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Studies on Osteoporoses. XII. Effect of Imidazoquinazolinones on Experimental Osteoporosis. A Preliminary Report
838
METABOLISM, ENDOCRINOLOGY AND IMMUNOLOGY
nonobstructive megaureter. If most of the dilatation is in the ureter rather than the pelvis the counting crystal should be positioned over the area of extreme ureterectasis during the test. Cass also has found a good (that is approximately 90 per cent) correlation between a positive diuretic urogram and other objective indications of obstruction. L.R.K. In a small series of 20 children the authors claim 83 per cent accuracy for identifying obstruction and 94 per cent over-all specificity for the diuretic renogram. Technical details regarding the performance of the diuretic renogram are provided. However, the means by which the diagnosis of obstruction or no obstruction is formulated is not stated. There are only 5 children in this series with truly obstructed urinary tracts on the diuretic renogram and at the findings at operation. The authors suggest that diuretic renography may prove to be less invasive than direct renal perfusion studies to diagnose obstruction of the urinary tract. It appears that there currently is no true gold standard in the diagnosis of urinary tract obstruction. Rather, the urologist must synthesize all facts available to him, including clinical history, physical examination, findings of delayed drainage on excretory urography, retrograde pyelography, voiding cystourethrography, renal scan and, perhaps, a Whitaker test, before formulating a clinical diagnosis. At our institution the diuretic renogram has been most reliable when brisk drainage from the upper urinary tract is effected by the intravenous administration of furosemide. When drainage is delayed obstruction may or may not be present. Further insight into the mechanisms that may confuse the interpretation of the diuretic renogram is needed. M.M.
Localization of Osteoid Osteomas-Use of Radionuclide Scanning and Autoimaging in Identifying the Nidus V.
J. VIGORITA AND B. GHELMAN, Departments of Pathology and Radiology, The Hospital for Special Surgery, New York, New York
Amer. J. Clin. Path., 79: 223-225 (Feb.) 1983 The intraoperative localization of osteoid osteomas is difficult. Their size rarely is > 1 cm. and location within cortical bone makes it hard for the pathologist to identify it in submitted specimens. The radionuclide technique was used in 3 patients to localize the lesion during operation. The patients were injected preoperatively with 99 mmethylene diphosphonate in the usual manner for radionuclide scanning. At operation the localization of increased radioactivity was done using a scale rate meter coupled with a sterilized sodium-iodine scintillation probe. The probe was placed in contact with the involved bone and the surgeon was directed to remove samples at sites of high radioactivity counts. The specimens were placed in formalin and laid to rest for 2 to 8 hours in plastic jars over x-ray cassettes, which contained rare earth intensifying screens and undeveloped x-ray film. In all 3 cases autoimaging on undeveloped x-ray film was positive and, furthermore, the fragment with most intense autoimaging corresponded to the microscopically proved nidus. C.E.M. 3 figures, 6 references
METABOLISM, ENDOCRINOLOGY AND IMMUNOLOGY Studies on Osteoporoses. VIII. Effect of Estrogen on Steroid Induced Osteoporosis
