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Background The patellofemoral joint is a challenging environment for treating chondral defects. Among the surgical options for the treatment of chondral defects, the single-stage AMIC procedure uses a collagen I/III membrane to enhance bone-marrow stimulation. However, longer term outcomes data are rare for this specific indication. In order to provide real-world information, an ongoing registry has been established in order to record patient data and outcomes when AMIC is used to treat chondral and osteochondral lesions, which for this study were those of the patella.Methods Patient data were retrieved from an ongoing, prospective, multisite registry of patients who had undergone surgical repair of chondral defects via AMIC. We identified 65 patients, all of whom had been treated by one of the authors and for whom pre-operative and at least 1 post-operative score was available. Outcomes were assessed via the KOOS and the Lysholm scores. Outcomes at the post-operative time-points were analysed using a factorial ANOVA with post-hoc testing while linear regression was used to assess associations between the change in the Lysholm score and lesion size.Results The mean lesion size was 3.1 ± 1.4 cm2. The most common surgical approach was mini-open, the most common fixation was via fibrin glue and the mean length of follow-up of 5.8 years (range 1–10 years). There was a significant improvement in the KOOS scores from pre-operative to the 1st year post-operative (p 0.001) as well as in ADL and QOL (p > 0.001 for both) were maintained throughout the follow-up.Conclusions The forces exerted on the patellofemoral joint make this a challenging scenario for chondral repair. Our data demonstrates that the AMIC procedure is an effective treatment for retropatellar cartilage lesions, and provides reliable results, with decreased pain and improved function. Importantly, these improvements were maintained through the follow-up period.

Objective A systematic review and meta-analysis of Autologous Matrix-Induced Chondrogenesis (AMIC®) outcomes for grade III/IV chondral and osteochondral lesions of the knee treated with Chondro-Gide®. Design Studies with a minimum follow-up of 1 year providing clinical results of AMIC repair in the knee were included based on PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Methodological quality was assessed by the modified Coleman Methodology Score (mCMS). The meta-analysis was comparing pain VAS (Visual Analog Scale), Lysholm score, and IKDC score (International Knee Documentation Committee) between baseline and follow-up after 1 or 2 years and after >3 years. Results Twelve studies (375 patients) were included. The mCMS demonstrated a suboptimal study design (ranking between 52 and 80). The mean age was 36.2 years (14-70 years). The mean defect size was 4.24 cm2 (0.8-22 cm2). The results from the random effects model indicated a clinically significant ( P < 0.05) improvement of pain VAS from baseline to follow-up at year 1 to 2 of −4.02(confidence interval −4.37; −3.67), still significant after 3 years. Lysholm score at year 1 or 2 improved significantly and remained highly significant after 3 years. IKDC score showed highly significant improvement of 32.61 between 1 and 2 years versus baseline values maintained after 3 years. Conclusions The AMIC procedure significantly improved the clinical status and functional scoring versus preoperative values. Evidence was obtained in a non-selected patient population, corresponding to real-life treatment of knee chondral and osteochondral defects. The evidence is sufficient to recommend AMIC in this indication.

Background: Autologous matrix-induced chondrogenesis (AMIC) is a well-established treatment for full-thickness cartilage defects. Purpose: To evaluate the long-term clinical outcomes of AMIC for the treatment of chondral lesions of the knee. Study Design: Case series; Level of evidence, 4. Methods: A multisite prospective registry recorded demographic data and outcomes for patients who underwent repair of chondral defects. In total, 131 patients were included in the study. Lysholm, Knee injury and Osteoarthritis Outcome Score (KOOS), and visual analog scale (VAS) score for pain were used for outcome analysis. Across all patients, the mean ± SD age of patients was 36.6 ± 11.7 years. The mean body weight was 80.0 ± 16.8 kg, mean height was 176.3 ± 7.9 cm, and mean defect size was 3.3 ± 1.8 cm2. Defects were classified as Outerbridge grade III or IV. A repeated-measures analysis of variance was used to compare outcomes across all time points. Results: The median follow-up time for the patients in this cohort was 4.56 ± 2.92 years. Significant improvement ( P < .001) in all scores was observed at 1 to 2 years after AMIC, and improved values were noted up to 7 years postoperatively. Among all patients, the mean preoperative Lysholm score was 46.9 ± 19.6. At the 1-year follow-up, a significantly higher mean Lysholm score was noted, with maintenance of the favorable outcomes at 7-year follow-up. The KOOS also showed a significant improvement of postoperative values compared with preoperative data. The mean VAS had significantly decreased during the 7-year follow-up. Age, sex, and defect size did not have a significant effect on the outcomes. Conclusion: AMIC is an effective method of treating chondral defects of the knee and leads to reliably favorable results up to 7 years postoperatively.

