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Biomass has the potential to make a major contribution to a renewable future economy. If biomass is gasified, a wide variety of products (e.g., bulk chemicals, hydrogen, methane, alcohols, diesel) can be produced. In each of these processes, gas cleaning is crucial. Impurities in the gas can cause catalyst poisoning, pipe plugging, unstable or poisoned end products, or harm the environment. Aromatic compounds (e.g., benzene, naphthalene, pyrene), in particular, have a huge impact on stable operation of syngas processes. The removal of these compounds can be accomplished by wet, dry, or hot gas cleaning methods. Wet gas cleaning methods tend to produce huge amounts of wastewater, which needs to be treated separately. Hot gas cleaning methods provide a clean gas but are often cost intensive due to the high operating temperatures and catalysts used in the system. Another approach is dry or semi-dry gas cleaning methods, including absorption and adsorption on solid matter. In this work, special focus was laid on adsorption-based gas cleaning for syngas applications. Adsorption and desorption test runs were carried out under laboratory conditions using a model gas with aromatic impurities. Adsorption isotherms, as well as dynamics, were measured with a multi-compound model gas. Based on these results, a temperature swing adsorption process was designed and tested under laboratory conditions, showing the possibility of replacing conventional wet gas cleaning with a semi-dry gas cleaning approach. [ABSTRACT FROM AUTHOR]

An increasing share of power production from sun and wind energy in Europe led to an increasing interest in novel energy storage technologies. The production of hydrogen from electricity via electrolysis enables the conversion of electrical energy into chemical energy, which can be stored with high energy density, if further process steps are applied. The Fischer-Tropsch process is well-known for the production of diesel fuel from different fuel types. Within the present work, results of an experimental campaign with a laboratory-scale Fischer-Tropsch plant are illustrated. The described experimental campaign was executed to determine the performance of a diesel fuel production from biomass. Furthermore, the investigation included the integration of hydrogen from wind power promoting a combined power-to-gas and biomass-to-liquid process. As a result, the investigated process is aiming at the storage of wind energy by the use of a chemical process enabling high energy density. Therefore, extensive measurement data was collected illustrating the influence of load changes on the operated laboratory-scale Fischer-Tropsch plant. The experimental campaign showed that an increased gas stream feed, enabled by the addition of hydrogen from wind power, leads to an increased output of Fischer-Tropsch products. Furthermore, the executed experimental campaign proved the suitability of different catalysts with respect to fluctuating load changes. [ABSTRACT FROM AUTHOR]

Since 2011, a pilot plant for the production of mixed alcohols (MAs) from biomass-derived synthesis gas has been in operation. The pilot plant uses synthesis gas provided by a biomass-based combined heat and power plant (CHP) in Güssing, in which the fixed bed reactor is filled with a sulfidized molybdenum catalyst (MoS). The advantage of a sulfidized catalyst is resistance to sulfur components. Sulfur resistance significantly lowers the operating costs of such a plant. The main parts of the mixed alcohol synthesis plant in Güssing are a steam reforming unit, a glycol scrubber, a compression step, a fixed bed reactor for the synthesis itself, a condensation vessel for the separation of alcohols from the gas stream, and an expansion valve. The main aim of this project in the last year was to perform parameter variation to investigate the optimal operation point of the plant and to use these parameters to conduct long-time trials over several days. Parameter variation showed the impact of reaction temperature, pressure, and space velocity on product yield and distribution. The influence of the gas composition on the product distribution and side products was also investigated. This study was dedicated to investigating the influence of the ethylene content in the synthesis gas on the formation of propanol and ethyl mercaptan (CHS). During the experiments, several liters of MAs were produced. The alcohols consisted mainly of alcohols from carbon numbers between one and three. One of the main results of the first experiments was that the ethylene content in the synthesis gas has a high impact on the product distribution and is also responsible for side reactions to sulfur components. [ABSTRACT FROM AUTHOR]

