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Discussion to Manuscripts Published in the December, 1946 Issue of the Journal, Volume 7, No. 6
DISCUSSION TO MANUSCRIPTS PUBLISHED IN THE DECEMBER, 1946 ISSUE OF THE JOURNAL, VOLUME 7, NO. 6 EXPERIMENTAL ASPECTS OF PENICILLIN SENSITIZATION WITH ESPECIAL REFERENCE TO CONJOINT SENSITIZATION TO SUPERFICIAL FUNGUS DISEASE
GEORGE M. LEWIS, M.D. xi FRANK E. CORMIA, M.D.
Dr. Samuel M. Peck: My group has been working along parallel lines for about 15 months. The work has divided into several phases. The sensitivity reactions to penicillin and trichophytin were studied in individuals ranging from 2 months to over 60 years of age. Many animal experiments were also carried out. My approach to the problem has been somewhat different from that of Doctors Lewis and Cormia. In a recent paper ("The Production of an Antibiotic Substance Similar to Penicillin by Pathogenic Fungi (Dermatophytes)", Peck, S. M. and Hewitt, Wm. L., Public Health Reports, Vol. 60, No. 6, pp. 148—153, February 9, 1945), we were able to show that the dermatophytes including those clearly causing dermatophytosis were capable of produc-
ing in vitro antibiotics. One of the antibiotics could be identified as penicillin
G. This lead us to study the possibility that the unusual high incidence of spontaneous sensitivity in patients to penicillin might be due to the fact that they had been previously sensitized to the penicillin produced by their derniatophytosis. Indeed, our research seems to support such a contention. However, contrary to the work of Doctors Lewis and Cormia, we believe that the antigen giving rise to the trichophytin reaction is not identical with penicillin nor is there cross-sensitivity between the two. The important thing from all
this research is that the dermatophytes are capable of producing multiple antigens—one of which is peniciffin, another is that which elicits the trichophytin test, still another antigen is the one described in—"Trichophytin—II. The Apparent Separation of the Skin-Reactive Factor from the Therapeutic Principle in Trichophytin," (Peck, S. M., Glick, A. and Weissbard, E., Arch. of Derm. and Syph., Vol. 44 pp. 816—836, Nov. 1941), and, perhaps, there are many others which as yet have not been identified.
Discussion by Dr. Harry Templeton: Doctors Lunsford, Allington and I recently read a paper on the subject of sensitization to penicillin, but inasmuch as most of it was clinical, only one phase would be of interest here. We did some work attempting to show that there are circulating antibodies in the serum of patients with reactions to penicillin. We took sera from five patients suffering from urticaria, caused by penicillin, and injected them intradermally in five girls. Then, 48 hours later we injected a therapeutic dose of penicillin intra-
musuclarly and observed them for several days. No reaction took place at the site of the donor sera. Then, seven more volunteers were injected intradermally with these same penicillin-sensitive, urticarial donor sera, and after 48 hours patch tests were applied to the sites of the intradermal injections. 49
50
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
No reactions occurred. Next we took the same seven normal volunteers and injected them intradermally with the urticarial sera. Then, after 48 hours we did scratch tests at the sites of the injections. We secured a number of weakly positive reactions to these scratch tests. We felt, therefore, that we had evidence of a positive Prausnitz-Kuestner reaction, demonstrating the presence of circu-
lating antibodies. The reason for not getting any positive patch tests was insufficient transepidermal penetration.
Dr. George M. Lewis: I wish to thank Doctors Peck and Templeton for their discussions. Emphasis should be made on the fact that this is a report of a preliminary study. We all have impressions but at this time not too many conclusions can be drawn. We know that penicillin is a complex substance, so that until we have the fractions available for experimentation we will not be in a position to speak with finality. However, we may make the assertion now that there is a distinct link between pre-existing fungous disease and some of the reactions following the administration of penicillin. MELANIN PIGMENTATION THROUGH THE AGES
S. WILLIAM BECKER, M.D.
Dr. Samuel M. Peck: I am filled with admiration for this intelligent achieve-
ment. In the work we have done it seemed to us that there was a marked difference, at least in rabbits, between ectodermal and mesodermal pigment formation. We could not, in our work, see any relationship to neural origin, nor that there was migration of mesodermal melanoblasts to the ectoderm. In recalling some of these sections, the most interesting speculations were concerned with the work done on transplants. ("Pigment Studies in Skin Grafts on Experimental Animals"; Lewin, M. L. and Peck, S. M., The Jour, of Invest. Derm., Vol. 4, No. 6, Dec. 1941). In these experiments we transplanted pig-
mented to non-pigmented areas. After the transplant the skin adjacent to the transplant acquired pigment function. When we transplanted hair which was colorless, or gray, to these pigmented areas the hair remained gray, and did
not assume any pigment function, nor did the hair in the vicinity of the pigmented graft assume any pigment function. Dr. Schwartz pointed out to me that in his experiments he too found that the pigment formation in the hair was not affected. Dr. Fred Weidman: I would like to ask Dr. Becker whether in his reference to "origin of the pigment" he is alluding to physiological processes or simply morphologic ones? Certainly in the morphologic, there is evidence of relationship of melanin to nerve tissue. I can cite the report of Netherton* concerning a child with a most extensive bathing trunk type of pigmented nevus, who died with convulsive symptoms due to pressure of figmented nevus tissue upon the meninges, as necropsy disclosed. The dura of both cerebrum and spinal cord *Netherton, E. W.: Extensive Figmented Nevus Associated with Primary Milanobla8ts of Leptomeninges of Brain and Spinal Cord. Arch. D. & S. 33: 238 (Feb.) 1936.
