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Cutaneous Sarcoidosis As an Expression of Syphilis
CUTANEOUS SARCOIDOSIS AS AN EXPRESSION OF SYPHILIS* REPORT AND DISCUSSION OF A CASE
EUGENE TRAUGOTT BERNSTEIN, M.D. AND MORRIS LEIDER, M.D.
The following case is reported as an instance of an eruption which was clinically and histologically compatible with the diagnosis of Boeck's sarcoid but which proved to be of syphilitic origin. The implications of this situation are important and will be discussed. CASE REPORT
M. M., aged 33 years, white, female, a housewife, contracted syphilis 18 years ago (at 15 years of age) and received an intensive course of antisyphilitic treatment at that time. Thirteen years ago (at 20 years of age) she suffered an episode of pleurisy with effusion. Follow-up examinations with x—rays were negative for tuberculosis. Serologic examinations for syphilis were negative up to the date of recent history. One and one half years
ago an eruption appeared on the right arm. In the course of time this eruption spread and appeared on the other arm and on the trunk. Physical examination at the start of this observation revealed no significant pathology except the dermatosis and discrete lymphadenopathy in the cervical and axillary regions. The skin showed an extensive papulo-nodular, erythematous and violaceous eruption distributed over the arms and trunk. The right side was more involved than the left. The individual lesions, which were either pea sized papules or bean sized nodules, grouped themselves in circinate or serpiginous arrangements. (See Figs. 1 and 2) The laboratory findings were as follows.: Serologic tests for syphilis: Wasserman: 4 plus Kline: 4 plus Blood Count: Normal limits Urinalysis: Negative X-ray of the Chest: Negative Tuberculin Tests (intracutaneous, quantitative, with Old Tuberculin Koch): 1:1,000,000: one plus 1:100,000: one to two
plus
1:10,000: two to three plus
BCG vaccination (diagnostic):
Visible reaction
within 24—48 hours, proceeding rapidly through stages of erythema,
pustulation, ulceration and scar-healing. Biopsy of a lesion (interpreted by Dr. Wilbert Sachs): Throughout the mid and upper cutis there are numerous epithelioid cells arranged in tubercle formation. The surrounding blood vessels are dilated and about them is a moderate small round cell infiltration. The overlying epidermis is slightly acanthotic papulovesiculation,
* Presented before the Section of Dermatology and Sypbilology of the New York Acad emy of Medicine in March and April 1949.
t This procedure, originally suggested by Lemming (Acta Med. Scandinav., 103: 400, 1940, and 110: 151, 1942) has been developed and extended by Leider, M. and Sulzberger, Marion B. (J. Invest. Dermat., 13: 249, Nov. 1949) as a means of analysing tuberculin reactivity. Received for publication January 17, 1950. 75
OF THE ERUPTION ON THE ARM.
TRUNK.
FIG. 2. CLINICAL APPEARANCE OF THE ERUPTION
I,
FIG. 1. CLINICAL APPEARANCE
I. ON THE
a
C C
H H
H
a
H U)
z
C H
z
H
0
H
CUTANEOUS SARCOIDOSIS AS AN EXPRESSION OF SYPHILIS
77
but otherwise shows no important change. Giant cells are not seen. There is no granular degeneration. The microscopic diagnosis is sarcoid. (See Fig. 3)
Antisyphilitic treatment was institnted with penicillin and in four weeks a total dose of 11,300,000 units wore administered. Instantly the eruption began to melt away and by
the end of this course of therapy, nothing but very slight erythema and pigmentation could be seen.
'-
a
— -a,
—
•
t S
fr
V
,
C
4. Fm. 3. llIsToPATHoaooY OF THE ERUPTION DISCUSSION
It would appear from the voluminous literature and from the frequent discussions at medical meetings that not only is the cause of sarcoidosis a matter of continuous dispute, but the very concept of sarcoidosis as a clinico-pathologic picture is without unanimity. If it is permissible to enter the argument from the point of reference of this one case, we submit the following two propositions as possibilities: 1. Sarcoidosis is a disease entity, of unknown but unitary causation, and this case is not properly designated.ns one of sarcoidosis.
