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Biomedical subjects

S Winter

Publications and source records attributed to S Winter.

At least 55 records · Page 3Linked to original sources
PubMed1999

Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity.

Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma.

Animals↗
PubMed1999

Using at least 5x10(6)/kg CD34+ cells for autologous stem cell transplantation significantly reduces febrile complications and use of antibiotics after transplantation.

For autologous stem cell transplantation, it is common practice to infuse at least 2 x 10(6)/kg CD34+ cells to ensure rapid engraftment. However it was recently claimed that increasing the threshold to 5 x 10(6)/kg leads to a faster platelet engraftment. To evaluate these threshold values in our patient population we undertook a retrospective analysis of 127 autologous transplants performed at our institution between 1992 and 1998. Diagnoses included Hodgkin's and non-Hodgkin's lymphoma, myeloma, acute leukaemias and solid tumours. The transplant was peripheral blood stem cells in 107 cases and CD34-selected peripheral blood stem cells in 20 cases. The median number of transplanted CD34+ cells was 3.2 x 10(6)/kg (range 0.64-25.9 x 10(6)/kg). Haematopoietic recovery to a neutrophil count >0.5 x 10(9)/l took a median of 10 (range 5-16) days from transplant. When comparing patients receiving at least 5 x 10(6)/kg and 2-5 x 10(6)/kg CD34+ cells we found a significant reduction in the median number of days with fever (1 vs 3.5 days, P = 0.0025), incidence of fever (78.8 vs 92.1%, P = 0.032) as well as duration of antibiotic treatment (7 vs 10 days, P = 0.038). This was paralleled by a faster neutrophil recovery to 0.5 x 10(9)/l (9 vs 10 days, P = 0.047). There was no significant difference in the number of platelet or red cell transfusions between the two groups. We conclude that transplantation with a stem cell dose of at least 5 x 10(6)/kg CD34+ cells reduces infectious complications and should thereby increase the safety of this type of therapy while reducing duration (and cost) of antibiotic therapy. The transplantation threshold should thus not remain at 2 x 10(6)/kg particularly in patients with a good stem cell mobilisation capacity.

Adolescent↗
PubMed1999

Molecular dynamics of labeled oligonucleotide probes used for the detection of point mutations in DNA.

The fluorescent label BODIPY 576-589 linked to the 5-end of an oligonucleotide via alkyl chain linkers can be used as a probe to detect point mutations in DNA. We have employed fluorescence anisotropy decay and dynamic fluorescence resonance energy transfer (FRET) in order to investigate the molecular origin of the fluorescence lifetime aberrations of BODIPY in the presence of a mismatched base. The results show that both, an increased flexibility of the alcyl chain linker to the BODIPY molecule as well as relaxation of the secondary structure of the whole complex, contribute to the decreased fluorescence lifetimes reported previously.

Base Pair Mismatch↗
PubMed1999

[Effect of hyperphosphorylation on structure of TAU protein].

Effect of hyperphosphorylation on structural properties and conformational stability of tau-protein was investigated by methods of circular dichroism and fluorescence decay. The normal protein displayed an unusual secondary structural elements--an extended left-handed helix. It is suggested that the structure of the normal tau-protein includes a globular C-terminal part with rigid extended tail, i.e., it is of a "tadpole" type. The normal protein structure is practically unaffected by changes in pH values. Hyperphosphorylation leads to some perturbation within the extended part of the protein molecule. Decrease in pH transforms the globular part of the hyperphosphorylated protein into the molten globule-like conformation.

Amino Acid Sequence↗
PubMed1999

[Affective, somatoform and anxiety disorders in Germany--initial results of an additional federal survey of "psychiatric disorders"].