Background Postoperative autologous retransfusion of drainage blood might reduce the transfusion of red blood cell concentrates after major orthopaedic surgery. Objectives Our primary objective was to evaluate the effectiveness of a blood collection and retransfusion system. Secondary objectives included safety issues and the quality of the drainage blood collected. Design Combined retrospective and prospective cohort study. Setting Swiss regional hospital, from 1 January to 31 December 2015 (retrospective cohort) and 1 January to 31 August 2018 (prospective cohort). Patients The retrospective and prospective cohort included 216 and 46 patients, respectively, who underwent elective hip or knee replacement. Interventions Use of a postoperative blood collection and retransfusion system. Main outcome measures The primary outcome was the postoperative haemoglobin in patients with and without autotransfusion. Secondary outcomes were percentage of patients with transfusion of allogeneic blood products and with adverse events with and without autotransfusion. Tertiary outcomes were laboratory levels of specific inflammation and coagulation parameters in collected drain blood directly after surgery and 6 h postoperatively. Results Autologous retransfusion was performed in 50 patients (23%) in the retrospective analysis. Postoperative haemoglobin level was increased by 5 g dl (P = 0.017) in retransfused patients compared with those without retransfusion. However, there was no difference in the number of transfused allogeneic red blood cell concentrates. Mild adverse transfusion reactions were reported in 13 retransfused patients (26%). Laboratory analyses for the second prospective part detected massively elevated concentrations of myeloperoxidase and IL-6 in the drainage blood, but C-reactive protein and procalcitonin concentrations were within normal ranges at both time points. D-dimers levels were above the upper normal level in 37 and 24% at the two time points, respectively, and tended to decrease over time (P = 0.060). Conclusion Our study questions the effectiveness of postoperative autotransfusion as part of a patient blood management programme. In addition, the obvious signs of inflammatory reactions and coagulation activation raise safety concerns. Trial registration The cohort study was not registered in a trial registry.

Introduction Autologous Matrix-Induced Chondrogenesis (AMIC) is an innovative treatment for localized full-thickness cartilage defects combining the well-known microfracturing with collagen I/III scaffold. The purpose of this analysis was to evaluate the medium-term results of this enhanced microfracture technique for the treatment of chondral lesions of the knee. Methods and materials Patients treated with AMIC (Chondro-Gide®, Geistlich Pharma, Switzerland) were followed using the AMIC Registry, an internet-based tool to longitudinally track changes in function and symptoms by the Lysholm score and VAS. Results A series of 57 patients was enrolled. The average age of patients (19 females, 38 males) was 37.3 years (range 17–61 years). The mean defect size of the chondral lesions was 3.4 cm2 (range 1.0–12.0 cm2). All defects were classified as grade III (n = 20) or IV (n = 37) according to the Outerbridge classification. Defects were localized at the medial (n = 32) or lateral (n = 6) condyle, at the trochlea (n = 4) and at the patella (n = 15). The follow-up period was 2 years. The majority of patients were satisfied with the postoperative outcome, reporting a significant decrease of pain (mean VAS preop = 7.0; 1 year postop = 2.7; 2 years postop = 2.0). Significant improvement of the mean Lysholm score was observed as early as 1 year after AMIC and further increased values were noted up to 2 years postoperatively (preop. 50.1, 1 year postop. 79.9, 2 year postop. 85.2). Conclusions AMIC is an effective and safe method of treating symptomatic chondral defects of the knee. However, further studies with long-term follow-up are needed to determine if the grafted area will maintain structural and functional integrity over time. Level of evidence Prognostic study, Level IV.

A comparison of the frequency of hypertension, diabetes mellitus, urate gout, hemochromatosis, azotemia and hyperparathyroidism in 28 pseudogout patients and 22 control subjects with osteoarthritis of the large weight-bearing joints failed to provide statistical evidence of intergroup differences. This may be related to the relatively small number of patients studied and the relatively low incidence of the associated diseases as three patients had findings suggestive of mild, clinically inapparent hemochromatosis, three had histologically proved or chemical hyperparathyroidism and three had urate gout in the pseudogout group. None of the control subjects had hemochromatosis, two had urate gout, and one patient with osteoarthritis had chemical hyperparathyroidism. Immunoreactive parathyroid hormone (PTH) levels were increased in most patients in both groups; serum calcium levels correlated significantly with the PTH values, as did roentgenographic evidence of knee joint degeneration in the women patients. If the associated diseases are causally related to calcium pyrophosphate crystal deposits, these findings suggest that pseudogout, like urate gout, has multiple etiologies. A hypothesis relating the possible effects of sustained low grade hyperparathyroidism to the genesis of the articular lesions has been advanced.

The responsiveness of bone and kidney to highly purified bovine PTH was evaluated in normal (N) and uremic dogs. One group of uremic dogs (uremic-constant solute intake; U-CSI), maintained on a diet containing 1500 mg of phosphorus (P) daily developed the adaptive increases in phosphate excretion (FEPO4) and PTH levels characteristic of uremia. A second group of uremic dogs (uremic-proportional reduction of solute; U-PRS), in which dietary P intake was reduced in proportion to the reduction in GFR, exhibited normal FEPO4 and PTH values. During PTH infusion tubular reabsorption of phosphate per nephron mass decreased 2.5 mg100 ml in U-PRS but only 1.4 in U-CSI (p < .001) and 1.1 in N (p < .001). After PTH the calcemic response was significantly and equally decreased in both U-CSI and U-PRS compared to N. In conclusion, the blunted calcemic response to PTH in uremia does not appear to be the only or predominant factor in the pathogenesis of hyperparathyroidism since the uremic dog treated with proportional reduction of phosphorus intake, which maintains a normal PTH level, also demonstrates this abnormality. The PTH-induced rise in phosphate excretion in the uremic nephron depends on the pre-existing degree of inhibition of renal tubular phosphate reabsorption. Finally, the uremic animals in which an adaptive phosphaturia was prevented (U-PRS) exhibited a magnified response in phosphate excretion per nephron to exogenous PTH infusion.

A new classification of hyperparathyroidism is proposed, based on data obtained by immunoassay of parathyroid hormone (PTH). The customary modifiers "primary," "secondary" and "tertiary" are avoided because they no longer have precise meaning. The frequency of transition from one form of hyperparathyroidism to another is described as maladaptation to a variety of possible stimulators of PTH secretion. The need for clinical research focused on the antecedents of hypercalcemia is stressed.

