A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodeling in normal human volunteers.

The effects of recombinant human growth hormone (rhGH) on biochemical markers of bone turnover and bone mineral content (BMC) were investigated in 20 normal male volunteers (aged 22-31 years) randomized to treatment for 7 days with either rhGH (0.1 IU/kg subcutaneously twice a day) or placebo. Serum somatomedin C rose during treatment (p less than 0.001) but was not significantly different from baseline at day 14. The fasting urinary hydroxyproline/creatinine (p less than 0.001) and calcium/creatinine ratios (p less than 0.01) increased during treatment and remained elevated for 4 and 2 weeks, respectively. Serum bone gamma-carboxyglutamic acid-containing protein (BGP) increased during treatment (p less than 0.001) and remained elevated for 6 months (p less than 0.02). Serum bone alkaline phosphatase (B-AP), after an initial fall in the treatment period (p less than 0.001), increased slightly in the following months (p less than 0.01). In the rhGH group BMC was significantly higher than the prestudy value at day 14 (p less than 0.05) but was unaltered at the end of study. The simultaneous increase in markers of bone resorption and formation during rhGH treatment followed by a decline in resorption parameters within a few weeks and the prolonged effect on BGP and B-AP demonstrate that rhGH treatment stimulates osteoblasts and activates bone remodeling.

Acute effect of 1,25-dihydroxyvitamin D3, prednisone, and 1,25-dihydroxyvitamin D3 plus prednisone on serum osteocalcin in normal individuals.

Suppression of osteoblastic function plays an important pathogenic role for the development of glucocorticosteroid-induced osteoporosis. Serum osteocalcin (OC) is a sensitive marker of bone formation. The diurnal rhythm in serum OC can be changed by administration of single doses of either 1,25-(OH)2D3 or prednisone. However, the two steroids have opposing effects: 1,25-(OH)2D3 increases and prednisone decreases serum OC. The aim of the present study was to examine whether 1,25-(OH)2D3 can oppose the acute suppressive effect of prednisone on serum OC in normal subjects. We compared the effect of a combined dose of 2 micrograms 1,25-(OH)2D3 and 10 mg prednisone on the diurnal rhythm of serum OC with the effect of 2 micrograms 1,25-(OH)2D3 + placebo in a crossover study. Seven normal subjects aged 23-36 years were investigated twice at an interval of 1 week. Blood samples were collected every 60 minutes from 1900 until 1100 h the following day. Study drugs were given at 2000 h. The data from the present investigation were compared with data obtained from a similar study with placebo and prednisone in the same subjects. After administration of 1,25-(OH)2D3 serum OC followed the placebo curve during the first 8 h, but in contrast to the placebo curve it then continued to increase and remained elevated throughout the observation period (p less than 0.05). Prednisone inhibited and reversed the nocturnal rise in serum OC levels (p less than 0.01). The course of serum OC after administration of 1,25-(OH)2D3 + prednisone almost paralleled the course after placebo. We conclude that 1,25-(OH)2D3 and prednisone have opposing effects on serum OC.

Short-term treatment with growth hormone stimulates osteoblastic and osteoclastic activity in osteopenic postmenopausal women: a dose response study.

To investigate the potential use of growth hormone (GH) in Activate-Depress-Free-Repeat treatment of postmenopausal osteoporosis, we measured changes in serum levels of biochemical markers of bone turnover, insulin-like growth factor-I (IGF-I), calciotropic hormones, and bone mineral density in 40 postmenopausal women with osteopenia (ages 52-73 years) in response to 7 days of treatment with either placebo or GH (0.05, 0.10, or 0.20 IU/kg/day) administered subcutaneously in the evening. GH treatment increased serum osteocalcin (p < 0.01) and C-terminal type-I procollagen propeptide (p < 0.01) and also serum levels of type-I collagen telopeptide (p < 0.001), fasting urinary hydroxyproline/creatinine (p < 0.05), pyridinoline/creatinine (p < 0.05), and deoxypyridinoline/creatinine (p < 0.01) in a dose-dependent fashion. Even the lowest dose of GH tested induced a significant increase in these parameters; however, the effects were transient lasting only 1-2 weeks. In the highest dose group, however, a somewhat prolonged effect (30 days) on serum osteocalcin was observed. Furthermore, GH increased serum levels of IGF-I, insulin, and tri-iodothyronin. No effect on serum 1,25-dihydroxyvitamin D3 or parathyroid hormone could be demonstrated. Adverse effects were mainly related to fluid retention. They were clearly dose-dependent and rapidly reversible. In conclusion, short-term GH treatment stimulates bone formation and bone resorption in postmenopausal women with osteopenia.

