Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.

Effect of inappropriate and continuous therapy with alendronate for ten years on skeletal integrity - observations in two elderly patients.

Alendronate is a potent aminobisphosphonate that has been used worldwide to decrease fracture risk in millions of post-menopausal women with and without osteoporosis, men with low bone mass, and in those with glucocorticoid- induced osteoporosis. A recent report of 9 patients with spontaneous atypical non-vertebral fractures during treatment with alendronate for up to 8 yr raised questions suggesting the possibility of severe suppression of bone turnover and resultant susceptibility to fracture. Our recent observations in 2 elderly women with inactive monostotic Paget's disease of bone who had been treated elsewhere continuously for this disease with alendronate for 10 yr at doses overall of 2 and 4 times the osteoporotic dose provided an opportunity to engage in the ongoing controversy over long-term safety of bisphosphonate therapy. Despite such therapy, skeletal integrity was maintained with normal bone densities and the absence of skeletal fractures. These observations do not support the suggestion of deleterious effects with longterm alendronate therapy.

A case of thyroxine thyrotoxicosis.

A 57-year-old woman presented with palpitations, muscle weakness, bilateral proptosis, goiter, and tremor. The thyroxine (T4) level and the free T4 index were increased while the total triiodothyronine (T3) level was normal. Iodine 123 uptake was increased, and a scan revealed an enlarged gland with homogeneous uptake. Repeated studies again revealed an increased T4 level and free T4 index and normal total and free T3 levels. A protirelin test showed a blunted thyrotropin response. Treatment with propylthiouracil was associated with disappearance of symptoms and normal T4 levels, but after 20 months of therapy, hyperthyroidism recurred and the patient was treated with iodine 131. This was an unusual case of T4 toxicosis because the patient was not elderly and was not exposed to iodine-containing compounds or drugs that impair T4-to-T3 conversion. There was no evidence of abnormal thyroid hormone transport or antibodies.

Myasthenia gravis and premature ovarian failure.

Myasthenia gravis is believed to be an autoimmune disorder that results from antibodies directed against acetylcholine receptors. Not infrequently, it is associated with other autoimmune diseases, and, recently, several cases have been reported of coexistent premature ovarian failure. A 25-year-old nullgravida woman with myasthenia gravis became amenorrheic and then had ovarian failure with increased gonadotropin and negligible estrogen levels. Other endocrine functions were normal. An in vitro assay demonstrated the presence, in serum, of an inhibitor of binding to the luteinizing hormone (LH) receptor that suggested the possibility of a similar autoimmune process underlying the myasthenia gravis and premature ovarian failure. This could be the first case in which both disorders occurred with evidence for an LH receptor antagonist.

Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study.

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.

Metyrapone test in Cushing's disease.

The urinary 17-hydroxycorticosteroid response to 2 g of metyrapone given orally at 10 PM was compared with that following the standard test in which 750 mg of metyrapone was given at 4 hourly intervals for 6 doses. Both tests were performed on four occasions in 3 patients with Cushing's disease. Increments in urinary 17-hydroxycorticosteroid excretion during the modified test were 7.0, 7.5, 8.4 and 23.3 mg/day, whereas with the standard test, increments ranged from 29.5 to 56.8 mg/day. The urinary 17-hydroxycorticosteroid response to the 2 g dose of metyrapone at 10 PM was marginal in 3 of the 4 studies. Urinary 17-hydroxycorticosteroid excretion with the modified metyrapone test varied from 10.7 to 44% of that found with the standard test. Since urinary steroid excretion may vary considerably in patients with Cushing's syndrome as was evident in 2 of the 3 patients studied, the data suggest that the modified metyrapone test should not be used in preference to the standard test in evaluating Cushing's syndrome. It appears that the modified test could lead to erroneous conclusions.

Urinary cyclic nucleotide levels in patients with hyper- and hypothyroidism.

