Robert F. Klein

Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone.

A variety of solid tumors secrete proteins that are immunochemically distinct from parathyroid hormone (PTH) but activate PTH-responsive adenylate cyclase. Such PTH-like proteins have been proposed as mediators of the hypercalcemia and hypophosphatemia frequently associated with malignancies. We purified to apparent homogeneity a PTH-like protein with a molecular weight of 6,000, that is produced by human renal carcinoma cells. The amino-terminal sequence of the PTH-like protein and that of human PTH were found to display at least five identities in the first 13 positions. The purified protein bound to PTH receptors, activated adenylate cyclase in renal plasma membranes, and stimulated cAMP formation in rat osteosarcoma cells. The PTH-like protein reproduced two additional effects of PTH, stimulation of bone resorption in fetal rat limb bone cultures and inhibition of phosphate uptake in cultured opossum kidney cells. These properties are consistent with a role for PTH-like proteins as mediators of the syndrome of malignancy-associated hypercalcemia.

Increased Serum Levels of a Parathyroid Hormone-like Protein in Malignancy-Associated Hypercalcemia

STUDY OBJECTIVEnTo measure the serum levels of a newly described parathyroid hormone-like protein (PLP) which was isolated from malignant tumors associated with hypercalcemia, and determine whether PLP is a humoral factor in malignancy-associated hypercalcemia.nnnDESIGNnA cross-sectional study of serum levels of PLP using a newly developed radioimmunoassay.nnnSETTINGnA university-affiliated Veterans Administration hospital in San Francisco, California, a University hospital in Hong Kong, and a private hospital in Danville, Pennsylvania.nnnPATIENTSnPatients with hypercalcemia (calcium greater than 2.65 mmol/L) and a diagnosis of malignancy were studied. Control groups included normocalcemic patients with malignancy, patients with hyperparathyroidism, and normal subjects.nnnMEASUREMENTS AND MAIN RESULTSnSerum immunoreactive PLP (iPLP) levels in normal subjects were less than 2.5 pmol eq/L (10 pg/mL), and 68% of subjects had undetectable levels. The serum concentration of iPLP was normal in 15 of 16 hypercalcemic patients with hyperparathyroidism. Serum iPLP was increased (greater than 2.5 pmol eq/L) in 36 of 65 (55%) patients with malignancy-associated hypercalcemia, with a mean value of 6.1 +/- 0.9 pmol eq/L (24 pg/mL). In a subgroup of patients with solid tumors serum iPLP was increased in 30 (71%) of 42 hypercalcemic patients, with a mean value of 6.5 +/- 0.9 pmol eq/L. Serum iPLP was elevated in only 3 of 23 normocalcemic patients with cancer. In patients with solid malignancies (n = 59), levels of iPLP were positively correlated with the total serum calcium (r = 0.43, P less than 0.01).nnnCONCLUSIONnThe data indicate a relation between the serum concentration of iPLP and the presence of hypercalcemia in solid malignancies. The results support a role for PLP as a humoral mediator of hypercalcemia in most patients with solid tumors. Measurement of iPLP should be useful in the differential diagnosis of hypercalcemia.

Fat Mobilization in Man.

Excerpt The process of fat mobilization has become accessible to study in man with the recognition that the albumin-bound nonesterified or free fatty acids are the major form of transport of lipid ...

The Physiologic Response to Conformity Pressure in Man

Excerpt Experiments conducted in our laboratory and in those of others have demonstrated that many emotional stimuli cause marked changes in the body. These changes are most likely to result in sym...

THE EFFECT OF 2-DEOXY-D-GLUCOSE INFUSIONS ON LIPID AND CARBOHYDRATE METABOLISM IN MAN

At the present time, the direction of change of the plasma free fatty acid (FFA) level is considered to serve as an index to the pattern of fat metabolism, representing an indicator of the balance between fat storage and fat mobilization. In the fasting, nonexercising individual, a rising plasma FFA level suggests net fat mobilization and a falling FFA level suggests net fat storage. If the status of carbohydrate metabolism does relate to fat metabolism, then plasma FFA levels may be expected to change in a number of experimental situations. Dole Was the first to (lemonstrate that glucose and insulin administration decreased fasting FFA levels (1) and Bierman, Dole and Roberts that patients with diabetes niellitus have high FFA levels (2). Experimental inteference with carbohydrate metabolism might also be expected to influence plasma FFA levels. The availability of 2-deoxy-D-glucose (2-DG) has made it possible to test this hypothesis. 2-DG is phosphorylated to 2-deoxyglucose-6-phosphate (2-DG-6-P), and it has been postulated that the 2-DG-6-P may compete for transport into the cell with glucose-6-phosphate (3). The purpose of this study was to observe the effect of 2-DG administration on FFA levels in normal human subjects and to study in addition the effect of glucose, insulin, fructose and lactate upon the pattern of response to 2-DG.

Use of the saline infusion test to diagnose the cause of primary aldosteronism

Angiotensin II has a major effect on mineralocorticoid hormone synthesis in patients with idiopathic hyperaldosteronism; it has little or no effect in those with an aldosterone-producing adenoma. To determine if this difference could be of use in clinically separating these two forms of primary aldosteronism, saline infusion tests were performed in 20 patients--14 with surgically proved aldosterone-producing adenoma and six with idiopathic hyperaldosteronism. With the patients receiving a balanced diet containing 120 meq of sodium, 1,250 ml of isotonic saline was infused intravenously between 8 A.M. and 10 A.M. after overnight recumbency. Plasma samples were obtained immediately before and after the infusion. Plasma cortisol level decreased appropriately in both groups, but plasma renin concentration decreased only in those patients with idiopathic hyperaldosteronism (p less than 0.05). Aldosterone and 18-hydroxycorticosterone levels decreased in both groups. To account for the circadian variation in adrenocorticotropin levels during the course of saline infusion, 18-hydroxycorticosterone/cortisol and aldosterone/cortisol ratios were examined. Both ratios increased in every patient with aldosterone-producing adenoma (p less than 0.01 and p less than 0.001, respectively), but these ratios remained unchanged or decreased in the patients with idiopathic hyperaldosteronism. This divergent variation in ratios after saline infusion allows for the differentiation of patients with an aldosterone-producing adenoma from those with idiopathic hyperaldosteronism. In patients with primary aldosteronism, an 18-hydroxycorticosterone/cortisol ratio of less than 3.0 or an aldosterone/cortisol ratio of less than 2.2 after saline infusion is diagnostic of idiopathic hyperaldosteronism.

Meeting report from the 25th annual meeting of the American society for bone and mineral research

• Chondrocytes: Old Friends and New Acquaintances – Ernestina Schipani • Genetics of Osteoporosis: Of Mice and Men – Serge Ferrari • How Many Osteos Does It Take to Have a Blast? – Nabanita S. Datta and Laurie K. McCauley • Osteoclasts: Before or After Fusion? – Agnès Vignery • The Osteocyte: The “Third” Cell of Bone Gets to Center Stage – Teresita Bellido • FGF23: The Matrix Reloaded – Gordon J. Strewler • Osteocytes Come to the Forefront – Charles H. Turner • Imaging and Finite Element Analysis of Bone – Yebin Jiang • Treatment of Osteoporosis – Ego Seeman