811 different drug is
prescribed for a patient on antiepileptic drug is metabolised in the liver.
treat-
ment, especially if this E.M.
is an
LN.S.E.R.M. scientific research worker.
Centre Saint Paul, F 13009 Marseille, France, and
Neurological Teaching Hospital, Bordeaux
C. DRAVET E. MESDJIAN
B. CENRAUD J. ROGER
MELANOCYTE-STIMULATING-HORMONE LEVELS
cin. Perhaps the Black skin is more sensitive to the pigmentary action of the drug. The effect did not seem to be dependent upon ultraviolet light since skin which was not exposed to the sun was also involved. Serum from the first two patients was assayed for &bgr;-M.S.H.7 and K-M.s.H." activity by radioimmunoassay. M.S.H.-induced hyperpigmentation is associated with values greater than 100 ng/1, but concentrations of &bgr;-M.S.H. (47 and 10 ng/l, respectively) and a-M.S.H. (36 and 64 ng/1, respectively) were normal in both patients, as were plasma-cortisol and serum-electro-
lytes.
IN DOXORUBICIN-INDUCED HYPERPIGMENTATION
Our
SIR,-Longitudinal pigmented banding of the nails has been reported in patients receiving doxorubicin (’Adriamycin’).’ Cyclophosphamide and other chemotherapeutic agents produce a similar effect. 1-4 The pigment is presumed to be melanin, although the pathogenesis of the increased pigmentation has not been established. Melanin pigmentation of the nails occurs in hypoadrenalism,56 and it has been suggested that adriamycin may suppress hormone production by the adrenal gland, thereby causing excessive release of melanocytesumulating hormone (M.s.H.) by the pituitary gland.’ Assay of serum-M.s.H. activity in patients with adriamycin-induced hyperpigmentation may help to elucidate the cause of the pigmentary disturbance. We have cared for three Black women with histologically proven hepatocellular cancer all of whom developed hyperpigmentation of the skin and nails while
findings make it unlikely that increased secretion of by the pituitary is the cause of the pigmentary change and argue against the drug exerting a suppressive effect on adrenocortical hormone production. Normal M.S.H. levels also exclude the possibility that either hypoadrenalism secondary to adrenal destruction by metastases or ectopic production of M.S.H. by the liver cancer was responsible. Although it is conceivable that the tumours may have been secreting peptide fragments with M.S.H. activity which did not cross-react with either of the assays, the appearance of the hyperpigmentation after only the second injection of adriamycin and the fact that the pigment began to fade after stopping the drug do not support this possibility. Although the cause of adriamycin-induced hyperpigmentation has not been established, it seems to be independent of both M.S.H. activity and ultraviolet light. A direct effect of the drug on melanocytes seems likely. M.S.H.
Department
of
Medicine,
Johannesburg and Baragwanath Hospitals and University of the Witwatersrand, Johannesburg, South Africa
M. C. KEW DUME MZAMANE
Department of Dermatology, Royal Victoria Infirmary and University of Newcastle upon Tyne, Newcastle upon Tyne NE1 4LP
A. G. SMITH SAM SHUSTER
SPECIFIC CELL-MEDIATED IMMUNE DEFECT IN CONGENITAL CYTOMEGALOVIRUS INFECTION
SIR,-Infants with congenital cytomegalovirus (c.ns.v.) infection manifest clinical and virological evidence of infection for many months or years despite their ability to develop humoral antibodies to C.M. v.1This suggests an underlying cellmediated defect in the host’s immune response to the virus. We have studied the in-vitro lymphocyte proliferative response to concentrated, purified c.M.v. antigen in two patients with con-
Patchy increased pigmentation of the palm in case 2. A nonnatly pigmented palm (that of a Black nurse) is shown
tor
comparison.