• Urea recycling has potential to improve nitrogen efficiency of ruminants. • Low rumen ammonia concentrations stimulate productive ruminal use of recycled urea. • Dietary nitrogen should be supplied in such a way that supports urea recycling. • Postruminal delivery may expand the use of urea as a ruminant feed ingredient. • Further understanding of urea absorption, metabolism, and recycling is warranted. Ruminants have evolved with the capability to recycle endogenous urea to the gastrointestinal tract (GIT). Ruminal ammonia derived from urea recycling makes a net contribution to digestible N flow if it is used to synthesise microbial protein. The dynamics of urea recycling and its quantitative importance to the N economy of ruminants are affected by dietary and physiological factors. In general, the transfer of endogenous urea to the GIT is related positively to blood urea concentration and rumen-fermentable energy supply and negatively to ruminal ammonia concentration. After consumption of a meal rich in rumen-degradable N, ruminal ammonia concentrations peak and can exceed the rate of carbohydrate fermentation, resulting in inefficient ammonia capture by microbes. These periods are characterised by greater ruminal ammonia efflux and reduced urea influx. A low ruminal ammonia concentration over time can stimulate recycling of endogenous urea-N to the rumen and its capture into microbial protein and reduce N excretion. Shifting protein digestion to the postruminal GIT can reduce ruminal ammonia concentration and increase plasma urea concentration, conditions that should promote greater reliance on urea recycling to meet N requirements of the rumen. Their ability to use non-protein N, of dietary or endogenous origin, to synthesise metabolisable protein and subsequently meat and milk contributes positively to the human-edible protein efficiency of ruminants. Dietary urea is rapidly degraded to ammonia in the rumen, and high rates of ammonia absorption across the rumen wall when a urea-rich meal is consumed can lead to hypophagic and toxic effects associated with urea feeding. Non-protein N absorbed in the postruminal GIT can contribute substantially to net urea and ammonia uptake into the portal vein, which reflects the potential for targeted urea release in postruminal sections of the GIT. In this review, we suggest that the regulation of urea recycling to the rumen is a critical step towards improved efficiency of ruminal N utilisation. We describe an approach by which postruminal urea supplementation, as an alternative to its ruminal application, may allow a slow and steady return of N to the rumen, avoid peaks in ammonia concentration associated with feeding, confer a greater and more efficient microbial synthesis, and improve fibre digestion compared with conventional urea supplementation. [ABSTRACT FROM AUTHOR]

Rice straw (RS) has generally not been considered as an ingredient in dairy heifer or cow rations in the developed world, at least partly due to its tough physical character. However, recent research aimed at developing harvesting methods that increase mixability and reduce animal-sorting problems has identified straw-preparation methods with substantially improved physical properties. A 'slicer' baler method was used to prepare RS for use in two feeding studies, so as to determine effects of RS versus wheat straw (WS) as ingredients in a total mixed ration (TMR) on dairy heifer performance. The WS-TMR-fed heifers in Experiment 1 had substantially higher frame growth than did RS-TMR-fed heifers, and maintained body condition score, while RS heifers lost body condition score. A main reason for reduced performance with the RS-TMR-fed heifers was at least partly due to reduced DM intake, which may have been due to slower-degrading fibre and/or a higher dietary cation-anion difference (DCAD) of the RS-TMR. However, the large treatment differences may also have been due to compensatory growth in WS-TMR-fed heifers as all heifers had been fed the RS-TMR before initiation of the study. The WS-TMR-fed heifers in Experiment 2 had the same frame growth, but somewhat higher BCS accumulation, than did RS-TMR-fed heifers, which may have been due to the lower straw-inclusion levels in the diets, smaller treatment differences in DCAD versus Experiment 1 and/or a lack of compensatory growth, since all heifers had been fed a higher-energy diet before the study. However, after a further 28-day period, when all calves were fed the WS-TMR, measures of skeletal growth and BCS had converged. Overall, results support a lower nutritional value of RS than WS, while demonstrating the practical utility of using energy restriction-realimentation regimes to increase heifer growth efficiency. Rice straw has generally not been considered as a feed for dairy cattle in the developed world, partly due to its tough physical character. While our results confirmed the lower nutritional value of rice vs. wheat straw, they demonstrated the practical utility of using energy restriction/re-alimentation feeding systems to increase heifer growth efficiency. [ABSTRACT FROM AUTHOR]