Urinary cyclic AMP, cyclic GMP and creatinine excretion were measured in 38 patients with hyperthyroidism, 32 patients with hypothyroidism and in 57 normal subjects. The excretion of both cyclic nucleotides was significantly increased in hyperthyroid females, but not in hyperthyroid males. The cyclic nucleotides/creatinine ratios, however, were uniformly elevated in both male and female hyperthyroid subjects and this was due, in part, to decreased creatinine excretion. Cyclic AMP excretion was significantly decreased in the hypothyroid subjects, but the cyclic AMP/creatinine ratios were not significantly different from normal. There were no significant alterations in cyclic GMP and cyclic GMP/creatinine ratios in the male hypothyroid patients, but ratios in the female patients were slightly greater than in the normals. These results demonstrate that hyper- and hypothyroidism may be associated with appreciable alterations in urinary cyclic nucleotide levels and that there may be sex-related differences in the patterns of urinary excretion of these nucleotides. The cyclic nucleotide levels herein described in patients with hyper- and hypothyroidism are qualitatively and, in some instances, quantitatively similar to those found in patients with hyper- and hypoparathyroidism, respectively.

Circadian rhythms in the urinary excretion of cyclic 3',5'-adenosine monophosphate (cyclic AMP) and cyclic 3',5'-guanosine monophosphate (cyclic GMP) in human subjects.

Significant circadian rhythns in urinary excretion of cyclic AMP, cyclic GMP, creatinine, 17-hydroxycorticosteroids and inorganic phosphorus were demonstrated in three normal subjects (two males and one post-menopausal female) who collected serial 4-h specimens for periods of 33, 22, and 14 days, respectively. Peak excretion of the above substances occurred, respectively, at approximately 1500-1700, 2300-0200, 1700-1800, 1100-1300, and 1800-2200 h. The estimated amplitudes of the rhythms expressed as a percentage of the mean 4-h excretion rate were 12-13%, 9-13%, 9-15%, 30-78% and 22-26%, respectively. With the possible exception of cyclic GMP, all of the observed rhythms appeared to be sinusoidal, with normal periods of 24 h. The rhythms in both cyclic AMP and creatinine excretion, but not in the remaining substances may be explained largely in terms of the known rhythm in glomerular filtration rate. The factors responsible for the rhythm in cyclic GMP excretion are unknown.

Urinary excretion of cyclic 3',5'-adenosine monophosphate and cyclic 3',5'-guanosine monophosphate during and after pregnancy.

Urinary cyclic AMP and cyclic GMP excretions were measured in 24-h urine specimens obtained from 89 women at various times during their normal uncomplicated intrauterine pregnancies and from 49 women at various times after the births of their normal healthy infants. Cyclic AMP excretion increased steadily from the beginning of the second trimester or earlier until late in the third trimester, reaching a peak excretion approximately 40% greater than that of normal nonpregnant women. The cyclic AMP excretion dropped abruptly by the first day after parturition to levels which were not significant different from those of normal non-pregnant women. In contrast, cyclic GMP excretion increased rapidly during the first trimester and remained relatively constant during the remainder of the pregnancy, reaching a peak excretion of about 140% greater than that of normal nonpregnant women. Furthermore, it decreased slowly toward normal levels, but was still significantly elevated six weeks after parturition. The factors responsible for the increased excretion of cyclic AMP during pregnancy and for the increased cyclic GMP during and after pregnancy are not known.

Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone.

Alendronate, an aminobisphosphonate, is much more potent than etidronate, an older bisphosphonate, in inhibiting osteoclast-mediated bone resorption, and unlike etidronate, therapeutic doses of alendronate are not associated with abnormal mineralization. In the present study, we compared the effectiveness, safety, and tolerability of 6 months of daily oral administration of alendronate (40 mg) with those of etidronate (400 mg) in 89 patients with clinically active Paget's disease. The primary efficacy end point was the percent change in serum alkaline phosphatase. Other end points included changes in urinary deoxypyridinoline excretion, pain, functional impairment scores, and radiological osteolysis. Tetracycline-labeled bone biopsies were obtained for histomorphometric analysis from a subset of 43 patients at the 6-month visit. The alendronate-treated group had significantly greater decreases in both serum alkaline phosphatase (79% vs. 44%) and urinary deoxypyridinoline (75% vs. 51%) than the etidronate-treated group (P < 0.001 in both cases). Normalization of serum alkaline phosphatase was much more frequent in alendronate-treated patients (63.4% vs. 17.0%; P < 0.001). Alendronate was well tolerated and had a safety profile similar to that of etidronate. Histomorphometry revealed decreased bone turnover and no qualitative abnormalities, including no direct negative effects on bone mineralization, with alendronate treatment. One patient receiving etidronate developed frank osteomalacia. Alendronate appears to be a highly effective treatment for Paget's disease of bone that offers an important therapeutic advance over etidronate.

Idiopathic hypoparathyroidism with extensive brain calcification and persistent neurologic dysfunction.

