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PubMed1990

Antimalarial action of flavin analogues seems not be due to inhibition of glutathione reductase of host erythrocytes.

A series of 10-(4'-chlorophenyl)-3-substituted flavins (1a-f) were examined with respect to their antimalarial properties. They were tested against Plasmodium falciparum in vitro and Plasmodium vinckei vinckei in vivo. The proposition that they might act through glutathione reductase (GR) (EC 1.6.4.2) inhibition has been studied. Inhibition of P. falciparum in vitro by these compounds shows only slight variation between analogues; in contrast, inhibition of human erythrocyte GR by members of the same series is highly variable, indicating that this is probably not their primary mode of antimalarial action. Results of the P. vinckei vinckei screen showed that 10-(4'-chlorophenyl)-3-methyl,3-ethyl and 3-propyl substituted flavins are active in vivo over the dose range screened (10-70 mg/kg).

Animals↗

PubMed1994

Neuroprotective effect of remacemide hydrochloride in focal cerebral ischemia in the cat.

The neuroprotective effects of remacemide hydrochloride ((+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide hydrochloride) have been assessed with permanent occlusion of one middle cerebral artery in chloralose-anesthetized cats in which key physiologic variables have been monitored throughout the post-ischemic period. An infusion of remacemide hydrochloride (278 micrograms/kg/min; total dose 25 mg/kg) initiated 90 min prior to middle cerebral artery occlusion and discontinued at occlusion, reduced significantly (P < 0.02) the volume of ischemic damage (from 2505 +/- 454 mm3 of vehicle-treated cats to 1266 +/- 54 mm3 of remacemide hydrochloride-treated cats).

Acetamides↗

PubMed1994

Cyclodextrins as enantioselective mobile phase modifiers for chiral capillary electrophoresis. Effects of pH and cyclodextrin concentration.

When cyclodextrins (CDs) are used as enantioselective mobile phase modifiers for capillary electrophoresis, optimization of chiral resolution is usually carried out by varying operational parameters such as the choice of CD type, CD concentration and pH of the operating buffer. This work describes the effects of the above variables on the resolution of five chiral basic pharmaceuticals with different functional groups, using three different beta-cyclodextrin (BCD) modifiers (BCD, 2-hydroxypropyl BCD and methyl BCD). In order to more clearly determine the specific role of pH, CD type and CD concentration on chiral resolution, the running buffers used in this work contained only the buffer salts and enantioselector. Very good resolution was achieved for chlorpheniramine and terbutaline; propranolol was able to be partially resolved. The degree of resolution achieved for these compounds is explained by examining the balance of specific and non-specific interactions between the solutes and the BCDs. Although the migration behavior of atropine and metoprolol indicates that they undergo marked interactions with the cyclodextrins in the running buffer, these interactions were not enantioselective, and these solutes were unable to be optically resolved under any of the conditions in our study.

Cyclodextrins↗

PubMed1990

Long-term effects of Org OD 14 on lipid metabolism in post-menopausal women.

The effects of 2.5 mg/day 7 alpha, 17 alpha-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (Org OD 14) on lipid metabolism, with particular reference to high-density lipoprotein (HDL)-related variables, were assessed in 14 healthy post-menopausal women after 12 and 36 mth of treatment. There were significant reductions in the following variables after both treatment periods: total phospholipids, total triglycerides, HDL-phospholipids and apolipoprotein A1. No changes were observed in total cholesterol or low-density lipoprotein (LDL) cholesterol over the entire treatment period. A significant but temporary decrease was observed in HDL-cholesterol after 12 mth, with a return to pretreatment values after 36 mth of treatment. The findings of this study clearly show that Org OD 14 has no adverse effects on the atherogenic variables, viz. LDL-cholesterol and triglycerides. Indeed, since the latter were lowered, its action is in fact beneficial. Moreover, its effect on HDL-cholesterol, the anti-atherogenic variable, is only temporary. We concluded from this study that although the composition of HDL changes during Org OD 14 treatment (especially as regards its cholesterol content), there is no evidence that reverse cholesterol transport is impaired.

Anabolic Agents↗

PubMed2000

Effects of the partial glycine agonist D-cycloserine on cognitive functioning in chronic low dose MPTP-treated monkeys.

