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Effect in plasma thromboplastin component (PTC) deficiency of intravenous administration of plasma fraction IV
Western Society for Clinical Research tolerance of constriction of the pulmonary artery was compared before and after the administration of ouabain. In two-thirds of the animals ouabain had a measurable effect upon the heart in permitting tolerance of more constriction and postponing the physiologic fatigue from overloading. It is concluded therefore that ouahain exerts a favorable effect upon the dog’s normal heart under stress. ROLE
OF
THYROTROPHIC
HORMONE
IN
THE
Benjamin Simkin, * Paul Starr* and Charles Hancock, Dept. of Medicine, Univ. of Southern California School of Medicine, Los Angeles, Calif. PATHOGENESIS OF EXOPHTHALMOS.
Last year we presented data showing that thyroid-stimulating doses of thyrotrophic hormone (TSH) do not produce exophthalmos in man. Further observations indicate that relatively much larger doses of the same preparation of TSH administered to the guinea pig produces clear-cut exophthalmos in this species. Serum TSH assays were made in twenty patients exhibiting exophthalmos, with the following results (normal eye measurements range from 10 to 17 mm.).
Thyroid Status
Exophthalmometer ~~~ of Readings (mm.) Patients -OD
Increase MACH (/J)
OS
I Euthyroid.
6
Hyperthyroid..
8
Hypothyroid.
6
_!
121.2321.61
I
+0 .15 (no serum
TSH) +0 13 (no serum TSH) +O. 82 (serum TSH present)
The serum TSH assay results in these patients with exophthalmos are similar to those obtained in patients with the corresponding thyroid states but without exophthalmos (previously reported by us). It may be concluded that serum TSH levels in patients with exophthalmos are dependent on their thyroid status rather than the presence or absence of exophthalmos. Another study concerned the distribution of TSH labelled with radioactive iodine in the orbital tissues of the thyroidectomized rat following intracardiac injection of the labelled hormone in this species. Control observations SEPTEMBER,
1953
421
were made with labelled serum albumin. It was found that there is no selective localization of TSH in the retro-orbital fat or extraocular muscles of the thyroidectomized rat. All of the observations cited above are consistent with the theory that TSH per se is not the factor that causes exophthalmos. SYNDROME IN Two MALES AND ONE FEMALE WITH CONGENITAL HEART DISEASE. Frank H. Tyler, * Hans H. Hecht * and Avery .4. Sandberg, Dept. of Internal Medicine, College of Medicine, Univ. of Utah, Salt Lake City, Utah. TURNER’S
‘Ilie have observed three patients with Turner’s syndrome during the past two years who presented certain features which contrast with previous reports of this disorder. Specifically, two of the patients were males and each of the patients had congenital heart disease which on complete study proved to be other than coarctation of the aorta. Patient
- tSex Age Gonads ._-p/ .M
11
c. s.
