Biomedical subjects

C Zimmer

Publications and source records attributed to C Zimmer.

At least 73 records · Page 4Linked to original sources

PubMed1998

DNA sequence recognition by bis-linked netropsin and distamycin derivatives.

We studied the interaction of cis-diammine Pt(II)-bridged bis-netropsin, cis-diammine Pt(II)-bridged bis-distamycin and oligomethylene-bridged bis-netropsin with synthetic DNA fragments containing pseudosymmetrical AT-rich nucleotide sequences and compared it with the interaction of the parent compounds netropsin and distamycin A. For fragments containing multiple blocks of (AIT)4 and (T/A)4 separated by zero, one, two and three GC-base pairs, DNase I footprinting and CD spectroscopy studies reveal that 5'-TTTTAAAA-3' is the strongest affinity binding site for cis-diammine Pt(II)-bridged bis-netropsin and bis-distamycin. They both bind less strongly to a DNA region containing the sequence 5'-AAAATTTT-3'. Netropsin, distamycin A and oligomethylene-bridged bis-netropsin exhibit far less sequence discrimination.

Base Sequence↗

PubMed1998

Determination of molsidomine and its active metabolite in human plasma using liquid chromatography with tandem mass spectrometric detection.

Pharmacokinetic studies of molsidomine require a sensitive analytical method to allow the determination of concentrations of this compound and its active metabolite 3-morpholinosydnonimine (Sin-1) in the ng/ml range in plasma. The method developed is based on on-line LC-MS-MS using pneumatically assisted electrospray ionisation as an interface, preceded by off-line solid-phase extraction (SPE) on disposable extraction cartridges (DECs). The SPE operations were performed automatically by means of a sample processor equipped with a robotic arm (automated sample preparation with extraction cartridges; ASPEC system). The DEC, filled with phenyl-modified silica, was first conditioned with methanol and water. The washing step was performed with water. Finally, the analytes were successively eluted with methanol containing formic acid (0.2%) and water. The liquid chromatographic separation of molsidomine and Sin-1 was achieved on an RP-8 stationary phase (5 microns). The mobile phase was a mixture of methanol-water-formic acid (65:35:0.1, v/v/v). The HPLC system was then coupled to a MS-MS system with an atmospheric pressure ionisation interface in the positive ion mode. The chromatographed analytes were detected in the multiple reaction monitoring mode. The MS-MS ion transitions monitored were (m/z) 243-->86 for molsidomine and 171-->86 for Sin-1. The method developed was validated. The absolute recoveries evaluated over the whole concentration range were 74 +/- 3 and 55 +/- 5% for molsidomine and Sin-1, respectively. The method was found to be linear in the 0.5-50 ng/ml concentration range for the two analytes (r2 = 0.999 for both molsidomine and Sin-1). The mean RSD values for repeatability and intermediate precision were 3.4 and 4.8% for moldsidomine and 3.1-7.7% for the metabolite. The method developed was successfully used to investigate the bioequivalence of oral doses of molsidomine between a generic tablet and a reference product.

Area Under Curve↗

PubMed1998

Binding of 2-azaanthraquinone derivatives to DNA and their interference with the activity of DNA topoisomerases in vitro.

We have investigated the binding ability to DNA of compounds belonging to the 2-azaanthraquinone-type structure and have examined the effect on the activity of DNA gyrase as well as on mammalian topoisomerases in vitro. Using different biophysical techniques it was found that one of these ligands, 9-((2-dimethylamino)ethyl)amino)-6-hydroxy-7-methoxy-5, 10-dihydroxybenzo[g]isoquinoline-5,10-dione (TPL-I), is an intercalating DNA binding agent, whereas the parent compound tolypocladin (TPL) and a derivative (TPL-II) showed almost no similar affinity to DNA. CD measurements demonstrated a significant and selective binding tendency of TPL-I to alternating purine/pyrimidine sequences with some preference for poly(dA-dT). poly(dA-dT). Tm values were increased of the ligand complex with the alternating AT-containing duplex polymer. The binding to various DNAs was characterized by CD and visible absorption spectral changes. From the latter, different binding constants of 6.2 x 10(5) and 1.5 x 10(5) M-1 were obtained for poly(dA-dT).poly(dA-dT) and poly(dA). poly(dT), respectively. Sedimentation measurements with supercoiled pBR322 plasmid DNA clearly indicated an intercalative binding mechanism associated with an unwinding angle of about 18 degrees. These results suggest that the intercalative binding of TPL-I is promoted by the 2-(dimethylamino)ethylamino group substituted on carbon 9 of the anthraquinone system. The cytotoxic compound TPL-I, but not TPL or TPL-II, effectively inhibited the DNA supercoiling reaction of DNA gyrase and the activity of mammalian topoisomerases I and II as measured by the relaxation assay. TPL-I affects the cleavage reaction of topoisomerases on a single site located in alternating purine-pyrimidine sequence regions. The inhibitory potency of TPL-I can be ascribed to a blocking of cleavage sites on the DNA substrate, which correlates with the sequence preference of the ligand.

