0013-7227/87/1203-1027$02.00/0 Endocrinology Copyright, (c) 1987 by The Endocrine Society
Vol. 120, No. 3 Printed in U.S.A.
Cyclic Hormonogenesis in Gray Collie Dogs: Interactions of Hematopoietic and Endocrine Systems* CLINTON D. LOTHROP, JR., P. A. COULSON, H. LYNN NOLAN, BARBARA COLE, J. B. JONES, AND W. L. SANDERS University of Tennessee College of Veterinary Medicine (C.D.L., H.L.N., B.C., J.B.J.), and the Agricultural Experiment Station, University of Tennessee (W.L.S.), Knoxville, Tennessee 37901; and the Tennessee Endocrine Reference Laboratory (P.A.C.), Maryville, Tennessee 37801
ABSTRACT. Cortisol, ACTH, T4, and T3 concentrations were determined in six cyclic hematopoietic (CH) dogs to determine if hormonal cycles were a feature of this hematopoietic disorder. It was determined that there were 12- to 14-day cycles of these hormones in CH dogs. Plasma cortisol and ACTH concentrations peaked 4-8 days after the onset of neutropenia and were concurrent with peak neutrophil counts. The peak ACTH concentration occurred 1-2 days before or concurrent with the cortisol peak concentration. T4 and T3 peak concentrations were opposite the cortisol cycles, and maximal concentrations were seen when cortisol levels were lowest.
C
ANINE cyclic hematopoiesis (CH) was first described as a model of human cyclic neutropenia in 1967 (1). Alternating peripheral blood cell numbers with apparently normal cellular function is characteristic of both human cyclic neutropenia and canine CH (1, 2). Since canine CH was first described, bone marrow transplantation studies (3-5) and in vitro cell culture studies (6-8) have indicated that cyclic hematopoiesis is almost certainly a disease of the most primitive hematopoietic stem cell and, thus, affects all hematopoietic cell lineages. Clinical symptoms in affected dogs include fever, gingivitis, diarrhea, respiratory infections, lymphadenitis, lameness, and mild but abnormal hemorrhagic episodes. Clinical disease in most CH dogs occurs during or after the periodic (12- to 13-day periodicity) neutropenic episodes and is most severe during the postweaning period (9). Without supportive clinical treatment, most dogs die before adulthood. Even with optimal medical care, most dogs die before 2 yr of age due to hepatic and/or renal failure associated with severe amyloidosis (10). Secondary amyloidosis has also been documented in human Received June 4, 1986. Address requests for reprints to: Clinton D. Lothrop, Jr., DVM, Ph.D., Department of Environmental Practice, University of Tennessee College of Veterinary Medicine, P.O. Box 1071, Knoxville, Tennessee 37901. * This work was supported by NIH Grant HL-15647-13.
ACTH, GH-releasing factor and TRH response tests were performed in the CH dogs. No frank deficiencies in hormone production were seen with the ACTH, GH-releasing factor, and TRH responses in CH dogs relative to those in normal dogs. It was concluded that cyclic hormonogenesis is a central feature of CH disease. These findings are the first demonstration of extrahematopoietic system cyclicity in this rare disease and suggest the presence of common regulatory factors in the hematopoietic and endocrine systems. (Endocrinology 120: 10271032, 1987)
patients with cyclic neutropenia (11). For unknown reasons, CH in collie dogs is always associated with a diluted coat color, hence the term gray collie syndrome. Melanocytes are apparently present in normal numbers in gray collies, but with probable decreased function (12). It is not known if melanocytes cycle like hematopoietic cells. The cycles of neutropenia are accompanied by almost concurrent cycles of thrombocytosis and reticulocytosis and are closely followed by a marked monocytosis. Bone marrow cytology has shown an alternating erythroidmyeloid pattern compatible with the peripheral cell changes (13, 14). Accumulated data indicate that blood cell formation stops and starts in CH dogs, but the mechanism for this switch is not known. Recent work on characterization of CH platelet aggregation responses to hormonal agonists suggests that a defect may exist in a second messenger pathway of signal transduction (15). Actively dividing hematopoietic cells and endocrine cells are dependent on second messenger pathways using adenylate cyclase and phospholipase C for appropriate activation or inhibition by signal molecules. In a marrow transplantation study of CH dogs, erythropoietin (EPO) was found to cycle in a normal dog made cyclic with marrow cells transplanted from a CH dog (16). This peculiar, apparently marrow-mediated cycle 1027
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CANINE CYCLIC HORMONOGENESIS
of EPO remains unexplained. The fact that the hormone EPO cycled in synchrony with the cycles of hematopoiesis together with an observation that three CH dogs died after treatment with corticosteroids (17) raised the possibility that other hormonal systems might be altered in the CH dog. Plasma cortisol, ACTH, serum T 4 and T 3 concentrations were measured in normal and CH dogs to determine if there were extra hematopoietic cycles of hormones in this rare disease. It was determined that CH dogs had hormonal cycles with an approximate 14day periodicity. We have hypothesized that the hormonal cycles in CH disease are inherent to the CH trait and may demonstrate a nonhematopoietic cellular defect in this rare genetic disease.
