Prevention of osteoporosis in heart transplant recipients: a comparison of calcitriol with calcitonin and pamidronate.

Bone loss and osteoporotic fractures are common in cardiac transplant recipients. To compare two prophylactic medical regimens after heart transplantation, 26 consecutive heart transplant recipients were randomized to receive either continuous oral calcitriol (0.5 microg/day) combined with nasal salmon calcitonin (200 U/day) for the first 3 months (group A) or intermittent intravenous pamidronate (0.5 mg/kg body weight) every third month (group B). Bone mineral density (BMD) and biochemical indices of bone turnover were measured at baseline and 3, 6, 12, and 18 months after transplantation. The mean pretransplant BMD, measured by dual energy X-ray absorptiometry (DXA) was significantly lower in the patients compared with age-matched healthy controls. During the first year of treatment, rates of bone loss at the lumbar spine and femoral neck were slightly but significantly slower in the patients treated with pamidronate, but there was no longer a significant difference between the two groups after 18 months of heart transplantation. Irrespective of the mode of osteoporosis prevention, osteocalcin levels increased whereas urinary deoxypyridinoline decreased after transplantation, and significant bone loss was observed in both treatment groups. We found no relationship between initial BMD, markers of bone turnover, cumulative glucocorticoid dose, or cyclosporine levels and the rate of bone loss after cardiac transplantation. In summary, we found that the rapid and severe bone loss following heart transplantation could be attenuated by two preventive measures, pamidronate or calcitriol with calcitonin.

Insulin-like growth factor-I lowers fasting and postprandial triglyceride levels without affecting chylomicron clearance in healthy men.

OBJECTIVES: To study whether IGF-I treatment alters the postprandial lipid and lipoprotein metabolism. DESIGN: Randomized, crossover study. SETTING: University Hospital, Zürich, Switzerland. SUBJECTS: Seven young healthy male subjects (aged 27+/-4 years, body mass index (BMI) 21.8+/-1.7 kg m(-2)). INTERVENTIONS: Each subject was studied two times at 2-week intervals, treated with saline 0.9% (S) and IGF-I (8 microg kg(-1) h(-1)) by a continuous subcutaneous infusion. 60 h after the start of treatment a vitamin A loading test was performed after an overnight 12-h fast. MAIN OUTCOME MEASURES: Glucose, insulin, total and free IGF-I, FFA, triglycerides and retinyl palmitate, total cholesterol, HDL and LDL cholesterol, lipoprotein (a) and apolipoprotein B were measured in serum before and after the fatty meal. RESULTS: Total IGF-I levels rose from 29.0+/-3.3 nmol L(-1) to 113.3+/-9.0 nmol L(-1) (P<0.02) and free IGF-I from 0.24+/-0.05 to 1.08+/-0.28 nmol L(-1) (P<0.02) during IGF-I treatment. IGF-I administration reduced insulin concentrations by 50% (P<0.02), as assessed by the area under the curve. Serum triglyceride levels were significantly lower at baseline and after the fat load during IGF-I treatment (P<0.02), whereas the retinyl palmitate concentrations in chylomicron and nonchylomicron lipoprotein fractions were similar during both treatment periods. CONCLUSIONS: IGF-I treatment reduces the triglyceride levels most probably by decreasing insulin secretion and the production of VLDL particles, and possibly by increasing their turnover. IGF-I treatment has no significant effect on the metabolism of intestine-derived triglyceride-rich lipoproteins after a high fat meal in healthy young men.

[Idiopathic primary hyperaldosteronism: significance of functional diagnosis]. / Idiopathischer primärer Hyperaldosteronismus: Bedeutung der Funktionsdiagnostik.

Primary aldosteronism is a rare cause of hypertension caused by increased aldosterone secretion. The two essential stimuli for aldosterone production, potassium and angiotensin II, tend to be low. At a time when imaging procedures are becoming more common, more patients are being found with adrenal masses, and patients with incidentalomas and low renin hypertension could be considered as candidates for surgery. Apart from an appropriate work-up for the diagnosis of primary aldosteronism, the differential diagnosis between unilateral adenoma and idiopathic ("hyperplasia") hyperaldosteronism is relevant for the choice of therapy. Based on data from the literature and four patients we observed as outpatients in 1997, we suggest that a properly conducted and carefully interpreted postural stimulation test can be useful in identifying patients who are successfully treated by drugs.

Effects of short-term insulin-like growth factor-I (IGF-I) or growth hormone (GH) treatment on bone metabolism and on production of 1,25-dihydroxycholecalciferol in GH-deficient adults.

