Outcome of lower L-thyroxine dose for treatment of congenital hypothyroidism

The appropriateness of the recommended L-thyroxine dose (10-15 micrograms/kg/day) for the treatment of congenital hypothyroidism has been questioned because of the risk of iatrogenic hyperthyroidism. We report the outcome of 23 newborns with congenital primary hypothyroidism treated with 25 micrograms L-thyroxine per day (5.3-9.2 micrograms/kg/day) and followed for an average of 59 months. Serum thyroxine (T4) values increased (X = 11.4 +/- 2.7 micrograms/dL) within 4 weeks posttherapy; eight infants had T4 levels > or = 13 micrograms/dL on only half the currently recommended dose. Thyroid-stimulating hormone (TSH) values remained elevated in 18 of 21 patients for 2-21 months despite a high-normal T4. Psychometric tests were performed in 19 of the 23 patients. The mean Full Scale IQ for the congenital hypothyroid group (n = 16) was 101.4 +/- 13.2 with comparable Verbal and Performance IQ scores. Patients with a bone age (BA) of < or = 32 weeks or T4 < 2 micrograms/dL at initial evaluation had significantly Lower Verbal IQ scores. A standardized parent-report assessment of behavioral and emotional functioning revealed subgroup scale scores that were indistinguishable from nonclinical norms. We conclude that (1) average range IQ scores and positive behavioral adaptation are observed in congenitally hypothyroid children treated with L-thyroxine doses lower than currently recommended; (2) the L-thyroxine dose should be individualized to prevent iatrogenic hyperthyroidism; (3) TSH normalization should not be a primary objective of treatment, and (4) a prospective study comparing the advantages and risks of different doses of L-thyroxine is needed.     

Estimation of cholesterol sulphate in blood plasma and in erythrocyte membranes from individuals with Down's syndrome or diabetes mellitus type I

OBJECTIVES: Plasma and erythrocyte membrane cholesterol sulphate (CS) were measured in patients suffering from diabetes and Down's syndrome. DESIGN AND METHODS: The procedure for separation and determination of CS comprised HPTLC (high-performance thin-layer chromatography) and densitometry. RESULTS: The mean plasma and RBC membranes CS concentrations (+/- SD) of the control group (n = 16) was 188 +/- 47 micrograms/dL and 343 +/- 57 micrograms/10(12) RBC, respectively. In 15 patients with diabetes and 12 Down's syndrome patients substantially higher CS levels were found (diabetes: plasma-348 +/- 60 micrograms/dL; RBC membranes-646 +/- 113 micrograms/10(12) RBC; Down's syndrome: plasma-245 +/- 54 micrograms/dL; RBC membranes 427 +/- 74 micrograms/10(12) RBC). Analysis of variance and multiple comparison (Newman-Keuls test) show statistically significant differences between all samples both for erythrocytes, F(2.41) = 52.24, p < 0.05, and plasma, F(2.41) = 34.92, p < 0.05. CONCLUSIONS: It is postulated that differences in CS levels may contribute to changes of erythrocyte properties in these pathological states.     

Atrial natriuretic factor and digoxin-like immunoreactive factor in diabetic patients: their interrelation and the influence of the autonomic nervous system

In diabetic patients, several factors contribute to volume expansion and have to be counteracted by humoral and neuronal feedback control systems. We investigated N-terminal proatrial natriuretic factor (ANF1-98) and digoxin-like immunoreactive factor (DLIF), which are two counteracting hormones, and their interrelationship, with additional consideration given to autonomic nervous function in diabetic patients. ANF1-98 and DLIF were measured in 64 diabetic patients. Autonomic nervous function was assessed using nine autonomic nervous function tests. The patients were subdivided into two groups, one with four or more (group 1) and one with less than four abnormal results in autonomic function tests (group 2). Compared with group 2, group 1 demonstrated detectable DLIF levels less often (17.2 vs. 45.7, P = 0.0195) and increased levels of ANF1-98 (mean +/- SEM: 850.0 +/- 108.8 vs. 554.8 +/- 45.9 pmol/L, P = 0.0099). However, the groups did not differ in blood pressure, daily sodium, and daily potassium excretion. The number of abnormal autonomic function tests correlated significantly with ANF1-98 (P = 0.0002). In patients with detectable DLIF, DLIF correlated with ANF1-98 (P = 0.0080). These results demonstrate close interactions between the autonomic nervous system and the two natriuretic hormones. In patients with autonomic nervous dysfunction, higher levels of ANF may possibly compensate for the lack of the natriuretic DLIF to counteract hypertension and chronic volume expansion.     

