Retinoic acid (RA) exerts its pleiotropic effects on cell growth and differentiation through the activation of a family of transcription factors-the RA receptors (RARs). Three subtypes of these receptors exist, RARa, RAR(3, and RARly. The receptors are differentially expressed in different cell types and stages of development, suggesting that they may regulate different sets of genes. We have identified a synthetic retinoid with the characteristics of a selective RARa antagonist. This antagonist counteracts RA effects on HL-60 cell differentiation and on B-lymphocyte polyconal activation.Beyond its potential practical relevance, this and other specific antagonists will be useful to dissect the RAR system and to assign to one given receptor each of the many RA-regulated functions.The natural retinol (vitamin A) derivative retinoic acid (RA) is known to have profound effects on cell growth and differentiation (1) and to be essential for normal embryonic development (2). While RA and some synthetic analogs (retinoids) are useful in the control of some tumors (3) as well as of nonmalignant hyperproliferative conditions of the skin (4), they are, at high concentrations, teratogenic (5).The pleiotropic effects of retinoids are mediated by two known families of nuclear receptors, both belonging to the steroid-thyroid hormone receptor superfamily of ligandinducible transcriptional regulators (6, 7). The RA receptor (RAR) gene family comprises three subtypes-RARa (8, 9), RAR,[8][9][10][11][12], and RAR'y (13, 14)-with each gene encoding a variable number of isoforms arising by differential splicing of two primary . All receptors of the RAR family bind RA with comparable affinity (18). The retinoid receptors of the second family (RXR) do not bind the major form of RA (all-trans-RA) (19). They bind instead the 9-cis stereoisomer of RA (20, 21).Transcription of some RAR genes themselves is RA sensitive (22-25). Also, the expression of some of the cellular retinol-or RA-binding proteins (CRBP and CRABP), putatively involved in the storage, transport, and/or metabolism of retinol and RA, is differentially regulated by RA in a receptor-specific manner (26-28). The RA-related molecules represent, therefore, an autoregulated system. RAR types and isoforms, as well as RXRa and RXRB, are differentially expressed both spatially and temporally (15-18, 29-32). They might therefore regulate different target genes during embryonic and adult life, as well as in specific cell types at different stages of differentiation. RARa is the most ubiquitously expressed, while RAR8 and RARy display a more restricted pattern of distribution, with RARy being predominantly expressed in the skin (31).It seems reasonable to assume that the multiple effects of RA could be dissociated by specific ligands for each of the known receptors, and/or by receptor-specific antagonists, so as to obtain the desired beneficial effects while limiting the unwanted side effects. Retinoids with a good degree of selectivity have been described (33), and we have o...

A lipase from Thermomyces lanuginosus and cutinases from Thermobifida fusca and Fusarium solani hydrolysed poly(ethylene terephthalate) (PET) fabrics and films and bis(benzoyloxyethyl) terephthalate (3PET) endo-wise as shown by MALDI-Tof-MS, LC-UVD/MS, cationic dyeing and XPS analysis. Due to interfacial activation of the lipase in the presence of Triton X-100, a seven-fold increase of hydrolysis products released from 3PET was measured. In the presence of the plasticizer N,N-diethyl-2-phenylacetamide (DEPA), increased hydrolysis rates of semi-crystalline PET films and fabrics were measured both for lipase and cutinase. The formation of novel polar groups resulted in enhanced dye ability with additional increase in colour depth by 130% and 300% for cutinase and lipase, respectively, in the presence of plasticizer.

Moderate cognitive and motor deficits, behavioral problems, and impairment in some aspects of quality of life frequently remain after stroke in childhood. Visuospatial functions are more often reduced than verbal functions, independent of the hemispheric side of lesion. This indicates a functional superiority of verbal skills compared to visuospatial skills in the process of recovery after brain injury. Compared to the cognitive outcome following stroke in adults, cognitive sequelae after childhood stroke do indicate neither the lateralization nor the location of the lesion focus. Age at stroke seems to be the only determining factor influencing cognitive outcome.

A 36-kDa diheme c-type cytochrome abundant in Fe(III)-respiring Geobacter sulfurreducens, designated MacA, was more highly expressed during growth with Fe(III) as the electron acceptor than with fumarate.

After paediatric stroke neuropsychological problems are present in about 75% of children. Younger age at stroke as well as an emergence of epilepsy were predictors for worse prognosis.

