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Osteoporosis and 1-year fracture risk were studied in 197,848 postmenopausal American women from five ethnic groups. Weight explained differences in BMD, except among blacks, who had the highest BMD. One SD decrease in BMD predicted a 50% increased fracture risk in each group. Despite similar relative risks, absolute fracture rates differed. Introduction: Most information about osteoporosis comes from studies of white women. This study describes the frequency of osteoporosis and the association between BMD and fracture in women from five ethnic groups. Materials and Methods: This study was made up of a cohort of 197,848 community-dwelling postmenopausal women (7784 blacks, 1912 Asians, 6973 Hispanics, and 1708 Native Americans) from the United States, without known osteoporosis or a recent BMD test. Heel, forearm, or finger BMD was measured, and risk factor information was obtained; 82% were followed for 1 year for new fractures. BMD and fracture rates were compared, adjusting for differences in covariates. Results: By age 80, more than one-fifth of women in each ethnic group had peripheral BMD T scores

Results from the Women's Health Initiative showed that postmenopausal hormone replacement therapy (HRT) prevents fractures but has an overall unfavorable risk:benefit ratio, leading to the recommendation that HRT be used only for women with troublesome menopause symptoms, and for as short a time as possible. This recommendation has important implications for the timing and duration of HRT and the prevention of osteoporosis. The large number of women participating in the National Osteoporosis Risk Assessment (NORA) program provided the opportunity to evaluate bone mineral density (BMD) and 1-year fracture risk in analyses stratified by duration and recency of HRT.Participants were 170,852 postmenopausal women aged 50 to 104, without known osteoporosis, who were recruited from primary physicians offices across the US. BMD was measured at one of four peripheral sites, and the 1-year risk of osteoporotic fracture was assessed by questionnaire.At baseline, current HRT users had the highest T-scores at every age. Among current hormone users, women who had used HRT longest had the highest BMD levels. Women who had stopped HRT more than 5 years previously, regardless of duration of use, had T-scores similar to never-users. Current but not past hormone use at baseline was associated with a 25% to 29% lower risk of osteoporotic fracture (P0.0001) in 1 year, compared with nonusers. These findings were independent of age, ethnicity, body mass index, lifestyle, years postmenopausal, and site of BMD measurement.We conclude that postmenopausal BMD and fracture are closely associated with current, but not prior, HRT use. Use of HRT for 5 years or less, as proposed for treatment of symptomatic women during menopause transition, is unlikely to preserve bone or significantly reduce fracture risk in later years.

Low bone mineral density (BMD) is a risk factor for fracture. Although the current "gold standard" test is DXA of the hip and spine, this method is not universally available. No large studies have evaluated the ability of new, less expensive peripheral technologies to predict fracture. We studied the association between BMD measurements at peripheral sites and subsequent fracture risk at the hip, wrist/forearm, spine, and rib in 149,524 postmenopausal white women, without prior diagnosis of osteoporosis. At enrollment, each participant completed a risk assessment questionnaire and had BMD testing at the heel, forearm, or finger. Main outcomes were new fractures of the hip, wrist/forearm, spine, or rib within the first 12 months after testing. After 1 year, 2259 women reported 2340 new fractures. Based on manufacturers' normative data and multivariable adjusted analyses, women who had T scores < or = -2.5 SD were 2.15 (finger) to 3.94 (heel ultrasound [US]) times more likely to fracture than women with normal BMD. All measurement sites/devices predicted fracture equally well, and risk prediction was similar whether calculated from the manufacturers' young normal values (T scores) or using SDs from the mean age of the National Osteoporosis Risk Assessment (NORA) population. The areas under receiver operating characteristic (ROC) curves for hip fracture were comparable with those published using measurements at hip sites. We conclude that low BMD found by peripheral technologies, regardless of the site measured, is associated with at least a twofold increased risk of fracture within 1 year, even at skeletal sites other than the one measured.

Bone densitometry, regardless of the specific technique, is not perfectly reproducible even when consistently performed in exact accordance with the manufacturer's recommendations. Precision must be quantified at each densitometry facility in precision studies of the various skeletal sites used for monitoring. The precision, as the root-mean-square standard deviation or root-mean-square coefficient of variation, is then used to determine the change in bone density that constitutes the least significant change and the minimum interval between follow-up measurements. Until precision studies are performed, the least significant change cannot be determined for any level of statistical confidence, making the interpretation of serial studies impossible.

