Endogenous digoxin-like factor: serum concentration and interrelations with the electrolyte picture in normal subjects

Endogenous Digitalis-Like Factor (DLF) is a putative hypothalamic Na+,K+-ATPase inhibitor that mediates natriuresis in response to intravascular volume expansion or sodium loading. The precise structure of this substance remains unknown; however, it cross-reacts with antibody to digoxin. Using a radioimmunoassay, we measured DLF concentrations in 26 normal subjects: mean value of this factor was 0.512 ng digoxin-equivalents/ml +/- 0.038 SEM; DLF correlated significantly with serum sodium levels (r = 0.59 - p less than 0.01) and daily urinary sodium excretion (r = 0.48 - p less than 0.05). Our results confirm that endogenous digitalis-like factor has a physiological role as regulator of natriuresis, in response to plasma sodium concentrations.     

Pharmacokinetics of methimazole in normal subjects and hyperthyroid patients

Serum and urinary concentrations of methimazole (MMI) were measured by high-performance liquid chromatography (HPLC) with an electrochemical detector (ECD) in 10 normal subjects and 43 hyperthyroid patients after intravenous and oral administration of the drug. The pharmacokinetic parameters of MMI were estimated in 5 normal subjects and 15 hyperthyroid patients according to a two-compartment model after intravenous injection of a 10 mg dose. The mean half-life of the distribution phase (T1/2 alpha) was 2.7 +/- 1.0 h (mean +/- SD) and 3.1 +/- 1.4 h and that of the slower-phase (T1/2 beta) was 20.7 +/- 9.6 h and 18.5 +/- 12.9 h in normal subjects and hyperthyroid patients, respectively. There were no significant differences between pharmacokinetic parameters of normal subjects and those of hyperthyroid patients. No correlations between free T4 index (FT4I) and pharmacokinetic parameters were observed. Maximum serum MMI concentrations (Cmax) (213 +/- 84 and 299 +/- 92 ng/ml) were attained 1.8 +/- 1.4 h and 2.3 +/- 0.8 h after a single dose of 10 mg in 5 normal subjects and in 15 hyperthyroid patients, respectively. In hyperthyroid patients the time taken to reach the peak concentration (Tmax) after a single dose of 10 mg was similar to that after a single 15 mg and 30 mg dose. The pharmacokinetic parameters, except Cmax and the area under the curve (AUC), were not affected by the administered dose and those, except Cmax, were not affected by the thyroid function. All urine was collected at intervals of 3 h for the first 12 h and then at 24 h and 48 h after intravenous and oral administration of MMI. In all subjects, MMI rapidly appeared in the urine and the rate of excretion was highest in the first 3 h. The cumulative urinary excretion of MMI was 5.5-8.5% of administered doses in normal subjects and hyperthyroid patients. These findings in the present study are compatible with the assumption that the extent of absorption of MMI is high, if not complete, and hyperthyroidism does not affect the kinetics of MMI, and that interindividual variation is observed in the time taken to reach the peak concentration after oral administration.     

5''-Methylthioadenosine in urine from normal subjects and cancer patients

A new type of device can prepare liposomes continuously, in large quantities and with excellent aqueous space capture efficiency. At initial lipid concentration of 300 mumol/ml these liposomes capture approx. 75% of cytosine arabinoside used as an aqueous space marker. Liposome size can be reduced by increasing the number of times the preparations are recycled through the microemulsifier. Liposomes less than 0.1 micron in diameter, as shown by electron microscopy, can be made easily. Liposomes prepared at 300 mumol/ml, composed of phosphatidylglycerol/phosphatidylcholine/cholesterol in a 0.1:0.4:0.5 molar ratio leaked less than 1% of entrapped cytosine arabinoside (Ara-C) at 4 degrees C, and less than 10% Ara-C at 37 degrees C plus serum, over a 48 h period. These liposomes could be useful for a number of applications including diagnostics, therapeutics and model membrane studies.     