MELANIN PIGMENTATION THROUGH AGES
51
were heavily loaded with these melanotic, evidently nevus cells, and I myself have seen such a case at necropsy. Dr. Becker has catalogued a number of circumstances under which this pigment
occurs in the lower animals. I am rather surprised that he did not mention the salamander or the amphiuma. These animals are most useful in studies of this sort, by reason of the extremely large size of all the cells of the animal, and they should be taken advantage of. At the Philadelphia Zoological Garden we have seen a number of interesting examples of peculiarities of melanin pigmentation. The sacred python of India has large plaques of depigmentation which look like vitiligo, but perhaps the animal has been burned in some fire ritual or otherwise, and the lesion may represent scar tissue. Dr. S. William Becker: The point brought out by Dr. Peck is important, because it is necessary to appreciate just where the pigment is ;—pigment of the hair and pigment of the epidermis do not run parallel. Individuals or animals may have very black hair, but the epidermis may contain no pigment whatever. On the other hand, in fowls, such as the Japanese silkie, the epidermis is non-pigmented, although most of the interval tissues are deeply melanotic. Dr.Wiedman mentions the patient of Dr. Netherton's—I had always thought this child had a melanoma which originated in the pia mater—in human beings pigment is normally present in that region. I may have called the two animals amphibians, but they were salamanders
on which the experiments were done. I have some reference in the paper relative to Albinos, which I did not have the opportunity to read. Albino animals are worshipped in some countries. In Moby Dick the white whale mentioned may have been an Albino.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
24. Wynn, C. H. and Iqbal, M.: Isolation of rat
skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.
human epidermis, p. 511, The Epidermis
Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-
No warranty is given about the accuracy of the copy.
Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.
Cell Biol., 27: 603, 1965.
27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-
C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.
30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.
31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-
lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.
32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.
33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.
34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:
Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.
43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.
44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.
45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.
46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,
Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by
Res., 33: 176, 1964.
GEORGE M. LEWIS, M.D. xi FRANK E. CORMIA, M.D.
Dr. Samuel M. Peck: My group has been working along parallel lines for about 15 months. The work has divided into several phases. The sensitivity reactions to penicillin and trichophytin were studied in individuals ranging from 2 months to over 60 years of age. Many animal experiments were also carried out. My approach to the problem has been somewhat different from that of Doctors Lewis and Cormia. In a recent paper ("The Production of an Antibiotic Substance Similar to Penicillin by Pathogenic Fungi (Dermatophytes)", Peck, S. M. and Hewitt, Wm. L., Public Health Reports, Vol. 60, No. 6, pp. 148—153, February 9, 1945), we were able to show that the dermatophytes including those clearly causing dermatophytosis were capable of produc-
ing in vitro antibiotics. One of the antibiotics could be identified as penicillin
G. This lead us to study the possibility that the unusual high incidence of spontaneous sensitivity in patients to penicillin might be due to the fact that they had been previously sensitized to the penicillin produced by their derniatophytosis. Indeed, our research seems to support such a contention. However, contrary to the work of Doctors Lewis and Cormia, we believe that the antigen giving rise to the trichophytin reaction is not identical with penicillin nor is there cross-sensitivity between the two. The important thing from all
this research is that the dermatophytes are capable of producing multiple antigens—one of which is peniciffin, another is that which elicits the trichophytin test, still another antigen is the one described in—"Trichophytin—II. The Apparent Separation of the Skin-Reactive Factor from the Therapeutic Principle in Trichophytin," (Peck, S. M., Glick, A. and Weissbard, E., Arch. of Derm. and Syph., Vol. 44 pp. 816—836, Nov. 1941), and, perhaps, there are many others which as yet have not been identified.