Low prevalence of microalbuminuria in young Italian insulin-dependent diabetic patients with short duration of disease: a population-based study. Piedmont Study Group for Diabetes Epidemiology

Objectives of this study were to determine the prevalence of microalbuminuria and the level of glycaemic control obtained in a young Italian population-based cohort of subjects with short duration of insulin-dependent diabetes mellitus (IDDM). Out of 298 subjects with onset of IDDM in the period 1984-88, 211 were examined (71%) in 1991-92 (duration of disease 3-9 years). Microalbuminuria was defined as albumin excretion rate (AER) 20-200 micrograms min-1 in an overnight urine collection or alb/creat > 2.5 mg mmol-1 in men and > 4.5 mg mmol-1 in women in one first morning urine sample. Twelve subjects had AER 20-200 micrograms min-1 and 4 had elevated alb/creat ratio. Prevalence of microalbuminuria was 7% (95% Cl 4.0-11.1) in subjects with duration of IDDM 3-9 years and 4% (0.3-7.7) in subjects with duration 3-5 years. Only 1 microalbuminuric subject was found out of 52 aged < or = 14 years. Duration of IDDM was significantly higher (6.9 +/- 1.9 years vs 5.7 +/- 1.6, p = 0.007) and HDL-cholesterol lower (1.22 +/- 0.21 mM vs 1.42 +/- 0.34, p = 0.025) in micro- than in normoalbuminuric subjects, even after adjustment for age, systolic and diastolic blood pressure, BMI, and HbA1c. In almost 50% of the cohort, HbA1c levels were over 9%, whereas only in 10.9% HbA1c levels were lower than 6.6% (mean +3 SD). In conclusion, this Italian population-based study showed low prevalence of microalbuminuria in young subjects with short duration of IDDM, even if the glycaemic control obtained was far from ideal.     

Risk factors for contrast nephropathy in diabetic patients undergoing cardioangiography

Risk factors for contrast nephropathy were prospectively studied in 17 patients with non-insulin dependent diabetes mellitus undergoing cardioangiography. Contrast nephropathy, defined as a serum creatinine increase of greater than 25% at 3 day after angiography, occurred in 29.4% of diabetic patients. Patients who developed contrast nephropathy had significantly higher serum creatinine (Cr), fractional excretion of sodium (FENa), urinary albumin excretion rate (AER), and lower 24hr Ccr than patients who did not (Cr: 1.5 +/- 0.3 mg/dl vs. 0.8 +/- 0.1 mg/dl, FENa: 1.9 +/- 0.5% vs. 0.6 +/- 0.1%, AER: 522 +/- 335 micrograms/min vs. 27 +/- 13 micrograms/min, 24hr Ccr: 39.1 +/- 11.6 ml/min vs. 86.2 +/- 9.3 ml/min, P < 0.05). Contrast nephropathy developed in all of two patients with overt proteinuria (AER more than 200 micrograms/min), but none of eight patients with normoalbuminuria (AER below 15 micrograms/min). Three of seven patients with microalbuminuria developed contrast nephropathy, and two of them had advanced nephropathy. FENa obtained next day was significantly elevated over baseline in patients with contrast nephropathy (1.9 +/- 0.5% vs. 9.7 +/- 4.5%, P < 0.05), but unchanged in patients without contrast nephropathy. The rise in C beta 2-microglobulin/Ccr and enzymuria was noted in both group. Percentage decrease of Ccr on the next day was positively correlated with FENa before angiography (r = 0.645, p < 0.01). Of 24hr Ccr, AER, and FENa before angiography, FENa was revealed as a statistically significant discriminant factor for contrast nephropathy by stepwise discriminant analysis (p = 0.0008). These results suggest that contrast nephropathy develops predominantly in the stage not of incipient but of overt diabetic nephropathy indicated by a decline of glomerular filtration, overt proteinuria, and tubular dysfunction. Of them, tubular dysfunction may be the most important risk factor for contrast nephropathy.     