The effect of single oral doses of prednisone on the circadian rhythm of serum osteocalcin in normal subjects.

Serum osteocalcin (OC), which is a sensitive marker of bone formation, is reduced during chronic glucocorticoid treatment in accordance with the finding of reduced bone formation, and even short term glucocorticoid treatment reduces serum OC. In a double blind placebo-controlled study, we measured the effects of 2.5 and 10 mg prednisone, orally, on the circadian variation of serum OC in 15 normal subjects (8 women and 7 men), aged 22-46 yr. All subjects were studied twice at an interval of 1 week. Blood samples were collected every 60 min from 1630 until 1700 h the following day. Prednisone or placebo was given at 2000 h. Serum OC was measured by an in-house RIA. After placebo administration serum OC increased from 2230 h to a peak value around 0230 h, followed by a gradual decline to a nadir around 1500 h. Both doses of prednisone inhibited and even reversed the nocturnal rise in serum OC levels; the inhibition occurred within 3-4 h. There was no significant difference in the time from prednisone ingestion to maximal decrease (7.2 h vs. 9.8 h) or in the maximal decrease (52% vs. 54%). However, the duration of the inhibition was significantly shorter after 2.5 mg than after 10 mg prednisone (approximately 6 h vs. 12 h; (p less than 0.01). We conclude that serum OC is sensitive to small doses of prednisone, and that serial serum OC measurements may be a sensitive marker of the effect of exogenous glucocorticoids on osteoblastic activity in vivo.

Inhibition of the morning cortisol peak abolishes the expected morning decrease in serum osteocalcin in normal males: evidence of a controlling effect of serum cortisol on the circadian rhythm in serum osteocalcin.

Osteocalcin (OC) in serum varies in a remarkably constant circadian rhythm with zenith at night and nadir in the morning. The factors controlling this rhythm are unknown, but several studies indicate that serum cortisol could be of major importance. We tested this hypothesis in a double-blind, placebo-controlled, cross-over study comprising 10 normal male volunteers (aged 23-31 yr) by measuring the response in serum OC and cortisol rhythms to a single dose of metyrapone (30 mg/kg body weight) administered at midnight. During placebo, serum cortisol consistently peaked early in the morning before 0730 h. Ingestion of metyrapone at 2400 h significantly postponed and flattened this peak (P less than 0.01). On both occasions, serum OC increased towards peak levels around 0300 h (P less than 0.01) with no overall differences in the OC profiles. However, when the serum OC time series were synchronized according to the individual cortisol nadirs, we found a significant (P less than 0.01) decrease in serum OC on the placebo day approximately 4 h after the cortisol nadir, whereas no significant changes (P greater than 0.50) were seen on the metyrapone day. Moreover, the mean serum OC level tended to be higher (P less than 0.10 in the interval 0-12 h, and P = 0.06 in the interval 4-8 h) on the metyrapone day compared with the placebo day. On the placebo day, the mean level of serum cortisol during the interval 0-4 h correlated inversely with the mean level of serum OC in the interval 4-8 h (r = 0.77, P less than 0.05). This relation was not found on the metyrapone day. In conclusion, administration of metyrapone, which reduced and postponed the early morning cortisol peak, abolished the normal morning decrease in serum OC. This strongly supports that changes in endogenous serum cortisol are of major importance for the circadian rhythm in serum OC.

Changes in biochemical markers of osteoblastic activity during the menstrual cycle.

