Biomedical subjects

F R Althaus

Publications and source records attributed to F R Althaus.

At least 19 recordsLinked to original sources

PubMed2006

[Swiss veterinary drug compendium as a tool for reconversions].

The new Swiss ordinance on veterinary drugs poses a new challenge to the veterinarians, specially those working with farm animals. A complete overview about the registered veterinary drugs and immunobiologicals is absolutely necessary to cope with these new tasks: the internet version of the Swiss Veterinary Drug Compendium is a versatile tool to satisfy this needs (http://www.tierarzneimittel.ch). Due to the frequent updates and powerful search possibilities, this database is a reliable and comprehensive information system regarding Swiss veterinary drugs. We will demonstrate how this system can be used as a valuable help in the case of reconversions of drugs (e.g. use of small animal drugs in farm animals).

Animals↗

PubMed2005

[Suspected adverse drug reactions in 2004].

We received 62 reports of suspected adverse events (SARs) for the year 2004. Their number and repartition according to affected animals and active substances were comparable with the previous year. The distributors or manufacturers submitted most of the declarations, but the proportion submitted by practicing veterinarians is slowly growing. 72% of the declarations dealt with adverse reactions in small animals (cats and dogs), followed by cattle and horses. Antiparasitics, anti-inflammatory drugs and immunologicals were the most frequently mentioned therapeutic classes, which are listed here according to the international ATCvet classification. A report from abroad about a fatality following injection of an antibiotic preparation for cattle prompted Swissmedic to review the security of this medication also sold on the Swiss market. It was decided to modify the package insert to warn about the danger of inadvertent self-injection in humans, to reduce the risk of similar accidents in Switzerland. We hope that the pharmacovigilance system will enjoy an increasing awareness by the practicing veterinarians.

Adverse Drug Reaction Reporting Systems↗

PubMed2004

[Pharmacovigilance for veterinary drugs in Switzerland].

Pharmacovigilance is a system concerned with the acquisition, evaluation and classification of informations about suspected adverse drug reactions (SADR). Such a system was developed in Switzerland under the supervision of Swissmedic after the introduction of the federal law on therapeutic products on January 1st 2002. By sending declarations about SADRs, veterinary practitioners play a central role in this scheme. The reports are processed according to international standards (ABON) and provide useful hints to enhance the safety of drug usage by both patients and owners. The system acquired 58 reports in its first complete year of operation (2003). Analysis of these reveals that trends observed in foreign countries are also applicable to Switzerland: most of the reports concerned the use of antiparasitic or antibiotic drugs in small animals. The first year also revealed a high percentage of declarations coming from the pharmaceutical companies and the authors would therefore like to encourage practitioners to take a more active part in this scheme.

Adverse Drug Reaction Reporting Systems↗

PubMed2004

[Computer-based information system (CliniTox) for the management of poisoning in small animals].

Because cases of poisoning are observed rarely, veterinary practitioners have only limited knowledge of clinical toxicology and may face considerable problems in handling toxicological emergencies. In this report, we describe a novel decision support system for the management of poisonings in companion animals that provides rapid access to the current knowledge of clinical toxicology. For that purpose, relevant reports from the peer-reviewed literature were evaluated and organised according to the requirements of a structured database. The information provided for each toxic substance includes a summary of its chemical and physical properties, sources, commercial uses or natural occurrences, toxicokinetic data, mechanisms of action, threshold doses, clinical symptoms with brief case reports, sampling and analytical results, post-mortem findings, differential diagnoses, therapeutic guidelines and references to the literature. This decision support system has been programmed with two user-friendly search functions: a search tool that allows to choose clinical symptoms, and another function that serves to find a substance using its chemical name, the class of compounds to wich it belongs, a possible source or one of its main applications. CliniTox can be accessed directly via our webserver (http://www.clinitox.ch).

Animals↗

PubMed2002

Poly ADP-ribosylation in two L5178Y murine lymphoma sublines differentially sensitive to DNA-damaging agents.

PURPOSE: To characterize the response to X-irradiation of the poly ADP-ribosylation system in two closely related murine lymphoma sublines, L5178Y-R (LY-R) and L5178Y-S (LY-S), with differential sensitivity to various DNA damaging agents (UV-C and ionizing radiation, hydrogen peroxide). MATERIALS AND METHODS: LY cells were X-irradiated (2 Gy). NAD+ was determined in cell extracts by high-pressure liquid chromatography. ADP-ribose polymers were purified and analysed by densitometry after polyacrylamide gel electrophoresis. Nuclear matrix proteins were separated by SDS-polyacrylamide gel electrophoresis and processed for ADP-ribose polymer blots to estimate their ability to bind poly(ADP-ribose). RESULTS: In the radiosensitive LY-S cells, the constitutive levels of ADP-ribose polymers were twofold higher than in radioresistant LY-R cells, but unresponsive to a challenge with 2 Gy X-rays. The concentrations of NAD+ - the substrate for poly(ADP-ribose) synthesis - were identical in the two cell lines. X-rays (2 Gy) depleted NAD+ only in LY-S cells. These cells also produced shorter poly(ADP-ribose) molecules as compared with LY-R cells. Nuclear matrix preparations of LY-S cells exhibited lower poly(ADP-ribose)-binding capacity than those of LY-R cells. CONCLUSION: The results demonstrate disturbances in the poly ADP-ribosylation response of the radiosensitive LY-S cells and reduced poly(ADP-ribose)-binding affinity of the nuclear matrix of these cells.

