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A GIS-based system for decision support in wood procurement management was developed in order to identify energy wood harvesting alternatives during the integrated planning of harvesting operations. The system uses the information content of existing stand databases and an estimation method which is based on three major modules: i) modelling of energy wood volumes, ii) modelling of costs of haulage to the roadside and road transportation, and iii) economical allocation analysis of material flows. An application of this technology demonstrates how estimation of the total potential of residuals for local energy use can be integrated into wood procurement planning in Finland. Three experiments were prepared for testing this application. Based on the thinning regulations laid down by the Finnish national forest management organization Tapio, wood harvesting on permanent sample plots was simulated by two alternative procedures, one based on the empirical diameter distribution and the other on a theoretical Weibull distribution derived from the mean variables. The effects of these procedures on the extent of the residual energy wood potential were investigated. The third test compared this system with another system often used in Finland. The experimental results suggest that the theoretical distribution produces unreliable estimates in the case of untreated or young stands. Furthermore, the conventional system underestimates the potential of the residual energy wood. The implications of these results for improving the strategic planning of energy wood procurement in Finland are discussed.

Objective: Caffeine counteracts various effects of traditional benzodiazepines (BZDs). As zolpidem, a short-acting hypnotic, is an atypical GABAA-BZD agonist, we investigated when caffeine would counteract the effects of zolpidem as well. Methods: In daytime study I, zolpidem 10 mg (capsule) and caffeine 150 or 300 mg (in decaffeinated coffee) were given, alone and in combinations, to parallel groups (n= 15–17) of healthy students in double-blind and placebo-controlled manner. Objective and subjective tests were done before and 45 min and 90 min after intake. Ranked Δ values (changes from baseline) were analysed by one-way contrast ANOVA and Scheffe's tests. In daytime study II, four healthy subjects took zolpidem 10 mg alone, and together with blinded caffeine 250 mg or (at −45 min) erythromycin 750 mg. Objective and subjective effects were measured and plasma zolpidem concentrations assayed at baseline and 45 min and 90 min after zolpidem intake. Results: In study I, practice effects after placebo (ad + 30%) were seen for letter cancellation and digit symbol substitution but not for flicker fusion tests. Zolpidem alone significantly impaired (P < 0.05 vs Δ-placebo) letter cancellation and digit symbol substitution at 45 min and 90 min, lowered the flicker fusion threshold at 45 min, and caused subjective drowsiness, mental slowness, clumsiness and feeling of poor performance. Caffeine alone showed a non-significant trend to improve objective performance. The combined effects of zolpidem and either dose of caffeine matched those measured after zolpidem alone. Zolpidem + caffeine 300 mg was not stronger than zolpidem + caffeine 150 mg in impairing immediate memory and causing subjective sedation. In study II, zolpidem caused objective and subjective sedation; neither caffeine nor erythromycin modulated the effects of zolpidem or plasma zolpidem concentrations. Conclusion: The sedative effects of 10 mg of zolpidem are not antagonized by 150–300 mg of caffeine in pharmacodynamic or pharmacokinetic terms.

All animals require molecular oxygen for aerobic energy production, and oxygen availability has played a particularly important role in the evolution of aquatic animals. This study investigates how previous exposure to hypoxia (preconditioning) primes protective transcriptional responses in a hypoxia-tolerant vertebrate species, the epaulette shark ( Hemiscyllium ocellatum). The epaulette shark is a basal cartilaginous fish that in its natural environment experiences cyclic hypoxic periods. We evaluated whether the transcription of a set of crucial prosurvival genes is affected differently by a single short-term (2 h) exposure to sublethal hypoxia compared with eight such successive hypoxia exposures (hypoxia preconditioning). We discovered that hypoxia preconditioning amplifies transcriptional responses compared with animals that experienced a single hypoxic bout. In the heart we observed that hypoxic preconditioning, but not a single hypoxic exposure, resulted in higher transcript levels of genes that regulate oxygen and energy homeostasis, including those of hypoxia-inducible factor-1 alpha, adenosine signaling pathway components, and genes affecting circulation [prostaglandin synthetase 2 ( cox-2) and natriuretic peptide C]. This suggests that in a single short-term hypoxic bout, the responses to low oxygen are regulated at the level of pre-existing proteins or translational and posttranslational machinery, whereas transcriptional responses are induced in experiments that parallel the natural environmental cycles of oxygen availability. These findings have general implications for understanding how vertebrates regulate protective gene expression upon physiological stress.

Blends of polypropylene (PP) and liquid crystalline polymer (LCP) processed without melting the LCP were compared with conventional melt processed blends. In a first stage, PP was blended with 20 wt.% of LCP in a twin-screw extruder with the take-up speed varied to achieve blends with different LCP fibre dimensions. In the second stage these blends were processed both below and above the T m of the LCP by extrusion and injection moulding. At lower temperatures (180–200°C), where the material was processed without melting the LCP, a real composite structure was formed with solid LCP fibres in the PP matrix. When processed above the T m of the LCP (280°C) all the material was molten during processing and a composite-like blend morphology was created in-situ during cooling of the oriented melt phase. These blends exhibited a skin/core morphology, whereas the composites contained fibres throughout the sample. Due to this difference the impact strength of the composites was significantly higher than that of the blends. The blends exhibited higher modulus than the composites. Moreover, additional drawing can greatly improve the strength and stiffness of the blends. In composites the solid LCP fibres slightly increased the viscosity of PP, while in blends the molten LCP reduced the matrix viscosity and acted as a processing aid.

