Ornithine transcarbamylase variant in a male patient.
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Amino Acids↗
Biomedical subjects
A Roscher
Publications and source records attributed to A Roscher.
The osteoporosis index. An educational approach to maximize prevention.
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Family Practice↗
[Sweat collection and osmometry in the diagnosis of cystic fibrosis: a new method].
Two methods of sweat testing (Gibson and Cooke's vs. sweat osmolality) for the diagnosis of cystic fibrosis were compared in 33 subjects (26 healthy subjects and 7 patients aged 23 days to 28 years). Sweat was collected with a "macroduct"-sweat collection-system, osmolality was measured with the Wescorvapor-pressure osmometry. In a further 18 subjects (13 healthy, 5 patients) electrolytes were determined from filter-paper and the Vescor-macroduct-system. The osmolality in sweat of healthy subjects and patients with CF differed significantly (p less than 0.001). In healthy subjects maximum osmolality was 198 mmol/kg (means 158 +/- 21.3 mmol/kg), in patients with CF 283.9 +/- 10.2 mmol/kg. Assessment of sweat osmolality is a highly reliable procedure for confirming the diagnosis of CF provided borderline-values between 180 and 220 mmol/kg are reevaluated with the conventional filter-paper assay.
Cystic Fibrosis↗
Very long chain fatty acids in genetic peroxisomal disease fibroblasts: differences between the cerebro-hepato-renal (Zellweger) syndrome and adrenoleukodystrophy variants.
Very long chain fatty acids were investigated by gas chromatography in fibroblasts of patients with genetic peroxisomal diseases (cerebro-hepato-renal (Zellweger) syndrome, childhood adrenoleukodystrophy, adrenomyeloneuropathy, neonatal adrenoleukodystrophy) and of controls. Concentrations of C 26:0 were increased to about the same extent in all disorders investigated. C 26:1 concentrations, on the other hand, were considerably elevated only in the cerebro-hepato-renal syndrome. In all control, adrenoleukodystrophy, and adrenomyeloneuropathy cases the C 22:0 concentration was higher than the respective C 26:0 concentration; the reverse was found in the cerebro-hepato-renal syndrome. These differences seem to reflect different impairment of peroxisomes in the cerebro-hepato-renal syndrome and adrenoleukodystrophy variants, respectively. Additional experiments to characterize C 26:1 by thin layer chromatography, gas chromatography and mass spectrometry revealed the presence of two straight-chain C 26:1 isomers with similar fragmentation patterns.
Abnormalities, Multiple↗
Infantile type of sialic acid storage disease with sialuria.
We describe a male infant of Austrian ancestry, the main clinical features including attacks of dyspnea due to laryngomalacia, severe mental and motor retardation, pronounced splenohepatomegaly and vacuolisation of peripheral lymphocytes. The clinical condition deteriorated progressively and the child died at the age of 21 months. Phase and electron microscopy of cultured skin fibroblasts showed multiple vacuoles and inclusions suggestive of a lysosomal storage disorder. Increased excretion of free sialic acid was demonstrated by resorcinol staining after routine thin-layer screening for urinary oligosaccharides. Quantitative analyses of urine, leucocytes and cultured fibroblasts revealed 10 to 30-fold increased concentration of free sialic acid. In addition, 3-fold elevated amounts of sialyloligosaccharides were found in the urine. The activities of a variety of lysosomal enzymes, including sialidase, were normal. Our case is compared with infantile sialic acid storage disease recently observed by other authors. The close convergence of clinical, morphological and biochemical signs support the concept of a distinct lysosomal disease entity. The basic defect is so far unknown.
Carbohydrate Metabolism, Inborn Errors↗
Infantile sialic acid storage disease: the fate of biosynthetically labeled N-acetyl-(3H)-neuraminic acid in cultured human fibroblasts.
