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Amino acid dysbalance in liver failure is favourably influenced by recirculating albumin dialysis (MARS).

INTRODUCTION: Dysbalance between branched chain (BCAA) and aromatic amino acids (AAA), which can be quantified by a low Fischer's Index (SigmaBCAA/SigmaAAA), as well as elevated levels of free tryptophan in plasma are common in hepatic failure and may contribute to the development of hepatic encephalopathy. AIM: To evaluate the influence of a new extracorporeal detoxification system for liver failure (Molecular Adsorbents Recirculating System, MARS(R), i.e. dialysis against a recirculating albumin solution cleaned online by charcoal and an anion exchange resin) on plasma tryptophan and Fischer's Index. METHODS: Plasma samples were taken before, during and after MARS treatments (n = 11, mean blood flow 135 ml/min, mean dialysate flow 120 ml/min, high flux polysulfone membrane). Simultaneous to blood sampling, aliquots of the albumin dialysate were taken between the elements of the dialysate circuit. RESULTS: Fischer's Index in systemic blood increased during MARS by 24% (from 1.44 to 1.79, P < 0.001; mean treatment duration, 5.5 h). Systemic tryptophan level was significantly reduced at the same time (-25%, n = 8). Amino acid removal rates from plasma during a single dialyser passage ranged from 10 to 53%. In particular, AAA were preferentially removed (42-44% throughout treatment), while BCAA removal was 28-46% initially and later declined to 24-28%. A maximum concentration gradient between plasma and dialysate was maintained for the AAA throughout treatment through their apparently complete removal by the charcoal adsorber. Conversely, BCAA removal at both adsorbers was only minor. As a result, Fischer's Index showed a significant increase in the processed plasma, which became even more pronounced with increasing treatment duration. CONCLUSIONS: MARS enables an elevation of a pathologically decreased Fischer's Index as well as a reduction of systemic tryptophan levels in patients with liver failure. The effects of MARS on plasma amino acid dysbalance may contribute to an improvement of hepatic encephalopathy.

Amino Acids↗

Albumin dialysis: single pass vs. recirculation (MARS).

The single pass albumin dialysis (SPAD) was reported to be an alternative to the Molecular Adsorbent Recirculating System (MARS) for the effective removal of protein bound substances in liver failure. Three SPAD experiments using different albumin concentrations and dialysate flow rates were performed. In each experiment, 1000 ml human donor plasma, spiked with 250 mg unconjugated bilirubin, 200 mg sulfobromophthalein (BSP) and 115 mg glycocholic acid (N-[3alpha,7alpha,12alpha-trihydroxy-24-oxycholan-24-yl]glycine) - a conjugated bile acid (BA), circulated in a closed loop with 150 ml/min and was dialysed against albumin solution. These substances are bound to the different binding sites of albumin and have different association constants. For the comparison, the standard MARS experiment was performed using the same plasma flow rate of 150 ml/min. Moreover, the clearances of bilirubin for MARS and SPAD during clinical treatments were calculated using own data and those reported by Seige, Kreymann, Jeschke, et al. in Transplant Proc 1999; 31: 1371-5. The concentrations of bilirubin, BSP and BA were measured in plasma and dialysate and for these substances clearances (Cl) were calculated. It is known that the elimination rate of bilirubin is not very high during albumin dialysis in comparison to other substances, like bile acids, due to the high association constant. An increase of albumin concentration or the flow rate improved the efficacy but also raised the costs substantially. In this study, we have shown that MARS is the more effective kind of albumin dialysis for the important substances like bile acids. By SPAD an improvement of efficacy can be reached only by dramatic increase of the costs. Also, the earlier experiments showed that MARS is safer because of the removal of the stabilizers, which are normally included in the commercial albumin solutions.

Bile Acids and Salts↗

Geology and insolation-driven climatic history of Amazonian north polar materials on Mars.

