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  • 1
    Electronic Resource
    Electronic Resource
    Effects of grass pasture and concentrate-based feeding systems for spring-calving dairy cows in early spring on performance during lactation (2005)
    Oxford, UK : Blackwell Science Ltd
    Grass and forage science 60 (2005), S. 0 
    Details
    ISSN: 1365-2494
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: The effect of offering a total mixed ration of silage and concentrate (proportionately 0·44 silage) system [indoor feeding system (IF)] was compared with grazing at a high daily herbage allowance with a low level of concentrate supplementation [early grazing system (EG)] in early spring on the performance of spring-calving dairy cows in Ireland. Sixty-four spring-calving Holstein–Friesian dairy cows (mean calving date, 2 February) were allocated to one of two systems between 16 February and 4 April 2004. An equal number of primiparous and multiparous cows were assigned to each system. The dairy cows on the IF system were housed for a 7-week period and offered a diet of 10·9 kg DM cow−1 d−1 (s.d. 2·3) of concentrate, the remainder of the diet was 8·6 kg DM cow−1 d−1 (s.d. 1·9) of grass silage. The dairy cows on the EG system were offered a mean daily herbage allowance of 15·1 kg DM cow−1 d−1 (s.d. 3·7) and were supplemented with 3·0 kg DM cow−1 d−1 (s.d. 1·0) of concentrate. There was no difference in milk yield between the two systems but the cows in the EG system had a higher milk protein concentration (2·9 g kg−1) and a higher milk protein yield than in the IF system. Milk fat concentration was higher for cows in the IF than EG system (3·0 g kg−1). There was no difference in total daily dry-matter intake between the systems, measured in week 6 of the study. Mean live weight of the cows in the IF system was greater than in the EG system. The results of the study suggest that a slightly greater performance can be achieved by a system offering a high daily herbage allowance to spring-calving dairy cows in early lactation compared with a system offering a total mixed ration containing a high proportion of concentrate with grass silage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-2494.2005.00481.x
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Genotyping single nucleotide polymorphisms by primer extension and high performance liquid chromatography (1999)
    Springer
    Human genetics 〈Berlin〉 104 (1999), S. 89-93 
    Details
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We have investigated the possibility of genotyping single nucleotide polymorphisms (SNPs) by primer extension and high performance liquid chromatography (HPLC). Using three polymorphisms of current interest to our group (an A/G polymorphism in the proneurotensin gene and A/G and T/C polymorphisms in the 5HT2a receptor gene), we show that robust signal is obtained using this simple analytic method which has the added advantages that sample loading and analysis are essentially automated, analytic time is brief, and no further purification step after primer extension is required. We also show that all stages of the HPLC-primer extension genotyping can be multiplexed which, together with automation, suggests that this system may be suitable for linkage studies based upon emerging SNP maps.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004390050915
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  • 3
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    Is nitrous oxide a genotoxic carcinogen? (2015)
    Oxford University Press
    Details
    Publication Date: 2015-06-17
    Description: Nitrous oxide (N 2 O) has been widely used as a dental and surgical anaesthetic for over 150 years. However, results from a recent study suggested that increased DNA damage was seen in lymphocytes from surgical patients and this led to its continued clinical use to be questioned. The data can be challenged on technical grounds and must be considered with other studies in order to assess any possible risk. There are other studies indicating that N 2 O has weak genotoxicity in man, but these are confused by exposure of the populations to other anaesthetic gases including isoflurane and sevoflurane, both of which have also been reported to increase DNA damage. It should be noted that the suggested genotoxic mechanisms are all indirect, including folate deficiency, oxidative stress and homocysteine toxicity. Further, results from in vitro studies indicate that N 2 O has no direct DNA reactivity as negative results were obtained in a bacterial mutation (Ames) test and an assay for mutation at the hprt locus in Chinese hamster lung cells. Although not performed to definitive study designs, no evidence of carcinogenicity was seen in two long-term tests in mice and another in rats. Although there is some evidence that N 2 O is weakly genotoxic in humans, this appears to be similar to that reported for isoflurane and sevoflurane and all the postulated mechanisms have clear thresholds with no evidence of direct DNA reactivity. Because any potential genotoxic mechanism would have a threshold, it seems reasonable to conclude that neither occasional high exposure to patients as an anaesthetic nor low-level exposure to staff within published recommended exposure limits presents any significant carcinogenic risk.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Micronucleus induction in the bone marrow of rats by pharmacological mechanisms. I: glucocorticoid receptor agonism (2013)
    Oxford University Press
    Details
    Publication Date: 2013-02-14
