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C Schulz

Publications and source records attributed to C Schulz.

At least 73 records · Page 4Linked to original sources

A caudal homologue in the short germ band beetle Tribolium shows similarities to both, the Drosophila and the vertebrate caudal expression patterns.

We have isolated a homologue to the Drosophila caudal (cad) gene from the flour beetle Tribolium castaneum and have studied its expression pattern. The Tribolium caudal (Tc-cad) gene arrangement is unusual in that there is a partial duplication of the gene resulting in alternative transcripts with identical 5'-exons, but different 3'-exons encoding two different homeoboxes. Expression analysis was done by whole-mount in situ hybridization and by staining with an antibody raised against the N-terminal part of the protein that is common to both transcripts. At early stages we observe a homogeneously distributed maternal mRNA which is initially also translated throughout the embryo. A little later, a posterior to anterior CAD protein gradient is formed, very similar to that in Drosophila. However, because of the differences in the fate map between Drosophila and Tribolium, the CAD protein expression at blastoderm stage covers the prospective head and thoracic region and not the abdomen as in Drosophila. Expression of Tc-cad in the prospective abdomen is only seen during further germband growth where it becomes restricted to the growth zone in which the segments are formed. This expression is very similar to the growth zone expression in the somitogenic region seen for cad homologues in vertebrates. After the completion of the segmentation process Tc-cad expression becomes confined to a terminal stripe which resembles a similar stripe at late blastoderm stages in Drosophila.

Alternative Splicing↗

Rapid and sensitive determination of catecholamines and the metabolite 3-methoxy-4-hydroxyphen-ethyleneglycol using HPLC following novel extraction procedures.

In the present study assays were improved for the determination of free catecholamines and 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), the major metabolite of peripheral and central noradrenaline. The compounds were extracted by a fluid phase extraction: a diphenyl boric acid method for the purification of catecholamines and an ethyl acetate extraction for MHPG were used, respectively. High-performance liquid chromatography with electrochemical detection was employed for quantitative analysis. In previous studies, significant differences between plasma concentrations of these substances in normal volunteers and hospital patients were demonstrated. Therefore, we established valid reference values for a hospital population. Blood and urine samples of 59 patients without disorders and medication affecting catecholamine synthesis and metabolism or the activity of the sympatho-adrenal system were collected and analyzed for free and total (free plus conjugated) MHPG, noradrenaline (NA), adrenaline (A) and dopamine (DA); total MHPG was assayed after enzymatic hydrolysis of conjugates. Our data clearly demonstrate that these methods are sensitive, specific, rapid, and can easily be standardized. The intra- and inter-assay precision were high (CV 2.6-5.3% and 4.3-6.9% for plasma, CV 3.8-4.9% and 5.1-8.2% for urine, respectively). For plasma, the mean concentrations +/- SD were determined to be 20.82+/-4.70 pmol/ml for free MHPG, 68.43+/-16.21 pmol/ml for total MHPG, 2.11+/-0.24 pmol/ml for NA and 0.31+/-0.08 pmol/ml for A. For 24h-urine the mean concentrations +/-SD were determined to be 0.44+/-0.13 mmol/24h for free MHPG, 8.79+/-2.13 mmol/24h for total MHPG, 169.8+/-58.25 nmol/24h for NA, 62.19+/-21.79 nmol/24h for A and 757.2+/-382.6 nmol/24h for DA. In summary, these novel and rapid methods can clearly be employed in a routine clinical setting.

Adolescent↗

Physiological and neurochemical aspects of corticotropin-releasing factor actions in the brain: the role of the locus coeruleus.

Corticotropin-releasing factor (CRF) is both a major regulator of the hypothalamo-pituitary-adrenal (HPA) axis and the activity of the autonomic nervous system. Besides, it exerts numerous effects on other physiological functions such as appetite control, motor and cognitive behavior and immune function. The basis for these effects is constituted by its distribution in hypothalamic and extra-hypothalamic brain areas, the latter being represented by limbic structures such as the central nucleus of the amygdala or by brain stem neurons such as the locus coeruleus (LC) or nucleus of the solitary tract (NTS). The effects of CRF are mediated through recently described CRF-receptor subtypes, whose molecular biology, biochemistry and pharmacological regulation are discussed in detail. In the second part of this review, we will focus on the physiology of CRF-systems in the brain, with a particular emphasis on cardiovascular regulation, respiration, appetite control and stress-related behavior. Finally, the role of the locus coeruleus in the control of CRF-mediated behavioral activities is discussed. The interaction of noradrenergic and CRF-neurons clearly implies that CRF appears to directly activate LC neurons in a stressful situation, thus ultimately coordinating the bodily response to a stressful stimulus.

