Biomedical subjects

C Zimmer

Publications and source records attributed to C Zimmer.

At least 91 records · Page 5Linked to original sources

PubMed1996

[The meningeal sign: a new appraisal].

PURPOSE: To evaluate the occurrence of the meningeal sign in meningiomas and metastases. MATERIAL AND METHODS: We studied 20 patients with meningiomas and 17 patients with cerebral metastases adjacent to the dura. MRI studies (Siemens, Magnetom 1,5) included axial T1-weighted and T2-weighted unenhanced as well as gadolinium-DTPA enhanced T1-weighted (axial, coronal, sagittal) SE imaging. In all patients the tumours were resected with the attached dura mater. Histopathological examinations were done, which corresponded to the area of marked enhancement by gadolinium-DTPA. There was no correlation between the occurrence of the meningeal sign and the histopathological examinations. RESULTS: In 20 patients with meningiomas adjacent to the dura we found the meningeal sign in 11 cases. Histologically we observed an increase of collagen fibres and fibrocytes. In 5 of 17 cases with superficial cerebral metastases the meningeal sign was seen, histologically as dura infiltrations and microbleedings. CONCLUSION: The meningeal sign is not specific for meningiomas and can be observed in a wide variety of pathological entities.

Brain Neoplasms↗

PubMed1996

Deformyldistamycin-DNA interaction; DNA conformational changes as revealed by titration rotational viscometry.

The conformational changes of a natural DNA species on binding of deformyl-distamycin (dDst) have been analysed, at 22 degrees C and 7.6 degrees C, in terms of changes of apparent persistence length (a) and of apparent contour length (L), by means of titration rotational viscometry with both high and low molar mass calf thymus (ct) DNA molecules. Next to ligand binding mediated alterations in DNA stiffness, changes of a are the result of helix bending and also of unbending of intrinsic helix bends. A test for the latter are viscosity measurements at different temperatures. Changes of L, on binding of non-intercalating ligands, are interpreted as the result of changes in the intrinsic solenoidal structure components of the natural eukaryotic DNA. Such tertiary-structure components do exist if base sequence dependent helix bends of (nucleosomal) DNA are phased with the helix screw [Drew & Travers, JMB 186, 773 (1985); Reinert et al., JBSD 9, 537 (1991)]. Hence, the measured very small changes of L at ligand/DNA-P ratios r < 0.02 are mainly understood as a partial abolition of intrinsic tertiary structure components and the following negative ones as a respective reinforcement of such structures by dDst binding to AT rich binding sites. Several r-intervals with different slope of the viscosity changes could be resolved at r < 0.05. The resolution of more than four modes of dDst interaction with ctDNA at very low r values is comparable to DNA interaction of Nt and several other ligands but not of distamycin. Advanced titration rotational DNA-viscometry is again able to resolve subtle quantitative details of ligand mediated DNA conformational changes of high stereochemical relevance.

Animals↗

PubMed1996

Different effects of nonintercalative antitumor drugs on DNA triple helix stability: SN-18071 promotes triple helix formation.

The interaction of the nonintercalating bisquaternary ammonium heterocyclic drugs SN-18071 and SN-6999 with a DNA triple helix has been studied using thermal denaturation and CD spectroscopy. Our data show, that both minor groove binders can bind to the triple helix of poly(dA).2poly(dT) under comparable ionic conditions, but they influence the stability of the triplex relative to the duplex structure of poly(dA).poly(dT) in a different manner. SN-18071, a ligand devoid of forming hydrogen bonds, can promote triplex formation and thermally stabilizes it up to 500 mM Na+ concentration. SN-6999 destabilizes the triplex to duplex equibilirium whereas it stabilizes the duplex. The binding constant of SN-18071 is found to be greater than that to the duplex. The stabilizing effect of SN-18071 is explained by electrostatic interactions of three ligand molecules with the three grooves of the triple stranded structure. From the experiments it is concluded that SN-6999 binds to the triplex minor groove thereby destabilizing the triplex similar as previously reported for netropsin.

Antineoplastic Agents↗

PubMed1996

Reversal of the Z- to B-conformation of poly(dA-dT) center dot poly(dA-dT) induced by netropsin and distamycin A.

