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TREATMENT OF ARTERIAL THROMBI WITH STREPTOKINASE
1385
early stages of embryogenesis 9; and (2) by the hypothesis presented by Lyon on the irregular expression of bodies in
X-linked genes.1o The rarity of abnormalities in the egg would suggest that one X chromosome is always required. The XOindividual is thus the true neuter of our species, this X being genetically active, neither forming Barr body nor synthesising late in the S-period. Cells with the XO constitution but with a " hot " X chromosome are not known as stem cells, although they may be transient segregation products in multiple mosaics.ll An aberrant X chromosome in the XY-zygote, 12 which is isopyknotic, should be of maternal origin and at times carry inter-X exchanges, whilst the paternal X always must carry intra-X aberrations of the types listed above. Christie Hospital and Holt Radium Institute, Manchester.
S. MULDAL.
PREMEDICATION WITH ATROPINE SIR,-Dr. Laurie Smith (Dec. 1) might be interested to know that not all doctors, even though they understand the mechanism and treatment of glaucoma, agree with him regarding atropine premedication. Prof. David A. Rosen, professor of ophthalmology at Queen’s University, Kingston, Ontario, writes 13: "
It is frequently stated that patients with glaucoma should not given atropine for their premedication for fear of precipitating acute glaucoma or of aggravating existing chronic glaucoma. The dangers attending this are, in the author’s view, mythical. The amount of atropine that would reach the eye in the doses of atropine ordinarily employed would be infinitesimally small compared with the amount delivered by topical administration of this drug. One drop of 1 per cent atropine contains 0-6 mg. of this drug and a sizable fraction of this is probably absorbed into the eye. Considering that the weight of the averageeye is 15 gm., the amount of atropine that would be present in the entire eye were this drug uniformly distributed in a 70-kilogram individual given 0-05 mg. of atropine in premedication would be only 0.0001 mg. Patients who have an anatomical predisposition to angle-closure glaucoma may develop an acute attack as a result of the stress surrounding the surgical procedure in general. Atropine should not be considered an important culprit in this regard." J. SHEGOG RUDDELL. be
"
Lethbridge,
TREATMENT OF ARTERIAL THROMBI WITH STREPTOKINASE
SIR,-We are glad to see that Dr. Verstraete and Dr. Amery (Dec. 8) are in complete agreement with us that serial arteriography is an essential control for fibrinolytic therapy aimed at dissolving thrombi in arteries. Only such a series of arteriograms illustrated by fig. 1 of our paper (Nov. 28) can offer final proof that a thrombus has been dissolved.
We have
now
treated six
cases
and serial
arteriograms of this type leave us in no doubt that streptokinase is an effective thrombolytic agent, in that it has been shown to clear long segments of recently formed arterial thrombi. Our series is not yet large enough to evaluate the full clinical potential of streptokinase and we
are
most
interested
to
hear of Dr. Verstraete’s
results. The total doses we have used have not exceeded 350,000 units given by continuous local intra-arterial infusion for periods up 10 hours. The average infusion-rate has been 42,000 units per hour, very similar to the 49,000 units per hour of the Belgian workers. The difference in the total dosage in our cases and those of Dr. Verstraete is therefore simply the result
to
9. Glenister, T. W. Nature Lond. 1956, 117, 1135. 10. Lyon, M. Lancet 1961, ii, 434. 11. Grumbach, M. M., Morishima, A. Acta Cytol. 1962, 6, 46. 12. Elves, M. W., Israels, M. C. G. Lancet, Nov. 3, 1962, p. 909. 13. Canad. Anœsth. Soc. J. 1962, 9, 545.
of the shorter time for which our infusions were given. We no longer give a loading dose unless systemic intravenous therapy is contemplated. Many problems remain to be solved in relation to the dosage and route of administration. We are currently investigating some of these problems in animal experiments, some of which have already been published.1 King’s College Hospital Medical School, London, S.E.5.