2. This proposition is essentially that advanced by J. Jadassohn and his school; namely that sarcoidosis is a fairly clear-cut clinical and even more clearcut histopathologic picture that may occur as a phase, or as an expression, of several infectious diseases and some non-infectious disease mechanisms. This case, then, is an illustration of cutaneous sarcoidosis (at least cutaneous so far as can be told) that was of syphilitic causation. Without detailing all the general evidence and without citing all the authorities, it seems to us that proposition 2. is the true state of affairs. In extension of
78
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
this opinion we would say that the classical clinical and histologic picture of sarcoidosis may appear in certain specifically acquired immunebiologic states of
the following diseases, viz., leprosy, tuberculosis, syphilis, leishmaniasis, the deep mycoses and perhaps some other granulomatous infectious diseases. In other words, sarcoidosis may be conceived as a leprid, a tuberculid, a syphilid, a mycid, etc., depending upon the initiating micro-organism. In contrast, the sarcoid tissue response is the natural reaction (i.e., not a specifically altered capacity to react, not an allergic transformation) of certain animals to certain micro-organisms in high doses of inoculation (e.g., the rat and mule with respect to the tubercle bacillus—W. Jadassohn and others). Finally, something like sarcoidosis is the common tissue response to certain inert substances like silica, beryllium and other materials of similar quality.
Correlating the latter two events (sarcoid responses to inert substances and the "nuller" phenomenon*) with the former (sarcoid response as a specifically acquired immunebiologic event), we suggest that diseases like leprosy, tuberculosis, syphilis, etc., sometimes produce immunebiologic states of such quality that their causative organisms are thereby converted into, or are treated like, foreign bodies with resultant sarcoid tissue responses. The more common immunebiologic states developed in these diseases are the hypersensitive varieties
that are characterized by rapid fulminating, necrotizing and amputating responses. The acquired sarcoid response is less common, is torpid, noncaseating and infiltrative. We think it probable too that the several diseases have different rates of ability to engender immunebiologic states of sarcoid quality. We imagine
that leprosy develops them most frequently, tuberculosis fairly frequently, syphilis and the deep mycoses less readily. If this is correct, then where both leprosy and tuberculosis are equally common, more cases of sarcoidosis will be of leprous origin; where tuberculosis is common and leprosy rare, most cases of sarcoidosis will be of tubercle bacillus causation; everywhere syphilis and the deep mycoses will be rare and but occasional causes of sarcoidosis because, no matter how great their prevalence, their incidence of production of the proper immunebiologic state for sarcoidosis is inherently very small. In those parts of the world where tuberculosis is common, there are many who are reluctant to consider sarcoidosis as of tuberculous causation even as a working hypothesis. The main arguments for this position are that the condition does
not look nor behave like known forms of tuberculosis, and that the tubercie bacillus has not been demonstrated in it unequivocally or regularly. It is usually futile to counter-argue that upon such desiderata most visceral and central nervous system syphilis could not be proved to be syphilitic. Antagonists of the tuberculous theory of sarcoid causation end with the relatively barren position that sarcoidosis is probably an infection and that the organism is unknown. While this may sadly be the true situation, we have one further consideration against it. No one has much objection to accepting an occasional case of sarcoidosis as being of leprous origin or as a rare syphilitic or mycotic expression, *
The clinically indifferent response of certain hosts to ordinarily highly virulent pathogens.
CUTANEOUS SARCOIDOSIS AS AN EXPRESSION OF SYPHILIS
79
but there is vast prejudice against admitting even one case to be caused by the tubercie bacillus. If it is granted that occasional cases may be tuberculous, then where are such cases? In our view they are the run of the mill cases one sees hereabout. SUMMARY
1. A case is described which fulfilled clinical and histologic criteria for sarcoidosis and was of syphilitic causation. 2. This report is submitted to call attention to an adjuvant measure for differ-
ential diagnosis and investigation of mechanism, namely the use of B.C.G. inoculation for differential diagnostic purposes, as introduced by Lemming and Leider and Sulzberger. This procedure as well as the quantitative tuberculin testing of J. Jadassohn proved valuable in supporting the other evidence of the syphilitic causation of the lesions, e.g. the history and course, the serologic reactions and the therapeutic test with penicillin. 3. In connection with these findings the various concepts of the causation of sarcoidosis and its pathogenesis are discussed once again. The new evidence is shown to strongly support J. Jadassohn's conceptions of tuberculous, leprous, syphilitic and other causes of sarcoid lesions.