Materials and Methods Hormone quantifications on CH dogs in this study were made on six different dogs (three females and three males) over a period of 1.5 yr. The CH dogs used in these studies were of at least two separate parentages. The colony management has been previously described (8). All dogs were housed in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care. All studies were conducted on dogs in apparent good health and free of intercurrent infections. Normal control dogs were mongrels obtained from local municipal pounds. They were vaccinated for common infectious diseases, treated for parasites, and observed for 30 days before their use in these studies. Blood samples were collected by jugular venipuncture between 0800 and 1000 h each day of a study. Plasma or serum for hormone quantification was prepared within 45 min of collection and kept at —70 C until assayed. The CH dogs' cycles of neutropenia were constantly monitored with daily total and differential leukocyte counts. The first day (day 1) of the recurrent (13 ± 1 days) cycles of neutropenia was designated as the first day the absolute neutrophil count fell below 1600 mm3. Each of the subsequent 1213 days of the cycle were numbered consecutively. Materials Cortisol, T4, and T 3 RIA radioimmunoassay kits were purchased from a commercial manufactor (Clinical Assays, Inc, Cambridge, MA), as were the ACTH and aldosterone RIA kits (Radioassay Systems Laboratories, Carson, CA). The validity of these particular assays for canine hormone quantification has been previously established (18, 19) (Golden, D. L., and C. D. Lothrop, submitted). All RIA procedures were carried out as suggested by the manufacturer. Reagents for homologous canine GH assay were prepared by Arthur Parlow and donated through the National Hormone and Pituitary Program. Synthetic ACTH (Cortrosyn) was obtained from Organon (West Orange, NJ). Human GH-releasing factor (GRF) was purchased from Peninsula Laboratories (Belmont, CA), and TRH was obtained from Sigma (St. Louis, MO).
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ACTH stimulation test A fasting blood sample for resting cortisol and aldosterone determinations was obtained, and ACTH (0.5 IU/kg) was administered iv. One hour later, post-ACTH stimulation samples were obtained for cortisol and aldosterone determinations. GRF stimulation test Fasting blood samples for resting GH determination were obtained, and GRF (1 Mg/kg) was administered iv. Serial blood samples were collected 15, 30, 45, 60, and 120 min later for determination of GRF effects on serum GH concentrations. TRH stimulation test The TRH stimulation tests were performed essentially as previously described using 1 mg TRH as a stimulus (19). The serum T4 response to TRH rather than to TSH was determined due to the lack of a sensitive assay for canine TSH. Statistical methods To ascertain the relationship between hematopoietic cortisol and time, under the hypothesis (h0) of a cyclic relationship, a Fourier series with two harmonics was fitted on an individual dog basis for each of the six CH dogs and one normal animal. The mathematical model which was fitted was: Yy = u + bj [sin (c*day)] + b2 [cos (c*day)] + b3 [2*sin (c*day)] + b4 [2*cos (cday)] «„ where, Y;J is the natural log of cortisol; bj, b2, b3, and b4, are regression coefficients to be estimated from the data; c is the cycle frequency constant; and etj is the random error. These analyses were completed via PROC NLIN in SAS. PROC NLIN was chosen because the model with the cycle frequency constant included is intrinsically nonlinear, and models of this type can be fitted with reasonable ease in PROC NLIN.