Anthraquinones↗

PubMed1998

TBJ murine neuroblastoma resists dibutyryl cyclic AMP-induced differentiation and effects on metalloproteinase secretion.

BACKGROUND: Nonmetastatic C1300 murine neuroblastoma and TBJ, a metastatic variant, exhibit different mechanisms of metastasis and invasion. METHODS: In this study, they were examined for response to 1 mmol/L dibutyryl cyclic AMP in vitro. RESULTS: (1) dCAMP induced morphological differentiation in 20% to 40% of C1300 cells, whereas TBJ resisted differentiation. (2) Untreated TBJ expressed 92-kDa metalloproteinase, whereas C1300 expressed none. These results were not affected by dCAMP. (3) Growth curves of untreated C1300 and TBJ were exponential. Dibutyryl CAMP induced a plateau in C1300 growth that was confirmed by increased S-phase cells by cell cycle analysis. CONCLUSIONS: TBJ growth was unaffected by dCAMP. Apoptosis, as assayed by Hoechst-merocyanine staining test, was not involved in the growth plateau.

Animals↗

PubMed1998

An indicator of pesticide environmental impact based on a fuzzy expert system.

Pesticide use options available to farmers differ strongly with respect to the risks they pose to the environment. This paper proposes a fuzzy expert system to calculate an indicator "Ipest" which reflects an expert perception of the potential environmental impact of the application of a pesticide in a field crop. We defined four modules, one reflecting the presence (rate of application) of the pesticide, the other three reflecting the risk for three major environmental compartments (groundwater, surface water, air). The input variables for these modules are pesticide properties, site-specific conditions and characteristics of the pesticide application. For each input variable two functions describing membership to the fuzzy subsets Favourable (F) and Unfavourable (U) have been defined. These functions are based on criteria drawn from the literature or on the authors' expert judgment. The expert system calculates the value of modules according to the degree of membership of the input variables to the fuzzy subsets F and U and according to sets of decision rules. The four modules can be considered individually or can be aggregated (again according to membership to fuzzy subsets F and U and a set of decision rules) into the indicator Ipest. The system is flexible and can be turned to expert perception, it can be used as a decision aid tool to rank or choose between alternative pesticide application options with respect to their potential environmental impact. Results of a sensitivity analysis and module and Ipest scores for some pesticide application cases are presented. An agro-ecological indicator IPEST, based on the expert system, is proposed as a tool to assess the environmental impact of all pesticide applications related to a crop within a year. The practical implementation of the expert system and its validation are discussed.

Biodegradation, Environmental↗

PubMed1998

Structure-dependent effects of minor groove binders on the DNA triple helix motif poly(dA).2poly(dT): influence of antitumoractive nonintercalative bisquaternary ammonium heterocycles.

The interaction of a series of bisquaternary ammonium heterocycles (BQA) with the triple helix of poly(dA).2poly(dT) was investigated using thermal denaturation and circular dichroism spectroscopy. The BQA-bound triplexes undergo two distinct transitions during thermal melting: a first melting step from the triplex to the duplex state with the BQA ligand remaining bound and a second step from the duplex to single strands. The ionic strength dependence of the triplex stability at increasing ligand concentration was analyzed by phase diagrams. The results demonstrate that some BQA ligands thermally stabilize the triplex at Na+ concentrations of < or = 150 mM and destabilize this structure above the range 150-220 mM Na+, indicating promotion of triplex formation under low ionic strength and diminution of the affinity of the major groove-bound third strand in the triplex at high ionic strength. SN-6999 most strongly destabilizes the triplex structure but stabilizes the DNA duplex, while SN-16814 showed no effect at all on the triplex stability. In contrast, SN-18071 exclusively promotes triplex formation and is the most potent triplex stabilizer of the BQA ligands investigated, which is also more effective than spermine. The differential triplex-stabilizing and -destabilizing effects of BQA ligands are discussed on the bases of variations in their DNA binding properties.

