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Relation of plasma cell growth to abnormal serum protein components and bence jones proteinuria in multiple myeloma
Southern Society for Clinical Research flow is increased by the use of dinitrophenol and decreased following sciatic nerve stimulation. No evidence was found to support the hypothesis of “renal bypasses.” STIJDIESOF HEPATIC FUNCTION IN PATIENTS ON THE “RICE DIET.” J. 0. Myers, MB.
and (by invitation) R. J. F. Murphy, M.D. Dunham, N.C. (From the Department of Medicine,
Duke
University
School
af
Medicine.) ‘The hepatic blood flow, splanchnic oxygen consumption, net splanchnic glucose output and the hromsulfalein clearance have been estimated in a. group of subjects treated with the Kempnet “rice diet.” The data so obtained have been compared with similar figures obtained on control individuals without significant disease and with another series of patients with arterial hypertension but not receiving the rice diet. The hepatic blood flow and splanchnic oxygen consumption have been found normal in the subjects on the rice diet. The net splanchnic qiucose production is reduced in some individuals. A decided decrease in bromsulfalei~ clearance makes its appearance during the first several weeks on the diet and persists thereafter for as long as three months. The BSP clearance is reduced not only in comparison to normal subjects but in comparison with the non-treated hypertensives, also. The disability in removal of RSP from the blood parallels in general the reduction in serum cholesterol which these patients characteristicaliy show. Supplementation of the diet with cholesterol has thus far not prevented the fall in either BSP clearance or in serum cholesterol values. _A POSSIBLE MECHANISM FoR 'rLiETYPO-
TISNSIVEEFFECT OF THIOCYANATES. #orman S. Olsen, M.D. (introduced by Henry A. S~.h~oeder,M.D.) St. Louis, MO. {From the Hypertension Internal
Division,
Medicine,
Department Washington
of Uni-
versity School of Medicine.) Thiocyanates have been used successfully in therapeutically lowering blood pressure in selected hypertensive patients. Inasmuch as little is known concerning its mechanism of action, the effect of this ion was studied in vi&~. Two distinct actions of thiocyanate have been found in this study. The first, a general toxic effect on tissue oxidation, is probably a reflection of the untoward symptoms noted in patients. 1% z&o the toxic effect is obtained at levels of about SEPTEMBER.
1950
9%
O.lM thiocyanate. It was also found that cyanide in concentrations of 0.001 A4 produced the same result and a mixture of the two inhibitors results in no further action. The second action seems to be an inhibition of amino acid oxidation at a concentration of about 0.0005M thiocyanate. at which concentration little change is found in basal tissue oxidations. At these concentrations cyanide produces no inhibition of amino acid oxidation. Thiocyanate exerts no effect on the oxidation of added amines at these low concentrations. It has been postulated that faulty amino acid and amine metabolism are important in the pathogenesis of essential hypertension. If pressor amines are of significance in causing or maintaining hypertension, any agent which diminishes the production of amines from this parent amino acid should produce a hypotensive effect. It is found that thiocyanate produces a hypotensive effect at concentrations five times greater than those required to inhibit amino acid metabolism.
RELATION OF PLASMA CELI. GROWTH TO ABNORMAL SERUM PROTEIN COMPONENTS .4NDBENCEJONES PROTEINIJRL~IN MULTIPLE MYELOMA. R. IV. Rundles, .21.D. and (by invitation) M. L. Dillon, M.D., Edith S’. Di~~ou, M.D. and G. R. Cooled, :M.D. Durham, ,V.C. (From the Department of Medicine.