Results A typical example of cyclic fluctuation of neutrophils and monocytes by a CH dog is illustrated in Fig. 1A. The episodes of neutropenia are closely associated with periods of thrombocytosis and reticulocytosis, which occur near the onset of neutropenia. The neutropenic periods are followed by a relative monocytosis. The lifelong cycles repeat with a periodicity of 11-14 days. Daily plasma cortisol and ACTH concentrations as well as serum T4 and T 3 concentrations were determined in six CH dogs and two normal dogs for a period of 30 days. The six CH dogs exhibited remarkably similar results, and a typical example of one dog is shown in Figs. IB and 2. Absolute plasma cortisol concentrations were not significantly different from cortisol concentrations in normal dogs (15-60 ng/ml). However, cyclic variations of cortisol within the normal range were evi-
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1029
CANINE CYCLIC HORMONOGENESIS ACTH
Neutrophil and Monocyte Cycles
O)
a 30-
11
13 1
3
1 3 5
S
7 9 1 1 1 3
1
3
5 7
9 1 1 1 3
1
3
Cycle Days
Cycle Days
Triiodothyronine .9-
Cortisol 40-
.8-
I 30-
.6-
O)
I
CH-232
.7-
1-
20
O)
o
S -4-
o
10.21
3
5
7
9 11 13 1 3 5 Cycle Days
7
9 11 13 1
3 5
FIG. 1. A, CH in a dog homozygous for the CH gene. Total and differential cell counts were performed as described in the text. The first day the absolute neutrophil count fell below 1600 mm3 was designated day 1 of the cycle. B, Cortisol cycles in a dog (CH-232) homozygous for the CH trait. Sample collection and hormone quantification were as described in the text.
.1-
B 3
5
7 9 11 13 1 3 5 7 Cycle Days
9 11 13 1
Thyroxine 40-i 30-
dent (Fig. IB). The peak cortisol concentrations occurred at midcycle (cycle days 4-8) when normal numbers of neutrophils were present. In the five other CH dogs, cortisol cycles were remarkably similar to that graphed (Fig. IB), with the peak cortisol concentrations also occurring at midcycle (data not shown). To determine if the apparent cortisol cycles were statistically significant, we evaluated cortisol using a Fourier series with two harmonics as described above. The ho: (bi = b2 = b 3 = b4 = 0) was tested and rejected for all CH dogs. However, the same hypothesis could not be rejected for the normal dog. This suggests that all CH dogs were indeed cycling while the control dog was not. Estimates of c for each of the dogs suggest that most CH dogs were cycling with a periodicity of 10-14 days. Plasma ACTH concentrations were also cyclic in CH dogs and are illustrated for one dog in Fig. 2A. The peak ACTH concentration was found to precede the peak cortisol concentration by 1 or 2 days or was concurrent with the peak cortisol concentration in each of the six
3 5
CH-232
2 20£ 10i
i
i
i
i
1 3 5 7 9
i
11 13 1 3 5 Cycle Days
79
11 13 1
35
FlG. 2. Cyclic hormonogenesis in a dog (CH-232) homozygous for the CH gene. Sample collection and hormone quantification were as described in the text. A, ACTH (picograms per ml); B, T3 (nanograms per ml); C, T4 (nanograms per ml). T4 concentrations for a normal dog simultaneously sampled are shown for comparison.
CH dogs tested. Serum T 3 and T4 concentrations are summarized in Fig. 2, B and C. The cycles of T 3 and T4 were not concurrent with the cycles of cortisol and ACTH. In fact, the peak T 3 and T4 concentrations were inversely related to the cortisol concentration and occurred at the cortisol nadir in this dog and the five other CH dogs (data not shown).
