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Biomedical subjects

R Forster

Publications and source records attributed to R Forster.

At least 19 recordsLinked to original sources
PubMed2001

Careers in toxicology in Europe--options and requirements. Report of a workshop organized on behalf of the Individual Members of EUROTOX during the EUROTOX Congress 2000 in London (September 17-20, 2000).

In view of the lack of information regarding careers for toxicologists in Europe, the Individual Members of EUROTOX organised a workshop on careers in toxicology during the EUROTOX Congress 2000 in London. Toxicologists are mainly employed in academia, regulatory agencies, contract research organisations (CROs) and the chemical and pharmaceutical industries. There are also a few governmental institutes involved with toxicological work other than teaching or regulation. Toxicologists can also work as independent consultants, especially for commercial organisations. The requirements for starting a career in any of the above organisations, the need and the advantages and disadvantages of specialisation, and further career prospects are summarised and briefly discussed. The organisations, and also working as an independent toxicology consultant, offer interesting professional work of relevance to modern-day society. There is currently a shortage of toxicologists not only in the traditional field of risk assessment but also especially in new areas, e.g. toxicogenomics. This shortage may be at least in part due to insufficient training opportunities. Further consideration of career opportunities is planned and will be published in due course.

Career Mobility↗
PubMed2001

Reduction in corneal haze and apoptosis by amniotic membrane matrix in excimer laser photoablation in rabbits.

PURPOSE: To determine whether preserved human amniotic membrane can reduce corneal haze and keratocyte apoptosis induced by excimer laser photoablation in rabbit corneas. METHODS: Excimer photoablation was performed bilaterally in 30 rabbits with a 6.0 mm ablation zone and 120 microm depth using the VISX Star laser with the phototherapeutic keratectomy (PTK) mode. One eye was randomly covered by preserved human amniotic membrane secured with 4 interrupted 10-0 nylon sutures, and the other eye served as the control. The amniotic membranes were removed at 1 week, and corneal haze was graded with slitlamp biomicroscopy by 3 masked corneal specialists biweekly for the ensuing 12 weeks until the rabbits were killed. Another 18 rabbits were divided into 4 subgroups and received PTK alone, PTK with membrane, PTK with sham sutures, or PTK with tarsorrhaphy. All eyes were studied histologically, and 3 eyes in each group were studied by in situ terminal deoxynucleotidyl transferase deoxy-UTP-nick end labeling assay at 1, 3, and 7 days and 12 weeks, respectively. RESULTS: A consistent grading of differences in corneal haze scoring between the control corneas and the amniotic-membrane-covered corneas was noted among the 3 masked observers. Organized reticular post-PTK corneal haze peaked at 7 weeks in both groups, and the corneal haze score in the amniotic-membrane-covered group was significantly less than in the control group from 7 to 12 weeks (all P < .001). Compared to the control corneas, the amniotic-membrane-covered corneas had less inflammatory response at 1 and 3 days, less keratocyte apoptosis in the ablated anterior corneal stroma at 1, 3, and 7 days (P < .001), and less stromal fibroblast cellularity and epithelial hyperplasia at 12 weeks. CONCLUSIONS: Amniotic membrane matrix introduced at an early stage of the corneal wound healing process effectively reduced corneal haze induced by excimer laser photoablation in rabbits. Studies linking suppression of apoptosis in the acute wound-healing process with reduction of subsequent corneal scarring may have useful clinical applications.

Amnion↗
PubMed2001

Xpa and Xpa/p53+/- knockout mice: overview of available data.

DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life Sciences Institute (ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair deficient models respond to genotoxic carcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.

Academies and Institutes↗
PubMed2000

Unique distribution of the anion exchange protein in the sea lamprey, Petromyzon marinus.

The purpose of the present study was to examine the distribution of the anion exchange protein in the sea lamprey. Southern blots showed that genomic DNA of juvenile lampreys possesses several regions that are similar to segments of the AE gene from other vertebrates. However, physiological experiments examining rapid anion fluxes across the red blood cell (rbc) membrane and molecular experiments examining mRNA transcript levels both indicated that the anion exchange protein is absent in sea lamprey rbcs. In contrast, lamprey kidney, skeletal muscle, liver and heart tissue all appeared to possess mRNA transcripts for an AE protein. Further evidence for the presence of an AE protein in kidney tissue was obtained from Western blots. In order to evaluate the impact of the apparent rbc anion exchange limitations, the bicarbonate permeability of lamprey rbcs was also evaluated using mass spectrometry. The bicarbonate permeability of the lamprey rbc membrane was an order of magnitude lower than that of trout rbcs. Taken together, these results indicate that the gene for the AE protein is indeed present in lampreys, but it is not expressed in the rbc. Moreover, the process of CO2 transport in lamprey probably does not involve bicarbonate transport across the rbc membrane.