Idiopathic hypoparathyroidism is an uncommon cause of movement disorders. The following case illustrates the persistence of a parkinsonian gait 2 years after the restoration of normal serum calcium levels. The extensive calcifications in the brain presumably account for this as well as for the persistent mild dementia. The importance of identifying hypoparathyroidism early in the course is graphically illustrated.

Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis.

OBJECTIVE: Oral alendronate sodium is a potent, specific inhibitor of osteoclast-mediated bone resorption. To assess its efficacy and safety, a 3-year, randomized, double-blind, multicenter study of 478 postmenopausal women with osteoporosis was conducted. PATIENTS AND METHODS: Subjects received either placebo, alendronate 5 or 10 mg/day for 3 years, or 20 mg/day for 2 years followed by 5 mg/day for 1 year (20/5 mg). All subjects received 500 mg/day of supplemental calcium. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DXA). RESULTS: After 3 years, alendronate 10 mg induced marked increases in BMD of the lumbar spine (9.6 +/- 0.4%), femoral neck (4.7 +/- 0.7%) and trochanter (7.4 +/- 0.6%) (mean +/- SE; each P < or = 0.001) versus decreases of 0.8 to 1.6% with placebo. Progressive increases at these sites in the alendoronate 10 mg group were significant during both the second and third years. Alendronate 10 mg increased total body BMD (1.6 +/- 0.3%, P < or = 0.001), and prevented loss but did not increase BMD at the 1/3 forearm site. Alendronate 20/5 mg was no more effective, whereas alendronate 5 mg was significantly less effective than 10 mg at all sites. Bone turnover decreased to a stable nadir over 3 months for resorption markers (urine deoxypyridinoline) and over 6 months for formation markers (alkaline phosphatase and osteocalcin). Mean loss of stature was reduced by 41% in alendronate treated subjects (P = 0.01). CONCLUSION: The safety profile of alendronate was similar to that of placebo. At 10 mg, there were no trends toward increased frequency of any adverse experience except for abdominal pain, which was usually mild, transient, and resolved with continued treatment. Thus, alendronate appears to be an important advance in the treatment of osteoporosis in postmenopausal women.

C-cell hyperplasia of the thyroid in a patient with goitrous hypothyroidism and Hashimoto's thyroiditis.

A 63-year-old man with a goiter and primary hypothyroidism due to Hashimoto's thyroiditis was found to have hypercalcitonemia and, though hypothyroid, markedly elevated serum total and free T3 levels. The latter findings were attributable to circulating T3 autoantibodies and interference with radioimmunoassay. An infusion of calcium and pentagastrin resulted in abnormal increases in serum calcitonin levels. Because there was no evidence of a nonthyroidal cause for the hypercalcitonemia, the patient had a total thyroidectomy. Pathological examination of the thyroidectomy specimen revealed typical Hashimoto's thyroiditis and extensive C-cell hyperplasia symmetrically distributed throughout the upper and middle thirds of each lobe. The C cells stained strongly with immunoperoxidase stains for calcitonin, chromogranin, and CEA using absorbed polyclonal anti-CEA antibody. Less extensive staining for CEA was obtained using the monoclonal antibodies for CEA, 374/14, 250/183, and 431/31; only a few reactive cells were noted using 431/31. Postoperatively, serum calcitonin levels fell to normal and did not rise with a repeat calcium-pentagastrin infusion test. This patient appears to be the first instance of C-cell hyperplasia associated with Hashimoto's thyroiditis, while elsewhere an association with medullary thyroid carcinoma has been reported. These observations raise questions regarding a possible pathogenetic relationship between Hashimoto's thyroiditis and C-cell neoplasia.

A longitudinal study of changes in body mass index and total body composition after radioiodine treatment for thyrotoxicosis.