The metabolism of bovine parathyroid hormone (PTH) by the perfused rat liver was studied. Labeled hormone, with or without cold hormone, was infused into the circulating perfusion medium containing various calcium concentrations. Pefusate samples at various time periods after the introduction of PTH into the system were chromatographed on Bio-gel P-10; radioactivity and/or immunoreactivity were measured in eluted fractions. Before the perfusion, all immuno- and radioactivity eluted in a single peak, with an apparent mol wt of 9,500 (peak I). After perfusion for 15 min, two other peaks with approximate mol wt of 7,000 (peak II) and 3,500 (peak III) were discernible. Peak I contained both NH2-terminal and COOH-terminal immunoreactivity and was biologically active at all time periods tested. The relative contribution of NH2-terminal and COOH-terminal immunoreactivity to the total immunoreactivity remained constant in this peak throughout the perfusion. In every respect, peak I had the characteristics of intact hormone. At all times, peak II consisted of only COOH-terminal immunoreactivity and was biologically inactive. At early time periods, peak III contained predominantly NH2-terminal immunoreactivity and was biologically active. With time, the relative contribution of NH2-terminal immunoreactivity decreased strikingly while that of COOH-terminal immunoreactivity increased. The three peaks identified in these experiments were analogous in size, biological activity, and immunological characteristics to those we have previously described for fractionated human hyperparathyroid serum. The rate of metabolism of PTH appeared to be regulated by the calcium concentration in the medium. At a high concentration of calcium (greater than 11 mg/100 ml), PTH metabolism was greatly retarded. At a low concentration of calcium (smaller than 5 mg/100 ml), the rate of metabolism was greatly increased. The physiological significance of our observations on the metabolism of PTH by isolated perfused rat liver is not known. However, since such metabolism results in a biologically active fragment, it is suggested that metabolism of intact hormone may be required before full biological expression is possible.

Reversal of hyperparathyroidism in response to dietary phosphorus restriction in the uremic dog. The role of phosphorus in the genesis of uremic hyperparathyroidism is well established. Prophylactic reduction of dietary phosphorus intake (PRS-P) in exact proportion to GFR reduction prevents renal hyperparathyroidism, but its effects on established hyperparathyroidism, serum calcium and phosphate concentration, and phosphorus balance are not known. Seven chronically uremic dogs (2 to 5 months) were housed in metabolic cages and maintained on a controlled phosphorus intake of 1,200 mg/day. After a control period of 10 days, the dogs were subjected to PRS-P. Control GFR averaged 16 ± 4 ml/min; serum phosphate concentration (S P ), 4.3 ± 0.2 mg/dl; serum ionized calcium concentration (S ICa ), 4.67 ± 0.29 mg/dl; parathyroid hormone level (PTH), 610 ± 91 µl · Eq/ml; and 24-hr urine phosphate excretion (U PO 4 V), 845 ± 84 mg. During PRS-P, no change in GFR or S P occurred (17 ml/min and 4.3 mg/dl, respectively). S ICa increased significantly by day 2 and plateaued by day 4 at 5.13 ± 0.20 mg/dl. PTH fell progressively over the 16 days of PRS-P to 170 ± 49 µl · Eq/ml. U PO 4 V fell on day 1 of PRS-P and plateaued by day 2. Stool phosphorus excretion averaged 43% of intake. Total phosphorus excretion (urine plus stool) did not differ significantly from measured intake. Tubular maximum phosphate reabsorption/GFR averaged 2.7 ± 0.4 mg/100 ml before PRS-P and increased significantly to 4.9 ± 0.2 mg/100 ml after 18 days of PRS-P. In summary, dietary therapy with PRS-P appears to be an effective method, not only for preventing uremic hyperparathyroidism, but for reversing established uremic hyperparathyroidism. In view of the growing evidence that PTH may be a major "uremic toxin", PRS-P could represent an important element in the future therapy of chronic renal failure. Reversion de l'hyperparathyroicarondisme en reponse a la restriction alimentaire de phosphate chez le chien uremique. Le role du phosphore dans la genese de l'hyperparathyroicarondisme est bien etabli. La reduction prophylactique de l'apport alimentaire de phosphore (PRS-P) dans la meme proportion que celle du debit de filtration glomerulaire empeche l'hyperparathyroicaron;disme mais son effet sur l'hyperparathyroicaron;disme installe, sur les concentrations plasmatiques de calcium et de phosphore et sur le bilan de phosphore, ne sont pas connus. Sept chiens uremiques chroniques (2 a 5 mois) ont ete installes dans des cages metaboliques et maintenus a un apport de 1200 mg de phosphore/jour. Apres une periode controle de 10 jours les chiens ont ete soumis a PRS-P. Le debit de filtration glomerulaire pendant la periode controle etait de 16 ± 4 ml/min; le phosphate plasmatique (S P ) de 4,3 ± 0,2 mg/dl; le calcium ionise du plasma (S ICa ) de 4,67 ± 0,29 mg/dl; l'hormone parathyroĭdienne (PTH) de 610 ± 91 µl · Eq/ml; l'excretion urinaire quotidienne de phosphate (U PO 4 V) de 845 ± 84 mg. Pendant PRS-P GFR et S P n'ont pas ete modifies (17 ml/min et 4,3 mg/dl, respectivement). S ICa a augmente significativement a partir du 2eme jour pour atteindre un plateau au 4eme, a 5,13 ± 0,20 mg/dl. La PTH a diminue progressivement pendant les 16 jours de PRS-P jusqu'a 170 ± 49 µl · Eq/ml. U PO 4 V a diminue des le premier jour jusqu'au plateau atteint le 2eme jour. L'excretion fecale de phosphore a ete de 43% de l'apport. L'excretion totale de phosphore (urine et selles) n'etait pas significativement differente de l'apport mesure. La reabsorption tubulaire maximum de phosphate/GFR etait en moyenne de 2,7 ± 0,4 mg/100 ml avant PRS-P et a augmente significativement a 4,9 ± 0,2 mg/100 ml apres 18 jours. En resume, PRS-P parait une methode efficace non seulement pour empecher l'hyperparathyroicaron;disme mais aussi pour obtenir sa reversion. Du fait de l'accumulation des preuves que la PTH est une toxine uremique, PRS-P pourrait etre un element important dans le traitement futur de l'insuffisance renale chronique.