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CANINE CYCLIC HORMONOGENESIS
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ACTH stimulation test To determine if abnormalities in adrenal function other than cyclic hormonogenesis were associated with CH disease, serum aldosterone and plasma cortisol concentrations were measured before and after ACTH stimulation (Table 1). Cortisol and aldosterone concentrations in the CH dogs, both before and after ACTH stimulation, were not different from those in the normal control dogs. GRF response test Serum GH concentrations were determined before administration of human GRF (1 /*g/kg) in three CH and six normal dogs (Table 2). Basal and post-GRF GH concentrations were similar in both groups of dogs. TRH response test The serum T4 response to TRH administration was determined for five CH dogs. In each dog, the TRH response test was performed twice on different days of the cycle (Table 3). Although the T4 response seemed to vary slightly among those dogs tested, there were no obvious deficiencies in T4 response to TRH administration, and there was no obvious correlation between T4 response and cycle day. Discussion Cyclic hormonogenesis is apparently a feature of the CH trait and must be added to the list of previously documented features of CH disease, such as cyclic hematopoiesis, coat color dilution, and platelet aggregation defects. The cycles of ACTH preceded, by 1-2 days, the cycles of cortisol or were concurrent with the cycles of cortisol, suggesting that the cortisol cycles may be secondary to ACTH cycles. It is unlikely the ACTH and cortisol cycles were solely a systemic response to the stress of the neutropenic episodes, because the peak ACTH and cortisol concentrations occurred concomitantly with the peak neutrophil counts (cycle days 4-8). Peak cortisol values were found during cycle days 4-8 when the CH dogs were most healthy and least stressed and, therefore, least
Endo«1987 Vo! 120-No 3
likely to have a stress-induced release of ACTH and cortisol. The nadir of the cortisol cycles was associated with peak T4 and T 3 concentrations. It is not known if the T4 and T 3 cycles are secondary to the cortisol cycles or occur independent of the cortisol cycle. Since glucocorticoids are known to exert an inhibitory effect on pituitary TSH release in man and dogs, it is possible the T4 and T 3 cycles might be secondary to cortisol cycles (20-24) (Lothrop, C. D., submitted). The cycles graphed in Figs. IB and 2 could be related to cyclic fluctuations in the clearance of cortisol, T3, T4, and ACTH, since our data reflect the presence but not the actual production of these hormones. This seems highly unlikely because circulatory lifespans for these molecules are universally short, and the observed cycles were 13 ± 1 days in length for each of the hormones. It is not known if alterations exist in the pituitary-gonadal axis in CH dogs. Healthy male and female CH dogs are fertile, but females have an increased incidence of fetal loss and abortion. The basic genetic defect in CH has yet to be identified. Recent studies with platelets from CH dogs suggest a basic defect in the second messenger pathways mediating activation of phospholipase C by platelet agonists (15, 25). Since the second messenger pathways of cell activation are similar in most cells, including platelets and endocrine cells, the cyclic hormonogenesis phenomena noted in the CH dog may indicate that a defect exists in the second messenger pathways of endocrine organ cells as well as the hematopoietic cells. In platelets, the cAMP second messenger pathway is inhibitory to platelet activation, while the diacylglycerol and Ca2+ pathways are stimulatory (26, 27). In pituitary, thyroid, and adrenal cells, both pathways are stimulatory and result in increased hormone production (26-28). Since both pathways are stimulatory in most endocrine cells, except perhaps parathyroid cells, this may explain the normal ACTH, GRF, and TRH stimulation tests while platelet responses to agonists are defective. Bone marrow transplantation between normal and CH dogs demonstrated that the hematopoietic aspects of this disease could be corrected by transplantation and that cyclic hematopoiesis could be induced by transplanting CH bone marrow in normal dogs (5). If the hormonal
TABLE 1. Cortisol and aldosterone concentrations before (Pre) and after (Post) ACTH stimulation in normal and CH dogs Hormone cone. Experimental classification CH (n = 3) Normal (n = 7)
Cortisol (ng/ml)
Aldosterone (ng/dl)
Pre
Post
Pre
Post
13.0 ± 2.3 11.6 ± 2.6
88.3 ± 14.4 72.5 ± 6.4
21.7 ± 5.5 20.3 ± 7.1
51.9 ±9.5 39.7 ±9.4
Sample collection and the ACTH response test were performed as described in the text. There was no significant (P > 0.05) difference between normal and CH dogs, as determined with Student's t test. The results are presented as the mean ± SD.
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CANINE CYCLIC HORMONOGENESIS
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TABLE 2. Serum GH concentrations before and after GRF stimulation in normal and CH dogs GH (ng/ml): Time after GRF (min)
Pre-GRF Normal (n = 6) CH (n == 3)
4.0 ± 3.4 6.2 ± 2.5
15
30
45
60
16.6 ± 11.6 14.2 ± 7.0
11.2 ± 9.8 13.2 ± 9.3
11.4 ± 8.4 7.0 ± 2.7
6.7 ± 3.5 5.1 ± 2.5
Sample collection and the GRF response test were performed as described in the text. There was no significant (P > 0.05) difference between normal and CH dogs, as determined with Student's t test. The results are presented as the mean ± SD. TABLE 3. Serum T4 response to TRH stimulation in CH dogs T4 (ng/ml) Dog
Cycle day
1
3 11 2 8 9 6 10 2 10
2
3 4 5
Normal range
Pre 10 17 11 16 26 20 14
15.5 26
10-40
endocrine neoplasias (33). Genetically induced cyclic hormonogenesis offers a new experimental approach to the study of endocrine regulation and disease.
