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Biomedical subjects

M Kirchner

Publications and source records attributed to M Kirchner.

At least 19 recordsLinked to original sources
PubMed2026

Genomic characterisation of Enterococcus cecorum isolated from broiler chickens in the United Kingdom.

Enterococcus cecorum is an important poultry pathogen associated with lameness and increased mortality, leading to major welfare and economic impacts. Treatment is often challenging because disease is frequently detected late and the organism can localise in bone and joints, limiting antimicrobial efficacy. Presence of antimicrobial resistance (AMR) genes may further complicate treatment. Despite increasing global genomic research, only one recent study has investigated the phylogeny of E. cecorum from conventional UK broiler farms, using limited samples and a restricted time frame. In this study, 283 E. cecorum isolates were analysed, including 158 from the United Kingdom and 125 global non‑UK isolates. UK isolates comprised 123 archived by the Animal and Plant Health Agency (APHA) between 2003 and 2022, predominantly from clinical outbreaks with increased welfare culling and mortality, and 35 isolates from a UK study including clinical and environmental samples. Genome sequencing was used to assess phylogeny, AMR determinants and virulence factors (VFs). Single nucleotide polymorphism phylogenetic analysis identified eight major UK lineages with limited intra‑lineage diversity, indicating that UK isolates were genetically distinct from non‑UK populations. Using a 60‑SNP threshold, APHA isolates formed 18 subclusters, consistent with long‑term persistence and recurrent farm transmission, while multiple subclusters detected on some farms suggested repeated introductions. UK isolates carried fewer AMR genes than non‑UK isolates, with erm(B), lnu(C), tet(M) and tet(L) most prevalent. Screening of VF genes identified nine genes present in all isolates, with the remainder variably distributed. A subset of 60 UK isolates was examined for 13 previously described virulence‑associated genes, with phylogenetic clustering indicating associations between gene presence or absence and clinical status or mortality classification. The capsular polysaccharide gene cpsO was assessed in this subset and most non‑clinical or environmental isolates were cpsO‑negative, although several isolates from high‑mortality outbreaks also lacked this gene. Overall, this study provides insight into the phylogeny, AMR profiles and virulence gene diversity of E. cecorum within the UK broiler sector, supporting targeted surveillance and investigation of pathogenic mechanisms.

Antimicrobial resistance↗
PubMed1998

Atrial mapping and radiofrequency catheter ablation in patients with idiopathic atrial fibrillation. Electrophysiological findings and ablation results.

BACKGROUND: Knowledge of the electrophysiological substrates and the cure of atrial fibrillation (AF) is still unsatisfactory. The goal of this study was to evaluate the electrophysiological features of idiopathic AF and their relationship to the results of radiofrequency (RF) catheter ablation of AF and the safety and effectiveness of this procedure. METHODS AND RESULTS: Sixteen patients with idiopathic AF underwent atrial mapping during AF and then RF ablation in the right atrium. The atrial activation was simultaneously recorded in four regions in the right atrium: high lateral wall (HL), low lateral wall (LL), high septum (HS), and low septum (LS) and in the left atrium through the coronary sinus (CS). In these regions, we evaluated the atrial fibrillation intervals (FF) and the morphological features of AF recordings by Wells' classification. No complications occurred during RF ablation. Of the 16 patients, 9 (56%) without AF recurrences during the follow-up (11 +/- 4 months) were considered successfully ablated. These patients showed a significantly shorter mean FF interval in the HS and the LS (122 +/- 32 and 126 +/- 28 ms, respectively), than in the HL and LL (159 +/- 24 and 156 +/- 28 ms, respectively). Moreover, the septum had more irregular electrical activity with greater beat-to-beat changes in FF and a higher prevalence of type III AF than the lateral region. The CS had similar behavior to the septum. Conversely, patients with unsuccessful ablation had an irregular atrial activity in the lateral wall, septum, and CS with no significant differences between the different sites. CONCLUSIONS: Right atrial endocardial catheter ablation of AF is a safe procedure and may be effective in some patients with idiopathic AF. The atrial mapping during AF showed a more disorganized right atrial activation in the septum than in the lateral wall in patients with successful ablation.

