidiasis (1978). Murphy J. W., Gregory J.A., Larsh H.W. Skin testing of guinea pigs and footpad testing of mice with a new antigen for detecting delayed hypersensitivity to Cryptococcus neoformans. Infect. Immun., 1974; 9: 404-409 Howard D.H., Otto V. Experiments on lymphocite-mediated cellular immunity in murine histoplasmosis. Infect. Immun., 1977; 16: 226-231 Artz R.P., Bullock W.e. Immunoregulatory responses in experimental disseminated histoplasmosis: depression of T-cell-dependent and T-effector responses by activation of splenic suppressor cells. Infect. Immun., 1979; 23: 893-902 Beaman L., Pappagianis D., Benjamini E. Significance of T cells in resistance to experimental murine coccidioidomycosis. Infect. Immun., 1977; 17: 580-585 Galgiani J.N., Isemberg R. A. Stevens D.A. Chemotaxigenic activity of extracts from the mycelial and spherule phases of Coccidioides immitis for human polymorphonuclear leukocytes. Infect. Immun., 1978; 21: 862-865 Diamond R.D., Krzesicki R. Mechanisms of attachment of neutrophils to Candida albicans pseudohyphae in the absence of serum, and of subsequent damage to pseudohyphaeby microbicidal processes of neutrophils in vitro. J. Clin. Invest., 1978; 61: 360-369 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

36. E. Reiss D. Armstrong T. Kiehn P.F. Lehmann Kiehn T.E., Bernard E.M., Gold J.W.M., Armstrong D. Candidiasis: detection by gas-liquid chromatography of D-arabinitol, a fungal metabolite, in human serum. Science, 1979; 206: 577-580 Wong B., Brauer K.L. Enantioselective measurement of fungal D-arabinitol in the sera of normal adults and patients with candidiasis. J. Clin. Microbiol., 1988; 26: 1670-1674 Switchenko A.C., Miyada C.G., Goodman T.C., Walsh T.J., Wong B, Becker M.J., Ullman E.F. An automated enzymatic method for measurement of D-arabinitol, a metabolite of pathogenic Candida species. J. Clin. Microbiol., 1994; 32: 92-97 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272 Reiss E., Lehmann P.F. Galactomannan Antigenemia in Invasive Aspergillosis. Infect. Immun., 1979; 25: 357-365 Lehmann P.F., Reiss E. Invasive aspergillosis: antiserum for circulating antigen produced after immunization with serum from infected rabbits. Infect. Immun., 1978; 20: 570-572 1979 Timothy E. Kiehn, Edward M. Bernard, Jonathan W.M.Gold, and Donald Armstrongdiscovered significant titers of arabinitol in the serum of patients with disseminated candidiasis by liquid gas cromatography (1979) , while Errol Reiss and Paul F. Lehmann detected the circulating antigen galactomannan in case of invasive aspergillosis (1979)thereby identifying potential diagnostic markers.

37. J. Galgiani 1982 John N. Galgiani (1982) was deputed by the National Committe for Clinical Laboratory Standard (NCCLS), now renamed Clinical Laboratory Standard Institute (CLSI), to form a sub-committe to define the guidelines for the drug susceptibility testing of antifungal drugs against yeasts (1992) and moulds (1995). • M27-A2 (2002) Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard - Second Edition • M27-S2 (2006) Quality Control Minimal Inhibitory Concentration (MIC) Limits for Broth Microdilution and MIC Interpretative Breakpoints; Informational Supplement - Second Edition • M38-A (2002) Reference Method for Broth Dilution Antifungal Susceptilibity Testing of Filamentous Fungi; Approved Standard • M44-A (2004) Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts: Approved Guideline • M44-S1 (2005) Zone Diameter Interpretive Standards and Corresponding Minimal Inhibitory Concentration (MIC) Interpretative Breakpoints; Informational Supplement Galgiani J. (VA Medical center at Tucson) 1993. Personal communication

38. D. Soll 1985 David R. Solland coworkers reported that Candida albicans hereditarily and reversibly varied with high frequency through different phenotypes characterized by the morphology (white/opaque) of the colony in agar (1985).Thisfinding led them to considerthat the phenotypicswitchingoccurring in C. albicans and other fungi could be at the basis of theirinvasiveness, organtropism, immunoevasion and drugresistance. Slutsky B., Buffo J., Soll D.R. High frequency switching of colony morphology in Candida albicans. Science, 1985; 230: 666-669 Morrow R.T., Srikantha T., Soll D.r. Trascription of the gene for a pepsinogen PEP1 is regulated by white-opaque switching in Candida albicans. Mol. Cell. Biol., 1992; 12. 2297-3005 Srikantha T., Soll D.R. A white specific gene in the white-opaque switching system of Candida albicans. Gene, 1993, 131: 53-60 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

