Heterogeneity in maple syrup urine disease: Aspects of cofactor requirement and complementation in cultured fibroblasts

Fibroblast strains derived from six patients with maple syrup urine disease have been investigated for their requirements of the cofactors NAD, CoASH, Mg⁺⁺ and TPP in comparison with 10 normal control strains. The reconstitution of the decarboxylase function of branched chain α-keto acid (BCKA) dehydrogenase complex in lysed cells was studied with respect to the substrates u-keto-isocaproic acid, α-keto-isovaleric acid, and α-keto-β-methylvaleric acid (KIC, KIVA, MEVA). The enzyme activity of all normal control strains for the substrates KIC and KIVA was not reconstituted by TPP + Mg⁺⁺ alone, but CoASH + NAD could reconstitute the enzyme activity with KIC and KIVA in different degrees. Only two control strains were tested with MEVA as substrate, and these showed in contrast that TPP + Mg⁺⁺ could partly reconstitute the enzyme activity. In contrast to the relative homogeneiy in the reconstitution profiles of normal strains, the five classical and one intermittent MSUD strains showed heterogeneity in cofactor requirements.
Complementation analysis using heterokaryons prepared from fibroblasts of four patients with classical MSUD and one patient with intermittent MSUD showed, in contrast to experiments with normal controls, a partial amelioration of the defect in two combinations; it is suggested that the defect in these strains is located at different functional subunits of the multienzyme complex.     

An iron metabolism study in humans by means of stable tracers

An investigation of iron metabolism in a female patient volunteer by administration of stable iron isotopes as tracers was performed. The applied methodology had already been tested in rabbits in comparison with radioactive tracer technique. The subject under study was given 58Fe solution intravenously and about 45 min later 57Fe solution orally. Ten blood samples were drawn at different times within 522 min from injection. Single iron isotopes content in plasma samples was determined by proton nuclear activation. A Compton suppressor system was utilized to improve the detector limits. The characteristic parameters of iron plasma clearance and of iron intestinal absorption were determined.     

Effects of age and size in the ears of gekkonomorph lizards: middle-ear morphology with evolutionary implications

The function of the ear depends in part on its absolute size and internal proportions. Thus, in both young individuals and small species, the middle ear is expected to be allometrically enlarged despite its smaller absolute size. Here we aim to compare the ontogenetic allometry of relevant middle-ear structures as observed within gecko (gekkonomorph lizards) species, with the evolutionary allometry observed interspecifically. These observations also provide middle-ear data for future evaluation of variation in auditory sensitivity. The material comprised 84 museum specimens of geckos, representing nine species of three gekkonomorph subfamilies. The results of dissections and measurements show that different reports notwithstanding, the middle-ear ossicular chain is indeed structured as described for geckos by Werner and Wever. Some sexual dimorphism is indicated, but this requires further study. During postnatal ontogeny, the allometric growth in the ratio of the columellar footplate area to body length differed between the intraspecific and interspecific levels, hence species differences in the middle ear do not merely result from animal size. The ratio of the tympanic membrane area to the columellar footplate area increased during ontogeny. In this, geckos resemble birds and probably also mammals. Similarly, when the comparison was among adults representing different species, the ratio of the tympanic membrane area to the columellar footplate area increased with body size. In this, however, the geckos differed from birds and mammals, in which this ratio varied taxonomically, irrespective of body size. It would thus seem that middle-ear proportions have evolved among geckos to produce small interspecific differences, but among amniote tetrapods they have evolved according to different principles in the classes reptiles, birds, and mammals.     

Quantitative aspects of enhanced liver tumour formation in CF-1 mice by dieldrin

The dose-response characteristics of dieldrin-mediated enhancementof liver tumour formation in CF-1 mice were analysed, usingexisting tumour data from chronic feeding studies at six levelsof continuous exposure, involving a total of > 1500 animals.The dose-response relationship can be expressed as: D_x x T_x= D₀ x T₀ = constant, where T₀ = the median liver tumour inductionperiod in control CF-1 mice, T_x = the median liver tumour inductionperiod in dieldrin-treated mice at a dose level D_x, D₀ = thebackground dose equivalent for the induction of ‘spontaneous’liver tumours, D_x = the sum of background dose (D₀) and actualdieldrin dose (_x). The relationship, which is a Druckrey equation(D x Tⁿ = constant) where n = 1, indicates that: (i) the velocityof liver tumour development is proportional to the daily doselevel (D_x), (ii) the total tumourigenic dose is constant acrossall doses, (iii) the effects of dieldrin on the neo-plasticprocess in mouse liver are essentially irreversible and cumulative,and (iv) there is no evidence for a threshold level. However,when _x «D₀, the actual contribution of dieldrin to tumourformation is expected to be negligible.     

Membrane-coating granules in "dry" non-eczematous skin of patients with atopic dermatitis. A quantitative electron microscopic study

In recent years much interest has been focused on the functions of the membrane-coating granules (MCGs). These granules seem to play an essential role in the formation of the barrier of the stratum corneum by extruding their lipid-rich content into the extracellular space of the corneocytes. The dry non-eczematous skin in atopic dermatitis has been reported to have defective barrier function. In the present study a quantitative electron microscopic analysis was made of the volume of MCGs in the transition zone between the stratum granulosum and stratum corneum in dry skin of patients with atopic dermatitis. The relative volume of MCGs was significantly greater than that in normal skin. This finding may indicate a disturbance of the "maturation" of the MCGs, leading to a defect in the barrier function in atopic dermatitis.     

