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Background: Estramustine phosphate (EMP) and estramustine binding protein antibody (EMBP-AB) accumulate in the mouse prostate. The distribution of radioiodinated EMBP-AB in tumor mice was investigated to assess its therapeutic potential against prostate cancer., Materials and Methods: Mice with DU-145 prostate cancer xenografts received 243 microCi of I-125-labeled EMBP-AB (RI-EMBP-AB). The concentration of activity in different organs was measured 4 h after the injection., Results: The blood contained 0.45% of the injected dose per gram, the prostate 2.4%, the testes 0.95% and the tumor 0.65%. Radioactivity in these organs decreased more rapidly than in other organs. The doses of radiation absorbed by the prostate and the tumor, assuming a 1 mCi injected dose, were 1.81 and 0.92 cGy, respectively., Conclusion: Most other organs would receive relatively high doses of radioactivity, were I-125 to be used in therapeutic doses. Therefore, RI-EMBP-AB is not beneficial in radionuclide treatment as compared to possible EMP applications.

13-cis-Retinoic acid treatment causes insulin resistance and disturbances in lipid and glucose metabolism. We studied how 13-cis-retinoic acid affects inflammatory factors and adiponectin. A total of 23 healthy patients (age, 24.9 +/- 0.9 years; body mass index, 22.6 +/- 0.7 kg/m(2)) who received 13-cis-retinoic acid treatment of acne participated in the study. The patients were studied before the treatment, after 3 months of therapy, and 1 month after the treatment. Inflammatory parameters were measured, and a 4-hour oral glucose tolerance test was performed at each visit. Treatment with 13-cis-retinoic acid resulted in a significantly elevated serum adiponectin concentration (from 24.9 +/- 2.5 to 29.4 +/- 3.6 mg/L, P < .05), hemoglobin A(1c) (from 5.27% +/- 0.05% to 5.42% +/- 0.06%, P < .01), C-peptide area under the curve (from 314.2 +/- 16.6 to 350.0 +/- 21.0 (nmol . min)/L, P < .05), and triglycerides (from 0.97 +/- 0.06 to 1.29 +/- 0.10 mmol/L, P < .05), whereas high-density lipoprotein cholesterol decreased (from 1.50 +/- 0.07 to 1.38 +/- 0.08 mmol/L, P < .05). The increase in adiponectin during 13-cis-retinoic acid therapy correlated with baseline triglycerides (r = 0.51, P < .02). Many inflammatory markers, which were nonsignificantly elevated during therapy, decreased significantly after cessation of treatment. These were C-reactive protein (median from 1.78 to 1.23 mg/L, P < .05), soluble intercellular adhesion molecule 1 (from 210 +/- 10 to 204 +/- 10 microg/L, P < .02), ceruloplasmin (256 +/- 17 to 231 +/- 17 microg/L, P < .02), and erythrocyte sedimentation rate (from 6.4 +/- 1.3 to 4.7 +/- 0.9 mm/h, P < .02). Interleukin 6 concentration was unaffected by the therapy, but decreased significantly after the treatment (from 2.18 +/- 0.46 to 1.65 +/- 0.43 ng/L, P < .05). In conclusion, although treatment with 13-cis-retinoic acid results in disturbances in glucose and lipid metabolism, paradoxically serum adiponectin concentration increases. 13-cis-Retinoic acid has profound effects on the regulation of inflammatory markers.

Background: Inflammation is an established contributor in atherosclerosis and several other common diseases including diabetes. Therefore the study was to investigate how inflammatory factors affect lipid metabolism during recovery from hyperinsulinaemia in healthy individuals., Materials and Methods: A total of 22 healthy subjects [aged 27.7 +/- 1.8 years; body mass index (BMI) 24.1 +/- 0.8 kg m(-2)] participated in the study. After a 4-h euglycaemic hyperinsulinaemia (55.9 +/- 2.2 mU L(-1)) insulin infusion was stopped and baseline blood samples were taken. Glucose infusion at a decreasing rate continued for 120 min to maintain euglycaemia throughout the study., Results: The free fatty acid (FFA) concentration at the 120-min time-point was associated with baseline alpha-1-acid glycoprotein (A1GP) (r = 0.57, P < 0.01), C-reactive protein (CRP) (r = 0.54, P < 0.02) and serum amyloid A (r = 0.53, P < 0.02); in total they accounted for 54% of the variation in FFA concentration at the 120-min time-point. Baseline A1GP was also associated with the triglyceride concentration at the 120-min time-point (r = 0.66, P < 0.001). Insulin sensitivity was the most important factor associated with glucose disposal at the 120-min time-point, thus explaining 30% of the variation (P < 0.01). Interleukin-6 (positive correlation) and fibrinogen (negative correlation) increased the proportion to 48% (P < 0.01). There was no significant change in the most acute-phase proteins between baseline and the 120-min time-point., Conclusion: Inflammation is an important contributor to lipid and glucose metabolism during recovery from hyperinsulinaemia.

Aims: To investigate how reduction of hyperglycaemia affects acute phase serum proteins in poorly controlled type 1 diabetic patients., Methods: 24 patients (age 31.7 +/- 2.0 years, HbA1c 9.3 +/- 0.2%, BMI 24.2 +/- 0.7 kg/m2, diabetes duration 15.3 +/- 1.7 years) participated in the study. The treatment was optimised for 16 weeks. Blood samples were taken at baseline and at the end of the study. 16 healthy age- and BMI-matched subjects were chosen for a control group., Results: At baseline, the patients had higher C-reactive protein (CRP) (1.09, median [range 0.24-18.82] mg/l vs. 0.66 [0.18-2.46] mg/l, p < 0.02), mean adiponectin (16.06 +/- 1.31 vs. 8.85 +/- 0.93 mg/l, p < 0.001), ceruloplasmin (306 +/- 16.1 vs. 205.4 +/- 5.5 mg/l, p < 0.001), fibrinogen (3.41 +/- 0.26 vs. 2.38 +/- 0.07 g/l, p < 0.001), soluble intercellular adhesion molecule-1 (sICAM-1) (255.4 +/- 10.3 vs. 194 +/- 10.6 microg/l, p < 0.001), soluble vascular adhesion molecule-1 (sVCAM-1) (533.4 +/- 21.8 vs. 422.9 +/- 20.7 microg/l, p < 0.01) and interleukin-6 (2.89 +/- 0.49 vs. 1.35 +/- 0.30 ng/l, p < 0.01) concentrations than the controls. During intensified treatment, HbA1c decreased (to 8.5 +/- 0.2%, p < 0.001). This resulted in reduced sE-selectin (from 44.6 +/- 2.6 to 38.8 +/- 2.6 microg/l, p < 0.01), alpha-1-acid-glycoprotein (A1GP) (from 622.9 +/- 47.9 to 525.7 +/- 27.9 mg/l, p < 0.01), sICAM-1 (from 255.4 +/- 10.3 to 240.8 +/- 9.1 microg/l, p < 0.05) and IL-6 (from 2.9 +/- 0.5 to 2.1 +/- 0.4 ng/l, p < 0.01). Serum amyloid A (SAA) and CRP did not change 12.00 (0.7-222.0) vs. 12.00 (1.6-277.0) mg/l for SAA and 1.09 (0.24-18.82) vs. 1.09 (0.18-23.08) mg/l for CRP, baseline vs. treatment, respectively., Conclusions: Poorly controlled type 1 diabetic patients have increased values of adiponectin, CRP, ceruloplasmin, fibrinogen, sICAM-1, sVCAM-1 and IL-6. Reduction of hyperglycaemia results in decreased sE-selectin, A1GP, sICAM-1 and IL6, while other inflammatory factors including CRP, SAA and adiponectin are not affected.