Patients treated for thyrotoxicosis often complain of increases in body weight after treatment of their thyroid disorder. The objective of this study was to define the extent of changes in body mass and composition following treatment of thyrotoxicosis with radioiodine 131I. We prospectively measured body mass index (BMI) in 75 patients (18 males, 57 females), ranging in age from 15-88 years treated for thyrotoxicosis with 131I (doses ranging from 5.2 to 25.7 mCi) between 1978 and 1994. BMI pre- and post-radioiodine treatment were recorded for up to 10 years after treatment. Body composition studies were performed on a subgroup of 9 patients (1 male, 8 females), aged 24 to 74 years treated with 6.0 to 12.2 mCi 131I. Bone mineral content, lean mass, and fat content were determined prior to and following 131I treatment through whole body scanning with a Hologic QDR-1000/W dual energy x-ray densitometer. Sustained increases in BMI averaging 2.33 kg/m2 above baseline (p < .01) were observed from the initial 6 months through the first 5 years after 131I therapy. BMI was no different from pretreatment levels over the remainder of the 10-year follow-up period. Lean mass increased significantly (p = .0004) by an average of 7.2 kg. Although both fat and mineral content appeared to increase, these changes were not statistically significant. Weight gain occurs within the first year after 131I treatment of patients with thyrotoxicosis and is predominantly due to increased lean mass (20.2%, p < .0005) although bone mineral content increased only marginally (4.62%, p = .10).

Recurrence of Cushing's disease 10 years after transsphenoidal adenomectomy: report of a case.

OBJECTIVE: To report a case of recurrent Cushing's disease after an apparent cure and long-term surveillance. METHODS: We describe in detail the follow-up course of a woman who underwent transsphenoidal resection of a corticotropin-secreting pituitary microadenoma in 1981. RESULTS: For 2 years postoperatively, the patient exhibited adrenocortical insufficiency. In 1983, the pituitary-adrenal axis was normal. She remained eucorticoid until May 1992, when features of Cushing's syndrome redeveloped. Plasma and urine cortisol and plasma corticotropin levels were once again increased in conjunction with a loss of diurnal variation and abnormal responses to dexamethasone suppression. A magnetic resonance imaging scan of the pituitary gland was consistent with a small lesion on the left side, and petrosal sinus sampling after ovine corticotropin-releasing hormone stimulation was consistent with increased activity on the right side. CONCLUSION: This 10-year interval between apparent cure and recurrence appears to be the longest thus far reported for a patient with Cushing's disease. These observations reinforce the impression that permanent cure of this disorder is uncertain and indicate the need for indefinite follow-up.

Nelson's syndrome due to an intracavernous corticotropin-secreting adenoma.

OBJECTIVE: To report the first case of Nelson's syndrome due to an ectopic intracranial corticotropin-secreting tumor arising entirely within the cavernous sinus. METHODS: We present a case report of Nelson's syndrome with clinical, laboratory, and radiologic features throughout a 25-year period. RESULTS: A 54-year-old woman had been treated for Cushing's disease with bilateral adrenalectomy in 1971. Subsequently, Nelson's syndrome developed, and she had severe generalized hyperpigmentation and substantially increased plasma corticotropin levels. In 1976, she underwent a transsphenoidal hypophysectomy. Postoperatively, despite the development of panhypopituitarism and diabetes insipidus, she remained hyperpigmented and had persistently increased plasma corticotropin levels. Throughout the years, efforts to identify the site of the corticotropin-secreting tumor were unsuccessful until 1988, when magnetic resonance imaging revealed a mass in the right cavernous sinus; subsequently, petrosal sinus cannulation corroborated the intracavernous source of excess corticotropin. Cobalt-60 gamma knife radiotherapy in 1992 was followed by a clinical and hormonal response 4 1/2 years later. CONCLUSION: This report describes only the second reported case of an intracranial corticotropin-secreting tumor arising entirely within the cavernous sinus and the first such case associated with Nelson's syndrome. Although rare, the possibility of an ectopic intracranial or extracranial pituitary adenoma should be considered in patients with pituitary hypersecretion without clear-cut intrasellar abnormalities or those with no response to surgical resection of the pituitary gland.

Intravenously administered pamidronate in the treatment of Paget's disease of bone.