Serum levels of osteocalcin [OC; bone Gla protein (BGP)] and bone alkaline phosphatase (B-AP) are both correlated to osteoblastic activity, which may be regulated by several hormones, including estrogen, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], and PTH. Estrogen shows reproducible variations during the menstrual cycle, while available data on variations in serum 1,25-(OH)2D3 and serum immunoreactive PTH show midcyclic increases or no changes. In the present study we evaluated osteoblastic activity by measuring serum OC and B-AP during the menstrual cycle in eight healthy women, aged 20-47 yr. The cycles were synchronized by LH peaks, and follicular and luteal periods were normalized by lengths. Repeated measures analysis of variance showed that serum OC varied significantly (P less than 0.05), with highest levels during the luteal period. Although the same pattern was seen for serum B-AP, the variation just failed to reach significance (P less than 0.10), but the mean level was significantly higher during the luteal than during the follicular period (P less than 0.05). Gonadotropins and ovarian sex hormones showed significant variations. There were no significant changes in serum vitamin D-binding protein, serum total and free 1,25-(OH)2D3 index, or serum immunoreactive PTH-(1-84), but serum levels of somatomedin-C showed a significant variation, with the highest level during the luteal period (P less than 0.05). Blood levels and urinary excretion of minerals exhibited no significant variations. Cross-correlation studies between OC and estradiol showed the highest correlation coefficient, when OC was lagged about 7 days after estradiol (r = 0.69; P less than 0.05). Moreover, a high correlation was found between OC and somatomedin-C when matched at concurrent time points (r = 0.76; P less than 0.01). No significant correlations were found between the other calcium-regulating hormones and OC when matched at concurrent time points. In conclusion, we found a significant effect of the menstrual cycle on the serum levels of two osteoblastic bone markers, OC and B-AP. The changes indicated that osteoblastic activity is higher during the luteal period. However, whether the changes are caused by direct or indirect effects of the fluctuations in calciotropic hormones is still unresolved.

Triiodothyronine stimulates urinary excretion of calcium and hydroxyproline in autosomal dominant osteopetrosis.

Six patients with autosomal dominant osteopetrosis were treated orally with 100 mcg. triiodothyronine (T3) daily for seven days. The effect of T3 on bone remodelling was monitored. T3 treatment increased serum T3 from day 1 to 7 (p less than 0.02) with a corresponding fall in serum T4 (p less than 0.01) and serum TSH (p less than 0.02). The levels of thyroid hormones returned to initial levels within the observation period. The renal excretion of calcium and hydroxyproline increased significantly (p less than 0.05) on day 7 and 14 respectively, while there was no significant increase in phosphate excretion. No significant changes were observed in serum calcium, phosphate, or osteocalcin during the study. The observed changes suggest that bone resorption in autosomal dominant osteopetrosis is stimulated by exogenous administration of T3.

Serum vitamin D metabolites and nuclear uptake of (3H)-1,25-dihydroxyvitamin D3 in monocytes from patients with autosomal dominant osteopetrosis: a study of two radiological types.

The nuclear uptake of (3H)-1,25 dihydroxyvitamin D3 in freshly isolated human monocytes and the serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were investigated in 13 patients with autosomal dominant osteopetrosis and in sex- and age-matched controls. Seven patients had type I osteopetrosis characterized by diffuse, symmetrical osteosclerosis with pronounced sclerosis of the skull and increased thickness of the cranial vault. The other six patients had type II with "Rugger Jersey Spine" and "endobones" as characteristic findings. In type I osteopetrosis the serum 1,25-dihydroxyvitamin D was significantly reduced (p less than 0.05), whereas serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D receptor binding were normal. In type II osteopetrosis the serum vitamin D metabolites were normal, as was the maximal binding capacity (Bmax) of 1,25-dihydroxyvitamin D to the nuclear receptor. The dissociation constant (Kd), however, was significantly increased (p less than 0.01) indicating a modest resistance to 1,25-dihydroxyvitamin D. It is concluded that a general end-organ resistance to 1,25-dihydroxyvitamin D at the receptor level does not exist in type I osteopetrosis, but may contribute to some of the radiological and biochemical findings in type II.

Effects of short-term treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men.