in two of them serum levels of p and ex determined. The increased pigmentation, which was shown histologically to be due to melanin, appeared after the second injection of adriamycin (60 mg/m2 body-surface area intravenously) and increased until after the fourth (and final) injection. Thereafter it began to fade. The first patient died 2 months after the fourth injection and the second 3 weeks after the fourth injection. The third patient is alive 5 weeks after the last injection. One patient had increased pigmentation of the hands, feet, and face besides the nails while in the other two the nails and palms were pigmented (see figure), indicating a more widespread effect than has previously been reported with adriamy-
receiving adriamycin; M.s.H. were
1 Priestman, T J, James, K W. Br. med J 1975, i, 1337. Derm. 1972, 106, 765. 2 Inalsingh, Archs A 3 Solidoro, A., Saenz, R Cancer Chemother. 1966, 50, 265. 4 Markenson, A L., Chandra, M., Miller, D. R Lancet, 1975, ii, 128. 5 Bondy, P. K., Harwick, H J New Engl. J. Med. 1969, 281, 1056. 6. Bissell, G. W. J. Am med. Ass. 1971, 215, 1666.
genital c.M.V. c.M.v. (strain AD169) was grown in human diploid fibroblast (foreskin) cells, harvested from the extracellular fluid, and concentrated and purified by sucrose gradient and caesium-chloride gradient ultracentrifugation. The infectivity of the final preparation was approximately 10’’1 median tissueculture-infecting doses/0.1 ml. Mononuclear leucocytes from healthy control adult donors and patients with congenital c.M.v. were isolated by ’Ficoll-Hypaque’ density centrifugation and incubated with c.M.v. for 7 days at a cell concentration of 105 mononuclear cells per well in plastic microtitre plates. Cultures were done in triplicate. Response was determined by incorporation of tritiated thymidine into new D.N.A. in dividing lymphocytes. Peak responses for control lymphocytes were obtained at dilutions of 1/5
to
1/50 in all donors with
c.M.v.
immunofluor-
seronegative donor showed no response at any concentration of antigen. Two patients with congenital c.M.v. (a 3-month-old girl and a 4-year-old boy) were excreting virus when studied and had antibodies to c.M.v. (see table). No proliferative response was induced by c.M.v. in
escence
antibody titrs;
a
7. Thody, A.J., Plummer, N A. J Endocr. 1973, 58, 263 8. Thody, A. J., Penny, R. J., Clark, D, Taylor, C ibid. 1975, 67, 385. 1. Melish, M. E., Hanshaw, J. B. Am. J. Dis. Child. 1973, 126, 190.
812 IN-VITRO LYMPHOCYTE PROLIFERATION TO PURIFIED C.M.V.
ANTIGEN
CONCENTRATED,
PATIENTS OF BOTH GROUPS WITH SAME OUTCOME OF HEAD
IN PATIENTS WITH CONGENITAL C.M.V.
INJURY
AFTER
6
MONTHS
INFECTION AND HEALTHY CONTROLS
*Expressed as mean incorporation of tritiated thymidine in counts/min triplicate culture. measured by complement fixation only in this patient.
in
either
patient (table). Responses
to
phytohaemagglutinin, concommon antigens
canavalin-A, pokeweed mitogen, and several
normal in these children. Patients with congenital c.M.v. thus seem to have a selective defect in recognition of c.M.v. antigen. This may reflect immune tolerance resulting from antigenic challenge early in gestation when self-recognition may not yet be established. We have started treating these patients with dialysable transfer factor prepared from c.M.v.-responsive lymphocytes in an attempt to reverse this antigen-specific cell-mediated immune defect. were
This work was supported by the Research and Education Fund of St Paul Children’s Hospital, and U.S. Public Health Service research grants HL06314 and AM18883. St Paul Children’s Hospital, St Paul, Minnesota 55102, U.S.A.
University of Minnesota Health Minneapolis
Sciences
R. C. GEHRZ Center,
S. C. MARKER H. H. BALFOUR, JR
DIFFERENCE IN NEUROTRANSMITTER METABOLISM IN FRONTOTEMPORAL-LOBE CONTUSION AND DIFFUSE CEREBRAL CONTUSION
the control group, nor between group 1 and group 2. Levels of 5-H.I.A.A. of group 1 (20.6::1 4.9 ng/ml) are significantly decin comparison with the control group creased (p
prescribed for a patient on antiepileptic drug is metabolised in the liver.
treat-
ment, especially if this E.M.
is an
LN.S.E.R.M. scientific research worker.