Duke
University
School
of’
Medicine.) The relationship of plasma cell proliferatioil to the abnormal serum proteins and to Bencc _Jones proteinuria in multiple myeloma has been studied during urethane therapy. In most patients 90 to 300 gm. of urethane given in a period of six to ten weeks reduces the nurnhet of abnormal plasma cells in the bone marrow and produces tnorphologic changes indicative of arrested or retarded growth. Sixty electrophoretic analyses of the serum proteins were tnade in eleven patients followed from three to twenty-eight months. Six patients with hyperproteinetnia had large peaks of abnormal protein with gamma mobility. After two to four months of therapy
three of them had virtually
normal patterns, only slight homogeneity remaining in the gamma globulin. In a fourth patient protein with gamtna mobility was reduced about 50 per cent. In two there was no change. One patient had a large protein increment with mobility intermediate between gamma and
4.06
Southern Society for Clinical Research
beta globulin. He obtained a partial remission during the first treatment period but relapsed after three months. Urethane was then given continuously, 1,275 gm. in fourteen months. He relapsed under treatment and urethane was discontinued. The excretion of Bence Jones protein in the urine then declined from an average of 17 to 19 gm. per day to 0.25 to 0.4 gm., serum protein with the mobility of the abnormal component fell from 2.35 gm. to 1.0 gm. per 100 CC. and the hemoglobin which had fallen below 6.0 gm. per 100 cc. was again maintained at normal levels. In one of the four patients with a virtually normal serum protein pattern a definitely abnormal peak developed during an exacerbation of his disease after being followed for seventeen months. In another patient heavy Bence Jones proteinuria was reduced 75 per cent without altering the serum protein pattern. As plasma cell growth is inhibited by urethane in multiple myeloma, abnormal serum protein components, even those generally found not to represent Bence Jones proteinemia, are reduced or may virtually disappear. This change parallels the reduction or disappearance of Bence Jones During prolonged continuous adproteinuria. ministration of urethane myeloma cells may become dependent on the chemical.
CEREBRAL METABOLISMIN HYPERTHYROIDISM AND MYXEDEMA. Peritz Scheinberg, M.D. (introduced by Eugene A. Stead, Jr., M.D.). Durham, N.C. (From the Duke University School of Medicine.) Cerebral blood flow and metabolism were measured by means of the nitrous oxide technic in nine subjects with hyperthyroidism and in eight subjects with myxedema. Three patients with myxedema were restudied after clinical improvement on thyroid therapy. The subjects with hyperthyroidism showed no significant variation from normal in any of the measured cerebral metabolic functions. This is of interest in view of the 35 per cent increase in splanchnic oxygen consumption known to occur in a similar series of hyperthyroid patients. The patients with myxedema showed reductions in cerebral blood flow (38 per cent) and oxygen consumption (27 per cent) commensurate with the fall in cardiac output and total oxygen consumption which occurs in these patients. Cerebral glucose consumption decreased in proportion to the cerebral oxygen consumption. Cerebral vascular resistance was increased almost 100 per cent. All cerebral metabolic
functions returned toward normal along with clinical improvement in the three patients restudied after thyroid therapy. These data indicate that in hyperthyroidism the brain does not share in the general increase which occurs in body metabolism and that the clinical signs of mental dysfunction so commonly observed in myxedema may be accounted for by the decreased cerebral metabolism in this disease.
PATHOCENESIS OFJARISCH-HERXHEIMER REACTION IN RABBIT SYPHILIS: PRODUCTION BY THE INJECTIONOF SYPHILITIC SERUM. Walter H. Sheldon, M.D., Albert Heyman, M.D. and (by invitation) Lilian D. Evans, M.D. Atlanta, Ga. (From the Departments of Pathology Genitoinfectious versity
School
and
Medicine,
(Clinic
Diseases),
Emory
of Medicine,
and
for Uni-
Grady
Memorial Hospital.) Previous studies have shown that transient acute inflammatory changes occur in human syphilitic lesions during the Herxheimer reaction. Similar histologic changes occur in syphilitic lesions of rabbits following treatment. Injections of living or dead spirochetes failed to produce these changes. Herxheimer-like reactions occur in Spirillum minus. infections in which immobilizing and lysing antibodies are present. This infection produces skin lesions in rabbits. When serum from similarly infected rabbits was given, the recipient animals showed histologic changes in the lesions resembling the changes occurring in the Herxheimer reaction of syphilis. Twelve rabbits were inoculated intravenously and in multiple skin sites with Treponema pallidum, Nichols strain. After lesions appeared each of the six animals was given 70 cc. of serum intravenously from untreated syphilitic rabbits. The remaining animals received equal amounts of normal rabbit serum. Individual syphilomas were excised from each animal before and after injection. On histologic examination transient acute inflammatory changes were found in the syphilomas of five animals receiving syphilitic serum. No changes were observed in the six controls. Our findings suggest a relationship of serum antibodies in syphilitic and Spirillum minus infections to the mechanism of the Herxheimer reaction. Further studies on this problem are in progress.