Animals↗

PubMed2000

Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins.

Poly(ADP-ribose) is formed in possibly all multicellular organisms by a familiy of poly(ADP-ribose) polymerases (PARPs). PARP-1, the best understood and until recently the only known member of this family, is a DNA damage signal protein catalyzing its automodification with multiple, variably sized ADP-ribose polymers that may contain up to 200 residues and several branching points. Through these polymers, PARP-1 can interact noncovalently with other proteins and alter their functions. Here we report the discovery of a poly(ADP-ribose)-binding sequence motif in several important DNA damage checkpoint proteins. The 20-amino acid motif contains two conserved regions: (i) a cluster rich in basic amino acids and (ii) a pattern of hydrophobic amino acids interspersed with basic residues. Using a combination of alanine scanning, polymer blot analysis, and photoaffinity labeling, we have identified poly(ADP-ribose)-binding sites in the following proteins: p53, p21(CIP1/WAF1), xeroderma pigmentosum group A complementing protein, MSH6, DNA ligase III, XRCC1, DNA polymerase epsilon, DNA-PK(CS), Ku70, NF-kappaB, inducible nitric-oxide synthase, caspase-activated DNase, and telomerase. The poly(ADP-ribose)-binding motif was found to overlap with five important functional domains responsible for (i) protein-protein interactions, (ii) DNA binding, (iii) nuclear localization, (iv) nuclear export, and (v) protein degradation. Thus, PARPs may target specific signal network proteins via poly(ADP-ribose) and regulate their domain functions.

Alanine↗

PubMed2000

[Computer-supported poisonous plant information system for veterinary medicine].

Animals poisoned by plants are the subject of an increasing number of inquiries made to poison control centres. The most frequent questions are concerned with the identification of potentially toxic species and the choice of adequate therapeutic strategies. To meet this growing demand for information, we generated a database on poisonous plants to be used by veterinary practitioners. Relevant data were selected from the scientific literature and organised according to the requirements of a structured database. As a result, we now introduce a user-friendly decision support system that is equipped with several search functions for fast and efficient retrieval of data. The information provided for each plant includes the degree of toxicity, major toxic constituents, their mechanism of action, pathological findings, clinical symptoms with brief case reports, therapeutic guidelines and references. In addition, each species is accompanied by a botanical description with photographic illustrations. This information tool on poisonous plants is available via the internet (http:www.vetpharm.unizh.ch) or compact disc, and can be accessed on Macintosh, Windows or UNIX using a browser that supports HTML 3.

Animals↗

PubMed1999

[Ban on antimicrobial growth promoters: a safety advantage for consumers?].

The general ban of antimicrobial growth promoters seems reasonable and desirable to consumers, but is nevertheless problematic in a veterinary medical and political perspective. Rational risk management would imply that restrictive government decisions are evidence-based and provide the consumer with a higher safety level. The recent decision of the European Commission to ban avoparcin from the market was explicitly not based on scientific evidence, and apart from temporarily reducing consumer fears, the risk balance could even turn negative. The prejudicial nature of the avoparcin ban may encourage far reaching governmental interference on the market leading to the withdrawal of therapeutically important veterinary drugs on the basis of suspected side effects alone. Rational risk management would call for balancing the elimination of risks with the risks of elimination.

Animals↗

PubMed1999

Poly ADP-ribosylation: a DNA break signal mechanism.

Recent evidence obtained with transgenic knockout mice suggests that the enzyme poly(ADP-ribose)polymerase (PARP) does not play a direct role in DNA break processing. Nevertheless, inactivation of the catalytic or the DNA nick-binding functions of PARP affects cellular responses to genotoxins at the level of cell survival, sister chromatid exchanges and apoptosis. In the present report, we conceptualize the idea that PARP is part of a DNA break signal mechanism. In vitro screening studies revealed the existence of a protein family containing a polymer-binding motif of about 22 amino acids. This motif is present in p53 protein as well as in MARCKS, a protein involved in the regulation of the actin cytoskeleton. Biochemical analyses showed that these sequences are directly targeted by PARP-associated polymers in vitro, and this alters several molecular functions of p53- and MARCKS protein. PARP-deficient knockout mice from transgenic mice were found to exhibit several phenotypic features compatible with altered DNA damage signaling, such as downregulation and lack of responsiveness of p53 protein to genotoxins, and morphological changes compatible with MARCKS-related cytoskeletal dysfunction. The knockout phenotype could be rescued by stable expression of the PARP gene. We propose that PARP-associated polymers may recruit signal proteins to sites of DNA breakage and reprogram their functions.