Background: Adiponectin is a recently discovered plasma protein with many associations to glucose and lipid metabolism. Due to its central role in cardiovascular diseases and insulin resistance, we studied the relationship between serum adiponectin and factors reflecting glucose and lipid metabolism., Methods and Results: Thirty healthy participants (20M/10F, age 32.0 +/- 2.1 years, BMI 25.8 +/- 0.9 kg/m (2) and HbA (1c) 5.2 +/- 0.1 %) were studied four times at approximately one week intervals. The effects of a 4-hour euglycemic hyperinsulinemia (40 mU/m (2)/min), saline infusion (control), oral glucose, and oral fat load on serum adiponectin were studied. No significant correlation was found between serum adiponectin and insulin sensitivity before (r = 0.25) or after adjustment for age, BMI and gender (r = 0.04). Adiponectin concentration correlated inversely with HbA (1c) (r = - 0.43, p < 0.05), insulin concentration (r = - 0.38, p < 0.05) and triglyceride concentration (r = - 0.42, p < 0.05) but positively with HDL cholesterol (r = 0.38, p < 0.05). Metabolic procedures had no effect on serum adiponectin., Conclusions: Our findings favor the interpretation that adiponectin is not causally related to insulin sensitivity in healthy participants. The strongest associations of adiponectin in healthy participants are to be found to lipid metabolism. Serum levels of adiponectin are very stable and not acutely affected by hyperinsulinemia, oral glucose or fat load.

Aim: It has been shown that atherosclerosis is an inflammatory disease. Recent data suggest that inflammation precedes type 2 diabetes. Hence, we wanted to study the interrelationship between IL-6, insulin sensitivity, lipids and numerous acute-phase proteins., Methods: Twenty-one healthy individuals [16 males/5 females, age 27.9+/-1.8 years, body mass index (BMI) 24.1+/-0.8 kg/m(2)] participated in the study. Each patient went through a 4-h hyperinsulinaemic (40 mU/m(2)/min) euglycaemic clamp and 4-h saline infusion. Blood samples were taken before and at the end of the infusions., Results: Plasma interleukin (IL)-6 concentration correlated inversely with insulin sensitivity (M-value) (r=-0.49, p<0.05). Moreover, the plasma levels of IL-6 associated with c-peptide (r=0.49, p<0.05), fat% (r=0.43, p<0.05) and diastolic blood pressure (r=0.46, p<0.05). alpha-1-acid glycoprotein was related to HbA1(c) (r=0.47, p<0.05), insulin (r=0.55, p<0.01), diastolic blood pressure (r=0.58, p<0.01), systolic blood pressure (r=0.58, p<0.01) and triglycerides (r=0.58, p<0.01). Haptoglobin was correlated with insulin (r=0.46, p<0.05), total cholesterol (r=0.61, p<0.01), BMI (r=0.58, p<0.01), fat% (r=0.63, p<0.01) and lipid oxidation during clamp (r=0.43, p<0.05). Diastolic blood pressure decreased during the clamp (from 78.3+/-1.9 to 72.1+/-2.0 mmHg, p=0.001). Insulin infusion did not affect the serum levels of most acute-phase proteins., Conclusions: Our study suggests that low grade inflammation, as reflected by IL-6, A1GP and haptoglobin contributes to the regulation of insulin sensitivity, lipid metabolism and blood pressure in normal human physiology.

Tumors express MMP-2 and MMP-9 gelatinases, which are involved in the formation of tumor vasculature. This suggests that a tumor and its surrounding neovasculature can be visualized by a sensitive gelatinase recognition method. We have studied tumor radioimaging using a gelatinase inhibitory peptide CTTHWGFTLC (CTT), which in a mouse model targets the tumor site following an intravenous injection. We determined a solution NMR structure of CTT and its retro-inversion peptide, and prepared 125I and 99mTc-labelled CTT peptide derivatives. Radiolabelled CTT inhibited gelatinases in vitro, and homed to a tumor xenograft in mice. In normal mice, CTT was instead rapidly cleared from the circulation mainly through the kidney and, after 24 h, no significant radioactivity was accumulated in healthy tissues. Gamma camera imaging of a primary tumor in live mice was obtained with double-labelled liposomes, which were coated with 99mTc-CTT and encapsulated with 125I albumin. CTT also targeted liposomes to the lungs of tumor-bearing mice, which may indicate the existence of non-visible lung micrometastases. Our studies suggest that selective gelatinase-targeting compounds could be useful in the early detection and imaging of primary tumors and metastases.

The raccoon dog (Nyctereutes procyonoides) is a middle-sized canid with profound autumnal fattening followed by winter sleep. This study investigated the effects of prolonged fasting-induced winter sleep on the fat and nitrogen metabolism of the species. Half of the animals were treated with continuous-release melatonin implants to induce artificial short photoperiod. Autumnal accumulation of fat was characterized by low plasma free fatty acid (FFA), diacylglycerol (DG), and triacylglycerol (TG) levels. After transition to winter catabolism, the circulating lipid levels increased due to enhanced lipolysis. Two months of fasting resulted in a steady 3.1 kg weight loss (28% of body mass, 0.47% day(-1)). Storage fat was mobilized during the winter sleep reflected by the elevated FFA and DG concentrations. The lowered insulin levels could be a stimulator for TG hydrolysis. The plasma total amino acid concentrations, urea levels, and urea-creatinine ratios decreased due to fasting, whereas ammonia and total protein concentrations remained stable. The effects of melatonin on energy metabolism were modest. The results indicate that the raccoon dog is well adapted to long-term wintertime fasting utilizing fat as the principal metabolic fuel. The species can maintain its protein catabolism constant for at least 60 days. Decreased cortisol and thyroid hormone concentrations may contribute to protein sparing.

Bisphenol A (BPA), an environmental estrogen derived from the plastic industry, was given orally via incorporation into the food of 30 male and female polecats at 3 different doses (10, 50, or 250 mg/kg body weight/day) for 2 wk with 10 animals acting as controls. Several hormone levels in the plasma were determined as well as the activities of the phase I and II biotransformation enzymes 7-ethoxyresorufin O-deethylase (EROD), cytosolic glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT). BPA did not cause any macroscopic effects on body mass or the health of the animals. UDPGT and GST activities increased significantly in direct correlation with increasing BPA exposure in females and UDPGT increased in a dose-related manner in males. There was no change in the plasma T4 and testosterone concentrations of the males with increasing BPA exposure. Discriminant analysis indicated that the group receiving 10 mg BPA/kg body weight/d was not different from the control group but the groups receiving 50 and 250 mg/kg body weight/d were different from the control group. This suggests physiological changes in the groups receiving 50 or 250 mg BPA/kg body weight/d.

Background: Liver transplantation (Tx) has become an alternative treatment of malignant childhood liver tumors, and the importance of careful pretransplantation evaluation has been emphasized. Anti-alpha-fetoprotein (AFP) imaging has been suggested for evaluation of adult patients with AFP-positive tumors., Methods: Antibody imaging utilizing Tc-99 m-labeled monoclonal anti-AFP Fab' fragments was used to demonstrate pathologic uptake in hepatoblastoma (HB)., Results: Radical operation or liver Tx was not possible after four cycles of chemotherapy in a child with HB because of a single extrahepatic metastasis. Chemotherapy was continued, and reevaluation with anti-AFP imaging demonstrated a pathologic uptake only in the liver. Subsequently, a right liver lobe resection was performed. Along with a new rise in serum AFP, repeated anti-AFP imaging revealed active liver tumor but no metastases. A liver Tx was performed, and the child is well with a normal serum AFP level 18 months after the operation., Conclusion: This is the first case of pediatric HB in which anti-AFP imaging has been successfully used for patient management.

Systemic inflammation triggered by insults like sepsis and acute pancreatitis may play a role in development of indirect acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Because little is known about the course of systemic inflammation on the days preceding diagnosis of ARDS, we prospectively monitored immune inflammatory status in 52 patients at risk and we assessed the presence of ALI and ARDS on day 7 after admission to the intensive care unit. On admission, serum interleukin (IL) 8, IL-6, and soluble IL-2 receptor concentrations were significantly higher in patients with subsequent ALI (n = 18) than in patients without ALI (n = 30). During a 4-day follow-up, IL-8 and IL-6 levels of ALI patients remained high and those of non-ALI patients decreased. None of the markers discriminated ARDS patients (n = 9) from non-ARDS ALI patients (n = 9). Among 11 patients with acute pancreatitis, ALI patients had significantly higher IL-8, IL-6, and phagocyte CD11b expression levels than did non-ALI patients, whereas among 14 patients with massive transfusion, respective findings in ALI and non-ALI patients were comparable. Results give credence to the view that systemic inflammation plays a role in development of ALI triggered by pancreatitis, but not in that by massive transfusion. This finding, if confirmed in studies with sufficient statistical power, suggests that the patients with massive transfusion do not necessarily benefit from novel biotherapies aimed at altering the course of systemic inflammation.