Antineoplastic Agents↗

PubMed1997

["Pain under discussion--stages of chronicity and treatment outcome].

PROBLEM: "Pain under Discussion" aims at the education of patients with chronic headache and back pain by applying a standardized manual with detailed instructions for seven sessions in a group setting. Apart from encouraging a reconceptualization of the patients' pain experience with reference to a bio-psycho-social model, the program provides information about the vicious circle of pain, avoidance and demoralization and relies heavily on behavioral assumptions about the process of chronicity. Patients are offered participation in progressive relaxation according to Jacobson, they learn to engage in pleasant activities, and are instructed to more and more maintain an upright body position during various activities of every day life. The study evaluates the outcome of the training. Moreover, as an algorithm for grading pain patients according to their level of chronicity has recently been developed by Gerbershagen, we use this algorithm in order to investigate the relationship between the outcome of treatment and the assigned level of chronicity. In addition, we test the assumption that a higher level of chronicity is related to a lower level of psychological functioning pre treatment. METHODS: 35 patients with a diagnosis of a chronic low back syndrome (Toronto classification) and 30 patients with a diagnosis of tension-type headache (IHS classification) have been recruited from six facilities specialized in the treatment of chronic pain patients. An average pain duration of 11 years indicates a long career as a pain patient. At the initial assessment, patients were assigned to three levels of chronicity according to the algorithm. Before and six month after completion of the program, they were asked to fill in a pain diary and well-established pain questionnaires with good psychometric properties under inclusion of pain intensity and control over pain (diary) as well as sensory and affective dimensions of pain, coping, self-instructions, disability, well-being and depression. RESULTS: Analyses of variance indicate a close relationship between a higher level of chronicity and a lower degree of psychological functioning. T-Tests for paired samples and Bonferroni correction show significant changes in the affective dimension of the pain experience, in coping styles and self-instructions, as well as in well-being, when follow-up data are compared with the initial values. This indicates a favorable outcome of the training. Analysis of covariance, on the other hand, demonstrate that the outcome does not depend on the level of chronicity at the first assessment. CONCLUSION: Irrespective of the initial pain grading of the patients the training program has proven to be effective with regard to different outcome measures.

English Abstract↗

PubMed1997

Effects of bifunctional netropsin-related minor groove-binding ligands on mammalian type I DNA topoisomerase.

We investigated the effects of compounds with two covalently linked netropsin moieties (bis-netropsin) on the function of mammalian type I DNA topoisomerase (topo I) in vitro. We initiated these studies because earlier studies had shown that certain bis-netropsins possess a several-fold higher antitumor and antiviral activity than netropsin. We confirmed that the parent compound netropsin, but not its bifunctional derivatives, induce supercoils in closed DNA. We determined that bis-netropsins inhibit the binding of topo I to DNA more efficiently than netropsin and that bis-netropsins but not netropsin induce specific DNA strand cleavage in the presence of topo I. We discuss a model explaining the different effects of netropsin and bis-netropsins on topo I.

Antineoplastic Agents↗

PubMed1997

Tumor cell endocytosis imaging facilitates delineation of the glioma-brain interface.

We describe a method for measuring tumor cell endocytosis in vivo and provide the anatomic correlate of this tumor cell function using a superparamagnetic and histologically detectable marker for cell uptake (MION). Rats (n = 22) were intrahemispherically implanted with a thymidine kinase (TK)-positive 9L gliosarcoma cell line, where TK served as the tumor marker. Twenty-four hours after intravenous injection of 10 mg Fe/kg of MION, rat brains were removed and underwent MR imaging ex vivo at near-microscopic resolution (isotropic voxel size of 86 microm, 9.4 T) prior to histologic processing. The imaging probe accumulated within tumor cells adjacent to the hyperpermeable tumor-brain interface including microscopic deposits and along finger-like invasions of the tumor into brain, facilitating the demarcation of the true histologic tumor border in three dimensions by MR microscopy. The method has potential research and clinical implications for delineating the tumor-brain interface prior to therapy and/or for providing a rational basis for imaging nanocolloid drug delivery to solid tumors.