The clinical and biochemical data in 42 reported cases of oncogenous osteomalacia are reviewed, and data in two previously unreported cases are recorded. It is likely that the syndrome is more common than suggested by the paucity of reports and may account for a substantial fraction of nonfamllial, adult-onset "idiopathic" osteomalacia. Tumors associated with the syndrome are characteristically benign, of mesenchymal origin, highly vascular, and composed principally of giant and spindle cells. Complete excision of tumors results in cure of the osteomalacia in the majority of patients. The syndrome presumably represents an instance of humor-induced phosphaturia but supporting experimental data are scanty. Plasma levels of 1,25-dihydroxycholecalciferol are uniformly low, and treatment with this metabolite is generally very effective; however, abnormal vitamin D metabolism cannot by itself account for the syndrome.

During the past three years, new information concerning clinical parathyroid physiology has been generated rapidly. In much of the recent research, radio­ immunoassay of parathyroid hormone (PTH) has been the critical method. Mter the initial description of the assay in 1963, several years elapsed during which many attempts to develop reliable assays failed (1). Even in retrospect, these early difficulties are not readily explained. Problems that appeared formidable at first did not prove troublesome in the long run, but unsuspected problems emerged as experience was gained. Three major problems engendered delay: 1. Production of high affinity anti­ sera to bovine PTH was difficult. It is now known that many different immuniza­ tion schedules can be successfully employed for antibody production. The species of animal used for immunization is not critical since several species have yielded useful antisera. The early difficulties in antibody production can be at­ tributed, at least in part, to limited supplies of antigen. 2. Antisera possessing high affinity to bovine PTH cross-reacted poorly with PTH in human plasma or serum.2 Bovine hormone is most commonly used as the immunizing antigen since it is readily produced in quantity and can now be obtained commercially. The problem of low affinity of antibovine PTH sera to human PTH persists, but many antisera with sufficient binding of human PTH have been prepared so that sensitive assays in man can be performed. 3. Unavailability of a human PTH reference standard for expressing assay results posed a problem that only re­ cently has been recognized as illusory. Investigations from several laboratories have shown that even if human PTH were available in sufficient quantity for immunization, labeling, and stan­ dardization of assay results, the primary difficulty in PTH assays and their in­ terpretation-the heterogeneity of circulating PTH peptides-would not be resolved.

SummaryIt has been demonstrated that certain lymphoid cells of antibody forming lymph nodes agglutinate on their surface in vitro the bacteria with which the animals were immunized. The agglutinating cells which could be identified belonged to the plasma cell series, whereas typical small lymphocytes failed to show the phenomenon. These observations seem to show that it is the plasma cell rather than the lymphocyte which elaborates agglutinins.

In man, oral administration of 1 g of phosphorus resulted in a 60-125% increase in serum immunoassayable parathyroid hormone (PTH) concentration. Peak PTH levels were attained in 1 hr, and PTH returned to base line levels in 2 hr. This increase in PTH appeared to be initiated by a very small decrease of total and ionized calcium and was abolished by a calcium infusion. There was no correlation between serum phosphorus and PTH. The experiments show that oral phosphorus administration initiates a calcium-mediated control system for PTH secretion and that this system operates very sensitively in man.

1. 1. The kinetics of tracer amino acid appearance in the intracellular amino acid pool and in cellular protein was examined under steady-state conditions in the intact rat-diaphragm preparation and in isolated guinea pig and rabbit-lymph node cells. 2. 2. The concentration ratio of tracer amino acid between the extracellular and intracellular amino acid pools approached equilibrium exponentially whereas incorporation into cellular protein proceeded linearly from the earliest time period studied. 3. 3. A theoretical formulation is presented predicting the kinetics of amino acid incorporation into cellular protein if the total intracellular amino acid pool were an obligatory intermediate in protein synthesis. 4. 4. The marked deviation of experimental observations from those theoretically predicted has been interpreted to indicate functional heterogeneity (compartmentation) of the intracellular amino acid pool.

Circulating levels of immunoreactive parathyroid hormone (PTH) were measured in 40 patients with idiopathic hypercalciuria (IH) before and during reversal of hypercalciuria with thiazide, and in four normal subjects before and during induction of hypercalciuria with furosemide. 26 patients with IH had elevated serum PTH levels. The remaining patients had normal levels. Although the correlation was not complete, high PTH levels were generally found in patients who had more severe average urinary calcium losses. When initially elevated. PTH levels fell to normal or nearly normal values during periods of thiazide administration lasting up to 22 months. When initially normal, PTH levels were not altered by thiazide. Reversal of hyperparathyroidism by thiazide could not be ascribed to the induction of hypercalcemia, since serum calcium concentration failed to rise in a majority of patients. Renal hypercalciuria produced by furosemide administration elevated serum PTH to levels equivalent to those observed in patients with IH. The findings in this study help to distinguish between several current alternative views of IH and its relationship to hyperparathyroidism. Alimentary calcium hyperabsorption cannot be the major cause of IH with high PTH levels, because this mechanism could not elevate PTH. Idiopathic hypercalciuria cannot be a variety of primary hyperparathyroidism, as this disease is usually defined, because PTH levels are not elevated in all patients and, when high, are lowered by reversal of hypercalciuria. Primary renal loss of calcium could explain the variable occurrence of reversible hyperparathyroidism in IH, since renal hypercalciuria from furosemide elevates serum PTH in normal subjects. Consequently, a reasonable working hypothesis is that IH is often due to a primary renal defect of calcium handling that leads, by unknown pathways, to secondary hyperparathyroidism.