Animals↗

Regulation of the Tribolium homologues of caudal and hunchback in Drosophila: evidence for maternal gradient systems in a short germ embryo.

In short germ embryos, the germ rudiment forms at the posterior ventral side of the egg, while the anterior-dorsal region becomes the extra-embryonic serosa. It is difficult to see how an anterior gradient like that of bicoid in Drosophila could in these embryos be directly involved in patterning of the germ rudiment. Moreover, since it has not yet been possible to recover a bicoid homologue from any species outside the diptera, it has been speculated that the anterior bicoid gradient could be a late addition during insect evolution. We addressed this question by analysing the regulation of potential target genes of bicoid in the short germ embryo of Tribolium castaneum. We demonstrate that homologues of caudal and hunchback from Tribolium are regulated by Drosophila bicoid. In Drosophila, maternal caudal RNA is translationally repressed by bicoid. We find that Tribolium caudal RNA is also translationally repressed by bicoid, when it is transferred into Drosophila embryos under a maternal promoter. This strongly suggests that a functional bicoid homologue must exist in Tribolium. The second target gene, hunchback, is transcriptionally activated by bicoid in Drosophila. Transfer of the regulatory region of Tribolium hunchback into Drosophila also results in regulation by early maternal factors, including bicoid, but in a pattern that is more reminiscent of Tribolium hunchback expression, namely in two early blastoderm domains. Using enhancer mapping constructs and footprinting, we show that caudal activates the posterior of these domains via a specific promoter. Our experiments suggest that a major event in the evolutionary transition from short to long germ embryogenesis was the switch from activation of the hunchback gap domain by caudal to direct activation by bicoid. This regulatory switch can explain how this domain shifted from a posterior location in short germ embryos to its anterior position in long germ insects, and it also suggest how an anterior gradient can pattern the germ rudiment in short germ embryos, i.e. by regulating the expression of caudal.

Animals↗

Preoperative bronchoscopic assessment of airway invasion by esophageal cancer: a prospective study.

BACKGROUND: Bronchoscopy is frequently used to assess invasion of esophageal cancer into the tracheobronchial tree. Prospective studies evaluating the role of bronchoscopy in pretherapeutic staging of esophageal cancer are lacking. STUDY OBJECTIVES: To evaluate the diagnostic utility of fiberoptic bronchoscopy for the assessment of airway involvement by esophageal carcinoma and its resectability. PATIENTS AND METHODS: In a prospective study, we analyzed 150 bronchoscopies in 116 consecutive patients with potentially operable esophageal carcinoma, and correlated the findings with other staging modalities, intraoperative evaluation, and histopathologic data. RESULTS: One unknown additional bronchial cancer was found. In 32% of bronchoscopies performed in patients with esophageal cancer located above the tracheal bifurcation, some macroscopic abnormality was detected in the trachea and main bronchi, with mobile protrusion of the posterior tracheal wall being the most frequent abnormality (20.7%). When compared with histologic results, normal macroscopic appearance of the trachea and main bronchi had a negative predictive value of 98.5%, but the positive predictive value of all macroscopic abnormalities for the diagnosis of airway involvement was low, particularly after radiation therapy. The overall accuracy of bronchoscopy with multiple brush cytology and biopsy sampling in proving or excluding airway invasion in patients with otherwise operable conditions was 95.8% (95% confidence interval, 88.3 to 99.1%). Bronchoscopy was the sole decisive staging procedure, resulting in exclusion from surgery because of airway invasion, in 9.7% of patients with otherwise potentially operable conditions. The results of bronchoscopy and CT were discordant in 40% of the patients; the specificity and positive predictive value were higher for bronchoscopy than for CT. CONCLUSIONS: When performed as the last investigation in the staging workup, bronchoscopy with biopsy and brush cytology is a very accurate procedure in evaluating possible airway invasion of esophageal cancer; macroscopic findings alone are not reliable.