Poly(dA-dT) center dot poly(dA-dT) which adopts the Z-form at 5 M NaCl in presence of 95 mM Ni2+ions is reversed to the B-conformation by the nonintercalating drugs netropsin (Nt) and distamycin A (Dst). The drug-induced reversal from the Z-to B-form of poly(dA-dT) center dot poly(dA-dT) is evidenced by CD spectral changes at characteristic wavelengths around 295 nm and 248 nm. The drug-induced conformational transition is accompanied by a slow kinetic process. The results suggest the preference of these AT-specific drugs for the B-form and the inability of Nt and Dst to form a stable complex with the Z-form of poly(dA-dT) center dot poly(dA-dT).

Bacterial Proteins↗

PubMed1996

The antitumor agent cisplatin inhibits DNA gyrase and preferentially induces gyrB gene expression in Escherichia coli.

Cisplatin is a widely used anticancer agent that exerts its biological activity principally by damaging DNA. Although detailed knowledge exists concerning mechanisms that lead to cisplatin adducts in DNA, there are few insights into the processes that result in its antitumor action. To explore some of the cellular responses elicited by cisplatin treatment, we studied its influence on DNA supercoiling and DNA gyrase gene expression in E. coli. We found that cisplatin inhibits DNA gyrase in a concentration-dependent manner leading to a transient alteration of DNA supercoiling and to an induction of gyrase gene expression. The induction effect was asymmetrical, affecting gyrB stronger than gyrA. Furthermore, we studied the influence of cisplatin on the supercoiling activity of purified DNA gyrase in vitro and found that cisplatin was an efficient inhibitor of DNA gyrase in the standard assay. However, cisplatin was an excellent inhibitor when added to DNA gyrase before it could interact with its substrate. In this assay GyrB was also more affected by cisplatin than GyrA. This strongly suggests that cisplatin inhibits DNA gyrase primarily by direct interaction with the enzyme. The data from this work present evidence that further cellular responses following cisplatin treatment include DNA gyrase inhibition, altered DNA supercolling and enhanced DNA gyrase gene expression. This suggests an important role of DNA topology in the induction of defense mechanisms against the action of cisplatin in addition to the processes related to DNA damage and repair.

Antibodies↗

PubMed1995

Biochemical complementation studies in vitro of gyrase subunits from different species.

To investigate the functional equivalence of DNA gyrase subunits from different bacterial sources hybrid enzymes were formed using purified A and B subunits from three species of Streptomycetes, E. coli and B. subtilis. The activity of gyrase hybrids composed of heterologous gyr A and gyr B proteins and of the gyrases containing homologous subunits was characterized by binding studies and a cleavage assay with two different DNA fragments. Likewise the enzyme activity was monitored by the super-coiling and relaxation assay with pBR322 DNA. We found that cleavage reactions are largely determined by the source of the gyr B subunits whereas DNA supercoiling and relaxation reactions of pBR322 catalyzed by DNA gyrase are limited to a combination of homologous A and B subunits or of heterologous A and B subunits from the taxonomically related bacteria Streptomycetes.

Bacillus subtilis↗

PubMed1995

Metastasis of C1300 and TBJ murine neuroblastomas correlates with expression of matrix metalloproteinases.

Because metalloproteinases, specifically type IV collagenases, may mediate metastasis, 72- and 92-kDa collagenase activities were evaluated in two murine neuroblastoma cell lines: non-metastatic C1300 and metastatic TBJ. Zymogram analysis demonstrated that 72- and 92-kDa collagenases were associated only with metastatic TBJ. Three human neuroblastoma cell lines were then evaluated by zymogram and Western blot analyses: 72-kDa collagenase was found in metastatic SK-N-SH and IMR-32, but not in SK-N-MC, which may be a peripheral neuroectodermal tumor and not a neuroblastoma. Therefore, 72- and 92-kDa collagenases may be markers of metastasis in neuroblastoma and may aid in differentiation from other small blue cell tumors.

Animals↗

PubMed1995

MR lymphography with a lymphotropic T1-type MR contrast agent: Gd-DTPA-PGM.

