Calcitonin gene-related peptide in hepatorenal syndrome. A possible mediator of peripheral vasodilation?

In advanced cirrhosis and hepatorenal syndrome, peripheral vasodilation is a prominent feature and may be pathophysiologically relevant. To determine whether the potent vasodilator, calcitonin gene-related peptide (CGRP), circulates at abnormal levels in patients with these disorders, we observed eight patients with alcoholic cirrhosis and hepatorenal syndrome, seven with alcoholic cirrhosis and ascites without hepatorenal syndrome, and 10 healthy controls. Plasma CGRP levels were higher in patients with alcoholic cirrhosis and hepatorenal syndrome (364 +/- 166 pg/ml) than in healthy controls (143 +/- 54 pg/ml, p less than 0.01). In patients with cirrhosis and ascites without hepatorenal syndrome, plasma CGRP levels were less elevated (291 +/- 257 pg/ml, NS). The identity of immunoreactive CGRP and synthetic hCGRP was confirmed by high performance liquid chromatography. These results suggest that CGRP may play a role in hepatorenal syndrome. However, to establish whether circulating CGRP contributes to the hemodynamic change in hepatorenal syndrome requires study of a larger number of patients and additional control groups.

Intranasal salmon calcitonin treatment of Paget's disease of bone. Results in nine patients.

To ascertain whether salmon calcitonin, usually given parenterally, could control active Paget's disease when given by nasal insufflation, intranasal salmon calcitonin (INSC) was given to nine men with Paget's disease whose serum alkaline phosphatase (SAP) levels were elevated twofold or more. Treatment with 100, 200, and 400 IU/day for three to nine months was well tolerated. SAP fell 31%-51% in three patients and more than 20% in two others. Three of four men who had previously received salmon calcitonin (SC) by injection had no response of SAP but had a rise in antibodies to SC. INSC is mildly effective and more convenient than parenteral SC, but dose response and efficacy relative to parenteral SC have not been established, thereby raising questions of cost-effectiveness.

Human brain calcitonin gene-related peptide (CGRP) is concentrated in the locus caeruleus.

A quantitative survey of calcitonin gene-related peptide (CGRP) in brain, peripheral nerve and cerebrospinal fluid (CSF) was performed using radioimmunoassay (RIA) with antiserum against synthetic hCGRP. High levels (approximately 2000-15,000 fmol/mg protein) were found in the dorsal spinal cord, dorsal nerve and trigeminal nerve. Relatively large amounts (500-2000) were found in parts of the hypothalamic-pituitary axis, peripheral nerve and, for the first time, in the locus caeruleus. Low levels of CGRP (less than 500) were detected in the cerebrum, subcortical nuclei and cerebellum. CGRP, not previously reported in CSF, was detectable in all of 27 CSF specimens with mean values of 30 +/- 4.5 pmol/L (SE). Simultaneous plasma CGRP levels were higher and, when elevated by antihypertensive treatment were not increased in CSF, just as astronomical plasma levels of calcitonin in medullary carcinoma of the thyroid are not reflected in CSF. Our data confirm and extend the results of previous human and animal studies with evidence of species variation: humans have low CGRP levels in subcortical nuclei whereas high levels have been found in rat caudate-putamen and amygdala. The high level of CGRP in the locus caeruleus, the major source of noradrenergic neurotransmission in the CNS, is in harmony with the presumed functions of the LC and the very potent hemodynamic activity of CGRP.

Estrogen and bone. Marshall R. Urist's contributions.