Animals↗
PubMed2000

CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue.

Chemokine-directed migration of leukocyte subsets may contribute to the qualitative differences between systemic and mucosal immunity. Here, we demonstrate that in mice lacking the chemokine receptor CCR6, dendritic cells expressing CD11c and CD11b are absent from the subepithelial dome of Peyer's patches. These mice also have an impaired humoral immune response to orally administered antigen and to the enteropathic virus rotavirus. In addition, CCR6(-/-) mice have a 2-fold to 15-fold increase in cells of select T lymphocyte populations within the mucosa, including CD4+ and CD8+ alphabeta-TCR T cells. By contrast, systemic immune responses to subcutaneous antigens in CCR6(-/-) mice are normal. These findings demonstrate that CCR6 is a mucosa-specific regulator of humoral immunity and lymphocyte homeostasis in the intestinal mucosa.

Animals↗
PubMed2000

Effects of Isotricha, Dasytricha, Entodinium, and total fauna on ruminal fermentation and duodenal flow in wethers fed different diets.

The objective was to measure rumen fermentation and duodenal flow of amino acids and nonammonia N components in five groups of five ruminally and duodenally cannulated wethers that were fauna-free, or inoculated with the ciliate protozoa genera of Isotricha, Dasytricha, Entodinium, or a normal population (total) of fauna. They were used in two 25-d periods and fed a haycrop-based diet in the first period and a corn silage-based diet in the second period. Feces, duodenal digesta, and rumen contents were sampled in each period and analyzed. The number of Entodinium in wethers containing the Entodinium monofauna was higher than the total protozoa numbers, including Entodinium, in wethers containing total fauna population. The type of diet or fauna did not affect total volatile fatty acid concentrations in rumen fluid. The ammonia N concentration in rumen fluid was higher in wethers containing total fauna (25 mg/100 ml) than in fauna-free wethers fed the two diets (18 and 12 mg/ 100 ml). In comparison with the respective fauna-free wethers, the concentration of ammonia in wethers containing Entodinium was higher when fed the corn silage diet, but not different when fed the haycrop diet. Ruminal presence of total fauna or Entodinium decreased the nonammonia N by 16 and 17%, and total amino acid flows from the stomach by 20 and 19%, respectively. Flow of bacteria N was decreased in wethers fed the two diets when Entodinium or total fauna were present in the rumen. The presence of Isotricha resulted in higher flow of bacteria N in wethers fed the haycrop diet, but the presence of Dasytricha resulted in higher bacteria N flow in wethers fed the corn silage diet. Entodinium was the most detrimental of ciliate protozoa species concerning protein nutrition of the host ruminant.

Amino Acids↗
PubMed2000

[Many faces of deinstitutionalization--sociological interpretation].

The article summarizes in an international perspective what kind of results psychiatric deinstitutionalization has brought so far: a profound change of size and functions of the psychiatric hospital; better services for people with less severe problems; and the failing of community services to compensate for some of the functions of the former asylums, resulting in trans-institutionalization and/or neglect for many chronic patients. Three different sociological versions to explain the background and typical outcomes of psychiatric deinstitutionalization have been brought forward so far: political economy, professional dominance and post-structuralism. They are confronted with an approach using the concept of medicalisation which offers a more comprehensive understanding of the process.

Community Mental Health Services↗
PubMed1999

Distinct patterns and kinetics of chemokine production regulate dendritic cell function.

Dendritic cells (DC) have been showed to both produce and respond to chemokines. To understand how this may impact on DC function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-alpha or CD40 ligand, the inflammatory chemokines MIP-1alpha, MIP-1beta and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells for the afferent and efferent limb of the immune response.