Epidemiological studies have suggested that patients with rheumatoid arthritis (RA) have increased mortality due to cardiovascular disease. We studied cardiac performance in 12 asymptomatic male patients with RA and 14 control subjects to elucidate early disturbances in cardiac function. In echocardiography, isovolumic relaxation time was longer (64 +/- 6 vs. 49 +/- 3 ms, mean +/- SEM, P = 0.010) and peak filling rate (134 +/- 10 vs. 159 +/- 6 mm s-1, P = 0.015) lower in patients with RA than in control subjects, reflecting an impairment in left ventricular diastolic function. Left ventricular systolic function assessed by radionuclide angiocardiography at rest and during exercise was similar in both groups. There were no differences between the patients with RA and control subjects in the heart rate, systolic blood pressure and oxygen uptake during peak exercise. Left ventricular diastolic function is impaired in spite of normal left ventricular systolic function in patients with RA without clinically evident cardiovascular disease and this may contribute to the excess of cardiovascular mortality in patients with RA.

The effect of mixer type and processing conditions on the morphology of immiscible binary polyamide/polypropylene blend was studied. Blends were prepared in seven different mixers operating at various screw speeds. Changing the screw speed altered the shear stress and mixing intensity applied to the melt, and also the viscosity ratio. Average panicle sizes of the dispersed phase (PP) and the particle size distributions were determined for extruded and for subsequently injection moulded blends. The number average particle size level achieved in the melt blending was fairly well transferred to the injection moulded blend although the size distribution was broadened after the injection moulding due to the formation of both small (≍1 μm) and large (>10 μm) particles. The morphology of the skin region was very different from that of the core region in both the extruded and the injection moulded blends. The dispersed phase droplet size was dependent on screw speed to some degree. This dependency was greatest for the single screw extruder. Particle size correlated strongly with shear stress, specific mechanical energy input, and mixing intensity of the mixer. Shear stress, we were led to conclude, is a more important factor in controlling the morphology than the shear-rate-dependent viscosity ratio. Mechanical properties of the blends were poor due to weak adhesion at the interface of the blend components. Additionally, we found that melt blending promoted a better and more homogeneous dispersion in the injection moulded blend.

Autonomic nervous function was evaluated in 36 patients with insulin-dependent diabetes mellitus (IDDM), 39 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 48 control subjects, all without clinically evident cardiovascular disease. Valsalva ratio and heart rate variation during deep breathing were lower in both diabetic groups than in the control group. Autonomic nervous function score (ANFS) was more abnormal in patients with IDDM than in control subjects, but was not significantly increased in patients with NIDDM. There was a negative correlation between ANFS and left ventricular diastolic filling evaluated by echocardiography or peak heart rate during exercise in both diabetic groups. There were no correlations between ANFS and left ventricular systolic function at rest or during exercise in any of the groups. In conclusion, autonomic nervous function was abnormal in middle-aged diabetic patients, and it was associated with impaired left ventricular diastolic filling at rest and decreased heart rate response to exercise, but not with left ventricular systolic function.

99m Tc-labelled disodium cromoglycate particles and 111 In-labelled microspheres of disodium cromoglycate and polyacrylic acid were administered simultaneously to the nasal cavities of four healthy volunteers. The initial deposition patterns of the inhaled powder mixture as well as the drug removal due to the mucociliary clearance were monitored by a gamma camera. The double-labelling technique enabled in vivo comparison of simultaneously administered plain drug particles and polyacrylic acid microspheres of disodium cromoglycate. After administration, both the plain drug particles and the microspheres distributed equally effectively. On average, 27% of the 99m Tc-labelled plain drug particles and 50% of the 111 In-labelled microspheres were retained at the initial site of deposition 30 min after inhalation. Thus, the removal of microspheres from the nasal cavities was clearly impeded by polyacrylic acid.

Sixteenth-century Lutheranism had a number of ways to define justification. This conclusory chapter constructs five basic models of justification and assesses their compatibility. In doing so this study responds to the question of what the evangelical doctrine of justification is and suggests how it might function both in the spirituality of the church and in ecumenical practice. The models discussed here are as follows: Faith is participation in Christ and His merit; Faith is the renewal of the faculties of the soul by the Holy Spirit; Faith is connection with Christ's divine nature; Faith is a causal effect of the Holy Spirit; and Faith is participation in the person of Christ and His merit, which is effected by the Spirit. These five models form the basis of the formulations of Formula of Concord (FC). In conclusion, the doctrine of justification strenuously denies the meritorious nature of human deeds and love.Keywords: christology; doctrine of justification; Formula of Concord( FC); Holy Spirit; justifying faith; models of justification; sixteenth-century Lutheranism