N-acetyl-(3H)-mannosamine[(3H)-ManNAc] was used as a precursor for the metabolic labeling of N-acetyl-(3H)-neuraminic acid [(3H)-NANA] in cultured fibroblasts of a patient with infantile sialic acid storage disease (ISSD). The metabolic fate of free and bound (3H)-NANA, isolated by high-performance liquid chromatography, was followed under pulse-chase labeling conditions. Nonsaturable accumulation of free (3H)-NANA was observed in ISSD, while the metabolic flux from (3H)-ManNAc to NANA-glycoconjugates was unaffected. Accumulated free (3H)-NANA could not effectively be chased from ISSD cells although N-acetyl-(3H)-hexosamines [(3H)-HexNAc] were appearing in the chase medium. These metabolites could arise from (3H)-NANA bound to glycoconjugates which were cleaved at normal rates in ISSD. The finding that free (3H)-NANA was markedly increased relative to its major products (3H)-HexNAc is suggestive for an impaired degradation and reutilization of (3H)-NANA due to trapping in a metabolically unaccessible pool. In titration experiments with digitonin a clear-cut increase in the latency of labeled NANA relative to a cytoplasmic marker enzyme was evident in ISSD. The release of (3H)-NANA, however, followed closely the digitonin-induced release of the lysosomal enzyme beta-hexosaminidase. This is suggestive for a lysosomal location of the stored material.
Biological Transport↗
Plasma lipids and lipoproteins of a patient with cholesteryl ester storage disease.
The plasma lipids, lipoproteins and lipolytic enzymes of a patient suffering from cholesterol ester storage disease were investigated and followed over a time period of 3 years. The patient was hypertriglyceridaemic and cholesterolaemic and exhibited very low levels of high density lipoproteins. These lipoproteins consisted almost exclusively of the HDL-subfraction-3. Apolipoprotein-B was elevated and apoAI and AII were grossly reduced. The activity of lipoprotein lipase was normal, but hepatic lipase values were increased. Lecithin: cholesterol acyltransferase was in the upper normal range. The corresponding lipoprotein and enzyme values of one brother were within normal limits but some components measured in the plasma of the father were abnormal. It is speculated that the low plasma HDL levels in this disease may be a consequence of increased hepatic lipase activity in addition to a derangement in the reverse cholesterol flow.
Adolescent↗
The cerebrohepatorenal (Zellweger) syndrome: an improved method for the biochemical diagnosis and its potential value for prenatal detection.
The sequence of reactions involved in plasmalogen biosynthesis has been evaluated in cultured fibroblasts of patients with the cerebrohepatorenal syndrome. A double-label, double-substrate incubation using [1-14C] hexadecanol and 1-0-[9', 10'-3H]hexadecylglycerol was performed to monitor the relative rates of peroxisomal and microsomal biosynthesic steps. [14C] radioactivity associated with 1'-alkenyl groups of plasmalogens was found to be drastically reduced in fibroblasts of affected patients whereas [3H] incorporation was apparently normal. This finding is specific for cerebrohepatorenal syndrome fibroblasts since cell lines of patients with childhood adrenoleukodystrophy and neuronal ceroidlipofuscinosis utilized the lipid precursors of plasmalogen biosynthesis at normal rates. The results show that the defect in plasmalogen synthesis in the cerebro-hepato-renal syndrome is restricted to the peroxisomal steps. The finding of normal microsomal biosynthetic steps was exploited to devise a novel diagnostic assay in fibroblasts and amniocytes based on the comparison of [3H/14C] isotope ratios within aldehydes released from plasmalogens by acid hydrolysis. The procedure can be completed with a minimal amount of cells since it renders quantitative analyses unnecessary. Therefore, this technique appears ideally suited for the sensitive and safe prenatal diagnosis of the cerebro-hepato-renal syndrome.
Abnormalities, Multiple↗
Demonstration of receptor binding of two apo-B containing lipoproteins by differential labelling with colloidal gold.
The interaction of two types of apo-B containing lipoproteins, human low density lipoprotein (LDL) and lipoprotein-a (Lp(a], with cultured human skin fibroblasts was studied by differential colloidal gold labelling in conjunction with thin sectioning and surface replication techniques. After separate exposure of the fibroblasts to either gold labelled LDL or Lp(a) for 15 to 30 min at 37 degrees C, labelled lipoproteins were predominantly found in coated pit areas. Excess of unlabelled LDL or Lp(a) completely displaced the gold labelled lipoproteins, indicating specific binding by the LDL-receptor. Simultaneous exposure of fibroblasts to LDL-16 nm gold and Lp(a)-40 nm gold conjugates revealed that both LDL and Lp(a) are bound in the same coated pit and internalized into the same endosome. In contrast to native lipoproteins, gold labelled acetylated lipoproteins were found diffusely distributed on membrane surface areas predominantly representing fibronectin-containing fibrils.
Apolipoproteins B↗
The low-density-lipoprotein pathway of native and chemically modified low-density lipoproteins isolated from plasma incubated in vitro.