Animals↗

PubMed1997

Does dysphoric mood really predict the outcome of lumbar surgery? Methodological pitfalls in psychological research.

This study investigates the relationship between depression and continuous pain after lumbar surgery by means of the Beck Depression Inventory (BDI). To assess the possibility that some somatic symptoms are confounded with pain, the items of the inventory were divided into a cognitive-affective and somatic subscale. Data analysis is based on two assumptions: (1) continuous pain after surgery is more closely related to the somatic subscale than to the cognitive-affective subscale of the BDI; and (2) postsurgical pain can be better predicted by the somatic than by the cognitive-affective subscale presurgery. The sample consisted of 61 patients with lumbar nucleotomy and 107 patients with lumbar spondylodesis. Treatment outcome was evaluated 6 months after surgery in the nucleotomy patients and 9 months after surgery in the spondylodesis patients. At follow-up, subjects conducted a pain diary over a period of 2 weeks. Correlational methodology was applied. Data analysis of both samples confirms the first assumption, whereas the second assumption is only partly confirmed. Only in the spondylodesis sample was pain intensity at follow-up predicted by the total BDI score. Regarding the subscales, the cognitive-affective scale, but not the somatic scale, was related to surgical outcome in this sample. The relationship between presurgical depression and pain at follow-up failed to reach statistical significance in the nucleotomy sample. It is concluded that lack of awareness of the confounding effects of somatic items in questionnaires for the assessment of mood may contribute to erroneous conclusions drawn from studies reported in the literature.

Journal Article↗

PubMed1997

[The revised WHO classification of brain tumors. Radiological aspects of 4 new tumor entities].

PURPOSE: Characterisation of the classification of brain tumours authorized by the WHO. METHOD OF APPRAISAL: This classification was revised and published in its second version. In the revision, some tumours were regrouped histogenetically and some tumour variants were added. Radiologically relevant changes of the classification include the differentiation of four new tumour entities that are easily distinguished by MR imaging. These four tumours belong to the group of childhood tumours or tumours occurring in early adulthood and are characterized by a good prognosis after extirpation. RESULTS OF APPRAISAL: Central neurocytomas are small-cyst ventricular tumours associated with the foramen of Monroi and show moderate contrast enhancement. Infantile desmoplastic gangliogliomas/astrocytomas commonly consist of a solid tumour portion related to the leptomeninges with pronounced contrast enhancement and a typically very large cyst. Pleomorphic xanthoastrocytomas are circumscribed cortical tumours and usually show very moderate gyriform enhancement with only slight signs of a mass effect. Dysembryoblastic neuroepithelial tumours, which originate in the cortical/ subcortical region, likewise show no mass effect; they are characterised by thickening of the cortex from surrounding dysplastic tissue and erosion of the calotte.

Adult↗

PubMed1997

Violence and severe mental disorder in clinical and community populations: the effects of psychotic symptoms, comorbidity, and lack of treatment.

This paper examines links between violent behavior, type and severity of psychopathology, substance abuse comorbidity, and community mental health treatment, using matched data from two surveys: the National Institute of Mental Health Epidemiologic Catchment Area project and the Triangle Mental Health Survey (a North Carolina study of adults with severe and persistent mental illness). Multivariate logistic regression analysis was used to model the risk of violent acts attributable to three domains of independent variables: sociodemographic characteristics, clinical diagnoses and symptomatology, and mental health services utilization. Findings include: (1) Symptom severity was significantly greater in the clinically-selected sample than in the community survey of respondents with comparable diagnoses who self-reported using mental health services; (2) Violence risk was related to psychoticism/agitation in a curvilinear form; (3) In a multivariable model, violence was significantly associated with substance abuse comorbidity, particular psychotic symptoms (perceived threat and loss of internal cognitive controls), and absence of recent contact with a community mental health provider; (4) The relationship between lack of treatment and higher odds of violence was less pronounced among respondents with substance abuse comorbidity; (5) When clinical and services-use variables were taken into account, sociodemographic predictors were not significantly related to violence.