A circadian variation in serum calcium, albumin and PTH concentration in normal subjects has been demonstrated. The levels of the three blood constituents were remarkably constant during the day, but striking night and early morning changes occurred. Serum calcium levels were highest at 8:00 p.m. and reached a nadir between 2:00 and 4:00 a.m. Serum albumin levels were parallel to those of serum calcium. PTH levels began to rise after 8:00 p.m., reached the highest levels between 2:00 and 4:00 a.m., and fell to baseline values by 8:00 a.m. The nocturnal fall in serum calcium levels appears to be secondary to dilution of serum proteins by increasing blood volume. The nocturnal rise in PTH levels appears to be independent of serum calcium levels within the normal range but it can be abolished by induced hypercalcemia. Serum phosphate levels were lowest between 8:00 a.m. and 10:00 a.m. and highest between 2:00 a.m. and 4:00 a.m. The data presented suggest that circadian changes in serum phosphate levels are not mediated in toto by parathyroid hormone but they are exaggerated when the secretion of this hormone is inhibited. They are independent of growth hormone levels and activity but they are greatly modified during a prolonged fast.

SummaryAn antiserum to bovine parathyroid hormone with high affinity for bovine and human parathyroid hormone was produced in a chicken. It made possible sensitive and reproducible measurement of the hormone in normal and abnormal human sera by radioimmunoassay. Unequivocal separation of normal, hypoparathyroid, and hyperparathyroid sera was obtained.

Use of the Stryker frame in the care of the severely burned patient greatly facilitates nursing care, permits frequent change of position and increases the comfort of the patient. The use of a new burn dressing, semielastic gauze bandage, irrigating hand table and plastic intravenous needle, are worth while practical technics in the care of the burn patient.

SummarySera from patients with various forms of hyperparathyroidism were concentrated and fractionated on Bio-gel P-10 columns. Eluted fractions were assayed for immunoreactive PTH. In addition to ...

* Eric Reiss, Chairman, Department of Medicine, Michael Reese Hospital and Medical Center, Chicago, Illinois, and Professor of Medicine, Chicago Medical School; Director, Irene Walter Johnson, Institute of Rehabilitation, Washington University School of Medicine, St. Louis, Missouri; Malcolm Peterson, Assistant Professor of Medicine and Director Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri; Virginia Brodine, Editor, Nuclear Information

Healthy adult dogs were subjected to stepwise reduction of nephron population so as to create the transition from normal renal function to advanced renal insufficiency. Studies were performed at each level of renal function. Glomerular filtration rate (GFR), renal phosphate clearance, and serum radioimmunoassayable parathyroid hormone (PTH) levels were measured. Two groups of animals were studied. In one, phosphorous intake was maintained at 1200 mg/day. As GFR declined, fractional phosphate excretion rose reciprocally, and PTH levels increased over 20-fold. In the second group, phosphorous intake was maintained at less than 100 mg/day. As GFR fell, fractional phosphate excretion changed little, and no increment in PTH levels occurred. The data suggest that the control system regulating phosphate excretion contributes importantly to the pathogenesis of secondary hyperparathyroidism in advancing renal insufficiency.

Genetic and somatic effects of radiation in children are discussed, particularly with respect to medical and fallout radiation sources. Only a small fraction of naturally occurring mutations can be attributed to background radiation ( approximates 0.1 rad/yr). The dosage required to double the mutation rate in man is estimated to be between 10 and 100 rad, with 15 to 30 rad as the most probable value for acute exposure and 100 rad for chronic exposure; however, physicians treating young patients have a special obligation to keep gonadal exposure to a minimum, since even small changes of the mutation rate have serious long-range biologic and social implications. It is pointed out that the problem of radioinduced mutations is so important that ill-advised statements concerning negligible radiation exposure should be disregarded. The Committee on Environmental Hazards of the American Academy of Pediatrics has recently issued a statement that assesses the genetic effects of fallout in Japanese atomic bomb survivors as nonexistent. It is suggested that this statement is erroneous and embodies a misleading limitation. A highly probable genetic effect has, in fact, been observed in exposed Japanese populations; namely, a change in the sex ratio of children of irradiated parents in themore » direction of fewer males. The misleading aspect of the Academy's report also ignores the recessive character of most radioinduced mutations. These would not be readily detected in the first generation, but would become apparent in future generations when homozygotes are produced. The principal sources of radiation exposure are listed and their relative contributions to hereditary effects are indicated. The order of magnitude of radiation doses associated with various diagnostic studies is tabulated. The average radiologic examination of abdomen and colon, including the fluoroscopy, contributes a gonadal dose of 2 rad, or approximates 20 times yearly background exposure. Relative importance of vari.ous fallout radionuclides in contributing to the exposure of children is assessed. Cesium- 137 and C/sup 14/ contribute the largest genetically significant dose; since the Sr isotopes are concentrated in bone and I/sup 131/ in thyroid, they contribute little radioactivity to the gonads. A survey of radiation doses attributable to fallout from weapons testing in 1954-61 is given. Carbon-14 contributes a large fraction of the radiation dose to gonads as well as to other tissues. Its effect is protracted; only 10% of the total dose attributable to it will be biologically effective by the year 2000. By contrast, all the Cs/sup 137/ from past weapons testing is expected to have exerted its activity by that time. Estimates of genetic damage resulting from C/sup 14/ released during weapons testing depend on whether only the present generation or all future generations are considered. Radioinduced carcinogenesis in children is considered, especially with reference to thyroid cancer for x rays and I/sup 131/. (BBB)« less