Normal fasting human plasma was incubated for 24 h at 37 degrees C in the presence or absence of lecithin:cholesterol acyltransferase (LCAT) inhibitors. The low-density lipoprotein (LDL) fractions of incubated plasma (control LDL and LCAT-modified LDL) were studied with respect to their chemical and functional properties. LCAT-modified LDL differed from control LDL by a decreased phospholipid and free-cholesterol content, but increased cholesteryl esters. Furthermore, an increase of the relative protein content in LDL by 16-20% was found. Apolipoproteins of LCAT-modified LDL exhibited a 10-fold increase of apo AI, a 4-5-fold increase of apo E, and a 2-fold increase of apo C. All these apolipoproteins resided together with apo B on the same particles. LCAT-modified LDL displayed a higher electrophoretic mobility, a higher hydrated density, a decreased flotation constant and a smaller diameter. Cultured human fibroblasts bound and internalized LCAT-modified LDL to a lower extent than control LDL. The degradation, however, was faster. Modified LDL suppressed 3-hydroxy-3-methylglutaryl-CoA reductase activity to a lower extent than did control LDL. Our results demonstrate that LCAT action, together with lipid transfer and exchange processes, markedly alters the chemical and physiochemical properties of LDL. This in turn significantly influences LDL catabolism in vitro.
Cells, Cultured↗
The interaction of human apoB-containing lipoproteins with mouse peritoneal macrophages: a comparison of Lp(a) with LDL.
Cholesteryl ester accumulation in macrophages and foam cell formation is believed to play an important role in atherogenesis. The effect of Lp(a) on the incorporation of [14C]oleate into cholesteryl esters was studied in mouse peritoneal macrophages. In view of the physico-chemical similarities between Lp(a) and LDL, the results were compared with those obtained with LDL. Native Lp(a) and LDL did not stimulate cholesteryl ester formation. Incubation of macrophages with Lp(a)- or LDL-dextran sulfate complexes caused a significant increase in cholesteryl ester formation. A similar effect was observed when Lp(a) or LDL were incubated with macrophages in the presence of antibodies directed against the specific Lp(a) apoprotein or against LpB. Treatment of Lp(a) with acetic anhydride or malondialdehyde (MDA) was followed by precipitation of most of the lipoprotein. Therefore, these modifications were not suitable to study the uptake of modified Lp(a) by macrophages. Studies with acetyl-LDL or MDA-treated LDL caused the well-known stimulation of [14C]oleate incorporation into cholesteryl esters. Thus, the modification of Lp(a) by sulfated polysaccharides or by treatment with antibodies yields similar cholesteryl ester deposition in mouse peritoneal macrophages as observed with modified LDL. This might be one mechanism by which Lp(a) exerts its atherogenicity.
Animals↗
Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man.
The binding of 125I-lipoprotein (a) [Lp(a)] to cell surface receptors was studied on cultured human fibroblasts. The results were compared with corresponding data obtained with 125I-low density lipoproteins (LDL). Equilibrium binding studies showed that Lp(a) is bound with high affinity by the cell surface receptors. The maximum binding capacity for Lp(a) was 37% lower than for LDL. For Lp(a) and LDL, the Scatchard plots displayed linearity, indicating a single category of binding sites. Half-maximal saturation occurred at a concentration of 9.52 +/- 1.04 nM for Lp(a) and 7.76 +/- 1.29 nM for LDL. Competition binding experiments revealed that Lp(a) and LDL are nearly equally potent in competing each other for the binding sites. Binding of Lp(a) and LDL were followed by suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Cyclohexanedione treatment of Lp(a) and LDL completely abolished receptor binding. Neither Lp(a) nor LDL were specifically bound by fibroblasts obtained from a patient with homozygous familial hypercholesterolemia (FH). The removal mechanisms for Lp(a) and LDL were further compared by in vivo studies. Radioiodinated Lp(a) and LDL were injected intravenously into 12 normolipemic individuals to measure kinetic parameters of these two lipoproteins simultaneously in each subject. Mean fractional catabolic rate (FCR) of Lp(a) was 0.260 +/- 0.060 and mean FCR of LDL was 0.377 +/- 0.077 (mean +/- SD). In each subject, FCR of Lp(a) was lower than the FCR of LDL; the mean difference was 31%. The absolute synthetic rate of Lp(a) was significantly lower than the corresponding value of LDL. In each individual, the percentage of total Lp(a) that was contained in the intravascular space was higher than the corresponding value of LDL; the mean difference was 19%. A highly significant positive correlation was found between FCR of LDL and FCR of Lp(a) (r = 0.853, P less than 0.01). No relationship was found between the serum concentration of LDL-apolipoprotein B and Lp(a). The serum level of Lp(a) was positively related to the absolute rate of Lp(a) synthesis (r = 0.979, P less than 0.01). The serum level of LDL-apolipoprotein B was inversely related to FCR of LDL (r = 0.613, P less than 0.05). In a patient with homozygous FH, FCR of LDL was 0.205 and FCR of Lp(a) was 0.210. The results of these studies show that Lp(a) is specifically bound with high affinity to the same receptors of human fibroblasts as LDL. The affinity and maximum binding capacity are slightly lower for Lp(a) than for LDL. The results of the turnover studies are consistent with the assumption that Lp(a) is removed from the plasma by similar mechanisms as LDL.