Adult↗
PubMed1996

Peptide-mass profiles of polyvinylidene difluoride-bound proteins by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in the presence of nonionic detergents.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), in conjunction with enzymatic digestion of proteins and molecular weight search of peptide-mass database is a powerful technique for peptide/protein identification. Ideally, peptide mixtures should be compatible with both MALDI-TOF and microsequencing. In our laboratory, enzymatic digestion and extraction of peptides from polyvinylidene difluoride (PVDF)-bound proteins is performed in the presence of nonionic detergents. However, nonionic detergents have been shown to cause signal suppression in MALDI-TOF analysis. This study demonstrates that by using a modified matrix solution, peptide-mass fingerprinting of PVDF-bound proteins by MALDI-TOF can be obtained in the presence of nonionic detergents such as hydrogenated Triton X-100 (RTX-100), octylglucopyranoside, and Tween 20.

Amino Acid Sequence↗
PubMed1996

Amino acid polymorphism and rare electrophoretic variants of G6PD from natural populations of Drosophila melanogaster.

Identifying the amino acid changes responsible for electrophoretic variants is essential to understanding the significance of allozyme polymorphism in adaptation. The amino acid mutations responsible for the common G6PD allozyme polymorphisms in Drosophila melanogaster have been recently described. This study characterizes the amino acid changes associated with 11 rare electrophoretic G6PD variants. The 11 rare electrophoretic variants result from six independent amino acid mutations. The in vivo function of the rare variants was determined in an earlier study and most variants fell into one of two function classes. It is shown here that the function of the rare variants reflects the state of the Pro/Leu mutation responsible for the A/B allozyme polymorphism in each variant. Two mutations destabilize quaternary structure resulting in shifts from tetrameric dimeric alleles, and one of these also results in a variant with in vivo function intermediate to A and B. That mutation is an aspartic-acid-to-asparagine change that is two residues away from the Pro/Leu polymorphism responsible for the A/B dimertetramer quaternary shift. Structure-function relationships based on studies of human G6PD deficiency-associated mutations predict that these last two amino acid changes fall within the protein domain responsible for NADP binding.

Amino Acid Sequence↗
PubMed1996

Historical selection, amino acid polymorphism and lineage-specific divergence at the G6pd locus in Drosophila melanogaster and D. simulans.

The nucleotide diversity across 1705 bp of the G6pd gene is studied in 50 Drosophila melanogaster and 12 D. simulans lines. Our earlier report contrasted intraspecific polymorphism and interspecific differences at silent and replacement sites in these species. This report expands the number of European and African lines and examines the pattern of polymorphism with respect to the common A/B allozymes. In D. melanogaster the silent nucleotide diversity varies 2.8-fold across localities. The B allele sequences are two-to fourfold more variable than the derived A allele, and differences between allozymes are twice as among B alleles. There is strong linkage disequilibrium across the G6pd region. In both species the level of silent polymorphism increases from the 5' to 3' ends, while there is no comparable pattern in level of silent site divergence or fixation. The neutral model is not rejected in either species. Using D. yakuba as an outgroup, the D. melanogaster lineage shows a twofold greater rate of silent fixation, but less than half the rate of amino acid replacement. Lineage-specific differences in mutation fixation are inconsistent with neutral expectations and suggest the interaction of species-specific population size differences with both weakly advantageous and deleterious selection.

Animals↗
PubMed1995

Differential accumulation of the transcripts of 22 novel protein kinase genes in Arabidopsis thaliana.

22 novel members of the Arabidopsis thaliana protein kinase family (AKs) were identified by using degenerate oligonucleotide primers directed to highly conserved amino acid sequences of the protein kinase (PK) catalytic domain. Of these 22 genes, 16 turned out to carry intron sequences. Homologies of AK sequences were detected to S-locus receptor protein kinases (SRKs) from Brassica spp., to SRK-like PKs from maize and A. thaliana and to several other receptor PKs from A. thaliana. Sequence similarity was also detected to Ca(2+)-dependent PKs (CDPKs) from rape and soybean, to SNF1 and to CDC2 homologues. The genomic organization and the accumulation of the mRNAs from these 22 AK genes were investigated.