The present study was undertaken to evaluate the acute effect of 1,25-dihydroxy-vitamin D3 (1,25 (OH)2D3) on serum Ca, P and immunoreactive parathyroid (iPTH) and urinary Ca, P. and cyclic AMP. In 8 normal subjects, samples were collected over intervals of 30 to 60 min during a control day and on a treatment day following oral ingestion of 1,25(OH)2D3, 2.7 microgram. For the entire group there were no significant changes in serum Ca. P, iPTH or urinary P. Urinary Ca increased significantly 7 h after administration of 1,25(OH)2D3, and urinary cAMP decreased at 12 h. In 4 patients (group A). showing an increase in serum Ca by 0;2 to 0.4 mg/dl, serum iPTH decreased in 3, and the decrease in urinary cAMP appeared sooner. Among 4 patients showing no change in serum Ca after 1,25(HO)2D3 (group B), 3 showed an increase in iPTH. These data document the early onset of action of 1,25(OH)2D3 following its administration to normal man; increments in urinary Ca provide the most sensitive index of its action. The data provide no support for the view that 1,25(OH)2D3 exerts any direct inhibitory effect on the secretion of parathyroid hormone.

Interrelations entre phosphore, calcium, hormone parathyroïdienne et excrétion rénale de phosphate en résponse à une charge orale de phosphore chez le chien normal ou urèmique. Ce travail évalue les interactions séquentielles entre la phosphorémie la concentration sérique de calcium ionisé, la concentration circulante d'hormone parathyroïdienne (PTH), et les excrétions fractionnelle et absolute de phosphate après une charge orale en phosphore (100 ou 500 mg) chez le chien normal (N) ou appartenant à l'un des deux groupes urémiques. Un groupe de chiens urémiques (urémique—apport constant de substances dissoutes: U-CSI), maintenu à un régime contenant 1,500 mg de phosphore par jour, développe une augmentation adaptative de les excretions fractionnelle de phosphate et PTH caractéristique de l'urémie. Un second groupe de chiens urémiques (urémique—réduction proportionnelle de l'apport de substances dissoutes: U-PRS), dans lequel l'apport quotidien de phosphore est réduit en proportion de la réduction de GFR, a des valeurs normales de les excretions fractionnelle de phosphate et de PTH. Après une charge orale de phosphore l'augmentation de phosphorémie est plus grande chez U-CSI que chez N mais pas differérente de U-PRS. Pour une augmentation donnée de phosphorémie la chute de sérique de calcium ionese est identique chez N et U-CSI. La relation n'est pas significativement differente chez U-PRS mais il y a une possibilité d'une plus grande chute de phosphorémie pour une augmentation donnée de phosphorémie pour une augmentation donnée de phosphorémie. L'augmentation de PTH associée à la diminution de phosphorémie est plus grande, encore que non significative, chez U-CSI que chez N alors que la même diminution de phosphorémie détermine une augmentation de PTH significativement moindre chez N que chez U-CSI. La capacité maximale de réabsorption de phosphate est significativement inférieure chez U-CSI que chez N ou U-PRS. Enfin les deux groupes de chiens urémiques excrètent significativement moins de phosphate que N après une charge orale. Les deux groupes urémiques excrètent significativement plus de phosphate par unité de masse néphronique fonctionnelle que N. En conclusion l'axe phosphore-calcium-PTH du chien urémique fonctionne d'une façon complète et appropriée bien qu'à différents niveaux de sensibilité dèpendants de la fonction rénale et de l'apport alimentaire antérieur de phosphore.

We studied the effects of vitamin D metabolites on parathyroid hormone (PTH) secretion. Test materials were injected into the cranial thyroid artery of the dog, and immunoreactive PTH was measured frequently in serum samples from the inferior thyroid vein and the femoral vein. This model for the study of secretion had previously been validated with the use of known modulators on PTH secretion. In control experiments, injection of 100% ethanol, the vehicle in which cholecalciferol (D(3)) metabolites were suspended, resulted in no change in PTH secretion. Likewise, native vitamin D(3), in doses ranging from 250 to 1,250 ng had no effect on PTH secretion. 25-Hydroxycholecalciferol, 25-(OH)D(3), in doses of 125-240 ng, caused complete suppression of PTH secretion. When 24,25-dihydroxycholecalciferol, 24,25-(OH)(2)D(3), was injected in doses of 50-250 ng, suppression of PTH secretion was again complete; in doses of 5 ng, injection of this metabolite resulted in significant but incomplete suppression of secretion. In doses of 50-250 ng, 1,25-(OH)(2)D(3) strongly stimulated PTH secretion, but in a dose of 5 ng this metabolite had no effects. Injection of equal doses of 1,25-(OH)(2)D(3) and 24,25-(OH)(2)D(3) resulted in significant suppression of PTH secretion. Hypocalcemia-induced stimulation of PTH secretion was suppressed by 24,25-(OH)(2)D(3) while hypercalcemia-induced suppression of PTH secretion was stimulated by 1,25-(OH)(2)D(3). In all experiments showing suppression of PTH secretion, peripheral PTH decreased. Arguments are presented for considering the suppressive effects of D(3) metabolites as physiologic modulators. However, this stimulating effect of 1,25-(OH)(2)D(3) occurred only in pharmacologic doses and hence probably has no physiologic relevance.

