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Acetylcholinesterase (AChE) inhibitors from several chemical classes have been tested for the symptomatic treatment of Alzheimer's disease; however, the therapeutic success of these compounds has been limited. Recently, another AChE inhibitor, galanthamine hydrobromide (GAL), has shown increased clinical efficacy and safety. Using biochemical, behavioral and pharmacokinetic analyses, this report compares GAL with two of its analogs, 6-O-acetyl-6-O-demethylgalanthamine hydrochloride (P11012) and 6-O-demethyl-6-O[(adamantan-1-yl)-carbonyl]galanthamine hydrochloride (P11149), for their therapeutic potential. P11012 and P11149 were found to be potent, competitive and selective inhibitors of AChE, demonstrating central cholinergic activity, behavioral efficacy and safety. P11012 and P11149, though pharmacokinetic analyses, were shown to act as pro-drugs, yielding significant levels of 6-O-demethylgalanthamine. In vitro, 6-O-demethylgalanthamine was 10- to 20-fold more potent than GAL as an inhibitor of AChE, and it demonstrated greater selectivity for inhibition of AChE vs. butyrylcholinesterase. Like GAL, both P11012 and P11149 showed central cholinergic activity biochemically, by significantly inhibiting rat brain AChE; physiologically, by causing hypothermia; and behaviorally, by attenuating scopolamine-induced deficits in passive avoidance. In addition, GAL, P11012 and P11149 enhanced step-down passive avoidance, another measure of behavioral efficacy. By comparing efficacious doses with primary overt effects, P11012 and P11149 had better oral therapeutic indices than GAL. Oral pharmacokinetic analyses of GAL, P11012 and P11149 revealed differences. Although P11012 and P11149 exhibited similar area under the curve values, 191149 had slower, lower and more sustained concentration maximum levels. P11012 and GAL rapidly reached their concentration maximums, but GAL, in brain had the highest area under the curve and concentration maximum. Because of its composite profile, including duration of action, oral therapeutic index and pharmacokinetics, P11149 is considered the better therapeutic candidate for the treatment of Alzheimer's disease.

A new class of outer membrane lipid (OML) was isolated from the oral spirochete Treponema denticola strain ATCC 33521 using a phenol/chloroform/light petroleum procedure normally applied for lipopolysaccharide extraction. In addition to chemical analysis, Fourier transform infrared (FTIR) spectroscopy was applied to compare the biophysical properties of OML with lipopolysaccharides (LPS) and lipoteichoic acids (LTA). Isolated OML fractions represent 1.4% of the total dry cell weight, are about 4 kDa in size, and contain 6% amino sugars, 8% neutral sugars, 14% phosphate, 35% carbazol-positive compounds, and 11% fatty acids (containing iso- and anteiso-fatty acyl chains). Rare for outer membrane lipids, OML contains no significant amount of 3-deoxy-D-manno-octulosonic acids, heptoses, and beta-hydroxy fatty acids. The fatty acyl chain composition, being similar to that of the cytoplasmic membrane, is quite heterogeneous with anteiso-pentadecanoic acid (12%), palmitic acid (51%), and iso-palmitic acid (19%) as the predominant fatty acids present. Findings of a glycerol-hexose unit and two glycerol-hexadecanoic acid fragments indicate a glycolipid membrane anchor typically found in LTA. There was also no evidence for the presence of a sphingosine-based lipid structure. The results of FTIR measurements strongly suggest that the reconstituted lipid forms normal bilayer structures (vesicles) expressing a high membrane state of order with a distinct phase transition as typical for isolated LPS. However, in contrast to LPS, OML of T. denticola has a lower Tm near 22 degreesC and a lower cooperativity of the phase transition. The results suggest a different kind of permeation barrier that is built up by this particular OML of T. denticola, which is quite different from LPS normally essential for Gram-negative bacteria.