Post-TRH 27 27 24 22 24 21 19 36 33
150% prestimulation T4 cone.
Sample collection and TRH response testing were performed as described in the text.
cycles noted in the current study occur secondary to bone marrow cell proliferation cycles, it is likely that marrow transplantation would correct or induce hormonal cycles. Recently, Woloski et al. (30) demonstrated that activated monocytes secrete monokines with corticotropin-releasing activity. Therefore, it is possible that the cycles of ACTH and cortisol result from increase monocyte elaboration of these hormones during the monocytotic episodes of the cycle. Alternatively, it is possible that a defect exists in a second messenger pathway common to to many cells in the CH dog and that CH and cyclic hormonogenesis result from a common cellular lesion in different cells. It is impossible to differentiate between these alternative explanations for the hormonal cycles based on our current data, but bone marrow transplantation experiments should help to answer these questions. These data, documenting cyclic fluctuations of cortisol, ACTH, and thyroid hormones that were synchronous with the cycles of hematopoiesis, emphasize important new aspects of this disease. It now seems likely that the basic defect in CH is expressed in cells other than hematopoietic cells and is much more general in nature than previously realized. An understanding of the basic mechanism of cyclic hormonogenesis in CH may provide insight in understanding the pathogenesis of rare endocrine disorders such as cyclic Cushing's syndrome (31, 32) and multiple
References 1. Lund JE, Padgett GA, Ott RL 1967 Cyclic neutropenia in grey collie dogs. Blood 29:452 2. Page A, Good RA 1957 Studies on cyclic neutropenia: a clinical and experimental investigation. Am J Dis Child 94:623 3. Dale DC, Gray RG 1974 Transplantation of allogeneic bone marrow in canine cyclic neutropenia. Science 183:83 4. Weiden PL, Robinett B, Graham TC, Adamson JW, Storb R 1974 Canine cyclic neutropenia. A stem cell defect. J Clin Invest 53:950 5. Jones JB, Yang TJ, Dale JB, Lange RD 1975 Canine cyclic hematopoiesis: marrow transplantation between littermates. Br J Haematol 30:215 6. Dunn CDR, Jolly JD, Jones JB, Lange RD 1978 Erythroid colony formation in vitro from the marrow of dogs with cyclic hematopoiesis: interrelationship of progenitor cells. Exp Hematol 6:701 7. Dunn CDR, Jones JB, Jolly JD, Lange RD 1978 Cell proliferation of canine cyclic hematopoietic marrow in diffusion chambers. Proc Soc Exp Biol Med 158:50 8. Dunn CDR, Jones JB, Jolly JD, Lange RD 1977 Progenitor cells in canine cyclic hematopoiesis. Blood 50:1111 9. Jones JB, Lange RD, Jones ES 1975 Cyclic hematopoiesis in a colony of dogs affected with cyclic neutropenia. J Am Vet Med Assoc 166:365 10. Gregory R, Machado EA, Jones JB 1977 Animal model: amyloidosis associated with canine cyclic hematopoiesis in the gray collie dog. Am J Pathol 87:721 11. Lange RD, Crowder CG, Cruz P, Hawkinson SW, Lozzio CB, Machado E, Painter P, Terry W, Jones JB 1983 Cyclic neutropenia: a tale of two brothers and their family. Am J Pedjatr Hematol Oncol 3:127 12. Lund JE, Barkman D 1974 Color dilution in the gray collie. Am J Vet Res 35:265 13. Scott R, Dale D, Rosenthal A, Wolff S 1973 Cyclic neutropenia in grey collie dogs. Ultrastructural evidence for abnormal neutrophil granulopoiesis. Lab Invest 28:514 14. Machado EA, Jones JB, Aggio MC, Chernoff AI, Maxwell PA, Lange RD 1981 Ultrastructural changes of bone marrow in canine cyclic hematopoiesis (CH dog). Virchows Arch 390:93 15. Lothrop CD, Candler RV, Nolan HL, Jones JB 1985 Characterization of platelet aggregation defects in canine cyclic hematopoiesis: evidence for a defect in a common pathway of platelet aggregation. Blood 66:309 (Abstract) 16. Jones JB, Lange