333 is inherited as an autosomal dominant gene in these families. The 8 families could be separated into two distinct groups, one in which family members with bone fragility had normal teeth, the other in which family members with bone fragility had opalescent teeth, obliterated pulp cavities, and abnormally constricted coronal-radicular junctions. Among members of an individual family who had bone fragility, all had normal teeth or all had abnormal teeth. There was no relation within families between the severity of the bone disease, the degree of blueness of the sclerae, and the presence of dental abnormalities. These findings indicate that at least two autosomal dominant types of 0.1. exist. We suggest that "0.1. type i" be used when the teeth are normal and "0.1. type u" be used when the teeth are abnormal. It is not known whether these types of 0.1. are allelic disorders or are caused by mutations at different loci. The relationship between the "congenita" form of 0.1. and these two "tarda" forms is also unknown. The proposed classification is useful in clinical diagnosis, genetic counselling, and biochemical studies. o.t. in the children of an individual with 0.1. type ii who have opalescent deciduous teeth could be diagnosed before they have bone fractures. 0.1. in apparently normal individuals who have a child with o.i. type n may be found by looking at their dental abnormalities : abnormal teeth may occur in individuals who have not had fractures. Unless the different clinical types of 0.1. are recognised, studies of the basic biochemical defects in the disease may give confusing results. This investigation was supported in part by National Institutes of Health research career development award K04 DE 00021 (L.S.L.) and by biomedical research support grant 26010 FC 15 from National Institutes of Health to College of Dental Medicine, Medical University of South Carolina (C.F.S. and R.J.J.).
Departments of Otolaryngology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, U.S.A.
L. STEFAN LEVIN
Department of Oral Medicine, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina 29403, U.S.A.
CARLOS F. SALINAS RONALD J. JORGENSON
CYTARABINE AND LEUKÆMIA REMISSION
SIR,—Dr Raich* reported that, using cytarabine (cytosine arabinoside, ara-C), he could predict remission in patients not
receiving the drug. We have been measuring plasma ara-C concentrations by gas-liquid-chromatography/mass-spectroscopy. The concentration Raich used was 0.25 µg/ml, which is five to ten times higher than the concentration achieved in patients with constant intravenous infusion of 150 mg/24 h or 10-30 min after an intravenous bolus.2 Thus Raich’s results are unlikely to be closely related to the effect of the drug in vivo. Nevertheless, the results do suggest that failure to remit may be related to biochemical mechanisms of resistance to this concentration of ara-C. Ara-C is concentrated intracellularly in its active form, cytosine arabinoside triphosphate,3 which inhibits D.N.A. polymerase.4 At the intracellular concentrations that could be achieved by 0.25 µg/ml ara-C extracellularly, ara-C triphosphate may inhibit D.N.A. repair synthesis,’ and R.N.A. polymerase6 as well as being incorporated into D.N.A. and R.N.A.7 All the patients received at least one drug that may act at these sites. However, ara-C is deaminated to an inactive metabolite by
cytidine deaminase.8 Deamination in peripheral blasts does not correlate with remission,9 but Raich used bone-marrow. 48 h of incubation with 10’ cells could completely deaminate the amounts of ara-C present. It would have been helpful to know the ara-C concentrations at the end of the incubation since the variation in 3H-thymidine incorporation could have been due to this. Although it is important to know if ara-C catabolism is responsible for the results this would not explain the correlation with remission. One possibility would be that deamination would provide a source of deoxyuridine for use in the salvage D.N.A.
pathway.
M.R.C. Clinical
Pharmacology Unit, University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE
A.