Regulation of prepro-PTH and vitamin D receptor (VDR) mRNAs in the parathyroid glands was studied in chickens in vivo. The birds were raised to 21 days of age on a vitamin D-deficient diet with 1% calcium and 0.65% phosphorous. At the end of this period, the chicks exhibited marked hypocalcemia and enlarged parathyroid glands. In three separate trials, the birds were repleted for 6 days with vitamin D and different dietary calcium and phosphate concentrations, with 2 micrograms/kg 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and different dietary calcium concentrations (0.5%, 1.0%, or 1.8%), or with 2 or 10 micrograms/kg 1,25-(OH)2D3 and 0.6% or 1.9% calcium or were kept vitamin D3 deficient and fed 0.5%, 1.0%, or 1.8% dietary calcium. Vitamin D treatment when combined with a high level of dietary calcium resulted in an increase in plasma calcium from 6 mg/dl to greater than 10 mg/dl, a decrease in PTH mRNA of 65%, and a 6- to 8-fold increase in VDR mRNA. In another experiment in which no vitamin D source was given and the diets contained increasing levels of dietary calcium, plasma calcium increased significantly (5.5 vs. 7 mg/dl), while PTH mRNA decreased by 40% and VDR mRNA increased by 60%. Neither parathyroid gland weight nor total RNA was significantly affected. When chicks were repleted with 1,25-(OH)2D3, the increase in plasma calcium and VDR mRNA and the decrease in PTH mRNA were considerably more pronounced than those in the absence of the vitamin D source. Furthermore, in the presence of the hormone, parathyroid weight and total RNA decreased significantly with increasing concentrations of dietary calcium. When the chicks were repleted, respectively, with the two levels of 1,25-(OH)2D3, a marked positive interaction was evident between the hormone and dietary calcium in affecting levels of PTH and VDR mRNA. These results suggest that both 1,25-(OH)2D3 and calcium participate in the regulation of PTH and VDR gene transcription in the avian parathyroid gland. Whereas the action of 1,25-(OH)2D3 requires a minimal level of dietary calcium, calcium affects PTH and VDR gene transcription even in the absence of any vitamin D source.

Previous studies have shown that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] decreases levels of mRNA for prepro-PTH as well as PTH secretion after chronic exposure (24-48 h) of parathyroid cells in tissue culture. We have now extended these studies to determine the effects of the vitamin D3 metabolite on parathyroid secretory protein (PSP) gene expression. Primary cultures of bovine parathyroid cells were incubated with 10(-8) M 1,25-(OH)2D3 for periods of time ranging from 24-72 h. As observed in earlier experiments, prepro-PTH mRNA decreased to less than 50% of the control value after 72 h. In marked contrast, PSP mRNA showed a 2.5-fold increase by 24 h and greater than 7-fold stimulation by 72 h. In the same studies, PTH secretion was suppressed (to 60% of control), while PSP secretion was increased by 40% over control values. Exposure to high (2.5 mM) or low (0.5 mM) calcium had no effect on PSP mRNA, even though low calcium stimulated the secretion of PSP while high calcium suppressed secretion. These studies showed that 1,25-(OH)2D3 has opposite effects on the gene expression of PSP and PTH in bovine parathyroid cells in tissue culture.

Effectiveness research (a term we use in preference to the more confining and difficult health services or outcomes research) evaluates the clinical setting and the health care system on which it depends. It uses a variety of health care assessment techniques and the practical clinical trial to inform clinical practice, quality interventions, and health policy decisions. Effectiveness research had not had sufficient public or private funding to produce the information needed to facilitate evidence-based health care improvement. However, recent trends, such as the likelihood for continued substantial increases in health care costs and concern regarding the quality and safety of the US health care system, are among the important arguments for increasing its funding and capacity. We propose a new entity, a public-private consortium to expand and offer new capability and resources in this area. The consortium would consist of all relevant public and private entities. It would be organized into an executive committee, which would identify research priorities and panels to design requests for proposals. Competitive peer-reviewed proposals, transparency and balance of forces in choice of topics, conduct of research, and interpretation of results would be important features. Metrics for success would be use of the data derived from consortium projects in medical decision making and benefit design. The consortium would provide balance and potential mediation of conflicting or competing interests in which all stakeholders will be present to establish the rules. Broad representation of all interests would serve to avoid the economic, policy, and political issues that have bedeviled past efforts. Models for the consortium include the Health Effectiveness Institute, the Centers for Education and Research on Therapeutics, and the Transportation Research Board.

The clinical research infrastructure of the United States is currently at a critical crossroads. To leverage the enormous biomedical research gains made in the past century efficiently, a drastic need exists to reengineer this system into a coordinated, safe, and more efficient and effective enterprise. To accomplish this task, clinical research must be transformed from its current state as a cottage industry to an enterprise-wide health care pipeline whose function is to bring the novel research from both government and private entities to the US public. We propose the establishment of a unique public-private partnership termed the National Clinical Research Enterprise (NCRE). Its agenda should consist of informed public participation, supportive information technologies, a skilled workforce, and adequate funding in clinical research. Devoting only 0.25% of the budgets from all health care stakeholders to support the NCRE would permit adequate funding to build the infrastructure required to address these problems in an enterprise fashion. All participants in the US health care delivery system must come together to focus on system-wide improvements that will benefit the public.