To study the effects of treatment with glucocorticoid and calcitriol on biochemical markers of calcium and bone metabolism, 48 normal male volunteers (aged 21-54 years) were randomized to treatment for 7 days with either (A) prednisolone, 10 mg twice daily, (B) prednisolone, 10 mg twice daily, and calcitriol, 1 microg twice daily, (C) calcitriol 1 mg twice daily, or (D) placebo. The study period was 28 days. Renal calcium excretion increased (mean maximal increase +44.7%, p < 0.01) as well as serum parathyroid hormone (PTH) (max. +18.5%, p < 0.01) during prednisolone treatment. Concomitant treatment with calcitriol or calcitriol alone equally enhanced renal calcium excretion (max. +185.2%, p < 0.001) and decreased serum PTH (max. -43.1%, p < 0.001). Prednisolone administration was followed by prompt declines in markers of bone formation [serum osteocalcin (max. -34.7%, p < 0.001) and serum procollagen type I C-terminal propeptide (PICP) (max. -25.9%, p < 0.05)], whereas serum bone alkaline phosphatase (bone AP) remained unchanged. Calcitriol in combination with prednisolone attenuated the decrease in PICP (max. -8.9%, not significant), but it had no effect on osteocalcin (max. -40.1%, p < 0.001), and decreased bone AP (max. -22.2%, p < 0.05). Calcitriol alone increased osteocalcin (max. +37.8%, p < 0.03) and PICP (max. +26.0%, p < 0.05). Among markers of bone degradation, prednisolone suppressed serum C-terminal telopeptide of type I collagen (ICTP) (max. -28.4%, p < 0.001), but not the fasting renal excretion of hydroxyproline (OHP) and collagen type I N-terminal telopeptide (NTx). Calcitriol partially antagonized the decrease in ICTP (max. -17.2%, p < 0.001). Calcitriol alone had no effect on resorptive markers. Extraosseous matrix synthesis was suppressed by prednisolone evaluated by serum procollagen type III N-terminal propeptide (max. -30.8%, p < 0.001) and was not affected by concomitant treatment with calcitriol or calcitriol alone. In conclusion, short-term administration of prednisolone to healthy men leads to fast and protracted suppression of biochemical markers of bone formation and extraosseous connective tissue metabolism. The effect on bone was partially antagonized by simultaneous calcitriol treatment, and points toward a potential role of calcitriol in the prevention of steroid induced osteoporosis.

Dose-response effect of short-term calcitriol treatment on bone and mineral metabolism in normal males.

To evaluate the effects of short-term treatment with calcitriol on biochemical markers of calcium and bone metabolism, 36 normal male volunteers (aged 21-54 years) were randomized to oral treatment for 7 days with either (A) calcitriol, 1 microgram twice daily, (B) calcitriol, 0.5 microgram twice daily, or (C) placebo twice daily. Serum calcium increased slightly in a dose-dependent manner (maximal increase 2.5%, p < 0.05) followed by a heavy increase in both 24 h (max. 156.1%, p < 0.001) and fasting urinary calcium excretion (max. 123.1%, p < 0.001), and a striking reduction in serum PTH (max. -43.1%, p < 0.001). Biochemical markers of osteoblast activity and bone formation increased immediately in a dose-dependent manner [serum osteocalcin (max. 37.8%, p < 0.03) and serum procollagen type I C-terminal propeptide (PICP) (max. 26.0%, p < 0.05)], whereas there was no effect on serum bone alkaline phosphatase. Calcitriol treatment had no effect on biochemical markers of bone resorption [serum C-terminal telopeptide of type I collagen (ICTP) and fasting urinary excretion of hydroxyproline/creatinine (OHP)]. Extraosseous collagen matrix synthesis was not affected evaluated by serum procollagen type III N-terminal propeptide (PIIINP). In the follow-up period (15 weeks) no unequivocal changes were observed. The fast and protracted increase in biochemical markers of osteoblast activity and bone formation, without affecting bone resorption and extraosseous connective tissue metabolism points toward a selective effect of calcitriol on bone matrix formation.

Biomechanical competence of iliac crest trabecular bone in autosomal dominant osteopetrosis type I.

