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The concentration of cAMP increases in human mononuclear leukocytes after exposure to salmon calcitonin (SCT). This response is lost when the cells are separated into adherent (monocytic) and nonadherent (lymphocytic) cells, al-though the appropriate response to prostaglandin E2 remains in both groups. Adherent and nonadherent cells, each cultured alone for 16 h, do not regain the SCT response. Coculturing adherent and nonadherent cells together for 16 h restores the SCT response in the lymphocytes. The addition of a cyclooxygenase inhibitor to this culture system prevents development of the SCT response. The SCT response may be induced in nonadherent cells by culturing them for 16 h in medium previously conditioned by the growth of mixed mononuclear leukocytes. (Endocrinology 113: 1568, 1983)

The aim of this experiment was to test whether a chelating agent, D-myo-inositol-1,2,6-trisphosphate (PP56), could reverse cadmium-induced hypertension. Four groups of weanling female Long-Evans rats received ad libitum a rye-based, metal-poor diet and deionized water fortified with essential metals for 15 mo from the time of weaning. A control group received neither cadmium nor chelating agent. A second group had 0.1 ppm cadmium added to their water from weaning through mo 5. A third group had 60 ppm PP56 added to their water for mo 6-10. The fourth group had 0.1 ppm cadmium added to their water from weaning through mo 5 and 60 ppm PP56 from mo 6-10. All groups were followed without either cadmium or PP56 for mo 11-15. At approximately monthly intervals, systolic pressure was measured by the indirect tail cuff method in unanesthetized rats. Chronic cadmium feeding induced the expected hypertension, with an average increase in systolic pressure of about 15 mm Hg; the pressor effect persisted with little change for the 10 mo after cadmium was withdrawn. PP56 completely reversed the cadmium-induced hypertension, and the inhibition persisted for 5 mo after PP56 was withdrawn. PP56 by itself had no demonstrable depressor effect.

The biologically active PTH fragment 1-34 induces mononuclear leukocytes to produce a substance(s) capable of increasing bone resorption, as assayed in an organ culture system. The onset of the effect is evident at 2 days and lasts at least 7 days. The cell responsible for this effect appears to be an activated nonadherent lymphocyte (probably T-cell). PTH-(1-34) induces these cells to secrete this factor(s). The presence of adherent mononuclear leukocytes or appropriate conditioned medium appears to augment this response. Secretion of this factor(s) is specific for PTH-(1-34); it is not induced by biologically inactive PTH fragments, nor can it be induced by incubating mononuclear leukocytes with other hormones, including human PRL or lysine vasopressin. On the other hand, PTH-(1-34), human PRL, and lysine vasopressin all activate mononuclear leukocytes, as determined by [3H]thymidine incorporation. Biologically inactive PTH fragments do not. Thus, while lymphocyte activation may be a necessary prerequisite to lymphocyte modulation of bone resorption, it is not sufficient of itself. The PTH fragment 1-34 activates mononuclear leukocytes and specifically induces nonadherent lymphocytes to produce a substance(s) capable of increasing bone resorption. Preliminary characterization of this substance(s) shows that cellular components of the organ culture are necessary to demonstrate the increased resorptive capacity of PTH-stimulated lymphocyte supernatants. Secondly, this resorptive capacity is heat sensitive. Finally, this substance(s) appears to have a nominal molecular radius greater than 14,000 daltons, but less than 50,000 daltons.

Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system.

Cadmium is known to dissociate myocardial excitation-contraction coupling and to depress the excitability of the cardiac conduction system in vitro (1-7). Short-term feeding experiments concluding that cadmium increases conduction time through the atrioventricular node-His-Purkinje system have partially extended these in vitro observations to in vivo systems (8, 9). Although the cadmium content of the heart increases with age and exposure (10-14), the effects of cadmium have not been systematically analyzed for possible significance as a contributing factor to degenerative heart disease. This preliminary study was undertaken to investigate electrocardiographical, biochemical, and morphological changes in mammalian hearts associated with long-term, low-level cadmium feeding.Methods. Eighteen weanling female rats of the Long-Evans strain were obtained and housed as described (15). They received a special rye-based, low-cadmium diet and deionized water fortified with Mn, Co, Cu, Zn, and Mo, as described by S...

A low intake of dietary cadmium induces specific dose-dependent functional and biochemical changes in the cardiovascular tissues of rats. Maximum changes occur when the cadmium intake is 10 to 20 micrograms per kilogram of body weight per day. The changes reflect the accumulation of "critical" concentrations of cadmium in the cardiovascular tissues. The biologic activity of cadmium is demonstrated for intakes that approach those of the average American adult exposed to the usual environmental concentrations of the element but not to industrial concentrations. The sensitivity of the cardiovascular system to low doses of cadmium could not be anticipated by extrapolation from data on exposure to high concentrations of cadmium. The data support the hypothesis that ingested or inhaled environmental cadmium may contribute to essential hypertension in humans.

