Biomedical subjects
C Meier
Publications and source records attributed to C Meier.
cycloSaligenyl-5-[(E)-2-bromovinyl]-2'-deoxyuridine monophosphate (cycloSal-BVDUMP) pronucleotides active against Epstein-Barr virus.
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Regulation of genes involved in Schwann cell development and differentiation.
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On the symmetry of periodontal disease.
BACKGROUND/AIM: Symmetry is a common feature of biological systems, and can be observed in multiple aspects of the human body. The purpose of this study was to estimate the impact of symmetry on variance observed in intraoral topographic distribution patterns of chronic periodontitis. METHOD: This analysis was performed on a data set from 56 subjects, including clinical and microbiological variables, recorded at the mesial and distal aspect of every tooth in the entire dentition. The impact of contralateral conditions was determined on the level of the site, the tooth, and the quadrant. RESULTS: Significant correlations were detected between probing depths, recession, attachment levels, total cultivable bacterial counts and the plaque index recorded on the right and left side on all levels of analysis. The odds for bleeding on sampling, as well as for the presence of P. intermedia/nigrescens and A. actinomycetemcomitans increased significantly if the respective contralateral site was positive for the same parameter. In combining ipsilateral and contralateral parameters into the analysis it could be shown in several instances that this contralateral effect was stronger than the impact of other, ipsilateral factors. As an example, the odds for bleeding on sampling increased up to 10 fold if the contralateral site was bleeding, whereas the ipsilateral total cultivable count, determined at the same site, explained less than 30% of the variation in the bleeding tendency. CONCLUSION: These findings support the view that the development of periodontal disease in any site cannot be explained by the influence of local detrimental factors alone.
Antimicrobial properties of phenolic compounds from berries.
AIMS: To investigate the antimicrobial properties of phenolic compounds present in Finnish berries against probiotic bacteria and other intestinal bacteria, including pathogenic species. METHODS AND RESULTS: Antimicrobial activity of pure phenolic compounds representing flavonoids and phenolic acids, and eight extracts from common Finnish berries, was measured against selected Gram-positive and Gram-negative bacterial species, including probiotic bacteria and the intestinal pathogen Salmonella. Antimicrobial activity was screened by an agar diffusion method and bacterial growth was measured in liquid culture as a more accurate assay. Myricetin inhibited the growth of all lactic acid bacteria derived from the human gastrointestinal tract flora but it did not affect the Salmonella strain. In general, berry extracts inhibited the growth of Gram-negative but not Gram-positive bacteria. These variations may reflect differences in cell surface structures between Gram-negative and Gram-positive bacteria. Cloudberry, raspberry and strawberry extracts were strong inhibitors of Salmonella. Sea buckthorn berry and blackcurrant showed the least activity against Gram-negative bacteria. CONCLUSION: Different bacterial species exhibit different sensitivities towards phenolics. SIGNIFICANCE AND IMPACT OF THE STUDY: These properties can be utilized in functional food development and in food preservative purposes.
Gibberellin response mutants identified by luciferase imaging.
The gibberellin (GA) 20-oxidase encoded by Arabidopsis GA5 catalyzes the synthesis of active GAs. GA5 is a regulatory step in GA biosynthesis as GA5 mRNA levels are negatively regulated by its bioactive GA products. A fusion between the GA5 promoter and the firefly luciferase reporter (GA5-LUC) was shown to be similarly regulated, indicating GA feedback of GA5 occurs at the transcriptional level. The fidelity of the GA5-LUC reporter permitted a fusion genetic screen to identify mutants altered in transgene expression. This bioimaging screen identified two types of recessive mutants with increased LUC activity and apparent GA-related growth phenotypes, a dwarf (lue1) and two late flowering mutants (fpa1-3 and fpa1-4). Mutant progeny exhibited altered levels of LUC and of endogenous GA5 and other GA-regulated mRNAs. SSLP-based mapping localized lue1 to chromosome I near the ga2 locus, although complementation analyzes showed that lue1 is not allelic to ga2. Mapping and complementation analyzes showed that the late flowering mutants are allelic to fpa1. This provides genetic evidence for crosstalk between the autonomous and gibberellin-dependent flowering pathways.
Measuring mass transfer processes of octane with the help of an alkSalkB::gfp-tagged Escherichia coli.