The relationship of low bone mass and fracture in younger postmenopausal women has not been extensively studied. In a large cohort of postmenopausal women ≥50 years of age, we found the relationship of BMD measured at peripheral sites and subsequent 1-year fracture risk to be similar between women

Osteoporotic fractures are a prominent cause of disability, and hip fracture produces 20% excess mortality in the ensuing year. The expanding population of elderly is expected to raise both direct and indirect costs of fractures in the United States and elsewhere in the world. Risk factors for low bone mineral density (BMD) and the incidence of fractures during 12 months of follow-up were studied in 200,160 ambulatory postmenopausal women aged 50 years or older, none of whom had been diagnosed as osteoporotic. Follow-up data were available for 82% of the group, whose mean age was 64.5 years. Nearly 90% of the study population were white. BMD was measured variably in the forearm, finger, or heel. Nearly 4 in 10 of the women tested (39.6%) had osteopenia at one or more of the measurement sites, and another 7.2% had osteoporosis. Advancing age was the outstanding risk factor; the odds ratio for osteoporosis rose from 1.79 in women 55 to 59 years of age to 22.6 for those aged 80 and older. The risk also increased with the years since menopause (independently of age), but only for those at least 30 years postmenopausal. Poor self-rated health, a history of fracture, and a maternal history of either fracture after age 45 or osteoporosis all made osteoporosis significantly more likely. Asian and Hispanic women were more at risk than whites, whereas African American women had just over half the risk level of white women. Increasing body mass index correlated with a lower risk of osteoporosis, as did either the former or especially current use of estrogen postmenopausally. Current exercise also lowered the risk, as did consuming one to six alcoholic beverages per week. On follow-up, analysis using T-score categories showed that osteoporosis increased the risk of fracture 4-fold compared with normal BMD, and women with osteopenia had a 1.8-fold higher fracture rate. In a Cox proportional hazards model, osteoporosis and osteopenia increased the risk of fracture within 12 months by 2.74- and 1.73-fold, respectively. There seems no doubt that a large population of women expected to live well into the present century will be at risk of fracture. The risk exists at the time low BMD is recognized at peripheral skeletal sites.

The effects of high calcium and 1,25-(OH)2D3 on parathyroid cell growth, PTH secretion, and steady-state levels of pre-proPTH mRNA in proliferating bovine parathyroid cells were examined. Cells were established in primary tissue culture and then tested in passages 2 and 5. Cell proliferation was suppressed by 10(-9)-10(-7) M 1,25-(OH)2D3 but not by high calcium (2.5 mM). Cells at passages 2 and 5 were grown to subconfluence and then exposed for 72 h to 2.5 mM calcium or 10(-7) M 1,25-(OH)2D3. Pre-proPTH mRNA was decreased to approximately 50% of control by 2.5 mM calcium compared with 0.3 and 1.0 mM calcium. PTH secretion, as tested by low calcium stimulation for 1 h at the end of 72 h incubation, was inhibited by 50% in cells that had been exposed to high calcium compared with control. Incubation with 10(-7) M 1,25-(OH)2D3 caused a decrease in the levels of pre-proPTH mRNA and PTH release to 50% of control at 72 h. These results suggest that cultured bovine parathyroid cells, at least in early passages, have responses to high calcium and 1,25-(OH)2D3 similar to those in primary nonproliferating cultures studied earlier and that 1,25-(OH)2D3 inhibits the proliferation of parathyroid cells in a dose-responsive fashion.

Outcomes research is a rapidly evolving field that incorporates epidemiology, health services research, health economics, and psychometrics. Measurement of clinical and other outcomes has become increasingly important to the stakeholders in a rapidly changing health care environment. The desire to improve outcomes and control costs has stimulated greater interest in cost-effectiveness studies, which determine how well effective therapies work in the usual practice setting and how much they cost. The application of outcomes principles to the practices of health care providers has resulted in efforts to implement disease management programs. Unlike traditional programs carried out by physicians, these new efforts are based on systematic population-based approaches to identifying persons at risk, intervening with specific programs of care, and measuring clinical and other outcomes. The new efforts depend heavily on modern information systems.

The secondary hyperparathyroidism of chronic renal failure is a result of many factors which result in chronic stimulation of parathyroid hormone secretion and secondary hyperplasia of the parathyroid glands. The secretion and metabolism of parathyroid hormone and its fragments in chronic renal failure are complex and only partially understood. Constant elevated levels of PTH contribute to bone disease and other clinical features of chronic renal failure. Calcium supplementation, high calcium dialysis, control of plasma phosphate and judicious use of the vitamin D metabolites can, to a large extent, prevent or control the development of secondary hyperparathyroidism. Subtotal parathyroidectomy or total parathyroidectomy with autotransplantation is indicated in certain cases, sometimes on an emergency basis. Prevention of postoperative hypocalcemia requires careful management. Successful renal transplantation is usually associated with gradual healing of the bone disease and slow, but sometimes incomplete involution of the parathyroid hyperplasia.