Discussion by Dr. Harry Templeton: Doctors Lunsford, Allington and I recently read a paper on the subject of sensitization to penicillin, but inasmuch as most of it was clinical, only one phase would be of interest here. We did some work attempting to show that there are circulating antibodies in the serum of patients with reactions to penicillin. We took sera from five patients suffering from urticaria, caused by penicillin, and injected them intradermally in five girls. Then, 48 hours later we injected a therapeutic dose of penicillin intra-
musuclarly and observed them for several days. No reaction took place at the site of the donor sera. Then, seven more volunteers were injected intradermally with these same penicillin-sensitive, urticarial donor sera, and after 48 hours patch tests were applied to the sites of the intradermal injections. 49
50
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
No reactions occurred. Next we took the same seven normal volunteers and injected them intradermally with the urticarial sera. Then, after 48 hours we did scratch tests at the sites of the injections. We secured a number of weakly positive reactions to these scratch tests. We felt, therefore, that we had evidence of a positive Prausnitz-Kuestner reaction, demonstrating the presence of circu-
lating antibodies. The reason for not getting any positive patch tests was insufficient transepidermal penetration.
Dr. George M. Lewis: I wish to thank Doctors Peck and Templeton for their discussions. Emphasis should be made on the fact that this is a report of a preliminary study. We all have impressions but at this time not too many conclusions can be drawn. We know that penicillin is a complex substance, so that until we have the fractions available for experimentation we will not be in a position to speak with finality. However, we may make the assertion now that there is a distinct link between pre-existing fungous disease and some of the reactions following the administration of penicillin. MELANIN PIGMENTATION THROUGH THE AGES
S. WILLIAM BECKER, M.D.
Dr. Samuel M. Peck: I am filled with admiration for this intelligent achieve-
ment. In the work we have done it seemed to us that there was a marked difference, at least in rabbits, between ectodermal and mesodermal pigment formation. We could not, in our work, see any relationship to neural origin, nor that there was migration of mesodermal melanoblasts to the ectoderm. In recalling some of these sections, the most interesting speculations were concerned with the work done on transplants. ("Pigment Studies in Skin Grafts on Experimental Animals"; Lewin, M. L. and Peck, S. M., The Jour, of Invest. Derm., Vol. 4, No. 6, Dec. 1941). In these experiments we transplanted pig-
mented to non-pigmented areas. After the transplant the skin adjacent to the transplant acquired pigment function. When we transplanted hair which was colorless, or gray, to these pigmented areas the hair remained gray, and did
not assume any pigment function, nor did the hair in the vicinity of the pigmented graft assume any pigment function. Dr. Schwartz pointed out to me that in his experiments he too found that the pigment formation in the hair was not affected. Dr. Fred Weidman: I would like to ask Dr. Becker whether in his reference to "origin of the pigment" he is alluding to physiological processes or simply morphologic ones? Certainly in the morphologic, there is evidence of relationship of melanin to nerve tissue. I can cite the report of Netherton* concerning a child with a most extensive bathing trunk type of pigmented nevus, who died with convulsive symptoms due to pressure of figmented nevus tissue upon the meninges, as necropsy disclosed. The dura of both cerebrum and spinal cord *Netherton, E. W.: Extensive Figmented Nevus Associated with Primary Milanobla8ts of Leptomeninges of Brain and Spinal Cord. Arch. D. & S. 33: 238 (Feb.) 1936.
MELANIN PIGMENTATION THROUGH AGES
51
were heavily loaded with these melanotic, evidently nevus cells, and I myself have seen such a case at necropsy. Dr. Becker has catalogued a number of circumstances under which this pigment
occurs in the lower animals. I am rather surprised that he did not mention the salamander or the amphiuma. These animals are most useful in studies of this sort, by reason of the extremely large size of all the cells of the animal, and they should be taken advantage of. At the Philadelphia Zoological Garden we have seen a number of interesting examples of peculiarities of melanin pigmentation. The sacred python of India has large plaques of depigmentation which look like vitiligo, but perhaps the animal has been burned in some fire ritual or otherwise, and the lesion may represent scar tissue. Dr. S. William Becker: The point brought out by Dr. Peck is important, because it is necessary to appreciate just where the pigment is ;—pigment of the hair and pigment of the epidermis do not run parallel. Individuals or animals may have very black hair, but the epidermis may contain no pigment whatever. On the other hand, in fowls, such as the Japanese silkie, the epidermis is non-pigmented, although most of the interval tissues are deeply melanotic. Dr.Wiedman mentions the patient of Dr. Netherton's—I had always thought this child had a melanoma which originated in the pia mater—in human beings pigment is normally present in that region. I may have called the two animals amphibians, but they were salamanders
on which the experiments were done. I have some reference in the paper relative to Albinos, which I did not have the opportunity to read. Albino animals are worshipped in some countries. In Moby Dick the white whale mentioned may have been an Albino.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
24. Wynn, C. H. and Iqbal, M.: Isolation of rat
skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.
human epidermis, p. 511, The Epidermis
Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-
No warranty is given about the accuracy of the copy.
Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.
Cell Biol., 27: 603, 1965.
27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-
C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.
30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.
31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-
lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.
32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.
33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.
34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:
Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.
43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.
44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.
45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.
46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,
Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by
Res., 33: 176, 1964.