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Andreas Hartmann

Publications and source records attributed to Andreas Hartmann.

At least 19 recordsLinked to original sources
PubMed2007

Genetic toxicity assessment: employing the best science for human safety evaluation part III: the comet assay as an alternative to in vitro clastogenicity tests for early drug candidate selection.

Early screening of drug candidates for genotoxicity typically includes an analysis for mutagenicity in bacteria and for clastogenicity in cultured mammalian cells. In addition, in recent years, an early assessment of photogenotoxicity potential has become increasingly important. Also, for screening purposes, expert computer systems can be used to identify structural alerts. In cases where structural alerts are identified, mutagenicity testing limited to bacteria can be conducted. The sequence of computer-aided analysis and limited testing using bacteria allows for screening a comparatively large number of drug candidates. In contrast, considerably more resources, in terms of supplies, technical time, and the amount of a test substance needed, are required when screening for clastogenic activity in mammalian cells. In addition, the relatively large percentage of false positive results for rodent carcinogenicity associated with clastogenicity assays is of considerable concern. As a consequence, mammalian cell-based alternatives to clastogenicity assays are needed for early screening of mammalian genotoxicity. The comet assay is a relatively fast, simple, and sensitive technique for the analysis of DNA damage in mammalian cells. This assay seems especially useful for screening purposes because false positives associated with excessive toxicity appear to occur less frequently, only relatively small amounts of a test compound are needed, and certain steps of the test procedure can be automated. Therefore, the in vitro comet assay is proposed as an alternative to cytogenetic assays in early genotoxicity/photogenotoxicity screening of drug candidates.

Animal Testing Alternatives↗
PubMed2007

Treatment of arteriovenous malformations of the brain.

The treatment of ruptured and unruptured brain arteriovenous malformations (AVMs) is driven by the need to prevent incident or recurrent intracranial hemorrhages. Improving feasibility of the rapidly developing endovascular, neurosurgical, and radiotherapeutic procedures leads to invasive treatment of an increasing number of neurologically intact patients with accidentally diagnosed AVMs. Recent data confirm that the natural history risk of unruptured AVMs is significantly lower than the risk of those presenting with rupture, and the treatment risk of invasive management of unruptured AVMs seems higher than their natural history risk. The treatment decision algorithm for these patients remains unsettled, as no randomized clinical trial data exist on the benefit of invasive AVM treatment for patients with bled or with unbled AVMs. The recently launched study A Randomized Trial of Unruptured Brain AVMs (ARUBA) will be the first trial randomizing patients with nonhemorrhaged AVMs to invasive versus conservative management.

Aneurysm, Ruptured↗
PubMed2006

Fourth International Workgroup on Genotoxicity testing: results of the in vivo Comet assay workgroup.

As part of the Fourth International Workshop on Genotoxicity Testing (IWGT), held 9-10 September 2005 in San Francisco, California, an expert working group on the Comet assay was convened to review and discuss some of the procedures and methods recommended in previous documents. Particular attention was directed at the in vivo rodent, alkaline (pH >13) version of the assay. The aim was to review those protocol areas which were unclear or which required more detail in order to produce a standardized protocol with maximum acceptability by international regulatory agencies. The areas covered were: number of dose levels required, cell isolation techniques, measures of cytotoxicity, scoring of comets (i.e., manually or by image analysis), and the need for historical negative/positive control data. It was decided that a single limit dose was not sufficient although the required number of dose levels was not stipulated. The method of isolating cells was thought not to have a qualitative effect on the assay but more data were needed before a conclusion could be drawn. Concurrent measures of cytotoxicity were required with histopathological examination of tissues for necrosis or apoptosis as the "Gold Standard". As for analysing the comets, the consensus was that image analysis was preferred but not required. Finally, the minimal number of studies required to generate a historical positive or negative control database was not defined; rather the emphasis was placed on demonstrating the stability of the negative/positive control data. It was also agreed that a minimum reporting standard would be developed which would be consistent with OECD in vivo genotoxicity test method guidelines.

Animals↗
PubMed2006

ST-segment recovery and prognosis in patients with ST-elevation myocardial infarction reperfused by prehospital combination fibrinolysis, prehospital initiated facilitated percutaneous coronary intervention, or primary percutaneous coronary intervention.