Amino Acid Sequence↗
PubMed1994

Synthesis and SAR studies of novel triazolopyrimidine derivatives as potent, orally active angiotensin II receptor antagonists.

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These [1,2,4]-triazolo[1,5-c]pyrimidine and 1,2,4-triazolo[4,3-c]pyrimidine derivatives represent a new class of bicyclic antagonists that produced a potent, oral antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors and were found to be specific for the AT1 receptor subtype. A SAR study has shown the importance of the 8-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl for oral activity and the critical role of alkyl substituents at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c]series. UP 269-6 (5-methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl ]- [1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compound. It was shown to be a highly potent antihypertensive derivative (decrease in mean arterial pressure of 39.6 +/- 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which displayed a high affinity for adrenal AII receptors with a marked selectivity for the AT1 receptor subtype (Ki AT1 = 24 nM; Ki AT2 = 79,200 nM). This compound is currently undergoing extensive pharmacological and clinical development.

Administration, Oral↗
PubMed1994

Synthesis and angiotensin II receptor antagonist activity of C-linked pyrazole derivatives.

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to the discovery of compounds with potent oral antihypertensive activity in a renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors. In vivo structure-activity relationship study has shown the importance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for oral activity and the critical role of alkyl substituents at the 1- or 2-position. In the case of oral administration, 5-C derivatives were found to be, on the whole, more potent than 5-O derivatives. UP 221-78, 5-hydroxymethyl-3-n-propyl-1-(2,2,2-trifluoroethyl)-4- [[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equivalent antihypertensive activity to the well known antagonist Losartan at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-78, respectively.

Angiotensin Receptor Antagonists↗
PubMed1993

Evidence for adaptive evolution of the G6pd gene in the Drosophila melanogaster and Drosophila simulans lineages.

Proponents of the neutral theory argue that evolution at the molecular level largely reflects a process of random genetic drift of neutral mutations. Under this theory, levels of interspecific divergence and intraspecific polymorphism are expected to be correlated across classes of nucleotide or amino acid sequences with different degrees of functional constraint, such as synonymous and replacement sites. Nucleotide sites with reduced polymorphism should show comparably reduced levels of interspecific divergence. To examine this hypothesis, we have sequenced 32 and 12 copies of the glucose-6-phosphate dehydrogenase (G6pd) gene in Drosophila melanogaster and Drosophila simulans, respectively. Both species exhibit similar levels of nucleotide polymorphism at synonymous sites. D. melanogaster shows two amino acid polymorphisms, one associated with the cosmopolitan allozyme polymorphism and a second with an allozyme polymorphism endemic to European and North African populations. In contrast, D. simulans shows no replacement polymorphism. While synonymous divergence between species is 10%, which is typical of other genes, there are 21 replacement differences. This level of amino acid sequence divergence, when contrasted with levels of amino acid polymorphism, silent polymorphism, and divergence, is in 10-fold excess over that expected under the neutral model of molecular evolution. We propose that this excess divergence reflects episodes of natural selection on G6pd resulting in fixation of advantageous amino acid mutations in these two recently separated lineages.

Adaptation, Physiological↗
PubMed1993

Fish oil preparations rich in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists.

The effects of daily dietary supplementation for 6 weeks with either 4.5 g eicosapentaenoic acid (EPA) and 3.35 g docosahexaenoic acid (DHA) (group I, EPA/DHA = 1.33) or 3.5 g EPA and 6.4 g DHA (group II, EPA/DHA = 0.54) on platelet responsiveness to the stable prostaglandin (PG)-endoperoxide analogue 9,11-dideoxy,9 alpha-11 alpha-methanoepoxy-PGF2 alpha (U 46619) were studied in healthy volunteers. Dose-response curves (DRC) of U 46619-induced platelet aggregation were analysed by computerized non-linear curve fitting. In group I, the concentration of U 46619 required for half-maximum platelet aggregation (EC50) remained unchanged, whereas the Hill coefficient decreased from 6.2 to 3.3 (P < 0.02). In group II, characterized by a high intake of DHA, a considerable increase of EC50 from 0.3 to 1.4 microM was found (P < 0.02). These results suggest different effects of EPA and DHA on the platelet thromboxane/endoperoxide-amplifying system. The considerable shift of the DRC in group II suggests a direct effect of DHA on the presentation of the endoperoxide receptor and/or post-receptoral events.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

[Complete trisomy 22].

