Wijnhoven, Susan W P; Hoogervorst, Esther M; Waard, Harm de; Horst, Gijsbertus T J van der; Steeg, Harry van (2007-01-03)
Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) are - except for the skin - not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.
Under the EU Directive 2004/28/EC, an environmental risk assessment of new veterinary medicinal products is required. Given the nature of risk assessment for new applications, there is a need to model exposure concentrations. Critical evaluations are essential to ensure that the use of models by regulators does not result in the propagation of misleading information. The empirical validations of soil exposure models, previously discussed in this journal, indicate that it is impossible to analyse the contribution of every model parameter to the variability in the predictions. In particular, the prediction of the slurry concentration is challenged by uncertainties concerning dilution, mixing and dissipation of residues. Surface water and groundwater models generated highly deviating results compared to the field results, questioning the usefulness of the available screening models. Animal husbandry, slurry handling and environmental conditions throughout Europe are considered in order to define realistic worst case scenarios, to be used in conjunction with distribution models for the environmental risk assessment of veterinary medicinal products at registration. Given the variability in manure management practice throughout Europe, a deterministic approach for the manure-to-soil model was selected. Both worst case and best case scenario were developed. Several modelling assumptions applied in the surface water exposure model for fish nursery effluent were validated against newly available data. Since the available data give no proof that a settling tank contributes to the removal of pesticides from waste water, it is recommended for risk assessment purposes to consider the contribution of the settling tank to removal of pesticides and medicines to be negligible. Surface water dilution factors may be considered to be rather small, a factor of 2, for low flow situations.
Oostrom, A J H H M van; Plokker, H W M; Asbeck, B S van; Rabelink, T J; Kessel, K P M van; Jansen, E H J M; Stehouwer, C D A; Cabezas, M Castro (2006-04-01)
We investigated whether pro-inflammatory aspects of the postprandial phase can be modulated by rosuvastatin in premature coronary artery disease (CAD) patients. Herefore standardized 8 h oral fat loading tests were performed off-treatment and after rosuvastatin 40 mg/d in 20 male CAD patients (50 +/- 4 years). The expression of leukocyte activation markers CD11a, CD11b, CD62L and CD66b was studied using flowcytometry. Migration of isolated neutrophils towards chemoattractants was determined in a fluorescence-based assay. Rosuvastatin did not affect baseline leukocyte counts nor the postprandial neutrophil increment (maximum mean increase +10% pre- and +14% post-treatment, P < 0.01 for each). Rosuvastatin reduced baseline platelets (from 266 +/- 78 to 225 +/- 74 x 10(9) cells/L, P < 0.001) and blunted the postprandial platelet count change (maximum mean increase +6%, P = 0.01, and 0%, respectively). The baseline expression of CD11a, CD11b and CD62L increased on most types of leukocytes by rosuvastatin, whereas the postprandial responses were unaffected. Pretreatment, postprandial neutrophil migration increased dose-dependently, but there were no postprandial changes after rosuvastatin. The latter effect was unrelated to changes in lipoprotein concentrations. In conclusion, in CAD patients postprandial pro-inflammatory and pro-coagulant changes can be modified by rosuvastatin. These apparently lipid-lowering independent effects may render protection against atherosclerosis.
Wolfs, Marion; Jong, Nynke de; Ocké, Marga C; Verhagen, Hans; Monique Verschuren, W M (2006-10-01)
Postlaunch monitoring of functional foods can encompass monitoring of effectiveness under conditions of customary use. To this end, the effectiveness of phytosterol/-stanol enriched margarine consumption in free-living conditions was investigated with data from the Dutch "Doetinchem cohort study". In total, 4,505 subjects (aged 26-70 years) were examined in 1994-1998 and re-examined during 1999-2003. A general and a food frequency questionnaire and non-fasting blood samples for total and HDL cholesterol determination were obtained. Subjects were stratified into phytosterol/-stanol enriched margarine users (n = 84) and non-users (n = 4,421) based on the re-examination data, as these margarines were available on the Dutch market from 1999 onwards. Mean spontaneous daily use (g +/- SD) of phytosterol-containing margarine (n = 71) was 15 +/- 8 and of phytostanol-containing margarine (n = 13) 9+/-6. After five years, total blood cholesterol had increased with 0.26 mmol/l in non-users while it had not significantly changed in users. The difference in total blood cholesterol change in users versus non-users was -0.30 mmol/l (p < 0.001). The beneficial effect of the phytosterol/-stanol enriched margarine, used under customary conditions can be characterized as a stabilization of cholesterol levels. This is the first report finding a modest beneficial effect on blood cholesterol level under customary conditions thereby partly confirming findings from clinical trials.
