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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.

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 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.

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.

“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.

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.

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...

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 . . .

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...

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 . . .

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, . . .

In the first few weeks after the initiation of maintenance hemodialysis in nine patients with chronic renal failure, there was a progressive rise in both total and ionized serum calcium associated with a reciprocal and significant fall in the concentration of plasma parathyroid hormone. Studies in 36 additional patients with chronic renal failure already on hemodialysis indicated that this favorable trend did not continue; a progressive rise in parathyroid hormone concentration was associated with increasing duration of hemodialysis against the calcium concentration generally used by most centers. These observations are consistent with the increase in bone disease often associated with hemodialysis. Experimental increases in dialysate calcium concentration from 2.6 to 3.5 meq/liter for a 2-mo period failed to decrease parathyroid hormone secretion or cause a significant increase in predialysis calcium concentration in 36 uremic patients. Use of high calcium dialysis earlier in the course of the disease, alternate means of parathyroid suppression, and even subtotal parathyroidectomy may be necessary for the management of hyperparathyroidism in uremic patients undergoing hemodialysis.

Physiologic function of normal bovine parathyroid glands and of glands from patients with a variety of disorders of calcium metabolism was studied in an in vitro organ culture system. Calcium (Ca) concentration regulated both the synthesis and the secretion of parathyroid hormone (PTH) by normal tissue; magnesium (Mg) had an equivalent effect on hormone release. The relationship between cation concentration (Ca plus Mg) and hormone secretion was first-order. Evidence was obtained that PTH is synthesized in the glands as a protein that is altered to a smaller, immunologically related peptide before being released into the culture medium or plasma. The latter observation may help to explain some of the difficulties encountered in the radioimmunoassay of PTH in human blood. Most adenomas from patients with primary hyperparathyroidism were autonomous in organ culture, whereas most glands from patients with renal disease still remained responsive. Autonomous or "tertiary hyperparathyroidism" was documented in two patients.

AN earlier report from this laboratory1 described striking homologies in the amino-acid composition of the peptides obtained from trypsin cleavage of human placental lactogen (HPL) and human growth hormone (HGH) and established a firm biochemical basis for the similarities in biological and immunological activity of the two hormones. The intrachain disulphide bonds were placed in similar locations and the carboxyl-terminal amino-acid sequences were shown to be identical except for one out of fourteen residues2. In other studies3,4, the amino-terminal sequence was determined and noted to be homologous for eleven of the first seventeen residues. We now report the complete amino-acid sequence of HPL and a comparison with the revised structure for HGH recently reported4. These two protein hormones are strikingly similar in structure, being identical in 85% of the corresponding positions. Of twenty-eight amino-acid substitutions, twenty-five are favoured changes and all but two of the twenty-five can be explained in terms of a single base change in the triplet codon5.

HYPERCALCEMIA is a common complication of breast cancer usually associated with radiologic evidence of skeletal metastases or the administration of hormone therapy.1 , 2 Although the neoplasms associated with ectopic production of parathyroid hormone (PTH) have recently been reviewed,3 there is a striking absence of breast cancer among them. Furthermore, carcinoma of the breast has not been included among the tumors in which the presence of immunoreactive PTH-like activity has been documented.4 , 5 In the following ease the tumor tissue contained a PTH-like substance. Case Report A 44-year-old premenopausal woman underwent a radical mastectomy in 1966 for removal of a duct-cell carcinoma of . . .

THE two major hormones that regulate calcium homeostasis are parathyroid hormone and the active form of vitamin D3 (l,25-(OH)2D3).1 These hormones work in concert to mobilize calcium from bone and act separately to increase the reabsorption of calcium by the renal tubule (parathyroid hormone) and the absorption of calcium by the intestine (l,25-(OH)2D3). By stimulating the activity of the enzyme 1α-hydroxylase in the kidney, parathyroid hormone also enhances the production of l,25-(OH)2D3. What has been less clear is the relation between l,25-(OH)2D3 and the . . .

Dimeric ("big") human placental lactogen has been isolated in near homogeneous form from placental tissue. It consists of a disulfide-linked (stable) form and a noncovalently associated (unstable) form of the native hormone. The two forms were separated by exposure to denaturing conditions and resolution by gel exclusion chromatography. Both forms retained immunological activity, ability to bind mammary membranes, and ability to induce mammary N-acetyllactosamine synthetase in vitro. On a molar basis, stable dimeric placental lactogen was more active than placental lactogen in the radioimmunoassay indicating that the immunological determinants on both monomeric units could bind to antibody. On a molar basis, stable dimeric placental lactogen was equally active with monomeric placental lactogen in competing for mammary gland membrane binding sites, indicating that only one active site in the molecule could interact with the membrane at a time. Stable dimeric placental lactogen was also active in an in vitro bioassay using the induction of N-acetyllactosamine synthetase. It is concluded that dimer formation does not alter the biologically active portion of the placental lactogen molecule. Since the carboxyl-terminal region (residues 182-191) is involved in the interchain disulfide bonds of dimeric placental lactogen, this portion of the molecule is probably not necessary for its biological activity.