The results of parathyroid arteriography, venography and venous hormone assay were evaluated in 50 patients with proved hyperparathyroidism. Complete selective venous sampling representative of drainage sites in both upper and lower poles of the thyroid lobes was obtained in 94 per cent of the patients and was found to be an innocuous technic. Venous sampling alone provided correct localization and differentiation of parathyroid lesions in all patients without prior exploration. Venous sampling followed by limited arteriography provided specific identification of abnormal solitary parathyroid glands in 17 of 20 patients with unsuccessful prior explorations. Selective-magnification thyroid arteriography was positive in all patients retrospectively, but only a 77 per cent prospective accuracy could be achieved because of difficulty in differentiating thyroid lesions from parathyroid lesions. Venography without hormone assay was only occasionally helpful. These technics provided a significant contribution to the management of the previously explored patients. Furthermore, selective venous hormone assay should be considered in the routine preoperative evaluation of patients with primary hyperparathyroidism.

Because of increasing evidence for the heterogeneity of polypeptide hormones, studies of the molecular species of human placental lactogen (hPL) were initiated. When extracts of freshly delivered human placentas were passed over Sephadex G-100 in 0.05M ammonium carbonate, three immunoreactive peaks were detected. In addition to a peak corresponding to native hPL (Kav = 0.39) and one in the void volume, a consistent peak which eluted before hPL (Kav = 0.20) was present. The latter represented 2-25% of total hormonal activity and could be rerun without significant conversion to hPL. In 8M urea, the peak continued to behave as a large molecular weight form on both Sephadex chromatography and on polyacrylamide disc gel electrophoresis. Extraction procedures at both neutral and alkaline pH produced similar quantities of the larger material. [125I]iodo-hPL was not converted to the larger form by the conditions of extraction or analysis. These properties are consistent with a larger molecular weight, non-aggregated form of hPL. In comparison with the native hormone, the idsplacement curves for the larger form were parallel in radioimmunoassay studies. Sera obtained from pregnant women during various stages of gestation also showed consistent evidence for a large molecular weight form of the hormone. These observations provide direct evidence, both in placental tissue and in serum for "big" hPL.

“Big” human placental lactogen has been purified by affinity chromatography. On SDS 1 -polyacrylamide disc gel electrophoresis, “big” hPL had a molecular weight of about 45,000. Following reduction with mercaptoethanol, a single band with a molecular weight of 23,000 was noted. These observations suggest that “big” hPL consists of two peptide chains linked by a disulfide bond.

In a well-defined in vitro perifusion system, the effects of extracellular magnesium concentration (Mg) on parathyroid hormone (PTH) secretion by bovine parathyroid tissue were examined. At Mg less than 0.8 mM, the ability of the glands to secrete hormone maximally in response to low calcium (Ca) stimulation was progressively impaired. Low Mg also impaired the ability of isoproterenol, dibutyryl cyclic AMP and theophylline to stimulate hormone release. The defect in hormone release at low Mg observed in vitro was analogous to the well-documented inhibition of secretion observed in vivo. Increases in Mg from 0 to 0.8 mM rapidly repaired the defect in hormone secretion. At Mg above 1.0 mM there was a Ca-like effect on hormone release, with a progressive decrease in secretion at increased Mg. Although its mechanism is not yet clear, the low Mg effect appears to impair principally the process of hormone release rather than its biosynthesis or storage.

We have recently determined that high calcium concentrations, in parallel with their suppressive effects on parathyroid hormone (PTH) secretion, reversibly and specifically decrease preproPTH mRNA in cultured bovine parathyroid cells. In order to determine whether vitamin D metabolites also regulate the content of preproPTH mRNA, we tested their effects on bovine parathyroid cells in the same culture system. Levels of preproPTH mRNA were determined by dot-blot hybridization or blot hybridization with a labeled cloned cDNA probe. Incubation with 1,25-dihydroxycholecalciferol at doses varying from 10 pM to 0.1 microM caused a direct decrease in mRNA down to 50% of control values at 48 hr. There was no evidence that 1,25-dihydroxycholecalciferol, even at the highest concentrations, had any toxic effects on cell number or viability or on total RNA or RNA synthesis. Levels of alpha-actin mRNA did not change in the same experiments, and the suppression of preproPTH mRNA was reversible. When the relative potency of various vitamin D metabolites in suppressing preproPTH mRNA was evaluated, 1,25-dihydroxycholecalciferol greater than 24,25-dihydroxycholecalciferol greater than 25-hydroxycholecalciferol greater than vitamin D3 (cholecalciferol). These effects were highly specific and suggest that vitamin D metabolites play an important role in regulating the production of PTH.