F
7
W. F.
M
2
A. S.
-
Infantile testis Ovarian agenesis Undescended testes
Heart I____.___ __ ~lnteratrial septal defect Interventricular septal defect Pulmonary stenosis, aberrant pulmonary vein, patent foramen I ovale
1
EFFECT IN PLASMA THROMBOPLASTINCOMPONENT (PTC) DEFICIENCY OF INTRAVENOUS ADMINISTRATION OF PLASMAFRACTION IV. Sidney G. White, Paul M. Aggeler* and Byron E. Emery, Dept. of Medicine, Univ. of California School of Medicine, San Francisco, Calif., and the Cutter Laboratories, Berkeley, Calif. Plasma thromboplastin component (PTC) deficiency, which resembles hemophilia, does not respond to Fraction I of Cohn. An investigation was made of the various Cohn fractions in vitro by testing their effect on the PTC deficient patient’s defective prothrombin utilization. The PTC potency of Fractions II $ III, IV and IV-~ was high; of I and v slight; and of II and IV-~, none. Since Fraction III contained thrombin it could not be separately assayed for PTC nor administered intravenously. Although Fraction IV-1 was potent its solubility was too poor for intravenous use. A preparation of Fraction IV for intravenous use was made as follows: an 11 per cent concentration of the fresh fraction was mixed in a
422
Western Society for Clinical Research
Waring blender, passed through a sterilizing porcelain filter and frozen. After filtration it contained 9.2 per cent total solids, 6.5 per cent protein, 190 units prothrombin per cc. and 69 per cent of the proconvertin of an equivalent volume of plasma. Tests for sterility, pyrogenicity, toxicity and vasodepressor effects in rabbits were negative. In a typical experiment, before administration of the fraction the patient’s coagulation time was twenty-two minutes and serum prothrombin 100 per cent. At fifteen minutes, four hours, twenty-four hours and four days after administration of 85 cc. of the fraction the values were: twelve minutes and 17 per cent, twelve minutes and 24 per cent, sixteen minutes and 45 per cent, and twenty-three minutes and 88 per cent. These results compare favorably with those found after the administration of a comparable amount of Fraction I in hemophilia. THE NATUREOFTHEACTIONOFINSULIN.Arne N. Wick* and Douglas R. Drury, * The Scripps Metabolic Clinic, La Jolla, California and the Univ. of Southern California, Los Angeles, Calif. Recent work has indicated that insulin exerts its action at the surface of the cell, promoting there the entry of glucose into the cell. According to this view the apparent results of insulin administration-increased oxidation and storage of glucose-follow secondarily the increase in amount of glucose that has entered the cells. It has been suggested that this theory might be tested by seeing whether other hexoses, similar to glucose but not oxidized or otherwise metabolized even if they enter the cell, were transferred intracellularly at increased rates as a result of insulin action. To this end we have studied the metabolic reactions to insulin of several compounds closely related to glucose. Sorbitol, gluconic acid and fructose distribute in the body in the extracellular space only and do not enter the cell to more than an insignificant degree. On the other hand, galactose and mannose will enter the cells in relatively large amounts as a result of insulin action. These hexoses are not metabolized to any great extent after entry into the cell. These findings support the view that insulin acts by promoting the transfer of glucose into the cell. This action is relatively but not absolutely specific-carbohydrates with a chemical structure closely approximating that of glucose being acted on in the same way.
SIGNIFICANCE OF THE INDUCEDDIGITAL VASOCONSTRICTOR REFLEXES. Travis Winsor, * Hosp. of Good Samaritan, Los Angeles, Calif. The induced digital vasoconstrictive reflexes are involuntary vasoconstrictor reactions which may follow stimulation of sensory organs or may arise from other sources such as the cerebral cortex. This report deals with an analysis of these reactions which follow certain stimuli (inspiration, expiration, anticipation, cold, tickle, pain, a startling sound and a startling light). Five hundred reflexes were studied among 250 subjects to determine the nerve pathways involved and the clinical significance of these reactions. Although eight different stimuli were employed, the reaction was qualitatively but not quantitatively similar. The reaction to sound took place an average of 3.2 seconds after stimulation and was complete usually in 45 seconds. The reaction consisted of a decrease in the total volume and volume pulsation of the digit and was associated ordinarily with sweating, as shown by the simultaneously recorded psychogalvanogram. The reflex could be inhibited voluntarily by mental effort and could be fatigued by repeated stimulation for two to four minutes. The magnitude of the reflex was relative to the magnitude of the stimulus. The reflexes could be abolished by lesions in the receptor organ, afferent pathways or in the cerebrum, and by novocain injected into the sympathetic vertebral ganglia or peripheral nerves. Tetraethyl ammonium chloride, dimethyl, di-ethyl piperidinium chloride, the hydrogenated alkaloids of ergot and benzylimidazoline parenterally blocked these reflexes. Oral whiskey, 60 cc., failed to block the reflexes. Knowledge of these reactions aided in determining the extent of organic arterial disease present in twenty cases. The presence of a deep reflex signified a good result following lumbar sympathectomy in twenty cases. The simultaneous recording of this reflex from a digit of each extremity assisted in localizing obstructive lesions in the sympathetic nervous system in two patients. The presence of this reflex before and its absence soon after lumbar sympathectomy provided a means of determining the completeness of lumbar sympathectomy in thirty patients and repeated determinations at intervals of months provided a means of determining the rate of regrowth of sympathetic nerves after surgery in thirty cases. AMERICAN
JOURNAL
OF
MEDICINE
OF
THYROTROPHIC
HORMONE
IN
THE
Benjamin Simkin, * Paul Starr* and Charles Hancock, Dept. of Medicine, Univ. of Southern California School of Medicine, Los Angeles, Calif. PATHOGENESIS OF EXOPHTHALMOS.
