A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices.

GH replacement therapy has proved its efficacy and safety in short-term trials and in a few long-term trials with limited number of subjects. In this 1-center study, including 118 consecutive adults (70 men and 48 women; mean age, 49.3 yr; range, 22-74 yr) with adult-onset GH deficiency, the effects of 5 yr of GH replacement on body composition, bone mass, and metabolic indices were determined. The mean initial GH dose was 0.98 mg/d. The dose was gradually lowered, and after 5 yr the mean dose was 0.48 mg/d. The mean IGF-I SD score increased from -1.73 at baseline to 1.66 at study end. A sustained increase in lean body mass and a decrease in body fat were observed. The GH treatment increased total body bone mineral content as well as lumbar (L2-L4) and femur neck bone mineral contents. BMD in lumbar spine (L2-L4) and femur neck were increased and normalized at study end. Total cholesterol and low density lipoprotein cholesterol decreased, and high density lipoprotein cholesterol increased. At 5 yr, serum concentrations of triglycerides and hemoglobin A(1c) were reduced compared with baseline values. The treatment responses in IGF-I SD score, body fat as estimated by four- and five-compartment body composition models, total body protein and nitrogen, and lumbar bone mineral content and BMD were more marked in men than in women. One patient died during the period, four patients discontinued the study due to adverse events, and one dropped out due to lack of compliance. Four patients were lost to follow-up. However, all patients were retained in the statistical analysis according to the intention to treat approach used. In conclusion, 5 yr of GH substitution in GH-deficient adults is safe and well tolerated. The effects on body composition, bone mass, and metabolic indices were sustained. The effects on body composition and low density lipoprotein cholesterol were seen after 1 yr, whereas the effects on bone mass, triglycerides, and hemoglobin A(1c) were first observed after years of treatment.

Gastric emptying and glycemic response after ingestion of mashed bean or potato flakes in composite meals.

Two meals of mashed-bean or potato flakes and meat were served in random order to six healthy male subjects to determine effects on gastric emptying and glycemic reactions. The meals had comparable physical appearance and contained similar amounts of digestible carbohydrate, fat, and protein. No difference in gastric emptying, recorded by gamma camera after mixing 51Cr with the meals, was found between the meals. The bean-flakes meal gave significantly lower blood glucose (p less than 0.01) and serum insulin (p less than 0.05) concentrations than did the potato-flakes meal. The overall blood glucose response, calculated as incremental area under the curves for 2 h, also differed between the meals (p less than 0.05) whereas the overall insulin response did not differ significantly. The low glycemic response after bean flakes could not be explained by the gastric emptying rate, which provides additional evidence for the slow digestion of bean starch in the small intestine.

Reduction of gastric haemorrhage by fibrinolysis inhibition - an experimental study in rats.

Gastric ulcerations were induced in rats by pyloric ligature and instillation of 1.0 N HCl. After four hours all rats had developed ulcerations. Increased release of plasminogen activators from the mucosa during these conditions has previously been demonstrated. In the present study we investigated the role of fibrinolysis inhibition versus H2-receptor blockade on the gastric bleeding. Tranexamic acid - a synthetic inhibitor of the fibrinolytic system - was found to significantly (p less than 0.01) reduce blood loss into the gastric juice by 30% measured by 51Cr labelled red blood cells; cimetidine did not reduce the gastric haemorrhage under the experimental conditions used. Both treatment regimes significantly (p less than 0.02) reduced the secretion of gastric juice. These results indicate a contribution of the fibrinolytic system in gastric bleeding from experimentally induced gastric ulcerations.

The influence of trauma, Dextran 1000, and Dextran 40 on the lodgement of circulating tumor cells.

Earlier studies have shown that trauma and infusion of Dextran 1000 increased the formation of pulmonary metastases after i.v. tumor cell injection in rats. Infusion of Dextran 40 enhanced the pulmonary metastasis formation in traumatized but not in non-traumatized animals. In this study tumor cells labelled with a radioactive isotope were used to register the lodgement circulating tumor cells after trauma and infusion of Dextran 1000 and Dextran 40. It was found that the pulmonary lodgement of tumor cells was increased after trauma and infusion of Dextran 1000. Dextran 40 did not influence the lodgement in a significant way either in normal or in traumatized animals. Thus, the increased formation of metastases after trauma and infusion of Dextran 1000 seems to depend upon an increased tumor cell lodgement.