Martin Chemnitz, Melanchthon's student and a specialist in patristic theology, was one of the leading figures in early Lutheranism. His formulation of the doctrine of justification can be positioned in a category between Osiander and Flacius. This chapter concentrates mainly on Martin Chemnitz's view on justification. The analysis begins with Chemnitz's close friend and colleague, Joachim Morlin. Since justification has an incarnatory foundation for them - the merit of Christ being inseparable from His person - justification requires participation in Christ. Chemnitz is studied in more detail than his contemporaries because he has been regarded as the leading theologian of second-generation Lutheranism. Morlin's anti-osiandrian strategy culminated in the realistic nature of the communicatio idiomatum. This examination of Morlin and Chemnitz reveals their distance from the pneumatological anthropology of Melanchthon and his way of explaining the nature of justification and renewal.Keywords: anti-osiandrian strategy; communicatio idiomatum; doctrine of justification; Flacius; incarnated Christ; Joachim Morlin; Lutheranism; Martin Chemnitz; Melanchthon; patristic theology

Melanchthon's notion of justification evolved over the years so that the role of renewal in justification varied. In 1521, Melanchthon published the first edition of his introduction to theology, Loci Communes. The way Melanchthon refers to patristic theology indicates his christological views. Renovatio thus forms part of justification and means a change from a state of unbelief to one of faith. In the Augsburg Confession (CA, 1530), which was written by Melanchthon and deemed the most important confessional writing of Lutheranism, justification is described along the lines of Loci 1521. Melanchthon's Commentary on Romans (1532) defines justification as fixing the relation between the individual and God. Melanchthon's Commentary is a representative of a purely forensic doctrine of justification. Andreas Osiander brought the unio cum Christo theme back in to the discussion by claiming that Melanchthon had removed concept of ?indwelling' from justification.Keywords: Andreas Osiander; Augsburg Confession; Commentary on Romans ; forensic doctrine of justification; Loci Communes; Lutheranism; patristic theology; Philip Melanchthon; Renovatio; unio cum Christo

This chapter focuses on the Osiandrian controversy. After Luther's death, Andreas Osiander argued against Melanchthon's forensic soteriology, claiming that Melanchthon had corrupted Luther's teaching with his "frigid imaginations" of imputed righteousness. Both Gnesiolutherans and Philippists condemned Osiander's interpretation of Luther. One of the most important opponents of Osiander was Matthias Flacius Illyricus, who furthered the forensic style of Melanchthon. However, Flacius occupied the other extreme position, and his doctrine of justification was in danger of becoming mere fiction. Stancarus accused Osiander and Melanchthon of Arianism due to their claim that Christ's divine nature took part in satisfaction. Although Flacius repeated the forensic and extrinsic aspect of Melanchthon's doctrine of justification, it was the intrinsic that caused him problems. The examination of Osiander's and Flacius's thought shows the theological disunity and instability of early Lutheranism.Keywords: doctrine of justification; Francesco Stancarus; gnesiolutheran; Lutheranism; Matthias Flacius Illyricus; Melanchthon; Osiandrian controversy; Philippist

This chapter analyses Formula of Concord (FC)'s doctrine of justification. In order to examine the nature of justification in FC, the chapter analyzes its christological presuppositions about justification. A central problem in FC is the relation between Christ's person and His work. FC condemns the heresies of both Osiander and Stancarus, which regard only one nature of Christ as righteousness. The most extensive description of justification in BC is found in FC III, although FC also discusses the essence of faith in articles II (Free will) and IV (Good works). Compared to Luther and the texts of the formulators of FC, the relation between justification and Christ's presence is described in a perfunctory way. The idea of two unions was present in patristic writings, as in Cyril's theology (an example which Chemnitz made known). Luther also offers different forms of renewal in his Commentary on Galatians.Keywords: Chemnitz's christology; Christ's righteousness; Commentary on Galatians; Cyril's theology; doctrine of justification; Formula of Concord (FC); Lutheranism; Osiander

The bibliography section presents list of abbreviations, sources, documents and literatures as reference for this book Justification and Participation in Christ The unity of the early Lutheran reformation, even in the central themes such as justification, is still an open question. The book examines the development of the doctrine of justification in the works of the prominent first and second generation Lutheran reformers from the viewpoints of divine participation and effectivity of justification.Keywords: Christ; early Lutheran reformation

This chapter analyses Jacob Andreae, David Chytraeus, and Nicolaus Selnecker, the other second-generation Reformers and formulators of Formula of Concord (FC). Although their views concur with the christological thinking of Luther and Chemnitz they also use language typical of Melanchthon and Flacius. It briefly discusses three other well-known theologians of lesser influence. The views of Tileman Hesshus, Johannes Wigand and Jacob Heerbrand illustrate contemporary thinking on justification, although they did not influence FC directly. The effects of the Osiandrian controversy are evident in Andrea's texts, in which God's inhabitation are related to good works. Chytraeus's outline of the doctrine of justification is especially interesting. Selnecker identifies the former way of imputation as the Roman Catholic teaching on infused virtues, which function meritoriously. It is plain at any rate that 16th-century Lutheran theology did not employ a purely forensic doctrine of justification, except for Flacius.Keywords: christological thinking; David Chytraeus; forensic doctrine of justification; Formula of Concord(FC); Jacob Andreae; Johannes Wigand; Lutheran theology; Martin Chemnitz; Matthias Flacius; Nicolaus Selnecker

