Biomedical subjects
Publications and source records attributed to J Haas.
7078 histological cases of cold-knife conisation have been reevaluated. Because of the changes of the FIGO 1994 staging system, all microinvasive cancers in that material have been reclassified. This had major histomorphological and clinical consequences.
Pyrethroids have varying activities depending on vehicle or route of administration (oral, dermal, inhalational). Specific features like the sensory irritation potential of the alpha-cyano-pyrethroids on the respiratory tract can only be quantified adequately by inhalation testing. Thus equitoxic dosages can vary between inhalative and oral application, especially for alpha-cyano-pyrethrolds. The no-effect values for chronic exposures derived for permethrin (type I pyrethroid) and cyfluthrin (type II pyrethroid) show clearly, that each pyrethroid has to be considered as an individual substance toxicologically, and that any extrapolation from the oral to the inhalative route should only be done after a thorough assessment of the specific toxicological profile. The study of simulated pest control measures on carpets pretreated with permethrin showed, that no significant enrichment of permethrin in total dust could be seen from a carpet additionally treated with pyrethroids. The missing correlation between absolute (mg pyrethroid/m3 air) and relative (mg pyrethroid/kg dust) concentrations in air-borne dust as well as the low degree of translocation of pyrethroids from carpets (only about 0.044% x m(-2) x h(-1) of the cyfluthrin applied to the carpet can be regarded as possibly respirable) prove, that analyses of pyrethroids in household sedimented dust ("vacuum cleaner bag analyses") without knowing the absolute surface concentration and respective air concentrations are of little value for risk assessment. The data allow the conclusion, that a scientific assessment of health risks is only possible based on absolute concentrations of pyrethroids in indoor air.
The porphyrinogenic action of hexafluorobenzene was investigated and compared to that of hexachlorobenzene. Metabolite patterns in the urine of exposed rats were determined to quantify the extent of metabolism through cytochrome P450 catalysed oxidation and glutathione conjugation. Results obtained demonstrate an almost similar extent of formation of phenolic metabolites. However, in the urine of hexachlorobenzene exposed rats significantly higher levels of the N-acetyl-S-(pentahalophenyl)cysteine were observed than in the urine of hexafluorobenzene exposed rats. Hexafluorobenzene exposure did not result in induction of porphyria, whereas exposure to hexachlorobenzene did result in significantly elevated levels of urinary as well as liver porphyrins. Together these results indicate that if the reactive intermediate is indeed formed in the cytochrome P450 catalysed initial oxidative dehalogenation, the extent of its formation as well as its subsequent reactivity and reaction pathways vary with the type of the halogen substituents. Furthermore, the results seem to indicate that the extent of metabolism of hexahalogenated benzenes into urinary metabolites resulting from glutathione conjugation is a better indication of their porphyrinogenic action than their extent of metabolism to phenolic metabolites. Two explanations for this observation are presented.
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OBJECTIVE: To report the clinical and immunological response to immunosuppressive treatment with cyclophosphamide in two patients with paraneoplastic cerebellar degeneration. DESIGN: Case reports. Clinical and immunological follow-up data available for 4 1/2 years in the first patient and for 2 years in the second patient. SETTING: A 1500-bed university hospital and a 1200-bed university teaching hospital. INTERVENTION: Cyclophosphamide intermittent treatment. MAIN OUTCOME MEASURE: Clinical disability. RESULTS: One of the patients, who was treated from an early stage, recovered completely. The other patient showed a partial clinical response. While the two patients were receiving a maintenance regimen with cyclophosphamide, the conditions of both patients remained stable for at least 2 years. In both patients, intrathecal antibody synthesis declined considerably. CONCLUSION: Early induction of immunosuppressive therapy with cyclophosphamide should be tried in treating patients with paraneoplastic cerebellar degeneration.
To test the association between cytotoxicity and in vitro cell cycle perturbations we systematically studied cell cycle perturbations after exposing human ovarian cancer cells to nine commonly used cytotoxic agents. Three principal patterns of cell cycle alterations were observed: a sequential S-G2/M block after exposure to the non-phase-specific agents cis-platinum, 4-hydroperoxy-cyclophosphamide, and mitomycin C (Group I); an isolated G2/M block after exposure to the G2/M phase-specific drugs etoposide and vincristine and the non-phase-specific agent doxorubicin (Group II); and an isolated S block following exposure to the S phase-specific agents 5-fluorouracil, methotrexate, and cytosine arabinoside (Group III). Overall, there was no direct correlation between the degree of cell cycle perturbations and chemosensitivity. However, when the three subgroups of non-phase-specific agents, S phase-specific agents, and G2/M-specific agents were analyzed separately, positive correlations between the magnitude of cell kinetic alterations and chemosensitivity were observed. Cell kinetic alterations appeared to precede cytotoxicity.