Adolescent↗
The role of lecithin:cholesterol acyltransferase for the low density lipoprotein composition and specific binding to the B receptor.
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Acyltransferases↗
Relevance of second messengers in cystic fibrosis.
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Adrenergic beta-Antagonists↗
[The advantages of multiple choice tests in undergraduate teaching of pharmacology (author's transl)].
Multiple-choice tests in pharmacology were carried out with students who had no previous experience in this kind of examination. The curriculum in pharmacology was divided into four parts. Each part was followed by a test consisting of 90 questions. A special arrangement was made for those students who voluntarily participated in all four tests during academic year. Pass marks in all four completed tests were considered equivalent to a successful outcome in the one oral examination which is, at present, obligatory. In order to encourage a high level of participation amongst the students, failure in one or more of the tests had no adverse consequences. As a result, a markedly increased attendance at lectures, as well as a positive feed back of information for the faculty, were ascertained and assessment of the efficiency of the teaching methods facilitated. Application of multiple choice tests to the teaching of Pharmacology to undergraduate students proved to be recommendable, both as a test procedure and of advantage in the actual learning process.
Austria↗
[Blood propionic acid with hyperammonemic coma].
We report on a mature male newborn who presented clinically on the 2nd day of live with poor feeding and acidotic breathing. Laboratory findings like severe metabolic acidosis, hyperammonemia, hyperglycinemia, ketonuria and elevated urinary excretion of lactate and propionate suggested the presence of organoacidopathia. Propionic acidemia, however could be diagnosed definitively only when the characteristic urinary and blood metabolites were found during the state of a hyperammonemic coma provoked by a fully oral protein regimen. The diagnosis was affirmed by reduced propionate fixation and by reduced propionyl-CoA-carboxylase shown in the patient's skin fibroblasts.
Acidosis↗
Intrascrotal tumors in the older male.
Although the greatest incidence of testicular neoplasms is in the age group 20 to 35.9% of all intrascrotal tumors occur in males over 60. They may be classified into four major groups based on the tissue origin of the tumor. The most common group comprising 50% are lymphoreticular neoplasms or lymphomas. They occur in both blacks and whites, result in a diffuse enlargement of the testis and commonly involve the epididymis and cord. Prognosis is poor and survival is usually less than two years. Germ cell tumors comprise 25% and the tumors are usually large. Most of them are the classical seminoma which has a good prognosis following orchiectomy and retroperitoneal radiation. A few are the spermatocytic seminoma which is usually benign. Three percent are teratocarcinoma with embryonal elements which is highly malignant and survival less than two years. Ten percent are tumors of gonadal stromal origin. There are two types, the Leydig cell and the more rare Sertoli cell. About one-fourth of these patients develop gynecomastia and some a decrease in libido. The prognosis is good as less than 10% of these tumors are malignant. Neoplasms of supportive and paratesticular structures comprise a heterogeneous group of benign and malignant lesions and comprise about 15% of intrascrotal tumors. Most of them have the same features as tumors of similar tissues encountered throughout the body. They are the mesothelioma or adenomatoid tumor, fibroma, rhabdomyosarcoma, leiomyoma, lipoma, liposarcoma, mucinous cystadenocarcinoma, and leiomyosarcoma. As in all intrascrotal tumors, the diagnosis, treatment, and prognosis are based on the microscopic findings after removal of the tumor.
Age Factors↗