J. C.
ROBIN AND J. L. AMBRUS, Roswell Park Memorial Institute and Departments of Internal Medicine and Experimental Pathology, State University of New York, Buffalo, New York
J. Med., 13: 453-463, 1983 Osteoporosis often is a significant side effect of chronic administration of corticosteroids. Secondary estrogen deficiency has been implicated in steroid-induced osteoporosis. The efficacy of estrogen in preventing steroid-induced osteoporosis was tested in a well established animal model. Inbred C3H/St(Ha) and C51/BL6 (JACOBS) female mice, 5 to 8 or 15 to 18 months old, were divided into 4 treatment groups for each age and strain. The groups received prednisolone and/or conjugated estrogens for 3 months. Controls received normal saline. Animals were exposed to in vivo neutron activation analysis with irradiation performed in a pulstar reactor before treatment and 3 months later. Total skeletal calcium was calculated as 99 per cent of total calcium content and loss of calcium was used as an index of osteoporosis. After completion of the study the mice were dry ashed and results were verified by atomic absorption spectroscopy. The diagnosis of osteoporosis was confirmed by quantitative histomorphometric analysis. Prednisolone (50 mg./kg. daily) for 3 months resulted in significant osteoporosis in the C3H/St(Ha) mice of both age groups but did not cause significant bone loss in the C57BL6 (JACOBS) mice of either age group. Conjugated estrogens (20 mg./kg. daily) failed to prevent steroid accelerated osteoporosis. M.G.F. 2 figures, 22 references
Studies on Osteoporoses. XII. Effect of Imidazoquinazolinones on Experimental Osteoporosis. A Preliminary Report
J. C. ROBIN AND J. L. AMBRUS, Roswell Park Memorial Institute and Departments of Internal Medicine and Experimental Pathology, State University of New York, Buffalo, New York J. Med., 13: 465-472, 1983 A murine model of heparin-induced osteoporosis has been developed to test potential antiosteoporotic agents. Heparin is believed to cause osteoporosis by disruption of osteoblastic activity. The level of cyclic adenosine monophosphate in tissue is balanced by its rate of synthesis by adenylate cyclase and its breakdown by cyclic 3,5' -phosphodiesterase. As for other tissues, bone cell cyclic adenosine monophosphate phosphodiesterases have been shown to be of either low or high Km form. Low Km sites may maintain steady state conditions, such as osteoblastic control of osteoid formation, primary mineralization and membrane function. High Km sites may be important when cells are perturbed, such as initiation of resorption. This investigation is designed to study the ability of 6-methyl1,2,3,5-tetrahydroimidazel-(2,1-b )quinazolin-2-one hydrochlo-
METABOLISM, ENDOCRINOLOGY AND IMMUNOLOGY
ride monohydrate and 7-chloro-6-methyl-1H,2,3,4,5-tetrahydroimidaze(2,1-b)quinazolin-2-one hydrochloride, synthetic highly active low Km phosphodiesterase inhibitors, in preventing heparin-induced osteoporosis. Heparin (500 U./kg. twice daily) treatment for 3 months resulted in significant osteoporosis in L3H/St(Ha) female mice. The BL compounds 3459 and 4160 prevented osteoporosis in the murine model as measured by neutron activation analysis of total body calcium, since 99 per cent is in bone. M.G.F. 1 figure, 17 references Calmodulin Levels and Divalent Cation Pump Activities in Kidneys of Streptozotocin-Diabetic Rats B. HOSKINS AND J. M. SCOTT, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi Res. Comm. Chem. Path. Pharm., 39: 189-199 (Feb.) 1983
839
A total of 68 patients (11 per cent) had hypomagnesemia and 58 had hypermagnesemia. Charts were reviewed in 29 patients with hypomagnesemia. The following causes of magnesium depletion were identified: alcoholism in 7 cases (24 per cent), malnutrition, carcinomatosis and diabetes in 11 (38 per cent), diuretic therapy in 2 (7 per cent), chronic renal failure in 2 (7 per cent), and pregnancy in 5 (17 per cent). Of the patients 61 were assessed for calcium levels and were found to be hypocalcemic, 18 owing to renal failure. Of the remaining 43 cases 10 (23.3 per cent) were associated with hypomagnesemia. C.E.M. 2 figures, 17 references Disposition of Medroxyprogesterone Acetate and Drug Metabolism Activity H. u. SAARNI, A. RAUTIO, N. T. KARKI AND E. A. SOTANIEMI, Department of Pharmacology and Clinical Research Unit of Internal Medicine, University of Oulu, Oulu, Finland