Aim: To evaluate the effect of maternal diabetes on the concentrations of free and bound leptin at birth and during postnatal adaptation., Methods: Total, bound, and free leptin concentrations and the percentage of free leptin were measured in cord plasma and plasma at 3 days of age of 13 term infants of mothers with gestational diabetes mellitus (GDM) and 13 term infants of healthy mothers. Gestational age was 40.2 (1.4) weeks, and birth weight was 3693 (549) g (means (SD))., Results: At birth, infants of mothers with GDM had significantly higher concentrations of total, bound, and free leptin and a higher percentage of free leptin (all p < 0.05). In all infants, these concentrations were significantly lower at 3 days of age than at birth (all p < 0.003), and the differences in concentrations of total, bound, and free leptin between the two groups were no longer significant. In infants of mothers with GDM, the percentage of free leptin remained unchanged, and was higher (p<0.05) than in infants of healthy mothers; in the latter group the percentage of free leptin significantly declined (p = 0.02)., Conclusions: GDM appears to influence fetoplacental leptin metabolism. This effect may be mediated through altered maternal glucose metabolism, or insulinaemia, or both.

Background: Oral and transdermal postmenopausal hormone replacement therapy (HRT) affects lipid and glucose metabolism differently, which is of significance in the release of leptin by adipocytes. Moreover, oestrogen and progesterone can stimulate leptin secretion in women of reproductive age. Therefore, we compared the effects of oral and transdermal oestrogen plus progestin regimen on plasma leptin in 38 healthy postmenopausal women with normal body mass index (BMI), who wished to use HRT to control incapacitating climacteric symptoms., Methods: The women were randomized to treatment with oral HRT (2 mg oestradiol on days 1--12, 2 mg oestradiol plus 1 mg norethisterone acetate (NETA) on days 13--22, and 1 mg oestradiol on days 23--28, n = 19), or with transdermal HRT (50 microg/day of oestradiol on days 1--13, and 50 microg oestradiol plus 250 microg/day NETA on days 14--28, n = 19) for 1 year. Plasma samples were collected before and at oestradiol + NETA phase after 2, 6 and 12 months treatment and were assayed for leptin., Results: The baseline leptin, ranging from 3.3 to 34.9 microg/l, was significantly associated with BMI (r = 0.78, P < 0.0001 ), but showed no difference between women in oral HRT (geometric mean 13.9 microg/l, 95% confidence interval (CI) 10.1--17.6 microg/l) or transdermal HRT group (geometric mean 12.0 microg/l, 95% CI 9.7--14.3 microg/l). Neither oral nor transdermal oestradiol + NETA caused any significant changes in plasma leptin (or BMI) after 2, 6, or 12 months of treatment., Conclusion: Leptin is an unsuitable factor to detect oestradiol + NETA-induced metabolic changes in postmenopausal women.

We studied the effect of an oral fat load on plasma acylation stimulating protein (ASP) concentrations in 9 lean healthy (age 59+/-2 years, body mass index [BMI] 23.2+/-0.4 kg/m(2); both mean+/-SEM), 9 obese nondiabetic (58+/-2 years, BMI 29.4+/-0.5 kg/m(2)), and 12 type 2 diabetic (60+/-2 years, BMI 29.6+/-1.0 kg/m(2)) men. Because ASP is a cleavage product of complement protein C3 (C3adesArg) and its secretion is regulated by insulin, we also examined the subcutaneous adipose tissue expression of C3 mRNA before and after a 240-minute euglycemic hyperinsulinemic clamp in a subgroup of these men. Plasma ASP concentration and adipose tissue C3 mRNA expression were higher in the obese groups than in the lean men. Plasma ASP concentration did not change significantly after the fat load. Fasting plasma ASP concentration and C3 mRNA expression were correlated negatively with insulin sensitivity and positively with the magnitude of postprandial lipemia in nondiabetic but not in type 2 diabetic men. The expression of C3 mRNA was not regulated by insulin. These data suggest that ASP is associated with whole-body glucose and lipid metabolism in nondiabetic individuals, whereas metabolic disturbances in diabetes may overcome the regulatory role of ASP in lipid and glucose metabolism.

Leptin may have a role in human reproduction. The impact of IVF and of very early pregnancy on serum leptin concentrations was studied in 66 infertile patients, of whom 19 became pregnant. Ovarian suppression was accompanied by a fall in leptin concentrations (21 +/- 4%, mean +/- SE; P < 0.01) from the mid-luteal phase, and ovarian stimulation by a rise (76 +/- 8%; P < 0.0001) from suppression. The mid-luteal concentration of leptin after stimulation was 28 +/- 7% higher than that during the preceding normal cycle (P < 0.001). Concentrations of leptin and oestradiol were related before treatment, at ovarian suppression and at 8 days after oocyte retrieval. In addition, the rises in leptin and oestradiol concentrations during stimulation were correlated, but only in those patients who became pregnant (r = 0.69; P = 0.001). Women with a successful pregnancy had higher concentrations of leptin (18.7 +/- 4.8 microg/l) at 12 days after embryo transfer than those who had miscarriages (10.0 +/- 1.9 microg/l; P < 0.001), or those failing to become pregnant (11.6 +/- 1.2 microg/l; P < 0.0001). We concluded that leptin concentrations are influenced by ovarian function and that the relationship between leptin and oestrogen (but not a single leptin concentration), may be an important factor for the outcome of IVF.

Unlabelled: In the intervertebral disk, proteoglycans form the major part of the extracellular matrix, surrounding chondrocytelike disk cells. Keratan sulfate is a major constituent of proteoglycans., Methods: We have radioiodinated a monoclonal antibody raised against keratan sulfate. This antibody was injected into rats (n = 6), and the biodistribution was studied. A model of intervertebral disk injury was developed, and two tail disks in each animal with both acute (2 wk old) and subacute (7 wk old) injuries were studied for in vivo antibody uptake., Results: The biodistribution at 72 h was as follows: blood, 0.0018 percentage injected dose per gram of tissue (%ID/g); lung, 0.0106 %ID/g; esophagus, 0.0078 %ID/g; kidney, 0.0063 %ID/g; liver, 0.0047 %ID/g; spleen, 0.0046 %ID/g; heart, 0.0036 %ID/g; thyroid, 0.0034 %ID/g; muscle, 0.0017 %ID/g; and bone, 0.0016 %ID/g. In the subacute stage, a significant difference (P < 0.006) was found in antibody uptake between injured disks (n = 12) and adjacent healthy disks (n = 12). In vivo gamma imaging showed increased uptake in other animals having lumbar disk injuries (2, 7, and 17 d after injury). Cartilage tissue, such as the trachea, was studied separately and showed extremely high antibody uptake, 0.10 %ID/g. Rat trachea was also visualized on gamma images., Conclusion: Our data suggest that antibodies against nucleus pulposus components, such as proteoglycans, can be used for in vivo detection of intervertebral disk injury. This finding is in spite of the minimal circulation present in intervertebral disks.