Cholecystokinin and pancreatic polypeptide release in diabetic patients with and without autonomic neuropathy

The present study was undertaken to investigate postprandial responses of cholecystokinin (CCK) and pancreatic polypeptide (PP) and their interrelationship in patients with diabetes mellitus (DM) with and without autonomic neuropathy (AN). Twenty-two patients with DM (seven with AN and 15 without AN) and 14 age-matched healthy controls were studied. AN was diagnosed according to several tests of cardiovascular autonomic function. CCK and PP plasma levels were measured by specific radioimmunoassays before and at several time points after the oral administration of a test meal. Basal CCK plasma levels in DM patients were normal, whereas basal PP plasma levels were increased (139 +/- 18 vs 72 +/- 7 pg/ml; P < 0.01). Integrated postprandial CCK response was increased in DM patients (208 +/- 27 vs 110 +/- 14 pmol/liter/2 hr; P < 0.05), mainly due to the patients with AN. Postprandial PP response was increased in DM patients without AN (37,273 +/- 5241 vs 13,418 +/- 3299 pg/ml/2 hr; P < 0.001) but not in those with AN (8887 +/- 3461 pg/ml/2 hr). Moreover, PP response was closely (P < 0.002) correlated with the degree of AN. A direct and linear correlation between postprandial CCK and PP responses was found in healthy controls (r = 0.78; P < 0.005) but not in DM patients. We conclude that the CCK response to a meal is increased in diabetic patients with AN, whereas the PP response is increased only with an intact autonomic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles

Plasma levels of erythropoietin (mU/ml) were measured in patients with congestive heart failure (CHF) (n = 108) and in a control group of normal subjects (n = 45). In normal subjects, plasma levels of erythropoietin were 1.9 +/- 0.2. In patients with CHF, plasma levels of erythropoietin increased progressively according to New York Heart Association (NYHA) class (I: 1.4 +/- 0.2, n = 28; II: 5.4 +/- 0.8, n = 27; III: 9.6 +/- 2, n = 32; IV: 34 +/- 8, n = 21; F = 57.7, p < 0.001) and were significantly higher in NYHA classes II, III, and IV than in normal subjects. Plasma erythropoietin significantly decreased (from 43 +/- 14 to 12 +/- 3 mU/ml, p < 0.01) in patients with severe CHF (n = 9) when enalapril (20 mg/day administered orally) was added to long-term treatment for 3 weeks. Finally, in a subgroup of patients with NYHA class IV CHF (n = 9) and high plasma erythropoietin levels (37 +/- 9 mU/ml), packed red blood cell volume, assessed by the iodine-125-albumin dilution method, was higher than that in normal subjects (n = 11) (2,616 +/- 235 vs 2,028 +/- 119 ml, p < 0.05). The present study demonstrates that plasma erythropoietin levels are elevated in a large cohort of patients with CHF of varying etiology, and that this increase is related to the progression of the disease. The increase in circulating erythropoietin is associated with augmented packed red blood cell volume in patients with severe CHF. These results suggest a participation of erythropoietin in the complex neurohormonal response that occurs in CHF.     

Influence of molecular weight, protein core and charge of native heparin fractions on pulmonary artery smooth muscle cell proliferation

The need for cardiopulmonary resuscitation and repeated correction of persistent acidosis identifies extracorporeal membrane oxygenation patients more likely to develop an intracranial hemorrhage. The objective of this study was to identify risk factors for an intracranial hemorrhage (ICH) in infants on extracorporeal membrane oxygenation (ECMO). This study was a retrospective-matched, case-controlled study of infants with ICH on ECMO compared with infants without ICH on ECMO. Data collected included patient demographics, ventilator parameters, blood gases, coagulation parameters, the need for cardiopulmonary resuscitation (CPR), neurologic findings, and outcome. The Neonatal Intensive Care Nursery at Kosair Children's Hospital in Louisville, Ky., was the setting. Twenty-three infants who developed an ICH (excluding subarachnoid hemorrhage) on ECMO were matched with a control group of 23 infants without an ICH on ECMO. The presence of acidosis (pH < 7.19 or HCO3 < 17; p < 0.01 and p < 0.05, respectively) and the need for CPR (heart rate < or = 80 or mean blood pressure < or = 30 mm Hg, p < 0.003) shortly before or during cannulation correlated with the development of an ICH in infants on ECMO. The infants with an ICH required more frequent platelet transfusions (p < 0.005), had difficulty maintaining activated clotting times (ACTs) within a normal range (p < 0.03), and had abnormal neurologic examinations shortly before or after the ICH was detected with head ultrasound. The ultrasound was obtained as soon as possible after a change in the neurologic status. The need for CPR and repeated correction of persistent acidosis before or during cannulation identifies ECMO patients more likely to develop an ICH. We found that elevated ACTs and low platelet counts requiring transfusion showed a statistical association with the development of an ICH. Daily head ultrasounds and frequent neurologic checks are thus valuable tools in assessing the ECMO patient who demonstrates difficulty in maintaining coagulation values in the normal range or who requires frequent platelet transfusions.     