Calmodulin is a calcium-binding multifunctional protein that is able to maintain normal cell functions by calcium-dependent translocations from the unactive membrane-bound form to the calcium-bound active form, which preferentially can modulate the activities of a number of cellular enzymes and processes. Levels of calmodulin and activities of calcium and magnesium adenosine triphosphatases were determined in renal tissues of age-matched male rats after increasing durations of the following conditions: untreated streptozotocin-induced diabetes, streptozotocin-diabetic rats treated with insulin started 24 hours after streptozotocin administration and streptozotocindiabetic rats that received neutral protein Hagedorn insulin after being rendered diabetic without treatment for 1 to 3 weeks. Results were compared to those of age-matched control animals. Calmodulin levels were the same in renal tissues from all the groups of rats, as were magnesium-adenosine triphosphatase activities. After 2 weeks of untreated streptozotocin-diabetes calcium adenosine triphosphatase activities were significantly higher than control activities. The same observation was made on streptozotocin-diabetic rats treated with insulin after 1 to 3 weeks. Calcium adenosine triphosphatase activities of tissues from streptozotocin -diabetic rats treated with insulin after 24 hours of streptozotocin administration were no different from control values. These data suggest that prolonged deficiency of insulin results in insufficient passive transport of calcium from urine into tubular cells. C.E.M. 1 figure, 3 tables, 11 references
Kinetics of medroxyprogesterone acetate were studied in male rats. Hepatic drug metabolism was induced by phenobarbital or inhibited by ,6-diethyl-aminoethyl-2,2-diphenylvalerate. Plasma concentrations of unmetabolized medroxyprogesterone acetate and the amounts of medroxyprogesterone acetate-related residues in various tissues were higher in the ,6diethyl-aminoethyl-2,2-diphenylvalerate and slightly lower in phenobarbital-treated animals than in the controls. The disappearance of medroxyprogesterone acetate-related substances from the lung, skeletal muscle and brain was slow. There was an increase of medroxyprogesterone acetate residue in the phenobarbital and control rats at 24 hours. The same amounts of medroxyprogesterone acetate were excreted in the urine and intestine in the control rats. The induction of drug metabolism (phenobarbital) enhanced the urine excretion of medroxyprogesterone acetate, while its inhibition ,6-diethyl-aminoethyl2,2-diphenylvalerate increased intestinal elimination. The results show that plasma concentration of intact medroxyprogesterone acetate, its residues in various tissues and the main elimination routes are dependent on the hepatic metabolization of these drugs in rats. C.E.M. 2 figures, 1 table, 13 references
A High Prevalence of Hypomagnesemia and Hypermagnesemia in Hospitalized Patients
L. L. GERSHBEIN, J. D. GERSHBEIN AND R. FRENCH, Northwest Institute for Medical Research, Chicago, Illinois
E.T. WONG, R. K. RUDE, F. R. SINGER AND S. T. SHAW, JR., Departments of Pathology and Medicine, University of Southern California School of Medicine and Los Angeles County/ University of Southern California Medical Center, Los Angeles, California and the Orthopedic Hospital, University of Southern California Bone and Connective Tissue Laboratory, Los Angeles, California
Res. Comm. Chem. Path. Pharm., 39: 251-260 (Feb.) 1983
Behavior of Male Rats Fed Low Levels of Metallic Salts
Res. Comm. Chem. Path. Pharm., 39: 507-510 (Mar.) 1983
The exposure of animals to a variety of heavy metal trace elements has been known to elicit short-term or more permanent effects on behavior. The authors' study applies the criterion of exploratory behavior to male rats as based on the poke test. A comparison also is made of runway performance that, in contrast to the poke test, involved prior food deprivation. Male rats, 44 days old, were fed diets ad lib containing the Amer. J. Clin. Path., 79: 348-352 (Mar.) 1983 following in parts per million by weight: cobalt++ (75), copThere were 621 serum samples selected at random (from per++ (75), iron+++ (150), manganese++ (75), nickel++ (75), those submitted to the clinical laboratory for a 19-test panel of lead++ (10) and zinc++ (75), the controls receiving the ration. chemistry studies) to determine serum magnesium levels. Only At days 55 and 56 of feeding the rats were subjected to the inpatient serum was used. The reference range for serum mag- poke test and no remarkable differences could be discerned in nesium was established in this study as 1.2 to 1.9 mEq./1. from the 5-minute ratings. For the first I-minute scores a small but measurements of serum magnesium in 341 healthy volunteers. significant change was apparent with iron+++ versus lead++.