Objective: To investigate whether marker(s) of systemic inflammation detect, at an early stage of acute pancreatitis, patients who may ultimately develop severe disease., Design: Prospective study., Setting: University hospital emergency unit., Patients: Thirty patients with mild acute pancreatitis (SEV0 group) and 27 with severe acute pancreatitis. Of the latter, 11 did not develop organ failure (SEV1 group), whereas the other 16 patients developed acute respiratory failure and 9 of them also developed renal failure (SEV2 group)., Interventions: Blood samples were collected at admission to the hospital (T0), and at 12 hrs (T12) and 24 hrs (T24 after admission., Measurements and Main Results: The plasma concentrations of procalcitonin (PCT), soluble E-selectin (sE-selectin), soluble interleukin-2 receptor (sIL-2R), and the serum concentration of C-reactive protein (CRP) were monitored. PCT levels at T0 were significantly higher in the SEV1 group (median 0.4 ng/mL, range 0.2-2.3) and the SEV2 group (0.8 ng/mL, 0.2-73.5) than in the SEV0 group (0.3 ng/mL, 0.1-3, p < .05 and p < .001, respectively). At T12, PCT level in the SEV2 group was significantly higher than that in the SEV1 group (2.2 ng/mL, 0.2-86.6 vs. 0.4 ng/mL, 0.3-2.8, p = .05), as it also was at T24 (2.2 ng/mL, 0.4-73.3 vs. 0.5 ng/mL, 0.3-4, p < .01). Among SEV2 patients, PCT concentration correlated negatively with the time elapsed between admission and the diagnosis of organ failure. At T12, sIL-2R levels of the SEV1 group (1,011 U/mL, range 334-2,211) and the SEV2 group (1,495 U/ml, range 514-4,526) both differed significantly from the SEV0 group (636 U/ml, range 356-1,678, p < .05 and p < .001, respectively) as they also did at T24. Although CRP level in the SEV1 group at T12 did not differ from the SEV0 group, the difference between SEV2 (272 microg/mL, range 46-462) and SEV0 was significant (53 microg/mL, range 5-243, p < 0.01). sE-selectin levels did not differ between groups., Conclusions: At admission to hospital, concentrations of PCT, but not those of CRP, sE-selectin, or sIL-2R, are higher in patients with severe acute pancreatitis than in patients with mild pancreatitis. PCT test had sensitivity of 94% and specificity of 73% for development of organ failure. PCT may be useful to identify the patients who benefit from novel therapies aimed at modifying the course of systemic inflammation.

Aim: To study the effect of maternal pre-eclampsia on cord plasma leptin concentrations in preterm infants., Methods: Leptin concentration was analysed in cord plasma of 74 preterm infants, gestational age 24 to 32 weeks. Of these, 14 were born to pre-eclamptic mothers, in 10 intrauterine growth retardation (IUGR) was present, and 59 had been exposed antenatally to corticosteroids., Results: The mean (SD) concentration of cord plasma leptin was 1.31 (0.88) microg/l. A significant correlation was found between leptin concentration and gestational age (r = 0.336; p = 0.0037). Leptin levels were higher in infants of pre-eclamptic mothers (p = 0.0007), in those with IUGR (p = 0.0005), and in infants exposed antenatally to corticosteroids (p = 0.02). In multiple regression analysis, leptin was associated with gestational age and maternal pre-eclampsia (both p < 0.05), but not with antenatal corticosteroids., Conclusions: Increased fetal leptin in maternal pre-eclampsia may reflect a physiological adaptation to fetal stress such as hypoxia.

Systemic inflammation is common in patients with nephropathia epidemica (NE), a European form of hemorrhagic fever. Markers of inflammation were studied in a patient with NE with respiratory insufficiency (patient 1), 18 other patients with NE, and 13 patients with a viral infectious disease other than NE. Neutrophil and monocyte CD11b expression levels, determined by flow cytometry; soluble interleukin (IL)-2 receptor (sIL-2R), IL-6, and IL-8 concentrations, determined by means of Immulite; and soluble E-selectin, determined by ELISA, were higher in patients with NE than in healthy subjects. The findings were not specific for NE and did not correlate with serum creatinine levels, but the findings correlated inversely with mean arterial pressure (sIL-2R and monocyte CD11b expression) and minimum platelet count (sIL-2R, IL-6, neutrophil, and monocyte CD11b expression). Monocyte CD11b expression in patient 1 was extremely high, suggesting that monocytes may contribute to development of lung injury. Severity of inflammation in patients with NE is related to hypotension and platelet consumption but not to renal injury.

Aims/hypothesis: The purpose of this study was to examine whether fetal leptin concentration correlates with severity of chronic or subchronic fetal hypoxia as indicated by increased fetal concentrations of erythropoietin in fetuses of mothers with Type I (insulin dependent) diabetes mellitus., Methods: We measured leptin and erythropoietin concentrations in cord plasma and amniotic fluid with radioimmunoassay in 25 pregnancies (gestational age 37.2 +/- 1.0 weeks). Fetuses with amniotic fluid erythropoietin over 22.5 mU/ml were classified as hypoxic (n = 9) and those with amniotic fluid erythropoietin below 22.5 mU/ml (n = 16) as non-hypoxic., Results: The hypoxic fetuses had significantly higher cord leptin concentrations than non-hypoxic fetuses (median 36.8; range, 12.5-135.1 vs median 16.2; range, 3.7-52.2 micrograms/l), (p = 0.0066). Cord plasma leptin (n = 25) correlated directly with amniotic fluid erythropoietin (r = 0.727, p = 0.0001), with cord plasma erythropoietin (r = 0.644, p = 0.0005) and with the maternal last trimester HbA1C (r = 0.612, p = 0.0019) and negatively with cord artery pO2 (r = -0.440, p = 0.032), and pH (r = -0.414, p = 0.040)., Conclusion/interpretation: Fetal leptin concentrations increased concomitantly with erythropoietin during chronic or subchronic hypoxia. This phenomenon could indicate a role for leptin in fetal adaptation to hypoxia.

Objectives: Because estrogens stimulate the synthesis and release of leptin in the adipocytes, the effect of antiestrogens on the circulating leptin levels were studied., Methods: Thirty postmenopausal patients with breast cancer were randomized to start either with tamoxifen (20 mg/day, n=15) or toremifene (40 mg/day, n=15), and the patients were examined and serum leptin concentrations measured before the study and at 6 and 12 months., Results: The baseline leptin concentrations ranged from 4.4 to 60.0 microg/l (15.3+/-13.1 microg/l, mean+/-S.D.), and it correlated positively with the body mass index (BMI) of the subjects (r=0.73, P=0.0001). Taking as a whole the antiestrogen regimen was associated with elevated leptin levels at 6 months (19.5+/-13.8 microg/l, P=0.0001) but no excess increase in leptin levels were seen at 12 months (20.9+/-13.5 microg/l, NS). Subgroup analysis showed no difference between the effects of tamoxifen or toremifene on leptin. BMI increased in 21 women (from 26.2+/-4.3 to 27.3+/-4.8 kg/m2, P=0.0001) at 6 months, but not after that; in nine women BMI did not change. There was no significant correlation between the change in leptin levels and the change in BMI in either group implying that antiestrogens may specifically stimulate leptin production., Conclusions: Antiestrogens may stimulate the synthesis and release of leptin in the adipocytes. This effect of antiestrogens resembles the effect of estrogen and consequently stimulation of leptin production can be added to the estrogenic effects of antiestrogens.

Background: During experimental liver transplantation, neutrophil sequestration results in increased oxygen free radical production and correlates inversely with graft viability. Neutrophil activation in clinical liver transplantation is poorly understood., Methods: We assessed leukocyte sequestration and transhepatic differences of neutrophil and monocyte CD11b expression, neutrophil free radical production, and plasma concentrations of interleukin 6 and interleukin 8 in nine patients during liver transplantation., Results: Significant hepatic neutrophil sequestration occurred during initial graft rewarming with portal blood, after inferior vena cava declamping, and after hepatic artery declamping (all P<0.05). A positive transhepatic difference (i.e., outcoming - ingoing) in CD11b expression of neutrophils was observed after portal vein declamping (51+/-32 relative fluorescence unit [RFU]) and in CD11b expression of monocytes during initial graft rewarming (67+/-86 RFU, both P<0.05). A transcoronary increase in both unstimulated (74+/-80 RFU) and N-formyl-methionyl-leucylphenylalanine-stimulated (112+/-168 RFU) neutrophil free radical production took place after hepatic artery declamping (both P<0.05). A negative transcoronary difference of interleukin 6 occurred during initial graft rewarming (-192+/-176 pg/ml) and a positive difference of interleukin 8 occurred after hepatic artery declamping (17+/-23 pg/ml, both P<0.05)., Conclusions: Hepatic sequestration and transhepatic activation of neutrophils, and hepatic production of interleukin 8 occur during clinical liver transplantation. A splanchnic influx of interleukin 6 occurs to the graft, possibly modulating neutrophil-mediated graft reperfusion injury.