Limb salvage and survival rates among elderly patients with advanced limb ischemia

Beta-Thalassemia hemoglobin E (beta-thal/Hb E) is the commonest form of hemoglobinopathy in Thailand. Shortened red cell life span, rapid iron turnover and tissue deposition of excess iron are major factors responsible for functional and physiological abnormalities found in various forms of thalassemia. Increased deposition of iron had been found in renal parenchyma of thalassemic patients, but no systematic study of the effect of the deposits on renal functions has been available. The purpose of this study is to describe the functional abnormalities of the kidney in patients with beta-thal/Hb E and provide evidence that increased oxidative stress might be one of the factors responsible for the damage. Urine and serum samples from 95 patients with beta-thal/Hb E were studied comparing with 27 age-matched healthy controls. No difference in the creatinine clearance was observed. beta-thal/Hb E patients excreted significantly more urinary protein (0.8+/-0.5 vs. 0.3+/-0.1 g/day, p < 0.001). Aminoaciduria was found in 16 % of the patients. Analysis of urinary protein by SDS-PAGE electrophoresis and silver staining revealed abnormal pattern of protein with increased small molecular weight (<45 kD) bands. Morning urine analysis showed significant lower urine osmolality (578.3+/-164.6 vs. 762.4+/-169.9 mosm/kg, p < 0.001) in patients. Patients excreted more NAG (N-acetyl beta-D-glucosaminidase, 26.3+/-41.3 vs. 8.4+/-3.9 U/g Cr, p < 0.0001) and beta2-microglobulin, 124.3+/-167 vs. 71+/-65.5 microg/g Cr, p = 0.001. Plasma and urine MDA (malonyldialdehyde) levels were both raised (p < 0.0001). Nine patients were selected for renal acidification study. All were found to be normal, but showed poor response to DDAVP challenge (urine osmolality 533+/-71). This is the first report of renal tubular defects found associated with beta-thal/Hb E disease. The mechanism leading to the damage is not known but it might be related to increased oxidative stress secondary to tissue deposition of iron, as indicated by the raised levels of serum and urine MDA. It is not known whether these functional defects would have any long-term effects on the patients. Further studies are warranted and means of prevention of these defects should urgently be sought.     

Effect of administration and subsequent cessation of buserelin on cancellous bone of female rats

OBJECTIVE: Low-dose dopamine has been used in critically ill patients to minimize renal dysfunction without sufficient data to support its use. The aim of this study was to determine whether low-dose dopamine improves renal function, and whether dobutamine, a nondopaminergic inotrope, improves renal function. DESIGN: Prospective, randomized, double-blind trial. PATIENTS: Twenty-three patients at risk for renal dysfunction were entered into the study. Five patients were later withdrawn. Study data for the remaining 18 patients were: mean age 55 yrs; mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 18; mean weight 71 kg). The following conditions were present: mechanical ventilation (n = 17 [inverse-ratio ventilation, n = 6]); inotrope administration (n = 11); sepsis (n = 13); and adult respiratory distress syndrome or multiple organ failure syndrome (n = 9). INTERVENTIONS: The study patients were administered dopamine (200 micrograms/min), dobutamine (175 micrograms/min), and placebo (5% dextrose) over 5 hrs each in a randomized order. Ventilator settings, fluid management, and preexisting inotropic support were not altered during the study. MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamic values and indices of renal function (4-hr urine volume, fractional excretion of sodium, and creatinine clearance) were measured during the last 4 hrs of each infusion. Dopamine produced a diuresis (145 +/- 148 mL/hr) compared with placebo (90 +/- 44 mL/hr; p < .01) without a change in creatinine clearance. Conversely, dobutamine caused a significant increase in creatinine clearance (97 +/- 54 mL/min) compared with placebo (79 +/- 38 mL/min; p < .01), without an increase in urine output. CONCLUSIONS: In stable critically ill patients, dopamine acted primarily as a diuretic and did not improve creatinine clearance. Dobutamine improved creatinine clearance without a significant change in urine output.     

