MEDICAL CARE IN THE UNITED STATES
1
930 twelve weeks later); (c) the development of negative M.I.T.s in our animals after week 4 indicated that neither M.I.F. nor cytophilic antibodies were present; and (d) Ranlov and Hardt’s own experiments provide confirmatory evidence that preamyloidotic mice rapidly develop M.I.F. specific for casein. Perhaps Dr. Ranlov and Dr. Hardt would not be unsuccessful in showing subsequent alterations of M.l.F. production if they switched from the mouse to the guineapig, since the guineapig model is more suited to experimental manipulation over longer periods of time. We were also interested to learn that Dr. Hardt and Dr. Claesson have demonstrated nonspecific depression of cellular immunity in the Fl hybrid mouse model. These results recall similar findings published by us 19 showing that tolerance to diphtheria toxoid developed in preamyl- oidotic guineapigs if the nonspecific immunogen was introduced intradermally before or coincidentally with the first dose of subcutaneous casein. We even reached the same conclusion regarding the phenomenon of nonspecific tolerance (which indeed may be due to antigen competition as first reported by Liacopoulos and Neuen.2O). Finally, we wish to assure Dr. Hardt and his colleagues that we are well aware of current views on the phenomenon of tolerance. It would have been presumptuous for us to have invoked marrow-dependent cell unresponsiveness as the principal mediator of amyloid disease since we did not test marrow-dependent cell function in our animals. We are aware of recent work suggesting that marrow-dependent cells may produce antibodies and tolerance in the absence of thymus-dependent cells, but would like to point out that it still remains to be proven that high-dose tolerance is exclusively the function of marrow-dependent cells under all circumstances. Perhaps we should emphasise again that our hypothesis does not exclude the possibility that non-thymus-dependent cells may be involved in the patho- genesis of amyloid. Indeed, studies demonstrating the importance of thymus-marrow interaction in other forms of tolerance make it entirely possible that the unresponsive marrow-dependent cell plays a crucial role in the process. This might be an alternative explanation for the appearance of amvloid in manv patients with plasma-cell dvscrasias. Boston, Massachusetts. EDGAR S. CATHCART MICHAEL MULLARKEY ALAN S. COHEN. MEDICAL CARE IN THE UNITED STATES SIR,-I am sure letters such as that of Dr. Taitz (Sept.12, p. 573) make you all feel much better, both personally and in reference to the National Health Service. In the future, however, perhaps more knowledgeable opinions should take precedence. Emotional distorted comparisons in defence of the British system are destroying the " special relation- ship " of British medicine as an impartial concerned critic. The problem here is to convince a powerful well-ser- viced majority to make sacrifices to care for a numerous but distinct minority. Please, no more four-year experts. Restrain emotional defences of an obviously imperfect system. They are destroying your credibility as well as alienating potential advocates of a national health plan for the United States. We here, who are interested in reform face an uphill fight. We welcome your positive influence and example, but the best thing you could do for American medicine is to make your own system work well. Class of ’71, New York Medical College, New York, N.Y. ROBERT M. ADAMS, II. 19. Cathcart, E. S., Mullarkey, M., Cohen, A. S. J. clin. Invest. 1970, 49, 17a. 20. Liacopoulos, P., Neuen, T. Immunology, 1964, 7, 26. EMERGENCY CALL SERVICE SIR,-Mr. Houlson (Oct. 17, p. 822) states that it is easy to grade the urgency of a call when you know what the doctor diagnosed at a visit. One assumes he includes the physical implications of the diagnosis, since a single label, such as acute bronchitis, can imply anything from a minor complaint to a rapidly fatal illness. But there are two other variables which may radically alter the classification of the urgency of a call: the anxiety of the patient and family, and the attitude of the doctor to the patient and his illness. Stony Stratford, Bucks. J. S. COBB. EXPERIMENTAL &bgr;-HYDROXYISOVALERIC ACIDURIA INDUCED BY BIOTIN DEFICIENCY SIR,-We are interested in the report by Professor Eldjarn and his colleagues (Sept. 5, p. 521) on the discovery of a new inborn error of leucine metabolism, &bgr;-hyroxyiso- valeric aciduria. From biochemical findings, they suggest that this disease is due to a metabolic block at the stage of &bgr;-methylcrotonyl CoA carboxylase-one of several enzymes which contains biotin as an essential functional group. After our original discovery of isovaleric acidæmia1-3, we conducted an in-vivo investigation of leucine metabol- ism in experimental biotin deficiency, to compare it with that observed in human isovaleric acidasmia. -methyl- crotonyl CoA carboxylase is depressed in biotin deficiency, a finding which was brieflly mentioned in our previous publications.’, 3 Weanling albino rats were fed a biotin- deficient diet for seven weeks. They all manifested the typical skin lesions of biotin deficiency and weighed 90 to 100 g. at the end of seven weeks. Control rats were fed the same biotin-deficient diet for the same period, but had intraperitoneal injections of D-biotin (100 µg. twice a 1. Tanaka, K., Budd, M. A., Efron, M. L., Isselbacher, K. J. Proc. natn. Acad. Sci. U.S.A. 1966, 56, 236. 2. Tanaka, K., Isselbacher, K. J. J. biol. Chem. 1967, 242, 2966. 3. Tanaka, K., Orr, J., Isselbacher, K. J. Biochim. biophys. Acta, 1968, 152, 638. Fig. 1-Urinary excretion of leucine metabolites. Urine was collected for 24 hours after L-leucine administratio! (60 mg. per 100 g.).