The RNA polymerase III transcription initiation factor TFIIIB contains the TATA-box-binding protein (TBP) and polymerase III-specific TBP-associated factors (TAFs). Previous studies have shown that DNA oligonucleotides containing the consensus TATA-box sequence inhibit polymerase III transcription, implying that the DNA binding domain of TBP is exposed in TFIIIB. We have investigated the TATA-box DNA binding activity of Xenopus TFIIIB, using transcription inhibition assays and a gel mobility shift assay. Gel shift competition assays with mutant and nonspecific DNAs demonstrate the specificity of the TFIIIB-TATA box DNA complex. The apparent dissociation constant for this protein-DNA interaction is approximately 0.4 nM, similar to the affinity of yeast TBP for the same sequence. TFIIIB transcriptional activity and TATA-box binding activity cofractionate during a series of four ion-exchange chromatographic steps, and reconstituted transcription reactions demonstrate that the TATA-box DNA-protein complex contains TFIIIB TAF activity. Polypeptides with apparent molecular masses of 75 and 92 kDa are associated with TBP in this complex. These polypeptides were renatured after elution from sodium dodecyl sulfate-gels and tested individually and in combination for TFIIIB TAF activity. Recombinant TBP along with protein fractions containing the 75- and 92-kDa polypeptides were sufficient to reconstitute TFIIIB transcriptional activity and DNA binding activity, suggesting that Xenopus TFIIIB is composed of TBP along with these polypeptides.

The RNA polymerase III transcription initiation factor TFIIIB contains the TATA-box-binding protein (TBP) and polymerase III-specific TBP-associated factors (TAFs). Previous studies have shown that DNA oligonucleotides containing the consensus TATA-box sequence inhibit polymerase III transcription, implying that the DNA binding domain of TBP is exposed in TFIIIB. We have investigated the TATA-box DNA binding activity of Xenopus TFIIIB, using transcription inhibition assays and a gel mobility shift assay. Gel shift competition assays with mutant and nonspecific DNAs demonstrate the specificity of the TFIIIB-TATA box DNA complex. The apparent dissociation constant for this protein-DNA interaction is approximately 0.4 nM, similar to the affinity of yeast TBP for the same sequence. TFIIIB transcriptional activity and TATA-box binding activity cofractionate during a series of four ion-exchange chromatographic steps, and reconstituted transcription reactions demonstrate that the TATA-box DNA-protein complex contains TFIIIB TAF activity. Polypeptides with apparent molecular masses of 75 and 92 kDa are associated with TBP in this complex. These polypeptides were renatured after elution from sodium dodecyl sulfate-gels and tested individually and in combination for TFIIIB TAF activity. Recombinant TBP along with protein fractions containing the 75- and 92-kDa polypeptides were sufficient to reconstitute TFIIIB transcriptional activity and DNA binding activity, suggesting that Xenopus TFIIIB is composed of TBP along with these polypeptides.

A series of polypeptides containing increasing numbers of zinc fingers of Xenopus transcription factor IIIA has been generated and binding to the 5S RNA gene internal control region has been studied in order to elucidate the mode of interaction of the individual fingers with DNA. By using a combination of DNase I footprinting, methylation interference, and differential binding to mixtures of DNA fragments differing in length by single base pairs, the binding sites for individual fingers have been defined. These results have led to a model for the interaction of transcription factor IIIA with the internal control region in which fingers 1-3 bind in the major groove of the promoter C block, fingers 7-9 bind in the major groove of the A block, and finger 5 binds in the major groove of the intermediate element. Fingers 4 and 6 each bind across the minor groove, spanning these promoter elements.

Transcription of 5S rRNA and tRNA genes by RNA polymerase III (pol III) in cytosolic extracts of unfertilized Xenopus eggs and in a reconstituted system derived from Xenopus oocytes is repressed by the action of one or more mitotic protein kinases. Repression is due to the phosphorylation of a component of the pol III transcription apparatus. We find that the maturation/mitosis-promoting factor kinase (MPF, p34cdc2-cyclin B) can directly mediate this repression in vitro. Affinity-purified MPF and immune complexes formed with antibodies to the protein subunits of MPF (p34cdc2 and cyclin B) retain both histone H1 kinase activity and the capacity to repress transcription in the reconstituted transcription system. Transcription complexes of oocyte-type 5S RNA genes and tRNA genes are quantitatively more sensitive to MPF repression than the corresponding transcription complexes of the somatic-type 5S RNA gene. The differential transcription of oocyte- and somatic-type genes observed during early Xenopus embryogenesis has been reproduced with the reconstituted transcription system and affinity-purified MPF. This differential transcription may be due to the instability of transcription complexes on the oocyte-type genes and the heightened sensitivity of soluble transcription factors to inactivation by mitotic phosphorylation. Our results suggest that MPF may play a role in vivo in the establishment of the embryonic pattern of pol III gene expression.