L, HARRIS
RAISED URINARY PROSTAGLANDINS IN PATIENT WITHOUT BARTTER’S SYNDROME
SIR,—Patients with Bartter’s syndrome (both adults and have been reported to have increased urinary excretion of prostaglandins,1—4 though one of us’ has found enhanced excretion of P.G. E2 and P.G. F2&agr; consistently in children but never in adults. Enhanced urinary P.G. production is thought to be the primary determinant in Banter’s syndrome, but Dr M. B. Vallotton of Geneva has seen a case of relapse during indomethacin treatment (unpublished) and we have seen a patient with raised urinary P.G. excretion who did not have Bartter’s syndrome but whose laboratory findings resembled those seen in this syndrome. A 10-year-old boy had an episode of cyclic vomiting disease. He had been fasting and vomiting for 3 days before admission, resulting in a weight-loss of 2 kg (8% of body-weight). The child was conscious but very tired. His blood-pressure was 110/60 mm Hg, and his plasma electrolytes were low (sodium 114, potassium 1.8, chloride 63 mmol/l) and he had a metabolic alkalosis with a pH of 7.61 and a base excess of +9 mmol/l. Diuresis was 0.45 ml/h; urinary potassium 86 and sodium 23 mmola. His urinary aldosterone excretion was up to 48-55 µg in 24 h (normal below 15). Plasma-renin-activity (P.R.A.) (lying) was 35 ng/ml/h (normal 0.2-2). We observed a vascular resistance to angiotensin, tested by Kaplan’s method: an increased diastolic pressure of 20 mm Hg was not observed unless the rate of intravenous angiotensin infusion was raised to 46 ng/kg/min (normal below 15). Urinary. prostaglandin excretion was very high: p.G.Ez 799 ng in 24 h (normal range for a prepubertal child 37-171’) and r.u.F2« 3804 ng in 24 h (normal
children)
203-1028’). These biological disturbances,
except for the
hyponatrae-
mia, resembled those of Bartter’s syndrome. On the day of admission the child stopped vomiting and his biological disturbances were corrected. The plasma electrolytes returned to normal (sodium 136.5, potassium 5.1mmol/1) so did the P.R.A. (0.4 ng/ml/min). A significant increase in diastolic pressure was elicited by an intravenous angiotensin infusion of 10 ng/ml/min. Urinary aldosterone was slightly raised at 22 µg in 24 h. Urinary P.G. remained high (p.G.Ez 299, P.G.F2a 1089 ng in 24 h). The child left hospital on the 9th day after admission without any other treatment or special diet. 4 months later plasma electrolytes, P.R.A. angiotensin test, urinary aldosterone and urinary prostaglandin excretion of p.G.Ez and p.G.F2&agr; were all normal. Stewart, C. D., Burke, P. J. Nature, 1971, 233, 109. Smyth, J. F., Robins, A. B., Leese, C. L. Eur. J. Cancer, 1976, 12, 567. 1. Gill, J. R., Frolich, J. C., Bowden, R. E., Taylor, A. A., Keiser, M. R., Sey Berth, H. W., Oates, J. A., Bartter, F. C. Am. J. Med. 1976, 61, 43. 2. Fichman, M. P., Telfer, N., Zia, P., Speckart, P., Golub, M., Rude, R. ibid. 8. 9.
1. Raich, P. C. Lancet, 1978, i, 74. 2. Harris, A. L., Boutagy, J., Harvey, D. Unpublished. 3. Chou, T-C., Arlin, Z., Clarkson, B. D., Philips, F. S. Cancer Res. 3561. 4. Furth, J. J., Cohen, S. S. ibid, 1968, 28, 2061. 5. Stenstrom, M. L., Edelstein, M., Grisham, J. W. Expl. Cell Res. 439. 6. Chuang, R. Y., Chuang, L. F. Nature, 1976, 260, 549. 7. Graham, F. L., Whitmore, G. F. Cancer Res. 1970, 30, 2627.
1977, 37,
1976, 60, 785. Verberckmoes, E., Van Damme, B., Clement, J., Amery, A., Michielsen, P. Kidney Int. 1976, 9, 302. 4. Donker, A. J. M., Jong, R. E., Statius Van Eps, L. N., Brentjens, J. R. M., Barkker, K., Dooren, Bos, M. Nephron, 1977, 19, 200. 5. Dray, F. Clin. Sci. mol. Med. (in the press). 3.