Centre Saint Paul, F 13009 Marseille, France, and
Neurological Teaching Hospital, Bordeaux
C. DRAVET E. MESDJIAN
B. CENRAUD J. ROGER
MELANOCYTE-STIMULATING-HORMONE LEVELS
cin. Perhaps the Black skin is more sensitive to the pigmentary action of the drug. The effect did not seem to be dependent upon ultraviolet light since skin which was not exposed to the sun was also involved. Serum from the first two patients was assayed for &bgr;-M.S.H.7 and K-M.s.H." activity by radioimmunoassay. M.S.H.-induced hyperpigmentation is associated with values greater than 100 ng/1, but concentrations of &bgr;-M.S.H. (47 and 10 ng/l, respectively) and a-M.S.H. (36 and 64 ng/1, respectively) were normal in both patients, as were plasma-cortisol and serum-electro-
lytes.
IN DOXORUBICIN-INDUCED HYPERPIGMENTATION
Our
SIR,-Longitudinal pigmented banding of the nails has been reported in patients receiving doxorubicin (’Adriamycin’).’ Cyclophosphamide and other chemotherapeutic agents produce a similar effect. 1-4 The pigment is presumed to be melanin, although the pathogenesis of the increased pigmentation has not been established. Melanin pigmentation of the nails occurs in hypoadrenalism,56 and it has been suggested that adriamycin may suppress hormone production by the adrenal gland, thereby causing excessive release of melanocytesumulating hormone (M.s.H.) by the pituitary gland.’ Assay of serum-M.s.H. activity in patients with adriamycin-induced hyperpigmentation may help to elucidate the cause of the pigmentary disturbance. We have cared for three Black women with histologically proven hepatocellular cancer all of whom developed hyperpigmentation of the skin and nails while
findings make it unlikely that increased secretion of by the pituitary is the cause of the pigmentary change and argue against the drug exerting a suppressive effect on adrenocortical hormone production. Normal M.S.H. levels also exclude the possibility that either hypoadrenalism secondary to adrenal destruction by metastases or ectopic production of M.S.H. by the liver cancer was responsible. Although it is conceivable that the tumours may have been secreting peptide fragments with M.S.H. activity which did not cross-react with either of the assays, the appearance of the hyperpigmentation after only the second injection of adriamycin and the fact that the pigment began to fade after stopping the drug do not support this possibility. Although the cause of adriamycin-induced hyperpigmentation has not been established, it seems to be independent of both M.S.H. activity and ultraviolet light. A direct effect of the drug on melanocytes seems likely. M.S.H.
Department
of
Medicine,
Johannesburg and Baragwanath Hospitals and University of the Witwatersrand, Johannesburg, South Africa
M. C. KEW DUME MZAMANE
Department of Dermatology, Royal Victoria Infirmary and University of Newcastle upon Tyne, Newcastle upon Tyne NE1 4LP
A. G. SMITH SAM SHUSTER
SPECIFIC CELL-MEDIATED IMMUNE DEFECT IN CONGENITAL CYTOMEGALOVIRUS INFECTION
SIR,-Infants with congenital cytomegalovirus (c.ns.v.) infection manifest clinical and virological evidence of infection for many months or years despite their ability to develop humoral antibodies to C.M. v.1This suggests an underlying cellmediated defect in the host’s immune response to the virus. We have studied the in-vitro lymphocyte proliferative response to concentrated, purified c.M.v. antigen in two patients with con-
Patchy increased pigmentation of the palm in case 2. A nonnatly pigmented palm (that of a Black nurse) is shown
tor
comparison.