Complete ST-segment recovery (STR) is associated with favorable prognosis in ST-elevation myocardial infarction (STEMI). The optimal reperfusion strategy in patients presenting soon after symptom onset is still a matter of debate. STR for patients treated by prehospital combination fibrinolysis or prehospital initiated facilitated percutaneous coronary intervention (PCI) compared with primary PCI has not been assessed. In the Leipzig Prehospital Fibrinolysis Study, patients with STEMI (symptoms <6 hours) were randomized to prehospital combination fibrinolysis (1/2 dose reteplase + abciximab; n = 82, group A) or prehospital initiated facilitated PCI (n = 82, group B). Further, a control group of patients with primary PCI (n = 136, group C) was prospectively assessed. STR at 90 minutes was analyzed by blinded observers as percent resolution. Categorization was performed as complete resolution (>70%), intermediate resolution (70% to 30%), or no resolution (<30%). The percentage of patients with complete STR was highest in group B with 80% versus 52% in group A and 52% in group C (p <0.001, B vs A and C, p = NS; A vs C). Complete STR resulted in lower event rates for the combined clinical end point of death, myocardial reinfarction, and stroke compared with intermediate and no STR in groups A (complete 9.8%, intermediate 23.8%, no STR 36.8%, p = 0.04), B (7.7%, 18.2%, and 50.0%, p = 0.01), and C (8.6%, 18.4%, and 42.9%, p <0.001). In conclusion, prehospital initiated facilitated PCI results in the highest percentage of complete STR compared with prehospital combination fibrinolysis or primary PCI. In addition, STR has been confirmed to predict prognosis in timely optimized reperfusion strategies.

Abciximab↗
PubMed2006

Regional vulnerability of mesencephalic dopaminergic neurons prone to degenerate in Parkinson's disease: a post-mortem study in human control subjects.

Parkinson's disease (PD) is characterized by loss of dopaminergic (DA) neurons in the human midbrain, which varies greatly among mesencephalic subregions. The genetic expression profiles of mesencephalic DA neurons particularly prone to degenerate during PD (nigrosome 1 within the substantia nigra pars compacta-SNpc) and those particularly resistant in the disease course (central grey substance-CGS) were compared in five control subjects by immuno-laser capture microdissection followed by RNA arbitrarily primed PCR. 8 ESTs of interest were selected for analysis by real time quantitative reverse transcription PCR. DA neurons in the CGS preferentially expressed implicated in cell survival (7 out of 8 genes selected), whereas SNpc DA neurons preferentially expressed one gene making them potentially susceptible to undergo cell death in PD. We propose that factors making CGS DA neurons more resistant may be helpful in protecting SNpc DA neurons against a pathological insult.

Aged↗
PubMed2006

Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation.

BACKGROUND AND PURPOSE: The morbidity from spontaneous hemorrhage of untreated brain arteriovenous malformations (AVM) is not well described. METHODS: The 241 consecutive AVM patients (mean age 37+/-16 years, 52% women) from the prospective Columbia AVM Databank initially presenting with hemorrhage were evaluated using the Rankin Scale (RS) and the National Institute of Health Stroke Scale (NIHSS). From the 241 AVM patients, 29 (12%) had subsequent intracranial hemorrhage during follow-up. For further comparisons, 84 non-AVM patients with intracerebral hemorrhage from the Northern Manhattan Study (NOMAS) served as a control group. RESULTS: In 241 AVM patients presenting with hemorrhage the median RS was 2 and the median NIHSS was 1 (49% RS 0 to 1, 61% NIHSS <2). The median time between hemorrhage and clinical evaluation was 11 days (mean 219 days). Recurrent AVM hemorrhage during follow-up resulted in no significant increase in morbidity (median RS 2, P=0.004; median NIHSS 3, P=0.322; time between hemorrhage and study evaluation: median 55 days, mean 657 days). Among AVM-hemorrhage subtypes, parenchymatous AVM hemorrhage was associated with higher stroke morbidity (odds ratio, 2.9; 95% CI, 1.5 to 5.8 for NIHSS > or =2) than nonparenchymatous hemorrhages. Parenchymatous AVM hemorrhage had a significantly better outcome (median NIHSS 1) than non-AVM related hemorrhage (median NIHSS 12; P<0.0001). CONCLUSIONS: Hemorrhage, either at initial presentation or during follow-up of untreated AVM patients appears to carry a lower morbidity than intracranial hemorrhage from other causes. These findings support a careful weighing of risks from interventional treatment and natural history.

Adult↗
PubMed2006

Invasive treatment of unruptured brain arteriovenous malformations is experimental therapy.