D-Cycloserine, a partial agonist at the glycine recognition site of the N-methyl-D-aspartate (NMDA) receptor complex, has been shown to facilitate certain forms of memory formation and to improve visual recognition memory in normal monkeys. In the present study, the effects of D-cycloserine on spatial short-term memory deficits in monkeys induced by chronic low-dose 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) administration were examined. Chronic low-dose MPTP administration resulted in deficits in the performance of a variable delayed-response task (VDR). Single administration of D-cycloserine (320 or 1000 microgram/kg) significantly improved the performance on this task. High-dose D-cycloserine (8000 microgram/kg) or MK-801 (10-32 microgram/kg) administration had no effects on delayed-response performance but impaired performance on a visual discrimination (VD) task that was not adversely affected by MPTP administration. These results show that at low doses, D-cycloserine has cognition-enhancing properties in this model of early Parkinsonism.

Animals↗

PubMed2000

Synthesis and analytical characterization of the sodium salt of heptakis(2-O-methyl-3,6-di-O-sulfo)cyclomaltoheptaose, a chiral resolving agent candidate for capillary electrophoresis.

A pure, single isomer, strong electrolyte chiral resolving agent candidate for capillary electrophoresis, the sodium salt of heptakis(2-O-methyl-3,6-di-O-sulfo)cyclomaltoheptaose has been synthesized on the 100-g scale, in greater than 97% purity, through heptakis(2,6-di-O-tert-butyldimethylsilyl)cyclomaltoheptaose, heptakis(2-O-methyl-3,6-di-O-tert-butyldimethylsilyl)cyclomaltohep taose and heptakis(2-O-methyl)cyclomaltoheptaose intermediates. The structural identity of each intermediate and the final product was conclusively established by high-resolution MALDI-TOF mass spectrometry, variable-temperature 1H and 13C NMR spectroscopy and X-ray crystallography. The purity of each intermediate and the final product was determined by gradient high-performance liquid chromatography (HPLC) and indirect UV detection capillary electrophoresis.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Effect of subculture and elicitation on instability of taxol production in Taxus sp. suspension cultures.

The production of secondary metabolites through plant cell suspension cultures is challenging because the level and pattern of production is often unstable and unpredictable. To investigate the factors affecting instability of secondary metabolite production, high Taxol (paclitaxel)-producing Taxus cultures induced by methyl jasmonate elicitation and their low Taxol-producing counterparts were compared with respect to growth and Taxol production kinetics. With Taxus subcultures we observe alternating states of high and low productivity. Parental cultures and their subcultures from five different cell lines were used to test whether a high-producing culture grows more slowly or dies more rapidly than a low-producing one. These cell lines were of three types: (1) Taxol-producing with and without methyl jasmonate, (2) Taxol-producing only upon elicitation, and (3) nonproducing. High-producing cultures show growth inhibition upon subculture, whereas nonproducing elicited cultures show little growth inhibition. Thus, growth inhibition is primarily due to Taxol or taxane accumulation and not a direct result of methyl jasmonate treatment. Through media exchange between high- and low-producing cultures, it appears that culture components generated by cells alter culture properties. To assess variability as a function of culture lineage, two groups of replicate cultures were generated either with a mixing of the parental flasks or segregation of parental flasks at each subculture. Although parental culture mixing did not reduce flask-to-flask variation, the production level of Taxol in subcultures resulting from mixing inocula was sustained at a higher level relative to segregated subcultures. The results are consistent with the possibility of cell signaling within the population that can induce Taxol production.

Acetates↗

PubMed2005

Evidence of a self-inclusion phenomenon for a new class of mono-substituted alkylammonium-beta-cyclodextrins.

A new class of mono-substituted N-alkyl-N,N-dimethylammonium-beta-cyclodextrins has been synthesized in a three step procedure from the native beta-cyclodextrin. The structural analysis of these compounds undertaken by combined use of 1D and 2D NMR spectra indicate that the two methyl groups bound on the nitrogen are magnetically inequivalent due to a self-inclusion phenomenon of the alkyl chain inside the CD cavity. A variable-temperature 1H NMR study showed that these mono-substituted CD derivatives formed temperature-independent intramolecular complexes with their own alkylammonium substituent. The strength of the interaction between the alkyl moiety and the cyclodextrin cavity has been evaluated by a competitive method using an adamantane derivative. Finally, surface tension measurements demonstrated the surface active character of these compounds and confirmed their self-inclusion ability.

Magnetic Resonance Spectroscopy↗

PubMed1996

Phosphonamidate analogues of dipeptides with carboxypeptidase A and beta-lactamase-inhibitory activity: elucidation of the mechanism of beta-lactamase inhibition by electrospray mass spectrometry.