Mariner 9 and Viking spacecraft images revealed that the polar regions of Mars, like those of Earth, record the planet's climate history. However, fundamental uncertainties regarding the materials, features, ages and processes constituting the geologic record remained. Recently acquired Mars Orbiter Laser Altimeter data and Mars Orbiter Camera high-resolution images from the Mars Global Surveyor spacecraft and moderately high-resolution Thermal Emission Imaging System visible images from the Mars Odyssey spacecraft permit more comprehensive geologic and climatic analyses. Here I map and show the history of geologic materials and features in the north polar region that span the Amazonian period (approximately 3.0 Gyr ago to present). Erosion and redeposition of putative circumpolar mud volcano deposits (formed by eruption of liquefied, fine-grained material) led to the formation of an Early Amazonian polar plateau consisting of dark layered materials. Crater ejecta superposed on pedestals indicate that a thin mantle was present during most of the Amazonian, suggesting generally higher obliquity and insolation conditions at the poles than at present. Brighter polar layered deposits rest unconformably on the dark layers and formed mainly during lower obliquity over the past 4-5 Myr (ref. 20). Finally, the uppermost layers post-date the latest downtrend in obliquity <20,000 years ago.

Journal Article↗

Successful MARS treatment in severe cholestatic patients with acute on chronic liver failure.

Extracorporeal liver devices have gained great attention as a complementary approach to liver transplantation in patients with acute on chronic liver failure. Among others, Molecular Adsorbent Recycling System (MARS) is a hemodiafiltration against albumin able to remove low molecular weight toxins. We aimed to validate the use of MARS in patients presenting with acute on chronic liver failure with severe cholestasis. We enrolled 7 patients with acute on chronic liver failure, presenting with bilirubin >25 mg/dl and hepatorenal syndrome and/or hepatic encephalopathy grade >II. Liver biochemistry, coagulation, blood cell count, electrolytes, ammonia, lactate, blood urea nitrogen, creatinine, bile acids, Fischer ratio, and encephalopathy grade were assessed before and after each MARS treatment. MARS can represent a safe therapeutic choice to achieve a quick improvement of neurological status, a hemodynamic stability, and a better clinical outcome. In particular, our encouraging results suggest that also, patients with severe cholestasis may represent in the future a good indication for MARS treatment.

Adult↗

Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS).

PURPOSE: Toxicity is common in patients of epilepsy treated with phenytoin (PHT), requiring careful drug level monitoring and supportive care. Specific treatment options are limited, although charcoal haemofiltration has been used previously. We attempted to demonstrate that severe PHT toxicity can be treated successfully with the Molecular Adsorbents Recirculating System (MARS). The mechanism of drug removal by the system also was studied. METHODS: A 45-year-old patient of status epilepticus with acute renal failure and severe PHT toxicity, associated with cardiac arrhythmias, hepatotoxicity, and altered sensorium, was treated with the MARS, a blood-purification system based on albumin dialysis, and including a charcoal filter, for 11.5 h. Serum PHT levels and blood levels of oxygen-based free radicals (by electron paramagnetic resonance spectroscopy) were measured before and after treatment. RESULTS: Serum total and free PHT levels declined sharply (32 to 11 microM and 9.8 to 2.0 microM, respectively), with clinical improvement and a 65% reduction in measured oxidative stress. The mechanism of drug removal, deduced by measuring PHT in the dialysate collected from different segments of the MARS circuit, was by clearance from blood into the albumin dialysate, and ultimately removal by the charcoal filter. CONCLUSIONS: The observed removal of PHT by MARS, along with the clinical improvement of the patient and reduction of the associated oxidative stress after treatment, indicates that MARS offers a promising option in PHT toxicity.

Anticonvulsants↗

Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease.