The first Reformers typically understood salvation as the communion of the sinner and Christ. This is apparent not only in the texts of Luther, but also in the theology of other prominent first-generation reformers such as Johannes Bugenhagen and Johannes Brenz. This chapter briefly notes Luther's central ideas on justification as they are represented his Commentary on Galatians, and analyzes some of Luther's disputations. In the Promotion disputation of Hieronymus Weller and Nikolaus Medler Luther sets the scholastic faith and the receiving faith which makes Christ effective in us against each other. The relation of donum and renovatio was particularly problematic for students of Luther, even for Melanchthon. The unio cum Christo theme serves the purposes of pastoral counseling and certainty of salvation. Luther, Bugenhagen, and Brenz held a similar view of justification.Keywords: Commentary on Galatians; donum; forensic justification; Johannes Brenz; Johannes Bugenhagen; Lutheran reformation; Melanchthon; renovatio; unio cum Christo

Deposition of 99m Tc-labelled particles of disodium cromoglycate in the human respiratory tract after inhalation either from the conventional metered dose aerosol or from the new Ingelheim powder inhaler (FO II) was compared. Fractional deposition in the whole lung area, in the upper airways and in the device was measured using a gamma camera. Eight healthy informed volunteers participated in the inhalation test. The lung deposition of the inhaled drug was about 9% using the conventional aerosol actuator with the short plastic mouthpiece whereas, using the Ingelheim powder inhaler, on average 20% deposition in the whole lung area was achieved. In addition, with the Ingelheim inhaler drug particles seemed to be deposited in the more peripheral parts of the respiratory tract. The upper airway deposition was also reduced with the Ingelheim powder inhaler. On the other hand, a larger fraction of the drug dose was retained in the Ingelheim inhaler than in the aerosol actuator.

Aims: The purpose of the study was to assess the dynamic changes in left ventricular (LV) volume by transthoracic three-dimensional echocardiography (3DE) and to compare the results with those obtained by magnetic resonance imaging (MRI). Methods and Results: Thirty healthy children were studied by digitized 3DE and Doppler, and by MRI. Three-dimensional echocardiography of LV was performed by using rotational acquisition from the transthoracic apical view with ECG gating and without respiratory gating. The acquisition of 3DE data took 10–15 s. Threedimensional echocardiography gave similar values to MRI for EDV, ESV and LVM measurements, and the results correlated well. Peak emptying rates by 3DE and MRI were 236·6 and 169·6 ml/s and peak filling rates were 215·0 and 215·9 ml/s, respectively. Dynamic changes of LV volumes during the heart cycle were detectable with both methods. Conclusion: Digitized 3DE performed in the outpatient clinic and MRI were both useful methods for studying the physiological volume changes in left ventricle in children. These methods may be used for further study of the systolic and diastolic function of the left ventricle in various clinical conditions. (Eur J Echocardiography 2001; 2: 31–39)

The aim of this study was to compare the usefulness of breath-hold heavily T2-weighted sequences with gadolinium-enhanced three-dimensional fast low-angle shot (3D FLASH) MR urography in the evaluation of patients with acute flank pain.Forty consecutive patients with symptoms of acute flank pain underwent MR urography followed immediately by excretory urography. Heavily T2-weighted (combined thin-slice half-Fourier acquisition single-shot turbo spin-echo [HASTE] and thick-slab single-shot turbo spin-echo) and 3D FLASH sequences were evaluated separately and independently by two experienced radiologists for the presence, cause, level, and degree of obstruction. Interobserver agreement was calculated using the kappa statistic. Excretory urography and the final clinical diagnosis were used as reference.Twenty-six patients were found to have unilateral obstruction caused by ureteral stones. Both MR urography methods were excellent for detecting obstruction. In the detection of stones 3D FLASH was superior, with a sensitivity of 96.2% and 100% and specificity of 100% and 100% for observers A and B, respectively, compared with a sensitivity of 57.7% and 53.8% and a specificity of 100% and 100%, respectively, for T2-weighted sequences. The best degree of obstruction was seen with 3D FLASH, and the interobserver agreement was excellent for stone detection (kappa = 0.97).T2-weighted sequences alone are not sufficient for examining patients with acute flank pain. However, the combined use of both T2-weighted and 3D FLASH sequences will ensure better confidence in the evaluation of acute suspected renal colic. MR urography can replace conventional excretory urography when the latter is contraindicated or undesirable.

Caffeine (Caf) counteracts various effects of benzodiazepines (BZDs). Since the effects of zolpidem, a short-acting atypical GABA(A)-BZD agonist, were not antagonized by Caf, we studied an interaction between Caf and midazolam (Mid) in healthy volunteers.In Study 1, 108 healthy students divided to 6 parallel groups were given Mid 12 mg (capsule) and Caf 125 and 250 mg (in decaffeinated coffee), alone and in combinations in the double-blind placebo-controlled manner. Objective and subjective tests were done before and at 45 and 90 min after intake. Ranked delta-values (changes from baseline) were analyzed by one-way contrast ANOVA and Scheffe's tests. In Study 2, six healthy subjects took Mid 15 mg (tablet) with and without Caf 300 mg. The dynamic effects were analyzed as in Study 1 and the plasma concentrations were assayed.In Study 1, learn effects after placebo (ad + 15%) were seen for letter cancellation and digit symbol substitution tests. Midazolam alone significantly (p0.05 vs. delta-placebo) reduced letter cancellation and digit symbol substitution, lowered flicker fusion, impaired digit learning and caused subjective calmness on VAS. Caffeine alone did not differ from placebo objectively, yet improved quick-wittedness and contentedness on VAS. In the combinations, Mid + Caf 125 mg differed from placebo objectively as Mid alone, whereas Mid + Caf 250 mg did not. Mid + Caf 250 mg differed from Mid on digit substitution, but did not differ from Mid+Caf 150 mg in impairing memory and causing subjective sedation. In Study 2, Mid 15 mg caused sedation and Caf 300 mg increased plasma Mid at 45 min. Mid + Caf did not differ from Mid alone objectively, but did so subjectively on VAS (p0.05).In conclusion, in a parallel group study, sedative effects of Mid 12 mg were only moderately antagonized by Caf 250 mg but not by Caf 125 mg. In a cross-over study, a weak interaction was found subjectively but not in objective measures.