L. T. COTTON P. T. FLUTE M. J. C. TSAPOGAS.
THE "PROTEIN INTERFERENCE EFFECT" IN THE ROUTINE DETERMINATION OF SERUM AND PLASMA SODIUM LEVELS BY FLAME PHOTOMETRY
SIR,-Following the publication of our paper2 entitled A Reassessment of Normal Plasma-sodium Levels there appeared a letter from Dr. Hultman and Dr. Bergstrom 3 which suggested that the discrepancy between our observed normal sodium levels and those generally " accepted might be due to a protein interference effect " -an effect whereby the apparent sodium content of a serum was reduced compared with the figure obtained when protein-precipitation was carried out before spraying the fluid in the atomiser of a flame photometer. Determination by Hultman and Bergstrom of sodium levels in normal sera by a neutron-activation technique (not using a flame photometer) gave values closely agreeing with this hypothesis. We have confirmed that, using the instrument on which our published work was done, there is in fact a " protein interference effect " which would account for the discrepancy observed by us. We had relied (as we said in our paper) upon the fact that control sera purchased from several different firms gave results which agreed precisely with our own standards. But it appears that these commercial control sera fail to show the " protein interference effect", and so may not serve as critical controls when used as indicated by their suppliers. It will be necessary, therefore, for each laboratory to determine for itself the magnitude of the " protein interference effect " given by its own particular instruments. A technique which minimises the effect of pipette-errors, &c.,
is
as
follows:
1 ml. bulb pipette, calibrated " to deliver ", place 1 -0 ml. of serum under test in each of two containers labelled H2O and T.C.A. respectively. Add 4-0 ml. of water to the first container, and (using the same pipette) 4-0 ml. of 61/4% (w/v) trichloroacetic acid to the second. Mix the contents of each container, spin at 3000 r.p.m. for 3 minutes, and take 1-0 ml. of the supernatant from each into appropriately labelled 100 ml. volumetric flasks. Make up to 100 ml. with Na-free water, and prepare a blank from the same water by placing 0-8 ml. of the 61/4% trichloroacetic acid in another 100 ml. flask and making up to 100 ml. with water. The above volumes result in a final dilution of 1/500 of the test serum: if other dilutions are usually employed in routine work the final step can be altered accordingly, so that the supernatant ( =11/5 of test serum) is suitably further diluted. The difference in apparent sodium content between the " H;j0 " and " T.C.A." fluids is a measure of the " protein interference effect ". As it is not shown by all sera equally, a series of sera must be examined in this way. Sera which have been diluted 1/5 in water and kept for 3 days at 4°C do not show the effect. Sera which have been treated with ionexchange resin to remove sodium and potassium (and have
Using
a
1. Brit. Surg.J. 2. Lancet, 1962, 3. ibid. p. 1132.
1962, 50, i, 778.
334.
early stages of embryogenesis 9; and (2) by the hypothesis presented by Lyon on the irregular expression of bodies in
X-linked genes.1o The rarity of abnormalities in the egg would suggest that one X chromosome is always required. The XOindividual is thus the true neuter of our species, this X being genetically active, neither forming Barr body nor synthesising late in the S-period. Cells with the XO constitution but with a " hot " X chromosome are not known as stem cells, although they may be transient segregation products in multiple mosaics.ll An aberrant X chromosome in the XY-zygote, 12 which is isopyknotic, should be of maternal origin and at times carry inter-X exchanges, whilst the paternal X always must carry intra-X aberrations of the types listed above. Christie Hospital and Holt Radium Institute, Manchester.
S. MULDAL.
PREMEDICATION WITH ATROPINE SIR,-Dr. Laurie Smith (Dec. 1) might be interested to know that not all doctors, even though they understand the mechanism and treatment of glaucoma, agree with him regarding atropine premedication. Prof. David A. Rosen, professor of ophthalmology at Queen’s University, Kingston, Ontario, writes 13: "
It is frequently stated that patients with glaucoma should not given atropine for their premedication for fear of precipitating acute glaucoma or of aggravating existing chronic glaucoma. The dangers attending this are, in the author’s view, mythical. The amount of atropine that would reach the eye in the doses of atropine ordinarily employed would be infinitesimally small compared with the amount delivered by topical administration of this drug. One drop of 1 per cent atropine contains 0-6 mg. of this drug and a sizable fraction of this is probably absorbed into the eye. Considering that the weight of the averageeye is 15 gm., the amount of atropine that would be present in the entire eye were this drug uniformly distributed in a 70-kilogram individual given 0-05 mg. of atropine in premedication would be only 0.0001 mg. Patients who have an anatomical predisposition to angle-closure glaucoma may develop an acute attack as a result of the stress surrounding the surgical procedure in general. Atropine should not be considered an important culprit in this regard." J. SHEGOG RUDDELL. be
"
Lethbridge,
TREATMENT OF ARTERIAL THROMBI WITH STREPTOKINASE
SIR,-We are glad to see that Dr. Verstraete and Dr. Amery (Dec. 8) are in complete agreement with us that serial arteriography is an essential control for fibrinolytic therapy aimed at dissolving thrombi in arteries. Only such a series of arteriograms illustrated by fig. 1 of our paper (Nov. 28) can offer final proof that a thrombus has been dissolved.