1974, 89,
334 This case suggests that increased urinary prostaglandin excretion is not specific to Bartter’s syndrome but may appear in other clinical situations where the biological disturbances are similar. H. NIVET B. GRENIER de Pédiatrie Service B, J. C. ROLLAND Hôpital G. de Clocheville, 37000 Tours, France Y. LEBRANCHU INSERM FRA no. 8. URIA, Institut Pasteur, Paris
TABLE I-BACTERIA
ISOLATED FROM SPUTUM AT THE BEGINNING
(B) AND END (E) OF CYSTIC FIBROSIS
F. DRAY
BACTERIAL CONTENT AND IONIC COMPOSITION OF SPUTUM IN CYSTIC FIBROSIS
SIR,—Burns and May’ proposed the following pattern for the bacteriology of cystic fibrosis: Stage 1.—Staphylococcus aureus is the initial bacterial pathogen, and damage caused by it renders the lungs susceptible to infection by other species. Stage 2.-Control of S. aureus by antibiotics allows the influx of Hœmophilus influenzœ. Stage 3.-Pseudomonas ceruginosa is introduced and continued chemotherapy encourages its establishment. Stage 4.-P. œruginosa supplants S. aureus and H. influenza, becoming the sole pathogen.
suggested that patients are abnormally susrespiratory pathogen from birth.2 I have examined these ideas by quantitative culture3 of sputum from 20 patients seen at the Cystic Fibrosis Treatment and Research Center, University of Oregon Health Sciences Center from 1965 to 1977. The results accord with the original hypothesis of Burns and May.4,5 A current summary of the sputum bacterial flora of these patients is shown in table I. In 13 of the 20 patients the sputum bacterial flora changed as the hypothesis of Burns and May predicted. In 4 patients the sputum bacterial flora did not change, neither supporting nor refuting the hypothesis. In 2 patients the flora changed from S. aureus alone to S. aureus and a gram negative bacillus which was not P. ceruginosa. The change in 1 patient was contrary to the hypothesis, from S. aureus and P. ceruginosa to S. aureus alone at the time of death. In total, the changes in only 3 of 20 patients contradicted the hypothesis of Burns and May. Whether the consistency of the sputum in cystic fibrosis can be explained by its ionic composition is disputed.6-9 None of May
ceptible
et al. then to any
1. Burns, M. W., May, J. R. Lancet, 1958, i, 270. 2. May, J. R., Herrick, N. C., Thompson, D. Archs Dis. Childh. 1972, 47, 908. 3. Kilbourn, J. P., Campbell, R. A., Grach, J. L., Willis, M. D. Am. Rev. resp. Dis. 1968, 98, 810. 4. Kilbourn, J. P. Lancet, 1970, ii, 878. 5. Kilbourn, J. P. ibid. 1974, i, 405. 6. Matthews, L. W., Spector, S., Lemm, J., Potter, J. L. Am. Rev. resp. Dis.
1963, 88, 199. Potter, J. L., Matthews, L. W., Spector, S., Lemm, J. ibid. 1967, 96, 83. Potter, J. L., Matthews, L. W., Lemm, J., Spector, S. Ann. New York Acad. Sci. 1963, 106, 692. 9. Chernick, W. S., Barbero, G. J. Pediatrics, 1959, 24, 739. 7. 8.
* E. coli replaced P. ceruginosa. Abbreviations in parentheses represent additional potential respiratory pathogens isolated in significant numbers from the last sputum culture obtained before the patient died. c.A.=Candida albicans; E.c.=Escherichia coli;
H.I.=Hœmophilus influenzœ, S.P.=Streptococcus pneumoniœ; P.nt.=Proteus mirabilis.
these studies described the bacterial flora as well as the sputum ionic composition. Preliminary data (table II) shows a correlation between the ionic composition (Ca++, Na+, K+, and Cl-) and the categories of sputum bacterial flora suggested by Burns and May: (S. aureus; S. aureus/P. ceruginosa; P. ceruginosa). As in earlier work, Na+ and Cl- were approximately equal in concentration; the concentration of K+ was 1/2-1/3 that of Na+; and the concentration of Ca+’ was 1/40-1/200 that of Na+. In addition the concentration of Ca++ (0.00185 mmol/ml) in the sputum with S. aureus alone is twice that in sputum with P. œruginosa/S. aureus (0.0008 mmol/ml) or P. ceruginosa alone (0.00055 mmol/ml).. This preliminary data suggests that one of the primary sputum abnormalities in cystic fibrosis may be increased Ca++ which makes the sputum susceptible to colonisation by S. aureus. After infection the Ca++ concentration is reduced and the lung becomes susceptible to colonisation by other microorganisms including H. influenzae, P. aruginosa, and Escherichia coli. 3178 S. W. Fairmount Boulevard, Portland, Oregon 97201, U.S.A.