Interrelation of T(1) and diffusion of water was studied in rat models of acute global and focal cerebral ischemia. Cortical T(1), as quantified with an inversion recovery method, increased by 4-7% within a few minutes of global ischemia at 4.7 and 9.4 T, but a significantly smaller change was detected at 1.5 T. The initial T(1) change occurred within seconds of cardiac arrest, much earlier than the extensive diffusion drop after 1-2 min. Thus, the initial increase in T(1) upon acute cerebral ischemia is directly caused by cessation of blood flow. In transient middle cerebral artery occlusion (MCAO), prolonged T(1) relaxation was detected within 10 min, with a subsequent increase during the course of ischemia. Spin density did not change during the first hour, showing that T(1) increase was not caused by net accumulation of water. Interestingly, partial recovery of T(1) upon release of MCAO, occurring independent of long-term tissue outcome, was observed only in concert with diffusion recovery.

OBJECTIVE—To assess the dynamic changes in left atrial volume by transthoracic three dimensional echocardiography and compare the results with those obtained by magnetic resonance imaging (MRI). DESIGN AND PATIENTS—30 healthy children (15 boys and 15 girls, aged 8 to 13 years) underwent examination by three dimensional echocardiography and MRI. METHODS—Three dimensional echocardiography of the left atrium was performed using rotational acquisition of planes at 18° intervals from the parasternal window with ECG gating and without respiratory gating. Volume estimation by MRI was performed with a slice thickness of 4-8 mm and ECG triggering during breath holding in deep inspiration. A left atrial time-volume curve was reconstructed in each child. RESULTS—Left atrial maximum and minimum volumes averaged 24.0 ml/m2 and 7.6 ml/m2 by three dimensional echocardiography, and 22.1 ml/m2 and 11.9 ml/m2 by MRI. The greater left atrial minimum volume in the latter was at least in part a result of breath holding. Dynamic changes in left atrial volume during the heart cycle were detectable by both methods. The higher temporal resolution of three dimensional echocardiography allowed a more precise evaluation of different phases. CONCLUSIONS—Three dimensional echocardiography and MRI were both useful methods for studying the physiological volume changes in the left atrium in children. These methods may be used for further study of the systolic and diastolic function of the heart. Keywords: three dimensional echocardiography; magnetic resonance imaging; left atrial volume; children

Redox modulation is involved in the regulation of the intracellular free calcium concentration ([Ca2+]i) in several cell types. In thyroid cells, including thyroid FRTL-5 cells, changes in [Ca2+]i regulate important functions. In the present study we investigated the effects of the oxidizing compounds thimerosal and t-butyl hydroperoxide on [Ca2+]i in thyroid FRTL-5 cells. Thimerosal mobilized sequestered calcium, and evoked modest store-dependent calcium entry. Both compounds potently attenuated the increase in [Ca2+]i when store-operated calcium entry was evoked with thapsigargin. The entry of barium was not attenuated. Experiments performed with high extracellular pH, in sodium-free buffer and in the presence of vanadate suggested that thimerosal decreased [Ca2+]i by activating a calcium extrusion mechanism, probably a plasma membrane Ca2+-ATPase. All the observed effects were abrogated by the reducing agent beta-mercaptoethanol. The mechanism of action was apparently mediated via activation of protein kinase C, as thimerosal potently stimulated binding of [3H]phorbol 12, 13-dibutyrate, and was without effect on store-operated calcium entry in cells treated with staurosporine or in cells with down-regulated protein kinase C. Thimerosal did not depolarize the membrane potential, as evaluated using patch-clamp in the whole-cell mode. In immunoprecipitates obtained with an antibody against plasma membrane Ca2+-ATPase, we observed several phosphorylated bands in cells stimulated with thimerosal. In conclusion, we have shown that thimerosal attenuates an increase in [Ca2+]i, probably by activating a plasma membrane Ca2+-ATPase.

We present a novel method to integrate in vivo nuclear magnetic resonance spectroscopy (MRS) information into the clinical diagnosis of brain tumours. Water-suppressed 1H MRS data were collected from 33 patients with brain tumours and 28 healthy controls in vivo. The data were treated in the time domain for removal of residual water and a region from the frequency domain (from 3.4 to 0.3 p.p.m.) together with the unsuppressed water signal were used as inputs for artificial neural network (ANN) analysis. The ANN distinguished tumour and normal tissue in each case and was able to classify benign and malignant gliomas as well as other brain tumours to match histology in a clinically useful manner with an accuracy of 82%. Thus the present data indicate existence of tumour tissue-specific metabolite phenotypes that can be detected by in vivo 1H MRS. We believe that a user-independent ANN analysis may provide an alternative method for tumour classification in clinical practice.