Bronchial Neoplasms↗

Cell proliferation in the livers of male mice and rats exposed to the carcinogen P-dichlorobenzene: evidence for thresholds.

In a previous study, p-dichlorobenzene (pDCB), which is associated with tumorigenicity in male rat kidney and livers of mice of both genders, was found to produce acute increases in cell proliferation in those tissues. To determine whether sustained cell proliferation in the liver in susceptible species correlated with reported carcinogenic effects, we examined the effect of pDCB on cell proliferation in the livers and toxicity to the glutamine synthetase-expressing hepatocyte (GS+) subpopulation of male B6C3F1C3F1 mice and F344 rats. Mice were exposed for up to 4 weeks to 600, the maximally tolerated dose which increased liver tumors, 300 or 150 mg/kg. Rats were exposed to 300, 150 or 75 mg/kg for up to 4 weeks. In mice, the cumulative replicating fraction (CRF) in the livers of the high dose animals was significantly increased 16-fold at 1 week and 4-fold at 4 weeks. The CRF was also increased at 300 mg/kg at 1 week, but this subsided at 4 weeks. No increase was seen in the low dose group. In rats, the CRFs of the livers at 1 week were increased at 300 and 150 mg/kg, but returned to normal at 4 weeks. The size of the hepatic GS+ area was not affected in mice or in rats after 1 week of exposure, but comparable decreases were observed at all exposures at 4 weeks in mice. The data therefore suggest that sustained increases of cell division in the mouse liver may contribute to the increases in liver tumors. The transient increase in rat liver suggests that this is not sufficient to enhance tumor development. The absence of sustained increases of the CRFs at the low dose in mice, which was one-fourth of the hepatocarcinogenic dose, implies the existence of a threshold in pDCB hepatocarcinogenesis.

Animals↗

Good practice in multimedia courseware development.

The main goal of the European TALENT/ESPRIT project is to create a generic environment for developing multimedia courseware. The first phase of the project concerns itself with developing conversion tools for converting text based course material into multimedia format. The second phase of the project adds network support to the courseware in the form of the network tutoring and networked supply chain support. One year into the project specifications for developing multimedia have been made and can be found in the project's deliverables. Also a summary of good practice in multimedia courseware development has been drawn up. First phase demonstrators (converted text based courses) are currently being prepared. This article starts with a global overview of the TALENT project itself. In more detail an overview of best practice guidelines in multimedia courseware development will be given. The information shown was obtained from an extensive survey among experts in the field of computer based training. The survey was conducted early this year as part of one of the project's deliverables. Finally some comments will be made on a multimedia demonstrator which is currently under development at HISCOM.

Computer-Assisted Instruction↗

[Pyrethroids in house dust of the German housing population--results of 2 nationwide cross-sectional studies].

As a part of the German Environmental Surveys performed in 1985/86 (West Germany), 1990/91 (West Germany) and 1991/92 (East Germany), dust samples were collected in the households of about 1600 randomly selected adults (25 to 69 years) and an analysis of these samples was performed in respect of their content of 8 different pyrethroids and of the synergist piperonyl butoxide (PBO). In the 1990-92 survey about 90% of the samples contained permethrin in concentrations above the limit of quantification. This showed permethrin to be the most widespread of the 8 compounds investigated. The geometric mean of the permethrin content in domestic dust was 0.22 mg/kg. Only about 8% of the samples contained one or more of the other investigated substances (cyfluthrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, deltamethrin, empenthrin, d-phenothrin) in quantifiable amounts. About 76% of the samples contained quantifiable amounts of PBO. In East Germany the geometric mean of the PBO content (0.21 mg/kg) was significantly higher than in West Germany (0.07 mg/kg), but no difference for permethrin was found. Significant associations could be shown for the permethrin content and the application of biocides as well as for the PBO content and regional factors (size of community, type of dwelling area). Samples collected in 1985/86 (West Germany) showed a geometric mean for permethrin of 0.06 mg/kg and for PBO of 0.07 mg/kg. Comparing the values of 1985/86 and 1990/91, a significant increase can be observed for permethrin, whereas the PBO concentration remained constant.

Adult↗

[Stress osteotomy of the distal radius- and ulna metaphysis (Illarramendi procedure): an alternative treatment method in lunate necrosis].