PURPOSE OF REVIEW: Brain arteriovenous malformations (AVMs) are currently being treated in a variety of ways, including medical management, endovascular procedures, neurosurgery and radiotherapy. The widespread diffusion of these various treatment approaches is partially driven by the existence of variations in the perception about the risks of rupture, and how devastating such events would be. RECENT FINDINGS: Data from the most recent studies suggest the majority of AVM patients are diagnosed without signs of hemorrhage, further, that the natural history risk for the unruptured cohort is far more benign than for those presenting with rupture. In cases where hemorrhage occurs, the clinical syndrome is significantly less disabling than in patients with non-AVM related hemorrhage. For unruptured AVMs, current morbidity data suggest a higher risk for invasive management than for the natural history of untreated patients. SUMMARY: No randomized clinical trial data exist on the benefit of invasive AVM treatment, and the most contentious issue at present is whether intervention should be considered for AVMs that have not bled. In a scientific sense, invasive treatment for unruptured brain AVMs may be considered experimental therapy awaiting the results from 'A Randomized Trial of Unruptured Brain AVMs' (ARUBA), which is currently underway.

Brain↗
PubMed2006

The comet assay: a sensitive genotoxicity test for the detection of DNA damage and repair.

The comet assay (single-cell gel electrophoresis) is a simple and sensitive method for studying DNA damage and repair. In this microgel electrophoresis technique, a small number of cells suspended in a thin agarose gel on a microscope slide is lysed, electrophoresed, and stained with a fluorescent DNA-binding dye. Cells with increased DNA damage display increased migration of chromosomal DNA from the nucleus toward the anode, which resembles the shape of a comet. The assay has manifold applications in fundamental research for DNA damage and repair, in genotoxicity testing of novel chemicals and pharmaceuticals, environmental biomonitoring, and human population monitoring. This chapter describes a standard protocol of the alkaline comet assay and points to some useful modifications.

Comet Assay↗
PubMed2005

Determinants of staged endovascular and surgical treatment outcome of brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Therapy of brain arteriovenous malformations (AVMs) often requires the combination of different treatment modalities. Independently assessed data on neurologic outcome after multidisciplinary AVM therapy are scarce. METHODS: The 119 consecutive patients (49% women, mean age 34+/-13 years) with brain AVMs receiving endovascular embolization followed by surgical treatment were analyzed. Neurologic impairment was assessed prospectively by a neurologist using the modified Rankin Scale (mRS) before, during, and after completed AVM therapy. The association of demographic, clinical, and morphologic characteristics with new treatment-related neurologic deficits was calculated. RESULTS: The 119 patients were treated with 240 superselective embolizations (median, 2; range, 1 to 8) using n-butyl cyanoacrylate. Mean follow-up time after surgery was 9.6+/-13.2 months. On the Spetzler-Martin scale, 8% of the AVMs were grade 1, 27% grade 2, 40% grade 3, 22% grade 4, and 3% grade 5. Disabling treatment-related complications (mRS> or =3) occurred in 5% (95% confidence interval [CI], 1% to 9%) of the patients. Nondisabling new deficits were observed in another 42% (95% CI, 33% to 51%). No patient died. Nonhemorrhagic AVM presentation (odds ratio [OR], 5.00; 95% CI, 1.75 to 14.29), deep venous drainage (OR, 3.09; 95% CI, 1.43 to 6.64), AVM location in an eloquent brain region (OR, 2.42; 95% CI, 1.10 to 5.33), and large AVM size (OR, 1.05; 95% CI, 1.01 to 1.09) were independently associated with new treatment-related deficits. CONCLUSIONS: Our results suggest an increased treatment risk for patients with previously unbled AVMs from combined endovascular and surgical AVM therapy. Additional risk factors for treatment-related neurologic deficits may be large AVM size, deep venous drainage, and AVM location in eloquent brain regions.

Adolescent↗
PubMed2005

Towards the creation of an international toxicology information centre.

A pilot toxicology database system has been created which is accessible on-line via the world-wide web or in-house via an intranet. It is intended to be suitable as a source of toxicological information and to support structure-activity relationship studies, and it can be searched on chemical structural and substructural as well as toxicological and physico-chemical data. Successful completion of the pilot has led to an ongoing project to develop and expand the system.

Databases as Topic↗
PubMed2005

Proliferation of microglial cells induced by 1-methyl-4-phenylpyridinium in mesencephalic cultures results from an astrocyte-dependent mechanism: role of granulocyte macrophage colony-stimulating factor.