We have
now
treated six
cases
and serial
arteriograms of this type leave us in no doubt that streptokinase is an effective thrombolytic agent, in that it has been shown to clear long segments of recently formed arterial thrombi. Our series is not yet large enough to evaluate the full clinical potential of streptokinase and we
are
most
interested
to
hear of Dr. Verstraete’s
results. The total doses we have used have not exceeded 350,000 units given by continuous local intra-arterial infusion for periods up 10 hours. The average infusion-rate has been 42,000 units per hour, very similar to the 49,000 units per hour of the Belgian workers. The difference in the total dosage in our cases and those of Dr. Verstraete is therefore simply the result
to
9. Glenister, T. W. Nature Lond. 1956, 117, 1135. 10. Lyon, M. Lancet 1961, ii, 434. 11. Grumbach, M. M., Morishima, A. Acta Cytol. 1962, 6, 46. 12. Elves, M. W., Israels, M. C. G. Lancet, Nov. 3, 1962, p. 909. 13. Canad. Anœsth. Soc. J. 1962, 9, 545.
of the shorter time for which our infusions were given. We no longer give a loading dose unless systemic intravenous therapy is contemplated. Many problems remain to be solved in relation to the dosage and route of administration. We are currently investigating some of these problems in animal experiments, some of which have already been published.1 King’s College Hospital Medical School, London, S.E.5.
L. T. COTTON P. T. FLUTE M. J. C. TSAPOGAS.
THE "PROTEIN INTERFERENCE EFFECT" IN THE ROUTINE DETERMINATION OF SERUM AND PLASMA SODIUM LEVELS BY FLAME PHOTOMETRY
SIR,-Following the publication of our paper2 entitled A Reassessment of Normal Plasma-sodium Levels there appeared a letter from Dr. Hultman and Dr. Bergstrom 3 which suggested that the discrepancy between our observed normal sodium levels and those generally " accepted might be due to a protein interference effect " -an effect whereby the apparent sodium content of a serum was reduced compared with the figure obtained when protein-precipitation was carried out before spraying the fluid in the atomiser of a flame photometer. Determination by Hultman and Bergstrom of sodium levels in normal sera by a neutron-activation technique (not using a flame photometer) gave values closely agreeing with this hypothesis. We have confirmed that, using the instrument on which our published work was done, there is in fact a " protein interference effect " which would account for the discrepancy observed by us. We had relied (as we said in our paper) upon the fact that control sera purchased from several different firms gave results which agreed precisely with our own standards. But it appears that these commercial control sera fail to show the " protein interference effect", and so may not serve as critical controls when used as indicated by their suppliers. It will be necessary, therefore, for each laboratory to determine for itself the magnitude of the " protein interference effect " given by its own particular instruments. A technique which minimises the effect of pipette-errors, &c.,
is
as
follows:
1 ml. bulb pipette, calibrated " to deliver ", place 1 -0 ml. of serum under test in each of two containers labelled H2O and T.C.A. respectively. Add 4-0 ml. of water to the first container, and (using the same pipette) 4-0 ml. of 61/4% (w/v) trichloroacetic acid to the second. Mix the contents of each container, spin at 3000 r.p.m. for 3 minutes, and take 1-0 ml. of the supernatant from each into appropriately labelled 100 ml. volumetric flasks. Make up to 100 ml. with Na-free water, and prepare a blank from the same water by placing 0-8 ml. of the 61/4% trichloroacetic acid in another 100 ml. flask and making up to 100 ml. with water. The above volumes result in a final dilution of 1/500 of the test serum: if other dilutions are usually employed in routine work the final step can be altered accordingly, so that the supernatant ( =11/5 of test serum) is suitably further diluted. The difference in apparent sodium content between the " H;j0 " and " T.C.A." fluids is a measure of the " protein interference effect ". As it is not shown by all sera equally, a series of sera must be examined in this way. Sera which have been diluted 1/5 in water and kept for 3 days at 4°C do not show the effect. Sera which have been treated with ionexchange resin to remove sodium and potassium (and have
Using
a
1. Brit. Surg.J. 2. Lancet, 1962, 3. ibid. p. 1132.
1962, 50, i, 778.
334.