Bismuth concentration in blood and urine of children treated with ventrisol (polfa) preliminary study

The bismuth concentration was measured in the blood and urine of 21 children from 8 to 17 years old (13.12 +/- 2.67) treated with Ventrisol (Polfa)-tripotassium dicitrato bismuthate (TDB). One tablet of TDB-equivalent to 120 mg Bi2O3. One tablet was given orally to the patients four times a day. Blood and urine was taken for measurement of bismuth concentration in the morning, on fasting, before the administration of Ventrisol on the 6-8 days, the 27-28 days of the therapy and in the 4-5, 8-9 weeks after TDB therapy. The reason for TDB treatment was chronic gastritis and/or duodenal ulcers, which were diagnosed by endoscopic examination. No bismuth in the blood and a very low concentration in the urine were determined in 19 children before TDB treatment. After 6-8 days of TDB treatment the bismuth concentration in the blood was 40.85 +/- 31.05 micrograms/L and 75.11 +/- 82.07 micrograms/L in the urine. In the 27-28 days of the treatment the bismuth concentration in the blood was 37.67 +/- 25.06 micrograms/L, and 163.56 +/- 181.86 micrograms/L in the urine. In the 4-5 weeks after the TDB treatment the bismuth concentration in the blood was 7.77 +/- 10.56 micrograms/L, and 15.72 +/- 9.87 micrograms/L in the urine. The bismuth concentration level in the urine rose together with the rise of the bismuth concentration level in the blood, the correlation factor was r = 0.68. No symptoms of side effects caused by the TDB treatment were observed. Before the treatment a high bismuth concentration was found in the blood of two patients. These cases are discussed later.     

Transforming growth factor beta (TGF beta) activity in urine of patients with glomerulonephritis

Several lines of experimental evidence have shown that transforming growth factor beta (TGF beta) may play major role in glomerular diseases, mediating the inflammatory response through glomerulosclerosis. In the present study we evaluated TGF beta activity in occasional urine samples from 7 normal individuals and from 15 patients (10 with focal glomerular sclerosis and 5 with membranous glomerulonephritis) using a CCL-64 mink lung cell growth inhibition assay. Urinary TGF beta activity (reported in relation to urine creatinine concentration, Ucr, mean +/- SD) was higher in patients with focal glomerular sclerosis (mean = 17.32 +/- 15.75/10 micrograms Ucr) and patients with membranous glomerulonephritis (mean = 17.78 +/- 11.53/10 micrograms Ucr) than in normal individuals (mean = 0.8 +/- 0.44/10 micrograms Ucr). We also observed that TGF beta activity in urine from patients with focal glomerular sclerosis correlated with their plasma creatinine levels (r = 0.85), suggesting that TGF beta activity may be correlated with other indices of disease progression. Our data suggest that measurement of urinary TGF beta activity could be a useful noninvasive procedure for the evaluation of renal TGF beta production, which may be useful to assess prognosis and to evaluate therapeutic efficacy in patients with renal disease.     

Power spectral analysis of heart period variability of preceding sinus rhythm before initiation of paroxysmal atrial fibrillation