The effects of the 5-HT4 receptor agonists BIMU 8, BIMU 1, renzapride and of the 5-HT1p receptor agonist 5-hydroxyindalpine on basal and electrically evoked outflow of tritium were studied in guinea-pig longitudinal muscle myenteric plexus preparations preincubated with [3H]choline. Muscle contractions were recorded simultaneously. BIMU 8 caused a calcium dependent and tetrodotoxin sensitive increase in basal [3H]outflow that was assumed to represent release of [3H]acetylcholine. In addition, BIMU 8 enhanced the release of [3H]acetylcholine and twitch contractions evoked by submaximal electrical stimulation. Ondansetron (1 mumol/l) did not change the effects of BIMU 8, but DAU 6285 and tropisetron (each 1 mumol/l) competitively antagonized the various facilitatory effects of BIMU 8 with pA2 values of 7.0-7.2 (DAU 6285) and 7.0-7.3 (tropisetron). The phosphodiesterase inhibitors IBMX and rolipram did not increase the effects of BIMU 8. BIMU 1 and renzapride also concentration-dependently increased basal release of acetylcholine, and release and contractions caused by submaximal stimulation. The effects of BIMU 1 and renzapride were competitively antagonized by 1 mumol/l tropisetron (pA2 6.6-7.1). The EC50 values for the increase in the evoked [3H]acetylcholine release and contractions were closely similar. 5-Hydroxyindalpine did not change basal release and slightly inhibited the evoked release of [3H]acetylcholine. Release of acetylcholine and contractions elicited by submaximal stimulation were strongly inhibited by (+)-tubocurarine which indicates that nicotine ganglionic transmission is involved in this kind of release. The results suggest that BIMU 8, BIMU 1 and renzapride stimulate 5-HT4 receptors at cholinergic interneurones and thereby facilitate nicotinic ganglionic transmission in the myenteric plexus.(ABSTRACT TRUNCATED AT 250 WORDS)
Tumor invasion and metastasis formation largely depend on tumor-stroma interaction. In the present study morphological correlates of tumor-stroma interaction were examined in 344 melanoma lesions metastatic to the skin. In particular, the presence of simple infiltration into the surrounding dermis or subcutis without evident stromal reaction, the incorporation of pre-existent dermal collagen or subcutaneous fat cells into the tumor bulk, and the formation of a peritumoral capsule or intratumoral fibrous septa were evaluated. Our results showed that simple infiltration into the surrounding tissue as well as the incorporation of pre-existent stroma tissue without destruction is associated with poor outcome, whereas capsule and fibrous septa are favorable prognostic signs, particularly in subcutaneous lesions. Remarkably, simple infiltration is a prognostic indicator independent of the location of the metastasis (locoregional or distant), as shown by multivariate analysis. These data indicate that morphological aspects of tumor-stroma interaction in metastatic skin lesions of melanoma may reflect biological behavior of the tumor cells, may facilitate a pathological subclassification of metastatic melanoma in addition to clinical data, and are directly related to the patient's outcome.
The metastatic behavior of tumor cells largely depends on tumor-stroma interactions. In the present study, a particular morphological feature of tumor-stroma interaction was evaluated; hematoxylin-eosin-stained slides of 81 lesions of melanoma metastatic to the skin involving the subcutis were examined by automated image analysis for the presence of preexistent fat cells in the tumor. The area occupied by fat cells, expressed in micrometers squared per slide, was of prognostic significance; lesions with a fat cell area of < 41,000 microns 2 showed a 2-year survival rate of 42%, versus 10% in lesions with a fat cell area of > 41,000 microns 2 (log-rank test, z = 3.24; p < or = 0.01). The adverse effect of fat cell area on prognosis still was seen when age, sex, and site of metastatic spread were concomitantly taken into account in a Cox proportional-hazard model. These data indicate that melanoma deposits involving the subcutis with preservation of preexistent subcutaneous fat cells have high metastatic potential and a high risk for rapid internal dissemination.