Hyperleptinemia may be part of the insulin resistance syndrome. We studied serum leptin in preeclampsia, which is an insulin-resistant state, and sought associations between leptin and insulin or insulin sensitivity during and after pregnancy. Twenty-two proteinuric preeclamptic women and 16 normotensive controls were studied during the third trimester. Leptin was higher in preeclampsia (mean +/- SE, 34.6 +/- 3.9 v 20.0 +/- 3.3 microg/L, P = .002) and correlated directly with the level of proteinuria (r = .47, P = .03) and normal pregnancy (r = .52, P = .04), whereas insulin sensitivity as assessed by an intravenous glucose tolerance test showed no relationship to leptin. Leptin was 19.0 +/- 3.6 microg/L in 14 preeclamptic women and 10.1 +/- 2.0 microg/L (P = .11) in 11 controls 3 months after delivery. Leptin correlated directly with insulin both in preeclamptic puerperal women (r = .63, P = .02) and in controls (r = .81, P = .003). Leptin and insulin sensitivity correlated only in preeclamptic puerperal women (r = -.59, P = .02). In conclusion, (1) serum leptin is elevated in preeclampsia, (2) insulin is an important determinant of serum leptin in preeclamptic and normotensive women both during pregnancy and in the puerperium, and (3) hyperleptinemia may be part of the insulin resistance syndrome also in women with prior preeclampsia.

To obtain predictors of organ failure (OF), we studied markers of systemic inflammation [circulating levels of interleukin-6 (IL-6), IL-8, soluble IL-2 receptor (sIL-2R), soluble E-selectin and C-reactive protein, and neutrophil and monocyte CD11b expression] and routine blood cell counts in 20 patients with systemic inflammatory response syndrome and positive blood culture. Eight patients with shock due to community-acquired infection developed OF, whereas 11 normotensive patients and one patient with shock did not (NOF group). The first blood sample was collected within 48 h after taking the blood culture (T1). OF patients, as compared with NOF patients, had at T1 a lower monocyte count, a lower platelet count, higher levels of CD11b expression on both neutrophils and monocytes, and higher concentrations of IL-6, IL-8 and sIL-2R. C-reactive protein and soluble E-selectin concentrations did not differ between groups. No parameter alone identified all patients that subsequently developed OF. However, a sepsis-related inflammation severity score (SISS), developed on the basis of the presence or absence of shock and on the levels of markers at T1, identified each patient that developed OF. The maximum SISS value was 7. The range of SISS values in OF patients was 2-5, and that in NOF patients was 0-1. In conclusion, high levels of CD11b expression, depressed platelet and monocyte counts, and high concentrations of IL-6, IL-8 and sIL-2R predict OF in patients with community-acquired septic shock, and the combination of these markers may provide the means to identify sepsis patients who will develop OF.

There are substantial alterations in fuel homeostasis immediately after birth. Leptin is a putative regulator of energy metabolism. Consequently, the aim of this study was to examine whether there are changes in circulating leptin concentrations during the early postnatal period. Umbilical cord mixed blood samples were taken at delivery, and a venous blood sample was obtained at 3 d of age from 38 healthy newborn infants (20 male, 18 female; gestational age 36.3 to 41.9 wk) for analysis of leptin concentration with radioimmunoassay. Cord plasma leptin concentration was 9.7+/-5.2 microg/L (mean+/-SD), with no gender difference between male (8.6+/-4.6 microg/L) and female (10.9+/-5.6 microg/L) infants. In male newborns, cord plasma leptin concentration correlated with arm circumference (r = 0.48, p < 0.05), and in female newborns with body mass index (r = 0.62, p < 0.01), thickness of the s.c. fat (r = 0.54, p < 0.05), and arm circumference (r = 0.72, p < 0.01). By the third postnatal day, plasma leptin decreased similarly in male (to 1.8+/-0.4 microg/L, p < 0.001) and female (to 2.3+/-0.8 microg/L, p < 0.001) infants, when there was a significant gender difference in leptin levels (p = 0.01). At 3 d of age, plasma leptin correlated with weight (r = 0.49, p < 0.05) and arm circumference (r = 0.49, p < 0.05) in female but not in male newborns. In conclusion, 1) circulating leptin already correlates with adiposity at birth in female but not in male newborn infants and 2) leptin decreases markedly in both genders by the third postnatal day, and the gender difference with higher leptin levels in females develops by that time. Thus, the postnatal decrease in plasma leptin concentration may be a physiologically feasible adaptation to profound alterations in fuel homeostasis during the first days of extrauterine life.

There are changes in the ability to regulate energy balance and caloric intake with aging. Consequently, we investigated whether human aging modifies the levels of serum leptin, a novel hormone implicated in the regulation of energy balance. We studied 268 Caucasian men and women aged 22-85 years, and divided them into groups with mean ages of 30, 40, 50, 65, 75, 80 and 85 years. Fasting serum leptin concentrations were determined by radioimmunoassay. Subjects aged 65 or older were followed for five years after the blood sampling. There were no statistically significant differences in fasting serum leptin concentrations across different age groups in females (p = 0.090). Fasting serum leptin concentrations were also similar in different age groups in males, except that males in the 30-year age group had lower serum leptin levels than males in the 75-year age group (p = 0.042). Leptin levels were 2-3 fold higher in females than in males in each age group (p < 0.005 except p = 0.063 in the 75-year age group). Elderly women, who lived longer, had 47% higher (p < 0.05) serum leptin concentrations, and 17% higher (p < 0.001) BMI than the women who died within five years of blood sampling. Leptin levels were not statistically different in these women after adjusting for BMI. Thus, aging has no apparent effect on serum leptin levels in women or men, and the gender differences in leptin is present also in the older age groups. Higher leptin concentrations in the females who live longer may reflect a better nutritional status, and a greater adipose tissue mass rather than a primary factor for survival.

Background: Leptin is an adipocyte-derived hormone that is thought to provide a negative feedback signal to control body fat mass by interacting with its hypothalamic receptor. The present study was undertaken to examine the uptake of leptin in cerebrospinal fluid (CSF) space in humans and whether the transport of leptin into CSF space is an active phenomenon or due to free access through the blood-CSF barrier., Methods: We determined serum and CSF leptin concentrations by radioimmunoassay in 17 men [42 +/- 4 years, mean +/- SE; body mass index (BMI) 27.3 +/- 1.8 kg m-2] and 22 women (40 +/- 3 years, BMI 25.1 +/- 1.0 kg m-2). The function of the blood-CSF barrier was evaluated by determining the CSF/serum albumin ratio., Results: Serum leptin concentration was lower in male (5.8 +/- 1.6 microgram L-1) than in female subjects (13.1 +/- 1.7 microgram L-1, P = 0. 001), whereas the concentrations of leptin in CSF were virtually identical in male (0.34 +/- 0.03 microgram L-1) and female (0.36 +/- 0. 03 microgram L-1) subjects. Serum leptin was correlated positively with BMI both in men (r = 0.89, P < 0.01, n = 10) and in women (r = 0.61, P < 0.05, n = 14), whereas no correlation between CSF leptin concentration and BMI was found in either group. The CSF/serum leptin ratio correlated negatively with serum leptin concentration both in men (r = -0.93, P < 0.001) and in women (r = -0.77, P < 0. 001) and with BMI both in men (r = -0.75, P = 0.02, n = 10) and in women (r = -0.64, P < 0.02, n = 14). The CSF/serum albumin ratio was not correlated with the CSF/serum leptin ratio in either group. CSF leptin concentrations and the CSF/serum leptin ratio were virtually identical in subjects with impaired and normal blood-CSF barrier function., Conclusion: Thus, our data support the presence of a saturable and active transporter of leptin from circulation into intrathecal space.