RD, Yange TJ, Vodopick H 1975 Canine cyclic neutropenia: erythropoietin and platelet cycles after bone marrow transplantation. Blood 45:213 17. Jones JB, Lange RD 1983 Cyclic hematopoiesis animal models. Exp Hematol 11:571 18. Lothrop CD, Oliver JW 1984 Diagnosis of canine Cushing's syndrome based on multiple steroid analysis and dexamethasone turnover kinetics. Am J Vet Res 45:2304 19. Lothrop CD, Tamas PM, Fadok VK 1984 Canine and feline thyroid function assessment with the thyrotropin-releasing hormone response test. Am J Vet Res 45:2310 20. Wilbur JF, Utiger RD 1969 The effect of glucocorticoids on thy-
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rotropin secretion. J Clin Invest 48:2096 21. Otsuki M, Dakoda M, Baba S 1973 Influence of glucocorticoids on TRF-induced TSH response in man. J Clin Endocrinol Metab 36:95 22. Wartofsky L, Burman KD 1982 Alterations in thyroid function in patients with systemic illness: "the euthyroid sick syndrome." Endocr Rev 3:164 23. Woltz HH, Thompson FN, Kemppainen RJ, Munnell SF, Lorenz MD 1983 Effect of prednisone on thyroid gland morphology and plasma thyroxine and triiodothyronine concentrations in the dog. Am J Vet Res 44:2000 24. Peterson ME, Ferguson DC, Kintzer PP, Drucker WD 1984 Effects of spontaneous hyperadrenocorticism on serum thyroid hormone concentrations in the dog. Am J Vet Res 45:2034 25. Lothrop CD, Candler RV, Nolan HL, Jones JB, Defective platelet activation by platelet activating factor in human and canine cyclic hematopoiesis. Sandoz Research Symposia, Hilton Head Island, SC, 1985, p 87 26. Nishizuka Y 1984 Turnover of inositol phospholipids and signal
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transduction. Science 225:1365 27. Nishizuka Y 1984 The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308:693 28. Farese RV 1983 Phosphoinositide metabolism and hormone action. Endocr Rev 4:78 29. Nishizuka Y, Takai Y, Kishimoto A, Kikkawa V, Kaibuchi K 1984 Phospholipid turnover in hormone secretion. Recent Prog Horm Res 40:301 30. Woloski BMRNJ, Smith EM, Meyer WJ, Fuller GM, Blalock JE 1985 Corticotropin-releasing activity of monokines. Science 230:1035 31. Sakiyama R, Ashcraft MW, Van Herle AJ 1984 Cyclic Cushing's syndrome. Am J Med 77:944 32. Atkinson AB, Chestnutt A, Crothers E, Woods R, Weaver AJ, Kennedy L, Sheridan B 1985 Cyclic Cushing's disease: two distinct rhythms in a patient with a basophil adenoma. J Clin Endocrinol Metab 60:328 33. Leshin M 1985 Multiple endocrine neoplasia. In: Wilson JD, Foster DW (eds) Textbook of Endocrinology. Saunders, Philadelphia, pp 1274-1289
International Meeting on Cell to Cell Communication in Endocrinology Basic and Clinical Aspects Firenze, Italy, October 8-9, 1987 An International Symposium on "Cell to Cell Communication in Endocrinology" will be held in Firenze, Italy in October 1987. The meeting will be planned by an International Scientific Committee formed by: D. Armstrong (CND), C. W. Bardin (USA), P. Franchimont (B), V. H. T. James (UK), H. Imura (J), M. Motta (Chairman) (I), P. Munson (USA), M. Serio (I), A. Tixier-Vidal (F). The program will include invited lecturers as well as sessions of free communications and of poster presentations on the following topics: Morphological Aspects, Functional Significance, Intercellular Messengers, Therapeutical Implications. For further information regarding the program, please contact the Scientific Secretaries. For registration, travel and logistic information, please contact the Organizing Secretariat: Scientific Secretaries: F. Piva, G. Forti Department of Endocrinology University of Milano Via A. Del Sarto, 21 20129-Milano, Italy tel. 02-7385351/2 Organizing Secretariat: ARES-Serono Symposia Via Ravenna, 8 Roma, Italy
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