The etiology of Kienböck's disease is still unknown. Many operative procedures, usually based on biomechanical considerations, are recommended. Based on known effects of core decompression procedures on bone, we present a technique of core decompression of the metaphysis of the distal radius and ulna (MCD) as an easy, alternative biologic treatment. Ten cases with a mean follow-up of 10.8 years are analyzed. All patients had significant postoperative pain relief and returned to their previous activities. At the time of follow-up, comparative motion of flexion-extension of the wrist averaged 74%, mean grip strength was 81% of the nonaffected side. Radiographic follow-up did not slow significant postoperative collapse of the lunate (p > 0.05). No correlation was observed between post-operative results and ulnar variance. MCD is a simple, low-risk procedure. Clinical and radiological outcome supports a theory of biologic rather than biomechanic mechanisms related to fracture healing, that stimulate regeneration of the avascular lunate and relieve symptoms. A primary vascular etiology of idiopathic avascular necrosis of the lunate seems to be likely.

Adult↗

The internal burden of lead among children in a smelter town--a small area analysis.

Hettstedt, a city in former East Germany with a history of mining and smelting of nonferrous ores, has multiple lead waste deposits and the remains of a former lead and copper-silver smelter. A small-area analysis of lead concentrations in blood and in household dust was undertaken in a cross-sectional study to determine if children living near the sources had particularly high burdens of lead. The overall geometric mean of the region was 38.0 micrograms Pb/liter blood with a 95% confidence interval (CI) of 36.5-39.5. The burden of lead among children living in the region containing the lead tailings piles and adjacent smelters was almost twice as high (77.4 micrograms Pb/liter blood; 95% CI 65.0-92.0). It decreased in the areas farther northeast from the smelter. Lead levels in the children residing in areas southwest of the smelters were not appreciably elevated. The same pattern was found in house dust lead concentrations. This analysis helped target areas where follow-up is needed and found that not only distance from lead sources, but also meteorological factors played an important role in lead exposure.

Adolescent↗

Effects of beta 2-agonist- and dexamethasone-treatment on relaxation and regulation of beta-adrenoceptors in human bronchi and lung tissue.

1. Long-term treatment with beta 2-adrenoceptor agonists can lead to a decreased therapeutic efficacy of bronchodilatation in patients with obstructive pulmonary disease. In order to examine whether or not this is due to beta-adrenoceptor desensitization, human bronchial muscle relaxation was studied in isolated bronchial rings after pretreatment with beta 2-adrenoceptor agonists. Additionally, the influence of pretreatment with dexamethasone on desensitization was studied. 2. The effect of beta 2-agonist incubation alone and after coincubation with dexamethasone on density and affinity of beta-adrenoceptors was investigated by radioligand binding experiments. 3. In human isolated bronchi, isoprenaline induces a time- and concentration-dependent beta-adrenoceptor desensitization as judged from maximal reduction in potency by a factor of 7 and reduction of 73 +/- 4% in efficacy of isoprenaline to relax human bronchial smooth muscle. 4. After an incubation period of 60 min with 100 mumol l-1 terbutaline, a significant decline in its relaxing efficacy (81 +/- 8%) and potency (by a factor 5.5) occurred. 5. Incubation with 30 mumol l-1 isoprenaline for 60 min did not impair the maximal effect of a subsequent aminophylline response but led to an increase in potency (factor 4.4). 6. Coincubation of dexamethasone with isoprenaline (120 min; 30 mumol l-1) preserved the effect of isoprenaline on relaxation (129 +/- 15%). 7. In radioligand binding experiments, pretreatment of lung tissue for 60 min with isoprenaline (30 mumol l-1) resulted in a decrease in beta-adrenoceptor binding sites (Bmax) to 64 +/- 1.6% (P < 0.05), while the antagonist affinity (KD) for [3H]-CGP-12177 remained unchanged. 8. In contrast, radioligand binding studies on lung tissue pretreated with either dexamethasone (30 mumol l-1) or isoprenaline (30 mumol l-1) plus dexamethasone (30 mumol l-1) for 120 min did not lead to a significant change of Bmax (160 +/- 22.1% vs 142.3 +/- 28.7%) or KD (5.0 nmol l-1 vs 3.5 nmol l-1) compared to the controls. 9. In conclusion, pretreatment of human bronchi with beta-adrenoceptor agonists leads to functional desensitization and, in lung tissue, to down-regulation of beta-adrenoceptors. This effect can be counteracted by additional administration of dexamethasone. Our model of desensitization has proved useful for the identification of mechanisms of beta-adrenoceptor desensitization and could be relevant for the evaluation of therapeutic strategies to counteract undesirable effects of long-term beta-adrenoceptor stimulation.