Rhenium (Re)-188 is a generator (W-188/Re-188) produced high energy beta-emitter suitable for radionuclide therapy (T1/2 is 16.9 hrs and Emax 2.1 MeV (range 11 mm)). We have labelled monoclonal antibody (MAb) raised against vascular cell adhesion molecule-1 (VCAM-1) with Re-188 using glucoheptonate chelation technique and SnCl2 as reducing agent. The labelling efficiency, free perrhenate and reduced Re were controlled with thin layer chromatography and the purification of Re-188-MoAbs was performed using gel filtration. Our results indicate that Re-188-labelled antibodies remain in vitro stable and the labelling purity is > 90%. We also have applied these Re-188-MoAbs for detection of inflammatory disease in a mouse. The effective half-lives of organs of interest after an injection of Re-188-anti-VCAM1 were as follows: blood 5.2 hr, kidney 4.7 hr, and liver 9.6 hr. Re-188-anti-VCAM-1 was found to accumulate mainly in kidney and liver. One hour after the injection, the kidney contained in average as high as 12.5% and the liver 2.8 ID/g tissue. After 6 hr, the kidney contained 5.5% ID/g and the liver 2.6% ID/g. At 24 hr, the kidney uptake was 0.5% ID/g and the liver uptake 0.8% ID/g, respectively. The inflamed foci, subcutaneous lesions in the footpad skin, were visualized using gamma camera. From the distribution data the uptakes in the inflamed foci as follows: at 1 hr 2.18 (inflammation) and 1.72% ID/g (control), at 6 hr 1.42 (inflammation) and 0.85% ID/g (control), and at 24 hr 0.17 (inflammation) and 0.084% ID/g (control), respectively. Anti-VCAM-1 MAb showed better targeting as compared to control MoAbs in inflammation (caused by E.coli lipoplysaccaride). In conclusion, Re-188 is suitable for MAb labelling, and MAb against VCAM-1 may be used for detection of local inflammatory disease.

Leptin is a peptide hormone produced by adipocytes which provides a negative feedback signal to control the amount of body fat. The action of leptin on food intake and weight loss is thought to be mediated by interaction with its hypothalamic receptor. We examined the biodistribution and brain uptake of radioiodinated leptin (123I-leptin) by dynamic gamma imaging in six anaesthetized New Zealand white rabbits. Leptin uptake was seen in the brain, lungs, liver and kidneys. In the brain, increase in radioactivity as a function of time was seen in the choroid plexus area. The choroid plexus to brain radioactivity ratio (CP/BR) was used as the target to background ratio. The CP/BR ratio increased up to approximately 40-60 min, after which a steady state in CP/BR was achieved. The steady state uptake ratio was higher in the rabbits that had fasted for only 6-8 h before the experiment (CP/BR approximately 2.5) than in those that had fasted for 25-27 h before the experiment (CP/BR approximately 1.8). Thus, leptin uptake in vivo occurs in the choroid plexus region of the brain and in the lungs, kidney and the liver. The uptake of leptin in the choroid plexus appears to be saturable, as indicated by the achieved steady state in the CP/BR radioactivity curve 40-60 min following 123I-leptin injection. The lower steady state CP/BR after prolonged fasting may be the result of the downregulation of leptin receptors in the choroid plexus.

Leptin is an adipocyte-derived peptide hormone regulating energy balance in experimental animals. Although the physiological function of leptin in humans is still unclear, its secretion is closely related to fat mass in adult humans. To examine how fetal growth correlates with leptin levels at birth, an umbilical cord venous blood sample was obtained at the delivery from 50 term newborn infants. Twenty-eight of the newborn infants had birth weights appropriate for gestational age (AGA; mean +/- SEM, 3362 +/- 90 g; relative birth weight, -0.08 +/- 0.2 SD), 9 were large for gestational age (birth weight, 4655 +/- 165 g; relative birth weight, 3.2 +/- 0.3 SD; P < 0.001 vs. AGA newborn infants), and 13 were small for gestational age (SGA; birth weight, 2385 +/- 69 g; relative birth weight, -2.2 +/- 0.08 SD; P < 0.001 vs. AGA newborn infants). Leptin concentrations were higher in large for gestational age (35.7 +/- 8.0 micrograms/L; P < 0.005), but lower in SGA (3.3 +/- 0.5 micrograms/L; P < 0.001) than in AGA infants (14.5 +/- 2.8 micrograms/L). When adjusted for differences in body weight, mean leptin levels were similar in the three newborn groups. Leptin concentration correlated closely with both absolute and relative birth weights (r = 0.71; P < 0.001 in both), with cord blood insulin concentration (r = 0.67; P < 0.001), and with placental weight (r = 0.60; P < 0.001). These data suggest that leptin is synthesized in utero, and that the circulating leptin concentration relates to the intrauterine growth pattern.

Background: The purpose of this study was to determine the distribution of radioiodinated estramustine (RI-EMP) and a radioiodinated antibody against estramustine binding protein (RI-EMBP-AB) in mice., Methods: RI-EMP and RI-EMBP-AB were injected in male mice intravenously, and the activities of tissue samples were measured 1-31 hr from the injection. Pure iodine-125 (RI) was used as a control., Results: RI-EMP accumulated in the prostate, which contained 2.6% of injected activity (ID) per gram tissue at 7 hr. The liver had an activity of 21.4% ID/g at 1 hr, which decreased as RI-EMP was secreted in bile. The lung contained 2.3% ID/g at 7 hr, and it retained the activity longer than the prostate. RI-EMBP-AB accumulated in the prostate: The activity was 2.9% ID/g at 7 hr. The gallbladder contained 6.5% ID/g at 7 hr., Conclusions: Due to its cytotoxic and radiosensitizing properties, RI-EMP can possibly be used for treating prostate cancer and other tumors.

Objectives: Evaluation of the performance of a radioimmunoassay kit for measuring serum concentrations of the aminoterminal extension peptide of human type I procollagen, S-PINP., Design and Methods: S-PINP concentrations in 229 healthy subjects, 140 females, aged 3.8-81 years, and 89 males, aged 0.9-71 years, were measured with the kit. Because PINP and PICP (the carboxy-terminal propeptide of type I procollagen) are formed in equimolar concentrations, we also calculated the PICP/PINP ratio and compared the S-PINP values to those of S-PICP, which have been shown to correlate with bone formulation rate., Results: The sensitivity of the assay was 2.3 micrograms/L, the spiking recovery ranged from 95.5 to 100.3%, the dilution recovery from 79.3 to 103.1%. The intra-assay imprecision was 2.3 to 3.5% (CV), the interassay imprecision within one reagent lot 2.5-5.2% and, between several reagent lots, 2.7 to 6.1% (CV). S-PINP in females over 20 years old ranged from 12 to 90 micrograms/L (x = 39.7, SD = 14.7), in males over 25 years old, from 22 to 89 micrograms/L (x = 49.9, SD = 15.8); the PICP/PINP ratio ranged from 1.5 to 5.2 and from 1.8 to 4.9, respectively. In females under 20 years old, S-PINP ranged from 52 to 820 micrograms/L, in males aged 25 years or younger from 35 to 1404 micrograms/L; the PICP/PINP ratio was 0.44-2.3 and 0.38-2.8. In females under 20 years and males under 25 years, there was a significant negative correlation between S-PINP and age: r = -0.70, p < 0.001 for females, r = -0.52, p = 0.004 for males. In different groups of healthy subjects, the correlation of S-PINP and S-PICP was significant (r = 0.67-0.86, p < 0.001)., Conclusion: The assay performance is good. The significant positive relationship between S-PINP and S-PICP suggests that S-PINP also reflects bone formation rate. Because the clearance of PINP is probably less sensitive to hormonal changes, PINP may prove to be superior to PICP as a marker of bone formation.

Background: Plasma levels of leptin, the recently discovered satiety hormone, are associated with adiposity in humans., Objective: To determine whether genetic factors or body fat distribution affect the association between leptin levels and obesity., Participants: 23 healthy identical twin pairs (9 male pairs and 14 female pairs, 33 to 59 years of age) who were discordant for obesity (average weight difference, 18 kg)., Measurements: Fasting plasma leptin levels were measured by radioimmunoassay. Distribution of abdominal fat into visceral and subcutaneous compartments was estimated by use of magnetic resonance imaging., Results: Plasma leptin levels were threefold higher in obese twins than in lean twins (mean +/- SD, 18.7 +/- 12.5 micrograms/L compared with 6.4 +/- 4.8 micrograms/L; P < 0.001); a similar difference was seen when the entire study group was divided according to sex. Compared with lean twins, plasma leptin levels were 3.7-fold higher in the obese twins who had visceral fat accumulation greater than the median and 2.1-fold higher in the obese twins who had visceral fat accumulation less than the median. The intrapair differences in leptin levels correlated with the corresponding differences in percentage of body fat in women (r = 0.73; P = 0.003) but not in men and correlated with differences in visceral fat area in men (r = 0.79; P = 0.019) and women (r = 0.73; P = 0.007). In multiple regression analyses that included intrapair differences in visceral fat area and total body fat, the association between differences in visceral fat area and leptin levels was significant in men (P = 0.029) but not in women., Conclusions: Plasma leptin levels are increased in obese persons, independent of genetic background. Visceral fat may be of special importance in the regulation of leptin levels, but it is probably less important in women than in men.