Chemokines↗
PubMed1999

[In Process Citation]

Since 1996 thoracic surgery has been invoiced according to fixed reimbursement rates (Sonderentgelte, SE). The legislator argues that fixed reimbursement rates cover operation costs and justify a 20% reduction in reimbursement for nursing. In order to examine this assumption we performed a cost analysis of thoracic surgery. Taking into account the staff, equipment, and operating theatre supplies, we analyzed 30 cases of five different types of operation prospectivly: wedge resections with more than three wedges (AR: n = 8), lobectomies (LE: n = 8), pneumonectomies (PE: n = 5), thoracoscopic wedge resections (VR: n = 6) and resections of mediastinal tumors (MR: n = 3). Then we calculated the overall costs for each operation. The costs for a LE amounted to DM 9,927, which is DM 4,904 more than the corresponding fixed reimbursement rate. The costs were DM 11,562 for a PE, DM 12,477 for a VR and DM 7,532 for a MR. Thus the costs were DM 5,539, DM 2,435 or DM 1,907 higher than the corresponding fixed reimbursement rates. The fixed reimbursement rate for an AR was DM 866 higher than the actual cost of DM 6,922. Only for a small number of cases do the fixed reimbursement rates cover the actual costs of thoracic surgery. Thus operation costs still need to be at least partly covered by the reimbursement for nursing.

Journal Article↗
PubMed1999

Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats.

Tamoxifen is widely used to treat oestrogen-dependent carcinoma of the breast. Previous long-term studies have shown that oral administration of tamoxifen induces hepatoproliferative lesions and hepatocellular tumours in rats. 4-hydroxytamoxifen is an active metabolite of tamoxifen undergoing clinical evaluation for the treatment of various non-malignant breast diseases by topical application. In the present study, 4-hydroxytamoxifen was administered daily by cutaneous application for 101 weeks to groups of 50 female Sprague-Dawley rats at 20, 140 or 1000 microg/kg/day. The product was applied with no occlusive bandage and oral ingestion was avoided by application of an Elizabethan collar for 6 h after administration. Treatment with 4-hydroxytamoxifen was clinically well tolerated and induced changes such as decreased food consumption and body weight gain, uterine and ovarian atrophy, mucification of vaginal epithelium and reduced mammary development, all of which were attributed to its pharmacological action. Mortality was significantly lower in the treated animals. The number of animals with palpable masses was similarly reduced. The incidence of mammary tumours and hypophyseal tumours was markedly lower in 4-hydroxytamoxifen-treated animals. The incidence of chronic tubulo-interstitial nephropathies, a common cause of mortality, was also lowered. There was no evidence of a carcinogenic action of 4-hydroxytamoxifen on the liver, genital organs or skin. Plasma levels of 4-hydroxytamoxifen were stable over the duration of the study and were proportional to the administered dose, exceeding clinical plasma levels by 60-fold at the high dose-level. In conclusion, 4-hydroxytamoxifen is not carcinogenic in the rat and reduces the incidence of spontaneous mammary and hypophyseal tumours.

Administration, Cutaneous↗
PubMed1999

Subchronic toxicity study with ethylene-bis-(oxyethylene)-bis-(3-tert-butyl-4-hydroxy-5-methylhydro cin namate) in the cynomolgus monkey: lack of stimulation of the pituitary-thyroid-liver axis.

To evaluate the toxicological profile of the phenolic antioxidant ethylene-bis-(oxyethylene)-bis-(3-tert-butyl-4-hydroxy-5-methyl- hydrocinnamate) (EOC) in a non-human primate, male cynomolgus monkeys (Macaca fascicularis) were treated for 4 weeks by oral administration of 0, 200, or 1000 mg/kg body weight/day. Special attention was directed to parameters of the pituitary-thyroid-liver axis. Moderately increased liver weights and minimal to moderate hepatocellular hypertrophy were observed in treated animals. Otherwise, no treatment-related changes were detected in hematological, clinical chemistry, or urinalysis parameters or upon histopathological examination. Except for a slight induction of microsomal testosterone 16beta-hydroxylation, liver xenobiotic-metabolising enzyme activities and peroxisomal fatty acid beta-oxidation remained unchanged. Likewise, serum levels of thyroid stimulating hormone, thyroxine, 3,3',5-triiodothyronine and 3,3',5'-triiodothyronine as well as 5'-monodeiodinase type 1 mRNA levels in the liver, heart, cerebral cortex, and thyroid were found unchanged. The results demonstrate that, in the Cynomolgus monkey, EOC is only a very weak inducer of liver xenobiotic-metabolizing enzymes and has no effect on thyroid function. In contrast, upon feeding rats at dose levels up to 1000 ppm (equivalent to between 50 and 100 mg/kg body weight/day), EOC has been identified as a strong phenobarbital- and peroxisome proliferator-type inducer of hepatic xenobiotic-metabolizing enzymes, interfering with thyroid hormone homeostasis, causing thyroid follicular hypertrophy, and, upon chronic treatment, inducing thyroid gland follicular cell tumors (Thomas et al., 1995. In Toxicology of Industrial Compounds, pp. 319-339. Taylor and Francis). Thus, the results of this study with EOC in the cynomolgus monkey show that effects of xenobiotics on the pituitary-thyroid-liver axis as frequently observed in rodents can not necessarily be extrapolated to primates including man.