Fluconazole, an azole antifungal agent, moderately inhibits the CYP3A-mediated metabolism of midazolam in vitro. We therefore studied whether such an interaction takes place in vivo following oral administration of these drugs, given as relevant double blinded doses in capsule form. In study I parallel groups of healthy subjects received oral midazolam 10 mg (MID 10) or 15 mg (MID 15), placebo, or MID 10 mg + 150 mg fluconazole (FLU) given 2 h earlier. Objective and subjective performance tests were made before, and 30 and 90 min after the intake of midazolam. MID 10 and MID 15 moderately impaired performance on digit symbol substitution, letter cancellation and flicker fusion tests, and visual analogue scales revealed mild sedation. FLU + MID 10 had similar or slightly stronger effects than MID 10; it differed from MID 10 in that it lowered the flicker fusion threshold and produced subjective slowness and overall impairment. In study II 5 subjects received MID 10 after placebo, after FLU, and after 750 mg erythromycin (ERY) at 1-week intervals, following a crossover and double-blinded study design. Blood was sampled before MID intake and 30, 60 and 90 min after it, and performance was measured. FLU and ERY increased the effect of MID on flicker fusion and letter cancellation performances, and increased the HPLC-assayed plasma midazolam (ERY + 100%, FLU + 50%) in comparison to that measured after MID ingested alone. When the concentrations of midazolam together with its active metabolite alpha-OH-midazolam were assayed by radioreceptor technique the increases caused by ERY and FLU were less and compatible with the pharmacodynamic data.(ABSTRACT TRUNCATED AT 250 WORDS)

Nineteen beagles (8.8 +/- 0.1 months, 8.5 +/- 0.2 kg, mean +/- SEM) were oophorectomized (OX) at the beginning of the study. The dogs were randomly allocated into three groups: control group (OX, n = 5), OX+clodronate 20 mg/kg orally group (OX + 20, n = 7) and OX+clodronate 40 mg/kg orally group (OX + 40, n = 7). Clodronate administration began the day following oophorectomy and was continued for eight months. Bone mineral density (BMD) was evaluated by dual energy X-ray absorptiometry (DEXA) at baseline and at four and eight months and by quantitative computed tomography (QCT) at baseline and at eight months. Bone biopsies were taken at the beginning and at the end of the study. The change in BMD (g/cm2) during eight months was +2.0% (NS) in OX, +2.3% (NS) in OX + 20 and +10.0% (P0.01) in OX + 40 group when measured by DEXA, QCT revealed the same results but in a lesser extent. There were no differences in static and dynamic histomorphometric parameters between the groups at the end of the study. In conclusion, clodronate at a dose 40 mg/kg/day orally increases BMD in young oophorectomized dogs.

Pulmonary deposition of 99mTc-labelled sulbutamol was determined after delivery from a novel multiple dose powder inhaler (Easyhaler). The clinical efficacy of the inhalation powder, evaluated simultaneously with gamma camera detection, was compared with that obtained after drug delivery from a metered dose inhaler-spacer combination. The study was performed as an open, non-randomized cross-over trial. A single dose of radiolabelled inhalation powder was inhaled on the first and the inhalation aerosol, as control, on the second study day. Sulbutamol sulphate was labelled with 99mtechnetium, and the inhalation powder was formulated by mixing radioactive drug particles with carrier material. Aerodynamic properties of the radiolabelled inhalation powder were similar to those of the unlabelled salbutamol powder. Delivered dose from the breath-actuated powder inhaler was adjusted to be equal to two puffs from a conventional aerosol actuator with a short plastic mouthpiece. Twelve non-smoking asthmatic patients participated in the trial. The mean pulmonary deposition of 24% was obtained after drug delivery from Easyhaler powder inhaler. Clinical efficacy of the medications was similar in terms of area under the FEV1 curve, maximum FEV1 and the improvement ratio. Thus it can be suggested that powder delivery from Easyhaler powder inhaler and the aerosol delivery through the spacer are equally effective.

While bone mineral densitometry has become a common laboratory test, it is important to pay attention to the compatibility of the results from different instruments. In this study results from three commercially available bone densitometers are compared using both patient and phantom studies. Overall correlation between instruments was good but there were systematic discrepancies in the results. The three instruments provided bone mineral density (BMD) values that differed by as much as 13.5% due to differences as large as 6% in bone mineral content and as large as 7% in bone area. Thus, the BMD values obtained from different manufacturers' instruments are not directly comparable.

Disodium cromoglycate particles were labelled with 99mTc by spray-drying technique. The in vitro dissolution profile as well as the leakage of radioactivity from the drug particles were determined using a through-flow cell method. The radioactive drug particles were mixed with a lactose carrier and inhaled from a dry powder device by five healthy volunteers. The removal of the inhaled drug particles from the lungs was evaluated by a gamma camera. A close relationship between the dissolution of the drug as such and the leakage of radioactivity was noted. Gamma scintigraphy indicated a biphasic exponential removal of radioactivity from the lung region. The slow component with the halftime of about 55 min was mainly due to the dissolution of drug particles in the lungs. The halftime of the fast component describing mucociliary clearance was less than 10 min. This process was the dominating one for the removal of the drug from the lungs. The experiment thus showed that the main fraction of the inhaled dose was deposited in the tracheobronchial region. Accordingly, only a small portion of the dose initially deposited in the lung can be absorbed and induce a therapeutic effect.