Cylindrical horizontal iliac crest trabecular bone biopsies were obtained from 9 patients with autosomal dominant osteopetrosis type I and 18 normal controls of comparable age/sex match. Maximum compressive stress, maximum stiffness, energy absorption capacity and maximum strain were calculated from load-deformation curves after a compression test. Ash density of the bone samples was measured after incineration. The maximum compressive stress was significantly increased in the patient group (12.6 +/- 2.6 (SE) MPa vs. 3.3 +/- 0.4 MPa, p less than 0.01), as was the ash density (0.61 +/- 0.05 g/cm3 versus 0.27 +/- 0.02 g/cm3, p less than 0.01). After correction for ash density (normalized maximum stress) the strength of the trabecular bone samples was still significantly increased in the patients (19.7 +/- 6.4 MPa x cm3/g versus 12.0 +/- 1.2 MPa x cm3/g, p less than 0.01). The maximum stiffness and energy absorption capacity were higher in the patients (p less than 0.01), with a corresponding lower maximum strain value (p less than 0.05). The maximum compressive stress correlated closely to the maximum stiffness and energy absorption capacity in both patients and controls, whereas no correlation to maximum strain was found. The maximum compressive stress thus seems to be representative for the two other biomechanical parameters. No significant correlations between age and maximum compressive stress (R = 0.38), ash density (R = 0.08), or normalized maximum stress (R = 0.45) were observed in type I osteopetrosis, whereas significant age-dependent decreases in maximum compressive stress (R = -0.65, p less than 0.02) and in ash density (R = -0.57, p less than 0.02) were observed in normal individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of a short course of 1,25-dihydroxyvitamin D3 on biochemical markers of bone remodeling in adult male volunteers.

To investigate the stimulatory effect of vitamin D on biochemical markers of bone remodeling, 15 normal men (aged 26-45 years, mean 33.2) were treated orally with 1,25-dihydroxyvitamin D3, 2 micrograms daily for 7 days, and followed for a total of 16 weeks. Serum concentrations of 1,25-dihydroxyvitamin D3 rose 43% during the first week (p less than 0.01), with no significant alteration in the level of 25-hydroxyvitamin D3. Serum level of immunoreactive parathyroid hormone (1-84) (iPTH) decreased markedly (p less than 0.02), and the maximal renal reabsorption capacity of phosphate (TmP/GFR) increased (p less than 0.05), both indicating the impact of the raised vitamin D level on target tissues. Serum phosphate and serum calcium increased during the treatment week (p less than 0.05), as did the fasting renal excretion of phosphate and calcium (p less than 0.01). However, a gradual fall in the excretion of hydroxyproline was seen in the observation period. The serum activity of acid phosphatase increased in the first weeks after vitamin D treatment, reaching significance at the end of week 2 (p less than 0.05). Acid phosphatase activity was still increased at the end of the observation period (p less than 0.02). These observations suggest a synchronization and recruitment of new bone resorptive cells. The immediate response to 1,25-dihydroxyvitamin D administration on the biochemical markers of formative bone cells was a marked increase in the serum level of osteocalcin (BGP), (p less than 0.002) with a gradually fall during the next weeks. A secondary increase, however, was observed in the last two months of the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous acetylsalicylic acid--dose-related effects on platelet function and fibrinolysis in healthy males.

Low-dose acetylsalicylic acid (ASA) has been shown to be beneficial in patients with acute myocardial infarction and unstable angina pectoris. Oral administration of ASA is difficult in the acute phase of these syndromes. In this study we evaluated the effect of 25 mg, 50 mg or 100 mg of ASA given as an intravenous bolus injection on platelet function and fibrinolysis in healthy males and related this to plasma concentrations of ASA. No adverse effects were found. A complete inhibition of serum thromboxane B2 synthesis was demonstrated 5 min after injection of 100 mg ASA intravenously. ASA disappeared from the circulation within 60 min after bolus injection and at this time thromboxane B2 synthesis was inhibited dose-dependently by 71%, 90% and 100% for doses of 25 mg, 50 mg and 100 mg, respectively. Inhibition of thromboxane B2 synthesis after 100 mg of intravenous ASA was still 96.5% at 24 h and 93.4% at 48 h after the injection. The bleeding time measured at 30 min after ASA administration was significantly prolonged on the average by 70 s, 144 s and 211 s after 25 mg, 50 mg and 100 mg of ASA, respectively. Minor, but significant changes were found in tissue plasminogen activator antigen and in plasminogen activator inhibitor within the first hour after injection of low dose ASA, but similar changes were found after injection of saline. No change in tissue plasminogen activator activity was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Irradiation of bone metastases in breast cancer patients: a randomized study with 1 year follow-up.