Estrogens have profound effects on the maintenance of bone mass. Urist's early studies showed species differences in reactions of bone to estrogens and in their ability to inhibit endosteal resorption and to reduce the number of osteoclasts. It is now clear that estrogens are anticatabolic as quantified by kinetic and radiographic studies. The clinical use of this important action of estrogens for the prevention and treatment of osteoporosis has recently been accepted by the NIH Consensus on Treatment of Osteoporosis and by the Food and Drug Administration. The relation of hip fractures to osteoporosis and vertebral compressions, shown by Urist et al. in 1959, is now clarified by direct noninvasive measurement of vertebral spongiosa, which is preferentially involved. Prevention of bone loss and fractures by estrogen has now been established morphometrically and epidemiologically; dose-response curves are available for four preparations. Urist showed in 1948 that estrogens are ineffective in vitro; it is now known that bone lacks estrogen receptors. Their antiosteolytic action appears to be mediated by calcitonin. As a consequence of all these studies, the serious human and public health problem of postmenopausal osteoporosis, with fractures of the vertebrae, wrists, and hips, deformity, and death, is one of the few geriatric disorders for which effective and safe prophylaxis is now practical.

Osteoporosis: assessment by quantitative computed tomography.

The results presented in this article indicate that quantitative computed tomography provides a reliable means of evaluating and monitoring the many forms of osteoporosis and its various treatments. The greatest advantages of spinal QCT for noninvasive bone mineral measurement are its high precision, the high sensitivity of the vertebral spongiosa measurement site, and the potential for widespread application.

Quantitative computed tomography for spinal mineral assessment: current status.

Quantitative CT (QCT) is an established method for the noninvasive assessment of bone mineral content in the vertebral spongiosum and other anatomic locations. The potential strengths of QCT relative to dual photon absorptiometry (DPA) are its capability for precise three-dimensional anatomic localization providing a direct density measurement and its capability for spatial separation of highly responsive cancellous bone from less responsive cortical bone. The extraction of this quantitative information from the CT image, however, requires sophisticated calibration and positioning techniques and careful technical monitoring.

Assessment of metabolic bone diseases by quantitative computed tomography.

Advances in the radiologic sciences have permitted the development of numerous noninvasive techniques for measuring the mineral content of bone, with varying degrees of precision, accuracy, and sensitivity. The techniques of standard radiography, radiogrammetry, photodensitometry, Compton scattering, neutron activation analysis, single and dual photon absorptiometry, and quantitative computed tomography (QCT) are described and reviewed in depth. Results from previous cross-sectional and longitudinal QCT investigations are given. They then describe a current investigation in which they studied 269 subjects, including 173 normal women, 34 patients with hyperparathyroidism, 24 patients with steroid-induced osteoporosis, and 38 men with idiopathic osteoporosis. Spinal quantitative computed tomography, radiogrammetry, and single photon absorptiometry were performed, and a spinal fracture index was calculated on all patients. The authors found a disproportionate loss of spinal trabecular mineral compared to appendicular mineral in the men with idiopathic osteoporosis and the patients with steroid-induced osteoporosis. They observed roughly equivalent mineral loss in both the appendicular and axial regions in the hyperparathyroid patients. The appendicular cortical measurements correlated moderately well with each other but less well with spinal trabecular QCT. The spinal fracture index correlated well with QCT and less well with the appendicular measurements. Knowledge of appendicular cortical mineral status is important in its own right but is not a valid predictor of axial trabecular mineral status, which may be disproportionately decreased in certain diseases. Quantitative CT provides a reliable means of assessing the latter region of the skeleton, correlates well with the spinal fracture index (a semiquantitative measurement of end-organ failure), and offers the clinician a sensitive means of following the effects of therapy.

The aging skeleton.

The importance of bone loss with aging increases year by year. When Bismarck set the age of retirement at 65, it did not cost Prussia much because few lived to receive pensions. At the turn of the century, only 4.1 per cent of our population was 65 or older. But the present change in demography, called "The Graying of America," means that we now have 13 per cent of the population 65 or older: 35 million people, 20 million women and 15 million men. For the women who are now passing through menopause or who have had oophorectomies, the predictable deformities caused by fractures of the vertebrae, wrists, and hips will make up the single largest cause of hospitalization unless prophylaxis against postmenopausal bone loss is instituted. The best established prophylaxis is now low-dose estrogen-gestagen replacement therapy. Very promising is the combination of very-low-dose estrogen and high-dose oral calcium supplements (Fig. 17). For women who cannot or will not take estrogens, certain progestational agents offer equal protection to bone, though, of course, these agents do not protect against atrophy of the other target organs, most notably the vaginal mucosa.

Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy.

We assessed serially the bone mineral loss in 37 premenopausal women for 24 months after oophorectomy and determined the dose-response for conjugated estrogen therapy in preventing this loss. Spinal cancellous bone was measured by quantitative computed tomography and measurement of appendicular cortical bone by radial photon absorptiometry and metacarpal radiogrammetry. For the placebo and low-dose treatment groups, the mean annual bone mineral losses were 7% to 9% from the vertebral spongiosum and 1% to 3% from the peripheral cortex. The correlation between axial and appendicular loss was weak (r = 0.581), precluding a reliable estimate of spinal loss from peripheral measurements. For the maximal-dose group (0.6 mg/d), the mean annual bone mineral losses were less than 0.5% from the axial and appendicular sites, and were not significant. The results indicate that spinal quantitative computed tomography provides a highly sensitive measurement of bone mineral loss after oophorectomy, that bone mineral loss is five- to sevenfold greater from the spinal spongiosum than from the appendicular cortex, and that conjugated estrogen in doses of less than 0.6 mg/d are inadequate to prevent the vertebral mineral loss.

Spinal mineral loss in oophorectomized women. Determination by quantitative computed tomography.

Computed tomography (CT) provides precise anatomic localization coupled with quantitative x-ray attenuation information that can be used to determine bone mineral content. A precise and sensitive method for vertebral mineral measurement by CT is described and illustrated with results from an ongoing study of mineral loss in oophorectomized women. Spinal mineral loss measured by quantitative CT is compared with peripheral loss determined by photon absorptiometry and radiogrammetry. Vertebral cancellous bone loss was significant for the group as a whole at 12 months, while mean peripheral measurements showed no change. In two subjects in whom mineral change was significant at both sites, spinal loss was approximately five times greater than peripheral loss.

Dead wrong--estrogens, osteoporosis cancer and public policy.

Practicing physicians must constantly decide what is the best treatment for each patient. Their decisions are often influenced by prominent professors and by a climate of opinion created by the press and regulatory agencies. If these are wrong, because of pressure from 'consumer advocates', wrong interpretations, or the risks of litigation, physicians may be forced into making inactive decisions which can cause more harm than the treatment under attack. My attention was drawn to this problem by recent actions of the press and the FDA discouraging the use of estrogens because of a putative risk of endometrial cancer. Even if the danger were real, and I consider the evidence faulty, doctors would have to balance risks against benefits. We have 2,718 deaths each year, constant for ten years, from endometrial cancer and at least 50,000 female deaths because of preventable osteoporotic hip fractures. Recent data establish that the doses of estrogen needed to prevent postmenopausal bone loss are lower than those associated with any cancer. History abounds with similar examples. Semmelweis showed that handwashing prevented deaths from puerperal sepsis but was laughed into a madhouse. More recent examples are the long delays in the use of propranolol, cimetidine, bromcryptine, pulmonary surgery, antihypertensive therapy, poliomyelitis vaccination, penicillin and cardiac surgery. An approach to correction of this serious problem will be presented.

Aluminum uptake by the parathyroid glands.

Aluminum-containing drugs are used extensively to bind dietary phosphate and as antacids, but little is known about toxicity and tissue uptake of ingested aluminum. Aluminum concentrations were measured by neutron activation analysis in tissues taken from hyperparathyroid and normal human subjects and from rats. The parathyroid glands contained significantly more aluminum per unit mass than did thyroid or cervical muscle. The concentration of aluminum in the parathyroids appears to be linearly related to dietary aluminum intake.