A comparison between two emergency cricothyroidotomy instruments

As part of a training programme for younger doctors, two commercially available, emergency cricothyroidotomy sets were evaluated. Prior to the surgical procedure, half of the doctors in each group received an audiovisual lesson. In a simulated but realistic emergency situation, involving autopsy material, cricothyroidotomy was performed utilizing either the "Nutrake" or the "Gentofte" system. The audiovisual lesson increased the speed and the success rate of the doctors performing this procedure as well as strengthening their confidence. Both systems allowed positive pressure ventilation. The participating doctors achieved a higher success rate at a faster speed with the "Nutrake" set.     

Chemical,radiochemical, and radionuclide purity of eluates from different commercial fission99Mo/99mTc generators

Seven⁹⁹Mo/^99mTc generators (using fission⁹⁹Mo) obtained from seven different manufactures were studied in 1984 and 1985 to test the quality of the eluates. We present the findings concerning the elution efficiency, radionuclide purity,⁹⁹Mo breakthrough, radiochemical purity, pH, and aluminium content of the eluates. One generator was overloaded with⁹⁹Mo by about 40%, while one generator had^99mTc yields of only about 80%. The eluates generally (although with some exceptions) exhibited a high and satisfactory radionuclidic purity and good radiochemical purity. The low-level determination of⁹⁹Mo break-through using a commercially available dose calibrator with a⁹⁹Mo assay shiled indicated a misleadingly high⁹⁹Mo content. All of the eluates had pH values of between 5.0 and 5.5, and the aluminium content was always below the detection limit of 1 g per milliliter of eluate. The generators performed well and proved their capability of functioning as reliable sources of sodium pertechnetate Tc99m. In all cases, the pertechnetate produced met the requirements of the European Pharmacopeia.This report is based on work conducted within the scope of a research poject devised by the Ministry of the Interior of the Federal Republic of Germany (Hammermaier et al. 1985). The present report reflects the opinions of the authors and does not necessarily express the views of the Federal Ministry of the Interior     

Release of corticosteroids from human adrenals in vitro

From morphological criteria, it is often difficult to evaluate whether adrenocortical tumors secrete hormones or not. An increasing number of nonfunctioning tumors are detected using modern imaging techniques. In a consecutive series of 13 patients with adrenocortical disease, a functional characterization was done by determining the ability of the resected tissue to release cortisol and aldosterone in vitro. Significant secretion of aldosterone was only found in tumors from 4 patients with hyperaldosteronism, 1 of whom turned out to have a cortisol-secreting tumor as well. All other tumors, both from patients with Cushing's syndrome and patients judged to have nonfunctioning adenoma, released cortisol in vitro. The method provides valuable pathophysiological information on adrenal tumors.

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Resumen Con base en criterios morfológicos, frecuentemente es difícil determinar si los tumores adrenocorticales secretan hormonas o no. Con el uso de las modernas técnicas de imagenología, se détecta un numéro creciente de tumores no funcionantes. En una serie consecutiva de 13 pacientes con patología adrenocortical, se realizó una caracterización funcional determinando la capacidad del tejido resecado para liberar cortisol y aldosterona in vitro. Se encontró secreción significativa de aldosterona sólo en tumores provenientes de 4 de nuestros pacientes con hiperaldosteronismo, 1 de los cuales también presentó un tumor secretor de cortisol. Todos los otros tumores, tanto de pacientes con síndrome de Cushing como de pacientes que se considéró tenían adenoma no funcionante, liberaron cortisol in vitro. El método provee valiosa información patofisiologica sobre los tumores suprarrenales.

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Résumé Il est souvent difficile, à partir des critères morphologiques, d'évaluer si les tumeurs corticosurrénaliennes sont des tumeurs sécrétantes ou non. Un nombre croissant de tumeurs dites nonfonctionnantes sont détectées par l'utilisation des techniques modernes d'imagerie. Une caractérisation fonctionnelle est réalisée par les auteurs à partir d'une série consécutive de 13 patients présentant une pathologie corticosurrénalienne en determinant les capacités de sécrétion in vitro de cortisol et d'aldostérone du tissu réséqué. Une sécrétion significative d'aldostérone est présente seulement dans les tumeurs de 4 patients avec hyperaldostéronisme, l'un d'entre eux révéla posseder de même une tumeur sécrétant du cortisol. Dans tous les autres cas, aussi bien chez les patients avec un syndrome de Cushing que chez les patients considérés comme ayant un adénome nonfonctionnant, les auteurs observent une sécrétion de cortisol in vitro. Cette méthode donne une information physiopathologique précieuse sur les tumeurs surrénaliennes.

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Presented at the International Association of Endocrine Surgeons in Paris, September 1985.

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Supported by grants from the Swedish Medical Research Council (2330) and Karolinska Institute.     

Towards compatibility of EUnetHTA JCA methodology and German HTA: a systematic comparison and recommendations from an industry perspective

The European Journal of Health Economics - The transferability of the EU joint clinical assessment (JCA) reports for pharmaceuticals for the German benefit assessment was evaluated by...