Studies on mechanisms involved in metastasis formation from circulating tumor cells. Factors influencing tumor cell lodgement during normal and post-traumatic conditions.

As shown in earlier studies the formation of metastases after i.v. tumor cell injection in rats is increased in the immediate post-traumatic period and treatment with heparin, thrombocytopenia, and defibrinogenation decreases the formation of metastases. Thrombocytopenia also inhibits the stimulating effect of trauma on metastasis formation. The results of the studies reported in this paper show that the changes of metastasis formation induced by the factors mentioned above with few exceptions are well correlated to the lodgement of the injected tumor cells. Thus, heparin treatment and thrombocytopenia decrease the pulmonary lodgement of i.v. injected tumor cells. Trauma increases the pulmonary lodgement of i.v. injected tumor cells but when trauma is combined with thrombocytopenia, the effect of thrombocytopenia dominates and the pulmonary lodgement of tumor cells decreases when compared to control conditions. Despite this, trauma still gives rise to increased tumor cell lodgement during thrombocytopenia.

Intratumor distribution of blood flow and of vascular volume in a transplantable rat sarcoma.

The intratumor distribution of plasma volume and of blood flow was studied simultaneously by radioisotope techniques in a transplantable, slightly differentiated 20-methylcholanthrene-induced rat sarcoma. A significant change toward lower tumor blood flow was found in the sarcoma with increasing tumor growth, accompanied by a reduced plasma volume. The distributions of plasma volume and blood flow were similar in peripheral and central parts of tumors. However, no significant correlation between plasma volume and blood flow was found in separate tumor specimens.

Drug absorption from nifedipine hydrophilic matrix extended-release (ER) tablet-comparison with an osmotic pump tablet and effect of food.

The aim of the present study was to compare the bioavailability of nifedipine when administered as a hydrophilic matrix tablet (ER) and a push-pull osmotic pump tablet (XL) administrated after fasting, and to evaluate the effect of food for the hydrophilic matrix tablet. For this purpose, three separate studies were performed on healthy volunteers (n = 58) including gammascintigraphic monitoring of tablet erosion and localisation in the gastrointestinal tract for ER in one study. Both ER and XL provided almost constant drug delivery over 24 h, after administration under fasting conditions, and bioequivalence was obtained according to 90% confidence intervals of the difference between formulations within 80-125% for Cmax and AUC. Food significantly increased AUC for ER but no significant difference was obtained between ER and XL with food with respect to extent of bioavailability. The rate of absorption was increased to a higher degree for ER than for XL, as indicated by a Cmax which was almost twice as high for ER compared with XL. This finding was shown to be related to an increased tablet-erosion rate for ER, leading to more rapid drug release.

Influence of two prostaglandin synthesis inhibitors on the intratumor distribution of blood flow and vascular volume in a transplantable rat fibrosarcoma.

The intratumor and intramuscle distribution of blood flow and plasma volume was studied via isotope techniques in a transplantable rat fibrosarcoma. Administration of two prostaglandin synthesis inhibitors, indomethacin and diclofenac-sodium, had different effects. Indomethacin changed muscle plasma volume significantly towards higher values; a tendency to increased tumor plasma volume was also found. Diclofenac-sodium increased tumor blood flow, but had no significant influence on other parameters. These effects are discussed based on previous observations of reduction of tumor growth rate and tumor vascularization after administration of both drugs.

Influence of a prostaglandin synthesis inhibitor and of thrombocytopenia on tumor blood flow and tumor vascular permeability. Experimental studies in the rat.