Animals↗
PubMed1995

Protection by ITF 1300, a heparin ion-pair complex, against arrhythmias induced by regional ischemia and reperfusion in the isolated rat heart: possible mechanism of action.

We examined the effects of the heparin ion-pair complex ITF 1300 on ventricular fibrillation (VF) and other arrhythmias elicited by regional ischemia and by reperfusion in isolated rat hearts (n = 12 per group). During 30-min ischemia, 1, 3, and 10 mg/L ITF 1300 reduced the incidence of VF concentration dependently, with complete abolition of VF at the highest concentration (p < 0.05). Similar but weaker effects were observed for other arrhythmias [ventricular tachycardia (VT) and salvos]. Reperfusion-induced arrhythmias (elicited after 10- or 30-min regional ischemia) were affected similarly, with complete abolition of VF at the highest drug concentration (p < 0.05). Coronary blood flow (CBF), recovery of CBF during reperfusion, and occluded zone sizes were little affected (p = NS). ITF 1300 caused concentration-dependent bradycardia, PR interval widening, and QT widening. In further studies, we examined the roles of these changes in mediating the antiarrhythmic effects. Left atrial pacing at a rate close to control rate (300 beats/min) abolished the antiarrhythmic effects of ITF 1300 and the QT widening, indicating that bradycardia and QT widening were important in mediating the antiarrhythmic effects. Doubling the calcium concentration in the perfusion solution prevented ITF 1300-induced PR widening, indicating that calcium antagonist activity probably mediated the drug's effects on this variable. However, the antiarrhythmic effect of ITF 1300 was not affected by high calcium perfusion. ITF 1300 is an effective antiarrhythmic agent in a model of ischemic heart disease. Its effects are mediated primarily by heart rate-dependent QT widening and were not related to possible calcium antagonist activity.

Animals↗
PubMed1993

Iron protein succinylate: preclinical safety assessment.

In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF 282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopathological findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rat and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.

Animals↗
PubMed1992

Mutagenicity testing of imidazole and related compounds.

Ames tests have been performed with imidazole and its principal metabolites, hydantoin and hydantoic acid. N-Acetyl-imidazole, a potential metabolite resulting from the action of intestinal bacteria, and histamine, a structurally related compound which is widely distributed in mammalian tissues, have also been tested. Imidazole and histamine were also tested in the UDS assay in primary rat hepatocytes, while imidazole alone was tested in the M2-C3H mouse fibroblast malignant transformation assay. Imidazole gave consistently negative results in the Ames test, the UDS assay and the transformation assay. The three metabolites of imidazole, namely hydantoin, hydantoic acid and N-acetyl-imidazole, all gave negative results in the Ames test. Histamine gave no evidence of mutagenic activity in the Ames test or of genotoxicity in the UDS assay. These results indicate that imidazole and its metabolites are unlikely to present a mutagenic or carcinogenic hazard.

Animals↗
PubMed1991

Report of a comparative study of DNA damage and repair assays in primary rat hepatocytes with five coded chemicals.

We report the results of a collaborative study for the detection of chemical-induced DNA damage in primary cultures of rat hepatocytes. The methods include the detection of unscheduled DNA synthesis (UDS) with either autoradiography (5 laboratories) or liquid scintillation counting (2 laboratories) and the assessment of DNA single-strand breaks with the alkaline elution assay (1 laboratory). Interlaboratory standardization was omitted in order to prove the agreement of the assays under routine conditions. Five coded chemicals were tested. For 4 chemicals (2-acetylaminofluorene, thiourea, glycerine and potassium chloride) the UDS data were consistent in all laboratories, thus indicating a high consensus of the test systems applied in the different laboratories. Those 3 chemicals that were not expected to elicit genotoxic activity (thiourea, glycerine, and potassium chloride) yielded negative results in all laboratories. 2-Acetylaminofluorene, a known DNA-damaging agent in hepatocytes, gave strongly positive responses in all laboratories. In contrast, N-nitrosodiphenylamine led to equivocal responses.

2-Acetylaminofluorene↗