Summary. Very few mutations of the gene encoding for coagulation factor X (FX) have been found associated with intracranial haemorrhage (ICH) due to FX deficiency (FXD). No guidelines exist as to when prophylaxis in FXD should be started and how patients at risk for ICH can be identified. We report on a novel mutation causative for ICH in a family of Iranian origin and provide a summary of all published mutations in the FX gene related to ICH. The index patient is an infant with umbilical bleeding requiring blood transfusion in the postnatal period. The international normalized ratio (6.01) and activated partial thromboplastin time (117 s) were prolonged. Coagulation factor analysis was normal except for FX activity (<1%). At 4 months, the child suffered a spontaneous severe intracranial haemorrhage. The child was the product of a consanguineous union. Four of five available family members from three generations displayed minor bleeding symptoms and mildly reduced FX. Sequencing of FX gene demonstrated homozygosity for a novel duplication A (c.1402_1403dupA)* in exon 8 and heterozygosity in four family members. We compare this case to all 15 patients with FXD and ICH and their 11 known mutations described so far. This case illustrates a pattern of FXD (a male neonate with umbilical or gastrointestinal bleeding, very low FX:C (<1%) and an underlying homozygous genotype) who may be at high risk for ICH. In these cases, we recommend to start early prophylactic substitution of FX to prevent a possible life-threatening haemorrhage. [ABSTRACT FROM AUTHOR]

Upgrading of Fischer-Tropsch (FT) biowaxes to second-generation biofuels via hydroprocessing is the final step for increasing the fuel amount of the overall biomass conversion route: gasification of lignocellulosic biomass, FT synthesis, and hydroprocessing. The typical FT product portfolio consists of high molecular weight paraffinic waxes as the main product and FT fuels in the diesel and naphtha boiling range. OMV's objective and contribution to the project focus on achieving coprocessing of FT biowaxes with fossil feedstock using existing hydrotreating plants of crude oil refineries. Various test runs have been examined with a conventional refining catalyst under mild conditions (380-390°C, 5.8 MPa; WHSV, 0.7-1.3 h) in a pilot plant. Pure FT biowax is converted to gases, fuels, and an oil/waxy residue in a fixed-bed reactor with a porous catalyst layer technology. The presence of hydrogen in the reaction chamber reduces the fast deactivation of the catalyst caused by the formation of a coke layer around the catalyst particle surface and saturates cracked hydrocarbon fragments. Another approach is the creation of synthetic biodiesel components with excellent fuel properties for premium fuel application. Basically, premium diesel fuel differs from standard diesel quality by cetane number and cold flow properties. Hydroprocessed synthetic biodiesel (HPFT diesel) has compared to conventional diesel advantages in many aspects. Depending on the catalyst selected, premium diesel quality can be obtained by shifting cold flow operability properties of HPFT fuels to a range capable even under extreme cold conditions. In addition, a high-quality kerosene fraction is obtained to create bio jet fuels with an extremely deep freezing point, as low as −80°C. The isomerization degree, as well as the carbon number distribution of high paraffinic profile, and the branching degree have a major impact on the cold flow properties and cetane number. FT diesel has, compared to HPFT diesel, a slightly higher derived cetane number (DCN > 83) and a cloud point of −9°C, whereas HPFT diesel reaches values as low as −60°C. Although the HPFT naphtha obtained consists of high amounts of isoparaffins, the RON/ MON values are comparable to fossil straight-run naphtha. The reason is that the branching degree of isoparaffins from the naphtha fraction is not sufficiently high enough to reach the typical octane number values of gasoline products delivered at filling stations. Assuming the goal of launching a premium biodiesel or biokerosene fuel to the market, these hydroprocessed synthetic biofuels from FT biowaxes are ideal blending components. [ABSTRACT FROM AUTHOR]