The intratumor distribution of vascular permeability in two transplantable rat tumors was studied by calculating tissue-plasma ratios of two intravenously injected labeled albumins with an interval of five hours between albumin injections. The data were calculated and presented as the capillary permeability surface area product (PS) in multiple tumor biopsies. Furthermore, the intratumor distribution of blood flow was studied by the intratumor uptake of intravenously injected 86Rb. The same parameters were also studied in normal striated muscle. Prolonged administration of a prostaglandin synthesis inhibitor, diclofenac-sodium (Voltaren) changed significantly the tumor blood flow towards higher values. A similar change was observed in animals with induced thrombocytopenia. Tumor PS values were increased by administration of diclofenac-sodium, but not by induced thrombocytopenia. The intratumor distribution of plasma volume, calculated from tissue-plasma values of albumin injected 5 minutes before the animals were killed, was not significantly changed as well as blood flow, plasma volume and PS in normal muscle. There was no significant correlation between separate tumor blood flow and PS values, while such a significant correlation was found in normal muscle. The observations made in this study suggest that a release of both prostaglandins and serotonin might be included in the regulation of tumor blood flow and vascular permeability.

Influence of tranexamic acid on tumour blood flow.

The influence on the intratumour blood flow distribution in a transplantable rat sarcoma by a potent antifibrinolytic drug, tranexamic acid, administered intraperitoneally for 3 or 10 days was studied by the intratumour distribution of intravenously injected 86Rb. A local Xenon clearance technique was used to study the direct effect of tranexamic acid on local tumour blood flow. local tumour blood flow and the intratumour blood flow distribution after administration of tranexamic acid for 3 days were unchanged compared to controls. Prolonged administration of tranexamic acid changed the intratumour blood flow distribution significantly towards low flow values. This might be one mechanism behind the inhibiting effect of tranexamic acid in tumour growth rate, previously observed in both experimental and clinical studies.

Treatment of superficial basal cell carcinomas using topically applied delta-aminolaevulinic acid and a filtered xenon lamp.

OBJECTIVE: To evaluate the treatment of superficial basal cell carcinomas (SBCC) using photodynamic therapy with topically applied delta-aminolaevulinic acid (ALA) and a filtered short arc xenon lamp as a light source. METHOD: An oil-in-water emulsion containing 20% ALA was applied topically to the lesion sites which were then occluded for 3 h. Irradiation was performed in a single session of 10 min using 125 or 166 mW/cm2 in the wavelength range (620-670 nm, giving a radiation dose of 75 or 100 J/cm2, respectively. Urine samples obtained in connection with the treatment were examined for traces of porphobilinogen and porphyrin. The therapy outcome was determined by histological examination of punch biopsies or by clinical verification. A follow-up scheduled for 5 years was initiated. PATIENTS: A group of 37 patients with histologically verified SBCCs were included. A total of 190 SBCCs were treated. Also included were six patients with 10 nodular basal cell carcinomas and five patients with 18 Mb. Bowen. The urine samples from three patients showed traces of porphyrins. RESULTS: Of the 157 SBCCs followed-up for 6 months, 144 were cleared giving a clearance rate of 92%. Of the nodular basal cell carcinomas and Mb. Bowens, 2 of ten and 11 of 18 were cleared, respectively. CONCLUSION: Photodynamic therapy is well suited to the treatment of SBCCs giving good cosmetic results regardless of lesion size. The filtered xenon lamp proved to be particularly suitable for photodynamic therapy.

Selenium status and absorption of zinc (65Zn), selenium (75Se) and manganese (54Mn) in patients with short bowel syndrome.

Selenium level and activity of glutathione peroxidase in plasma were studied in seven patients with extensive short bowel resection due to Crohn's disease, before and during 27-54 weeks of intake of a vitamin and trace element supplement containing 50 micrograms of selenium as sodium selenite. Initial levels of selenium were normal in all except one of the patients. The supplementation had no or minor effects on plasma selenium levels and glutathione peroxidase activity. The absorption of zinc, manganese and selenium was measured with a radionuclide technique before and/or after the supplementation period in five of the patients. The absorption of zinc and manganese was similar to that observed earlier in healthy subjects, while the absorption of selenium was significantly lower. The results indicate that a higher selenium intake or a different form of selenium is needed in these patients to compensate for the impaired bowel function.

