917
IN-VITRO DISSOLUTION OF HUMAN CLOTS BY WHISKY
SiR,—The very high price of urokinase, the restricted availability of this human product, and the requirement of intravenous application clearly indicate the necessity for
We have treated synovial tissue with the gel-electrophoresis buffer alone and have subsequently obtained a peptide of the same molecular weight as the cyanogen-bromide peptide which has been used to quantitate type-in collagen. Care should therefore be taken when densitometric quantitation of cyanogen-bromide peptides is used as a measure of the amounts of type-in collagen present in synovia. Eyre and Muir dismiss our observations as "a possibility that there may be local variations in the relative proportions of type-i and type-in collagen". Differences in the total amount of the soluble type-ni collagen in normal and inflamed synovia are, however, striking and it is highly probable that
approaches to thrombolytic treatment. The investigations with synthetic fibrinolytic compounds are growing in popularity, as indicated by the proceedings of the First International Congress on Synthetic Fibrinolytic/Thrombolytic Agentsand by the fact that such a congress will be held every second year (the second one was held in Paris in 1974 and the third will be held in Glasgow in 1976). they are biologically significant. Very many compounds induce dissolution of human Departments of Rheumatology plasma-clots in the test-tube, primarily by inactivating JACQUELINE B. WEISS and Medical Biochemistry, inhibitors of the fibrinolytic enzyme system. A clot of C. ADRIAN SHUTTLEWORTH of University Manchester, human plasma exposed to whisky diluted to an alcohol R. BROWN Stopford Building, Manchester M13 9PT concentration of about 16% and with adjustment of the JOHN A. A. HUNTER pH to 7’4 will dissolve within hours upon incubation. In whisky the effective agent is the alcohol. We have found in SUDDEN-INFANT-DEATH SYNDROME AND our laboratory more than 500 compounds of very diverse IMMUNODEFICIENCY structure which induce clot lysis in the test-tube, their SIR,-Earlier this year one of us reported increased prevacommon denominator being that all are organic anions. lence of IgE antibodies to Dermatophagoides pteronyssinus, One of the most interesting of these compounds is niflumic Aspergillus fumigatus, and bovine -lactaglobulin in the sera acid which in vitro proved to be 1000 times more active in cases of sudden-infant-death syndrome (s.i.D.s.), which than whisky and which also induces fibrinolytic activity in vivo by an entirely different mechanism, thus inducing was interpreted as supporting an allergic pathogenesis.’ The IgE-antibody levels were comparable with those in children of fibrinolytic activity by two pathways. In addition, niflumic similar age, with positive skin tests. acid prevents in the test-tube platelet aggregation by Serum-immunoglobulins were also measured in the s.i.D.s. collagen and the aggregation of erythrocytes.2 study and a significant difference in serum-IgA was noticed, These and many similar observations clearly indicate that compared with an appropriate control group, which was interthere are different potential approaches for the development preted as elevation in the latter. Comparison with the data of of antithrombotic thrombolytic agents which should be Taylor et al,2 who showed transient IgA deficiency preceding extensively explored. Here we have to deal with a somethe development of infantile eczema and positive prick tests to what philosophical question: should we see what we allergens, suggests that this difference may be a deficiency in actually have and then try to make the best out of it, or the s.t.D.s. infants, which presumably led to their increased should we first define the desirable properties of an optimal IgE antibodies. Gardner3 and Ogra et aB.4 provided tissue-imdrug (synthetic, inexpensive, antithrombotic, and clotmunofluorescence evidence for virus (especially R.S.V.) infecdissolving oral drugs in this case) and then make all efforts tion in the respiratory tract of such infants, with little inflamto develop it? The second approach obviously requires matory reaction to it. Ogra et a1.4 failed to detect serum-IgA more ingenuity. deficiency in the 8 infants studied, but noted gross deficiency University of Colorado Medical of IgA in the bronchial washings of 2 and of the IgA-associated Center, polypeptide chain, secretory piece, in the bronchial washings 4200 East Ninth Avenue,
other
Denver, Colorado 80220, U.S.A.* ’
K. N.
VON
KAULLA.
Present address: Stechertweg 2, 78 Freiburg/Brsg, West Germany.
POLYMERIC TYPE-III COLLAGEN IN INFLAMED HUMAN SYNOVIA
Sm,—Dr Eyre and Dr Muir (Sept. 27, p. 609) contend that
genetically distinct collagens-typeand type iii are pressimilar proportions in normal and rheumatoid synovia. These results were based on "analysis of the total collagen in the tissue solubilised as characteristic peptides by chemical cleavage with cyanogen bromide". We reported previously (July 12, p. 85) that type-m collagen two ent in
could be isolated in substantial amounts, from inflamed, but not from age-matched normal synovia, both as a polymer and in a soluble form after pepsin digestion. The apparent discrepancy between these two reports may be explained by the following point. Chemical cleavage by cyanogen bromide has been used successfully to differentiate between known molecular species of collagen present in various tissues. Peptides so obtained, which are characteristic of typeand type III, are identified by gel electrophoresis in S.D.S. (a method which separates according to molecular weight) and quantitated by densitometric scanning. 1.