    Description: A novel selective glucocorticoid receptor (GR) agonist, AZD2906, was found to increase the incidence of micronucleated immature erythrocytes (MIE) in the bone marrow of rats given two oral doses at the maximum tolerated level. Because GR agonists as a class are considered not to be genotoxic and AZD2906 showed no activity in the standard in vitro tests or in vivo in a rat liver comet assay, investigative studies were performed to compare AZD2906 with a reference traditional GR agonist, prednisolone. Emphasis was placed on blood and bone marrow parameters in these studies because GR activation has been reported to induce erythropoiesis which, in turn, is known to increase MIE in the bone marrow. Both compounds induced almost identical, small increases in micronucleus frequency at all doses tested. Directly comparable changes in haematological and bone marrow parameters were also seen with significant decreases in lymphoid cells in both compartments and significant increases in numbers of circulating neutrophils. Although no evidence of increased erythropoiesis was seen as increased immature erythrocyte numbers either in the blood or in the bone marrow, histopathological examination showed focal areas in the bone marrow where the erythroid population was enriched in association with an atrophic myeloid lineage. This could have been due to direct stimulation of the erythroid lineage or a secondary effect of myelosuppression inducing a rebound increase in erythropoiesis into the vacant haematopoietic cell compartment. It was concluded that the increased MIE frequencies induced by both AZD2906 and prednisolone are a consequence of their pharmacological effects on the bone marrow, either by directly inducing erythropoiesis or by some other unknown effect on cellular function, and do not indicate potential genotoxicity. This conclusion is supported by the lack of carcinogenic risk in man demonstrated by decades of clinical use of prednisolone and other GR agonists.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    Micronucleus induction in the bone marrow of rats by pharmacological mechanisms. II: long-acting beta-2 agonism (2013)
    Oxford University Press
    Details
    Publication Date: 2013-02-14
    Description: AZD9708 is a new chemical entity with selective and long-acting β2-agonistic properties currently being evaluated by AstraZeneca for potential use in treatment of respiratory diseases by the inhaled route. As part of the toxicological characterisation of this compound, an increased incidence of micronucleated immature erythrocytes (MIEs) was seen in the bone marrow of rats following single intravenous doses near the maximum tolerated. This effect was seen in the absence of in vitro genotoxicity in bacterial and mammalian cells and no consistent evidence of in vivo DNA damage in the the bone marrow or liver using the comet assay was observed. Because of the lack of signals for mutagenic potential, combined with the observation that MIE frequencies appeared to be increased in only some of the rats and the clearest response was seen at the intermediate dose, it was hypothesised that the effect was secondary to β2-adrenergic receptor overstimulation. Because it appears that this has not been previously described for β2-agonists and because pharmacodynamic/pharmacokinetic factors may influence the response, studies using repeated dosing were performed to investigate whether this would lead to compound-induced tachyphylaxis with tolerance induction and decreased responses indicated by β2-effect biomarkers. A series of experiments confirmed that a sequence of five escalating daily doses leading to systemic exposure corresponding to that after a single dose led to symptomatic tolerance, declining or diminished effects on plasma biomarkers of β2-effects (plasma glucose and potassium) and elimination of the micronucleus response. This suggests that the increased MIE frequencies after single doses of AZD9708 are secondary to physiological overstimulation of β2-adrenergic receptors, not a consequence of genotoxicity.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 6
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    Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-24
    Description: Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates 〈0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 x 10 –4 ; odds ratio 2.60, P = 0.049).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    Chromosome aberration frequency in rat peripheral lymphocytes increases with repeated dosing with hexamethylphosphoramide or cyclophosphamide (2012)
    Oxford University Press
    Details
    Publication Date: 2012-08-21
    Description: Although there are several in vivo tests for potential genotoxicity, with the possible exception of the transgenic rodent mutation models, none is specifically intended to assess increasing damage with chronic administration. In principle, peripheral blood lymphocytes would be expected to accumulate DNA damage with repeated dosing because the majority are not in active division and appear to have limited DNA repair capability, and they are exposed to plasma levels of test materials and metabolites. However, there appear to be no published reports confirming this principle. Therefore, in the current study, after optimising culture conditions for rat lymphocytes in this laboratory, rats were given oral doses of cyclophosphamide or hexamethylphosphoramide (HMPA) for up to 28 days and peripheral lymphocytes analysed for chromosome aberrations at various time points. The results clearly show that, for both compounds, doses that gave no significant increases in aberration frequency after 2 days induced clear increases after 15 days with further damage detectable after 28 doses. With HMPA, it was shown that DNA damage persisted for at least 10 days after cessation of treatment. These data show that repeat dose studies in the rat measuring chromosome aberration frequency in lymphocytes can give a genuine indication that genotoxicity may increase with chronic administration and, therefore, maybe useful in assessing the risk of potentially genotoxic substances.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons (2013)