Adrenergic beta-2 Receptor Agonists↗

[Clinical and endocrine diagnosis of pheochromocytoma].

Pheochromocytomas are catecholamine-producing tumors, representing one of the most important causes of secondary hypertension. The classification of these tumors considers both sporadic and familial forms, intra- and extraadrenal localization as well as the dignity. Familial pheochromocytomas are primarily seen under the conditions of multiple endocrine neoplasia, von Hippel-Lindau disease or neurofibromatosis type 1. The list of clinical symptoms includes hypertension, which can be both continuous or intermittent, headache, tachycardia and sweating. It is most important to standardize the pre-analytical procedures, i.e. control for sampling conditions and adequate choice of parameters in plasma or urine. For screening sensitive methods will be employed (free catecholamines in 24h-urine) and for confirmation of the diagnosis, specific procedures are performed (Clonidine test, MIBG-scintigraphy). The endocrinological and biochemical procedures are completed by molecular genetic techniques in familial pheochromocytoma.

3-Iodobenzylguanidine↗

Ventilation perfusion scintigraphy and lung function testing to assess metal stent efficacy.

UNLABELLED: Stent implantation in malignant bronchial stenoses is a highly effective method of providing symptomatic relief by restoring bronchial patency. Whether an improvement in ventilatory conditions is paralleled by an increase in blood flow and gas exchange has not yet been determined. METHODS: Fourteen patients with malignant, high-grade obstruction of bronchi who had metal stent implantation were investigated. Before the intervention and again 8 days afterward, both quantitative technegas ventilation and 99mTc-MAA perfusion scans (V/Q scans) and lung function tests were performed. RESULTS: Stent implantation was successful in all patients, with a significant reduction in the degree of bronchial stenosis (pre-stent: 93% +/- 1.5%; post-stent: 16% +/- 3.5%). After stent implantation, ventilation scintigraphy revealed an improvement in tracer deposition by 65% (pre-stent: 37% +/- 8%; post-stent: 61% +/- 6%; p < 0.05) within the affected lung. A complementary increase of 71% by perfusion scintigraphy was obtained (pre-stent: 27% +/- 4%; post-stent: 46% +/- 5%; p < 0.01%). Based on scintigraphic criteria, stenting was successful in 93% (n = 13) of all patients. Lung function studies performed after the intervention showed significant improvement in vital capacity (VC, p < 0.01), forced expiratory volume in 1 sec (FEV1, p < 0.05), peak expiratory flow (PEF, p < 0.05), arterial oxygen (PaO2, p < 0.05) and carbon dioxide (PaCO2, p < 0.05) tension, and oxygen saturation (p < 0.05). CONCLUSION: Stenting of malignant high-grade bronchial obstructions leads to an increase in bronchial patency and in activity distribution of both ventilation and perfusion scintigraphy of the affected lung, accompanied by significant improvement in lung function parameters.

Alloys↗

Arsenic burden among children in industrial areas of eastern Germany.

The internal burden of arsenic among 5- to 14-year-old eastern German children in the heavily polluted areas of Hettstedt, a region of smelting and copper mining, and Bitterfeld, a center of chemical production and coal mining, was compared with that in a control area (Zerbst) by means of urinary arsenic concentrations in 1992-94. The unadjusted geometric mean among the 950 children was significantly higher in Hettstedt (5.1 micrograms/l; 95% C.I. 4.8-5.5) but not in Bitterfeld (4.3 micrograms/l; 95% C.I. 3.7-4.9) compared with the control area (4.0 micrograms/l; 95% C.I. 3.5-4.5). This difference persisted after adjustment for relevant confounders. Despite these regional differences, recent fish consumption was as strongly associated with urinary arsenic levels (42% increase, 95% C.I. 18-71%). Additionally, although the geometric mean among the children in Hettstedt (4.8 micrograms As/g creatinine; 95% C.I. 4.5-5.1) was higher than that found in an environmental survey of eastern German children (3.60 micrograms As/g creatinine; 95% C.I. 3.06-4.24), it was similar to that found among western German children (4.59 micrograms As/g creatinine; 95% C.I. 4.20-5.02). This suggests that the arsenic contamination in Hettstedt is not substantially increasing the internal burden of arsenic among children above that found in other German children.