Wilson's disease presenting as acute liver failure (ALF) is potentially fatal, and liver transplantation (LTx) is the only option. We report two patients with Wilson's disease and ALF treated with the Molecular Adsorbents Recirculating System (MARS). Both patients fulfilled criteria for poor prognosis. Because LTx was not available immediately in either case, MARS was used as a bridge to LTx. In Case 1, serum bilirubin decreased from 803 to 425 micromol/L after 3 treatments, but increased to 656 micromol/L during a break, decreasing again to 457 micromol/L with further treatment. Serum copper decreased from 53.7 micromol/L, to 35.8 micromol/L after first treatment session, and 17.4 micromol/L at treatment completion. In Case 2, MARS treatment over 2 weeks reduced serum bilirubin from 1200 to 450 micromol/L and copper from 35 to 13 micromol/L with marked improvement in encephalopathy and reduction in ammonia (59 to 34 micromol/L). Both patients were successfully bridged to LTx (days 9 and 28, respectively). Analysis of albumin-dialysate from the MARS circuit suggested that copper removal occurred mostly in the first few hours of treatment, partly being adsorbed by albumin and partly by the MARSFlux membrane (Teraklin AG, Rostock, Germany). These data suggest that MARS removes copper efficiently and can be used to bridge patients with Wilson's disease and ALF to LTx.

Acute Disease↗

Tectonic implications of Mars crustal magnetism.

Mars currently has no global magnetic field of internal origin but must have had one in the past, when the crust acquired intense magnetization, presumably by cooling in the presence of an Earth-like magnetic field (thermoremanent magnetization). A new map of the magnetic field of Mars, compiled by using measurements acquired at an approximately 400-km mapping altitude by the Mars Global Surveyor spacecraft, is presented here. The increased spatial resolution and sensitivity of this map provide new insight into the origin and evolution of the Mars crust. Variations in the crustal magnetic field appear in association with major faults, some previously identified in imagery and topography (Cerberus Rupes and Valles Marineris). Two parallel great faults are identified in Terra Meridiani by offset magnetic field contours. They appear similar to transform faults that occur in oceanic crust on Earth, and support the notion that the Mars crust formed during an early era of plate tectonics.

Journal Article↗

Ancient Maya documents concerning the movements of Mars.

A large part of the pre-Columbian Maya book known as the Dresden Codex is concerned with an exploration of commensurate relationships among celestial cycles and their relationship to other, nonastronomical cycles of cultural interest. As has long been known, pages 43b--45b of the Codex are concerned with the synodic cycle of Mars. New work reported here with another part of the Codex, a complex table on pages 69--74, reveals a concern on the part of the ancient Maya astronomers with the sidereal motion of Mars as well as with its synodic cycle. Two kinds of empiric sidereal intervals of Mars were used, a long one (702 days) that included a retrograde loop and a short one that did not. The use of these intervals, which is indicated by the documents in the Dresden Codex, permitted the tracking of Mars across the zodiac and the relating of its movements to the terrestrial seasons and to the 260-day sacred calendar. While Kepler solved the sidereal problem of Mars by proposing an elliptical heliocentric orbit, anonymous but equally ingenious Maya astronomers discovered a pair of time cycles that not only accurately described the planet's motion, but also related it to other cosmic and terrestrial concerns.

Journal Article↗

The physics, biology, and environmental ethics of making mars habitable.

The considerable evidence that Mars once had a wetter, more clement, environment motivates the search for past or present life on that planet. This evidence also suggests the possibility of restoring habitable conditions on Mars. While the total amounts of the key molecules--carbon dioxide, water, and nitrogen--needed for creating a biosphere on Mars are unknown, estimates suggest that there may be enough in the subsurface. Super greenhouse gases, in particular, perfluorocarbons, are currently the most effective and practical way to warm Mars and thicken its atmosphere so that liquid water is stable on the surface. This process could take approximately 100 years. If enough carbon dioxide is frozen in the South Polar Cap and absorbed in the regolith, the resulting thick and warm carbon dioxide atmosphere could support many types of microorganisms, plants, and invertebrates. If a planet-wide martian biosphere converted carbon dioxide into oxygen with an average efficiency equal to that for Earth's biosphere, it would take > 100,000 years to create Earth-like oxygen levels. Ethical issues associated with bringing life to Mars center on the possibility of indigenous martian life and the relative value of a planet with or without a global biosphere.