A series of phosphonamidate compounds with different P1' amino acid residues have been shown to be irreversible inactivators of the serine beta-lactamase from Enterobacter cloacae P99. The efficiency of inhibition (based on k2/K values) of P99 by these derivatives, ordered in decreasing potency, is: beta-phenyl-beta-Ala > L-Phe > beta-Ala > Gly > D-Phe > D-Pro > D-thiazolidine. The D- and L-Phe compounds also inhibit carboxypeptidase A. The proline and thiazolidine derivatives were phosphonamidate methyl esters, whereas the others were salts of diacids. Electrospray mass spectrometry showed that equimolar mixtures of the P99 enzyme with each of the following derivatives, Gly, D-Phe, L-Phe, beta-Ala and beta-phenyl-beta-Ala, effected efficient adduct formation (70-95% of enzyme modified), illustrating the particularly active nature of some of these compounds. All the primary amino acid derivatives gave a similar mass increment, which suggests the displacement of the variable P1' part of the molecule. This observation provides evidence that the compounds phosphonylate the active-site serine, with the phosphonamidate bond as the scissile bond and the amino acid as the leaving group. The thiazolidine derivative (phosphonamidate methyl ester) also appeared to work by the same mechanism. The comparable proline derivatives caused lower than expected mass shifts of 227-229, and therefore it is proposed that with these compounds both the amino acid and the phosphonamidate ester methoxy group were displaced at the phosphorus atom during the inhibition process. Therefore, electrospray mass spectrometry has provided both a measure of potency and a rationale for the mechanism of inhibition of P99 by these compounds.

Carboxypeptidases↗

PubMed1995

Clonality of thyroid nodules in sporadic goiter.

Clonality studies have suggested that neoplasms are monoclonal and hyperplasias are polyclonal. To investigate this question in thyroid, we analyzed the clonality of 26 morphologically characterized hyperplastic nodules from 19 patients with sporadic goiters. For comparison we studied six thyroid carcinomas. We used the highly informative M27 beta probe that maps to the X-chromosome DXS255 locus (X cen-p11.22). Material was obtained from 52 nodules; tissue from nine nodules was rejected because of contamination with normal elements, five patients (eight nodules) were homozygous at Pst I sites in nonnodular thyroid tissue, and three nodules were excluded for technical reasons. Methylation patterns after Hpa II digestion confirmed polyclonality in all nontumorous thyroids of informative patients. Seven hyperplastic nodules were polyclonal, and 18 were monoclonal; one showed loss of heterozygosity. One nodule exhibited aberrant methylation. Multiple nodules were obtained from four patients; in three, all were monoclonal with activation of the same allele. Three papillary carcinomas were monoclonal; two exhibited aberrant methylation. One follicular carcinoma showed loss of heterozygosity. Our data indicate that morphologically indistinguishable hyperplastic thyroid nodules may be monoclonal or polyclonal. These findings suggest that variable molecular mechanisms are involved in the pathogenesis of nodules in sporadic goiter. Future studies will need to explore the biological significance of nodules of variable clonal origin.

Adult↗

PubMed2002

The mcrA gene as an alternative to 16S rRNA in the phylogenetic analysis of methanogen populations in landfill.

Inferred amino acid sequences of the methyl coenzyme-M reductase (mcrA) gene from five different methanogen species were aligned and two regions with a high degree of homology flanking a more variable region were identified. Analysis of the DNA sequences from the conserved regions yielded two degenerate sequences from which a forward primer, a 32-mer, and a reverse primer, a 23-mer, could be derived for use in the specific PCR-based detection of methanogens. The primers were successfully evaluated against 23 species of methanogen representing all five recognized orders of this group of Archaea, generating a PCR product between 464 and 491 bp. Comparisons between the mcrA and 16S small subunit rRNA gene sequences using PHYLIP demonstrated that the tree topologies were strikingly similar. Methods were developed to enable the analysis of methanogen populations in landfill using the mcrA gene as the target. Two landfill sites were examined and 63 clones from a site in Mucking, Essex, and 102 from a site in Odcombe, Somerset, were analysed. Analysis revealed a far greater diversity in the methanogen population within landfill material than has been seen previously.

Bacterial Proteins↗

PubMed1982

Selected nucleic Acid precursors in studies of aquatic microbial ecology.