UNLABELLED: Administration of insulin-like growth factor-I (IGF-I) or growth hormone (GH) is known to stimulate bone turnover and kidney function. To investigate the effects of IGF-I and GH on markers of bone turnover, eight adult GH-deficient patients (48 +/- 14 yr of age) were treated with IGF-I (5 micrograms/kg/h in a continuous s.c. infusion) and GH (0.03 IU/kg/daily s.c. injection at 2000 h) in a randomized cross-over study. We monitored baseline values for three consecutive days before initiating the five-day treatment period, as well as the wash-out period of ten weeks. Serum osteocalcin, carboxyterminal and aminoterminal propeptide of type I procollagen (PICP and PINP, respectively) increased significantly within 2-3 days of both treatments (P < 0.02) and returned to baseline levels within one week after the treatment end. The changes in resorption markers were less marked as compared with formation markers. Total 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) rose significantly, whereas PTH and calcium levels remained unchanged during either treatment. CONCLUSIONS: Because the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF-I is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because PTH, calcium, and phosphate remained unchanged, IGF-I appears to stimulate renal 1 alpha-hydroxylase activity in vivo.

De Quervain's subacute thyroiditis presenting as a painless solitary thyroid nodule.

We describe a 39-year-old woman presenting with a painless solitary thyroid nodule, initially without signs suggesting thyroiditis. The serum level of thyrotropin was suppressed whereas those of thyroxine and triiodothyronine were normal. Fine needle aspiration cytology showed no signs of inflammation or malignancy. One week later, the patient felt pain and tenderness on her neck, and erythrocyte sedimentation rate and C-reactive protein were markedly elevated. Thyroid scintigraphy showed a suppressed thyroid pertechnetate uptake. At that time, the diagnosis of subacute thyroiditis was made. Upon treatment with steroids the patient's symptoms as well as the thyroid nodule resolved. This case illustrates that subacute thyroiditis de Quervain may present as a solitary, painless nodule with suppressed thyrotropin and should therefore be considered in the differential diagnosis of such lesions.

[Maturity-onset diabetes of the young (MODY)--a heterogeneous disease picture]. / Maturity-onset diabetes of the young (MODY)--ein heterogenes Krankheitsbild.

A family with maturity-onset diabetes of the young (MODY), a rare subtype of non-insulin-dependent diabetes mellitus (NIDDM), is described. This familial form of diabetes is characterized by an early age of onset and an autosomal dominant inheritance. All three patients developed diabetes at an early age and were not obese. The diabetes was always well controlled and none of the patients developed late complications. The clinical and molecular-genetic characteristics of the different forms of MODY are described, as well as the diagnostic work-up and therapeutic management.

IGF-I inhibits burst mass of pulsatile insulin secretion at supraphysiological and low IGF-I infusion rates.

Insulin-like growth factor I (IGF-I) shares structural and functional features with insulin, affects carbohydrate metabolism, and inhibits insulin secretion. Insulin secretion is pulsatile, and it is regulated by changing frequency and/or mass of secretory bursts. To examine the mechanism of IGF-I's inhibition of insulin secretion, eight healthy volunteers were studied three times. During glucose infusion (2.5 mg x kg(-1) x min(-1)) blood was sampled minutely at time 75-200 min for triplicate insulin concentration measurements by enzyme-linked immunosorbent assay (ELISA; coefficient of variation 2.1%). Time 125 min infusion of saline, low-dose IGF-I (0.025 microg x kg(-1) x min(-1)) or high-dose IGF-I (0.15 microg x kg(-1) x min(-1)) was commenced and continued until 200 min. Data were compared before (75-125 min) vs. during infusion (150-200 min). Insulin concentration time series were deconvolved, using validated pulse-detection criteria, to assess insulin secretory burst mass and frequency. During saline infusion no time effect occurred. After IGF-I infusion, serum C-peptide decreased (582 +/- 85 vs. 481 +/- 82 pM, low-dose IGF-I, P < 0.05; 539 +/- 84 vs. 427 +/- 69 pM, high-dose IGF-I, P < 0.01). Total insulin secretion rates decreased by 17 and 21%, respectively, via specific inhibition of the insulin secretory burst mass (31 +/- 8 vs. 20 +/- 4 pmol/ml, low-dose IGF-I, P = 0.06; 22 +/- 4 vs. 17 +/- 3 pmol/ml, high-dose IGF-I, P < 0.05), whereas the frequency was not affected (10.5 +/- 1.3 vs. 10.7 +/- 1.3 pulses/h, low-dose IGF-I, P = 0.85; 8.7 +/- 1.0 vs. 11.1 +/- 1.2 min/pulse, high-dose IGF-I, P = 0.15). We conclude that IGF-I inhibits pulsatile insulin secretion by specific inhibition of mass but not frequency of secretory bursts.

Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25 dihydroxyvitamin D3 production in healthy man.

OBJECTIVES: To find out whether insulin-like growth factor-I (IGF-I) mimics the stimulatory effects of growth hormone (GH) on bone turnover and renal tubular phosphate reabsorption. DESIGN: Randomized, crossover study. SETTING: University Hospital, Zürich, Switzerland. SUBJECTS: Seven young healthy male subjects. INTERVENTIONS: Each subject was studied three times at 2-week intervals, treated with saline 0.9% (S), IGF-I [8 micrograms kg-1 h-1] by a continuous subcutaneous infusion and finally with GH (6 U. twice daily s.c.) for 5 days. MAIN OUTCOME MEASURES: 36 h after the start of treatment, IGF-I, biochemical markers of bone turnover, calcium, calcium regulating hormones, kidney function and phosphate reabsorption were measured in serum and in 2 h urine in fasting state. RESULTS: Serum levels of IGF-I were 26.8 +/- 7.3 (S), 119.4 +/- 11.4 (IGF-I) (P < 0.02) and 58.4 +/- 12.9 nmol L-1 (GH) (P < 0.02), respectively. Serum osteocalcin and carboxyterminal propeptide of type I collagen (PICP) as well as the urinary deoxypyridinoline/creatinine and the calcium/ creatinine ratios were all significantly higher after IGF-I (P < 0.02) or GH (P < 0.02) than after saline treatment. PTH levels did not change in response to treatment. Total albumin-corrected calcium increased only after GH treatment (P < 0.05). The free calcitriol index rose from 2.2 +/- 0.5 x 10(-5) (S) to 2.81 +/- 0.25 x 10(-5) (IGF-I) (P < 0.03) and 2.45 +/- 0.25 x 10(-5) (GH), respectively. Serum phosphate and maximal tubular reabsorption divided by glomerular filtration rate (TmP/GFR) were significantly raised by GH (P < 0.03) but not by IGF-I as compared to saline 0.9%. CONCLUSIONS: (i) Similar to GH, IGF-I rapidly activates bone turnover. (ii) IGF-I does not mimic the effect of GH on renal phosphate reabsorption in spite of comparable effects on renal blood flow and glomerular filtration rate. (iii) IGF-I increases free calcitriol index in face of unchanged serum levels of calcium, phosphate and PTH, consistent with a direct stimulatory effect on 25-OHD-1a-hydroxylase.

[Diabetes mellitus type II: when convert to insulin?]. / Diabetes mellitus Typ II: wann soll auf Insulin umgestellt werden?

About 5% of patients with type II diabetes per year have to switch over to an insulin regimen because of critical metabolic disturbances. This becomes particularly urgent in catabolic states. Further situations necessitating an insulin regimen are secondary failure of oral antidiabetic therapy, painful peripheral neuropathy and late manifestations of type I diabetes (late autoimmune diabetes mellitus in adults, LADA). Today's state of knowledge suggests for the change to an insulin regimen to start with bedtime injections of depot insulin, eventually combined with oral medication over the day. This regimen allows to keep the weight increase lower than with two or more insulin injections. Exogen insulin substitution ameliorates typical abnormalities in type II diabetes, such as increased hepatic glucose production, reduced peripheral glucose utilization, reduced function of beta-cells and dyslipidemia. It carries, however, the risk for hypoglycemia and weight-increase.

[Chronic cholestatic liver disease and grand mal seizures]. / Chronische cholestatische Hepatopathie und Grand-mal-Anfall.

HISTORY AND CLINICAL FINDINGS: A 48-year-old woman was hospitalised because of grand-mal seizures. 3 years previously a malignant melanoma had been resected from the skin of the back. She was also known to have chronic cholestasis of unknown cause. On physical examination there were postictal signs, but no neurological abnormalities and no jaundice. INVESTIGATIONS: Biochemical tests demonstrated greatly increased alkaline phosphatase (576U/I). gamma-GT (1556U/I) and leucine aminopeptidase (258U/I). The transaminases were only slightly raised (GOT 113U/I, GPT 82U/I). Magnetic resonance imaging of the brain revealed a single intracerebral space-occupying lesion, compatible with a melanoma metastasis. Endoscopic retrograde cholangiopancreatography discovered a filiform, short stenosis in the choledochal duct, histologically an adenocarcinoma. TREATMENT AND COURSE: The cerebral metastasis was removed stereotactically without complications. A Whipple-type gastroduodenopancreatectomy was performed 2 months later. Histology of an intraoperative liver biopsy revealed Caroli's syndrome (focal intrahepatic biliary dilatation) with congenital hepatic fibrosis. Cholestasis persisted after the operation and was treated with ursodeoxycholic acid. The patient has now been free of symptoms for 3 years. CONCLUSIONS: Caroli's syndrome should be included in the differential diagnosis of chronic cholestasis of unknown cause. The case also demonstrates the justification, under certain conditions, of aggressive treatment even when there are two different malignancies.