Although it is well known that hypertension is often associated with primary hyperparathyroidism and that parathyroidectomy reverses or reduces this abnormality, the etiology of elevated blood pressure in hyperparathyroidism is still conjectural. We have analyzed serum calcium, blood pressure, and metabolites of adrenal cortical hormones before and after surgical therapy for hyperparathyroidism in 10 normotensive and six hypertensive patients with primary hyperparathyroidism. Successful parathyroidectomy lowered serum calcium (P less than 0.01) and diastolic blood pressure (P less than 0.05) in all subjects. Mean urinary aldosterone and Porter-Silber chromagens were within normal limits preoperatively in normotensive as well as hypertensive subjects. After parathyroidectomy, aldosterone levels as well as Porter-Silber chromagens decreased significantly in all patients (P less than 0.01). However, when normotensive and hypertensive subjects were analyzed separately, the decrease in aldosterone levels was significant only in the normotensive group (P less than 0.05) whereas the decrease in Porter-Silber chromagens reached significancy only in the hypertensive group (P less than 0.01). The results indicate that surgical therapy for hyperparathyroidism lowers serum calcium and blood pressure and is associated with a decrease in the excretion of adrenal steroid metabolites. It is suggested that the temporal relationship which exists between ionized calcium and steroidogenesis in hyperparathyroid patients contributes at least in part to the generalized decrease in blood pressure observed after successful parathyroidectomy.

• Symptomatic osteopenia accompanied by subclinical hyperthyroidism developed in three women who were receiving excess thyroid hormone medication. Excessive thyroid replacement therapy resulted in mild hypercalcemia, hyperphosphatemia, and hyperphosphatasemia associated with diffuse skeletal demineralization and multiple fractures. Nondecalcified sections of double tetracycline-labeled iliac crest bone showed an accelerated rate of bone turnover with marked osteoclastosis and resorption of the cortical as well as the trabecular bone, typical of endogenous hyperthyroidism. Since thyroid hormones are among the most frequently prescribed medications, bone loss caused by exogenous hyperthyroidism may be more common than previously recognized. ( Arch Intern Med 1983;143:442-444)

• Five young men had a similar syndrome of osteopenia and hypercalciuria, probably resorptive and absorptive, with histomorphometric data suggesting decreased bone mass with increased rate of bone formation. A search for causes of osteopenia, either primary or secondary, was unrewarding. ( Arch Intern Med 1982;142:1295-1298)

Excess endogenous and exogenous thyroid hormone has been previously associated with increased bone loss in vivo. 1-3 In this issue of theArchives, Coindre et al describe the pathologic changes in the bone of hypothyroid individuals before and after thyroid replacement. 4 Their data and those of others 5-7 indicate that hypothyroidism results in increased bone mass. They report that subsequent thyroid replacement to the euthyroid state results in loss of both cortical and trabecular bone and osteopenia. 4 These provocative findings are supported by a previously reported densitometric study demonstrating significant loss of lumbar bone mass in similar patients. 8 These studies are of particular concern as they are the first reports of increased bone loss associated with appropriate thyroid hormone levels. Thyroid hormones represent one of the most common medications administered, 9 particularly to white perimenopausal and postmenopausal women. This group is also specifically at risk to develop symptomatic bone loss. 10,11 Any unnecessary medication

• The efficacy of salmon calcitonin and etidronate disodium was compared in the therapy of Paget's bone disease in 37 patients. Nineteen patients received etidronate for six months with a mean alkaline phosphatase reduction to 53% of initial values. Bone scintophotographs improved in 12 and were unchanged in seven. Symptoms improved in 11 subjects, were unchanged in seven, and worsened in one. Twelve of these patients were then treated with calcitonin for six months with continued improvement in alkaline phosphatase values to 36% of initial values. All bone scintophotographs improved compared with initial studies. Seven patients continued to improve symptomatically; five described no change. Eighteen individuals were treated initially with calcitonin for six months. During therapy, the alkaline phosphatase level fell to 76% of initial values. Bone scintophotographs were worse in two patients, did not change in seven, and improved in nine. Eleven patients reported improvement in symptoms and seven reported no change. Seventeen of these patients were then treated with etidronate for six months with a decrease in alkaline phosphatase levels to 64% of initial values. Compared with initial tests, bone scintophotographs were worse in three with no change in five and improvement in nine. Symptomatically, three patients reported improvement; four noted no change, and ten reported increasing pain. Although the reason for the poor response to initial calcitonin therapy and/or subsequent etidronate therapy is not apparent, we have concluded that patients fare better when treated with an etidronate calcitonin sequence when compared with those treated with a calcitonin/ etidronate sequence. ( Arch Intern Med 1984;144:929-933)