TABLE 11-BACTERIAL AND IONIC COMPOSITION OF SPUTUM FROM CYSTIC FIBROSIS PATIENTS
s.A.=Staphylococcus aureus.
E.c.=Escherichia coli.
A.s.==Atpha4taemolytic Streptococcus
H.i.=Hamophilus influenzœ. P.A.=Pseudomonas ceruginosa.
N.B.=Neisseria sp. and/or Branhemella sp.
J. P. KILBOURN
Departments of Otolaryngology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, U.S.A.
L. STEFAN LEVIN
Department of Oral Medicine, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina 29403, U.S.A.
CARLOS F. SALINAS RONALD J. JORGENSON
CYTARABINE AND LEUKÆMIA REMISSION
SIR,—Dr Raich* reported that, using cytarabine (cytosine arabinoside, ara-C), he could predict remission in patients not
receiving the drug. We have been measuring plasma ara-C concentrations by gas-liquid-chromatography/mass-spectroscopy. The concentration Raich used was 0.25 µg/ml, which is five to ten times higher than the concentration achieved in patients with constant intravenous infusion of 150 mg/24 h or 10-30 min after an intravenous bolus.2 Thus Raich’s results are unlikely to be closely related to the effect of the drug in vivo. Nevertheless, the results do suggest that failure to remit may be related to biochemical mechanisms of resistance to this concentration of ara-C. Ara-C is concentrated intracellularly in its active form, cytosine arabinoside triphosphate,3 which inhibits D.N.A. polymerase.4 At the intracellular concentrations that could be achieved by 0.25 µg/ml ara-C extracellularly, ara-C triphosphate may inhibit D.N.A. repair synthesis,’ and R.N.A. polymerase6 as well as being incorporated into D.N.A. and R.N.A.7 All the patients received at least one drug that may act at these sites. However, ara-C is deaminated to an inactive metabolite by
cytidine deaminase.8 Deamination in peripheral blasts does not correlate with remission,9 but Raich used bone-marrow. 48 h of incubation with 10’ cells could completely deaminate the amounts of ara-C present. It would have been helpful to know the ara-C concentrations at the end of the incubation since the variation in 3H-thymidine incorporation could have been due to this. Although it is important to know if ara-C catabolism is responsible for the results this would not explain the correlation with remission. One possibility would be that deamination would provide a source of deoxyuridine for use in the salvage D.N.A.
pathway.
M.R.C. Clinical
Pharmacology Unit, University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE
A.
L, HARRIS
RAISED URINARY PROSTAGLANDINS IN PATIENT WITHOUT BARTTER’S SYNDROME
SIR,—Patients with Bartter’s syndrome (both adults and have been reported to have increased urinary excretion of prostaglandins,1—4 though one of us’ has found enhanced excretion of P.G. E2 and P.G. F2&agr; consistently in children but never in adults. Enhanced urinary P.G. production is thought to be the primary determinant in Banter’s syndrome, but Dr M. B. Vallotton of Geneva has seen a case of relapse during indomethacin treatment (unpublished) and we have seen a patient with raised urinary P.G. excretion who did not have Bartter’s syndrome but whose laboratory findings resembled those seen in this syndrome. A 10-year-old boy had an episode of cyclic vomiting disease. He had been fasting and vomiting for 3 days before admission, resulting in a weight-loss of 2 kg (8% of body-weight). The child was conscious but very tired. His blood-pressure was 110/60 mm Hg, and his plasma electrolytes were low (sodium 114, potassium 1.8, chloride 63 mmol/l) and he had a metabolic alkalosis with a pH of 7.61 and a base excess of +9 mmol/l. Diuresis was 0.45 ml/h; urinary potassium 86 and sodium 23 mmola. His urinary aldosterone excretion was up to 48-55 µg in 24 h (normal below 15). Plasma-renin-activity (P.R.A.) (lying) was 35 ng/ml/h (normal 0.2-2). We observed a vascular resistance to angiotensin, tested by Kaplan’s method: an increased diastolic pressure of 20 mm Hg was not observed unless the rate of intravenous angiotensin infusion was raised to 46 ng/kg/min (normal below 15). Urinary. prostaglandin excretion was very high: p.G.Ez 799 ng in 24 h (normal range for a prepubertal child 37-171’) and r.u.F2« 3804 ng in 24 h (normal
children)
203-1028’). These biological disturbances,
except for the
hyponatrae-
mia, resembled those of Bartter’s syndrome. On the day of admission the child stopped vomiting and his biological disturbances were corrected. The plasma electrolytes returned to normal (sodium 136.5, potassium 5.1mmol/1) so did the P.R.A. (0.4 ng/ml/min). A significant increase in diastolic pressure was elicited by an intravenous angiotensin infusion of 10 ng/ml/min. Urinary aldosterone was slightly raised at 22 µg in 24 h. Urinary P.G. remained high (p.G.Ez 299, P.G.F2a 1089 ng in 24 h). The child left hospital on the 9th day after admission without any other treatment or special diet. 4 months later plasma electrolytes, P.R.A. angiotensin test, urinary aldosterone and urinary prostaglandin excretion of p.G.Ez and p.G.F2&agr; were all normal. Stewart, C. D., Burke, P. J. Nature, 1971, 233, 109. Smyth, J. F., Robins, A. B., Leese, C. L. Eur. J. Cancer, 1976, 12, 567. 1. Gill, J. R., Frolich, J. C., Bowden, R. E., Taylor, A. A., Keiser, M. R., Sey Berth, H. W., Oates, J. A., Bartter, F. C. Am. J. Med. 1976, 61, 43. 2. Fichman, M. P., Telfer, N., Zia, P., Speckart, P., Golub, M., Rude, R. ibid. 8. 9.
1. Raich, P. C. Lancet, 1978, i, 74. 2. Harris, A. L., Boutagy, J., Harvey, D. Unpublished. 3. Chou, T-C., Arlin, Z., Clarkson, B. D., Philips, F. S. Cancer Res. 3561. 4. Furth, J. J., Cohen, S. S. ibid, 1968, 28, 2061. 5. Stenstrom, M. L., Edelstein, M., Grisham, J. W. Expl. Cell Res. 439. 6. Chuang, R. Y., Chuang, L. F. Nature, 1976, 260, 549. 7. Graham, F. L., Whitmore, G. F. Cancer Res. 1970, 30, 2627.
1977, 37,
1976, 60, 785. Verberckmoes, E., Van Damme, B., Clement, J., Amery, A., Michielsen, P. Kidney Int. 1976, 9, 302. 4. Donker, A. J. M., Jong, R. E., Statius Van Eps, L. N., Brentjens, J. R. M., Barkker, K., Dooren, Bos, M. Nephron, 1977, 19, 200. 5. Dray, F. Clin. Sci. mol. Med. (in the press). 3.
1974, 89,
334 This case suggests that increased urinary prostaglandin excretion is not specific to Bartter’s syndrome but may appear in other clinical situations where the biological disturbances are similar. H. NIVET B. GRENIER de Pédiatrie Service B, J. C. ROLLAND Hôpital G. de Clocheville, 37000 Tours, France Y. LEBRANCHU INSERM FRA no. 8. URIA, Institut Pasteur, Paris
TABLE I-BACTERIA
ISOLATED FROM SPUTUM AT THE BEGINNING
(B) AND END (E) OF CYSTIC FIBROSIS
F. DRAY
BACTERIAL CONTENT AND IONIC COMPOSITION OF SPUTUM IN CYSTIC FIBROSIS
SIR,—Burns and May’ proposed the following pattern for the bacteriology of cystic fibrosis: Stage 1.—Staphylococcus aureus is the initial bacterial pathogen, and damage caused by it renders the lungs susceptible to infection by other species. Stage 2.-Control of S. aureus by antibiotics allows the influx of Hœmophilus influenzœ. Stage 3.-Pseudomonas ceruginosa is introduced and continued chemotherapy encourages its establishment. Stage 4.-P. œruginosa supplants S. aureus and H. influenza, becoming the sole pathogen.