BACKGROUND AND AIMS: The paper informs about methods and field survey procedures used in the German National Health Interview and Examination Survey--Mental Health Supplement (GHS-MHS)--and provides 12-month prevalence estimates of affective, anxiety and somatoform disorders in the general population. Such data have previously not been available for Germany on a nationwide level. METHODS: Findings are based on a two-stage design: In the first stage all the 7124 participants of the German National Health Interview and Examination Survey (core survey) completed the Composite International Diagnostic-Screener (CIDS) for mental disorders. In the second stage 4181 probands (all screen-positive and a random sample of 50% of the screen-negative subjects) were interviewed with the full Composite International Diagnostic Interview (DIA-X-M-CIDI) by clinical interviewers. The overall response rate was 87.6%. RESULTS: Affective (12-months prevalence estimate: 6.3%), anxiety (9%) and somatoform disorders (7.5%) are widespread in all age groups (18 to 65 years) of the German population; women are significantly more often affected than men. The prevalence rates of somatoform and affective disorders were found to be significantly lower in the former East German Länder as compared to the former West, whereas no such difference was found with regard to anxiety disorders. All disorders resulted in considerable reduction of work productivity during the past month; affective disorders reported on average 1.3 days/month total impairment and 7.2 days/month partial impairment, indicated significantly higher reduction in work productivity than anxiety and somatoform disorders. CONCLUSIONS: Affective, somatoform and anxiety disorders are highly prevalent mental disorders (total: 17.3%) in the German population. The result of a lower morbidity of affective and somatoform disorders in former East Germany was unexpected and requires further clarification. The findings on impairment of work productivity emphasize the economic impact of psychiatric disorders on society.

Adolescent↗
PubMed1999

Therapy of metabolic disorders with intravenous (IV) access ports and long term intravenous L-carnitine therapy.

With the expansion of newborn screening to include many organic acidurias and fatty acid oxidation defects, effective therapies of these disorders will be needed. Currently severe disorders such as methylmalonic and propionic aciduria. conventional therapy with diet and oral L-camitine often prove ineffective in preventing failure to thrive and recurrent metabolic decompensations. L-carnitine provides a natural pathway for removal of the toxic metabolites in these disorders and is life saving therapy but, with poor oral absorption (25%), it is difficult to supply adequate carnitine to meet the metabolic needs of these patients. Long term intravenous L-carnitine therapy, administered through a subcutaneous venous access port in 5 patients with organic acidurias [propionic aciduria (2), methylmalonic aciduria (2), 3 methylglutaconic aciduria(1)] resulted in improved growth, lower frequency of metabolic decompensations and increased tolerance of natural protein in the diet. An added benefit was the ability to initiate fluid. electrolytes, and antibiotics during metabolic decompensations at home thus averting hospitalizations.

Carnitine↗
PubMed1998

Hyperphosphorylation induces structural modification of tau-protein.

The effect of hyperphosphorylation on the structural properties and conformational stability of bovine tau-protein was studied by means of circular dichroism and fluorescence lifetime techniques. Normal protein contains unusual secondary structure elements: extended left-handed helices. The structure of this protein was assumed to be of a 'tadpole' type - a globular C-terminal part with a long and rigid tail included in the extended left-handed helix. Either a decrease or an increase of pH induced only minor changes of the normal tau-protein surface. Hyperphosphorylation affected the extended part of the protein molecule; the decrease of pH in this case induced considerable structural rearrangements, and the conformation of the C-terminal part of the protein molecule was transformed into a molten globule-like state.

Animals↗
PubMed1998

Self-association of 8-anilino-1-naphthalene-sulfonate molecules: spectroscopic characterization and application to the investigation of protein folding.

It was suggested long ago that the reason for the considerable increase of 8-anilino-1-naphthalene-sulfonate (8-ANS) fluorescence intensity upon the transition from aqueous to organic solvents is the dissociation of 8-ANS associates. To clarify this point the dependence of spectral properties of the dye on concentration and solvent composition was investigated by means of steady-state and time-resolved fluorescence spectroscopy. It was shown that the increase of 8-ANS concentration leads to the changes in the shape of absorption and fluorescence spectra of the dye, accompanied by the decrease in its fluorescence decay time values. Such changes were observed in aqueous and organic solvents for Mg2+- and NH+4-salts of 8-anilino-1-naphthalene-sulfonateic acid and reflect the existence of self-association of the dye molecules in both media. However, the decrease in fluorescence intensity induced by the self-association of the probe molecules is too small to explain weak fluorescence of 8-ANS in water. At the same time, it expounds the difference between the decay times of protein-embedded 8-ANS molecules upon interaction of this probe with native and molten globule proteins.