Time domain analysis of heart period variability in patients without structural heart disease demonstrated increased parasympathetic modulation before paroxysmal atrial fibrillation (AF) occurring predominantly at night. However, diurnal differences in autonomic activity preceding AF episodes in a diverse patient population have not been assessed. Accordingly, we performed spectral analysis of heart period variability on Holter recordings during sinus rhythm preceding AF in 29 patients, 17 with night and 12 with day episodes. Samples taken 5, 10, and 20 minutes before AF onset were compared. Normalized high-frequency (HF) spectral power change was greater when comparing the interval 10 to 5 minutes with 20 to 10 minutes preceding AF in 26 of 29 patients (0.09 +/- 0.07 vs 0.03 +/- 0.02; p < 0.0001). HF spectral power increased before 3 of 12 AF episodes during the day compared with 15 of 17 AF episodes during the night (p = 0.001). Nocturnal AF episodes were preceded by increased HF spectral power in the 5- versus the 20-minute sample expressed as natural logarithm-transformed values (5.6 +/- 4.8 vs 4.2 +/- 4.0; p < 0.005) and normalized values (0.19 +/- 0.09 vs 0.10 +/- 0.07; p < 0.02), a decrease in low-frequency/HF ratio (1.05 +/- 0.61 vs 2.21 +/- 1.75; p < 0.05) and heart rate (60 +/- 13 vs 71 +/- 13 beats/min; p = 0.06). Structural heart disease was more common with daytime than nocturnal AF episodes (58% vs 18%, p < 0.05). In conclusion, HF spectral power change was increased preceding most AF episodes. However, diurnal differences were demonstrated. Contrary to daytime AF, increased parasympathetic activity preceded predominantly nocturnal AF, mostly in younger patients with structurally normal hearts.     

Impaired liver function tests in patients treated with antithymocyte globulin: implication for liver transplantation

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day -1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 +/- 37.7 U/l pre-treatment to 1394.4 +/- 488.7 U/l 3 days post-treatment (n = 16; p < 0.029), and then declined to 561.4 +/- 61.3 U/l 10 days post-treatment (n = 16; p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 +/- 11.3 U to 184.6 +/- 74.6 U (n = 16; p < 0.036), and then declined to 121.9 +/- 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 + 5.7 U to 152.0 +/- 67.0 U (n = 16; p < 0.44) and then declined to 46.0 +/- 14 (n = 16; p < 0.049). The mean tau-glutamyltransferase (GTP) levels increased from 93.0 +/- 34 to 188.0 +/- 36 (n = 16; p < 0.02), and were 168.0 +/- 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 +/- 1.9 microM l(-1) to 22.7 +/- 2.8 (n = 16); NS), at day +3 and to 31.9 +/- 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.     

Free and total insulin-like growth factors and insulin-like growth factor binding proteins during 14 days of growth hormone administration in healthy adults

The objective was to investigate the effect of growth hormone (GH) administration on circulating levels of free insulin-like growth factors (IGFs) in healthy adults. Eight healthy male subjects were given placebo and two doses of GH (3 and 6 IU/m2 per day) for 14 days in a double-blind crossover study. Fasting blood samples were obtained every second day. Free IGF-I and IGF-II were determined by ultrafiltration of serum. Total IGF-I and IGF-II were measured after acid-ethanol extraction. In addition, GH, insulin, IGF binding protein 1 (IGFBP-1) and IGFBP-3 were measured. Serum-free and total IGF-I increased in a dose-dependent manner during the 14 days of GH administration. After 14 days, serum-free IGF-I values were 610 +/- 100 ng/l (mean +/- SEM) (placebo), 2760 +/- 190 ng/l (3 IU/ m2) and 3720 +/- 240 ng/l (6 IU/m2) (p = 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.004 for 3 IU/m2 vs 6 IU/m2). Total IGF-I values were 190 +/- 10 micrograms/l (placebo), 525 +/- 10 (3 IU/m2), and 655 +/- 40 micrograms/l (6 IU/m2) (p < 0.0001 for 3 and 6 IU/m2 vs placebo; p = 0.04 for 3 IU/m2). There were no differences in the levels of free or total IGF-II during the three study periods. Insulin-like growth factor binding protein 1 was decreased during GH administration (p = 0.04 for placebo vs 3 IU/m2; p = 0.006 for placebo vs 6 IU/m2). In conclusion, fasting serum free IGF-I increased dose dependently during GH administration and free IGF-I increased relatively more than total IGF-I. This may partly be due to the decrease in IGFBP-1.     