Last year we presented data showing that thyroid-stimulating doses of thyrotrophic hormone (TSH) do not produce exophthalmos in man. Further observations indicate that relatively much larger doses of the same preparation of TSH administered to the guinea pig produces clear-cut exophthalmos in this species. Serum TSH assays were made in twenty patients exhibiting exophthalmos, with the following results (normal eye measurements range from 10 to 17 mm.).
Thyroid Status
Exophthalmometer ~~~ of Readings (mm.) Patients -OD
Increase MACH (/J)
OS
I Euthyroid.
6
Hyperthyroid..
8
Hypothyroid.
6
_!
121.2321.61
I
+0 .15 (no serum
TSH) +0 13 (no serum TSH) +O. 82 (serum TSH present)
The serum TSH assay results in these patients with exophthalmos are similar to those obtained in patients with the corresponding thyroid states but without exophthalmos (previously reported by us). It may be concluded that serum TSH levels in patients with exophthalmos are dependent on their thyroid status rather than the presence or absence of exophthalmos. Another study concerned the distribution of TSH labelled with radioactive iodine in the orbital tissues of the thyroidectomized rat following intracardiac injection of the labelled hormone in this species. Control observations SEPTEMBER,
1953
421
were made with labelled serum albumin. It was found that there is no selective localization of TSH in the retro-orbital fat or extraocular muscles of the thyroidectomized rat. All of the observations cited above are consistent with the theory that TSH per se is not the factor that causes exophthalmos. SYNDROME IN Two MALES AND ONE FEMALE WITH CONGENITAL HEART DISEASE. Frank H. Tyler, * Hans H. Hecht * and Avery .4. Sandberg, Dept. of Internal Medicine, College of Medicine, Univ. of Utah, Salt Lake City, Utah. TURNER’S
‘Ilie have observed three patients with Turner’s syndrome during the past two years who presented certain features which contrast with previous reports of this disorder. Specifically, two of the patients were males and each of the patients had congenital heart disease which on complete study proved to be other than coarctation of the aorta. Patient
- tSex Age Gonads ._-p/ .M
11
c. s.
F
7
W. F.
M
2
A. S.
-
Infantile testis Ovarian agenesis Undescended testes
Heart I____.___ __ ~lnteratrial septal defect Interventricular septal defect Pulmonary stenosis, aberrant pulmonary vein, patent foramen I ovale
1
EFFECT IN PLASMA THROMBOPLASTINCOMPONENT (PTC) DEFICIENCY OF INTRAVENOUS ADMINISTRATION OF PLASMAFRACTION IV. Sidney G. White, Paul M. Aggeler* and Byron E. Emery, Dept. of Medicine, Univ. of California School of Medicine, San Francisco, Calif., and the Cutter Laboratories, Berkeley, Calif. Plasma thromboplastin component (PTC) deficiency, which resembles hemophilia, does not respond to Fraction I of Cohn. An investigation was made of the various Cohn fractions in vitro by testing their effect on the PTC deficient patient’s defective prothrombin utilization. The PTC potency of Fractions II $ III, IV and IV-~ was high; of I and v slight; and of II and IV-~, none. Since Fraction III contained thrombin it could not be separately assayed for PTC nor administered intravenously. Although Fraction IV-1 was potent its solubility was too poor for intravenous use. A preparation of Fraction IV for intravenous use was made as follows: an 11 per cent concentration of the fresh fraction was mixed in a
422
Western Society for Clinical Research
Waring blender, passed through a sterilizing porcelain filter and frozen. After filtration it contained 9.2 per cent total solids, 6.5 per cent protein, 190 units prothrombin per cc. and 69 per cent of the proconvertin of an equivalent volume of plasma. Tests for sterility, pyrogenicity, toxicity and vasodepressor effects in rabbits were negative. In a typical experiment, before administration of the fraction the patient’s coagulation time was twenty-two minutes and serum prothrombin 100 per cent. At fifteen minutes, four hours, twenty-four hours and four days after administration of 85 cc. of the fraction the values were: twelve minutes and 17 per cent, twelve minutes and 