The use of radiolabeled nucleosides and nucleic acid bases to estimate the rates of RNA and DNA synthesis in naturally occurring microbial assemblages requires numerous assumptions, several of which are evaluated herein. Comparative time series analyses of the uptake and incorporation, labeling specificity, and extent of catabolism of [2-H]adenine, [methyl-H]thymidine, and [5-H]uridine were performed with pure bacterial and algal cultures, as well as with environmental samples. [H]thymidine yielded the most variable results, especially with regard to the extent of nonspecific macromolecular labeling. The pathways of [H]thymidine and [H]adenine metabolism were further evaluated by isotope dilution methods and by comparing incorporation patterns of thymidine labeled at different sites of the molecule. The advantages, uncertainties, and limitations of the use of radiolabeled nucleic acid precursors in studies of aquatic microbial ecology are discussed and a prospectus for future studies presented.

Journal Article↗

PubMed1995

X inactivation of the FMR1 fragile X mental retardation gene.

X chromosome inactivation has been hypothesised to play a role in the aetiology and clinical expression of the fragile X syndrome. The identification of the FMR1 gene involved in fragile X syndrome allows testing of the assumption that the fragile X locus is normally subject to X inactivation. We studied the expression of the FMR1 gene from inactive X chromosomes by reverse transcription of RNA followed by PCR (RT-PCR), both in somatic cell hybrids which retain an active or inactive human X chromosome and in a female patient with a large deletion surrounding the FMR1 gene. In both analyses, the data indicate that FMR1 is not normally expressed from the inactive X chromosome and is, therefore, subject to X chromosome inactivation. This finding is consistent with the results of previous studies of DNA methylation of FMR1 on active and inactive X chromosomes, verifies previous assumptions about the fragile X locus, and supports the involvement of X inactivation in the variable phenotype of females with full mutations of the FMR1 gene.

Animals↗

PubMed2003

Methacrylate-tethered analogs of the laser dye PM567--synthesis, copolymerization with methyl methacrylate and photostability of the copolymers.

The synthesis and characterization of new analogs of the laser dye PM567 (4,4-difluoro-1,3,5,7,8-pentamethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene) with the 8-position substituted by a linear chain with n methylenes (n = 1, 3, 5, 10 or 15) tethered with an acetoxy or methacryloyloxy group (PnAc and PnMA, respectively) is described. The monomeric dyes PnMA have been successfully copolymerized with methyl methacrylate (MMA), yielding linear copolymers of high optical quality where the covalently bonded chromophore is separated from the polymeric main chain by a spacer of variable length. The photostability of the solid polymeric materials under UV (310 nm) irradiation (method ASTM G 53-77) has been compared with those of the model dyes PnAc and PM567 as solid solutions in poly-MMA (PnAc-PMMA and PM567-PMMA, respectively). In all the cases, the chromophore bound to the polymer is more photostable than that simply dissolved in the same polymer, with photodegradation quantum yields in the range 2.3 x 10(-5) to 4.8 x 10(-5), which was interpreted as due to additional modes for the dissipation of the absorbed energy along the polymeric chain. In both polymer solutions and copolymers, the length of the polymethylene chain has low or null influence on the photostability. In ethanol solution, PnAc model dyes with polymethylene chains with three or more methylene groups show about the same photostability; this is of an order of magnitude higher than that of the parent dyes P1Ac and PM567 in the same solvent.

Journal Article↗

PubMed2006

Fatty acid methyl ester analysis to identify sources of soil in surface water.

Efforts to improve land-use practices to prevent contamination of surface waters with soil are limited by an inability to identify the primary sources of soil present in these waters. We evaluated the utility of fatty acid methyl ester (FAME) profiles of dry reference soils for multivariate statistical classification of soils collected from surface waters adjacent to agricultural production fields and a wooded riparian zone. Trials that compared approaches to concentrate soil from surface water showed that aluminum sulfate precipitation provided comparable yields to that obtained by vacuum filtration and was more suitable for handling large numbers of samples. Fatty acid methyl ester profiles were developed from reference soils collected from contrasting land uses in different seasons to determine whether specific fatty acids would consistently serve as variables in multivariate statistical analyses to permit reliable classification of soils. We used a Bayesian method and an independent iterative process to select appropriate fatty acids and found that variable selection was strongly impacted by the season during which soil was collected. The apparent seasonal variation in the occurrence of marker fatty acids in FAME profiles from reference soils prevented preparation of a standardized set of variables. Nevertheless, accurate classification of soil in surface water was achieved utilizing fatty acid variables identified in seasonally matched reference soils. Correlation analysis of entire chromatograms and subsequent discriminant analyses utilizing a restricted number of fatty acid variables showed that FAME profiles of soils exposed to the aquatic environment still had utility for classification at least 1 wk after submersion.