Sucralfate was labelled with 99mTc by the stannous reduction method. Tablets were compressed using 1 g of radioactive sucralfate and suitable additives. On the first test day, five fully informed healthy volunteers were given one radioactive tablet of sucralfate each, following 10 h fasting. On the second test day, the sucralfate tablet was given after a standard meal. The gastrointestinal transit of the 99mTc-labelled sucralfate was evaluated using gamma camera technique. The labelling of sucralfate with 99mTc by the stannous reduction method enables the deposition and the transition of sucralfate in the gastrointestinal tract to be monitored. The tablets disintegrated almost immediately after administration and the released sucralfate distributed homogenously over the entire stomach area, in both fasted and fed subjects. Transit from the stomach into the intestine was noted already 10 min after administration in fasted subjects, whereas the gastric emptying of sucralfate was markedly delayed in fed subjects. To achieve a wider and more homogenous distribution in the GI-tract, sucralfate tablets should be taken before eating.

The deposition patterns of 99mtechnetium labelled disodium cromoglycate particles administered either from a metered dose aerosol with a conventional nasal adaptor or from a dry powder nasal inhaler were studied using gamma camera. Disodium cromoglycate particles were firstly labelled with 99mTc using the spray drying technique. Both the metered dose aerosol and the dry powder dosage form were formulated using these radioactive drug particles. Seven healthy volunteers inhaled either three aerosol doses or one dry powder dose unit into one nostril. The drug dose reaching nasal cavity after administration from these two dosage forms was about the same. The deposition patterns as well as the changes in distribution due to the mucociliary transport were monitored by a gamma camera equipped with a low energy all purpose collimator. Initially drug doses deposited in a wider area of the nasal cavity when disodium cromoglycate particles were administered as a dry powder dosage form. In addition, retention index (%) which illustrates the movements of drug particles by mucociliary transport from the initial area of application seemed to be slightly higher for a metered dose aerosol than for a dry powder dosage form. At the end of the 30 minutes measuring period the area of the mucosal layer covered by radioactive drug particles was clearly wider for the dry powder dosage form than for the metered dose aerosol. Thus it is well possible to administer drug particles effectively into the nasal cavity as a dry powder dosage form.

A modified cascade impaction method as well as a radiotracer technique has been used to assess the effects of the 700 ml collapsible holding chamber (InspirEase) on the in vitro and in vivo deposition of inhaled metered dose aerosols. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the InspirEase-device was evaluated with the modified cascade impactor which method imitated the human respiratory tract. For the in vivo study the disodium cromoglycate particles were labelled with pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of gamma camera. InspirEase increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper passages and mouth clearly decreased. Thus using the InspirEase holding chamber not only a better lung penetration of the inhaled drug particles can be achieved but also the local side effects would be decreased.

The effect of the new spacer-device on the in vitro and in vivo deposition of inhaled drug particles was studied. The in vitro deposition of beclomethasone dipropionate 250 micrograms/dose aerosol administered either through the conventional aerosol actuator with the short plastic mouthpiece or through the new pear-shaped spacer-device was evaluated with the modified cascade impactor method. For the in vivo study the disodium cromoglycate particles were labelled with a pure gamma-radiator 99mTc using a coprecipitation technique based on spray drying. The deposition of the inhaled disodium cromoglycate particles in the human respiratory tract after administration of the drug doses from the devices tested was determined by means of a gamma camera. The new spacer-device increased both in the in vitro and in vivo tests the fraction of the drug dose deposited into the therapeutically significant regions of the respiratory tract. In addition, the therapeutically insignificant fraction deposited in the upper airways and mouth clearly decreased. Thus using the new spacer-device evaluated in this study the local side effects would be decreased.

Deposition of 99mTc-labelled particles of disodium cromoglycate in the respiratory tract was evaluated after inhalation from two dry powder inhalers. The inhalers tested were a new multiple dose powder device (Chiesi Farmaceutici) and the Rotahaler powder device (Glaxo). Fractional deposition in the whole lung area, the upper respiratory passages and the stomach, as well as in the inhaler, was measured using a gamma camera. Ten healthy volunteers participated in the inhalation test. The mean, whole lung deposition of the inhaled disodium cromoglycate particles was about 9 per cent of the dose for the both devices. The deposition patterns of the inhaled drug doses in the lung area given by the devices were, however, clearly different. The Chiesi powder inhaler was more efficient in dispersing the drug particles into the therapeutically important alveolar regions of the lungs. The fraction of the dose retained in the inhaler was significantly higher for the Rotahaler than for the Chiesi powder device. On the other hand, the deposition in the upper passages was somewhat larger for the Chiesi device than for the Rotahaler. According to the deposition results of this study, a new multiple dose powder inhaler can be useful in inhalation therapy.