Serial measurements of serum calcium and immunoreactive parathyroid hormone (PTH) were performed in two young patients with hypercalcemia of immobilization. Serum PTH was elevated in both patients. With mobilization, both serum PTH and serum calcium returned to normal levels and remained so during six months of follow-up. The hyperparathyroidism of immobilization is an unexplained, reversible disorder that should be treated by medical measures and aggresive attempts at early mobilization.

(1974). Long-Term Effects of High Phosphate Intake on Parathyroid Hormone Levels and Bone Metabolism. Acta Orthopaedica Scandinavica: Vol. 45, No. 6, pp. 801-808.

SummaryThe effect of parathyroid hormone (PTH) on the membrane bound enzyme adenylate cyclase in rat and cat liver tissue homogenates was studied. Bovine PTH increased the accumulation of cyclic AMP (cAMP) over a range of 6 × 10−8 − 1 × 10−6M . The synthetic N-terminal peptide (1–34 amino acids) of the hormone increased the accumulation of cAMP over a range of 6 × 10−9 − 6 × 10−7M. Compared to well studied stimulators of liver adenylate cyclase, glucagon and epinephrine, PTH produced a greater stimulation than epinephrine but less than glucagon. Calcitonin, thyrotropin, and gastrin did not stimulate the liver adenylate cyclase. Maximal concentrations of the 1–34 peptide and epinephrine were additive but maximal concentrations of the 1–34 peptide and glucagon were only partially additive.The concentration of PTH showing maximal stimulation of liver adenylate cyclase is equivalent to that reported for bone and kidney, the two well studied end organs for the hormone. Although the data suggest that the liver ...

Phosphorus homeostasis is maintained in animals and man by excretion through the kidneys of the same amount of phosphorus absorbed from the intestines on an ongoing basis. There is apparently little impairment of gastrointestinal phosphorus absorption in uremia (1); yet phosphorus balance is well maintained in animals and man with advancing chronic renal disease. This balance is accomplished by progressive increases in fractional excretion of phosphate (\((F{{E}_{P{{O}_{4}}}})\)) by the kidneys and associated increases in para-thyroid hormone (PTH) secretion (2–5).

24,25-dihydroxycholecalciferol [24,25-(OH)(2)D(3)], once considered a relatively inert metabolite of vitamin D(3), has been recently recognized as a metabolically active product in some species. In previous studies, we have shown that infusion of 24,25(OH)(2)D(3) into the thyroid artery of normal dogs results in prompt and complete suppression of parathyroid hormone (PTH) secretion. In this study, we have examined the metabolic consequences of oral administration of this metabolite in dogs with experimentally induced renal hyperparathyroidism. Dogs with comparable degrees of renal insufficiency (glomerular filtration rate, 10-15 ml/min) were treated for 3 wk with daily doses of either 2 mug of 24,25(OH)(2)D(3) or 50% ethanol, the vehicle in which the metabolite was suspended. After a 6-wk recovery period, treatments were reversed: dogs who had previously served as controls received the metabolite while dogs previously treated with metabolite received the vehicle. Administration of 24,25(OH)(2)D(3) resulted in a 40-60% decrease of immunoreactive PTH. This was associated with a small (0.1-0.2 mg/dl) but unequivocal decrease of serum ionized calcium. Calcium balance, which was slightly negative under control conditions, became slightly but definitively positive on treatment with 24,25(OH)(2)D(3). All other parameters measured, including total serum calcium, magnesium, phosphorus, creatinine, electrolytes, phosphorus excretion, and phosphorus balance, remained unchanged. The data support the hypothesis that 24,25(OH)(2)D(3) not only decreases PTH secretion but also functions as an anabolic hormone in bone under the conditions of this experiment.

Publisher Summary Endocrinology has been revolutionized by the development of the radioimmunoassay technique for measuring minute quantities of peptide hormones. First applied to insulin, the principles of the assay have been quickly adapted to the measurement of other circulating peptide hormones. This chapter provides an overview on the radioimmunoassay of parathyroid hormone (PTH). It discusses the biological significance and origin of circulating forms of immunoreactive PTH. An antiserum possessing high affinity for the N-terminal, biologically active portion of the molecule is best suited for the study of the parathyroid secretion control. When long-term secretory rates of the hormone are at issue, an antiserum possessing high affinity for long-lived fragments is useful. Despite limitations, the immunoassay of PTH has proved to be an extraordinarily powerful and useful tool in clinical investigation. The chapter also discusses the existence of predictable circadian changes in the levels of many hormones and electrolytes in blood and urine.

Effect of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone in man. The effects of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone (iPTH) were studied. Acute metabolic acidosis induced by administration of ammonium chloride (NH 4 Cl) produced a barely detectable increase in serum iPTH. Chronic NH 4 Cl administration produced a marked elevation of serum iPTH that was well correlated with the magnitude of acid-induced hypercalciuria but not with the degree of acidosis. Acetazolamide administration produced an equivalent degree of acidosis, but hypercalciuria was minimal and iPTH increased only marginally. Methionine administration caused moderate hypercalciuria and a significant but moderate increase in iPTH. Chronic NH 4 Cl-induced acidosis produced no hypercalciuria when dietary sodium intake was rigidly restricted, and under these conditions serum iPTH remained normal. When sodium intake was suddenly increased while maintaining the acid load, hypercalciuria appeared and was followed by progressive rise in serum iPTH equivalent to that observed during chronic NH 4 Cl-induced acidosis in subjects consuming salt ad lib . These results indicate that chronic acidosis elevates iPTH mainly by producing hypercalciuria and that acidosis itself is not a primary stimulus to PTH secretion.