Insulin is known to increase expression of the ob gene product leptin in adipose tissue of rodents. We determined whether insulin increases circulating leptin concentrations in humans, and whether this effect might be altered in patients with noninsulin-dependent diabetes mellitus (NIDDM). Plasma leptin concentrations were determined during an 8.5-h hyperinsulinaemic clamp (serum free insulin approximately 480 pmol/l) and during an 8.5-h infusion of physiological NaCl solution (saline) in eight normal subjects (age 51 +/- 3 years, BMI 26.3 +/- 0.6 kg/m2, fasting plasma glucose 5.6 +/- 0.2 mmol/l) and seven patients with NIDDM (age 54 +/- 2 years, 27.0 +/- 0.9 kg/m2, 11.1 +/- 0.8 mmol/l). Fasting serum insulin level correlated with plasma leptin (r = 0.72, p < 0.005), even after adjusting for the percentage of body fat (p < 0.005). During the insulin infusion, a significant increase in the plasma leptin concentration was observed after 6 h (37 +/- 14%; 5.2 +/- 0.8. vs 3.9 +/- 0.6 ng/ml, 6 vs 0 h, p < 0.05) in the normal subjects and after 8.5 h (38 +/- 11%; 7.1 +/- 1.0 vs 5.5 +/- 0.9 ng/ml, 8.5 vs 0 h, p < 0.05) in the patients with NIDDM. During the saline infusion, plasma leptin concentrations decreased significantly in the normal subjects by 11 +/- 1% (p < 0.005) and in the patients with NIDDM by 14 +/- 1% (p < 0.01) after 2 h. During the infusion of insulin as compared to saline, plasma leptin concentrations were 32 +/- 13 (p < 0.05), 53 +/- 14 (p < 0.001), 106 +/- 15 (p < 0.001) and 165 +/- 21 (p < 0.001) % higher at 2, 4, 6 and 8.5 h in the normal subjects, and 11 +/- 9 (p < 0.05), 27 +/- 10 (p < 0.05), 58 +/- 7 (p < 0.001) and 106 +/- 13 (p < 0.001) % higher in the patients with NIDDM, respectively. No differences were observed in plasma leptin concentrations between the normal subjects and patients with NIDDM, under any conditions. We conclude that prolonged exposure to insulin increases plasma leptin concentrations in humans implying a role for insulin in chronic but not acute regulation of plasma leptin concentrations. The decrease in plasma leptin concentrations during saline infusion was greater than that expected on the basis of change in serum insulin concentrations, suggesting that factors other than insulin also contribute to regulation of plasma leptin concentrations.

In order to examine the effect of short-acting insulin analogue on the exercise-induced hypoglycaemia in insulin-dependent diabetes mellitus (IDDM) patients we compared the glycaemic response of 40 min cycle ergometer exercise performed either shortly (40 min) or later (180 min) after a breakfast meal and subcutaneous injection of either short-acting insulin analogue [Lys(B28) Pro(B29)] or soluble human insulin (Humulin Regular) in ten IDDM patients with long duration of the disease. Both preparations had been used 1 month before respective studies. Changes in blood glucose, insulin and counterregulatory hormones were assayed. As compared to human insulin, after the analogue injection the peak insulin concentration came earlier, was 56% higher (p < 0.05) and disappeared faster, and the postprandial blood glucose response was lower (p < 0.05). In the analogue-treated patients the exercise-induced hypoglycaemia was 2.2-fold greater (p < 0.01) during the early exercise, but 46% less (p < 0.05) during late exercise as compared to the treatment with human insulin. Serum insulin or analogue concentration at the beginning of the exercise correlated closely with the fall in blood glucose during exercise (r = 0.74, p < 0.01; r = 0.73, p < 0.02, respectively). In the analogue-treated patients, fasting serum glucagon and adrenalin concentrations were higher than during human insulin therapy (p < 0.05) and remained so throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

As assessed by urine pyridinium cross-links, bone resorption increases at night. This has been ascribed to either the nocturnal rise of serum parathyroid hormone (PTH) or immobilization. ICTP is the carboxyterminal telopeptide region of type I collagen in bone, cross-linked via pyridinium cross-links and liberated during the degradation of type I collagen. To study whether the nocturnal rise in bone resorption is seen also in serum type I collagen carboxyterminal telopeptide (ICTP) and whether this rise is abolished by bedtime calcium or calcitonin, nine healthy postmenopausal women participated in three 24 hour sessions. At 2200 hours, either 1 g of oral calcium or 200 IU of intranasal calcitonin or no treatment (control session) were given. The participants were recumbent from 2200 hours to 0600 hours. Like urinary pyridinolines, serum ICTP showed a clearcut nocturnal rise during the control session, increasing from 3.7 +/- 0.3 micrograms/liter (mean +/- SE) at 2000 hours to 4.9 +/- 0.4 micrograms/liter at 0600 hours (P < 0.001). Administration of calcium did not affect either serum ICTP or urinary pyridinolines, although it decreased serum intact PTH by 18% (P < 0.001) as assessed by areas under curve (AUC) after 2200 hours. Serum ICTP and urinary pyridinolines remained unchanged also after administration of calcitonin which increased the AUC for serum intact PTH by 9% (P < 0.05). In conclusion, serum ICTP follows a circadian rhythm in healthy postmenopausal women. The nocturnal rise in markers of bone resorption is not due to PTH, and its dependency on the function of osteoclasts is open to question.

A pheochromocytoma from a 59-year-old woman was found to be immunoreactive to adrenocorticotropin (ACTH), chromogranin, neurofilament-200, neuron-specific enolase and S-100 protein. Northern blot analysis showed that both proopiomelanocortin (POMC) and corticotropin-releasing hormone (CRH) genes were expressed in the pheochromocytoma but not in the surrounding adrenal cortex. In primary culture, the POMC and CRH mRNAs were increased by dexamethasone (500 micrograms/l for 3 days) up to 10- and 15-fold of the control, respectively. The secretion of ACTH also was stimulated eightfold with the same treatment. The stimulatory effect of dexamethasone on POMC gene expression was inhibited 70% by nerve growth factor (NGF, 200 micrograms/l), 30% by 12-O-tetradecanoyl phorbol 13-acetate (TPA, 160 nmol/l) (a protein kinase-C activator) and 30% by (Bu)2cAMP (1 mmol/l). On the other hand, NGF alone increased the CRH mRNA accumulation up to 10-fold, and further enhanced the stimulatory effect of dexamethasone on the CRH mRNA twofold, and TPA inhibited (30%) the dexamethasone-induced CRH mRNA accumulation. Furthermore, the conditioned medium of the pheochromocytoma cells increased secretion of corticosterone fourfold in the primary culture of rat fetal adrenal cells. Our results indicate abnormal expression and regulation of POMC and CRH genes in this pheochromocytoma.

Two fully automated serum FT4 assays (Ciba Corning: ACS-180; Abbott Diagnostics: IMx) and two manual/semiautomated assays (Wallac: Delfia; Diagnostic Products Corp.: Coat-A-Count) were compared with a FT4 reference method based on equilibrium dialysis (ED) using routine clinical samples (n = 105-150). For the full range of FT4 concentrations the correlation with ED was good (r = 0.932-0.959), except for Coat-A-Count (r = 0.852), a single-step analogue-type method. Analytical inaccuracy of the automated methods at low FT4 concentrations was revealed by the differential plot: the IMx assay overestimated concentrations < 10 pmol l-1 and the ACS-180 assay concentrations < 6 pmol l-1. The between-assay CVs for the automated methods were not better than for the non-automated assays indicating problems of calibration curve stability for the automated assays.