"Evidenz" liefert ein Urteil nur dann und nur insofern, als es sich auf tatsächlich vorhandene Fakten bezieht. Urteile und Schlussfolgerungen, die auf Annahmen beruhen, bieten keine Evi-denz, auch wenn sie klug berechnet sind. Das gilt auch für die Evidenz basierte Medizin, EBM, wie man sehr gut am Beispiel der Lancet-Studie über Homöopathie von SHANG et al. aus dem Berner Institut für Sozial-und Präventivmedizin von Prof. Egger sehen kann [1]. Prof. Egger gilt als prominenter Vertreter von EBM. Seine Arbeitsgruppe kommt auf Grund einer Meta-Regression bekanntlich zum Schluss, dass Homöopathie nicht wirkungsvoller sei als Placebo. Bezieht sich dieses Urteil tatsächlich auf nachgewiesene Fakten? Nein. Die wesentlichen Schlussfolgerung sind Hypostasen, die auf theoretischen Annahmen und darauf aufbauenden probabilistischen Berechnungen beruhen. 1. Es wird angenommen, dass die Effekte der untersuchten Homöopathie-Studien homogen seien, denn nur unter dieser Voraussetzung ist das Herzstück der Studie, die gewählte Funnel Plot Methode sinnvoll. In Wirklichkeit umfassen die Studien jedoch unterschiedlichste Stu-dienmodelle und homöopathische Vorgehensweisen, so dass homogene Effektarten nicht zu erwarten sind. Bei inhomogenen Effektarten kann der Funnel Plot ähnlich schief werden wie in der vorliegenden Arbeit, auch ohne dass ein Publication Bias vorliegt [2]. Das ist bereits im Schlussbericht PEK im Hinblick auf Eggers Arbeit kritisert worden [3]. 2. Es wird von der Egger-Gruppe aus rein theoretischen Gründen angenommen, dass der schiefe Funnel Plot auf einem Publication Bias beruhe, ohne faktischen Nachweis. Dem Publication Bias sind jedoch schon LINDE et al. in ihrer Meta-Analyse von 1997 genauer nachge-gangen, indem sie systematisch nach nicht-publizierten Studien suchten und ihre Berech-nungen auch für einen hypothetischen Publication Bias adjustierten. Dadurch verminderte sich der gepoolte Effekt der Studien, er blieb aber immer noch signifikant positiv zu Gunsten der Homöopathie. Es wären je nach Berechnung 923 oder 4511 (!) "fehlende" Studien mit einem Null-Effekt nötig gewesen, um den Gesamteffekt unter die Signifikanzgrenze zu sen-ken [ 2]. Es gibt aber weltweit nicht genügend Arbeitsgruppen, um so viele Studien zustande zu bringen und sie erst noch zu verstecken. Im übrigen zeigen auch die meisten von LINDE et al. gefundenen nicht-publizierten Studien einen positiven Effekt. 3. Es wird rein theoretisch vorausgesetzt, dass die grossen Studien qualitativ besser seien als die kleineren. Die faktische Evidenz dafür wurde nicht geprüft. Bei der Klassischen Homöo-pathie ist eher das Gegenteil der Fall, nämlich dass ihre individualisierende Vorgehensweise in einer grossen Studie nicht gewährleistet ist oder dass nicht genügend kompetente Thera-peuten zu Verfügung stehen. Falsch negative Ergebnisse sind dann die Folge. Für konventio-nelle Therapien gilt wegen ihrer weitgehenden Standardisierung und der viel weiter gehen-den Unabhängigkeit der Medikamentengabe von der spezifischen Kompetenz der Ärzte nicht dasselbe....

The ether-cleaving O-demethylase isolated from syringate-grown cells of Acetobacterium dehalogenans (formerly named strain MC) consists of four proteins, components A, B, C and D. The enzyme system converts only phenyl methyl ethers with a hydroxyl group in the ortho position to the methoxyl moiety. The presence of a carboxyl group in the aromatic compound was not required for O-demethylase reaction. Component B mediated the conversion of vanillate to 3,4-dihydroxybenzoate in the presence of the Ti(III)-reduced corrinoid-containing component A. After addition of component D and tetrahydrofolate, methyl tetrahydrofolate was formed from vanillate in stoichiometric amounts. Titanium(III) citrate as a reductant could be replaced by H 2 , methyl viologen or ferredoxin, partially purified hydrogenase, purified component C obtained from A. dehalogenans, and ATP. From these findings, it was deduced that component B serves as vanillate :corrinoid protein methyltransferase (methyltransferase I) mediating the methyl transfer from vanillate to the reduced corrinoid protein component A. Component D functions as methylcorrinoid protein:tetrahydrofolate transferase (methyltransferase II). The role of component C is probably that of an activating protein reversing accidental oxidation of the protein-bound cob(I)alamin to cob(II)alamin in the presence of ATP and reducing equivalents supplied by the enzymatic oxidation of hydrogen.

The O-demethylase of the methylotrophic homoacetogenic bacterium strain MC was purified to apparent homogeneity. The enzyme system consisted of four different components that were designated A, B, C, and D according to their elution sequence from the anionic-exchange chromatography column. All four components were essentially required for catalysis of the transfer of the methyl group from phenyl methyl ethers to tetrahydrofolate. According to gel filtration and SDS-PAGE, components A and B were monomers with apparent molecular masses of approximately 26 kDa (subunit 25 kDa) and 36 (subunit 41 kDa), respectively; component C appeared to be a trimeric protein (195 kDa, subunit 67 kDa); and component D was probably a dimer (64 kDa, subunit 30 kDa). Component A contained one corrinoid per monomer. In crude extracts, component D appeared to be the rate-limiting protein for the complete methyl transfer reaction. Additional requirements for the reaction were ATP and low-potential reducing equivalents supplied by either titanium(III) citrate or H2 plus hydrogenase purified from strain MC.