Effect of thyroid hormone therapy on plasma insulin-like growth factor I levels in normal subjects, hypothyroid patients and endemic cretins

The effect of thyroid hormone therapy (L-T4 or L-T3) on plasma immunoreactive insulin-like growth factor I (somatomedin C, Sm-C) concentrations was studied in 8 normal controls, 14 primary hypothyroid subjects and in 7 patients with endemic cretinism. In normals basal levels of Sm-C (1.56 +/- 0.77 U/ml) increased to (2.46 +/- 1.0 U/ml; L-T4) and to (2.9 +/- 0.95 U/ml; L-T3). Plasma Sm-C basal levels were significantly lower in primary hypothyroid subjects (0.81 +/- 0.48 U/ml) and increased to 2.54 +/- 1.43 U/ml (L-T4) and to 2.16 +/- 0.83 U/ml (L-T3). A significant and positive correlation (r = 0.56) was found between Sm-C and serum T4 and T3 concentrations. Plasma Sm-C concentrations in endemic cretinism were initially normal in 4 patients, but low in the remaining 3 (mean +/- SD: 1.18 +/- 0.63 U/ml) and did not increase after 12 months (1.34 +/- 0.61 U/ml) or 18 months (1.01 +/- 0.43 U/ml) of L-T4 and L-T3 therapy. Plasma T4 levels and free T4 increased considerably in EC after therapy with a significant decrease in the previously elevated plasma TSH concentrations. The subnormal response of plasma Sm-C during effective thyroid thyroid hormone therapy could be an additional factor involved in growth failure of endemic cretins.     

Effect of dietary versus pharmacological correction of hypertriglyceridemia on red blood cell membrane sodium/lithium countertransport activity

An elevated red blood cell Na/Li countertransport (Na/Li CT) is often associated with high blood pressure and metabolic abnormalities. Recent studies suggested that a reduction in serum TG levels is associated with a decrease in Na/Li CT activity. However, it is still unclear if this phenomenon could be originated from systemic metabolic alterations or from modifications of the membrane dynamic properties. Aim of the present study was to investigate whether dietary or pharmacological TG lowering therapy might have a different effect on Na/Li CT activity and related metabolic parameters. Twenty normotensive hyper-TG patients were recruited from the Lipid outpatient Clinic: they had a baseline Na/Li CT activity significantly higher compared with age- and BMI-matched normolipidemic controls (386 ± 33 vs 274 ± 39 umol/l RBC/h, p < 0.05). The patients were randomly prescribed one of the following two-months treatment: Group 1)-triglyceride lowering diet; Group 2)-lipid lowering drug (Gemfibrozil 600 mg b.i.d.). Na/Li CT and metabolic and anthropometric variables were measured at baseline and after 1 and 2 months of treatment. At the end of intervention, there was in both groups a significant and comparable fall in plasma triglyceride (group 1: −2.61 ± 0.73 mmol/l p < 0.01; group 2: −4.29 ± 1.20 mmol/l p < 0.01). In the diet-treated group there were, in addition small but significant reductions in body weight (−3.7 ± 0.8 kg p < 0.01), fasting glucose (−0.36 ± 0.14 mmol/l p < 0.05) and insulin levels (−2. ± 0.5 mUl/l, p < 0.01), while no such changes were observed in the fibrate treated patients. Na/Li CT activity was significantly and comparably reduced at the end of treatment in both groups (group 1: −97 ± 28 umol/l cell/h, p < 0.01; group 2: −89 ± 30 umol/l cell/h, p < 0.01). In conclusion, these results indicate that the decrease in Na/Li CT associated with both dietary and drug treatment of hypertriglyceridemia is to be traced to a direct effect of plasma TG concentration on this transport system (probably as a result of modification in the membrane lipid environment) rather than to changes in plasma insulin levels or insulin resistance.     

Towards new boron carriers for boron neutron capture therapy: metallacarboranes and their nucleoside conjugates

Thymidine conjugates containing metallacarborane, {8-[5-(N(3)-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)}- (5) and {8-[5-(O(4)-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)}- (6) ions and several simple [3-cobalt bis(1,2-dicarbollide)]- ion (1) derivatives have been studied as potential boron carriers for BNCT. Compound 6 and some nonnucleoside derivatives of 1 were not toxic above 100 microM. The partition coefficient for both metallacarborane bearing thymidine conjugates 5 and 6 was more than 500 times higher than that of unmodified nucleoside. The cellular uptake studies showed accumulation of compounds 6 in V79 Chinese hamster cells but not of compound 5. The low toxicity of conjugate type of 6 together with its high partition coefficient suggest that judicially designed derivatives of metallacarboranes can be considered as potential boron carriers for BNCT.     