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.
EUGENE TRAUGOTT BERNSTEIN, M.D. AND MORRIS LEIDER, M.D.
The following case is reported as an instance of an eruption which was clinically and histologically compatible with the diagnosis of Boeck's sarcoid but which proved to be of syphilitic origin. The implications of this situation are important and will be discussed. CASE REPORT
M. M., aged 33 years, white, female, a housewife, contracted syphilis 18 years ago (at 15 years of age) and received an intensive course of antisyphilitic treatment at that time. Thirteen years ago (at 20 years of age) she suffered an episode of pleurisy with effusion. Follow-up examinations with x—rays were negative for tuberculosis. Serologic examinations for syphilis were negative up to the date of recent history. One and one half years
ago an eruption appeared on the right arm. In the course of time this eruption spread and appeared on the other arm and on the trunk. Physical examination at the start of this observation revealed no significant pathology except the dermatosis and discrete lymphadenopathy in the cervical and axillary regions. The skin showed an extensive papulo-nodular, erythematous and violaceous eruption distributed over the arms and trunk. The right side was more involved than the left. The individual lesions, which were either pea sized papules or bean sized nodules, grouped themselves in circinate or serpiginous arrangements. (See Figs. 1 and 2) The laboratory findings were as follows.: Serologic tests for syphilis: Wasserman: 4 plus Kline: 4 plus Blood Count: Normal limits Urinalysis: Negative X-ray of the Chest: Negative Tuberculin Tests (intracutaneous, quantitative, with Old Tuberculin Koch): 1:1,000,000: one plus 1:100,000: one to two
plus
1:10,000: two to three plus
BCG vaccination (diagnostic):
Visible reaction
within 24—48 hours, proceeding rapidly through stages of erythema,
pustulation, ulceration and scar-healing. Biopsy of a lesion (interpreted by Dr. Wilbert Sachs): Throughout the mid and upper cutis there are numerous epithelioid cells arranged in tubercle formation. The surrounding blood vessels are dilated and about them is a moderate small round cell infiltration. The overlying epidermis is slightly acanthotic papulovesiculation,
* Presented before the Section of Dermatology and Sypbilology of the New York Acad emy of Medicine in March and April 1949.
t This procedure, originally suggested by Lemming (Acta Med. Scandinav., 103: 400, 1940, and 110: 151, 1942) has been developed and extended by Leider, M. and Sulzberger, Marion B. (J. Invest. Dermat., 13: 249, Nov. 1949) as a means of analysing tuberculin reactivity. Received for publication January 17, 1950. 75
OF THE ERUPTION ON THE ARM.
TRUNK.
FIG. 2. CLINICAL APPEARANCE OF THE ERUPTION
I,
FIG. 1. CLINICAL APPEARANCE
I. ON THE
a
C C
H H
H
a
H U)
z
C H
z
H
0
H
CUTANEOUS SARCOIDOSIS AS AN EXPRESSION OF SYPHILIS
77
but otherwise shows no important change. Giant cells are not seen. There is no granular degeneration. The microscopic diagnosis is sarcoid. (See Fig. 3)
Antisyphilitic treatment was institnted with penicillin and in four weeks a total dose of 11,300,000 units wore administered. Instantly the eruption began to melt away and by
the end of this course of therapy, nothing but very slight erythema and pigmentation could be seen.
'-
a
— -a,
—
•
t S
fr
V
,
C
4. Fm. 3. llIsToPATHoaooY OF THE ERUPTION DISCUSSION
It would appear from the voluminous literature and from the frequent discussions at medical meetings that not only is the cause of sarcoidosis a matter of continuous dispute, but the very concept of sarcoidosis as a clinico-pathologic picture is without unanimity. If it is permissible to enter the argument from the point of reference of this one case, we submit the following two propositions as possibilities: 1. Sarcoidosis is a disease entity, of unknown but unitary causation, and this case is not properly designated.ns one of sarcoidosis.