Adult↗

PubMed1997

Hairpin polyamides that use parallel and antiparallel side-by-side peptide motifs in binding to DNA.

Pt-bis-netropsin is a synthetic sequence-specific DNA-binding ligand comprizing two netropsin-like fragments which are linked in a tail-to-tail manner via a cis-diammineplatinum (II) residue. The CD studies and thermodynamic characterization of the DNA-binding properties exhibited by this compound reveal that it forms two types of complexes with poly[d(AT)].poly[d(AT)] and DNA oligomers containing nucleotide sequences 5'-CC(TA)n CC-3', with n = 4, 5 and 6. The first type corresponds to the binding of Pt-bis-netropsin in the extended conformation and is characterized by the saturating ratio of one bound Pt-bis-netropsin molecule per 9 AT-base pairs. The second type of the complex corresponds to the binding of Pt-bis-netropsin to DNA in the folded hairpin form. The binding approaches saturation level when one Pt-bis-netropsin molecule is bound per four or five AT-base pairs. The hairpin form of Pt-bis-netropsin complex is built on the basis of parallel side-by-side peptide motif which is inserted in the minor DNA groove. The CD spectral profiles reflecting the binding of Pt-bis-netropsin in the hairpin form are different from those observed for binding of another bis-netropsin with the sequence Lys-Gly-Py-Py-Gly-Gly-Gly-Py-Py-Dp, where Py is a N-propylpyrrole amino acid residue and Dp is a dimethylaminopropylamino residue. The hairpin form of this bis-netropsin is formed on the basis of antiparallel side-by-side peptide motif. The CD spectra obtained for complexes of this polyamide in the hairpin form with poly[d(AT)].poly[d(AT)] exhibit positive CD band with a peak at 325 nm, whereas the CD spectral profiles for the second complex of Pt-bis-Nt with poly[d(AT)].poly[d(AT)] and short DNA oligomers have two intense positive CD bands near 290 nm and 328 nm. This reflects the fact that two bis-netropsins use different structural motifs on binding to DNA in the hairpin form.

Amino Acid Sequence↗

PubMed1997

DNA binding studies and influence on the activity of DNA topoisomerases of bis-netropsins: different effects of analogs containing cis and trans ethylene linkers.

Binding to DNA and synthetic duplex polymers of two bifunctional netropsins and effects on supercoiled plasmid DNA as well as their inhibitory potency on DNA topoisomerases have been investigated. Characteristic differences were found in the DNA binding properties of the two bis-netropsins containing a cis and trans tether as reflected by CD, thermal melting and sedimentation measurements. CD results indicate, that the bis-netropsins interact with DNA by a two-step binding mode depending on the ligand concentration. The trans bis-netropsin may form stable complexes with different DNA's at high salt concentration, whereas for cis bis-netropsin DNA complexes the second binding step is completely abolished. The variations in the DNA binding ability of trans and cis bis-netropsin show a close relationship to the differences observed in their inhibitory effects on DNA topoisomerases. It appeared that trans bis-netropsin more strongly blocks topoisomerase activity than the cis isomer and represents the most potent inhibitor of DNA gyrase. Differences in the DNA. binding ability of the bis-netropsins and their inhibitory potency on topoisomerase activity are explained in terms of bidentate and monodentate binding mode of the trans and cis isomer, respectively.

Binding, Competitive↗

PubMed1996

[Depressivity and successful outcome of spinal surgery].

INTRODUCTION: The relationship between depression and the outcome of low back surgery was investigated. Data analysis was based on two assumptions: (1) Presurgical assessments of depression are correlated with the outcome of surgery, and, therefore, depression can be interpreted as a risk factor for surgical failure. (2) Postsurgical assessments of depression are correlated with the outcome of surgery, and therefore, depression can be interpreted as a response to treatment failure. METHODS: The sample was made up of 78 patients who had undergone lumbar nucleotomy and 132 patients with lumbar spondylodesis. Treatment outcome was evaluated 6 months after surgery in the nucleotomy group and 9 months after surgery in the spondylodesis group. Depression was assessed with the Beck Depression Inventory (BDI). Measures of treatment outcome were an objective rating system for the surgical result, functional impairment, return to work, subjective estimations of the patient, and pain intensity. RESULTS: Presurgical depression scores showed no significant relationship with surgical outcome in nucleotomy patients. In spondylodesis patients, however, there was a significant negative correlation with the patients' subjective outcome ratings. Postsurgical depression scores, on the other hand, were significantly related to almost all of the outcome variables in both treatment groups. Patients with clinically relevant postsurgical depression scores were significantly more likely not to benefit sufficiently from surgery than those with clinically not relevant depression scores. DISCUSSION: Our findings favour assumption 2 over assumption. 1. In the light of our findings, depressiveness is interpreted as a response to a non-beneficial outcome of surgery. The need for an interdisciplinary approach combining psychological counseling or treatment and physical therapy for those patients who do not benefit from surgery is discussed.