METABOLISM, ENDOCRINOLOGY AND IMMUNOLOGY
nonobstructive megaureter. If most of the dilatation is in the ureter rather than the pelvis the counting crystal should be positioned over the area of extreme ureterectasis during the test. Cass also has found a good (that is approximately 90 per cent) correlation between a positive diuretic urogram and other objective indications of obstruction. L.R.K. In a small series of 20 children the authors claim 83 per cent accuracy for identifying obstruction and 94 per cent over-all specificity for the diuretic renogram. Technical details regarding the performance of the diuretic renogram are provided. However, the means by which the diagnosis of obstruction or no obstruction is formulated is not stated. There are only 5 children in this series with truly obstructed urinary tracts on the diuretic renogram and at the findings at operation. The authors suggest that diuretic renography may prove to be less invasive than direct renal perfusion studies to diagnose obstruction of the urinary tract. It appears that there currently is no true gold standard in the diagnosis of urinary tract obstruction. Rather, the urologist must synthesize all facts available to him, including clinical history, physical examination, findings of delayed drainage on excretory urography, retrograde pyelography, voiding cystourethrography, renal scan and, perhaps, a Whitaker test, before formulating a clinical diagnosis. At our institution the diuretic renogram has been most reliable when brisk drainage from the upper urinary tract is effected by the intravenous administration of furosemide. When drainage is delayed obstruction may or may not be present. Further insight into the mechanisms that may confuse the interpretation of the diuretic renogram is needed. M.M.
Localization of Osteoid Osteomas-Use of Radionuclide Scanning and Autoimaging in Identifying the Nidus V.
J. VIGORITA AND B. GHELMAN, Departments of Pathology and Radiology, The Hospital for Special Surgery, New York, New York
Amer. J. Clin. Path., 79: 223-225 (Feb.) 1983 The intraoperative localization of osteoid osteomas is difficult. Their size rarely is > 1 cm. and location within cortical bone makes it hard for the pathologist to identify it in submitted specimens. The radionuclide technique was used in 3 patients to localize the lesion during operation. The patients were injected preoperatively with 99 mmethylene diphosphonate in the usual manner for radionuclide scanning. At operation the localization of increased radioactivity was done using a scale rate meter coupled with a sterilized sodium-iodine scintillation probe. The probe was placed in contact with the involved bone and the surgeon was directed to remove samples at sites of high radioactivity counts. The specimens were placed in formalin and laid to rest for 2 to 8 hours in plastic jars over x-ray cassettes, which contained rare earth intensifying screens and undeveloped x-ray film. In all 3 cases autoimaging on undeveloped x-ray film was positive and, furthermore, the fragment with most intense autoimaging corresponded to the microscopically proved nidus. C.E.M. 3 figures, 6 references
METABOLISM, ENDOCRINOLOGY AND IMMUNOLOGY Studies on Osteoporoses. VIII. Effect of Estrogen on Steroid Induced Osteoporosis