Diffusion of octane from oily droplets in different microscale settings was measured using Escherichia coli expressing the stable green fluorescent protein (GFP) from the alkB promoter of Pseudomonas oleovorans. GFP fluorescence intensities were determined quantitatively at the single-cell level after 1.0 or 2.5 h incubation and compared with different calibration series using known concentrations of octane. By immobilizing the E. coli sensor cells on the bottom glass plate of a microscope flow chamber, it was possible to monitor the diffusion process for octane in aqueous solution as a function of time and distance from non-aqueous phase droplets of octane alone or oily octane mixtures. When a gas phase was included in the flow chambers, octane transport could be demonstrated from the oily mixtures to the cells through both gas and liquid phase. Assays of non-immobilized sensor cells in microdroplets in the presence or absence of soil particles incubated with octane through the vapour phase revealed a slight reduction in the total amount of induced E. coli cells in the presence of soil. Our results indicate the power of using GFP-marked single-cell biosensors in determining microscale bioavailability of organic pollutants.
Antiviral activity of cyclosaligenyl prodrugs of acyclovir, carbovir and abacavir.
The cyclosaligenyl (cycloSal) derivatives of the monophosphates of three acyclic or carbocyclic guanosine analogues, for example, acyclovir (ACV), carbovir (CBV) and abacavir (ABC), were investigated for their activity against retrovirus (HIV, Moloney sarcoma virus) and herpes simplex virus (HSV) activity in cell culture. The extent of the antiviral potency of the prodrugs depended on the nature of the nucleoside, the substituent on the cycloSal moiety and the virus investigated. Most notably, and unlike the parent compound ACV, cycloSal-ACV monophosphate (MP) prodrugs retained pronounced activity against ACV-resistant (thymidine kinase-deficient) HSV-1 and also gained anti-HIV activity. While the cycloSal-CBVMP prodrugs did not show enhanced activity compared with the parent compound CBV, the cycloSal-ABCMP prodrugs afforded markedly increased potency against both HSV and HIV. Our data indicate that the cycloSal prodrug approach can be useful to deliver directly the MP derivatives of nucleoside analogues into the intact, virus-infected cells, thus improving and extending the antiviral potency and spectrum of the drugs against retro- and herpesvirus strains.
TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study).
This study evaluated the effect of physiological, TSH-guided, L-thyroxine treatment on serum lipids and clinical symptoms in patients with subclinical hypothyroidism. Sixty-six women with proven subclinical hypothyroidism (TSH, 11.7 +/- 0.8 mIU/liter) were randomly assigned to receive L-thyroxine or placebo for 48 wk. Individual L-thyroxine replacement (mean dose, 85.5 +/- 4.3 microg/d) was performed based on blinded TSH monitoring, resulting in euthyroid TSH levels (3.1 +/- 0.3 mIU/liter). Lipid concentrations and clinical scores were measured before and after treatment. Sixty-three of 66 patients completed the study. In the L-thyroxine group (n = 31) total cholesterol and low density lipoprotein cholesterol were significantly reduced [-0.24 mmol/liter, 3.8% (P = 0.015) and -0.33 mmol/liter, 8.2% (P = 0.004), respectively]. Low density lipoprotein cholesterol decrease was more pronounced in patients with TSH levels greater than 12 mIU/liter or elevated low density lipoprotein cholesterol levels at baseline. A significant decrease in apolipoprotein B-100 concentrations was observed (P = 0.037), whereas high density lipoprotein cholesterol, triglycerides, apolipoprotein AI, and lipoprotein(a) levels remained unchanged. Two clinical scores assessing symptoms and signs of hypothyroidism (Billewicz and Zulewski scores) improved significantly (P = 0.02). This is the first double blind study to show that physiological L-thyroxine replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism. An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in low density lipoprotein cholesterol.
Control of specific gene expression by gibberellin and brassinosteroid.
We identified a recessive, brassinolide-insensitive mutant caused by a deletion allele (bri1-201) of the brassinosteroid (BR) receptor BRI1. The bri1-201 mutant displayed altered expression levels of genes differentially regulated by gibberellin (GA). RNA-blot analysis revealed that BR and GA antagonistically regulate the accumulation of mRNAs of the GA-responsive GASA1 gene, as well as the GA-repressible GA5 gene. Expression studies with cycloheximide indicated that the antagonistic effects of GA and BR on GA5 require de novo protein synthesis. Reporter transgene analyses and RNA-blot analysis showed that BR and GA modulate GA5 expression, at least in part, at the transcriptional level, and that the signals are independent and subtractive.
[Amiodarone-induced thyrotoxicosis].
Amiodarone is the most important drug in the treatment of ventricular arrhythmias and is widely used for atrial fibrillation. Thyrotoxicosis, a classical side effect, was thought to be iodine induced, but recent evidence suggests that other mechanisms play an important role (toxic effect on thyreocytes, immunological effects). Thyrotoxicosis due to amiodarone is difficult to treat and is further complicated by the pro-arrhythmic potential of thyrotoxicosis and the fading antiarrhythmic effect after amiodarone withdrawal. The mechanism, diagnosis and therapy of amiodarone-induced thyrotoxicosis are discussed in the light of the available literature.