The cell-free translation product of human placental lactogen mRNA is a precursor molecule larger than the mature hormone that circulates in plasma. To determine the structure of pre-placental lactogen, the poly(A)-rich RNA fraction of term placenta was isolated and translated in a wheat germ cell-free system. The mRNA programmed the synthesis of a major protein, 3000 daltons larger than placental lactogen, that was specifically precipitated by hormone antibodies. The immunoprecipitated protein was labeled separately with 20 radioactive amino acids and subjected to sequence analysis. The results showed the synthesis of pre-placental lactogen in which an extra piece 25 residues long preceded the NH2 terminus of the mature protein. The structure of the extra piece is as follows: Met-Pro-Gly-Ser-Arg-Thr-Ser-Leu-Leu-Ala-Phe-Ala-Leu-Leu-Cys-Leu-Pro-Trp-Leu-Gln-Glu-Ala-Gly-Ala-. Met1 is the initiator residue because only initiator [35S]Met-tRNAMet1, but not internal [35S]Met-tRNA2Met, donated NH2-terminal methionine. The structure of the extra piece showed little homology with that of unrelated hormones but striking homology (64%) with the extra piece of rat pre-growth hormone. Most amino acid substitutions involved a single base change in the codon. Mature human placental lactogen and rat growth hormone have 59% homology in sequence. Thus, our findings provide additional evidence to support the common evolutionary origin of these hormones, not only of the mature proteins but also of the extra piece segments.

The maintenance of a normal serum calcium concentration requires a stable equilibrium between mineral in the skeleton and the extracellular fluid and the carefully integrated and balanced actions of parathyroid hormone (PTH), vitamin D, and, to a much lesser extent, calcitonin. The amino acid sequences of bovine, porcine, and part of human PTH have recently been determined. It has been recognized that some of the difficulties encountered in measuring PTH by radioimmunoassay in serum are due to the conversion of the hormone into fragments, to the variable specificity and sensitivity of the antisera used in these determinations, and to the presence of a previously unrecognized precursor in the synthesis of the hormone. Parathyroid hormone appears to stimulate its target tissues (bone and kidney) through the adenyl cyclase mechanism, and it has now been appreciated that factors other than calcium have regulatory control over the secretion of hormone. The metabolism of vitamin D has been elucidated, and the active metabolite, 1,25-dihydroxy-cholecalciferol, has been identified. Production of this compound in the kidneys is under feedback control so that vitamin D takes on the characteristics of a hormone. Future developments involve the synthesis of more active and shorter-acting metabolites of vitamin D, drugs that will be of considerable usefulness to the clinician. Despite many years of research and a number of interesting biochemical, physiologic, and clinical studies, the importance of calcitonin in human physiology has not yet been determined. Nevertheless, its measurement in blood is a useful diagnostic aid in medullary carcinoma of the thyroid. Multiphasic screening programs have disclosed a surprisingly high prevalence of hypercalcemia in a random population. In most instances, the differential diagnosis can be made by carefully collecting a data base and using conventional laboratory procedures. Nevertheless, the assay for PTH has proven useful for diagnosis in some patients, particularly in the preoperative localization of parathyroid adenomas. The path is cleared for the development of more meaningful hormone assays and additional prospective studies on the management of asymptomatic patients with hyperparathyroidism. This review is written at an exciting time when major advances are being made in our understanding of calcium homeostasis, and rapid changes are occurring in the spectrum of hypercalcemic disorders being presented to the physician. Many of these research developments are summarized in relation to the clinical problem.

Twenty-six patients with chronic renal failure treated by long-term hemodialysis were studied. Radiologic parathyroid bone disease was observed in 15 patients, and in these, serum parathyroid hormone (PTH) levels were significantly higher ( p