In vivo XRF analysis of mercury: the relation between concentrations in the kidney and the urine.

The objective of this study was to determine the concentrations of mercury in organs of occupationally exposed workers using in vivo x-ray fluorescence analysis. Twenty mercury exposed workers and twelve occupationally unexposed referents participated in the study. Their mercury levels in kidney, liver and thyroid were measured using a technique based on excitation with partly plane polarized photons. The mercury levels in blood and urine were determined using atomic absorption spectrophotometry. The detection limit for mercury in the kidney was exceeded in nine of the exposed workers, but in none of the referents. The mean kidney mercury concentration (including estimates below the detection limits) was 24 micrograms g-1 in the exposed workers, and 1 microgram g-1 in the referents. The association between mercury in the kidney and in urine was statistically significant, but it was unclear whether the relation was linear. The measurements on liver (n = 10) and thyroid (n = 8) in the exposed workers showed mercury levels below the detection limit. The study shows that it is now possible to measure the mercury concentrations in kidneys of occupationally exposed persons, using in vivo x-ray fluorescence. The estimated concentrations are in reasonable agreement with the limited human autopsy data, and the results of animal studies.

In vitro and in vivo erosion of two different hydrophilic gel matrix tablets.

The aim of the present work was to establish in vivo predictive in vitro tests for the tablet erosion of two different compositions (A and B) of hydrophilic matrix tablets based on hydroxypropyl methylcellulose. The tablet erosion was studied in a modified USP II apparatus at different agitation intensities and ionic strengths according to 2(2) factorial design. The in vivo tablet erosion was studied in 8 healthy human volunteers by gamma scintigraphy after administration of the tablets together with breakfast. In vitro agitation intensity increased the erosion rate for both tablets whereas increased ionic strength caused a slower rate for tablet A and a faster rate for tablet B. The choice of in vitro testing conditions proved to be critical for the attainment of in vivo predictive results. The best in vitro/in vivo correlation for the two formulations was obtained at a paddle stirring rate of 140 rpm and a ionic strength of 0.14 obtained by addition of sodium chloride.

Point-wise measurements of MRS volume selection performance are insensitive to magnetic susceptibility effects of phantom materials.

The purpose was to analyse magnetic susceptibility effects on accuracy of point-wise measurements of signal profiles in the assessment of MRS volume selection performance. An existing phantom design consisting of a sphere with a movable signal source was used for the investigation. The influence from the phantom on magnetic field homogeneity was measured with phase sensitive 1H imaging and 31P spectroscopy on a 1.5 T whole body MR system. The susceptibility effects for such a phantom design can be separated in 1/ A variation in the background magnetic field, which is caused by the stationary structures and has a significant influence on spatial accuracy. 2/ A magnetic field distortion, which is caused by the movable signal source and has very little influence on accuracy. The spatial inaccuracy due to susceptibility effects in this phantom, was 0.03 mm for positions of the signal source covering a 40-mm VOI. Susceptibility effects from the movable signal source were substantial but had very little influence on spatial accuracy. Still, improvements of this phantom design are possible. Point-wise measurements using a phantom with a movable signal source is inherently insensitive to susceptibility effects from the signal source and permits accurate signal profile measurements of high spatial (sub-mm) resolution.

Performance of 2D 1H spectroscopic imaging of the brain: some practical considerations regarding the measurement procedure.

This paper deals with some of the practical considerations in the planning and performance of chemical shift imaging (MRSI or CSI) of the brain. It contains some aspects of 1) the imaging procedure (MRI), i.e., suggestions of an imaging protocol useful for the spectroscopic planning, 2) the planning of the spectroscopic volume, i.e., size and position, 3) evaluation and judgment of the preparation results, and 4) evaluation of the MRSI images. The paper also contains suggestions of developmental work and quality assessment to be done before patient studies are begun. Examples are given for MRSI studies of temporal lobe epilepsy. Several of the aspects described are obvious for the experienced spectroscopist but may be useful in the initiation of MRSI. The goal of this paper was to share our experiences of how to achieve high quality MRSI, experiences that we would had been grateful for in our prelude of MRSI experiments.