Vasoactive intestinal peptide-induced prolactin release in hypothyroid patients

VIP is an established prolactin-releasing factor. VIP gene expression at the anterior pituitary level and the central nervous system is regulated by thyroid hormones. On the other hand, primary hypothyroidism leads in many cases to amenorrhea, galactorrhea and hyperprolactinemia. In this study we assessed prolactin responses to VIP (75 micrograms iv infusion over 12 min) in a group of six hypothyroid women (mean age +/- SE, 38.8 +/- 3.3 yr; serum TSH levels, mU/L, 116.3 +/- 23.9), before treatment and after normalization of thyroid hormone levels during thyroxine (T4) replacement therapy (100-150 micrograms/day over 12-16 weeks). Furthermore, we assessed if VIP infusion had any effects on serum GH levels in these patients. In hypothyroid women, VIP infusion increased serum prolactin concentrations with peak levels being attained at 15 min (28.8 +/- 3.4 micrograms/L). The Area Under the Curve (AUC) was 1921 +/- 103 micrograms/L/2h. PRL responses to VIP were unchanged after T4 therapy, both in terms of peak levels (28.7 +/- 2.2 micrograms/L, NS) and of AUC (2079 +/- 261 micrograms/L/2h, NS). Serum GH levels were unaffected by VIP administration. In conclusion our study shows that, in hypothyroid patients, restoration of normal thyroid hormone levels by thyroxine replacement therapy does not affect lactotroph responsiveness to VIP. Therefore, our data do not support the hypothesis that VIP might contribute to the hypothyroid-induced hyperprolactinemia seen in man.     

Comparison of serial S-100 and NSE serum measurements after severe head injury

We investigated the time course of neuron specific enolase (NSE) and S-100 protein after severe head injury in correlation to outcome. We included 30 patients (GCS < 9), who had been admitted within 5 hours after injury, in a prospective study. Blood samples were taken on admission, 6, 12, and 24 hours and every 24 hours up to the fifth day after injury. The outcome was estimated on discharge using the Glasgow Outcome Scale. 70% reached a good outcome. All concentrations of NSE and 83% of the S-100 samples were elevated concerning the first probe (30.2 micrograms/l NSE mean and 2.6 micrograms/l S-100 mean). Patients with bad outcome had an NSE concentration of 38 micrograms/l (mean) compared with 26.9 micrograms/l (mean) in patients with good outcome. Patients with bad outcome had an S-100 concentration of 4.9 micrograms/l (mean) compared with 1.7 micrograms/l (mean) in patients with good outcome (p < 0.05). The mean values of NSE and S-100 decreased during the first 5 days. Four patients with increasing intracranial pressure showed a quick increasing concentration of NSE, in two patients the S-100 level showed a slower rise. The NSE serum levels did not correlate with intracranial pressure values. Our results show that the first serum concentration of S-100 seems to be predictive for outcome after severe head injury.     

Markers of bone turnover in hyperthyroidism and the effects of treatment

Serum osteocalcin (OC) and bone-specific alkaline phosphatase (B-ALP), reflecting bone formation, and urinary pyridinoline cross-link (Pyr) excretion, reflecting bone resorption, have been measured in 27 patients with hyperthyroidism and 30 age-matched controls using direct and novel immunoassays. Hyperthyroid patients had higher (P < 0.001) levels of all 3 markers compared with control values: Pyr, 246 +/- 181 nmol/mmol creatinine vs. 40 +/- 12 (+515%); OC, 55 +/- 23 vs. 23 +/- 7.4 micrograms/L (+139%); and B-ALP, 22 +/- 17 vs. 10.0 +/- 5.0 micrograms/L (+120%). OC and Pyr levels were elevated above the normal range in most patients and were significantly correlated with serum free T3 concentrations (r = 0.53; P < 0.01 and r = 0.76; P < 0.001; for OC and Pyr, respectively). B-ALP levels were elevated in 11 of the 27 patients and did not correlate with serum thyroid hormone concentrations. After therapy for hyperthyroidism, Pyr and OC levels returned to normal within 1 month, whereas B-ALP transiently increased after 1 month before falling to baseline levels. The relapse of hyperthyroidism observed in 1 patient was associated with a steep increase in bone markers. These results indicate that Pyr, measured using a new and convenient immunoassay, is a highly sensitive marker for altered bone metabolism in hyperthyroidism. The increases in OC and B-ALP were less impressive, suggesting an imbalance between resorption and formation with subsequent rapid bone loss in untreated hyperthyroidism. OC and B-ALP also appear to reflect different aspects of osteoblast metabolism during the treatment of hyperthyroid patients.     