To the Editor: In their interesting study, Kalviainen et al. investigated the hippocampus of 64 patients with temporal lobe epilepsy (TLE) by MRI.1 They divided the subjects into three groups: chronic drug-resistant patients (CDRPs) with large number of seizures, well-controlled patients (WCPs) with rare seizures, and newly diagnosed patients (NDPs). The authors found that CDRPs had significantly smaller hippocampus with longer T2 relaxation time on the side of spike focus than healthy controls. Neither NDPs nor WCPs showed significant hippocampal atrophy compared with control subjects. The authors’ interpretation is that recurrent seizures may cause hippocampal damage. In our opinion, this conclusion is unconfirmed because the results may have been caused by other factors. The authors did not consider many studies that found age dependency of development of hippocampal damage in epilepsy. Re-evaluating the data of Kalviainen et al.,1 we found significant differences regarding mean age and age at onset of epilepsy. WCPs were 10 years older on average than CDRPs. This difference is statistically significant (see table 1) and was not mentioned in the original article. Because median duration of epilepsy was practically equal, we suppose that in WCPs …

Synthetic fragments of apo-C-II, specifically labeled on their NH2-terminals with the 5-dimethylaminonaphthalene-1-sulfonyl (dansyl or DNS) fluorophore, have been prepared by solid phase peptide synthesis. When a complex is formed between bovine milk lipoprotein lipase and N-dansyl-apo-C-II peptides, resonance energy transfer occurs from the tryptophan residues of the enzyme to the dansyl-labeled peptides upon excitation at 280 nm. In the absence of lipid, the association constant increases 10-fold when the length of the DNS peptide is increased from apo-C-II-DNS(64-78) (0.04 X 10(6) M-1) to apo-C-II-DNS(60-78) (0.3 X 10(6) M-1). In the presence of lipid, the association constants are dependent on peptide chain length, and increase from 0.4 X 10(6) M-1 for apo-C-II-DNS(64-78) to 2.2 X 10(7) M-1 for apo-C-II-DNS(43-78). The interactions are specific for lipoprotein lipase, are disrupted by guanidinium chloride, are not affected by 1.0 M NaCl, and are competitive with the corresponding nondansylated peptide. Apolipoproteins C-III and A-I, at 5 to 1 molar ratios, had no effect on the interaction. These findings demonstrate the importance of the COOH-terminal region in the lipoprotein lipase-apo-C-II interaction and show that activation of the enzyme involves a specific protein-protein interaction.

The catalytic mechanism of triacylglycerol hydrolysis by lipoprotein lipase was studied. We found lipoprotein lipase to be inhibited by benzene boronic acid, with an apparent Ki of 8.9 micro M at pH 7.4. This indicates the presence of serine and histidine in the active site of the enzyme. Inhibition of lipoprotein lipase by benzene boronic acid is likely to be due to the formation of an inhibitor-enzyme complex having analogous bonding to the active site histidine and serine as the transition-state complex which precedes the formation of an obligatory acyl-enzyme intermediate. The presence of apolipoprotein C-II, the apolipoprotein activator of lipoprotein lipase, partly reverses the inhibition of lipoprotein lipase by benzene boronic acid. This reversal by apolipoprotein C-II has a distinct pH optimum in the range of 8-9.

Synthetic fragments of apo-C-II, specifically labeled on their NH2-terminals with the 5-dimethylaminonaphthalene-1-sulfonyl (dansyl or DNS) fluorophore, have been prepared by solid phase peptide synthesis. When a complex is formed between bovine milk lipoprotein lipase and N-dansyl-apo-C-II peptides, resonance energy transfer occurs from the tryptophan residues of the enzyme to the dansyl-labeled peptides upon excitation at 280 nm. In the absence of lipid, the association constant increases 10-fold when the length of the DNS peptide is increased from apo-C-II-DNS(64-78) (0.04 X 10(6) M-1) to apo-C-II-DNS(60-78) (0.3 X 10(6) M-1). In the presence of lipid, the association constants are dependent on peptide chain length, and increase from 0.4 X 10(6) M-1 for apo-C-II-DNS(64-78) to 2.2 X 10(7) M-1 for apo-C-II-DNS(43-78). The interactions are specific for lipoprotein lipase, are disrupted by guanidinium chloride, are not affected by 1.0 M NaCl, and are competitive with the corresponding nondansylated peptide. Apolipoproteins C-III and A-I, at 5 to 1 molar ratios, had no effect on the interaction. These findings demonstrate the importance of the COOH-terminal region in the lipoprotein lipase-apo-C-II interaction and show that activation of the enzyme involves a specific protein-protein interaction.

Left ventricular systolic and diastolic function was studied using systolic time intervals and echocardiography in 19 male and 17 female patients with Type 1 (insulin-dependent) diabetes, 24 male and 15 female patients with Type 2 (non-insulin-dependent) diabetes and 24 male and 24 female control subjects. The subjects for the present study were selected from a population based study in which 117 Type 1 and 510 Type 2 diabetic patients and 649 non-diabetic subjects were originally examined. After exclusions, none of the subjects had any evidence of coronary heart disease, hypertension or other diseases known to affect left ventricular function. There were no consistent differences in systolic time intervals or echocardiographic variables of systolic function between patients with Type 1 diabetes and non-diabetic control subjects; but patients with Type 2 diabetes showed an increased fractional shortening. Female patients with Type 2 diabetes showed an increased left ventricular mass not explicable by hypertension. Isovolumic relaxation period was longer in male (86±3 ms; mean±SEM) and female patients (84±6 ms) with Type 2 diabetes than in male (76±3 ms; p