English Abstract↗

PubMed1996

Parallel-stranded duplex DNA containing dA.dU base pairs.

DNA oligonucleotides with dA and dU residues can form duplexes with trans d(A.U) base pairing and the sugar-phosphate backbone in a parallel-stranded orientation, as previously established for oligonucleotides with d(A.T) base pairs. The properties of such parallel-stranded DNA (ps-DNA) 25-mer duplexes have been characterized by absorption (uv), CD, ir, and fluorescence spectroscopy, as well as by nuclease sensitivity. Comparisons were made with duplex molecules containing (a) dT in both strands, (b) dU in one strand and dT in the second, and (c) the same base combinations in reference antiparallel-stranded (aps) structures. Thermodynamic analysis revealed that total replacement of deoxythymine by deoxyuridine was accompanied by destabilization of the ps-helix (reduction in Tm by -13 degrees C in 2 mM MgCl2, 10 mM Na-cacodylate). The U-containing ps-helix (U1.U2) also melted 14 degrees C lower than the corresponding aps-helix under the same ionic conditions; this difference was very close to that observed between ps and aps duplexes with d(A.T) base pairs. Force field minimized structures of the various ps and aps duplexes with either d(A.T) or d(A.U) base pairs ps/aps and dT/dU combinations are presented. The energy-minimized helical parameters did not differ significantly between the DNAs containing dT and dU.

Base Composition↗

PubMed1996

Influence of minor groove binders on the eukaryotic topoisomerase II cleavage reaction with 41 base pair model oligonucleotides.

This report deals with the cleavage reaction of calf thymus (CT) topoisomerase II with oligonucleotides containing one main cleavage site and adjacent binding sites for minor groove binders. The sequences of the oligonucleotides were derived from a pBR 322 sequence, which contains one main topoisomerase II cleavage site. The cleavage reaction was performed under increasing concentrations of minor groove binders and it showed characteristic inhibition dependences of topoisomerase II to the binding sites and to the binding length of the minor groove binders. The extension of the minor groove binder length on DNA from 4 to 10 base pairs (bp) by netropsin and bis-netropsin, respectively, causes a strong increase of the topoisomerase II cleavage inhibition. The same is observed by the introduction of a second minor groove binder sequence symmetrically positioned around the topoisomerase II main cleavage site. The combination of two different minor groove binders can lead to an increased topoisomerase II inhibition but also to a prevention of total inhibition as shown with chromomycin A3 and distamycin A at concentrations of 0.1 and 0.25 microM, respectively.

Animals↗

PubMed1996

The detection of B-form/A-form junction in a deoxyribonucleotide duplex.

The transition of the 14-meric deoxyoligonucleotide duplex d-(ACCCCCTTTTTTTG).d-(CAAAAAAAGGGGGT) from the B- to the A-conformation in water/trifluorethanol (TFE) solution was studied with the use of circular dichroism. An increase in the fraction of TFE induces a two-step B-A transition. In the first step, up to 73% TFE, the A-form is generated from the GC-rich part; in the second step, 73-82% TFE, the AT-rich part shifts to the A-form. By this we suggest the existence of a B/A junction near 73% TFE. Emergence of the B/A junction has been directly confirmed with the use of distamycin A and netropsin, ligands known to selectively bind to AT stretches of B-DNA. It can be shown that both ligands suppress formation of the A-form in the B-philic part. The free energy value for the B/A junction was estimated to be 2.1 kcal/mol, which agrees well with known data for polymeric DNAs. The obtained results may have biological relevance in connection with recently published x-ray data about the occurrence of the B/A junction in the complex of DNA with reverse transcriptase of HIV.

Base Composition↗