This article presents aspects regarding the Fischer-Tropsch (FT) synthesis method. Several reactor types are taken into account and operation modes are presented with their advantages. Production of syngas from methane or coal and conversion of the syngas to a range of fuels and chemicals could become increasingly of interest as the reserves of crude oil are depleted and the price of crude oil rises, as seen in Figure 1 [7]. Experiments undertaken in Güssing, Austria, proved that biomass represented by woodchips can be a valuable feedstock for FT biodiesel production. [ABSTRACT FROM AUTHOR]

This work describes an experimental and numerical study of the TOX®- clinching process and its mechanical strength due to different surface conditions (blank, electro galvanized, corrosion protection primer (CPP) coated). The main purpose of using different types of surface conditions is to analyze their influences on the geometry and mechanical strength of the clinched joint. Finite element analysis (ABAQUSExplicit) is used to model the clinching process as well as the subsequent loading of the joint in the shear and cross tension test. The influence of the plastic anisotropy of the material is analyzed by evaluation of the punch force-displacement curve and the strength of clinched joint under these loading conditions. [ABSTRACT FROM AUTHOR]

Primary objective : To investigate the utility of using a new method of assessment for deficits in selective visual attention (SVA). Methods and procedures : An independent groups design compared six participants with brain injuries with six participants from a non-brain injured control group. The Sensomotoric Instruments Eye Movement system with remote eye-tracking device (eye camera) and two sets of eight stimuli were employed to determine if the camera would be a sensitive discriminator of SVA in these groups. Main outcomes and results : The attention profile displayed by the brain injured group showed that they were slower, made more errors, were less accurate and more indecisive than the control group. Conclusions : The utility of eye movement analysis as an assessment method was established, with implications for rehabilitation requiring further development. [ABSTRACT FROM AUTHOR]

Background: Arylsulfatase A (ASA)-deficient mice are a model for the lysosomal storage disorder metachromatic leukodystrophy. This lipidosis is characterised by the lysosomal accumulation of the sphingolipid sulfatide. Storage of this lipid is associated with progressive demyelination. We have mated ASA-deficient mice with mice heterozygous for a non-functional allele of UDP-galactose: ceramide-galactosyltransferase (CGT). This deficiency is known to lead to a decreased synthesis of galactosylceramide and sulfatide, which should reduce sulfatide storage and improve pathology in ASA-deficient mice. Results: ASA-/- CGT+/- mice, however, showed no detectable decrease in sulfatide storage. Neuronal degeneration of cells in the spiral ganglion of the inner ear, however, was decreased. Behavioural tests showed small but clear improvements of the phenotype in ASA-/- CGT+/- mice. Conclusion: Thus the reduction of galactosylceramide and sulfatide biosynthesis by genetic means overall causes modest improvements of pathology. [ABSTRACT FROM AUTHOR]

Primary objective : To explore the effects of religious identity, gender and socioeconomic status (SES) on public attitudes towards survivors of brain injury. Research design : An independent groups design was used to compare the attitudes of Northern Irish participants. Methods and procedures : The participants were asked to complete a modified form of the Community Attitudes to Mental Illness scale. The new questionnaire replaced the original scales’ emphasis on mental illness with that of brain injury. Complete data was available for 179 participants for the religious identity and gender analysis and 124 for gender and SES. Analyses of variance were conducted on these variables. Outcomes and results : Significant differences between male and female attitudes were found along with significant interactions between religious identity and gender and SES and gender. Conclusions : Religious, economic and gender-based divisions in society affect attitudes towards survivors of brain injury. [ABSTRACT FROM AUTHOR]