Almost 40 years have elapsed since Albright1 first suggested that the neoplastic tissue in a patient with renal-cell carcinoma and hypercalcemia might produce parathyroid hormone or a similar subst...

We have used a low-calcium diet providing only 2 mg/kg (body weight) per 24 hours of calcium to distinguish between "renal" and "absorptive" idiopathic hypercalciuria. Sixteen of 27 hypercalciuric subjects excreted calcium in excess of intake during days seven, eight and nine of he diet, suggesting some element of renal hypercalciuria; however, all patients had low or normal serum PTH and urine cAMP levels. In general, fasting urine calcium was elevated in these 16 subjects and normal in the remaining 11, who conserved calcium more normally. SErum 1,25(OH)2D3 levels were the same in patients and normal subjects, even though PTH levels of the patients were below those of he normal subjects. Urine magnesium excretion and phosphorus excretion were both increased in the patients who excreted calcium in excess of intake. Our findings suggest that renal and absorptive hypercalciuria may not be distinct entities but rather the two extremes of a continuum of behavior. A uniform elevation of intestinal calcium absorption and a variable defect of renal calcium reabsorption could explain our results far better than the hypothesis of distinct absorptive and renal forms of hypercalciuria.

DURING the past year approximately 40 hospitals in 10 states as well as the District of Columbia have begun using a computer program designed to help physicians manage patients with electrolyte and acid–base disorders. The program directs a dialogue during which the physician supplies clinical and laboratory information. When requested data are unavailable the program proceeds with incomplete information. On the basis of the abnormalities detected it then summons further questions as needed to characterize the electrolyte and acid–base disturbances. Upon completion of the interchange the program produces an evaluation note that resembles a remotely located consultant's discussion of the . . .

THAT man has daily rhythms of body temperature, excretion and many other functions has been known for a very long time. Only recently has it been widely appreciated, however, that these rhythms are...

ALTHOUGH it has long been recognized that the serum calcium is maintained within rigid physiologic limits, it is only in the past decade that the hormonal factors involved in this regulation have b...

CURRENT research has emphasized the importance of changes in hone resorption, not only in the regulation of calcium homeostasis, but also in the pathogenesis and therapy of metabolic bone disease. Only a few of the many agents that affect bone resorption are physiologic regulators (Table 1) — that is, factors that act directly on bone-resorbing cells, maintain homeostasis in the presence of a deficiency or excess of calcium and are essential for bone growth and remodeling. Thyroxine, glucocorticoids, growth hormone and pyrophosphate (as well as substances yet to be discovered), may be added to this list as evidence accumulates concerning . . .

To investigate the value of maternal human placental lactogen (HPL) as an index of functioning trophoblast, a controlled series of 111 pregnant patients was studied. Concentrations of HPL in maternal and fetal blood at term were determined by radioimmunoassay, and these values were correlated with placental weight and the weight of the newborn at delivery. Mean maternal HPL at term was 3.98 μg per milliliter (range, 0.4 to 15.6) and mean fetal HPL was 58.9 mμg per milliliter (range, 0.2 to 266.4). The rank correlation between maternal HPL and placental weight was 0.34 which, although positive, was too low to be of predictive value.

THE clinical use of digitalis is accompanied by a distressingly high prevalence of toxic manifestations, the most serious of which are arrhythmias and disturbances of conduction.1 , 2 Many factors contribute to the development of digitalis toxicity (Table 1). Perhaps the most important is the accumulation of excessive amounts of digitalis in the body and in the myocardium in particular. Although excessive digitalis accumulation occasionally reflects excessive dosage, it is more commonly due to diminished excretion. Largely as a result of the studies of Doherty3 4 5 6 7 and of Marcus8 9 10 and their collaborators, much has recently been learned about the factors that lead to . . .

MODERN therapeutic agents have contributed favorably to the physician's ability to influence the course of many diseases. Their use has also created a formidable health problem: 18 to 30 per cent of all hospitalized patients have a drug reaction,1 , 2 and the duration of their hospitalization is about doubled as a consequence.1 2 3 4 In addition, 3 to 5 per cent of all admissions to hospitals are primarily for a drug reaction,1 , 5 and 30 per cent of these patients have a second reaction during their hospital stay. The economic consequences are staggering: one seventh of all hospital days is devoted to the care . . .