Antarctic Regions↗

SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression.

Nuclear matrix attachment regions (MARs) are regulatory DNA sequences that are important for higher-order chromatin organization, long-range enhancer function, and extension of chromatin modifications. Here we characterize a novel cell type-specific MAR-binding protein, SATB2, which binds to the MARs of the endogenous immunoglobulin micro locus in pre-B cells and enhances gene expression. We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1. Mutations of the SUMO conjugation sites of SATB2 enhance its activation potential and association with endogenous MARs in vivo, whereas N-terminal fusions with SUMO1 or SUMO3 decrease SATB2-mediated gene activation. Sumoylation is also involved in targeting SATB2 to the nuclear periphery, raising the possibility that this reversible modification of a MAR-binding protein may contribute to the modulation of subnuclear DNA localization.

B-Lymphocytes↗

AHM1, a novel type of nuclear matrix-localized, MAR binding protein with a single AT hook and a J domain-homologous region.

Interactions between the nuclear matrix and special regions of chromosomal DNA called matrix attachment regions (MARs) have been implicated in various nuclear functions. We have identified a novel protein from wheat, AT hook-containing MAR binding protein1 (AHM1), that binds preferentially to MARs. A multidomain protein, AHM1 has the special combination of a J domain-homologous region and a Zn finger-like motif (a J-Z array) and an AT hook. For MAR binding, the AT hook at the C terminus was essential, and an internal portion containing the Zn finger-like motif was additionally required in vivo. AHM1 was found in the nuclear matrix fraction and was localized in the nucleoplasm. AHM1 fused to green fluorescent protein had a speckled distribution pattern inside the nucleus. AHM1 is most likely a nuclear matrix component that functions between intranuclear framework and MARs. J-Z arrays can be found in a group of (hypothetical) proteins in plants, which may share some functions, presumably to recruit specific Hsp70 partners as co-chaperones.

Amino Acid Sequence↗

Induction of the mar operon by miscellaneous groceries.

AIM: To investigate the potential of non-antibacterial consumer products to act as inducers of the multiple antibiotic resistance (mar) operon of Escherichia coli SPC105. METHODS AND RESULTS: Wells were cut into chemically defined agar medium (CDM) contained within Petri dishes. Molten agar slurries were prepared by mixing known quantities of 35 consumer products with molten CDM and these were pipetted into each well. Plates were overlaid with molten CDM (5 ml), containing 40 microg ml(-1) X-gal and approx. 1000 CFU ml(-1) of an overnight culture of E. coli SPC105 containing a chromosomal marOII::lacZ fusion. After incubation (37 degrees C, 24 h), plates were examined for zones of growth inhibition and the presence of a blue coloration, indicative of mar (marOII::lacZ) induction. Of the 35 products tested (nine herbs and spices, 19 food and drinks and seven household products), 24 (69%) of the items produced inhibitory zones and 22 (63%) of the items induced mar expression. Apple puree was inhibitory but did not induce marOII::lacZ. Mustard, chilli and garlic were shown to be powerful inducers of marOII::lacZ. Overall six products were shown to be powerful marOII::lacZ inducers. None of these made hygiene claims. CONCLUSIONS: In addition to induction by specific biocides and antibiotics, mar is induced by the exposure of bacteria to natural substances, many of which are common to a domiciliary setting. SIGNIFICANCE AND IMPACT OF THE STUDY: Concern that the overuse of antibacterials within consumer products might select for mar-mediated resistance is shortsighted and fails to recognize the ubiquity of inducers in our environment.

Drug Resistance, Multiple, Bacterial↗

Outcome from molecular adsorbent recycling system (MARS) liver dialysis following drug-induced liver failure.