2. This proposition is essentially that advanced by J. Jadassohn and his school; namely that sarcoidosis is a fairly clear-cut clinical and even more clearcut histopathologic picture that may occur as a phase, or as an expression, of several infectious diseases and some non-infectious disease mechanisms. This case, then, is an illustration of cutaneous sarcoidosis (at least cutaneous so far as can be told) that was of syphilitic causation. Without detailing all the general evidence and without citing all the authorities, it seems to us that proposition 2. is the true state of affairs. In extension of
78
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
this opinion we would say that the classical clinical and histologic picture of sarcoidosis may appear in certain specifically acquired immunebiologic states of
the following diseases, viz., leprosy, tuberculosis, syphilis, leishmaniasis, the deep mycoses and perhaps some other granulomatous infectious diseases. In other words, sarcoidosis may be conceived as a leprid, a tuberculid, a syphilid, a mycid, etc., depending upon the initiating micro-organism. In contrast, the sarcoid tissue response is the natural reaction (i.e., not a specifically altered capacity to react, not an allergic transformation) of certain animals to certain micro-organisms in high doses of inoculation (e.g., the rat and mule with respect to the tubercle bacillus—W. Jadassohn and others). Finally, something like sarcoidosis is the common tissue response to certain inert substances like silica, beryllium and other materials of similar quality.
Correlating the latter two events (sarcoid responses to inert substances and the "nuller" phenomenon*) with the former (sarcoid response as a specifically acquired immunebiologic event), we suggest that diseases like leprosy, tuberculosis, syphilis, etc., sometimes produce immunebiologic states of such quality that their causative organisms are thereby converted into, or are treated like, foreign bodies with resultant sarcoid tissue responses. The more common immunebiologic states developed in these diseases are the hypersensitive varieties
that are characterized by rapid fulminating, necrotizing and amputating responses. The acquired sarcoid response is less common, is torpid, noncaseating and infiltrative. We think it probable too that the several diseases have different rates of ability to engender immunebiologic states of sarcoid quality. We imagine
that leprosy develops them most frequently, tuberculosis fairly frequently, syphilis and the deep mycoses less readily. If this is correct, then where both leprosy and tuberculosis are equally common, more cases of sarcoidosis will be of leprous origin; where tuberculosis is common and leprosy rare, most cases of sarcoidosis will be of tubercle bacillus causation; everywhere syphilis and the deep mycoses will be rare and but occasional causes of sarcoidosis because, no matter how great their prevalence, their incidence of production of the proper immunebiologic state for sarcoidosis is inherently very small. In those parts of the world where tuberculosis is common, there are many who are reluctant to consider sarcoidosis as of tuberculous causation even as a working hypothesis. The main arguments for this position are that the condition does
not look nor behave like known forms of tuberculosis, and that the tubercie bacillus has not been demonstrated in it unequivocally or regularly. It is usually futile to counter-argue that upon such desiderata most visceral and central nervous system syphilis could not be proved to be syphilitic. Antagonists of the tuberculous theory of sarcoid causation end with the relatively barren position that sarcoidosis is probably an infection and that the organism is unknown. While this may sadly be the true situation, we have one further consideration against it. No one has much objection to accepting an occasional case of sarcoidosis as being of leprous origin or as a rare syphilitic or mycotic expression, *
The clinically indifferent response of certain hosts to ordinarily highly virulent pathogens.
CUTANEOUS SARCOIDOSIS AS AN EXPRESSION OF SYPHILIS
79
but there is vast prejudice against admitting even one case to be caused by the tubercie bacillus. If it is granted that occasional cases may be tuberculous, then where are such cases? In our view they are the run of the mill cases one sees hereabout. SUMMARY
1. A case is described which fulfilled clinical and histologic criteria for sarcoidosis and was of syphilitic causation. 2. This report is submitted to call attention to an adjuvant measure for differ-
ential diagnosis and investigation of mechanism, namely the use of B.C.G. inoculation for differential diagnostic purposes, as introduced by Lemming and Leider and Sulzberger. This procedure as well as the quantitative tuberculin testing of J. Jadassohn proved valuable in supporting the other evidence of the syphilitic causation of the lesions, e.g. the history and course, the serologic reactions and the therapeutic test with penicillin. 3. In connection with these findings the various concepts of the causation of sarcoidosis and its pathogenesis are discussed once again. The new evidence is shown to strongly support J. Jadassohn's conceptions of tuberculous, leprous, syphilitic and other causes of sarcoid lesions.
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.