Transcript of MEDICAL CARE IN THE UNITED STATES
930
twelve weeks later); (c) the development of negativeM.I.T.s in our animals after week 4 indicated that neitherM.I.F. nor cytophilic antibodies were present; and (d)Ranlov and Hardt’s own experiments provide confirmatoryevidence that preamyloidotic mice rapidly develop M.I.F.specific for casein. Perhaps Dr. Ranlov and Dr. Hardtwould not be unsuccessful in showing subsequent alterationsof M.l.F. production if they switched from the mouse to theguineapig, since the guineapig model is more suited to
experimental manipulation over longer periods of time.We were also interested to learn that Dr. Hardt and
Dr. Claesson have demonstrated nonspecific depression ofcellular immunity in the Fl hybrid mouse model. Theseresults recall similar findings published by us 19 showingthat tolerance to diphtheria toxoid developed in preamyl-oidotic guineapigs if the nonspecific immunogen was
introduced intradermally before or coincidentally with thefirst dose of subcutaneous casein. We even reached thesame conclusion regarding the phenomenon of nonspecifictolerance (which indeed may be due to antigen competitionas first reported by Liacopoulos and Neuen.2O).
Finally, we wish to assure Dr. Hardt and his colleaguesthat we are well aware of current views on the phenomenonof tolerance. It would have been presumptuous for us tohave invoked marrow-dependent cell unresponsiveness asthe principal mediator of amyloid disease since we did nottest marrow-dependent cell function in our animals. Weare aware of recent work suggesting that marrow-dependentcells may produce antibodies and tolerance in the absenceof thymus-dependent cells, but would like to point out thatit still remains to be proven that high-dose tolerance is
exclusively the function of marrow-dependent cells underall circumstances. Perhaps we should emphasise againthat our hypothesis does not exclude the possibility thatnon-thymus-dependent cells may be involved in the patho-genesis of amyloid. Indeed, studies demonstrating theimportance of thymus-marrow interaction in other formsof tolerance make it entirely possible that the unresponsivemarrow-dependent cell plays a crucial role in the process.This might be an alternative explanation for the appearanceof amvloid in manv patients with plasma-cell dvscrasias.
Boston,Massachusetts.
EDGAR S. CATHCARTMICHAEL MULLARKEYALAN S. COHEN.
MEDICAL CARE IN THE UNITED STATES
SIR,-I am sure letters such as that of Dr. Taitz (Sept.12,p. 573) make you all feel much better, both personally and inreference to the National Health Service. In the future,however, perhaps more knowledgeable opinions should takeprecedence. Emotional distorted comparisons in defenceof the British system are destroying the " special relation-ship " of British medicine as an impartial concerned critic.The problem here is to convince a powerful well-ser-
viced majority to make sacrifices to care for a numerous butdistinct minority. Please, no more four-year experts.Restrain emotional defences of an obviously imperfectsystem. They are destroying your credibility as well asalienating potential advocates of a national health plan forthe United States. We here, who are interested in reformface an uphill fight. We welcome your positive influenceand example, but the best thing you could do for Americanmedicine is to make your own system work well.
Class of ’71,New York Medical College,
New York, N.Y. ROBERT M. ADAMS, II.
19. Cathcart, E. S., Mullarkey, M., Cohen, A. S. J. clin. Invest. 1970,49, 17a.
20. Liacopoulos, P., Neuen, T. Immunology, 1964, 7, 26.
EMERGENCY CALL SERVICE
SIR,-Mr. Houlson (Oct. 17, p. 822) states that it is easyto grade the urgency of a call when you know what thedoctor diagnosed at a visit. One assumes he includes the
physical implications of the diagnosis, since a single label,such as acute bronchitis, can imply anything from a minorcomplaint to a rapidly fatal illness. But there are two othervariables which may radically alter the classification of theurgency of a call: the anxiety of the patient and family, andthe attitude of the doctor to the patient and his illness.
Stony Stratford, Bucks. J. S. COBB.
EXPERIMENTAL &bgr;-HYDROXYISOVALERICACIDURIA INDUCED BY BIOTIN DEFICIENCY
SIR,-We are interested in the report by ProfessorEldjarn and his colleagues (Sept. 5, p. 521) on the discoveryof a new inborn error of leucine metabolism, &bgr;-hyroxyiso-valeric aciduria. From biochemical findings, they suggestthat this disease is due to a metabolic block at the stageof &bgr;-methylcrotonyl CoA carboxylase-one of several
enzymes which contains biotin as an essential functionalgroup.
After our original discovery of isovaleric acidæmia1-3,we conducted an in-vivo investigation of leucine metabol-ism in experimental biotin deficiency, to compare it withthat observed in human isovaleric acidasmia. -methyl-crotonyl CoA carboxylase is depressed in biotin deficiency,a finding which was brieflly mentioned in our previouspublications.’, 3 Weanling albino rats were fed a biotin-deficient diet for seven weeks. They all manifested thetypical skin lesions of biotin deficiency and weighed 90 to100 g. at the end of seven weeks. Control rats were fed thesame biotin-deficient diet for the same period, but hadintraperitoneal injections of D-biotin (100 µg. twice a
1. Tanaka, K., Budd, M. A., Efron, M. L., Isselbacher, K. J. Proc.natn. Acad. Sci. U.S.A. 1966, 56, 236.
2. Tanaka, K., Isselbacher, K. J. J. biol. Chem. 1967, 242, 2966.3. Tanaka, K., Orr, J., Isselbacher, K. J. Biochim. biophys. Acta, 1968,
152, 638.
Fig. 1-Urinary excretion of leucine metabolites.Urine was collected for 24 hours after L-leucine administratio!
(60 mg. per 100 g.).