Luijten, Mirjam; Speksnijder, Ewoud N; Alphen, Niels van; Westerman, Anja; Heisterkamp, Siem H; Benthem, Jan van; Kreijl, Coen F van; Beems, Rudolf B; Steeg, Harrym van (2006-04-11)
Chronic use of phenacetin-containing analgesics has been associated with the development of renal cancer. To establish genotoxicity as a possible cause for the carcinogenic effect of phenacetin, we exposed wild type and DNA repair deficient Xpa-/- and Xpa-/-/Trp53+/- mice (further referred as Xpa and Xpa/p53 mice, respectively), carrying a reporter lacZ gene, to 0.75% (w/w) phenacetin mixed in feed. Xpa mice completely lack the nucleotide excision repair pathway, and as such they are sensitive to some classes of genotoxic compounds. Phenacetin exposure induced a significant increase of lacZ mutations in the kidney of both Xpa and Xpa/p53 mice. A minor response was found in liver, whereas no lacZ mutation induction was observed in the spleen of these animals. Interestingly, the observed phenacetin-induced mutant frequencies were higher in male than those found in female mice. This gender difference is probably due to a difference in metabolic rate. Phenacetin-induced mutations mainly consisted of point mutations rather than deletions. The mutational spectra in the kidney of treated WT and Xpa mice were quite similar. Taken together, these results demonstrate that the human carcinogen phenacetin acts as a weak genotoxic agent in an in vivo mouse model system.
Vredenbregt, M J; Blok-Tip, L; Hoogerbrugge, Ronald; Barends, D M; Kaste, D de (2006-03-03)
We describe a near-infrared spectroscopy (NIRS) method for fast-screening Viagra tablets, counterfeit Viagra tablets, and imitations of Viagra. The method can (1) check the homogeneity of a batch; (2) distinguish counterfeits and imitations from authentic Viagra; (3) screen for the presence of sildenafil citrate, the pharmacologically active substance in Viagra, irrespectively of the excipients present; (4) and detect whether similar samples have been previously analysed. We applied the method to 103 samples with a diversity of appearance, chemical composition, and origin. Other analytical methods confirmed the positive screening results for sildenafil citrate and the presence of other pharmacological active substances. The NIRS screening indicated the absence of sildenafil citrate in the presence of another pharmacological substance for only 2 samples, where the reference methods showed the presence of sildenafil citrate in addition to that of clomifene citrate. Otherwise, the method gave no false positive or negative results. The NIRS screening method is very fast and reliable for detecting counterfeits and imitations, and it correctly predicts the presence or absence of sildenafil citrate in 98% of the samples.
Smith, Noel H; Kremer, Kristin; Inwald, Jacqueline; Dale, James; Driscoll, Jeffrey R; Gordon, Stephen V; Soolingen, Dick van; Hewinson, R Glyn; Smith, John Maynard (2006-03-21)
A phylogeny of the Mycobacterium tuberculosis complex has recently shown that the animal-adapted strains are found in a single lineage marked by the deletion of chromosomal region 9 (RD9) [Brosch et al., 2002. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc. Natl Acad. Sci. USA 99 (6), 3684-3689]. We have obtained the spoligotype patterns of the RD9 deleted strains used to generate this new evolutionary scenario and we show that the presence of spoligotype spacers 3, 9, 16, 39, and 40-43 is phylogenetically informative in this lineage. We have used the phylogenetically informative spoligotype spacers to screen a database of spoligotype patterns and have identified further members of a group of strains apparently host-adapted to antelopes. The presence of the spoligotype spacers is congruent with the phylogeny generated by chromosomal deletions, suggesting that recombination is rare or absent between strains of this lineage. The phylogenetically informative spacers, in concert with the previously identified single nucleotide mutations and chromosomal deletions, can be used to identify a series of clades in the RD9 deleted lineage each with a separate host preference. Finally, we discuss the application of the ecotype concept to this series of clades and suggest that the M. tuberculosis complex may best be described as a series of host-adapted ecotypes.