2.
Kaulla, K. N., Davidson, J. F. (editors). Synthetic Fibrinolytic/ Thrombolytic Agents: Chemical, Biochemical, Pharmacological and Clinical Aspects. Springfield, III., 1975. von Kaulla, K. N. Experientia, 1974, 30, 959.
von
and tissues of 6. This supports the view that defects of the secretory immunity system contribute to this phenomenon. The interpretation of the significance of associations with such a complex phenomenon as immunodeficiency is always difficult. Since both infection and allergy can be effects of immunodeficiency, the association between one of these and a syndrome may not be aetiological, since the disease may be due to the other, or to a third unsuspected effect of the immunodeficiency. It is not clear, then, whether immunodeficiency leads to S.LD.S. by allergy or by infection, or by both, or neither. It is likely that there is more than one cause of S.LD.S., but these findings suggest that immunodeficiency may play a part in many. Since much such deficiency is transient, identification of the vulnerable minority, and avoidance of suboptimal environmental factors (perhaps house-dust mite or feeding on cow’s milk) may prevent these sad and common disasters. Clinical Immunology Unit, Princess Margaret Hospital,
Subiaco, Western Australia. of Immunology, Institute of Child Health, London WC1N 1EH.
K.
J.
TURNER
Department
J. F. SOOTHILL
B. A., Hilton, J. M. N. Br. med. J. 1975, i, 357. A. P., Orgel, H. A., Stokes, C. R., Turner, M. W, Soothill, J. F. Lancet, 1973, ii, 111. 3. Gardner, P. S. in S.I.D.S. (edited by R. R. Robinson); p. 287. Canadian Foundation for the Study of Infant Deaths, 1974. 4. Ogra, P. L., Ogra, S. S., Coppola, P. R. Lancet, Aug. 30, 1975, p. 387
1. Turner, K. 2. Taylor, B.,
J., Baldo, Norman,
IN-VITRO DISSOLUTION OF HUMAN CLOTS BY WHISKY
SiR,—The very high price of urokinase, the restricted availability of this human product, and the requirement of intravenous application clearly indicate the necessity for
We have treated synovial tissue with the gel-electrophoresis buffer alone and have subsequently obtained a peptide of the same molecular weight as the cyanogen-bromide peptide which has been used to quantitate type-in collagen. Care should therefore be taken when densitometric quantitation of cyanogen-bromide peptides is used as a measure of the amounts of type-in collagen present in synovia. Eyre and Muir dismiss our observations as "a possibility that there may be local variations in the relative proportions of type-i and type-in collagen". Differences in the total amount of the soluble type-ni collagen in normal and inflamed synovia are, however, striking and it is highly probable that
approaches to thrombolytic treatment. The investigations with synthetic fibrinolytic compounds are growing in popularity, as indicated by the proceedings of the First International Congress on Synthetic Fibrinolytic/Thrombolytic Agentsand by the fact that such a congress will be held every second year (the second one was held in Paris in 1974 and the third will be held in Glasgow in 1976). they are biologically significant. Very many compounds induce dissolution of human Departments of Rheumatology plasma-clots in the test-tube, primarily by inactivating JACQUELINE B. WEISS and Medical Biochemistry, inhibitors of the fibrinolytic enzyme system. A clot of C. ADRIAN SHUTTLEWORTH of University Manchester, human plasma exposed to whisky diluted to an alcohol R. BROWN Stopford Building, Manchester M13 9PT concentration of about 16% and with adjustment of the JOHN A. A. HUNTER pH to 7’4 will dissolve within hours upon incubation. In whisky the effective agent is the alcohol. We have found in SUDDEN-INFANT-DEATH SYNDROME AND our laboratory more than 500 compounds of very diverse IMMUNODEFICIENCY structure which induce clot lysis in the test-tube, their SIR,-Earlier this year one of us reported increased prevacommon denominator being that all are organic anions. lence of IgE antibodies to Dermatophagoides pteronyssinus, One of the most interesting of these compounds is niflumic Aspergillus fumigatus, and bovine -lactaglobulin in the sera acid which in vitro proved to be 1000 times more active in cases of sudden-infant-death syndrome (s.i.D.s.), which than whisky and which also induces fibrinolytic activity in vivo by an entirely different mechanism, thus inducing was interpreted as supporting an allergic pathogenesis.’ The IgE-antibody levels were comparable with those in children of fibrinolytic activity by two pathways. In addition, niflumic similar age, with positive skin tests. acid prevents in the test-tube platelet aggregation by Serum-immunoglobulins were also measured in the s.i.D.s. collagen and the aggregation of erythrocytes.2 study and a significant difference in serum-IgA was noticed, These and many similar observations clearly indicate that compared with an appropriate control group, which was interthere are different potential approaches for the development preted as elevation in the latter. Comparison with the data of of antithrombotic thrombolytic agents which should be Taylor et al,2 who showed transient IgA deficiency preceding extensively explored. Here we have to deal with a somethe development of infantile eczema and positive prick tests to what philosophical question: should we see what we allergens, suggests that this difference may be a deficiency in actually have and then try to make the best out of it, or the s.t.D.s. infants, which presumably led to their increased should we first define the desirable properties of an optimal IgE antibodies. Gardner3 and Ogra et aB.4 provided tissue-imdrug (synthetic, inexpensive, antithrombotic, and clotmunofluorescence evidence for virus (especially R.S.V.) infecdissolving oral drugs in this case) and then make all efforts tion in the respiratory tract of such infants, with little inflamto develop it? The second approach obviously requires matory reaction to it. Ogra et a1.4 failed to detect serum-IgA more ingenuity. deficiency in the 8 infants studied, but noted gross deficiency University of Colorado Medical of IgA in the bronchial washings of 2 and of the IgA-associated Center, polypeptide chain, secretory piece, in the bronchial washings 4200 East Ninth Avenue,
other
Denver, Colorado 80220, U.S.A.* ’
K. N.
VON
KAULLA.
Present address: Stechertweg 2, 78 Freiburg/Brsg, West Germany.
POLYMERIC TYPE-III COLLAGEN IN INFLAMED HUMAN SYNOVIA
Sm,—Dr Eyre and Dr Muir (Sept. 27, p. 609) contend that
genetically distinct collagens-typeand type iii are pressimilar proportions in normal and rheumatoid synovia. These results were based on "analysis of the total collagen in the tissue solubilised as characteristic peptides by chemical cleavage with cyanogen bromide". We reported previously (July 12, p. 85) that type-m collagen two ent in
could be isolated in substantial amounts, from inflamed, but not from age-matched normal synovia, both as a polymer and in a soluble form after pepsin digestion. The apparent discrepancy between these two reports may be explained by the following point. Chemical cleavage by cyanogen bromide has been used successfully to differentiate between known molecular species of collagen present in various tissues. Peptides so obtained, which are characteristic of typeand type III, are identified by gel electrophoresis in S.D.S. (a method which separates according to molecular weight) and quantitated by densitometric scanning. 1.
2.
Kaulla, K. N., Davidson, J. F. (editors). Synthetic Fibrinolytic/ Thrombolytic Agents: Chemical, Biochemical, Pharmacological and Clinical Aspects. Springfield, III., 1975. von Kaulla, K. N. Experientia, 1974, 30, 959.
von
and tissues of 6. This supports the view that defects of the secretory immunity system contribute to this phenomenon. The interpretation of the significance of associations with such a complex phenomenon as immunodeficiency is always difficult. Since both infection and allergy can be effects of immunodeficiency, the association between one of these and a syndrome may not be aetiological, since the disease may be due to the other, or to a third unsuspected effect of the immunodeficiency. It is not clear, then, whether immunodeficiency leads to S.LD.S. by allergy or by infection, or by both, or neither. It is likely that there is more than one cause of S.LD.S., but these findings suggest that immunodeficiency may play a part in many. Since much such deficiency is transient, identification of the vulnerable minority, and avoidance of suboptimal environmental factors (perhaps house-dust mite or feeding on cow’s milk) may prevent these sad and common disasters. Clinical Immunology Unit, Princess Margaret Hospital,
Subiaco, Western Australia. of Immunology, Institute of Child Health, London WC1N 1EH.
K.
J.
TURNER
Department
J. F. SOOTHILL
B. A., Hilton, J. M. N. Br. med. J. 1975, i, 357. A. P., Orgel, H. A., Stokes, C. R., Turner, M. W, Soothill, J. F. Lancet, 1973, ii, 111. 3. Gardner, P. S. in S.I.D.S. (edited by R. R. Robinson); p. 287. Canadian Foundation for the Study of Infant Deaths, 1974. 4. Ogra, P. L., Ogra, S. S., Coppola, P. R. Lancet, Aug. 30, 1975, p. 387
1. Turner, K. 2. Taylor, B.,
J., Baldo, Norman,