Introduction: Clinical variability associated with the common 22q11.2 microdeletion is well known, and has led to a broad application of FISH diagnostics with probes for loci TUPLE1 or D22S75 (N25), although, rarely reported atypical deletions associated with the same phenotypic spectrum would not be discovered by these probes. As most types of 22q11.2 deletions occur between low copy repeats within the region (LCR22), we assumed that atypical deletions should be more common than has been reported. To address this question and the possibility of a deletion size related genotype-phenotype correlation, we systematically assessed the frequency of typical and atypical 22q11.2 deletions in a large cohort of patients. Methods: We used a set of 10 fluorescent in situ hybridisation (FISH) DNA probes, capable of detecting all reported and hypothetical deletions between the LCR22, and analysed 350 patients. Deletion sizes in atypical deletions were established by use of further FISH probes. Frequency of certain atypical deletions was analysed in controls by FISH and quantitative PCR. Results: Patients with conotruncal heart defects (ctCHD) and with typical VCFS phenotype showed the common 3 Mb or nested 1.5 Mb deletions (in 18.5% and 78.6%, respectively), but no atypical deletion, while 5% (3/63) of patients with a mildly suggestive, atypical phenotype showed atypical distal deletions, which were not detected in patients with mental retardation of unknown origin or in healthy controls. Discussion: These statistically significant differences demonstrate that atypical distal 22q11.2 deletions are very uncommon in patients with ctCHDs, while atypical congenital heart defects and mild dysmorphism are recognisable feature of atypical distal deletions. Further phenotype-genotype analysis disclosed association of significant developmental delay with the distal part of the common deletion region, and choanal atresia and atypical CHDs with the adjacent distal deletion region. [ABSTRACT FROM AUTHOR]

Arylsulfatase A (ASA) knockout mice represent an animal model for the lysosomal storage disease metachromatic leukodystrophy (MLD). Stem cell gene therapy with bone marrow overexpressing the human ASA cDNA from a retroviral vector resulted in the expression of high enzyme levels in various tissues. Treatment partially reduces sulfatide storage in livers exceeding 18 ng ASA/mg tissue, while complete reduction was observed in livers exceeding 50 ng ASA/mg tissue. This corresponds to about 80% and 200% of normal enzyme activity. Similar values seem to apply for kidney. A partial correction of the lipid metabolism was detectable in the brain where the galactoerebroside/sulfatide ratio, which is diminished in ASA-deficient mice, increased upon treatment. This partial correction was accompanied by amelioration of neuropathology; axonal cross-sectional areas, which are reduced in deficient mice, were significantly increased in the saphenic and sciatic nerve but not in the optic nerve. Behavioral tests suggest some improvement of neuromotor abilities. The gene transfer did not delay the degeneration occurring in the acoustic ganglion of ASA-deficient animals. The limited success of the therapy appears to be due to the requirement of unexpected high levels of ASA for correction of the metabolic defect. [ABSTRACT FROM AUTHOR]

The inherited deficiency of arylsulfatase A (ASA) causes lysosomal accumulation of sulfoglycolipids (mainly sulfo-galactosylceramide, S-GalCer ) and leads to metachromatic leukodystrophy in humans. Among visceral organs, kidneys are particularly affected. In the present study, the regional distribution and temporal development of sulfoglycolipid storage in kidneys of ASA-/- mice was investigated histochemically (alcian blue) and ultrastructurally. Furthermore, the sulfoglycolipid storage was examined in kidneys of double-knockout mice, which are incapable of: (a) degrading any sulfolipids (ASA-/-) and (b) synthesizing the major sulfolipid S-GalCer because of deficiency for galactosylceramide synthase (CGT), with the aim to search for additional ASA substrates. In ASA-/- mice, the nephron segments could be ranged in the order of decreasing sulfolipid storage: thin limbs of long-looped nephrons ~ thick ascending limbs > distal convoluted tubules > collecting ducts ~ short thin limbs. Macula densa and proximal tubules were unaffected. In ASA-/-/CGT-/- mice, the long thin limbs and distal convoluted tubules resembled those of ASA-/-/CGT+/+ mice, while the other segments showed less storage. The results suggest that the turnover of sulfolipids in general is highest in the distal nephron except macula densa, and that long thin limbs and distal convoluted tubules are the main sites for turnover of a minor sulfolipid species, which is known to be synthesized in the kidney of CGT-/- mice. [ABSTRACT FROM AUTHOR]