STUDIESON AN HOMOI.OGOUSBRAIN TISSUE ANTIGEN IN DOGS. Lezcis Thomas, -M.D.> AMERICAN
JOURNAL
OF
MEDICINE
and (by invitation) R. J. F. Murphy, M.D. Dunham, N.C. (From the Department of Medicine,
Duke
University
School
af
Medicine.) ‘The hepatic blood flow, splanchnic oxygen consumption, net splanchnic glucose output and the hromsulfalein clearance have been estimated in a. group of subjects treated with the Kempnet “rice diet.” The data so obtained have been compared with similar figures obtained on control individuals without significant disease and with another series of patients with arterial hypertension but not receiving the rice diet. The hepatic blood flow and splanchnic oxygen consumption have been found normal in the subjects on the rice diet. The net splanchnic qiucose production is reduced in some individuals. A decided decrease in bromsulfalei~ clearance makes its appearance during the first several weeks on the diet and persists thereafter for as long as three months. The BSP clearance is reduced not only in comparison to normal subjects but in comparison with the non-treated hypertensives, also. The disability in removal of RSP from the blood parallels in general the reduction in serum cholesterol which these patients characteristicaliy show. Supplementation of the diet with cholesterol has thus far not prevented the fall in either BSP clearance or in serum cholesterol values. _A POSSIBLE MECHANISM FoR 'rLiETYPO-
TISNSIVEEFFECT OF THIOCYANATES. #orman S. Olsen, M.D. (introduced by Henry A. S~.h~oeder,M.D.) St. Louis, MO. {From the Hypertension Internal
Division,
Medicine,
Department Washington
of Uni-
versity School of Medicine.) Thiocyanates have been used successfully in therapeutically lowering blood pressure in selected hypertensive patients. Inasmuch as little is known concerning its mechanism of action, the effect of this ion was studied in vi&~. Two distinct actions of thiocyanate have been found in this study. The first, a general toxic effect on tissue oxidation, is probably a reflection of the untoward symptoms noted in patients. 1% z&o the toxic effect is obtained at levels of about SEPTEMBER.
1950
9%
O.lM thiocyanate. It was also found that cyanide in concentrations of 0.001 A4 produced the same result and a mixture of the two inhibitors results in no further action. The second action seems to be an inhibition of amino acid oxidation at a concentration of about 0.0005M thiocyanate. at which concentration little change is found in basal tissue oxidations. At these concentrations cyanide produces no inhibition of amino acid oxidation. Thiocyanate exerts no effect on the oxidation of added amines at these low concentrations. It has been postulated that faulty amino acid and amine metabolism are important in the pathogenesis of essential hypertension. If pressor amines are of significance in causing or maintaining hypertension, any agent which diminishes the production of amines from this parent amino acid should produce a hypotensive effect. It is found that thiocyanate produces a hypotensive effect at concentrations five times greater than those required to inhibit amino acid metabolism.
RELATION OF PLASMA CELI. GROWTH TO ABNORMAL SERUM PROTEIN COMPONENTS .4NDBENCEJONES PROTEINIJRL~IN MULTIPLE MYELOMA. R. IV. Rundles, .21.D. and (by invitation) M. L. Dillon, M.D., Edith S’. Di~~ou, M.D. and G. R. Cooled, :M.D. Durham, ,V.C. (From the Department of Medicine.