in two of them serum levels of p and ex determined. The increased pigmentation, which was shown histologically to be due to melanin, appeared after the second injection of adriamycin (60 mg/m2 body-surface area intravenously) and increased until after the fourth (and final) injection. Thereafter it began to fade. The first patient died 2 months after the fourth injection and the second 3 weeks after the fourth injection. The third patient is alive 5 weeks after the last injection. One patient had increased pigmentation of the hands, feet, and face besides the nails while in the other two the nails and palms were pigmented (see figure), indicating a more widespread effect than has previously been reported with adriamy-
receiving adriamycin; M.s.H. were
1 Priestman, T J, James, K W. Br. med J 1975, i, 1337. Derm. 1972, 106, 765. 2 Inalsingh, Archs A 3 Solidoro, A., Saenz, R Cancer Chemother. 1966, 50, 265. 4 Markenson, A L., Chandra, M., Miller, D. R Lancet, 1975, ii, 128. 5 Bondy, P. K., Harwick, H J New Engl. J. Med. 1969, 281, 1056. 6. Bissell, G. W. J. Am med. Ass. 1971, 215, 1666.
genital c.M.V. c.M.v. (strain AD169) was grown in human diploid fibroblast (foreskin) cells, harvested from the extracellular fluid, and concentrated and purified by sucrose gradient and caesium-chloride gradient ultracentrifugation. The infectivity of the final preparation was approximately 10’’1 median tissueculture-infecting doses/0.1 ml. Mononuclear leucocytes from healthy control adult donors and patients with congenital c.M.v. were isolated by ’Ficoll-Hypaque’ density centrifugation and incubated with c.M.v. for 7 days at a cell concentration of 105 mononuclear cells per well in plastic microtitre plates. Cultures were done in triplicate. Response was determined by incorporation of tritiated thymidine into new D.N.A. in dividing lymphocytes. Peak responses for control lymphocytes were obtained at dilutions of 1/5
to
1/50 in all donors with
c.M.v.
immunofluor-
seronegative donor showed no response at any concentration of antigen. Two patients with congenital c.M.v. (a 3-month-old girl and a 4-year-old boy) were excreting virus when studied and had antibodies to c.M.v. (see table). No proliferative response was induced by c.M.v. in
escence
antibody titrs;
a
7. Thody, A.J., Plummer, N A. J Endocr. 1973, 58, 263 8. Thody, A. J., Penny, R. J., Clark, D, Taylor, C ibid. 1975, 67, 385. 1. Melish, M. E., Hanshaw, J. B. Am. J. Dis. Child. 1973, 126, 190.
812 IN-VITRO LYMPHOCYTE PROLIFERATION TO PURIFIED C.M.V.
ANTIGEN
CONCENTRATED,
PATIENTS OF BOTH GROUPS WITH SAME OUTCOME OF HEAD
IN PATIENTS WITH CONGENITAL C.M.V.
INJURY
AFTER
6
MONTHS
INFECTION AND HEALTHY CONTROLS
*Expressed as mean incorporation of tritiated thymidine in counts/min triplicate culture. measured by complement fixation only in this patient.
in
either
patient (table). Responses
to
phytohaemagglutinin, concommon antigens
canavalin-A, pokeweed mitogen, and several
normal in these children. Patients with congenital c.M.v. thus seem to have a selective defect in recognition of c.M.v. antigen. This may reflect immune tolerance resulting from antigenic challenge early in gestation when self-recognition may not yet be established. We have started treating these patients with dialysable transfer factor prepared from c.M.v.-responsive lymphocytes in an attempt to reverse this antigen-specific cell-mediated immune defect. were
This work was supported by the Research and Education Fund of St Paul Children’s Hospital, and U.S. Public Health Service research grants HL06314 and AM18883. St Paul Children’s Hospital, St Paul, Minnesota 55102, U.S.A.
University of Minnesota Health Minneapolis
Sciences
R. C. GEHRZ Center,
S. C. MARKER H. H. BALFOUR, JR
DIFFERENCE IN NEUROTRANSMITTER METABOLISM IN FRONTOTEMPORAL-LOBE CONTUSION AND DIFFUSE CEREBRAL CONTUSION
the control group, nor between group 1 and group 2. Levels of 5-H.I.A.A. of group 1 (20.6::1 4.9 ng/ml) are significantly decin comparison with the control group creased (p