J. C.
ROBIN AND J. L. AMBRUS, Roswell Park Memorial Institute and Departments of Internal Medicine and Experimental Pathology, State University of New York, Buffalo, New York
J. Med., 13: 453-463, 1983 Osteoporosis often is a significant side effect of chronic administration of corticosteroids. Secondary estrogen deficiency has been implicated in steroid-induced osteoporosis. The efficacy of estrogen in preventing steroid-induced osteoporosis was tested in a well established animal model. Inbred C3H/St(Ha) and C51/BL6 (JACOBS) female mice, 5 to 8 or 15 to 18 months old, were divided into 4 treatment groups for each age and strain. The groups received prednisolone and/or conjugated estrogens for 3 months. Controls received normal saline. Animals were exposed to in vivo neutron activation analysis with irradiation performed in a pulstar reactor before treatment and 3 months later. Total skeletal calcium was calculated as 99 per cent of total calcium content and loss of calcium was used as an index of osteoporosis. After completion of the study the mice were dry ashed and results were verified by atomic absorption spectroscopy. The diagnosis of osteoporosis was confirmed by quantitative histomorphometric analysis. Prednisolone (50 mg./kg. daily) for 3 months resulted in significant osteoporosis in the C3H/St(Ha) mice of both age groups but did not cause significant bone loss in the C57BL6 (JACOBS) mice of either age group. Conjugated estrogens (20 mg./kg. daily) failed to prevent steroid accelerated osteoporosis. M.G.F. 2 figures, 22 references
Studies on Osteoporoses. XII. Effect of Imidazoquinazolinones on Experimental Osteoporosis. A Preliminary Report
J. C. ROBIN AND J. L. AMBRUS, Roswell Park Memorial Institute and Departments of Internal Medicine and Experimental Pathology, State University of New York, Buffalo, New York J. Med., 13: 465-472, 1983 A murine model of heparin-induced osteoporosis has been developed to test potential antiosteoporotic agents. Heparin is believed to cause osteoporosis by disruption of osteoblastic activity. The level of cyclic adenosine monophosphate in tissue is balanced by its rate of synthesis by adenylate cyclase and its breakdown by cyclic 3,5' -phosphodiesterase. As for other tissues, bone cell cyclic adenosine monophosphate phosphodiesterases have been shown to be of either low or high Km form. Low Km sites may maintain steady state conditions, such as osteoblastic control of osteoid formation, primary mineralization and membrane function. High Km sites may be important when cells are perturbed, such as initiation of resorption. This investigation is designed to study the ability of 6-methyl1,2,3,5-tetrahydroimidazel-(2,1-b )quinazolin-2-one hydrochlo-
METABOLISM, ENDOCRINOLOGY AND IMMUNOLOGY
ride monohydrate and 7-chloro-6-methyl-1H,2,3,4,5-tetrahydroimidaze(2,1-b)quinazolin-2-one hydrochloride, synthetic highly active low Km phosphodiesterase inhibitors, in preventing heparin-induced osteoporosis. Heparin (500 U./kg. twice daily) treatment for 3 months resulted in significant osteoporosis in L3H/St(Ha) female mice. The BL compounds 3459 and 4160 prevented osteoporosis in the murine model as measured by neutron activation analysis of total body calcium, since 99 per cent is in bone. M.G.F. 1 figure, 17 references Calmodulin Levels and Divalent Cation Pump Activities in Kidneys of Streptozotocin-Diabetic Rats B. HOSKINS AND J. M. SCOTT, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi Res. Comm. Chem. Path. Pharm., 39: 189-199 (Feb.) 1983
839
A total of 68 patients (11 per cent) had hypomagnesemia and 58 had hypermagnesemia. Charts were reviewed in 29 patients with hypomagnesemia. The following causes of magnesium depletion were identified: alcoholism in 7 cases (24 per cent), malnutrition, carcinomatosis and diabetes in 11 (38 per cent), diuretic therapy in 2 (7 per cent), chronic renal failure in 2 (7 per cent), and pregnancy in 5 (17 per cent). Of the patients 61 were assessed for calcium levels and were found to be hypocalcemic, 18 owing to renal failure. Of the remaining 43 cases 10 (23.3 per cent) were associated with hypomagnesemia. C.E.M. 2 figures, 17 references Disposition of Medroxyprogesterone Acetate and Drug Metabolism Activity H. u. SAARNI, A. RAUTIO, N. T. KARKI AND E. A. SOTANIEMI, Department of Pharmacology and Clinical Research Unit of Internal Medicine, University of Oulu, Oulu, Finland