Insulin-like growth factor-I in man enhances lipid mobilization and oxidation induced by a growth hormone pulse.

Growth hormone (GH) secretion is suppressed during insulin-like growth factor-I (IGF-I) administration. The aim of the study was to examine whether IGF-I alters the metabolic response to a GH pulse. Seven healthy male subjects (age 27 +/- 4 years, BMI 21.8 +/- 1.7 kg/m2) were treated with NaCl 0.9% (saline) or IGF-I (8 micrograms.kg-1.h-1) for 5 days by continuous subcutaneous infusion in a randomized, crossover fashion while receiving an isocaloric diet (30 kcal.kg-1.day-1). On the third treatment day an intravenous bolus of 0.5 U GH was administered. Forearm muscle metabolism was examined by measuring arterialized and deep venous blood samples, forearm blood flow by occlusion plethysmography and substrate oxidation by indirect calorimetry. IGF-I treatment significantly reduced insulin concentrations by 80% (p < 0.02) and C-peptide levels by 78% (p < 0.02), as assessed by area under the curve. Non-esterified fatty acid (NEFA), glycerol and 3-OH-butyrate levels were elevated and alanine concentration decreased. Forearm blood flow rose from 2.10 +/- 0.43 (saline) to 2.79 +/- 0.37 ml.100ml-1. min-1 (IGF-I) (p < 0.02). GH-pulse: 10 h after i.v. GH injection serum GH peaked at 40.9 +/- 7.4 ng/ml. GH did not influence circulating levels of total IGF-I, C-peptide, insulin or glucose, but caused a further increase in NEFA, glycerol and 3-OH-butyrate levels, indicating enhanced lipolysis and ketogenesis. This effect of GH was much more pronounced during IGF-I: NEFA rose from 702 +/- 267 (saline) and 885 +/- 236 (IGF-I) to 963 +/- 215 (saline) (p < 0.05) and 1815 +/- 586 mumol/l (IGF-I) (p < 0.02), respectively; after 5 h, 3-OH-butyrate rose from 242 +/- 234 (saline) and 340 +/- 280 (IGF-I) to 678 +/- 638 (saline) (p < 0.02) and 1115 +/- 578 mumol/l (IGF-I) (p < 0.02) respectively. After injection of GH, forearm uptake of 3-OH-butyrate was markedly elevated only in the subjects treated with IGF-I: from 44 +/- 195 to 300 +/- 370 after 20 min (p < 0.03) and to 287 +/- 91 nmol.100 ml-1. min-1 after 120 min (p < 0.02). In conclusion, the lipolytic and ketogenic response to GH was grossly enhanced during IGF-I treatment, and utilization of ketone bodies by skeletal muscle was increased.

Insulin-like growth factor-I in the therapy of non-insulin-dependent diabetes mellitus and insulin resistance.

Recombinant DNA technology has made large amounts of insulin-like growth factor-I (IGF-I) available for studies in animal models and humans. It has been shown that treatment with IGF-I is associated with increased insulin sensitivity in normal subjects as well as in patients with growth hormone deficiency, Type 1 and Type 2 diabetes mellitus and type A insulin-resistance. The metabolic effects of IFG-I appear to be beneficial in these conditions. The reported side effects of IGF-I, which may be largely due to overdosage, have limited its use to small and mostly short-term clinical studies.

Analytical biochemistry of seminal vesicle secretion: a challenge to andrological laboratories.

Chemical characterization of seminal vesicle secretion through seminal vesicle proteins would have the following advantages: (1) to judge on the secretory competence of the gland, (2) to recognize atypical secretory patterns, (3) to identify specific molecules and their epitopes for anatomical, diagnostic, therapeutic, anti-fertility and forensic purposes, and (4) to study physiologically active proteins or peptides of seminal plasma. There are different approaches for collection of the specific samples, each of which has peculiar advantages and disadvantages: ejaculate collection in the presence of protease inhibitors, use of split or multi-split ejaculates, utilization of autopsy or surgical material. Liquefied proteins are submitted to different chromatographic and electrophoretic procedures. One must keep in mind, however, that a whole series of biochemical processes can rapidly and irreversibly alter in vivo and in vitro the secretory proteins. The study of the secretion from male accessory sex glands and their interaction with spermatozoa therefore still deserves an absolute research priority.