In a 2 6/12-years-old girl a complete trisomy 22 was verified with the G-banding (CTG-technique). She presented with Pierre-Robin-Sequence, cardiac and renal malformations, craniofacial dysmorphia and psychomotoric retardation as it often occurs in trisomy 22. Additionally, we observed tonic-clonic seizures, remarkable dumbles on both elbows and a clavicular anomaly.

Abnormalities, Multiple↗
PubMed1992

Phospholipase A2 inhibition by alkylbenzoylacrylic acids.

3-(4-Alkylbenzoyl)acrylic acids (ABAAs) were synthesized by acylation of alkylbenzenes with maleic anhydride and then screened in vitro for inhibition of phospholipase A2 (PLA2) from snake venom and from porcine pancreas. The inhibitory potency of ABAAs increased with the length of the alkyl residues resulting in IC50 values of between 10(-7) and 10(-4) mol/L. The most potent inhibitors of the snake venom PLA2 were the 4-(n)-hexadecyl and octadecyl (OBAA) derivatives. Kinetic experiments referred to a time-dependent inhibitory reaction. Irreversibility was examined by dilution and dialysis. A molar ratio of inactivation of OBAA of nearly 20 was estimated. Double reciprocal replots of the apparent inactivation constants to the concentration of OBAA gave a (pseudo) first order rate constant of inactivation of 2.3 min-1. For the dissociation constant of the enzyme-inhibitor intermediate, a value of 6 x 10(-6) mol/L was obtained. On the other hand, the PLA2 from porcine pancreas seemed hardly to be inhibited by ABAAs. The present data are discussed in relation to the proposed model for PLA2 inactivation by manoalide. In human PMNs leukotriene B4 and 5-HETE production was essentially reduced. In human platelets the thrombin-induced TxA2 production was reduced. Since these effects disappeared after addition of arachidonic acid, these findings refer to a PLA2 inhibition. The immunologically induced bronchospasm in guinea pigs was significantly and dose-dependently inhibited by OBAA. This indicates that ABAAs might be useful in treating allergic diseases, such as asthma, eczema, allergic shock and others.

Acrylates↗
PubMed1991

Determination of picomole amounts of lipoxins C4, D4 and E4 by high-performance liquid chromatography with electrochemical detection.

A method for the sensitive determination of the sulphopeptide lipoxins (LXs) C4, D4 and E4 by high-performance liquid chromatography with subsequent electrochemical detection is described. The best results were obtained when the analysis was carried out with the solvent system methanol-water-trifluoroacetic acid (66:34:0.008, v/v/v). The acquired half-wave potentials were different for all investigated compounds: +1.18 V for LXC4 +1.3 V for LXD4 and +1.25 V for LXE4. The detection limits of LXC4, LXD4 and LXE4, based on a signal-to-noise ratio of 3:1, were found to be 200-700 fmol. Although sulphopeptide lipoxins possess a high molar absorptivity, electrochemical detection still is three times more sensitive than ultraviolet detection.

Arachidonic Acids↗
PubMed1991

Delayed spontaneous pubertal growth spurt in girls with the Ullrich-Turner syndrome.

By means of an appropriate mathematical model (Sager's 2-components-concept) a delayed spontaneous pubertal growth spurt can be demonstrated in girls with 45,X Ullrich-Turner syndrome (UTS) (n1 = 45) as well as in those with 45,X/46,XX mosaicism (n2 = 14) never treated with any growth stimulating drug. On the average, this growth spurt begins later and its extent is smaller (mean growth rate = 3.10 and 2.79 cm, respectively, in the 15th year of chronological age) than in normal girls. The delay in acute growth spurt corresponds very well to the delay of skeletal maturation in the UTS (on the average 2 to 3 years of chronological age).

Adolescent↗
PubMed1991

Who pays for new technology?

New medical technology presents an interesting dilemma. While it can offer improvements in patient care, it is often quite expensive. Thus, many health care payers may not be as willing to cover care involving new technologies.

Commerce↗