Calmodulin is a calcium-binding multifunctional protein that is able to maintain normal cell functions by calcium-dependent translocations from the unactive membrane-bound form to the calcium-bound active form, which preferentially can modulate the activities of a number of cellular enzymes and processes. Levels of calmodulin and activities of calcium and magnesium adenosine triphosphatases were determined in renal tissues of age-matched male rats after increasing durations of the following conditions: untreated streptozotocin-induced diabetes, streptozotocin-diabetic rats treated with insulin started 24 hours after streptozotocin administration and streptozotocindiabetic rats that received neutral protein Hagedorn insulin after being rendered diabetic without treatment for 1 to 3 weeks. Results were compared to those of age-matched control animals. Calmodulin levels were the same in renal tissues from all the groups of rats, as were magnesium-adenosine triphosphatase activities. After 2 weeks of untreated streptozotocin-diabetes calcium adenosine triphosphatase activities were significantly higher than control activities. The same observation was made on streptozotocin-diabetic rats treated with insulin after 1 to 3 weeks. Calcium adenosine triphosphatase activities of tissues from streptozotocin -diabetic rats treated with insulin after 24 hours of streptozotocin administration were no different from control values. These data suggest that prolonged deficiency of insulin results in insufficient passive transport of calcium from urine into tubular cells. C.E.M. 1 figure, 3 tables, 11 references
Kinetics of medroxyprogesterone acetate were studied in male rats. Hepatic drug metabolism was induced by phenobarbital or inhibited by ,6-diethyl-aminoethyl-2,2-diphenylvalerate. Plasma concentrations of unmetabolized medroxyprogesterone acetate and the amounts of medroxyprogesterone acetate-related residues in various tissues were higher in the ,6diethyl-aminoethyl-2,2-diphenylvalerate and slightly lower in phenobarbital-treated animals than in the controls. The disappearance of medroxyprogesterone acetate-related substances from the lung, skeletal muscle and brain was slow. There was an increase of medroxyprogesterone acetate residue in the phenobarbital and control rats at 24 hours. The same amounts of medroxyprogesterone acetate were excreted in the urine and intestine in the control rats. The induction of drug metabolism (phenobarbital) enhanced the urine excretion of medroxyprogesterone acetate, while its inhibition ,6-diethyl-aminoethyl2,2-diphenylvalerate increased intestinal elimination. The results show that plasma concentration of intact medroxyprogesterone acetate, its residues in various tissues and the main elimination routes are dependent on the hepatic metabolization of these drugs in rats. C.E.M. 2 figures, 1 table, 13 references
A High Prevalence of Hypomagnesemia and Hypermagnesemia in Hospitalized Patients
L. L. GERSHBEIN, J. D. GERSHBEIN AND R. FRENCH, Northwest Institute for Medical Research, Chicago, Illinois
E.T. WONG, R. K. RUDE, F. R. SINGER AND S. T. SHAW, JR., Departments of Pathology and Medicine, University of Southern California School of Medicine and Los Angeles County/ University of Southern California Medical Center, Los Angeles, California and the Orthopedic Hospital, University of Southern California Bone and Connective Tissue Laboratory, Los Angeles, California
Res. Comm. Chem. Path. Pharm., 39: 251-260 (Feb.) 1983
Behavior of Male Rats Fed Low Levels of Metallic Salts
Res. Comm. Chem. Path. Pharm., 39: 507-510 (Mar.) 1983
The exposure of animals to a variety of heavy metal trace elements has been known to elicit short-term or more permanent effects on behavior. The authors' study applies the criterion of exploratory behavior to male rats as based on the poke test. A comparison also is made of runway performance that, in contrast to the poke test, involved prior food deprivation. Male rats, 44 days old, were fed diets ad lib containing the Amer. J. Clin. Path., 79: 348-352 (Mar.) 1983 following in parts per million by weight: cobalt++ (75), copThere were 621 serum samples selected at random (from per++ (75), iron+++ (150), manganese++ (75), nickel++ (75), those submitted to the clinical laboratory for a 19-test panel of lead++ (10) and zinc++ (75), the controls receiving the ration. chemistry studies) to determine serum magnesium levels. Only At days 55 and 56 of feeding the rats were subjected to the inpatient serum was used. The reference range for serum mag- poke test and no remarkable differences could be discerned in nesium was established in this study as 1.2 to 1.9 mEq./1. from the 5-minute ratings. For the first I-minute scores a small but measurements of serum magnesium in 341 healthy volunteers. significant change was apparent with iron+++ versus lead++.