Zusammenfassung Die Beobachtungen beim Fall des Meteoriten von Stannern am 22. Mai 1808 werden zusammenfassend dargestellt. Der Eukrit von Stannern besitzt eine Porosität von 15 % und besteht nach mikroskopischen Beobachtungen aus ophitischen und brecciösen Partien, welche 33 Vol.-% Bytownit (An84),11 Vol.-% Hypersthen (Fs55), 49 Vol.-% Pigeonit (Fs55En35Wo10), etwa 5 Vol.-% Quarz und geringere Mengen von Ilmenit, Troilit und Chromit enthalten. Alle these Mineralien werden näher beschrieben. Eine neue chemische Analyse wird mitgeteilt, die mit dem mikroskopischen Befund gut übereinstimmt. Aus einer Schmelze bildeten sick zuerst Bytownit und Hypersthen in nahezu eutektischem Mengenverhältnis. Danach wurde der Hypersthen unter gleiehzeitiger starker mechanischer Beanspruchung des ganzen Gesteins (Breccienbildung) zum größten Teil in Pigeonit umgewandelt und es kam zusätzlicher Pigeonit zur Abscheidung. Nach Abschluß der Breccienbildung entstanden als letzte Bildungen Quarz, Ilmenit und Troilit. In den letzten Phasen der Bildung spielten möglicherweise flüchtige Bestandteile eine Rolle, die heute nicht mehr im Meteoriten vorliegen. Die chemische Zusammensetzung des Eukrits von Stannern und die der übrigen Careichen Achondrite wird mit der der Chondrite und irdischen Basalte verglichen und es werden mögliche genetische Zusammenhänge diskutiert. Jedenfalls können Eukrite und Howardite nur auf nicht zu kleinen planetarisehen Körpern entstanden sein, wo Kristallisationsdifferentiation und lanusame Abkiihlung möglich waren. Die in der Atmosphäre gebildete Schmelzrinde der Steine von Stannern enthält viele Blasen, die durch des Sieden der Silikatschmelze erzeugt wurden. Aus dem Dampf schlug sick bei der Abkühlung in den Blasen und auf der Außenseite der Steine Wollastonit ab. Im Glas entstanden geringe Mengen Enstatit oder Klinoenstatit.

Zusammenfassung Es wird über einen Fall von akuter Porphyrie mit Polyneuritis und Hämoglobinurie berichtet. An Hand des Falles, der Literatur und eigener Tierversuche werden die Auffassungen über das Wesen, Einteilung und Nomenklatur der akuten Porphyrien besprochen.

Zusammenfassung Es wird über einen Fall von Parkinsonismus berichtet, der sich im engen zeitlichen Zusammenhang mit einem im wesentlichen psychischen Trauma durch Unfall entwickelte. Theoretische Folgerungen über die Ätiologie des Parkinsonismus und praktische Konsequenzen hinsichtlich der Begutachtung werden dargetan. Die Literatur wird kritisch verwertet. Der Zusammenhang ist gutachtlich anzuerkennen. Es handelt sich um einen außergewöhnlich eindeutig gelagerten Fall von traumatisch entstandenem Parkinsonismus, dessen Mitteilung für Ätiologie und Begutachtung von besonderem Wert sein kann.