The results from a prospective randomized trial comparing two different radiation schedules for treatment of painful bone metastases in women with recurrent breast cancer are presented. A total of 217 patients with painful bone metastases were randomized to either 30 Grey (Gy) in ten fractions, five fractions a week (5F/W) or 15 Gy in three fractions 2F/W. The effect of treatment was evaluated by pain assessment, the radiological response and the degree of side-effects. The patients were rated at start of treatment and after 1, 3, 6 and 12 months. No difference between the two radiation regimes was found, neither in achieved pain relief, improvement in level of activity and medication, nor was there any difference in radiological response and side-effects from treatment. Both regimes resulted in a significant improvement in both pain score and level of activity 1 month after treatment, an improvement which persisted during the follow-up period. We conclude that 15 Gy given in three fractions 2F/W is as effective as 30 Gy in ten fractions 5F/W, but more convenient to the patient and of less cost to society.

Porous polymer implants for repair of full-thickness defects of articular cartilage: an experimental study in rabbit and dog.

Full-thickness defects of articular cartilage were repaired by implantation of porous polymer implants in rabbits and dogs. The quality of the repair tissue was determined by collagen typing with antibodies. Implants with varying pore sizes and chemical composition were used. The effect of loading and motion was determined by inserting implants higher than, level with and lower than the surrounding cartilage. It appeared that healing took place by formation of fibrocartilaginous repair tissue containing both type I and type II collagen. Hyaline cartilage was observed in a minority of the rabbits used but not in the dog. Fibrocartilage formation in the dog was simulated by implantation of a porous polymer. Chemical composition of the polymer did not alter the results, neither did loading of the implant. It is concluded that the formation of fibrocartilaginous repair cartilage is stimulated by implantation of a porous polymer. This tissue seemed to function adequately in the dog but did show signs of degeneration in the rabbit.

Meniscal replacement using a porous polymer prosthesis: a preliminary study in the dog.

A porous polyurethane prosthesis was used to replace the lateral meniscus in the dog. After an initial ingrowth of fibrous tissue, the prostheses became filled with tissue strongly resembling normal meniscal fibrocartilage. Although less severe than seen after total meniscectomy, cartilage degeneration was frequent, possibly because tissue ingrowth in the prostheses occurred too slowly. Porous polymers can be useful for replacement of the meniscus, provided that chemical and physical properties are optimized.

Meniscal repair by fibrocartilage in the dog: characterization of the repair tissue and the role of vascularity.

Lesions in the avascular part of 20 canine menisci were repaired by implantation of a porous polyurethane. Seven menisci were not repaired and served as controls. The repair tissue was characterized by biochemical and immunological analysis. The role of vascularity in healing was studied by perfusion of menisci with Indian ink. Histologically, repair tissue inside the implants initially consisted of fibrous tissue containing type I collagen. After 2 months, fibrocartilaginous tissue developed inside the implants, whereas control defects only showed repair with fibrous tissue. Both type I and type II collagen, the two major collagen types of normal meniscal fibrocartilage, could be detected in this newly formed fibrocartilage. The implant guided vascular tissue from the periphery towards the lesion resulting in healing of the tear. After fibrocartilage had formed, vascularity decreased and was completely absent in mature fibrocartilage. Control defects remained filled with vascular connective tissue. Two-thirds of the longitudinal lesions were found to be healed partially or completely. It is concluded that implantation of a porous polymer does enhance vascularity sufficiently to result in healing of meniscal lesions extending into the avascular part. Healing takes place by repair tissue strongly resembling normal meniscal fibrocartilage.

Plasma thromboxane B2 as an early marker of acute graft rejection after heart transplantation: preliminary report.