A model system of a paramagnetic lymphotropic MR contrast agent (Gd-DTPA labeled polyglucose associated macrocomplex, PGM) for T1-weighted MR imaging of lymph nodes in rats and rabbits was evaluated. Pharmacokinetic (tissue accumulation) and MR imaging data (optimal dose and timing parameters) were obtained in normal rats (n = 88) after subcutaneous (SC) injection of paramagnetic, radiolabeled [111In]Gd-DTPA-PGM. A rabbit model of lymph node metastases (n = 8) was ultimately used to demonstrate the potential of MR imaging with Gd-DTPA-PGM for nodal tumor detection. Maximum concentrations of Gd-DTPA-PGM were found in popliteal and paraaortic lymph nodes within 24 h after SC administration, and highest lymph node SNR values were obtained by MR imaging at this time point. The optimum imaging dose was 6-12 mumol Gd/kg. Tumor-lymph node contrast increased from 0.0 +/- 1.2 precontrast to 19.2 +/- 6.5 (spoiled gradient echo sequence, TR 50/TE 7/flip angle 60 degrees) postcontrast and conspicuity of nodal metastases was improved. Gd-DTPA-PGM accumulates in lymph nodes after SC administration and significantly enhances lymph node signal intensity of normal animals but not metastatic lymph nodes.

Animals↗

PubMed1995

DNA interaction of the imidazole-containing lexitropsin ImPy: titration viscometric study in comparison to netropsin.

The imidazole (Im) containing lexitropsin ImPy related to netropsin (Nt) is a sequence reading DNA ligand which, in contrast to Nt, permits binding to a GC base pair. The ImPy induced DNA conformational changes differ significantly from those induced by Nt as monitored by titration viscometry, although interaction modes have also been resolved with boundaries at the same ligand to DNA phosphate ratio, r. Evidently ImPy covers similar binding sites (in the same sequence) as Nt for natural calf thymus DNA at r < 0.023. This result suggests that the preferred binding sites of ImPy are A tracts (cf. K.E.R. JBSD 9(1993) 973), in agreement with previous data. The respective DNA coil expansion, most probably caused by unbending (l.c.), is similar but smaller compared to the Nt-DNA interaction. These results again suggest that, at low r values, the van der Waals interaction in the narrowed minor groove of AT clusters provides a dominating energy contribution to ImPy binding. At r > 0.03 the DNA coil expansion increases to extremely high values in that r range where Nt binding (to mixed AT/GC sequences) induces no effect at all owing to steric hindrance with the amino group of guanine. On the basis of many quantitative results for the Nt-DNA systems these effects can be understood in terms of an unbending of intrinsic helix bends (l.c.). They are of considerable interest in connection with the ability of such compounds to influence the direction of the local regulatory relevant DNA curvature.

Animals↗

PubMed1995

Selective uptake of viral and monocrystalline particles delivered intra-arterially to experimental brain neoplasms.

In this study we investigated the intra-arterial delivery of viral and nonviral particles to experimental brain tumors. A herpes simplex virus (HSV) vector and monocrystalline iron oxide nanoparticles (MION) were injected into the internal carotid artery of Fisher 344 rats harboring intracerebral 9L gliosarcomas, using bradykinin to disrupt the blood-tumor barrier. Brain and internal organs were stained both for virus-mediated gene expression and for iron. Quantitative comparisons of gene expression and MION uptake with and without blood-tumor barrier disruption were performed in the center and at the periphery of the tumor mass, as well as in normal brain. In addition, MION distribution was traced in vivo by MR imaging. Delivery of HSV into 9L gliosarcoma cells was greatly enhanced by intra-carotid bradykinin infusion. Virus-mediated expression of the HSV-thymidine kinase (TK) and beta-galactosidase gene products was highest at the tumor periphery as compared to the tumor center. Selective HSV infection of multiple tumor foci was achieved in both hemispheres without affecting normal brain. MION uptake was high at the tumor periphery even without blood-tumor barrier disruption. Bradykinin increased MION uptake predominantly in the center of the tumor with virtually no effect at the periphery. These findings show that selective blood-tumor barrier disruption by bradykinin can be used to enhance HSV-mediated gene delivery to tumor cells in the periphery of brain tumors. A crucial aspect in the treatment of malignant brain tumors is the eradication of tumor cells infiltrating the brain; bradykinin may facilitate access of vectors to these areas by selective disruption of their neovasculature.

Animals↗

PubMed1995

Cerebral iron oxide distribution: in vivo mapping with MR imaging.

PURPOSE: To map the distribution of an iron oxide label in the central nervous system with in vivo magnetic resonance (MR) imaging. MATERIALS AND METHODS: Unilateral osmotic disruption of the blood-brain barrier (BBB) in rats (n = 40) was followed by injection of monocrystalline iron oxide nanoparticles (MION) into the carotid artery. MR images (1.5 T) were obtained in and ex vivo, and results were correlated with histologic section-matched iron maps. RESULTS: A mean of 0.2% of the injected MION was found in the brain 24 hours after unilateral osmotic disruption of the BBB. The spatial distribution of iron oxide within the brain correlated with areas known to have high relative perfusion. Iron was found in cell bodies and dendrites of cortical neurons and astrocytes and in the interstitial space. The threshold in concentration for detection of MION in the brain was 62.2 ng Fe/mm2. CONCLUSION: MR imaging is well suited to noninvasive in vivo mapping of the intracerebral iron oxide distribution.