There is evidence that an inflammatory microglial reaction participates in the pathophysiology of dopaminergic neuronal death in Parkinson's disease and in animal models of the disease. However, this phenomenon remains incompletely characterized. Using an in vitro model of neuronal/glial mesencephalic cultures, we show that the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) stimulates the proliferation of microglial cells at concentrations that selectively reduce the survival of DA neurones. The mitogenic action of MPP+ was not the mere consequence of neuronal cell demise as the toxin produced the same effect in a model system of neuronal/glial cortical cultures, where target DA neurones are absent. Consistent with this observation, the proliferative effect of MPP+ was also detectable in neurone-free microglial/astroglial cultures. It disappeared, however, when MPP+ was added to pure microglial cell cultures suggesting that astrocytes played a key role in the mitogenic mechanism. Accordingly, the proliferation of microglial cells in response to MPP+ treatment was mimicked by granulocyte macrophage colony-stimulating factor (GM-CSF), a proinflammatory cytokine produced by astrocytes and was blocked by a neutralizing antibody to GM-CSF. Thus, we conclude that the microglial reaction observed following MPP+ exposure depends on astrocytic factors, e.g. GM-CSF, a finding that may have therapeutic implications.

1-Methyl-4-phenylpyridinium↗
PubMed2005

Reactive oxidative and nitrogen species in the nigrostriatal system following striatal 6-hydroxydopamine lesion in rats.

Oxidative stress is a major contributing factor in the pathogenesis of Parkinson's disease. We therefore investigated the effect of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) on hydroxyl-free radical and peroxynitrite formation in the intrastriatal 6-OHDA rat model of Parkinson's disease. The hydroxylation product of salicylate (2,3-dihydroxy-benzoic acid) as well as the hydroxylation and nitration products of d-phenylalanine (2- and 3-hydroxyl-phenylalanine, nitrotyrosine and nitrophenylalanine) were assessed in tissue samples of the striatum and, for the first time, the substantia nigra of adult rats at four different time points (25 min, 2 h, 4 h and 7 days) after unilateral stereotaxic intrastriatal injection of 6-OHDA. In the striatum, maxima of hydroxylating and nitrating markers were found at early time points after 6-OHDA lesion. These results suggest a direct interrelation between 6-OHDA-autoxidation and/or the increased dopamine turnover and hydroxyl-free radical and peroxynitrite formation. In the substantia nigra, i.e., at a distance from the injection site of the neurotoxin, an increase in hydroxyl-free radical formation was observed at 7 days after 6-OHDA lesion, with this modification possibly being independent of 6-OHDA autoxidation and rather representing a long-term effect of the toxin. Furthermore, we conclude that apart from the formation of reactive oxygen species, the production of reactive nitrogen species occurs in this experimental Parkinson's disease model. Finally, the similarity between the 6-OHDA model and Parkinson's disease supports the notion that reactive oxygen species as well as reactive nitrogen species may play an important role in the pathogenesis of this neurodegenerative disorder.

Adrenergic Agents↗
PubMed2005

Comparison of pre-hospital combination-fibrinolysis plus conventional care with pre-hospital combination-fibrinolysis plus facilitated percutaneous coronary intervention in acute myocardial infarction.

AIMS: Early and complete reperfusion is the main treatment goal in ST-elevation myocardial infarction (STEMI). The timely optimal reperfusion strategy might be a pre-hospital initiated pharmacological reperfusion with subsequent facilitated percutaneous coronary intervention (PCI). This approach has been compared with pre-hospital combination-fibrinolysis only to determine whether either one of these methods offer advantages with respect to final infarct size. METHODS AND RESULTS: Patients with STEMI were randomized to either pre-hospital combination-fibrinolysis (half-dose reteplase+abciximab) with standard care (n=82) or pre-hospital combination-fibrinolysis with facilitated PCI (n=82). Primary endpoint was the infarct size assessed by delayed enhancement magnetic resonance. Secondary endpoints were ST-segment resolution at 90 min and a composite of death, re-myocardial infarction, major bleeding, and stroke at 6 months. The infarct size was lower after facilitated PCI with 5.2% [interquartile range (IQR) 1.3-11.2] as opposed to 10.4% (IQR 3.4-16.3) after pre-hospital combination-fibrinolysis (P=0.001). Complete ST-segment resolution was 80.0% after facilitated PCI vs. 51.9% after pre-hospital combination-fibrinolysis (P<0.001). After facilitated PCI, there was a trend towards a lower event rate in the combined clinical endpoint (15 vs. 25%, P=0.10, relative risk 0.57, 95% CI 0.28-1.13). CONCLUSION: In patients with STEMI, additional facilitated PCI after pre-hospital combination-fibrinolysis results in an improved tissue perfusion with subsequent smaller infarct size as opposed to pre-hospital combination-fibrinolysis alone. This translates into a trend towards a better clinical outcome.