Adenosine Diphosphate Ribose↗

PubMed1998

Selected nuclear matrix proteins are targets for poly(ADP-ribose)-binding.

Recent evidence suggests that poly(ADP-ribose) may take part in DNA strand break signalling due to its ability to interact with and affect the function of specific target proteins. Using a poly(ADP-ribose) blot assay, we have found that several nuclear matrix proteins from human and murine cells bind ADP-ribose polymers with high affinity. The binding was observed regardless of the procedure used to isolate nuclear matrices, and it proved resistant to high salt concentrations. In murine lymphoma LY-cell cultures, the spontaneous appearance of radiosensitive LY-S sublines was associated with a loss of poly(ADP-ribose)-binding of several nuclear matrix proteins. Because of the importance of the nuclear matrix in DNA processing reactions, the targeting of matrix proteins could be an important aspect of DNA damage signalling via the poly ADP-ribosylation system.

Animals↗

PubMed1998

Poly(ADP-ribose) modulates the properties of MARCKS proteins.

In mammalian cells, the formation of DNA strand breaks is accompanied by synthesis of poly(ADP-ribose). This nucleic acid-like homopolymer may modulate protein functions by covalent and/or noncovalent interactions. Here we show that poly(ADP-ribose) binds strongly to the proteins of the myristoylated alanine-rich C kinase substrate (MARCKS) family, MARCKS and MARCKS-related protein (also MacMARCKS or F52). MARCKS proteins are myristoylated proteins associated with membranes and the actin cytoskeleton. As targets for both protein kinase C (PKC) and calmodulin (CaM), MARCKS proteins are thought to mediate cross-talk between these two signal transduction pathways. Dot blot assays show that poly(ADP-ribose) binds to MARCKS proteins at the highly basic effector domain. Complex formation between MARCKS-related protein and CaM as well as phosphorylation of MARCKS-related protein by the catalytic subunit of PKC are strongly inhibited by equimolar amounts of poly(ADP-ribose), suggesting a high affinity of poly(ADP-ribose) for MARCKS-related protein. Binding of MARCKS-related protein to membranes is also inhibited by poly(ADP-ribose). Finally, poly(ADP-ribose) efficiently reverses the actin-filament bundling activity of a peptide corresponding to the effector domain and inhibits the formation of actin filaments in vitro. Our results suggest that MARCKS proteins and actin could be targets of the poly(ADP-ribose) DNA damage signal pathway.

Actins↗

PubMed1998

Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions.

DNA strand breaks are potential interaction sites for the nuclear enzyme poly(ADP-ribose) polymerase (PARP; E.C. 2.4.2.30) and the tumor suppressor protein p53. Both proteins bind and respond to DNA breaks and both play a role in DNA damage signaling. A temporary colocalization and complex formation between these proteins has been demonstrated in mammalian cells. Here we show that free and poly(ADP-ribose) polymerase-bound ADP-ribose polymers target three domains in p53 protein for strong noncovalent interactions. The polymer binding sites could be mapped to two amino acid sequences in the sequence-specific core DNA binding domain of p53 (amino acid positions 153-178 and 231-253) and another one in the oligomerization domain (amino acids 326-348). In mobility shift experiments, poly(ADP-ribose) effectively prevented and reversed p53 binding to the palindromic p53 consensus sequence. Additionally, poly(ADP-ribose) also interfered with the DNA single strand end binding of p53. The results suggest that ADP-ribose polymers could play a role in regulating the DNA binding properties of p53.

Animals↗

PubMed1997

[Veterinary services on the Internet].

The world wide web (www) on the internet is already a rich source of veterinary informations and offers several world wide discussion fora for problems of veterinary practice. With this article, we provide practical tips for first-time users of the www and encourage exploration of this new information technology for continuing education. The Swiss Drug Compendium is now accessible on www and-in the near future-the exchange and interpretation of laboratory results and diagnostic images via internet seems feasible.

Animals↗

PubMed1996

The role of poly(ADP-ribosyl)ation in the adaptive response.