RATIONALE: Fulminant liver failure from drug ingestion is associated with a high mortality, and the introduction of liver transplantation has improved the mortality significantly if done in a timely fashion. Recently, molecular adsorbent recycling system (MARS) liver dialysis has been introduced as a support for liver failure with varying results. We review our experience with drug-induced liver failure and the impact of MARS liver dialysis on the outcome, in a setting where cadaveric liver transplantation is rarely available. RESULTS: A total of 13 patients were treated, and 40 sessions of MARS liver dialysis were conducted in the intensive care unit. The majority of cases were because of herbal medicine toxicity. Total bilirubin, conjugated bilirubin, and delta bilirubin were significantly reduced, with no change in unconjugated bilirubin. All patients satisfied the criteria for urgent liver transplantation with an average Model End Stage Liver Disease (MELD) score of 35. Only one patient received a liver transplantation from a live donor (right lobe). Overall mortality was 85%. Median time-to-death from the start of MARS was 8 days. CONCLUSIONS: MARS liver dialysis in a setting without timely liver transplantation is associated with a poor outcome. It does, however, provide a window of time for consideration of living donors in the setting of limited cadaveric donors.

Adult↗

Indirect mixed antiglobulin reaction (MAR) as a screening procedure for antisperm antibodies. I. Methodological studies.

Direct mixed antiglobulin reaction (MAR) cannot always be carried out because it requires motile spermatozoa in the patient's ejaculate. Therefore, the indirect MAR for IgG and IgA using donor spermatozoa sensitized with serum or seminal plasma from patients was investigated with the aim of developing a practical screening procedure for antisperm antibodies involving a characterization of the Ig-class of the antibodies. Samples from 23 men, 13 men with and 10 men without agglutinating antisperm antibodies, were used for the methodological experiments with the indirect MAR. Among three procedures to diminish the amount of nonbound immunoglobulin after sensitizing the donor spermatozoa with serial dilutions of serum or seminal plasma, a swim-up method was found to be optimal. The indirect MAR was carried out with glutaraldehyde-fixed sheep erythrocytes coated with IgG or IgA and various dilutions of anti-IgG and anti-IgA, respectively. These experiments led to a standardization of the indirect MAR, making it sensitive, easy to read, and allowing the reactions for IgG and IgA to be compared on an approximately equimolecular basis.

Autoantibodies↗

An Australian experience with the molecular adsorbents recirculating system (Mars).

The molecular adsorbents recirculating system (MARS) is a form of artificial extracorporeal liver support which has the potential to remove substantial quantities of albumin-bound toxins postulated to contribute to the pathogenesis of liver cell damage, hemodynamic instability and multi-organ failure in patients with acute liver failure and acute-on-chronic liver failure (AoCLF). We assessed the efficacy of MARS therapy in a cohort of patients with severe liver damage unresponsive to intensive medical therapy. MARS therapy was instituted late in the clinical course of six patients with severely impaired liver function refractory to intensive medical therapy, including four with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease. Outcome measures included markers of hemodynamic stability, renal function, serum bilirubin and bile acid levels, arterial ammonia levels, the arterial ketone body (acetoacetate/beta-hydroxybutyrate) ratio, hepatic encephalopathy grade and the plasma disappearance rate of indocyanine green. The rates of discharge from the intensive care unit and in-hospital mortality were determined. Our findings suggest that MARS treatment might be associated with some clinical efficacy even in patients with advanced multi-organ dysfunction occurring in the setting of severe liver damage and in whom treatment is instituted late in the clinical course. However, the overall survival rate (1/6; 17%) was poor. More data obtained from larger cohorts of patients enrolled in randomized controlled studies will be required in order to identify categories of liver failure patients who might benefit most from MARS treatment and to ascertain the most appropriate timing of intervention.

Adult↗

Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar) Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction.