Anilino Naphthalenesulfonates↗
PubMed1998

Chemotherapy primes malignant glioma cells for CD95 ligand-induced apoptosis up-stream of caspase 3 activation.

The cytotoxic cytokine, CD95 ligand, is an experimental anti-cancer agent. Here, we describe a novel pathway of drug-mediated augmentation of CD95 ligand-induced apoptosis. We report that prolonged pre-exposure of human malignant glioma cells to different cytotoxic agents, VM26, cytarabine and cisplatin, induces strong sensitization to CD95 ligand-induced apoptosis. CD95 gene transfer does not prevent sensitization, suggesting that sensitization is not mediated by drug-induced CD95 expression. Priming with cytotoxic drugs greatly increases CD95 ligand-induced caspase 3 activity, indicating that the cytotoxic drugs positively modulate the CD95-dependent signalling cascade up-stream of caspase 3 activation.

Antineoplastic Agents↗
PubMed1998

Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression.

Teniposide (VM26) enhanced the anti-glioma activity of the cytotoxic cytokine, CD95 ligand. Synergy was observed at concentrations of teniposide that were insufficient for cleavable DNA topoisomerase II complex formation. CD95 ligand did not modulate the formation or removal of such complexes after teniposide treatment. These processes were also unaffected by ectopic expression of bcl-2. Teniposide enhanced CD95 expression in a glioma cell line with wild-type p53 (LN-229) but not in two p53 mutant cell lines (T98G, LN-308). Forced expression of a transdominant negative p53 mutant prevented the teniposide induced augmentation of CD95 expression in LN-229 cells but did not prevent the synergy of CD95 ligand and teniposide. Teniposide did not alter CD95 ligand expression, and forced expression of CD95 did not modulate sensitivity to VM26. Thus, teniposide-induced DNA lesions and alterations in CD95 or CD95 ligand are not necessary for teniposide-induced sensitization of human malignant glioma cells to CD95-mediated apoptosis.

Antineoplastic Agents, Phytogenic↗
PubMed1998

The topoisomerase I inhibitors, camptothecin and beta-lapachone, induce apoptosis of human retinal pigment epithelial cells.

The aim of the study was to determine whether the topoisomerase I inhibitors, camptothecin and beta-lapachone, are suitable agents for the adjuvant pharmacotherapy of proliferative vitreoretinopathy (PVR). The effects of the drugs on cultured human retinal pigment epithelial (RPE) cells were examined using growth assays, cytotoxicity assays, single cell agarose gel electrophoresis, in situ DNA end labeling and immunoblot analysis for apoptosis-regulatory proteins. Both agents killed RPE cells in a concentration-and time-dependent manner. Cell death was apoptotic as assessed by single cell agarose gel electrophoresis and in situ DNA end labeling. Camptothecin, but not beta-lapachone, induced accumulation of p53 and the major growth arrest-associated p53 response protein, p21. Both drugs enhanced expression of the proapoptotic BAX protein. Camptothecin, but not beta-lapachone, synergistically enhanced RPE cell apoptosis induced by the cytotoxic cytokine, CD95 ligand (CD95L). This effect was linked to camptothecin-induced inhibition of RNA synthesis. Atypical topoisomerase I inhibitors may be promising agents for the adjuvant pharmacotherapy of PVR. Experimental studies to assess possible ocular toxicity upon local administration and to confirm its therapeutic efficacy in an animal model of PVR are required.

Apoptosis↗
PubMed1998

Extracorporeal shock wave lithotripsy and glycosaminoglycans in urine.

In 50 calcium oxalate stone-forming patients, the total excretion of glycosaminoglycans (GAGs) and of four of its subgroups [chondroitin-4-sulfate (CS-A), chondroitin-6-sulfate (CS-C), dermatan sulfate (DS), and hyaluronic acid (HY)] were investigated before ESWL and on the following 5 days. The standard value was determined by reference to a group of healthy test subjects. The excretion of GAGs was significantly higher in healthy test persons than in stone-forming patients. Twenty-four hours after ESWL, GAG excretion increased significantly but returned to normal values in the course of three days. ESWL had no influence on the proportional composition of GAG subgroups CS-A, CS-C, DS and HY. The increase in GAG excretion after ESWL indicates a transient injury of renal tissue and of the mucous layer lining the urothelium, respectively. This lesion, however, can be regarded as temporary with restitutio ad integrum later.