Computer simulations have been used frequently in the life sciences to investigate the mechanisms of morphologic pattern formation. The cellular automaton program SMN5 is designed to simulate tumor growth and to estimate biologic properties by comparing real tumor patterns with computer-simulated reference patterns. This method was applied to 195 cases of primary melanoma of the skin. S-100-stained sections were evaluated by image analysis and compared statistically to a reference set of 4000 simulated patterns. Estimates of tumor cell proliferation, motility, cell loss, cohesion, stroma destruction, and intercellular signals (autocrine and paracrine factors affecting growth, motility, and cell loss) were calculated. Twelve of 18 estimated parameters correlated significantly with tumor progression, as indicated by vertical tumor thickness (linear regression analysis: p < or = 0.05), and 13 of 18 parameters carried prognostic significance (log rank test: p < or = 0.05). Poor prognosis was associated particularly with a pronounced increase in the estimates of proliferation, tumor cell motility, and stromal degradation. Poor prognosis was also associated with a decrease in the estimates of cell loss, tumor cell cohesion, and paracrine growth factor dependence. In multivariate analysis using Cox's proportional hazard model, stromal degradation and motility showed prognostic information in addition to conventional prognostic parameters. The study shows that analytical comparison of real tumors with computer-simulated patterns of a cellular automaton facilitates a functional interpretation of tumor morphology, which carries prognostic significance in cutaneous melanoma.
OBJECTIVES: Is there a correlation between cell cycle perturbations and cytotoxicity in ovarian cancer cells exposed to cytotoxic drugs in vitro? METHODS: We tested the association between cytotoxicity and in vitro cell cycle perturbations after exposure of human ovarian cancer cells to seven cytotoxic agents. RESULTS: Three principal patterns of cell cycle alterations were observed; a sequential S-G/M block after exposure to the non phase-specific agents cis-platinum, 4-hydroperoxy-eyclophosphamide, and mitomycin C (Group I); an isolated G2/M block after exposure to the G2/M phase-specific drugs etoposide and vincristine (Group II); and an isolated S block following exposure to the S phase-specific agents 5-fluorouracil and cytosine arabinoside (Group III). Overall, there was no direct correlation between the degree of cell cycle perturbations and cytotoxicity. However, when the three subgroups of phase non-specific agents, S phase-specific agents, and G2/M specific agents were analyzed separately, positive correlations between the magnitude of cell kinetic alterations and cytotoxicity were observed. CONCLUSIONS: Cell kinetic alterations appeared to precede cytotoxicity. The experimental model may be particularly useful to study cell kinetic effects after high-dose chemotherapy since, in contrast to conventional chemotherapy, the magnitude of cell kinetic perturbations after this kind of treatment is significantly increased.
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We evaluated 49 paired cerebrospinal fluid (CSF) and serum samples of 35 patients infected with the human immunodeficiency virus type 1 (HIV-1) for laboratory evidence of cytomegalovirus (CMV) infection. The patients were grouped according to clinical criteria as probable CMV encephalitis/polyradiculomyelitis, CMV retinitis, cerebral toxoplasmosis, progressive multifocal leukoencephalopathy, HIV-1-related cognitive/motor complex, HIV-1-associated myelopathy, and other neurological diseases. Paired CSF and serum samples were analysed for CMV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR), quantitative intrathecal synthesis of immunoglobulin G (IgG) antibodies specific for recombinant phosphoprotein 150 (pp150) of CMV and CMV-specific serum IgM. Intrathecal synthesis of pp150-specific IgG was detected in 26% of patients (9/35), serum IgM was found in 23% of patients (8/35), and PCR of CSF was positive in 11% of patients (4/35). Detection of CMV-specific DNA in CSF preceded the intrathecal antibody synthesis in three patients for whom serial samples were available. PCR results of the CSF became negative in one patient with CMV polyradiculomyelitis after successful therapy with 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (DHPG). PCR has a higher diagnostic specificity in the acute phase of CMV infection than intrathecal antibody synthesis. The serum IgM response to CMV cannot be used to monitor a compartmentalized immune response in the central nervous system while an intrathecal immune response seems to be associated with recovery either spontaneously or as a result of treatment.
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This study aimed to determine whether quantitative measurements of fetal fibronectin in cervical vaginal secretions reflect the prognosis for imminent premature delivery. 166 patients, who were pregnant from between 25 and 36 weeks, were included in the study over a six months' period. Group A included 60 women with premature contractions, which ceased after tocolytic therapy. Group B consisted of 25 women, who delivered prematurely within 1 week. Group C contained 22 patients, with confirmed PROM and group D contained 24 patients in whom PROM was suspected, but not confirmed. The control group (group E) consisted of 35 patients with uneventful pregnancies. Fetal fibronectin levels in groups B and C differed significantly from those in the other groups. Therefore, the positive predictive value of elevated fetal fibronectin levels for premature delivery was 86.1%.