An involvement of the poly(ADP-ribosyl)ation system in the expression of the adaptive response has been demonstrated with inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase. This enzyme is a key component of a reaction cycle in chromatin, involving dynamic synthesis and degradation of variably sized ADP-ribose polymers in response to DNA strand breaks. The present report reviews recent work focussing on the response of the poly(ADP-ribosyl)ation system in low dose adaptation. The results suggest that adaptation of human cells to minute concentrations of an alkylating agent involves a different activation mechanism for poly(ADP-ribose) polymerase than DNA break-mediated stimulation after high dose treatment. Moreover, adaptation induces the formation of branched polymers with a very high binding affinity for histone tails and selected other proteins. High dose challenge treatment of adapted cells further enhances formation of branched polymers. We propose that apart from sensing DNA nicks, poly(ADP-ribose) polymerase may be part of pathway protecting cells from downstream events of DNA damage.

Adaptation, Physiological↗

PubMed1996

Biochemical changes associated with the adaptive response of human keratinocytes to N-methyl-N'-nitro-N-nitrosoguanidine.

Exposure of cells to low doses of radiation or chemicals renders them more resistant to higher doses of these agents. This phenomenon, termed adaptive response, was studied in quiescent human keratinocytes exposed to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The cells were adapted with 2.5 nM MNNG for 60 min and challenged immediately thereafter with 2.5 microM MNNG for 30, 45 or 60 min. Clonogenic survival studies revealed that adapted cells were more resistant to the subsequent challenge treatment (up to 30% higher survival) than unadapted cells. In addition, formation of DNA strand breaks was lower in adapted cells. We monitored poly-ADP-ribosylation activity during expression of the adaptive response both at the substrate as well as the product level. NAD+ utilization in adapted and non-adapted cells exposed to the high dose of MNNG was similar, but recovery from NAD+ depletion was faster in low-dose pretreated cells. Induction of poly(ADP-ribose) formation was more than 2 times higher in low-dose adapted cells and this was associated with the formation of a distinct class of ADP-ribose polymers, i.e., branched polymers. These polymers exhibit a very high binding affinity for histones and can displace them from DNA. Elevated levels of poly(ADP-ribose) and, particularly, synthesis of branched polymers may play a critical role in low-dose adaptation.

Adaptation, Physiological↗

PubMed1996

Response of human keratinocytes to extremely low concentrations of N-methyl-N'-nitro-N-nitrosoguanidine.

Since alkylating agents are widely present in the environment and constitute a continuous challenge to genome integrity, cells and organisms have developed defense mechanisms to remove such lesions. We monitored the response of human keratinocytes to a very low concentration of a methylating agent, namely 2.5 nM N-methyl-N'-nitro- N-nitrosoguanidine (MNNG). The effect of a 60-min exposure of quiescent cells to 2.5 nM MNNG was studied in terms of DNA integrity, poly(ADP-ribose) metabolism, clonogenic survival and DNA synthesis. We observed two waves of DNA strand break formation and resealing. Interestingly, the amount of DNA strand breaks in exposed cells was lower than in unexposed control cells. This phenomenon was also observed when cells were exposed to MNNG in the presence of a protein synthesis inhibitor, or when they were maintained on ice during the treatment. A dose of 2.5 nM MNNG stimulated poly(ADP-ribose) turnover, reduced the intracellular NAD+ content, stimulated DNA synthesis and caused a remarkable increase in clonogenic survival. Thus, the cellular responses to extremely low concentrations of MNNG differ sharply from those observed at higher doses of this carcinogen. We conclude that the very low dose response cannot be extrapolated from usual dose-response analyses.

Carcinogens↗

PubMed1995

Poly(ADP-ribose) quantification at the femtomole level in mammalian cells.

ADP-ribose polymers were isolated from living mammalian cells, separated by polyacrylamide gel electrophoresis, visualized in the gel with a novel silver staining agent, and quantified by computer-aided scanning densitometry. This method detects as little as approximately 40 fmol of ADP-ribose polymers of a particular size class and reduces the gel exposure times required for conventionally radiolabeled polymers from 2 months to about 1 h. The method also detects polymers with slow turnover which may be underestimated by techniques requiring metabolic radiolabeling of poly(ADP-ribose).

Adenosine Diphosphate Ribose↗

PubMed1995

Xenopus egg lysates repair heat-generated DNA nicks with an average patch size of 36 nucleotides.

Base excision repair (BER) is an essential DNA repair pathway since it processes spontaneous (endogenous) DNA damage such as abasic sites, oxidized and alkylated bases, as well as mismatches arising from deamination of cytosine and 5-methylcytosine. Some of these lesions are repaired by the exchange of a single deoxynucleotide [Dianov, G. et al. (1992) Mol. Cell. Biol. 12, 1605-1612; Wiebauer, K. and Jiricny, J. (1990) Proc. Natl. Acad. Sci. USA, 87, 5842-5845] or a few deoxynucleotides [Matsumoto, Y. et al. (1994) Mol. Cell. Biol., 14 6187-6197]. Here we report that DNA single strand breaks induced by hyperthermic conditions are repaired with an average patch size of approximately 36 nt in Xenopus laevis egg lysates.

Animals↗