Hypocalcemia frequently presents as an acute medical emergency or a chronic disorder which is difficult to control. Occasionally, it is found in routine blood screening tests when it is not anticipated. Recent developments in basic endocrine science have contributed greatly to our understanding and treatment of hypocalcemic disorders. The maintanance of a normal serum calcium concentration depends on the balanced actions of parathyroid hormone (PTH), vitamin D, and, to a lesser extent, calcitonin, Recent work on PTH secretion has defined the factors controlling its secretion in normal and abnormal states. In primary hypoparathyroidism, hormone secretion is decreased or absent, while in most other forms of hypocalcemia, secretion is stimulated secondarily by the hypocalcemia. However, acute or chronci disorders associated with hypomagnesemia may also decrease effective PTH secretion. Patients with the rare disorder, pseudohypoparathyroidism, have defects of hormone action and usually have elevated levels of PTH prior to therapy. Several forms of pseudohypoparathyroidism have been recognized, each representing a defect as a different site of PTH action. Calcitonin excess, as noted in medullary carcinoma of the thyroid, could theorectically cause hypocalcemia, but rarely does so. Vitamin D undergoes a series of two carefully controlled hydroxylation reactions leading to the final active metabolite, 1,25-hihyroxycholecalciferol. Chronic ingestion of certain drugs can lead to osteomalacia and hypocalcemia by potentiating the metabolism of vitamin D to inactive compounds. At least one form of rickets has been shown to result from a specific enzyme defect in the vitamin D pathway. Severe renal damage limits the conversion of vitamin D to its active form and contributes to vitamin D resistance. Current progress in the area depends on the development of procedures for the measurement of the metabolites in plasma and assessing the role of the vitamin (hormone) in normal and abnormal physiology. Although the therapy of acute hypocalcemia is usually readily accomplished, chronic hypocalcemia remains a very difficult therapeutic problem. Vitamin D, the hallmark of therapy, is a long-acting drug with a narrow therapeutic range. The complications of the disease and therapy are sometimes irreversible. The unraveling of vitamin D metabolism has led to the development of new therapeutic agents which might provide better relief of chronic hypocalcemic states. This review related new information about calcium homeostasis to the clinical situation encountered in the patient with hypocalcemia.

Previous studies have shown that thiazide diuretic agents reverse secondary hyperparathyroidism and reduce circulating 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and intestinal calcium absorption rates in patients with idiopathic hypercalciuria of the renal-leak variety. We have investigated whether thiazides can reverse the secondary increase in serum parathyroid hormone (PTH) and 1,25(OH)2D3 levels or intestinal calcium absorption induced by feeding rats a diet low in calcium (LCD, 0.02% calcium) but adequate in phosphorus and vitamin D. We found that LCD increased circulating immunoreactive PTH [chow vs. LCD, 0.52 +/- 0.06 vs. 1.06 +2- 0.1 (SE) ng/ml, P less than 0.001], 1,25(OH)2D3 (chow vs. LCD, 101 +/- 15 vs. 325 +/- 38 pg/ml, P less than 0.001), calcium uptake by everted gut sacs from duodenum, ileum, and descending colon, and net calcium absorption by descending colon studied in Ussing chambers in vitro. Chlorothiazide (CTZ) prevented the increase in PTH during LCD (chow + CTZ vs. LCD + CTZ, 0.69 +/- 0.07 vs. 0.73 +/- 0.06, NS) but not the increase in 1,25(OH)2D3 (chow + CTZ vs. LCD + CTZ, 88 +/- 10 vs. 277 +/- 31, P less than 0.002) or intestinal calcium transport. The drug caused no change in serum 1,25(OH)2D3 or intestinal calcium absorption in rats fed normal chow. In rats given exogenous 1,25(OH)2D3 to stimulate intestinal calcium absorption, CTZ reduced urine calcium excretion greatly but did not alter intestinal calcium absorption.

76 kidney transplant recipients who were up to 4 years post transplant, were studied to assess the incidence of secondary hyperparathyroidism. All patients had good renal function with a mean serum creatinine of 1.4 mg/100 ml. Secondary hyperparathyroidism, as evidenced by increased serum parathyroid hormone levels, was present in 53 of the 76 patients (66%) and radiologic bone disease in 26 of the 76 patients (34%), while hypercalcemia (serum calcium greater than 11.0 mg/100 ml) occurred in only 6 patients (8.5%). The incidence of secondary hyperparathyroidism decreased slightly with time following transplantation, but the degree of secondary hyperparathyroidism as indicated by the levels of serum parathyroid hormone at various times following renal transplantation was essentially similar. The causes for the persistence of this condition are not totally known, but it was found that its incidence was related to the duration of dialysis prior to transplantation.

Four patients with primary parathyroid hyperplasia were treated by total parathyroidectomy and autotransplantation of parathyroid tissue into the forearm muscle. All patients remained normocalcemic after vitamin D and oral calcium replacement therapy were stopped at 1 1/2, four, nine and 13 months, respectively. Graft function was documented further by detection of a higher concentration of parathyroid hormone in plasma from the basilic vein draining the graft bed than from the basilic vein in the contralateral arm. Intravenous calcium infusion suppressed parathyroid hormone secretion from the graft whereas hypocalcemia induced by ethylenediaminetetra-acetic acid markedly stimulated hormone release. In two patients histologic examination of a grafted fragment revealed hyperplastic parathyroid tissue. This method of treatment offers a suitable alternative to radical subtotal parathyroidectomy in selected patients with hyperparathyroidism.