Six patients undergoing heart transplantation were followed up by serial endomyocardial biopsies to detect signs of graft rejection and the plasma level of thromboxane B2 was measured at the same time. During the operative procedure and concomitant with histologic signs of acute graft rejection, the plasma level of thromboxane B2 significantly increased. After immunosuppressive treatment with steroids and either antithymocyte globulin or monoclonal antibody, regression of the histologic signs of rejection and a significant fall in the level of thromboxane B2 were documented. We conclude that the plasma level of thromboxane B2 may be useful as an early marker of acute graft rejection after heart transplantation.

Differentiation between renovascular and essential hypertension by means of changes in single kidney 99mTc-DTPA clearance induced by angiotensin-converting enzyme inhibition.

Blood pressure (BP), plasma renin concentration (PRC), and 99mTc-labeled diethylenetriaminepenta acetate (DTPA) renography with determination of single kidney 99mTc-DTPA clearance and parenchymal mean transit time (MTT) were measured in exactly the same way on two consecutive days in 14 patients with renovascular hypertension (RVH), unilateral renal artery stenosis in nine and bilateral stenosis in five, and ten patients with essential hypertension (EH). The examination on day 1 served as a control for day 2 during which captopril (25 mg) was given orally one hour before measurements of PRC and DTPA clearance. Blood pressure was reduced by captopril in both groups, but the maximum decrease in systolic BP was slightly more pronounced (P less than .01) in RVH (22%, median) than EH (13%). Plasma renin concentration increased to a much greater extent (P less than .01) after captopril in RVH (366%) than in EH (46%), Single kidney 99mTc-DTPA clearance was significantly (P less than .01) reduced (-39.5%) and MTT considerably prolonged (170%) on the affected/most affected side in RVH, but both parameters were only slightly changed or unchanged on the unaffected/least affected side (-6.5%, -2% respectively) and were not significantly changed in any of the sides in EH. The degree of renal artery stenosis was significantly correlated to the increase in PRC (rho = -0.786, n = 14 patients, P less than .01), to the reduction in single kidney 99mTc-DTPA clearance (rho = 0.729, n = 19 kidneys, P less than .01) and to the prolongation in MTT (rho = -0.785, n = 16 kidneys, P less than .01). By analysis of the captopril-induced changes in 99mTc-DTPA clearance and MTT, it was possible to predict the existence of a moderate to several renal artery stenosis in arterial hypertension with a very high degree of probability, and the use of changes in 99mTc-DTPA clearance and MTT after angiotensin-converting enzyme (ACE) inhibition may become a valuable tool in differentiation between RVH and EH.

The effects of short-term, high-dose treatment with prednisone on the nuclear uptake of 1,25-dihydroxyvitamin D3 in monocytes from normal human subjects.

Animal and cell culture studies indicate glucocorticoid regulation of 1,25-dihydroxyvitamin D3 receptors and interference with cellular effects of vitamin D. These investigations prompted us to examine the effects of prednisone on the nuclear uptake of 1,25-dihydroxyvitamin D3 in freshly isolated human monocytes. Eighteen normal subjects were studied in a randomized, double-blind, placebo-controlled study. Analysis of receptor kinetics revealed that the maximal nuclear uptake (Bmax) of (3H)-1,25-dihydroxyvitamin D3 in monocytes decreased 40% (P less than .001) after prednisone treatment. In the group treated with prednisone (40 mg/d for 5 days) s-1,25-dihydroxyvitamin D increased 46% (P less than .01). S-25-Hydroxyvitamin D, S-phosphat, S-calcium, and S-iPTH remained unchanged. Osteoblastic production of the matrix protein, bone gla protein (BGP) is stimulated by 1,25-dihydroxyvitamin D3. However, despite increased serum levels of 1,25-dihydroxyvitamin D3, the prednisone-treated group revealed a 75% reduction in s-BGP. The present data indicate that corticosteroids decrease the nuclear uptake of 1,25-dihydroxyvitamin D3 in human monocytes. Further investigations are necessary, however, to elucidate the biologic mechanism for this observation and whether the mechanism is operative in other human tissues including bone.