Psychophysiology and psychoacoustics of music: Perception of complex sound in normal subjects and psychiatric patients

Perception of complex sound is a process carried out in everyday life situations and contributes in the way one perceives reality. Attempting to explain sound perception and how it affects human beings is complicated. Physics of simple sound can be described as a function of frequency, amplitude and phase. Psychology of sound, also termed psychoacoustics, has its own distinct elements of pitch, intensity and tibre. An interconnection exists between physics and psychology of hearing.Music being a complex sound contributes to communication and conveys information with semantic and emotional elements. These elements indicate the involvement of the central nervous system through processes of integration and interpretation together with peripheral auditory processing.Effects of sound and music in human psychology and physiology are complicated. Psychological influences of listening to different types of music are based on the different characteristics of basic musical sounds. Attempting to explain music perception can be simpler if music is broken down to its basic auditory signals. Perception of auditory signals is analyzed by the science of psychoacoustics. Differences in complex sound perception have been found between normal subjects and psychiatric patients and between different types of psychopathologies.     

Boron uptake in normal melanocytes and melanoma cells and boron biodistribution study in mice bearing B16F10 melanoma for boron neutron capture therapy

Information on (10)B distribution in normal tissues is crucial to any further development of boron neutron capture therapy (BNCT). The goal of this study was to investigate the in vitro and in vivo boron biodistribution in B16F10 murine melanoma and normal tissues as a model for human melanoma treatment by a simple and rapid colorimetric method, which was validated by HR-ICP-MS. The B16F10 melanoma cell line showed higher melanin content than human melanocytes, demonstrating a greater potential for boronophenylalanine uptake. The melanocytes showed a moderate viability decrease in the first few minutes after BNCT application, stabilizing after 75 min, whereas the B16F10 melanoma showed the greatest intracellular boron concentration at 150 min after application, indicating a different boron uptake of melanoma cells compared to normal melanocytes. Moreover, at this time, the increase in boron uptake in melanoma cells was approximately 1.6 times higher than that in normal melanocytes. The (10)B concentration in the blood of mice bearing B16F10 melanoma increased until 90 min after BNCT application and then decreased after 120 min, and remained low until the 240th minute. On the other hand, the (10)B concentration in tumors was increased from 90 min and maximal at 150 min after application, thus confirming the in vitro results. Therefore, the present in vitro and in vivo study of (10)B uptake in normal and tumor cells revealed important data that could enable BNCT to be possibly used as a treatment for melanoma, a chemoresistant cancer associated with high mortality.     

Plasma catecholamine levels in normal subjects and in patients with secondary hypertension

We compared normal values for human venous norepinephrine (NE) and epinephrine (E) as reported in the literature with values determined in this laboratory and we measured and contrasted NE levels in patients with primary and secondary hypertension. Analysis of published data from many laboratories involving more than 800 supine, resting, healthy subjects indicated an average circulating level of venous NE of 260 pg/ml and of E, about 35 pg/ml. Supine levels of NE normally double when normal subjects stand for 5 min. This simple test provides one assessment of overall sympathetic nervous system integrity. Levels of catecholamines have been extensively studied in essential hypertension but much less so in secondary hypertension. Of the groups we studied with secondary hypertension (diabetes mellitus, primary hyperaldosteronism, polycystic kidney disease, chronic bilateral renal parenchymal disease, and unilateral renal arterial stenosis), only the group with renal parenchymal disease had supine NE levels significantly higher than the control group. Patients with essential hypertension and diabetes had a blunted increase in NE on standing. Plasma levels of NE do not reliably differentiate these groups of secondary hypertension from one another or from patients with primary hypertension.     

Visual classification of erythrocytes in blood smears from normal subjects and patients

Erythrocytes on specially prepared and coloured blood smears can be classified not only by idcture analysis but also by phase contrast microscopy. Parameters of change for the peripheral zone area and pallor area (phase contrast value PW and index of erythrocyte changes Ev-I) serve as classificators of visual technique. 449 blood smears of the same number of male and female grown-up persons, whose diagnosis was unknown at the time of evaluation, were used for evaluation. In 145 cases these were healthy test persons in clinical and laboratory respect (group I). 163 test persons were ill, but without any malignous neoplasias (group II), and in 141 patients an ensured malignous neoplasia could be found (group III). From those 308 test persons or patients respectively in group I + II 11 blood smears were falsely classified as positive (= 3.6%). In 5 from 141 cases in group III blood smears were falsely evaluated as negative (= 3.6%). The findings were statistically ensured by the t-test. Clinical parameters of evaluation gained with visual techniques of classification are in accordance with those gained with automatic picture analysis. The reasons for the good separating ability of PW and Ev-I are discussed. Visual techniques of classification are suitable for institutions of all grades of equipment.