The results of studies performed in nine patients who had undergone successful parathyroidectomy and gland transplantation are presented. Transplantation of parathyroid tissue to the forearm, performed for therapeutic reasons, provided a unique opportunity to sample parathyroid gland effluent and to assess secretory function in vivo. The relationship of calcium to immunoreactive parathyroid hormone (iPTH) release was studied during calcium and ethylenediamine tetraacetic acid (EDTA) infusions as well as dialysis against a low calcium bath (low calcium dialysis) in patients with chronic renal failure. Calcium infusions caused an abrupt decrease in hormone release down to a persistent base line within 30 minutes, whereas EDTA infusion caused a sharp increase which peaked between 30 to 60 minutes and returned towards base line despite continuation of the hypocalcemic stimulus. Low calcium dialysis caused an irregular release of hormone which appeared to deplete gland reserves during the period of the stimulus. Ready access to the venous effluent of the transplanted tissue makes this an excellent model for studying parathyroid physiology in man.

The secretory response of abnormal parathyroid glands obtained surgically from eleven patients with primary and secondary hyperparathyroidsm was tested in vitro. Short term flask studies were used to measure release of parathyroid hormone (PTH) at high (3.0 mM) and low (0.5 mM) calcium. Of eight adenomas, all but one showed increased release of hormone when exposed to low calcium ("responsive to calcium"), the degree of stimulation at three hours ranging from 15 to 209%. By comparison, two normal human glands were stimulated an average of 180%. Glands from three patients with secondary hyperplasia were also responsive to calcium. Thus, parathyroid glands from patients with primary and secondary hyperparathyroidism were characterized by a spectrum of responsiveness to calcium, and absolute "autonomy" was unusual. Even at high calcium concentrations, hormone release persisted at a low but definite level ("basal secretion"). The total number of functioning parathyroid cells is therefore a principal determinant in the oversecretion of PTH in hyperparathyroidism.

THOSE of us concerned with clinical disorders of hemostasis face problems with a wide range of urgency. Often, we are afforded the opportunity to unravel, in a logical and orderly sequence, a compl...

IT should come as no shocking news that the law affecting physicians and hospitals has radically changed in the last decade. The law has changed and is changing because society in general now presses for such change. The law responds to those societal pressures and attempts to meet the expressed needs of the public. That has been one of the traditional functions of the law. Many years ago Justice Holmes in his classic work, The Common Law, stated a definition of law that is appropriate to our present discussion: The life of law has not been logic: It has been . . .

HUMAN hemoglobin has probably been studied more carefully than any other protein. The traditional biochemical approach is first to purify a protein and then to study its properties under controlled...

Plasma parathormone, calcium and phosphorus were measured during calcium infusion in patients with chronic renal failure treated by intermittent hemodialysis. Subjects with osteitis fibrosa cystica had elevated plasma concentrations of parathormone when compared with similarly dialyzed subjects without osteodystrophy (2.6±0.4 vs. 0.6±0.2 ng/ml, p

THE major infectious disease problems in most hospitals today are those that occur in the hospital — so-called nosocomial infections. In this discussion I shall define briefly the scope of the problem, explore some of the causes of the unacceptably high prevalence of hospital-acquired infections, evaluate some of the current preventive measures, and speculate on developments that may improve prevention and therapy. I shall focus on bacterial infections, although in certain classes of patients other organisms at times may be etiologic. The Problem Prevalence In 1959, Rogers1 presented data from an autopsy study confirming that the types of infection causing . . .

Summary In a well-studied physiologically functioning in vitro system for the study of parathyroid hormone (PTH) secretion, both theophylline and dibutyryl cyclic adenosine monophate (dAMP) caused significant stimulation of PTH secretion. The quantity of PTH in the medium paralleled the release of cyclic 3′, 5′-AMP (CAMP) from incubated tissues. These studies suggest strongly that adenyl cyclase is the mediator of the known effects of calcium ion on PTH secretion.

The two disulfide bonds of human placental lactogen (hPL) and human growth hormone (hGH) were chemically modified, and the lactogenic and immunologic activities of the derivatives were compared with those of the native unmodified hormones. Reduction and alkylation with iodoacetamide and iodoacetic acid selectively disrupted the two bonds, resulting in the formation of the S—carbamidomethyl and S—carboxymethyl derivatives, respectively. Performic acid oxidation converted the half—cystine residues to cysteic acid, oxidized the methionine residues to methionine sulfone and destroyed the single tryptophan residue in each hormone. The lactogenic potency of the derivatives, as measured by the stimulation of casein synthesis in vitro in mammary gland explants, was completely retained; immunologic activity, on the other hand, was markedly decreased or abolished. Neither the tertiary structure contributed by the two disulfide bonds in each molecule nor the presence of intact methionine and tryptophan residues is e...