suggested that patients are abnormally susrespiratory pathogen from birth.2 I have examined these ideas by quantitative culture3 of sputum from 20 patients seen at the Cystic Fibrosis Treatment and Research Center, University of Oregon Health Sciences Center from 1965 to 1977. The results accord with the original hypothesis of Burns and May.4,5 A current summary of the sputum bacterial flora of these patients is shown in table I. In 13 of the 20 patients the sputum bacterial flora changed as the hypothesis of Burns and May predicted. In 4 patients the sputum bacterial flora did not change, neither supporting nor refuting the hypothesis. In 2 patients the flora changed from S. aureus alone to S. aureus and a gram negative bacillus which was not P. ceruginosa. The change in 1 patient was contrary to the hypothesis, from S. aureus and P. ceruginosa to S. aureus alone at the time of death. In total, the changes in only 3 of 20 patients contradicted the hypothesis of Burns and May. Whether the consistency of the sputum in cystic fibrosis can be explained by its ionic composition is disputed.6-9 None of May
ceptible
et al. then to any
1. Burns, M. W., May, J. R. Lancet, 1958, i, 270. 2. May, J. R., Herrick, N. C., Thompson, D. Archs Dis. Childh. 1972, 47, 908. 3. Kilbourn, J. P., Campbell, R. A., Grach, J. L., Willis, M. D. Am. Rev. resp. Dis. 1968, 98, 810. 4. Kilbourn, J. P. Lancet, 1970, ii, 878. 5. Kilbourn, J. P. ibid. 1974, i, 405. 6. Matthews, L. W., Spector, S., Lemm, J., Potter, J. L. Am. Rev. resp. Dis.
1963, 88, 199. Potter, J. L., Matthews, L. W., Spector, S., Lemm, J. ibid. 1967, 96, 83. Potter, J. L., Matthews, L. W., Lemm, J., Spector, S. Ann. New York Acad. Sci. 1963, 106, 692. 9. Chernick, W. S., Barbero, G. J. Pediatrics, 1959, 24, 739. 7. 8.
* E. coli replaced P. ceruginosa. Abbreviations in parentheses represent additional potential respiratory pathogens isolated in significant numbers from the last sputum culture obtained before the patient died. c.A.=Candida albicans; E.c.=Escherichia coli;
H.I.=Hœmophilus influenzœ, S.P.=Streptococcus pneumoniœ; P.nt.=Proteus mirabilis.
these studies described the bacterial flora as well as the sputum ionic composition. Preliminary data (table II) shows a correlation between the ionic composition (Ca++, Na+, K+, and Cl-) and the categories of sputum bacterial flora suggested by Burns and May: (S. aureus; S. aureus/P. ceruginosa; P. ceruginosa). As in earlier work, Na+ and Cl- were approximately equal in concentration; the concentration of K+ was 1/2-1/3 that of Na+; and the concentration of Ca+’ was 1/40-1/200 that of Na+. In addition the concentration of Ca++ (0.00185 mmol/ml) in the sputum with S. aureus alone is twice that in sputum with P. œruginosa/S. aureus (0.0008 mmol/ml) or P. ceruginosa alone (0.00055 mmol/ml).. This preliminary data suggests that one of the primary sputum abnormalities in cystic fibrosis may be increased Ca++ which makes the sputum susceptible to colonisation by S. aureus. After infection the Ca++ concentration is reduced and the lung becomes susceptible to colonisation by other microorganisms including H. influenzae, P. aruginosa, and Escherichia coli. 3178 S. W. Fairmount Boulevard, Portland, Oregon 97201, U.S.A.
TABLE 11-BACTERIAL AND IONIC COMPOSITION OF SPUTUM FROM CYSTIC FIBROSIS PATIENTS
s.A.=Staphylococcus aureus.
E.c.=Escherichia coli.
A.s.==Atpha4taemolytic Streptococcus
H.i.=Hamophilus influenzœ. P.A.=Pseudomonas ceruginosa.
N.B.=Neisseria sp. and/or Branhemella sp.
J. P. KILBOURN