Chromosomal multiple-antibiotic-resistant (Mar) mutants of Escherichia coli, selected on agar containing low concentrations of tetracycline or chloramphenicol, were 6- to 18-fold less susceptible to the fluoroquinolones than were their wild-type E. coli K-12 or E. coli C parental strains. The frequency of emergence of such mutants was at least 1,000-fold higher than that of those selected by the fluoroquinolone norfloxacin directly. When Mar mutants, but not wild-type cells, were plated on norfloxacin, mutants resistant to high levels of norfloxacin (2 micrograms/ml) appeared at a relatively high (approximately 10(-7] frequency. In addition to decreased amounts of OmpF, Mar mutants had other outer membrane protein changes and were four- to eightfold less susceptible to fluoroquinolones than was an ompF::Tn5 mutant lacking only OmpF. Accumulation of [3H]norfloxacin was more than threefold lower in the Mar mutants than in wild-type cells and twofold lower than in the OmpF-deficient derivative. These differences were not attributable to a change in the endogenous active efflux system for norfloxacin in E. coli. Norfloxacin-induced inhibition of DNA synthesis was threefold lower in intact cells of a Mar mutant than in susceptible cells, but this difference was not seen in toluene-permeabilized cells. Insertion of Tn5 into marA (min 34.05 on the chromosome) led to a return of the wild-type patterns of norfloxacin accumulation, fluoroquinolone and other antimicrobial agent susceptibilities, and outer membrane protein profile, including partial restoration of OmpF. These findings together suggest that marA-dependent fluoroquinolone resistance is linked to decreased cell permeability, only part of which can be accounted for by the reduction in OmpF. Once mutated to marA, cells can achieve high levels of quinolone resistance at a relatively high frequency.

Anti-Infective Agents↗

Genetic relationship between soxRS and mar loci in promoting multiple antibiotic resistance in Escherichia coli.

Multiple antibiotic resistance in Escherichia coli has typically been associated with mutations at the mar locus, located at 34 min on the E. coli chromosome. A new mutant, marC, isolated on the basis of a Mar phenotype but which maps to the soxRS (encoding the regulators of the superoxide stress response) locus located at 92 min, is described here. This mutant shares several features with a known constitutive allele of the soxRS gene, prompting the conclusion that it is a highly active allele of this gene. The marC mutation has thus been given the designation soxR201. This new mutant was used to examine the relationship between the mar and sox loci in promoting antibiotic resistance. The results of these studies indicate that full antibiotic resistance resulting from the soxR201 mutation is partially dependent on an intact mar locus and is associated with an increase in the steady-state level of mar-specific mRNA. In addition, paraquat treatment of wild-type cells is shown to increase the level of antibiotic resistance in a dose-dependent manner that requires an intact soxRS locus. Conversely, overexpression of MarA from a multicopy plasmid results in weak activation of a superoxide stress response target gene. These findings are consistent with a model in which the regulatory factors encoded by the marA and soxS genes control the expression of overlapping sets of target genes, with MarA preferentially acting on targets involved with antibiotic resistance and SoxS directed primarily towards components of the superoxide stress response. Furthermore, compounds frequently used to induce the superoxide stress response, including paraquat, menadione, and phenazine methosulfate, differ with respect to the amount of protection provided against them by the antibiotic resistance response.

Alleles↗

Multiple antibiotic resistance (mar) locus protects Escherichia coli from rapid cell killing by fluoroquinolones.

The multiple antibiotic resistance (mar) locus in Escherichia coli consists of two divergently expressed operons (marC and marRAB), both of which contribute to the Mar phenotype. Overexpression of the marRAB operon protected E. coli against rapid cell killing by fluoroquinolones. Inactivation of the operon in mar mutants restored a wild-type bactericidal susceptibility. Both operons of the locus were required for protection from the quinolone-mediated bactericidal activity in mar locus deletion mutants. The effect was lost at high concentrations of fluoroquinolones, unlike the case for the previously described genes hipA and hipQ. The inducible mar locus appears to specify a novel antibactericidal mechanism which may play a role in the emergence of fluoroquinolone-resistant clinical E. coli isolates.

Anti-Infective Agents↗