Duke
University
School
of’
Medicine.) The relationship of plasma cell proliferatioil to the abnormal serum proteins and to Bencc _Jones proteinuria in multiple myeloma has been studied during urethane therapy. In most patients 90 to 300 gm. of urethane given in a period of six to ten weeks reduces the nurnhet of abnormal plasma cells in the bone marrow and produces tnorphologic changes indicative of arrested or retarded growth. Sixty electrophoretic analyses of the serum proteins were tnade in eleven patients followed from three to twenty-eight months. Six patients with hyperproteinetnia had large peaks of abnormal protein with gamma mobility. After two to four months of therapy
three of them had virtually
normal patterns, only slight homogeneity remaining in the gamma globulin. In a fourth patient protein with gamtna mobility was reduced about 50 per cent. In two there was no change. One patient had a large protein increment with mobility intermediate between gamma and
4.06
Southern Society for Clinical Research
beta globulin. He obtained a partial remission during the first treatment period but relapsed after three months. Urethane was then given continuously, 1,275 gm. in fourteen months. He relapsed under treatment and urethane was discontinued. The excretion of Bence Jones protein in the urine then declined from an average of 17 to 19 gm. per day to 0.25 to 0.4 gm., serum protein with the mobility of the abnormal component fell from 2.35 gm. to 1.0 gm. per 100 CC. and the hemoglobin which had fallen below 6.0 gm. per 100 cc. was again maintained at normal levels. In one of the four patients with a virtually normal serum protein pattern a definitely abnormal peak developed during an exacerbation of his disease after being followed for seventeen months. In another patient heavy Bence Jones proteinuria was reduced 75 per cent without altering the serum protein pattern. As plasma cell growth is inhibited by urethane in multiple myeloma, abnormal serum protein components, even those generally found not to represent Bence Jones proteinemia, are reduced or may virtually disappear. This change parallels the reduction or disappearance of Bence Jones During prolonged continuous adproteinuria. ministration of urethane myeloma cells may become dependent on the chemical.
CEREBRAL METABOLISMIN HYPERTHYROIDISM AND MYXEDEMA. Peritz Scheinberg, M.D. (introduced by Eugene A. Stead, Jr., M.D.). Durham, N.C. (From the Duke University School of Medicine.) Cerebral blood flow and metabolism were measured by means of the nitrous oxide technic in nine subjects with hyperthyroidism and in eight subjects with myxedema. Three patients with myxedema were restudied after clinical improvement on thyroid therapy. The subjects with hyperthyroidism showed no significant variation from normal in any of the measured cerebral metabolic functions. This is of interest in view of the 35 per cent increase in splanchnic oxygen consumption known to occur in a similar series of hyperthyroid patients. The patients with myxedema showed reductions in cerebral blood flow (38 per cent) and oxygen consumption (27 per cent) commensurate with the fall in cardiac output and total oxygen consumption which occurs in these patients. Cerebral glucose consumption decreased in proportion to the cerebral oxygen consumption. Cerebral vascular resistance was increased almost 100 per cent. All cerebral metabolic
functions returned toward normal along with clinical improvement in the three patients restudied after thyroid therapy. These data indicate that in hyperthyroidism the brain does not share in the general increase which occurs in body metabolism and that the clinical signs of mental dysfunction so commonly observed in myxedema may be accounted for by the decreased cerebral metabolism in this disease.
PATHOCENESIS OFJARISCH-HERXHEIMER REACTION IN RABBIT SYPHILIS: PRODUCTION BY THE INJECTIONOF SYPHILITIC SERUM. Walter H. Sheldon, M.D., Albert Heyman, M.D. and (by invitation) Lilian D. Evans, M.D. Atlanta, Ga. (From the Departments of Pathology Genitoinfectious versity
School
and
Medicine,
(Clinic
Diseases),
Emory
of Medicine,
and
for Uni-
Grady
Memorial Hospital.) Previous studies have shown that transient acute inflammatory changes occur in human syphilitic lesions during the Herxheimer reaction. Similar histologic changes occur in syphilitic lesions of rabbits following treatment. Injections of living or dead spirochetes failed to produce these changes. Herxheimer-like reactions occur in Spirillum minus. infections in which immobilizing and lysing antibodies are present. This infection produces skin lesions in rabbits. When serum from similarly infected rabbits was given, the recipient animals showed histologic changes in the lesions resembling the changes occurring in the Herxheimer reaction of syphilis. Twelve rabbits were inoculated intravenously and in multiple skin sites with Treponema pallidum, Nichols strain. After lesions appeared each of the six animals was given 70 cc. of serum intravenously from untreated syphilitic rabbits. The remaining animals received equal amounts of normal rabbit serum. Individual syphilomas were excised from each animal before and after injection. On histologic examination transient acute inflammatory changes were found in the syphilomas of five animals receiving syphilitic serum. No changes were observed in the six controls. Our findings suggest a relationship of serum antibodies in syphilitic and Spirillum minus infections to the mechanism of the Herxheimer reaction. Further studies on this problem are in progress.
STUDIESON AN HOMOI.OGOUSBRAIN TISSUE ANTIGEN IN DOGS. Lezcis Thomas, -M.D.> AMERICAN
JOURNAL
OF
MEDICINE