Adult↗
PubMed1998

Favorable outcome of patients with relapsed or refractory Hodgkin's disease treated with high-dose chemotherapy and stem cell rescue at the time of maximal response to conventional salvage therapy (Dex-BEAM).

BACKGROUND: Disease status before high-dose chemotherapy with autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT) is an important predictor of transplantation-related toxicity and event-free survival (EFS) for patients with relapsed or refractory Hodgkin's disease (HD). We performed a phase II study in patients with relapsed or refractory HD to evaluate the feasibility of four cycles of Dexa-BEAM followed by high-dose chemotherapy with ABMT or PBSCT. PATIENTS AND METHODS: Twenty-six patients (median age 30, range 20-40 years) were treated with 2-4 courses of dexamethasone, carmustine, etoposide, cytarabine and melphalan (Dexa-BEAM) as salvage chemotherapy in order to attain maximal response. Patients achieving complete response (CR) or partial response (PR) received high-dose chemotherapy with ABMT or PBSCT. The conditioning regimen used was CVB (cyclophosphamide, carmustine, etoposide). RESULTS: Eighteen patients responded to Dexa-BEAM, resulting in a response rate of 69%. At the time of transplant 16 patients were in CR two patients in PR. At present 14 patients transplanted are in continuous CR (median follow-up 40 months, range 14-60 months). Two patients with PR after four courses of Dexa-BEAM relapsed and died three months posttransplantation. Two patients with CR at the time of transplant relapsed after nine and 13 months respectively. Eight patients had rapid progressive disease after 2-4 cycles of Dexa-BEAM. One patient with progressive disease died in gram-negative sepsis after four cycles of Dexa-BEAM. There was no transplantation-related death. CONCLUSION: These data suggests the use of high-dose chemotherapy followed by stem cell transplantation at the time of maximal response.

Adult↗
PubMed1998

Defective endothelially mediated pulmonary vasodilation in systemic sclerosis.

STUDY OBJECTIVES: Obliterative pulmonary vascular disease manifested clinically as pulmonary hypertension (PHT) may complicate systemic sclerosis (SSc). The aim of this study was to investigate possible endothelial dysfunction in patients with SSC complicated by PHT. DESIGN: Prospective, randomized trial. SETTING: Postgraduate teaching hospital. PATIENTS: Patients having SSc with PHT (SSc-PHT) and SSc without PHT (SSc), confirmed using Doppler echocardiography, and normal individuals (control subjects). INTERVENTIONS: I.v. infusion of the endothelially dependent vasodilator, substance P (maximum dose, 100 pmol/min), and the nonendothelially dependent vasodilator, adenosine (maximum dose, 0.05 mg/kg/min). MEASUREMENTS AND RESULTS: Effective pulmonary capillary blood flow (cardiac output minus right-to-left shunt) was measured in inert gas rebreathing, and calculated stroke index (SI) was used to reflect changes in pulmonary vascular resistance. During adenosine infusion, patients with SSc-PHT (n=5; mean age, 53+/-18 years) displayed a 25+/-16% increase in SI (p<0.05 compared with baseline), but no significant changes in SI were detected in the SSc (n=7; 54+/-6 years) or control (n=5; 35+/-5 years) groups. During infusion of substance P, SI rose by 32+/-18% in the control group at the maximum dose (p<0.05), but no change was observed in the SSc group. However, a fall in SI of -6+/-7% was detected in patients with SSc-PHT (p<0.05). CONCLUSIONS: Substance P-mediated pulmonary vasodilation is absent in patients with systemic sclerosis, suggesting that endothelial dysfunction occurs early in the course of the illness, but some responsiveness to adenosine remains.

Adenosine↗
PubMed1998

Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan involves inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression.