Adult↗
PubMed2005

The in vivo comet assay: use and status in genotoxicity testing.

The in vivo comet assay (single cell gel electrophoresis assay) in its alkaline version (pH >13) is being increasingly used in genotoxicity testing of substances such as industrial chemicals, biocides, agrochemicals, food additives and pharmaceuticals. Recommendations for an appropriate performance of the test using OECD guidelines for other in vivo genotoxicity tests have been published. In this review, we critically discuss the biological significance of comet assay effects in general and the status of the test in current strategies for genotoxicity testing. Examples for practical applications of the in vivo comet assay and potential consequences of positive and negative test results are given. The significance of comet assay results for hazard identification and risk assessment is discussed. In accordance with international guidelines for genotoxicity testing the in vivo comet assay is recommended for follow-up testing of positive in vitro findings. It is particularly useful as a tool for the evaluation of local genotoxicity, especially for organs/cell types which cannot easily be evaluated with other standard tests. A positive result in an appropriately performed in vivo comet assay indicates genotoxicity of the test compound in the tissue tested and gains particular significance when a mutagenic potential of the test compound has already been demonstrated in vitro. Such findings will have practical consequences in the risk assessment processes and further development of substances.

Animals↗
PubMed2005

Granulocyte colony-stimulating factor is not protective against selective dopaminergic cell death in vitro.

In the present study, we evaluated the potential neuroprotective effect of granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor in two different culture models in which dopaminergic (DA) neurons die selectively: first, in a culture model in which death of DA neurons occurs spontaneously and second, in a toxin-based paradigm, the in vitro 1-methyl-4-phenylpyridinium model of PD. In neither of the two models, a treatment with G-CSF, could prevent or halt the progressive neurodegeneration. However, we cannot rule out that G-CSF might exert neuroprotective or even deleterious effects in in vivo models of PD, based on the significant increase in the number of microglial cells observed after G-CSF treatment.

1-Methyl-4-phenylpyridinium↗
PubMed2005

Gene expression profiling of Lewy body-bearing neurons in Parkinson's disease.

Lewy bodies (LB) are a pathological hallmark of Parkinson's disease (PD). Whether LBs are neuroprotective, cytotoxic, or an age-related epiphenomenon is still debated. In the present study, the genetic fingerprints of mesencephalic dopaminergic (DA) neurons containing LBs versus mesencephalic DA neurons not containing LBs were compared in five PD patients. Total RNA from single neurons of both neuronal subpopulations was obtained by immuno-laser capture microdissection. Subsequently, RNA arbitrarily primed PCR was employed to generate expression profiles from the extracted RNA. Differentially displayed polymorphic fragments were dissected from silver-stained polyacrylamide gels. Most of these expressed sequence tags (ESTs) were homologous to known human sequences (56/64, 87.5%). Based on the potential significance of individual ESTs in neurodegenerative disorders, 5 ESTs of interest were selected for further quantitative expression analysis by real-time quantitative reverse transcription PCR (rtq RT-PCR). DA neurons without LBs preferentially expressed molecules beneficial for cell survival, whereas genes preferentially expressed in DA neurons containing LBs may support a cytotoxic role of LBs. Thus, we favor the view that LB-positive DA neurons are sicker than their LB-negative counterparts, and that inhibition of LB formation may indeed represent a therapeutic strategy in PD.

Aged↗
PubMed2005

Neuroinflammatory processes in Parkinson's disease.

In Parkinson's disease (PD), post-mortem examination reveals a loss of dopaminergic (DA) neurons in the substantia nigra (SN) associated with a massive astrogliosis and the presence of activated microglial cells. Similarly, microglial activation has also been reported to be associated with the loss of DA neurons in animal models of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, annonacine and lipopolysaccharide (LPS). Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, raising the possibility that toxic substances released by glial cells could be involved in the propagation of neuronal degeneration. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in PD.

Encephalitis↗