Animals↗

PubMed1995

MR imaging of phagocytosis in experimental gliomas.

PURPOSE: To determine whether phagocytosis can be observed in vivo in glioma cells. MATERIALS AND METHODS: Rat C6 glioma cells were studied in culture and after intracerebral implantation into 13 rats. Monocrystalline iron oxide nanoparticles (MION), a model marker of phagocytosis, was administered intravenously to tumor-bearing rats at 2-20 mg of iron per kilogram. Magnetic resonance (MR) imaging was performed at multiple time points. RESULTS: Glioma cells in culture showed uptake of MION in amounts of up to 10 ng of iron per 10(6) cells, corresponding to approximately 50,000 particles per cell. Fluorescently labeled MION was found to be located primarily in tubular lysosomes. Intracerebral gliomas showed characteristic changes in signal intensity at MR imaging that peaked 12 hours after administration of MION and lasted up to 5 days; these changes corresponded to uptake and subsequent biodegradation of MION by tumor cells. CONCLUSION: Phagocytosis of glioma cells can be detected in vivo with iron oxide-enhanced MR imaging, and this may permit accurate delineation of tumor margins.

Animals↗

PubMed1995

MR imaging of neuronal transport in the guinea pig facial nerve: initial findings.

Certain dextran coated iron oxides such as MION (monocrystalline iron oxide nanocompound) coupled to wheat germ agglutinin (MION-WGA) have been shown to exhibit i) neuronal uptake ii) axonal transport and iii) strong magnetic effects on tissues (superparamagnetism) in which they are localized. In the current study, we utilized such an agent to visualize axonal transport in the facial nerve in vivo by magnetic resonance (MR) imaging. Following injection of the compound into the facial nerves of guinea pigs, MR images were obtained at multiple time points (1, 3 and 5 days) and the imaged tissues were processed for subsequent histological examination. In nerves that had been injected with MION-WGA, the entire nerve appeared as a uniformly hypointense structure with a calculated transport rate of 5 mm/day. By 3 days, the agent within the facial nerve was traceable by MRI from a site of injection in the buccal branch to the stylomastoid foramen. Fluorescence and autoradiography studies confirmed axonal transport. These results show that MION-based magnetopharmaceuticals can be used to demonstrate slow axonal transport, and thereby visualize functional peripheral nerves in vivo by MR imaging. The method holds promise for developmental neuroscience research as well as a method to detect neural abnormalities by MR imaging.

Animals↗

PubMed1994

Effect of netropsin, distamycin A and chromomycin A3 on the binding and cleavage reaction of DNA gyrase.

The influence of netropsin (Nt), distamycin A (Dst-3) and chromomycin A3 (CHR) on the binding of gyrase from Streptomyces noursei to an 162 bp-fragment of pBR 322 containing a strong gyrase cleavage site and on the gyrase mediated cleavage of this fragment was analyzed. Binding of the enzyme to the fragment is effectively inhibited by the GC-specific drug CHR, but poorly influenced by Dst-3, while Nt is ineffective. Cleavage of the fragment catalysed by the enzyme is inhibited by all three ligands but to different extent. Dst-3 and Nt inhibit the enzyme cleavage reaction at 20- or 250-fold higher concentration than that required for CHR. The inhibitory mechanism of CHR on gyrase-DNA binding and cleavage may be related to a competitive interaction of the ligand to GC sequences located at and around the gyrase cleavage site. The fact that AT-specific minor groove binders Dst-3 and Nt poorly inhibit the binding of gyrase to the fragment due to the low amount of the AT basepair sequences contained in the fragment and their inhibitory influence on the cleavage step underlines the role of the DNA minor groove during enzyme action.

Base Sequence↗

PubMed1994

DNA topoisomerases from Streptomyces noursei: influence of coumarins and quinolones on the enzymic activity.

DNA topoisomerases have been purified from Streptomyces noursei. DNA gyrase and topoisomerase I show a differential sensitivity against quinolones and coumarins compared to the E. coli enzymes. Streptomyces gyrase is resistant to much higher levels of various drugs than is the E. coli enzyme. The observed differences between the gyrases from streptomycetes and E. coli are discussed in the light of present literature data.