The inherited deficiency of arylsulfatase A (ASA) in humans causes lysosomal accumulation of sulfatides in visceral organs and in the nervous system and leads to wide-spread demyelination (metachromatic leukodystrophy, MLD). ASA-deficient mice have previously been generated by means of targeted gene disruption. In the present study, visceral organs of ASA-deficient mice were investigated. A simple technique for the histochemical detection of accumulated sulfatides was elaborated using pre-embedding staining with alcian blue. The gall bladder, intrahepatic bile ducts, exocrine pancreatic ducts, respiratory epithelium and, with low degree, testicular Sertoli cells, showed sulfolipid storage. The storage pattern in the kidney will be described in a separate publication. Hepatocytes, pancreatic islets, adrenal glands, and gastric epithelium were unaffected. Ultrastructurally, the intralysosomal storage material displayed parallel and concentric lamellar patterns. Apart from some differences, the topographic distribution of the sulfatide storage resembled that in human MLD. In addition to being an animal model of the human disease, the ASA-deficient mouse may be useful for investigating the cell biology of sulfolipids in visceral organs. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy of humans is an inherited sulfatide lipidosis due to deficiency of arylsulfatase A (ASA). As an animal model, ASA(-/-) mice have been generated. A previous study showed that the mice lose most of their spiral (acoustic) ganglion cells and develop deafness by the end of the first year of life. The present report describes the sulfatide histochemistry and ultrastructure of the inner ears of ASA(-/-) mice at 0.5–26 months of age. Lysosomal accumulation of sulfatides was observed in various cell types such as Schwann cells that maintain the myelin sheaths around the spiral and vestibular ganglion cells, periaxonal Schwann cells, macrophages, and spiral and vestibular ganglion cell perikarya. In the spiral ganglion, the only surviving neurons were those which are primarily non-myelinated (type 2 cells). However, the myelinated spiral neurons and their processes were rarely encountered within the process of dying, suggesting that this was a rather rapid process. Since the myelin sheaths around dying perikarya and axons appeared structurally normal, the primary cause of the neuronal cell death seems to reside in the neuron. In contrast to the spiral ganglion, the vestibular ganglion as a whole survived throughout the period of observation. The organ of Corti and the vestibular apparatus appeared preserved at the light microscopic level, despite massive sulfatide storage in the vestibular hair cells. [ABSTRACT FROM AUTHOR]

Copyright of Clinical Research in Cardiology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Clinical Research in Cardiology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Reports on a case of a premature newborn who developed spontaneous aortic thrombosis and was successfully treated with recombinant tissue plasminogen activator. Association of aortic thrombosis with umbilical artery catheterization; Complications of condition; Necessity of immediate treatment; Diagnosis of patient with having activated protein C resistance due to heterozygosity for factor V Leiden.

Rats were trained to discriminate the effects of nicotine (0.4 mg/kg SC) plus midazolam (0.2 mg/kg SC) from those of saline in a two-bar operant conditioning procedure involving a tandem schedule of food reinforcement. After discrimination training, the component drugs of the mixture produced very considerable amounts of drug-appropriate responding when given separately. Mecamylamine and Ro 15-1788 only slightly attenuated the discriminative response to the mixture when given separately, but completely blocked the response when administered together. In different groups of rats trained to discriminate nicotine or midazolam separately from saline, neither drug appreciably altered the dose-response curve for the other, suggesting a minimal role for pharmacological interactions when effects of mixtures were assessed. The results suggest that the two components of a compound drug-produced stimulus can be perceived separately rather than being blended into a homogenous entity. Knowledge of the characteristics of compound drug-produced stimuli may aid interpretation of the discriminative effects of single drugs with wide spectra of action. [ABSTRACT FROM AUTHOR]

The purpose of the present investigation was to examine whether or not a di-cationic amphiphilic compound that is known ( 1) to be accumulated in lysosomes and ( 2) to form insoluble complexes with sulfated glycosaminoglycans (sGAG) in vitro, is able to interfere with the lysosomal degradation of sGAG, thus causing mucopolysaccharidosis (MPS) in cultured cells. Acridine Orange (AO) was chosen for this study since it is known to meet the above requirements. Cultured fibroblasts from rat cornea were exposed to AO (0.7 μ M to 30 μ M) for 72 h; tilorone served as reference compound. AO (1.75 μ M to 10 μ M) caused MPS in a concentration-dependent manner, higher concentrations were cytotoxic. MPS was demonstrated by cytochemical staining with cuprolinic blue and by measuring the intracellular accumulation of [S]-GAG. The sGAG-complexing properties of AO were demonstrated by using it as a fixative for the intralysosomal sGAG accumulated in tilorone-treated cells. The present findings give support to the working hypothesis that the MPS induced by di-cationic amphilphilic drugs is due to the formation of insoluble sGAG-drug complexes, with the result that the sGAG become resistant to lysosomal degradation. [ABSTRACT FROM AUTHOR]