Topotecan is a novel topoisomerase I inhibitor that may have a role in the adjuvant chemotherapy of several solid tumors, including malignant glioma. Here, we have characterized the time- and concentration-dependent toxicity of topotecan in four human malignant glioma cell lines, LN-18, LN-229, LN-308 and T98G. High micromolar concentrations of topotecan, which are unlikely to be achieved in plasma in human patients in vivo, were cytotoxic within 48 hr, induced DNA fragmentation, did not induce major cell cycle changes, failed to consistently alter BCL-2 or BAX protein levels but inhibited RNA synthesis and induced cleavable DNA/topoisomerase I complex formation. Prolonged exposure for 72 hr to high nanomolar to low micromolar concentrations of topotecan augmented p21 protein levels and induced G2/M arrest but failed to consistently alter BCL-2 and BAX protein levels, did not induce significant DNA/topoisomerase I complex formation and did not inhibit RNA synthesis. Neither short-term nor long-term topotecan toxicity was blocked by ectopic expression of bcl-2 or wild-type p53. Transfer of a mutant p53 gene enhanced topotecan sensitivity in wild-type p53 LN-229 but not mutant p53 LN-18 cells. CD95 ligand (CD95L)-induced apoptosis was synergistically enhanced by short-term/high concentration but not long-term/low concentration exposure to topotecan, suggesting that topotecan sensitizes human malignant glioma cells to CD95L-induced apoptosis via inhibition of RNA synthesis. These data suggest that topotecan needs to be administered in high concentrations, such as an intratumoral polymer, to limit glioma cell growth in synergy with CD95L in vivo.

Animals↗
PubMed1997

Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone.

Beta-lapachone and camptothecin are structurally unrelated agents thought to inhibit topoisomerase-I activity through distinct mechanisms. We find that beta-lapachone is much more potent than camptothecin in inducing acute cytotoxic effects on human malignant glioma cells. Acute cytotoxicity induced by both drugs is apoptotic by electron microscopy, but not blocked by inhibitors of RNA or protein synthesis and not associated with changes in the expression of bcl-2, bax, p53, p21 or GADD45 proteins. In contrast, prolonged exposure of glioma cells to both drugs for 72 hr results in growth inhibition and apoptosis, with EC50 values around 1 microM. None of 7 glioma cell lines tested were resistant to either drug. LN-229 cells which have partial p53-wild-type activity show enhanced expression of p53, p21 and bax protein, whereas bcl-2 levels decrease, after exposure to camptothecin. In contrast, beta-lapachone increases bax protein expression in the absence of p53 activation. T98G cells are mutant for p53. In these cells, p53 levels do not change and p21 is not induced. bax accumulation in T98G cells is induced by both drugs, with bcl-2 levels unaltered. Surprisingly, ectopic expression of murine bcl-2 fails to abrogate the toxicity of either drug. Camptothecin, but not beta-lapachone, sensitizes human malignant glioma cells to apoptosis induced by the cytotoxic cytokines, tumor necrosis factor-alpha and CD95 ligand. Thus, both drugs have potent anti-glioma activity that may be mediated by enhanced bax expression but is not inhibited by ectopic bcl-2 expression. Camptothecin-like agents are particularly promising for immunochemotherapy of malignant glioma using cytotoxic drugs and CD95 ligand.

Apoptosis↗
PubMed1997

Fluorescence and binding properties of phenazine derivatives in complexes with polynucleotides of various base compositions and secondary structures.

The interactions of two phenazine derivatives, one with a neutral chromophore (glycoside) and the other with a cationic one (quaternary salt), with various synthetic single- and double-stranded polynucleotides and natural DNA were studied by fluorescence techniques, conducting measurements of steady-state fluorescence intensity and polarization degree as well as fluorescence lifetime. These dyes show fluorescence quenching upon intercalation into the GC sequences of the double-stranded nucleic acids and an increase in fluorescence emission and lifetime upon incorporation into the AT and AU sequences. GC base pairs in continuous deoxynucleotide sequences were found to be preferred as binding sites for both phenazines, in contrast to AT base pairs. On the contrary, the continuous ribonucleotide GC sequence binds the phenazines more weakly than does the AU sequence. With regard to the interaction of the phenazines with single-stranded polynucleotides, a stacking interaction of the dye chromophores with the nucleic bases was observed. In that case the guanine residue quenches the cationic phenazine fluorescence, while the stacking interaction with the other bases results in an increase in the fluorescence quantum yield. Unlike the cationic dye, the fluorescence of the neutral phenazine was quenched by both purine bases.

Journal Article↗