Adolescent↗

Regionalization of donor organ procurement: first experiences in southern Bavaria and results of a regional donor hospital survey.

In order to improve organizational, qualitative, and economic aspects of organ procurement, a model of regionalization was established in the local area of southern Bavaria, as from September 1993, with the following characteristics. A collaborative 24 h-duty schedule with surgeons from all active regional transplant programs. Surgeons are grouped according to their operative qualification level: (1) Group I, capable of retrieving all abdominal organs (liver, pancreas, kidney), (2) Group II, capable of removing kidneys, and (3) Group III, surgical assistance in procurement procedures. All donor organs in the local region are explanted by the local team and foreign recipient centers are supplied with the organs removed by a standardized technique. Only three times during the first, and not once during the second year, did a foreign team insist on traveling to our region to perform a liver retrieval. A survey clearly documented univocal acceptance of this model by donor hospital executives. Simplified organization and less disturbance in operating theaters were among the most frequent arguments in favor, and the familiarity of explant teams in donor hospitals was considered advantageous. Most donor hospitals do not expect to profit in terms of financial savings. When asked for further possible measures to improve organ donation, a clearer legal situation, but also the need for more information and education programs, including better media representation of transplant issues, were cited most frequently. An improvement in financial reimbursements for the donor hospitals as an instrument to enhance willingness for organ donation was not considered essential. In conclusion, our model of regionalization of organ procurement proved to be effective in achieving a high quality of organ retrieval and a reduction in personnel requirements for the transplant centers. In addition, the response from donor hospitals was unequivocally positive and may, thus, positively influence donor activity. Relevant financial savings can result from reduced on-call duties and minimized traveling costs. Further attempts to rationalize organ procurement could possibly include heart(-/lung)surgeons in the regionalized teams.

Hospitals↗

Diethylnitrosamine exposure-responses for DNA damage, centrilobular cytotoxicity, cell proliferation and carcinogenesis in rat liver exhibit some non-linearities.

The exposure-responses for several effects of limited exposures to diethylnitrosamine (DEN) in the livers of male Fischer 344 rats were measured and phenobarbital promotion was used to enhance expression of initiation of carcinogenesis. Five doses ranging from a cumulative total of 0.5 to 4 mmol DEN per kg body weight were given as weekly i.p. injections for 10 weeks. This was followed by 4 weeks recovery, after which the groups were maintained on either a basal diet or 0.05% phenobarbital (PB) to promote liver tumor development. All doses of DEN produced ethylation in liver DNA, which increased with dose. Indicative of toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was reduced in relationship to exposure up to a cumulative exposure of 3 mmol/kg. The two lower exposures to DEN produced no increase in cell proliferation, whereas higher exposures resulted in marked increases, approximately 4-fold between 1.0 and 2.0 mmol/kg cumulative. At the end of the recovery period (14 weeks), hepatocellular altered foci (HAF), which expressed the placental form of glutathione S-transferase, were induced by all exposures, with an increase of approximately 4-fold between the exposures of 1.0 and 2.0 mmol/kg being the greatest. In rats maintained on basal diet or PB for 24 weeks after exposure, HAF increased further and with exposures of 2.0 mmol/kg and above, all rats developed hepatocellular carcinomas. With 1.0 mmol/kg, no liver tumor occurred in 12 rats without promotion, whereas in those given PB, two adenomas and two carcinomas were present in 12 rats. At the lowest exposure of 0.5 mmol/ kg, no tumor occurred in rats on basal diet, although HAF increased approximately 7-fold. With PB promotion, only one adenoma developed in 12 rats and HAF increased another 2-fold. Thus, the findings document non-linearity for some of the effects of DEN and a near no-effect level for initiation of promotable liver neoplasms at the lowest exposure in spite of a substantial induction of HAF.

Alkylating Agents↗