Presentation of Case A 54-year-old man was referred to the hospital because of hypercalcemia. For 20 years his intake of alcohol had been heavy, but he was able to continue his work as a carpenter. Ten years before admission he was disabled by a "stroke," about which no further details could be obtained. At approximately that time he was informed that he had a duodenal ulcer; thereafter he consumed small amounts of Maalox and 2 quarts of milk daily. Six months before entry he began to experience exertional dyspnea on climbing stairs. One month before admission anorexia, polydipsia, polyuria and . . .

Starvation entails a progressive selection of fat as body fuel. Soon after a meal glucose utilisation by muscle ceases and fatty acids are used instead. Ketoacid levels in blood become elevated over the first week, and the brain preferentially uses these instead of glucose. The net effect is to spare protein even further, as glucose utilisation by brain is diminished. Nevertheless, there is still net negative nitrogen balance, but this can be nullified by amino acid or protein supplementation. Insulin appears to be the principal regulatory hormone. Recent data suggest that decreased levels of active T3 may play a role by sparing otherwise obligated calories by decreasing metabolic needs.

THE function of pancreatic glucagon has been questioned for several decades, but it now seems probable that glucagon, like insulin, is extremely important in the moment-to-moment control of the homeostasis of glucose, of certain amino acids and perhaps of free fatty acids. Normal alpha-cell function seems essential to optimal glucoregulation, and abnormal alpha-cell function may cause, contribute to or result from a variety of metabolic disorders, the most common being diabetes mellitus. Biologic Opposition of Glucagon and Insulin Glucagon has been shown to have potent glycogenolytic1 and gluconeogenic2 , 3 activity at concentrations within the physiologic range. In addition, it may have . . .

Evaluation by Radioimmunoassay of Factors Controlling the Secretion of Parathyroid Hormone: Intravenous Infusions of Calcium and Ethylenediamine Tetraacetic Acid in the Cow and Goat

ALTHOUGH we usually think of the small intestine in terms of its absorptive functions, it also has the capacity to secrete water and electrolytes. Its secretory capacity is impressively demonstrated by the diarrhea of cholera, which is almost entirely of small-bowel origin.1 An afflicted person at the height of his disease may excrete by rectum more than 1 liter of fluid every hour. It is not uncommon for patients to require fluid replacement in excess of their body weight over a period of several days.2 Probably an even greater amovint of fluid passes from the ileum into the colon, as . . .

The molecular properties of reduced carboxymethylated, reduced carbamidomethylated and oxidized human placental lactogen have been studied by UV absorption, fluorescence and circular dichroism. Reduction and alkylation of the two disulfide bonds in the presence of urea results in the loss of numerous noncovalent interactions of the native structure and the acquisition of new noncovalent interactions. Oxidized placental lactogen shows an even greater loss in native structure without the formation of new intramolecular bonds. Since lactogenic activity is completely retained in these modified forms of lactogen, it appears that its native three—dimensional structure is not necessary for lactogenic activity. It seems possible, therefore, that a fragment of the polypeptide chain may be sufficient to produce hormonal effects. (Endocrinology 91: 728, 1972)

Measurement by radioimmunoassay of secretory rates for parathyroid hormone in the cow shows that hypocalcemia is the major stimulus for hormone production; hypercalcemia quickly abolishes secretion. Phosphate causes no direct effect on secretion of the hormone. Analyses for parathyroid hormone and calcium in peripheral plasma showed a simple linear inverse function of hormone concentration vs. plasma calcium in the range of 4 to 12 mg/100 ml. This led to the conclusion that calcium regulates hormonal secretion predominantly through a proportional control mechanism. The half-life of parathyroid hormone in the circulation was found to be approximately 20 min. The speed with which secretion responds to changes in blood calcium and the short half-life of hormone in plasma are consistent with recent studies showing that parathyroid hormone effects rapid changes in blood calcium. These findings emphasize the importance of the hormone in the minute to minute regulation of blood calcium. (Endocrinology 83: 1043, ...

HEART disease, hypertension, arthritis, mental disease, visual impairment and orthopedic disability are all more common among the poor. Death rates from tuberculosis, syphilis, influenza, pneumonia...

RECOGNITION of the role of human hemoglobin variants in the pathogenesis of disorders associated with sickling and with thalassemia constituted one of the most important advances in hematology during the last 20 years. More recent has been the realization that variants of human hemoglobin may be associated with other clinical syndromes: variants having altered oxygen equilibria, such as the M hemoglobins, may produce cyanosis or erythrocytosis, whereas unstable variants are associated with congenital Heinz-body anemias. In few fields of clinical investigation can one so clearly relate the clinical presentation of the patient to the molecular aspects of his disorder. However, . . .