Giessen, J W B van der; Vries, A de; Roos, M; Wielinga, Peter; Kortbeek, L M; Mank, T G (2006-06-01)
Giardia duodenalis (syn. Giardia lamblia, Giardia intestinalis) is a protozoan organism that can infect the intestinal tract of many animal species including mammals. Genetic heterogeneity of G. duodenalis is well described but the zoonotic potential is still not clear. In this study, we analysed 100 Giardia DNA samples directly isolated from human stool specimens, to get more insight in the different G. duodenalis assemblages present in the Dutch human population. Results showed that these human isolates could be divided into two main Assemblages A and B within the G. duodenalis group on the basis of PCR assays specific for the Assemblages A and B and the DNA sequences of 18S ribosomal RNA and the glutamate dehydrogenase (gdh) genes. Genotyping results showed that G. duodenalis isolates originating from Dutch human patients belonged in 35% of the cases to Assemblage A (34/98) and in 65% of the cases to Assemblage B (64/98) whereas two human cases remained negative in all assays tested. In addition, we compared these human samples with animal samples from the Netherlands and human and animal samples from other countries. A phylogenetic analysis was carried out on the DNA sequences obtained from these Giardia and those available in GenBank. Using gdh DNA sequence analysis, human and animal Assemblage A and B Giardia isolates could be identified. However, phylogenetic analysis revealed different sub-clustering for human and animal isolates where host-species-specific assemblages (C, D, E, F and G) could be identified. The geographic origin of the human and animal samples was not a discriminating factor.
Fingermann, M; Fernández, J; Sisti, F; Rodríguez, M E; Gatti, B; Bottero, D; Graieb, A; Gaillard, M E; Ayala, S González; Mooi, F R; et al. (2006-04-24)
In Argentina, as in other countries, the number of pertussis cases has been increasing, even in highly vaccinated zones. Many reports suggest that the decline of vaccine efficacy due to antigenic shifts in the circulating Bordetella pertussis might be among the factors that contribute to pertussis re-emergence in different parts of the world. To evaluate the incidence of this factor in Argentina, we decided to characterize the circulating bacteria of an important demographic area of this country in comparison with the strain used for vaccine production. From 1997 to 2003 we collected nasopharyngeal samples from pediatric patients with signs of Bordetella infection hospitalized in the metropolitan area of Buenos Aires and La Plata, Argentina. From these samples we identified 28 B. pertussis, which were characterized by biochemical techniques, PCR, DNA fingerprint, prn and ptx genes sequencing, and lipopolysaccharides (LPS) pattern. BOX-PCR from B. pertussis isolates yielded one cluster containing 13 isolates and some smaller ones, being all fingerprints different from the vaccine strain. Differences between Argentinean circulating bacteria and the vaccine strain were also observed for the Prn and Ptx variants as well as for the LPS pattern. Moreover, this last pattern seemed to change over the years. In addition, we identified two B. bronchiseptica. The presence of this Bordetella species together with the observed differences between circulating B. pertussis and the strain used in vaccine production should be considered for the development of an improved vaccine.
Boxman, Ingeborg L A; Tilburg, Jeroen J H C; Loeke, Nathalie A J M te; Vennema, Harry; Jonker, Klaas; Boer, Enne de; Koopmans, Marion (2006-05-01)
Shellfish from oyster farms in the Netherlands and imported from other European countries were examined for viral contamination. A method that allows sequence matching between noroviruses from human cases and shellfish was used. The samples of shellfish (n = 42) were analyzed using a semi-nested RT-PCR that had been optimized for detection of norovirus in shellfish (SR primer sets). In addition, a different genome region was targeted using a second primer set which is routinely used for diagnosis of norovirus infection in humans (JV12Y/JV13I). To improve the detection limit for this RT-PCR a semi-nested test format was developed (NV primer sets). One of 21 oyster samples (4.8%) from Dutch farms was norovirus positive, whereas norovirus was detected in 1 out of 8 oyster samples (12.5%) and 5 out of 13 mussel samples (38.5%) collected directly after importation in the Netherlands. RNA from samples associated with an outbreak of gastro-enteritis in the Netherlands in 2001 was re-analyzed using the NV primer sets. At least one identical sequence (142/142 nt) was found in three fecal and in two oyster samples related to this outbreak. Further surveillance of norovirus by detection and typing of viruses from patients with gastroenteritis and shellfish is warranted to clarify the causes of future outbreaks.
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