Esters↗

PubMed1992

Experimental hydroxyapatite cement cranioplasty.

Hydroxyapatite cement is a calcium phosphate-based material that when mixed with water forms a dense paste that sets within 15 minutes and isothermically converts in vivo to a microporous hydroxyapatite implant. This cement was used to reconstruct bilateral 2.5-cm-diameter full-thickness critical-sized parietal skull defects in six cats. One side was reconstructed with 100 percent hydroxyapatite cement, and the other with a mixture of 50 percent hydroxyapatite cement and 50 percent ground autogenous bone by weight. These animals were sacrificed at 6 and 12 months after implantation. Positive and negative controls also were prepared. The anatomic contour of the soft tissue overlying all hydroxyapatite cement implants was well maintained, there were no wound infections or structural failures, and the implants were well tolerated histologically. None of the negative (unreconstructed) control defects was completely filled with repair bone, and all positive (methyl methacrylate) controls demonstrated foreign-body giant-cell formation and fibrous encapsulation of the implants. Examination of decalcified and undecalcified sections revealed progressive but variable replacement of the cement by new bone and soft tissue without a change in the shape or volume of the hydroxyapatite cement-reconstructed areas. New bone comprised 77.3 and 64.7 percent of the tissue replacing the hydroxyapatite cement and hydroxyapatite cement-bone implants, respectively. Replacement of the hydroxyapatite cement implants by new bone is postulated to occur by a combination of osteoconduction and implant resorption. These results indicate that further experimental research leading to the possible application of hydroxyapatite cement for full-thickness calvarial defect reconstruction in humans is warranted.

Animals↗

PubMed1996

The posterior gastric and superior polar arteries in human fetuses.

In 67 human fetuses 127-285 mm of crown-rump length (15 to 28 weeks of fetal age), the variability of the posterior gastric artery (PGA) and superior polar artery (SPA) was investigated. The vascular bed was injected with colored acrylic emulsion, and diaphanisation in methyl salicylate, taken from tissue blocks. The arteries were found in 62 fetuses (92.5%). In 40 cases (59.7%) only PGA, in 17 cases (25.3%) only SPA, and in 5 cases (7.5%) both arteries were observed. They usually originated from the pancreatic portion of the lienal artery or rarely from its terminal branches. PGA supplied part of the posterior wall of the stomach and in 4.5% it supplied also the posterior wall of the abdominal portion of the esophagus. SPA supplied the superior end of the spleen and through 1-3 branches it supplied the posterior wall of the fundus of the stomach.

Arteries↗

PubMedDate not supplied

Evaluation of an ex vivo murine local lymph node assay: multiple endpoint comparison.

The local lymph node assay (LLNA) is used to assess the skin sensitization potential of chemicals. In the standard assay, mice are treated topically on the dorsum of both ears with test substance for 3 days. Following 2 days of rest, the initiation of the hypersensitivity response is evaluated by injecting (3)H-thymidine into a tail vein, and then measuring the levels of radioisotope incorporated into the DNA of lymph node cells draining the ears. In the current study, BALB/c mice were treated with the contact sensitizers hexylcinnamic aldehyde (HCA) and oxazolone, and the nonsensitizer methyl salicylate. The proliferative response of lymph node cells was evaluated in an ex vivo assay, in which isolated cells were cultured in vitro with (3)H-thymidine. Treatment of mice with HCA at 5-50% resulted in concentration-related increases in (3)H-thymidine incorporation, with stimulation indices ranging from 3 to 14. Low animal-to-animal variability was seen in three replicate assays testing HCA at 25%. As anticipated, the proliferative response induced by the potent sensitizer oxazolone at 0.25% was greater than HCA at all concentrations tested. Stimulation indices of 1.5 and 3 were seen in two independent experiments with methyl salicylate. These equivocal findings were likely due to the irritancy properties of the compound. Importantly, measuring ex vivo (3)H-thymidine incorporation was more sensitive than evaluating lymph node weight and cellularity, and in vitro bromodeoxyuridine incorporation. Furthermore, the results of the ex vivo LLNA were comparable to the standard assay. This study provided evidence that supports the use of an ex vivo LLNA for hazard assessment of contact hypersensitivity.

Acrolein↗