EPR and Mössbauer studies of benzoyl-CoA reductase.
Benzoyl-CoA reductase catalyzes the two-electron transfer from a reduced ferredoxin to the aromatic ring of benzoyl-CoA; this reaction is coupled to stoichiometrical ATP hydrolysis. A very low reduction potential (less than -1 V) is required for the first electron transfer to the aromatic ring. In this work the nature of the redox centers of purified benzoyl-CoA reductase from Thauera aromatica was studied by EPR and Mössbauer spectroscopy. The results obtained indicated the presence of three [4Fe-4S] clusters. Redox titration studies revealed that the reduction potentials of all three clusters were below -500 mV. The previously reported S = 7/2 state of the enzyme during benzoyl-CoA-independent ATPase activity (Boll, M., Albracht, S. J. P., and Fuchs, G. (1997) Eur. J. Biochem. 244, 840-851) was confirmed by Mössbauer spectroscopy. Inactivation by oxygen was associated with the irreversible conversion of part of the [4Fe-4S] clusters to [3Fe-4S] clusters. Acetylene stimulated the benzoyl-CoA-independent ATPase activity and induced novel EPR signals with g(av) >2. The presence of simple cubane clusters in benzoyl-CoA reductase as the sole redox-active metal centers demonstrates novel aspects of [4Fe-4S] clusters since they adopt the role of elemental sodium or lithium which are used as electron donors in the analogous chemical Birch reduction of aromatic rings.
[Laparoscopic fundoplication for gastroesophageal reflux: experience with 49 surgical patients (1994-1999)].
INTRODUCTION: Chronic gastrooesophageal reflux disease (GERD) is the most common benign pathology of the upper gastrointestinal tract in the western world. We report our experience of laparoscopic antireflux surgery. PATIENTS AND METHODS: 49 patients underwent laparoscopic antireflux surgery at our clinic between 1994 and 1999. 48 patients were followed up in a retrospective study. Mean follow-up was 30 months (2-66). 31 patients (64.6%) were male and 17 female (35.4%). Mean age was 48 years (26-74). The surgical method was tailored to the case: total Nissen fundoplication (87.5%) was indicated after ruling out oesophageal motility disorders by manometry. In 6 patients (12.5%) with coexisting dysphagia or pathological manometry, partial posterior fundoplication (Toupet) was performed. RESULTS: Mean operating time of 215 minutes (125-420) for the first 10 Nissens was significantly reduced to 119 minutes (70-190) for the last 10 procedures with increasing experience of the surgeon. No severe intraoperative complications occurred and mortality was 0%. Conversion rate was 4.2%. Mean hospital stay was 6.1 days (1-36). At follow-up 93.7% were free of reflux symptoms without medication, and only one patient (2.1%) suffered from regular reflux which had to be treated with PPI daily. 2 patients (4.2%) took PPI only occasionally. Persistent dysphagia occurred in 7 patients (14.8%). 5 (10.5%) underwent one or more endoscopic dilatations, after which 3 patients (6.3%) reported an improvement of dysphagia. No patient needed reoperation on due to mechanical complications. 1 patient (2.1%) developed a paraoesophageal hernia 4.5 years after a Nissen procedure. According to the Visick Score, 95.8% of all patients were satisfied with their outcome (Visick I/II). CONCLUSIONS: With careful investigation and indication, laparoscopic antireflux surgery is a safe and effective alternative method to long-term medication with PPI in the treatment of gastrooesophageal reflux disease. Morbidity is low. Persistent postoperative dysphagia can be reduced with either a short and floppy total fundoplication or a partial wrap.
Interactions of conformationally biased north and south 2'-fluoro-2', 3'-dideoxynucleoside 5'-triphosphates with the active site of HIV-1 reverse transcriptase.
Molecular dynamics simulations of a ternary complex of HIV-1 reverse transcriptase (RT), double-stranded DNA, and bound dideoxynucleoside-5'-triphosphate (RT-DNA-ddNTP), utilizing the ddNTPs ddATP, betaFddATP, and alphaFddATP, explain the experimentally observed order of potency of these 5'-triphosphates as inhibitors of RT: ddATP > betaFddATP > alphaFddATP. On the basis of RT's known preference to bind the incoming dNTP (or ddNTP) with a north conformation at the polymerase site, alphaFddATP, which in solution prefers almost exclusively a north conformation, was predicted to be the most potent inhibitor. However, Tyr115, which appears to function as a steric gate to preclude the binding of ribonucleoside 5'-triphosphates, prevents the effective binding of alphaFddATP in its preferred north conformation. The south-biased betaFddATP, while able to bind to RT without hindrance by Tyr115, has to pay a high energy penalty to be flipped to the active north conformation at the polymerase site. Finally, the more flexible and less conformationally biased ddATP is able to switch to a north conformation at the RT site with a smaller energy penalty than betaFddATP. These results highlight the opposite conformational preferences of HIV-1 RT for alphaFddATP and betaFddATP and help establish conformational guidelines for optimal binding at the polymerase site of this enzyme.