24 per cent, sixteen minutes and 45 per cent, and twenty-three minutes and 88 per cent. These results compare favorably with those found after the administration of a comparable amount of Fraction I in hemophilia. THE NATUREOFTHEACTIONOFINSULIN.Arne N. Wick* and Douglas R. Drury, * The Scripps Metabolic Clinic, La Jolla, California and the Univ. of Southern California, Los Angeles, Calif. Recent work has indicated that insulin exerts its action at the surface of the cell, promoting there the entry of glucose into the cell. According to this view the apparent results of insulin administration-increased oxidation and storage of glucose-follow secondarily the increase in amount of glucose that has entered the cells. It has been suggested that this theory might be tested by seeing whether other hexoses, similar to glucose but not oxidized or otherwise metabolized even if they enter the cell, were transferred intracellularly at increased rates as a result of insulin action. To this end we have studied the metabolic reactions to insulin of several compounds closely related to glucose. Sorbitol, gluconic acid and fructose distribute in the body in the extracellular space only and do not enter the cell to more than an insignificant degree. On the other hand, galactose and mannose will enter the cells in relatively large amounts as a result of insulin action. These hexoses are not metabolized to any great extent after entry into the cell. These findings support the view that insulin acts by promoting the transfer of glucose into the cell. This action is relatively but not absolutely specific-carbohydrates with a chemical structure closely approximating that of glucose being acted on in the same way.
SIGNIFICANCE OF THE INDUCEDDIGITAL VASOCONSTRICTOR REFLEXES. Travis Winsor, * Hosp. of Good Samaritan, Los Angeles, Calif. The induced digital vasoconstrictive reflexes are involuntary vasoconstrictor reactions which may follow stimulation of sensory organs or may arise from other sources such as the cerebral cortex. This report deals with an analysis of these reactions which follow certain stimuli (inspiration, expiration, anticipation, cold, tickle, pain, a startling sound and a startling light). Five hundred reflexes were studied among 250 subjects to determine the nerve pathways involved and the clinical significance of these reactions. Although eight different stimuli were employed, the reaction was qualitatively but not quantitatively similar. The reaction to sound took place an average of 3.2 seconds after stimulation and was complete usually in 45 seconds. The reaction consisted of a decrease in the total volume and volume pulsation of the digit and was associated ordinarily with sweating, as shown by the simultaneously recorded psychogalvanogram. The reflex could be inhibited voluntarily by mental effort and could be fatigued by repeated stimulation for two to four minutes. The magnitude of the reflex was relative to the magnitude of the stimulus. The reflexes could be abolished by lesions in the receptor organ, afferent pathways or in the cerebrum, and by novocain injected into the sympathetic vertebral ganglia or peripheral nerves. Tetraethyl ammonium chloride, dimethyl, di-ethyl piperidinium chloride, the hydrogenated alkaloids of ergot and benzylimidazoline parenterally blocked these reflexes. Oral whiskey, 60 cc., failed to block the reflexes. Knowledge of these reactions aided in determining the extent of organic arterial disease present in twenty cases. The presence of a deep reflex signified a good result following lumbar sympathectomy in twenty cases. The simultaneous recording of this reflex from a digit of each extremity assisted in localizing obstructive lesions in the sympathetic nervous system in two patients. The presence of this reflex before and its absence soon after lumbar sympathectomy provided a means of determining the completeness of lumbar sympathectomy in thirty patients and repeated determinations at intervals of months provided a means of determining the rate of regrowth of sympathetic nerves after surgery in thirty cases. AMERICAN
JOURNAL
OF
MEDICINE