Seasonal effects on human physiological adaptation factors, thermotolerance and plasma fibronectin

Plasma fibronectin (PF) influences shock survival and basal levels increase with active conditioning that improves human physiological adaptation factors (PAF) and thermotolerance (TT). To evaluate further PF's relationship with PAF and TT, the effects of passive conditioning with seasonal change (spring vs. summer) in New England on PAF, TT, basal PF level and PF level during hot-humid exercise (HHE; bicycling; 40 +/- 4% VO2max; 35 degrees C; 70% rh; 45 min) were examined in male subjects (28.2 +/- 1.6 years; N = 7; values are means +/- SE). The spring and summer studies were separated by 2 months. In addition, 2 months prior to the spring study, a winter basal PF pre-screening was conducted. Winter (287 +/- 36 micrograms/ml), spring (272 +/- 21 micrograms/ml), and summer (278 +/- 19 micrograms/ml) basal PF levels were similar. The PF response during HHE was unremarkable with seasonal change. PAF were improved, since blood volume (6266 +/- 276 vs. 5895 +/- 251 ml), plasma volume (3896 +/- 198 vs. 3601 +/- 165 ml) and HHE sweat rate (18.7 +/- 5.5 vs. 12.9 +/- 6.4 ml/min) were elevated (p < 0.05) in the summer compared to the spring. However, this was not accompanied by improved TT, since spring and summer rectal temperatures during HHE were similar, while summer heart rate was elevated (p < 0.05) compared to the spring. In contrast to active conditioning, passively-induced improvements in PAF were not associated with elevations in TT or PF level. Unlike PAF, PF elevations might only occur when the conditioning resulted in increased TT, which suggests a potential for PF as a TT marker.     

Left atrial "stunning" following radiofrequency catheter ablation of chronic atrial flutter

Patients with autonomic neuropathy are more susceptible to insulin-induced hypotension than normal subjects, but the mechanisms are unclear. We quantitated the hemodynamic and metabolic effects of two doses of i.v. insulin (1 and 5 mU/kg.min, 120 min each) and several aspects of autonomic function in 28 patients with insulin-dependent diabetes mellitus (IDDM) and in 7 matched normal subjects under standardized normoglycemic conditions. The autonomic function tests included those predominantly assessing the integrity of vagal heart rate control (the expiration inspiration ratio during deep breathing and high frequency power of heart rate variability) and tests measuring sympathetic nervous function (reflex vasoconstriction to cold and blood pressure responses to standing and handgrip). During hyperinsulinemia, heart rate increased less (2 +/- 1 vs. 6 +/- 2 beats/min; P < 0.04) and diastolic blood pressure fell more (-3.1 +/- 1.2 vs. 0.9 +/- 2.1; P = NS) in the patients with IDDM than in the normal subjects. Forearm vascular resistance decreased significantly in the patients with IDDM [by -7.1 +/- 1.4 mm Hg/(mL/dL.min); P < 0.001 for high vs. low dose insulin], but not in the normal subjects (-0.1 +/- 2.5 mm Hg/(mL/dL.min; P = NS). Reflex vasoconstriction to cold was inversely correlated with the decreases in diastolic (r = -0.51; P < 0.005) and systolic (r = -0.59; P < 0.001) blood pressure and forearm vascular resistance (r = -0.53; P < 0.005), but not with the change in heart rate. The expiration inspiration ratio was, however, directly correlated with the insulin-induced change in heart rate (r = 0.63; P < 0.001), but not with diastolic or systolic blood pressure or forearm vascular resistance. Whole body (48 +/- 2 vs. 67 +/- 5 mumol/kg.min; P < 0.005) and forearm (44 +/- 4 vs. 67 +/- 8 mumol/kg.min; P < 0.05) glucose uptake were significantly lower in the IDDM patients than in the normal subjects. The latter could be attributed to a defect in the forearm glucose arterio-venous difference (1.5 +/- 0.1 vs. 2.2 +/- 0.2 mmol/L, respectively; P < 0.01), but not in blood flow. We conclude that both impaired vagal heart rate control and sympathetic nervous dysfunction exaggerate the hemodynamic effects of insulin in patients with IDDM and could contribute to insulin-induced hypotension.