OBJECTIVE: To evaluate the effect of intravenously administered pamidronate in patients with Paget's disease of bone. METHODS: We conducted a prospective nonrandomized study and reviewed the related literature. Eighty patients (52 women and 28 men, ranging in age from 53 to 93 years; mean age, 76) were treated with pamidronate intravenously in a total dose of 180 mg during a 6- or 3-week period. All patients had bone scintigraphy and x-ray findings characteristic of Paget's disease of bone. Serum alkaline phosphatase levels were increased in all patients, and findings on fractionation were consistent with a bone origin. Indications for therapy included extensive disease, pagetic deformities, neurologic complications, pagetic pain, and critical areas of involvement. Blood chemistry profile and complete blood cell counts were determined at baseline and after the last dose of pamidronate. Serum calcium levels were determined after the first and second infusions of pamidronate. Patients underwent clinical and biochemical follow-up assessments, with serum alkaline phosphatase measurements, at 2- to 4-month intervals. Many patients who did not have a remission (defined as normalization of serum alkaline phosphatase level) after the first cycle of therapy or who had a relapse with serum alkaline phosphatase levels increased above the normal range after remission were treated with one or more cycles of intravenously administered pamidronate. RESULTS: The mean serum alkaline phosphatase level was 1,051 U/L before therapy and 386 U/L after treatment, a decrease of 63% (P<0.0001). In 50 patients, the serum alkaline phosphatase level declined to normal. Such normalization was noted in 43 of 50 patients (86%) whose baseline alkaline phosphatase was less than 3 times the upper limit of normal (ULN), in 5 of 13 patients (38%) whose baseline alkaline phosphatase was 3 to 6 times the ULN, and in only 2 of 17 patients (12%) whose baseline alkaline phosphatase exceeded 6 times the ULN. Of 30 patients who did not have a remission, 22 received a second course of therapy, 2 of whom had normalization of the serum alkaline phosphatase level. Pamidronate was well tolerated; only nine patients reported a "flu-like" syndrome after the first infusion. Serum calcium levels decreased in many patients (to as low as 8 mg/dL), but no patients were symptomatic. CONCLUSION: With intravenous administration of pamidronate in a dose of 180 mg in patients with Paget's disease of bone, remissions are likely in those whose baseline serum alkaline phosphatase level is <3 times the ULN and unlikely when baseline alkaline phosphatase levels are higher-especially more than 6 times the ULN.

Intravenously administered pamidronate for treating refractory Paget's disease of bone.

OBJECTIVE: To report our experience with the use of intravenously administered pamidronate in 16 patients with refractory Paget's disease of bone. METHODS: We describe our treatment regimen and outline serum alkaline phosphatase levels at baseline and after pamidronate therapy in our study cohort. In addition, we summarize clinical symptoms and response to treatment. RESULTS: Although clinical experience with pamidronate in the treatment of Paget's disease of bone has been limited in the United States, elsewhere it has been shown to be an effective agent that inhibits the increased osteoclastic activity characteristic of this disease. Accordingly, in 16 patients with Paget's disease unresponsive to various other therapies, we administered pamidronate intravenously at a dose of 30 mg in 500 mL of 5% dextrose in water during a 4-hour period once weekly for 6 weeks. Serum alkaline phosphatase was determined at baseline and at regular intervals for at least 12 months after the onset of therapy. Many of these patients reported relief of pain and an increased flexibility or range of motion after treatment. The only adverse effect reported by these patients was an acute-phase reaction during the first infusion in two patients. In all patients, serum alkaline phosphatase levels declined, and significant (P = 0.0012) decreases from baseline were noted within 6 weeks after the initial infusion. Maximal responses were generally seen within 6 months after treatment, serum alkaline phosphatase levels decreasing as much as 91% from baseline. CONCLUSION: These data suggest that intravenous pamidronate therapy is an effective alternative to calcitonin and etidronate in the treatment of Paget's disease of bone, particularly in those patients refractory to such agents.

A direct current plasma emission spectrometric procedure for the assay of silicon in urine.

A method for the assay of silicon in urine has been developed using direct current plasma emission spectroscopy. Urine is directly aspirated into the argon plasma, and the silicon emission is measured at 251.6 nm. There is a moderate matrix effect which is not compensated by the addition of lithium chloride as an ionization suppressor. The use of calibration standards in an urine-like matrix gives the best analytical results as documented by serial dilution and standard addition studies. The method is linear over the entire range of urine concentrations normally encountered (0 to 50 mg per L). The lower detection limit is 0.05 mg per L and the coefficients of variation at the 2.7 mg per L and 5.9 mg per L levels are 5.8 percent and 11.5 percent, respectively. Urine from ten randomly chosen volunteers shows a considerable between subject variation in silicon concentration (mean 12.5 +/- 8.3 mg per L, range 1.8 to 51.6 mg per L) which is positively associated with vegetable intake. Urine from 39 hospital patients on a standardized diet shows much less variation in concentration (mean 4.1 +/- 3.2 mg per L, range 0.1 to 18.6 mg per L), indicating that the urine silicon assay is likely to be useful in metabolic studies only if diet is controlled.