    Oxford University Press
    Details
    Publication Date: 2013-10-09
    Description: The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B ( VAPB ) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) mice that heterologously express human wild-type (WT) and P56S VAPB under the control of a pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein expression were observed in the CSMNs and SMNs of P56S VAPB Tg mice. However, only a progressive loss of CSMNs but not SMNs was found in P56S VAPB Tg mice. In SMNs, P56S VAPB promoted a rather selective translocation of VAPB protein onto the postsynaptic site of C-boutons that altered the morphology of C-boutons and impaired the spontaneous rhythmic discharges of SMNs. Therefore, these findings provide new pathophysiological mechanisms of P56S VAPB that differentially affect the function and survival of CSMNs and SMNs in ALS8.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 9
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    Maximum dose levels for the rodent comet assay to examine damage at the site of contact or to the gastrointestinal tract (2013)
    Oxford University Press
    Details
    Publication Date: 2013-10-23
    Description: The comet assay can be applied to virtually any tissue and it has been noted that it can be particularly useful in evaluating directly acting genotoxins at their initial site of action. Consequently, it has become relatively common practice to use the stomach comet assay after oral administration to test chemicals that have given positive in vitro genotoxicity results in the absence of metabolic activation. However, to test nontoxic substances up to the limit doses of 1000/2000mg/kg formulations approaching molar concentrations must be used resulting in the stomach mucosa being exposed to excessively high levels. Evidence is beginning to accumulate which shows positive results that do not indicate that potential carcinogenicity may be associated with such high levels of exposure. For pharmaceutical agents, toxicokinetic data are usually available to demonstrate systemic exposure after oral administration. In such cases, it is proposed that exposure of any tissue to levels of the drug substance greater than those that have given positive in vitro results in the absence of metabolic activation is sufficient. However, it is recognised that toxicokinetic data are not available for all chemicals and there are also agents designed not to leave the gastrointestinal tract (GIT). Where it is necessary to examine the GIT, the dose levels selected for examination should cover the likely or intended exposure levels, not necessarily to achieve the maximum tolerated or limit doses, even if the higher doses are required for genotoxicity endpoints in other tissues to be valid. There are usually two or three dose levels in in vivo genotoxicity studies, so when both systemically exposed tissues and the stomach are being examined, it would be possible to use one of the lower doses for the latter without increasing the numbers of animals required. It is important to consider the local concentrations achieved in the stomach or other parts of the GIT in order to avoid the comet assay generating artefactual positive results and it is hoped this will be addressed in the imminent Organisation for Economic Co-operation and Development guideline.
    Print ISSN: 0267-8357
    Electronic ISSN: 1464-3804
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 10
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    An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis (2014)
    Morris, D. W., Pearson, R. D., Cormican, P., Kenny, E. M., O'Dushlaine, C. T., Perreault, L.-P. L., Giannoulatou, E., Tropea, D., Maher, B. S., Wormley, B., Kelleher, E., Fahey, C., Molinos, I., Bellini, S., Pirinen, M., Strange, A., Freeman, C., Thiselton, D. L., Elves, R. L., Regan, R., Ennis, S., Dinan, T. G., McDonald, C., Murphy, K. C., O'Callaghan, E., Waddington, J. L., Walsh, D., O'Donovan, M., Grozeva, D., Craddock, N., Stone, J., Scolnick, E., Purcell, S., Sklar, P., Coe, B., Eichler, E. E., Ophoff, R., Buizer, J., Szatkiewicz, J., Hultman, C., Sullivan, P., Gurling, H., Mcquillin, A., St Clair, D., Rees, E., Kirov, G., Walters, J., Blackwood, D., Johnstone, M., Donohoe, G., International Schizophrenia Consortium, SGENE+ Consortium, O'Neill, F. A., Wellcome Trust Case Control Consortium 2, Kendler, K. S., Gill, M., Riley, B. P., Spencer, C. C. A., Corvin, A.
    Oxford University Press
    Details
    Publication Date: 2014-05-23
    Description: Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (〉100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 ( P = 0.007) and evidence of replication in large independent European schizophrenia ( P = 0.052) and UK bipolar disorder case-control cohorts ( P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran–Mantel–Haenszel P -value = 2 x 10 –4 ; odds ratio (OR) = 11.3, 95% CI = 3.7, ]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 ( PAK7 , also called PAK5 ) which was in linkage disequilibrium with local haplotypes ( P = 2.5 x 10 –21 ), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene ( DISC1 ) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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