Coumarins↗

PubMed1994

Inhibition of collagenolytic activity relates to quantitative reduction of invasion in vitro in a c-Ha-ras transfected glial cell line.

The function of proteases in brain tumor invasion is currently not well established. For tumors of epithelial and fibromatous origin collagenase production can enhance the invasive capacity of cells to penetrate basement membranes. We showed previously that a c-Ha-ras transformed glial cell line (CxT24neo3) invaded hamster brain tissue in vivo. These cells were also capable of invading reconstituted basement membrane and embryonic chick hearts in vitro. Since the histopathology of CxT24neo3 tumors mimics that of glioblastoma multiforme in humans, CxT24neo3 was used as the model in vitro for this type of brain tumor. Presently, we detected by zymogram analysis a gelatinase that was secreted by CxT24neo3 and that had an apparent molecular mass of 62 kD. To verify whether gelatinase affected invasion in vitro of these glial cells we determined the efficacy of a substrate specific collagenase inhibitor on invasion in vitro. GM6001 is a synthetic polypeptide that specifically occupies the substrate binding sites of metalloprotease. Since this drug did not show cytotoxicity, its specificity for metalloprotease is a valuable tool to evaluate the physiological function of these enzymes on invasion. We found that treatment of CxT24neo3 with GM6001 reduced the fraction of invading CxT24neo3 cells through reconstituted basement membrane. These data suggest that metalloproteases can stimulate brain tumor invasion.

Amides↗

PubMed1994

Modulation of DNA supercoiling by interaction with netropsin and other minor groove binders.

The assay of DNA unwinding by ethidium, followed by sedimentation velocity techniques, was applied to complexes of supercoiled plasmid DNA with different non-intercalating drugs which strongly and sequence-specifically bind to DNA. Compared with the behaviour of naked DNA, most of the complexes exhibit an increase in the critical EB/nucleotide binding ratio associated with the principal minimum in the sedimentation profile. Using netropsin (Nt) as the paradigm of the minor groove binders investigated, the drug-induced alterations in various structural parameters of both the relaxed and supercoiled form of DNA are described. Whereas winding number, helical repeat (both being defined with reference to a surface normal), and linking number of the superhelical DNA remain constant in our experiments, its twist number, surface twist, number of superhelical turns as well as the absolute values of linking number difference, superhelix density, and writhing number increase on binding of Nt. Correspondingly, compared with the naked relaxed DNA a higher linking number (or twist number, or winding number), a higher average duplex winding angle and a lower helical repeat have to be assigned to the relaxed Nt-DNA complex. The various minor groove binders investigated were found to differ considerably in their efficiency to alter the structure of supercoiled DNA.

Base Sequence↗

PubMed1994

The influence of social networks and social support on violence by persons with serious mental illness.

OBJECTIVE: The authors examined the relationship between violent acts and threats by persons with serious mental illness, the size and composition of their social networks, and characteristics of the social support they received. METHODS: A group of 169 respondents with serious mental illness and 59 of their significant others were interviewed using structured and semi-structured protocols to elicit data on demographic characteristics, clinical characteristics, characteristics of respondents' social networks and of the social support they received, and perceptions of threat within the social network. Data on acts and threats of violence by respondents over an 18-month period were collected from self-reports by respondents and significant others and from hospital and court records. RESULTS: Fifty-six respondents either threatened violence or committed a violent act during the study period. Respondents with a diagnosis of schizophrenia were more likely to commit violent acts but were not more likely to threaten violence than were respondents with other diagnoses. Respondents in larger networks, those with networks composed primarily of relatives, and those who lived with unrelated persons were more likely to threaten violence. Financial dependence on family was associated with more violent threats and acts. Respondents who perceived hostility from others were more likely to engage in violent threats and acts, and those with confused thinking were less likely to act or threaten violence. More than half of the targets of violence were respondents' relatives, particularly mothers living with a respondent. Respondents who were violent perceived their significant others as threatening but did not perceive themselves as being threatening in return. CONCLUSIONS: The interpersonal and social contexts of respondents and their perceptions of these contexts are important considerations in assessing risk for violence by persons with mental illness. Mothers who live with an adult offspring with schizophrenia may be at increased risk for being a target of violence. Violence by persons with psychiatric disorders may be linked to their perceptions and experience of being threatened by others.

Adult↗