The purpose of the present investigation was to examine whether or not a di-cationic amphiphilic compound that is known ( 1) to be accumulated in lysosomes and ( 2) to form insoluble complexes with sulfated glycosaminoglycans (sGAG) in vitro, is able to interfere with the lysosomal degradation of sGAG, thus causing mucopolysaccharidosis (MPS) in cultured cells. Acridine Orange (AO) was chosen for this study since it is known to meet the above requirements. Cultured fibroblasts from rat cornea were exposed to AO (0.7 μ M to 30 μ M) for 72 h; tilorone served as reference compound. AO (1.75 μ M to 10 μ M) caused MPS in a concentration-dependent manner, higher concentrations were cytotoxic. MPS was demonstrated by cytochemical staining with cuprolinic blue and by measuring the intracellular accumulation of [S]-GAG. The sGAG-complexing properties of AO were demonstrated by using it as a fixative for the intralysosomal sGAG accumulated in tilorone-treated cells. The present findings give support to the working hypothesis that the MPS induced by di-cationic amphilphilic drugs is due to the formation of insoluble sGAG-drug complexes, with the result that the sGAG become resistant to lysosomal degradation. [ABSTRACT FROM AUTHOR]

The cationic dyes Cuprolinic Blue (CB) and Toluidine Blue (TB) were used to preserve the intralysosomal storage material accumulating in tilorone-induced mucopolysaccharidosis. As shown in previous studies, the stored glycosaminoglycans (GAGs) are leached during the conventional fixation procedure, with the result that the lysosomes appear empty. In the present study, the liver, spleen, and cornea-conjunctiva of tilorone-treated rats were examined. The application of CB in the presence of 0.1 M or 0.3 M MgCl simultaneously with, or subsequently to the primary fixative yielded electron-dense precipitates within the storage lysosomes. When TB (0.1%) was added to the primary fixative, the storage lysosomes contained filamentous structures arranged in reticular patterns. With increasing TB concentrations (up to 1%) the lysosomes increasingly often showed apparently amorphous storage material which was continuous with the reticular filamentous structures. Similar ultrastructural patterns were obtained with GAG-TB complexes prepared in vitro. The intralysosomal storage material preserved by TB is interpreted as GAG-TB precipitates. In conclusion, the use of CB provides a method which allows direct cytochemical demonstration of the subcellular sites of GAG-storage. The use of TB represents an easy method to obtain electron micrographs pathognomonic of the mucopolysaccharidosis induced by tilorone and congeners. Either method may be helpful to detect this adverse drug effect at the subcellular level. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic administration of certain cationic amphiphilic drugs to rats and other species induces generalized lysosomal storage of polar lipids. In rat, retinal pigment epithelium belongs to the tissues which are most susceptible toward this adverse drug action. Drug-induced lipidosis in retinal epithelium is characterized ultrastructurally by the occurrence of numerous cytoplasmic inclusion bodies with a crystalline-like internal structure. Freeze-fracture images of such inclusions indicate that they consist of phospholipids aggregated in a hexagonal phase. The quantitative and structural uniformity of lipidosis in retinal pigment epithelial cells appears to reflect the uniformity of the lipid load which is physiologically imposed on the digestive apparatus of the epithelium due to the phagocytosis of photoreceptor membranes. The pathophysiological significance of drug-induced lipidosis in pigment epithelium remains to be clarified. [ABSTRACT FROM AUTHOR]