The activating component of the anaerobic ribonucleotide reductase from Escherichia coli. An iron-sulfur center with only three cysteines.
Class III anaerobic ribonucleotide reductase small component, named protein beta, contains a (4Fe-4S) center. Its function is to mediate electron transfer from reduced flavodoxin to S-adenosylmethionine, required for the introduction of a glycyl radical in the large component, named protein alpha, which then becomes active for the reduction of ribonucleotides. By site-directed mutagenesis we demonstrate that the three cysteines of the conserved CXXXCXXC sequence are involved in iron chelation. Such a sequence is also present in the activase of the pyruvate formate-lyase and in the biotin synthase, both carrying an iron-sulfur center involved in reductive activation of S-adenosylmethionine. Even though they are able to bind iron in the (4Fe-4S) form, as shown by Mössbauer spectroscopy, the corresponding Cys to Ala mutants are catalytically inactive. Mutation of the two other cysteines of the protein did not result in inactivation. We thus conclude that the (4Fe-4S) cluster has, in the wild type protein, only three cysteine ligands and a fourth still unidentified ligand.
Self-rated health, life satisfaction and personal characteristics of post-menopausal women under estrogen replacement therapy.
OBJECTIVES: To describe the prevalence of oestrogen replacement therapy (ERT)-use among post-menopausal women in relation with personal and socio-economic characteristics and to examine the association of ERT-use with self-rated health and selected aspects of life satisfaction. METHODS: Population survey data were derived from a cohort study of 511 Bernese women, aged 55-65 years. Data were collected by means of telephone interviews. Overall prevalence of ERT-use, and selected associations with personal and socio-economic characteristics were investigated using descriptive statistical methods and logistic regression. The relations of ERT-use with five self-reported health measures were explored using Spearman's correlation coefficients. The associations of ERT-use with six dichotomous variables on satisfaction with various aspects of life were tested with chi-square tests in cross tabulations. RESULTS: The overall prevalence of self reported ERT-use was 17.6%. ERT was more prevalent women younger than 61 years than in women in the older age group. Women with a body mass index (BMI) under 25 reported ERT-use significantly more frequently than women with higher BMI (OR=3.16, CI 1.87-5.34). ERT-use was more prevalent in women with relatively high education: OR=2.01, CI 1.18-4.00. The self-reported health measures and the satisfaction items were not significantly associated with ERT-use. CONCLUSIONS: ERT-use among post-menopausal women was found to be associated with higher educational level and lower BMI. ERT-users did not report better health or life-satisfaction.
Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity.
Members of the newly discovered glycoprotein-associated amino acid transporter family (gpaAT-family) share a similar primary structure with >40% identity, a predicted 12-transmembrane segment topology and the requirement for association with a glycoprotein (heavy chain) for functional surface expression. Five of the six identified gpaATs (light chains) associate with the surface antigen 4F2 heavy chain (4F2hc = CD98), a ubiquitous plasma membrane protein induced in cell proliferation, and which is also highly expressed at the basolateral surface of amino acid transporting epithelia. The differing tissue localizations of the 4F2hc-associated gpaATs appear to complement each other. As yet, a single gpaAT (b(0,+)AT) has been shown to associate with rBAT, a 4F2hc-related glycoprotein mainly localized in intestine and kidney luminal brush-border membranes. The transport characteristics of gpaATs have been shown, by expression in heterologous systems, to correspond to the previously described transport systems L, y+L, xc- and b(o,+). These (obligatory) exchangers of broad substrate specificity (with the exception of xCT) are expected to equilibrate the concentrations of their substrate amino acids across membranes. Thus, the driving force provided by a transmembrane gradient of one substrate amino acid, such as that generated by a parallel functioning unidirectional transporter, can be used by a gpaAT to fuel the secondary active vectorial transport of other exchangeable species. Vectorial transport of specific amino acids is also promoted by the intrinsic asymmetry of these exchangers. The fact that genetic defects of the epithelial gpaATs b(0,+)AT and y+LAT1 cause non-type I cystinuria and lysinuric protein intolerance, respectively, demonstrates that these gpaATs perform vectorial secondary and/or tertiary active transport of specific amino acids in vivo.
Cell volume and water exchange in neural cells monitored by diffusion weighted 1H NMR spectroscopy.
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