Background: There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters. In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover., Methods: Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department. The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors. Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors., Results: Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations. Compared with healthy volunteers, they showed increased physical activity during the daytime. Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desynchronized diurnal activity rhythm. Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders. Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers., Conclusions: In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence.

Twelve healthy subjects received single oral doses of 0.4 mg suriclone (SU), 7.5 mg zopiclone (ZO) and placebo, alone and together with 50 mg chlorpromazine (CP), double blind and crossover, in Latin square order, at one-week intervals. Performance tests administered before and 1.5, 3.5 and 6 h after drug intake included digit symbol substitution and simulated driving combined in a "Global test", flicker fusion frequency, body balance and memory and subjective assessments. Changes from baseline were examined statistically. Performance and memory data were analysed from only 11 subjects. Compared to placebo, SU minimally affected "global" performance, although it slowed reactions and tended to impair digit substitution. ZO impaired "global" performance at 1.5 h, affected performance in several separate tests, and produced subjective muzziness. CP did not impair "global" performance, although it did impair digit substitution and render the subjects drowsy, weak and dreamy. The combinations SU + CP and ZO + CP definitely impaired "global" performance more than CP alone. This difference was also found in most objective tests but less so in the subjective tests. CP and its combinations produced similar increases in plasma prolactin. Active drugs and their combinations variably lowered blood pressure and increased heart rate, and one subject collapsed after CP. The treatments irregularly impaired spatial memory and learning acquisition. No pharmacokinetic interactions were seen in the plasma levels of suriclone, zopiclone and chlorpromazine. The impairment of performance after these combinations resembles that previously encountered after 2.5 mg lorazepam, or 15 mg diazepam + 100 mg remoxipride.

Background: Based on clinical observations in a series of studies on Finnish alcoholic, violent offenders, we asserted that the impulsive offenders represented an extreme group of type 2 alcoholics. We also observed that these subjects were vulnerable to hypoglycemia after the administration of oral glucose load. Furthermore, we believe that while being hypoglycemic, the impulsive offenders are particularly irritable and aggressive. In the present study, we addressed these issues by studying psychological trait and state variables in a new group of violent offenders and fire setters, and age- and sex-matched healthy volunteers., Methods: Fifty-eight alcoholic, violent offenders and impulsive fire setters and 21 healthy volunteers were administered the Karolinska scales of personality and the Rosenzweig picture frustration test after an oral aspartame and glucose challenge., Results: The psychological test results and the criminal histories of the offenders, together with biochemical measurements, suggest that a low 5-hydroxyindoleacetic acid concentration in cerebrospinal fluid in the alcoholic offenders is associated with irritability and impaired impulse control, and a high free testosterone concentration in cerebrospinal fluid is associated with increased aggressiveness, monotony avoidance, sensation seeking, suspiciousness, and reduced socialization., Conclusion: Finnish alcoholic, impulsive offenders have personality profiles characteristic of Scandinavian early-onset male alcoholics with antisocial traits, who have been also referred to as type 2 alcoholics.

We evaluated the ability of new thyrotropin (TSH) assays to separate hyperthyroid (n = 50) patients from clinically euthyroid subjects with low TSH values (nodular goiter, n = 20, and nonthyroidal illness, n = 22). Only patients whose serum TSH was < 0.1 mIU/L by immunoradiometric assay were included. We used a new immunofluorometric method based on time-resolved fluorescence (TR-IFMA) and a new immunochemiluminometric assay (ICMA) to measure TSH in serum. Although the differences between the hyperthyroid patients and the euthyroid patients differed from each other by both methods (P = 0.0012 for TR-IFMA and P < 0.0001 for ICMA), there was no cutoff point that could definitely separate the groups. Thus, it is not possible to draw any definite conclusions on whether a patient is hyperthyroid or not, solely on the basis of TSH concentration measured with these new TSH assays.

Radiolabeled monoclonal anti-CEA antibodies were used for radioimmunolocalization (RIL) of non-small cell lung cancer; in 30 patients with 111In labeled anti CEA F(ab')2 fragment (BW 431/31) and in 16 with 99mTc-labeled intact MoAb (BW 431/26). RIL results were compared with those of other imaging modalities. Paraffin sections from some patients were also studied immunohistochemically using anti-CEA antibody. Patients with 111In labeled MoAB were imaged twice 1-4 days after injection and for image enhancement pulmonary and liver/spleen subtraction were performed. Twenty-seven of 28 primary tumors were positive and metastases were detected in all patients. The total number of lesions was 78 of which 61 (78%) could be detected by RIL. For verification CT was applied to the study of 46 lesions detected by RIL. We found 6 unknown lesions subsequently verified histologically. Using subtraction techniques we detected 9 lesions in 4 patients, later verified as pulmonary metastases, not detected in unprocessed images. Pleural, mediastinal and pericardial lesions were also better delineated in subtracted images than in unprocessed images. Imaging of non-small cell lung cancer with 99mTc-labeled MoAB was performed twice 4-24 h after injection. RIL results were compared with other imaging methods; CT US, conventional radiography, and immunohistochemistry. Twelve out of 16 patients with suspected or known lung cancer had positive immunoscintigrams; 19 of 25 lesions could be detected by RIL. There were 5 false positive and 2 true negative findings. Immunoperoxidase (IP) stainings of paraffin sections of the tumours from 7 patients were performed using two different anti-CEA antibodies; BW 431/26 and ZCEA1. None of the seven tumors examined by immunohistochemistry were negative when stained by BW 431/26, which was the antibody used for immunoscintigraphy.

The effects of inhaled glucocorticoids on serum markers of bone formation were evaluated in asthmatic children. Serum total alkaline phosphatase (AP), bone alkaline phosphatase (BAP), osteocalcin, and the novel marker of bone formation, carboxypropeptide of type I procollagen (PICP), were measured. In the cross-sectional part, long-term glucocorticoid users were compared with sodium cromoglycate (SCG) users. In the boys (n = 16), but not in the girls (n = 11), PICP was significantly lower in the glucocorticoid users than in the SCG users. PICP correlated positively with BAP (n = 54; groups combined, r = 0.29, p < 0.05). In the longitudinal part, the effects of inhaled budesonide or SCG, both used for the first time, were evaluated before and after 1 and 5 months of treatment. The budesonide dose was 800 micrograms/m2/day for 1 month and thereafter half of that. The SCG dose was 30 mg/day throughout the study. Only during budesonide use did osteocalcin and PICP decrease, the median osteocalcin by 8% at 1 month (p < 0.05) and by 6% at 5 months (n = 15), and PICP by 5% at 1 month (p < 0.05) and by 28% at 5 months (n = 7, p < 0.01). AP and BAP did not change significantly. Decreased PICP suggests decreased bone formation rate. PICP might be clinically useful as a marker of early adverse effects of glucocorticoids on bone.

Complex contact activation systems may play a major role in the side effects of i.v. contrast media (CM). This is why quantitative measurements of several factors (plasma prekallikrein, hematocrit (hct), alpha-2-macroglobulin, alpha-1-antitrypsin, and C1-esterase inhibitor) were determined prior to and following the injection of CM during body CT examination in 5 patient groups, each (n = 10) receiving one of 5 different CM, including ioxaglate, meglumine iodamide, metrizamide, iohexol, and meglumine diatrizoate. The initial plasma prekallikrein level was available from 45 patients and was statistically lower in reactors (mean 90.6 mumol TAMe/ml/h; n = 13) than in nonreactors (mean 107 mumol TAMe/ml/h; n = 32) (p = 0.006), but there was no statistically significant difference in the decrease of plasma prekallikrein before and at 5 min after the injection for those 2 groups. The initial plasma C1-esterase inhibitor level was lower in reactors, while the plasma alpha-2-macroglobulin level was higher in that group than in nonreactors. The results indicate that the measurement of plasma prekallikrein combined with plasma C1-esterase inhibitor and alpha-2-macroglobulin measurement could be useful when predicting which patients are prone to CM reactions.