Several immunomodulatory drugs, all of them symmetrically substituted dicationic amphiphilic compounds, are known to cause lysosomal storage of sulfated glycosaminoglycans (GAGs) in intact animals and cultured fibroblasts. The storage is due to impaired GAG degradation. The standard compound is tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one). In the present study two bis-aminomethyl anthrachinones were examined for their ability to induce lysosomal GAG storage in cultured bovine corneal fibroblasts. For reference, a bis-aminoethoxy-anthrachinone compound (RMI-10.024) was included, which is known to be a potent inducer of lysosomal GAG storage. The present morphological, radiochemical, and biochemical results show that the bis-aminomethyl anthrachinone compounds investigated cause lysosomal storage of GAGs, although with significantly lower potencies than the bis-aminoethoxy anthrachinone. Dermatan sulfate contributed approximately 90% to the drug-induced increment of intracellular GAGs. The present results suggest that the length of the side chains, i. e., the distance between the aromatic ring system and the protonizable nitrogen of the side chains, and the position of the side chains relative to the aromatic ring system are important molecular features influencing the potency of inducing lysosomal GAG storage. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulphatase A (ASA; EC 3.1.6.8). Deficiency of this enzyme causes intralysosomal storage of the sphingolipid cerebroside sulphate. This lipid is abundant in myelin and it may thus not be surprising that storage mainly affects oligodendrocytes. Patients suffer from a progressive demyelination causing various neurological symptoms. The disease is fatal and treatment is not available. The human ASA gene has been cloned and more than 40 mutations have been analysed that cause metachromatic leukodystrophy. Few of these alleles are frequent among patients, whereas most mutant alleles have only been found in single families. Since MLD has only been described in humans and no naturally occurring animal model has been described, ASA-deficient mice have been generated by homologous recombination. The ASA knockout mice are unable to degrade sulphatide and store the lipid intralysosomally. The pattern of lipid storage in neuronal and nonneuronal tissues resembles that described for patients. In the nervous system, lipid storage is found in oligodendrocytes, astrocytes and some neurons. Animals display an astrogliosis and a decreased average axonal diameter. Purkinje cells and Bergmann glia of the cerebellum are morphologically aberrant. Demyelination is seen in the acoustic ganglion and occurs between the ages of 6 and 12 months. The animals are deaf at this age and display various neuromotor abnormalities. However, compared to humans the mice have a surprisingly mild phenotype, since they have a normal life span and do not develop widespread demyelination. ASA-deficient mice have been transplanted with bone marrow, which was transduced with a retroviral vector expressing arylsulphatase A. The majority of transplanted animals display sustained expression of arylsulphatase A from the retroviral construct up to 5 months after transplantation. However, preliminary data suggest that this therapeutic approach does not reduce storage material. [ABSTRACT FROM AUTHOR]

Rats were treated with several amphiphilic, cationic compounds that are known to cause generalized lipidosis (chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine). After prolonged drug treatment the neurohypophysis showed severe morphologic alterations particularly in Herring bodies (HB), perivascular cells, and pituicytes. HBs displayed the following abnormalities: (a) great accumulation of autophagic vacuoles that contained neurosecretory granules (NSG); (b) numerous coarse osmiophilic conglomerates; (c) masses of multilamellated material; (d) reduced numbers of intact NSGs. Perivascular cells accumulated large lamellated inclusion bodies. Pituicytes contained membrane-bound crystalloid inclusion bodies. The noxious effect of chlorphentermine and 1-chloro-amitriptyline was more pronounced than that of iprindole and clomipramine. The alterations in perivascular cells and in pituicytes are typical of drug-induced lipidosis. The lesions in HBs are tentatively explained as follows: HBs were previously proposed to be the sites of normally occurring intraaxonal disposal of excess neurosecretory material. The present experimental conditions interfere with this catabolic process. Incomplete digestion of the axoplasmic constituents due for disposal might result in abnormal accumulation of NSG-containing autophagic vacuoles, osmiophilic conglomerates, and multilamellated material. This eventually leads to degeneration of HBs. The functional implications of the neurohypophysial lesions remain to be elucidated by functional experiments. [ABSTRACT FROM AUTHOR]