On the prevention of secondary hyperparathyroidism in experimental chronic renal disease. Secondary hyperparathyroidism in chronic renal disease appears to begin with the first phase of nephron destruction and to progress in severity with advancing nephron loss. If phosphorus (P) intake remains constant during the evolution of chronic renal disease, each time that glomerular filtration rate (GFR) decreases, a transient period of P retention will follow. The ionized calcium concentration presumably will fall under these circumstances and the latter will stimulate the parathyroid glands. To prevent the development of secondary hyperparathyroidism, studies were performed in a group of seven dogs in which P intake was decreased in the diet proportionally to the decrease in GFR. P intake initially was 1200 mg/ 24 hrs and gradually was decreased to a mean of 234±15.7 mg/ 24 hrs. In control studies mean GFR was 56 ml/min and tubular reabsorption of phosphorus (TRP), 95 %. As GFR was decreased progressively to a mean of 12 ml/min, TRP remained at 92%. Parathyroid hormone (PTH) levels averaged 43 ± 4.6 µl equivalents per ml in the control phase and 45 ± 4.6 µl Eq/ml in the final phase of the study. These data provide support for the view that the adaptation in P excretion imposed by a constant P intake and a decreasing nephron population plays an important role in the pathogenesis of secondary hyperparathyroidism. Moreover, they suggest that if the necessity for the adaptation is obviated, hyperparathyroidism may be prevented, at least until the onset of vitamin D resistance.

The discrete effects of serum calcium and endogenous parathyroid hormone (PTH) secretion upon gastric acidity were studied in patients with primary and secondary hyperparathyroidism and in others with upper gastrointestinal pathology. There was no correlation between PTH and basal acid secretion. An increase in acid secretion from the stomach associated with calcium infusion occurred in patients in all three groups and was related to changes in serum calcium concentration but not to PTH. These studies suggest that in man, endogenous parathyroid hormone has no direct stimulatory effect on gastric acid secretion but influences this indirectly by regulating calcium ion concentration.

The wide spectrum of metabolic bone disease that occurs during the course of advancing renal insufficiency has been well documented in the recent literature.1At one end of the spectrum, the predominant skeletal abnormality is osteomalacia with defective mineralization of osteoid. At the other end of the spectrum, there is osteitis fibrosa. Between these extremes, many variations and combinations of metabolic bone disease occur. In the early 1960's, Dent et al2and Stanbury and Lumb3independently confirmed and extended the neglected observations of Liu and Chu in 1943,4according to which calcium malabsorption was a prominent feature of renal failure. Dent et al and Stanbury and Lumb documented the vitamin D-resistant state in renal failure and showed that the osteomalacic bone disease is curable by administration of adequate amounts of vitamin D. More recently, Avioli et al5demonstrated that abnormal metabolism of vitamin D in

IN a study of victims of the Coconut Grove fire, Cobb and Lindemann1 recorded a high incidence of emotional disturbances soon after burning and concluded that both the psychiatrist and the social w...

Parathyroid hormone (PTH) concentration was determined by radioimmunoassay in serum specimens in 26 unselected cases of sarcoidosis. Although only six of these patients had hypercalcemia, PTH was unmeasurably low in 19. Of the seven with normal levels, five received steroid therapy at the time of study. PTH levels were low regardless of the apparent activity of the disease and were not correlated with serum calcium concentrations. PTH was unmeasurably low in sarcoidosis even when complicated by moderate renal insufficiency, a condition that ordinarily provokes secondary hyperparathyroidism. Hypercalcemic sarcoid patients with high PTH concentrations were found to have coexistent parathyroid adenomas or hyperplasia. In such cases, hypercalcemia did not respond to steroid therapy, but was corrected by surgery. The data indicate that most patients with sarcoidosis have functional hypoparathyroidism. This fits well with the recognized abnormalities of calcium metabolism in sarcoidosis, since excessiv...

Three distinct immunoreactive species of parathyroid hormone (PTH) are present in human serum. One has an estimated mol wt of 9,500 and probably represents glandular hormone, the second 7,000-7,500 mol wt, and the third 4,500-5,000 mol wt. In order to assess the biological activity of these circulating forms of PTH, we determined their ability to activate renal cortical adenylate cyclase. The 9,500 mol wt and 4,500-5,000 mol wt fractions produced four- to sixfold increases in cyclic 3′,5′-AMP accumulation above control; the 7,000-7,500 mol wt fraction was inactive. None of the fragments had any effects on phosphodiesterase activity. Antiserum to bovine PTH did not block the activation of adenylate cyclase by either the gragments or bovine PTH. The data suggest that a large proportion of circulating immunoreactive human PTH is biologically active and that the biologically and immunologically active sites of the hormone are distinct.

Serum parathyroid hormone (PTH) was measured in five children with untreated,active hypophosphatemic vitamin D-resistant rickets before, during, and after an infusion of calcium. During the calcium infusion, serum PTH decreased while the tubular resorption of phosphate increased. Although these data clearly indicate that some degree of hyperparathyroidism accompanies the disease, it is apparent that the degree of hyperparathyroidism recorded in these studies is not sufficient to explain the severity of the phosphaturia. One of the basic defects in the disease may involve excessive sensitivity of the renal tubule to the phosphaturic effects of PTH.

The radioimmunoassay of PTH has provided a powerful new tool for clinical investigation. Although much remains to be learned about the details of the assay, rapid progress is being made in many laboratories. The subtlety of PTH response in various disease states is becoming evident. The great variety of clinical circumstances under which primary hyperparathyroidism occurs suggests multiple etiologies of the disease. It is possible that primary hyperparathyroidism is the consequence of long-term adaptation and therefore represents not a primary disease but the consequence of other diseases. If this proves true, the study of primary parathyroid disease will assume a new meaning in clinical practice.