Signal profile measurements of single- and double-volume acquisitions with image-selected in vivo spectroscopy for 31P magnetic resonance spectroscopy.

The volume-selection performance was studied for single- and double-volume-of-interest (VOI) acquisition with the volume-selection method image-selected in vivo spectroscopy for 31P magnetic resonance spectroscopy. High-resolution signal profiles were measured using a phantom simulating a brain. Inside the phantom there was a small, remotely controlled, movable signal source filled with ortho-phosphoric acid. Signal profiles of the VOI were measured in three perpendicular directions for 1VOI (single VOI) and 2VOI (double VOI) acquisition. The measured signal profiles for both acquisitions were very similar, but they showed a discrepancy with regard to the intended VOI (iVOI). The transition regions were on average 3.8 mm and the average full width at half maximum of the signal profile was 30 mm for an iVOI size of 30*30*30 (mm3). No displacement was observed in the signal profiles. To avoid overlapping signal profiles, the minimum separation between two iVOIs was found to be 10 mm in our magnetic resonance (MR) system. A substantial negative signal contribution from regions outside the iVOI was measured in the y-direction for 1VOI acquisition and one of the two VOIs in 2VOI acquisition. The other VOI in 2VOI acquisition exhibited only minor contamination. The measurements presented underline the importance of detailed knowledge on the volume selection performance in in vivo magnetic resonance spectroscopy.

Determination of potassium in the skeletal muscles by whole-body counting.

Changes in muscular function are related to nutritional status, disease and physical activity. To study these relationships, it is desirable to be able to determine the whole body potassium content, which is characteristic to the muscular tissue. This can be achieved by measurements in a whole-body counter, identifying contributions from the upper and lower parts of the body. In a whole-body counter with large plastic scintillators, a special measuring methodology is required. Such a method of measuring (40)K in the leg muscles, extracting the part of the detector signal originating from the lower part of the body, has been developed and tested by independent phantom measurements. The results suggest that it is suited to perform regional measurements of body potassium but validation and implementation into clinical research are still necessary.

A method to obtain the same levels of CT image noise for patients of various sizes, to minimize radiation dose.

The aim of this study was to develop a method of obtaining the same levels of CT image noise for patients of various sizes to minimize radiation dose. Two CT systems were evaluated regarding noise characteristics using phantoms and dosimetric measurements. Both CT systems performed well at dose levels used in normal clinical imaging, but only one was found to be suitable for low radiation dose applications. The CT system with the lowest noise level was used for further detailed studies. A simple strategy for manual selection of patient-specific scan parameters, considering patient size and required image quality, was implemented and verified on 11 volunteers. Images were obtained with at least the prescribed image quality at significantly reduced radiation dose levels compared with standard scan parameters. Depending on the diameter of the tomographic section, i.e. size of the subject, the dose levels could be reduced to 1-45% of the radiation dose with standard scan parameters (120 kV, 250 mAs, 10 mm). The results indicate a general potential for dose reduction in CT for slim patients. For tissue volume determination, large dose reductions can be achieved by adjusting the scan parameters for each individual. The concept of patient-specific scan parameters could be fully automated in the CT system design, but would require the scan to be specified in terms of image quality rather than X-ray tube load.

Absorption of acetylsalicylic acid from enteric-coated tablets in relation to gastric emptying and in-vivo disintegration.

The absorption of acetylsalicylic (ASA) acid from enteric coated tablets was studied in relation to gastric emptying and in-vivo disintegration. ASA tablets labelled with 51Cr were given to six healthy subjects under fasting and non-fasting conditions. The position and disintegration of the 51Cr-labelled tablets was followed by external radiation measurement and the amount of salicylic acid in blood and urine was analysed. The absorption of ASA from the studied enteric coated tablets was usually correlated with gastric emptying and in-vivo disintegration. However in some cases the absorption can be delayed between 10-20 h even if gastric emptying and disintegration of the tablet have occurred.