39. J. E. Cutler 1988 Jim E. Cutler and coworkers isolated a DNA probe that may become useful in the direct detection of Candida albicans in clinical specimens (1988). They isolated a DNA fragment that hybridized specifically with DNA from C. albicans but did not hybridize with DNA from other infectious agents or from the host thus introducing to the field of diagnostic molecular medical mycology. J. E. Cutler and coworkers isolated a DNA probe that may become useful in the direct detection of Candida albicans in clinical specimens (1988). They isolated a DNA fragment that hybridized specifically with DNA from C. albicans but did not hybridize with DNA from other infectious agents or from the host thus introducing to the field of diagnostic molecular medical mycology. Cutler J.E., Glee P.M., Horn H.L. Candida albicans and Candida stellatoidea – specific DNA fragJ. E. Cutler and coworkers isolated a DNA probe that may become useful in the direct detection of Candida albicans in clinical specimens (1988). They isolated a DNA fragment that hybridized specifically with DNA from C. albicans but did not hybridize with DNA from other infectious agents or from the host thus introducing to the field of diagnostic molecular medical mycology. ments. J. Clin. Microbiol., 1988; 26: 1720-1724 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

40. R. A. Calderone 1988 Richard A. Calderone and coworkers focused on the identification of the receptors on Candida albicans that bind complement as well as the potential pathogenic role of these receptors (1988). Calderone R.A., Linehan L., Wadsworth E., Sandberg A.L. Identification of C3d receptors on Candida albicans. Infect. Immu., 1988; 56: 252-258 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

41. 1988-1991 Beatrice B. Magee and Paul T. Magee suggested that Candida albicans had seven chromosomes and assigned genes to them by hybridization (1988). On the basis of more advanced methods of pulsed-field electrophoresis and studies of genetic linkages, B. Wickes and coworkers reported that the basic number of chromosomes for C. albicans was eight (1991). Magee B.B., Koltin Y., Gorman J.A., Magee P.T. Assignment of cloned genes to the seven electrophoretically separated Candida albicans chromosomes: Mol. Cell. Biol., 1988; 8: 4721-4726 Wickes B.,Staudinger J., Magee B.B., Kwon-Chung K.J., Magee P.T. Physical and genetic mapping of Candida albicans: several genes previously assigned to chromosome 1 map chromosome R, the rDNA-containing linkage group. Infect. Immun., 1991; 59: 2480-2484 Espinel-Ingroff A. History of Medical Mycology in the United States. Clin. Microbiol. Rev., 1996; 2: 235-272

42. Besides… Further scientists have performed basic researches or developed diagnostic procedures with results worthy to be admired. Their work will be at the basis of further discoveries and inventions which will be significant for the future. The task to prosecute the work performed by the founders and contemporary people, as well as to capitalize their legacy, is delegated to the new generations of scientists and, in particular to those so talented and enthusiastic to put forward the milestones of knowledge in Medical Mycology. N. Conant, A. F. Di Salvo, H. Levine, D. W. R. Mackenzie, C. Silva Lacaz, F. C. Odds, E. S. Beneke, L. Kaufman, F. Staib, G. S. Kobayashi, A. Gonzales-Ochoa, A. Restrepo, R. Negroni, P. L. Fidel, A. Castellani, A. Casadevall, L. Polonelli, J.P. Lopez-Ribot, S. De Hoog, D. W. Warnock, G. T. Cole, M. D. Connole, G. S. Deepe, L. De Repentigny, D. W. Denning, J. P. Latgè, A. Cassone, A. Espinel-Ingrof, M. Viviani, F. Dromer, B. Dupont, D. H. Ellis, M. R. McGinnis, J. N. Faergemann, H. C. Gugnani, R. J. Hay, M. A. Ghannoum, N. A. R. Gow, J. R. Graybill, M. Gordon, F. Bistoni, D. H. Howard, B. Hube, R. A. Samson, S. M. Levitz, E. S. Mahgoub, G. Midgley, T. G. Mitchell, M. Monod, P. M. Stockdale, J. Müller, N. Nolard, S. Shadomy, D. Pappagianis, J. R. Perfect, M. A. Pfaller, H. Ogawa, J. Ponton, K. J. Kwon-Chung, D. Poulain, L. Travassos, L. Romani, D. Coleman, J. W. Rippon, H. S. Randhawa, M. D. Richardson, M. G. Rinaldi, E. Segal, R. Ruchel, R. Sentandreu, I. F. Salkin, D. Sanglard, R. C. Summerbell, G. San-Blas, H. J. Shadomy, J. D. Sobel, D. Swinne, J. M. Torres-Rodriguez, P. E. Verweji, E. Roilides, and many others … T. J. Walsh,

43. Conclusions Thislecturehaspresented a reviewalong the years of some relevantcontributions to MedicalMycology from the springtimes of the discipline untiltoday. Other significant contributions may have been omitted for reasons of time or ignorance. These neglected or ignored aspects, however, can be considered or reported in the “History of Medical Mycology” available online on the ISHAM website written by this speaker. Anyone who knows of discoveries or inventions not included in the "History of Medical Mycology", or intends to correct the present, is invited to propose them for inclusion, or modification, after proper evaluation by the Editor in charge of the Journal of the Society "Medical Mycology “.

44. The page of “History of Medical Mycology” in the ISHAM web site Thank you for attention