Nicotinamide adenine dinucleotide phosphate (reduced form) is formed more rapidly after the addition of thiosulfate to suspensions of intact Thiobacillus neapolitanusin the absence of CO2than nicotinamide adenine dinucleotide (reduced form). Measurement of acid-stable metabolites shows this phenomenon to be the result of rapid reoxidation of nicotinamide adenine dinucleotide (reduced form) by 3-phosphoglyceric acid and other oxidized intermediates, which are converted to triose and hexose phosphates, and that, in reality, the rate of nicotinamide adenine dinucleotide (oxidized form) reduction exceeds that of nicotinamide adenine dinucleotide phosphate (oxidized form) by approximately 4.5-fold. The overall rate of pyridine nucleotide reduction by thiosulfate (264 nmol per min per mg of protein) is in excess of that rate needed to sustain growth. Pyridine nucleotide reduction, adenosine triphosphate synthesis, and carbohydrate synthesis are prevented by the uncoupler m-Cl-Carbonylcyanide phenylhydrazone. Sodium amytal inhibits pyridine nucleotide reduction and carbohydrate synthesis are prevented by the uncoupler m-Cl-carbonylcyanide observations are reproduced when sulfide serves as the substrate. The rate of pyridine nucleotide anaerobic reduction with endogenous substrates or thiosulfate is less than 1% of the aerobic rate with thiosulfate. We conclude that the principal, if not the only, pathway of pyridine nucleotide reduction proceeds through an energy-dependent and amytal-sensitive step when either thiosulfate or sulfide is used as the substrate.

Background: Even though tumours are considered to occur frequently in pet hamsters, there is only a small number of scientific reports in current literature. Methods: Pathological reports from 177 hamsters were evaluated. Results: Of these, 78 were male and 75 were female. Median age of affected hamsters was 12 months (range 2–34). Integumental tumours were the most common neoplasms (62%, 109/177). As far as species was known, the number of Syrian hamsters (52%, 30/58) affected by tumours seemed to be lower than the number of affected dwarf hamsters (85%, 47/55). Tumours of the hematopoietic system were the second most frequently neoplasms (17%, 30/177). Relative number of neoplasms of the endocrine system, tumours of the digestive system (1.7%, 3/177) and other tumours (4%, 7/177 each) was low. The majority of integumental tumours were epithelial (66%; 91/126). Conclusion: This study aimed to analyze data from veterinary surgeries and pathological institutes about the occurrence of spontaneous tumours in Syrian hamsters and dwarf hamsters to give information about the frequency of tumours, prognosis and survival time. This is the first study about tumours in pet hamsters in Germany so far.

Tetracycline was orally administered to pregnant does and/or their newborn pups. This treatment was effective in reducing both the incidence and severity of nonlipid, medial aortic lesions in rabbits belonging to families normally highly susceptible to these lesions.

This is a study of leucocyte inhibitory factor (LIF) in patients with Behçet's disease using an extract from a reactive (pathergic) lesion as an antigen and, as a control, an extract from normal skin of a normal subject. The purpose is to search for the possible existence of an antigen in the skin that may explain the development of this reactive lesion following a trivial trauma.

Foraging theory's central premise assumes that behavioral actions that affect the acquisition of food also ultimately affect fitness. However, very few investigations in behavioral ecology actually demonstrate ultimate fitness consequences of any particular behavior. Many studies focus on short-term estimates of fitness in animals with considerable life spans. I investigated whether differences in foraging performance, as related to patch choice and behavioral dominance, show consistent patterns over extended periods of an animal's life such that they translate into differences in reproductive success. In one experiment, I focused on the ability of single female water strider (Gerris remigis) to discriminate between foraging patches of differing prey abundances in laboratory streams simulating natural conditions. In another experiment, I focused on competitive interactions within groups of three female water striders foraging in laboratory streams where resource availability varied with position in a patch. The first experiment showed that, overall, the individuals detected and preferred to forage in the richer patch, which directly increased their foraging success and their lifetime fecundity. However, there was marked variability among individuals in their ability to respond to the differences in food availability, ranging from no tracking to fast tracking when the patch qualities were switched. In the second experiment, both the foraging position of individuals in the stream and their dominance rank were reasonably consistent over their entire reproductive life. Foraging position and dominance rank were significant predictors of lifetime fecundity, the former being the better predictor due to an imperfect correlation between the two variables. In both experiments, the increase in fecundity was achieved by higher oviposition rates rather than by extending the oviposition period or by inducing first reproduction at an earlier age. [Behav Ecol 1991; 2: 46-55)