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Biomedical subjects

B Schaefer

Publications and source records attributed to B Schaefer.

At least 19 recordsLinked to original sources
PubMed1997

Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: an EORTC early clinical studies group investigation.

BACKGROUND: JM216 is a new oral platinum complex with dose-limiting toxicity myelosuppression, now undergoing phase II evaluation. PATIENTS AND METHODS: JM216 was evaluated as first line therapy in non-small-cell lung cancer. Seventeen patients received 120 mg/m2/day for five days repeated every three weeks. RESULTS: Toxicity was manageable, the commonest side-effects being nausea, vomiting, diarrhoea, constipation and asthenia. Myelososuppression was generally grade < 2 and there were no cases of neutropenic sepsis or bleeding. Thirteen patients were fully evaluable for response. No sustained objective responses were reported. One patient was reported as stable disease had a partial response after three courses but was progressing again after four. An additional five patients had stable disease (46.2%). CONCLUSIONS: Although some patients may have had useful palliation, JM216 did not appear to have significant antitumour activity in non-small-cell lung cancer.

Administration, Oral↗
PubMed1997

[Effects of various feeding regimens in multiple trauma patients on septic complications and immune parameters].

OBJECTIVE: The aim of this study was to investigate the incidence of septic complications, the immunological changes by the course of lymphocyte subsets and metabolic parameters on polytraumatised patients when given nutritional support in form of early enteral and total parenteral nutrition. Furthermore, we looked for differences between a standard enteral diet and a diet supplemented with arginine, omega-3-fatty acids, nucleotide, and selenium. METHODS: 30 polytraumatised patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II)-Score > 10 points, who received nutritional support for a minimum of 7 days, were randomised to a "supplemented enteral group" (group 1), an "enteral standard group" (group 2), or a "parenteral group" (group 3). In the first both groups there were early enteral feeding. The patients of group 3 were fed isonitrogenous and isocaloric to group 2. Leucocytes, lymphocytes, CD3(+)-, CD4(+)-, CD3+HLA-DR(+)-, CD8(+)-, CD19(+)-subsets, natural killer-cells (CD56+) and metabolic parameters were measured on days 1, 3, 5, 7. RESULTS: Septic complications occurred in 2 patients in group 1, in 1 patient in group 2 and in 4 patients in group 3. The total number of lymphocytes had an increase on day 7 in group 1 (1420/microliter) and group 2 (1620/microliter) and were higher compared with group 3 (1044/microliter). On day 7 T-cells (CD3+) were 1107/microliter in group 1, 1014/microliter in group 2 and 770/microliter in group 3, T-helper-cells (CD4+) rose on day 7 higher in the enteral fed groups (group 1:746/microliter, group 2:719/microliter) than in group 3 (570/microliter). No significant differences between the groups were seen by CD3+HLA-DR(+)-cells, T-suppressor-cells (CD8+), B-cells (CD19+) and natural killer-cells (CD56). CONCLUSION: Early enteral nutrition seems to stabilise the immunosuppression of polytraumatised patients in an earlier phase. There is a consolidation of the lymphocyte counts, and of T(CD3+)- and T-helper-cells (CD4+). This could be the immunological correlate for the number of septic complications in the enteral fed groups. Therefore polytraumatised patients should be fed rather early enteral than parenteral when possible. In the initial phase after the trauma the way of nutritional support has more importance on the immune system as nutritional contents. So, in this form of studying, there is no advantage of immunonutrition.

APACHE↗
PubMed1997

Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.

PURPOSE: To assess activity and toxicity of topotecan in previously treated small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Patients with measurable SCLC, progressive after one first-line regimen, were eligible for the study. Two groups of patients were selected: (1) patients who failed first-line treatment < or = 3 months from chemotherapy discontinuation (refractory group); and (2) patients who responded to first-line treatment and progressed greater than 3 months after chemotherapy discontinuation (sensitive group). Topotecan was administered as a 30-minute daily infusion at a dose of 1.5 mg/m2 for 5 consecutive days, every 3 weeks. RESULTS: One hundred one patients were entered onto the study and 403 courses were administered. Ninety-two patients (47 refractory and 45 sensitive) were eligible and assessable for response. Among refractory patients, there were two partial responses (PRs) and one complete response (CR), for an overall response rate of 6.4% (95% confidence interval [CI], 1.3% to 17.6%), whereas in the sensitive group, there were 11 PRs and six CRs, for an overall response rate of 37.8% (95% CI, 23.8% to 53.5%). Overall median duration of response was 7.6 months. Median survival was 5.4 months; median survival of refractory patients was 4.7 months, whereas that of sensitive patients was 6.9 months (P = .002). Median survival of responding patients was 12.5 months. Toxicity was mainly hematologic. Leukopenia, although short-lived, was universal, with grade III and IV neutropenia occurring in 28% and 46.8% of cycles, respectively. Nonhematological toxicity was mild. Fatigue/malaise was reported in 39.3% of cycles and transient elevation of liver enzymes in 17%. CONCLUSION: Topotecan has significant activity in SCLC, particularly in patients sensitive to prior chemotherapy, with predictable and manageable toxicity. The incorporation of topotecan in combination chemotherapy regimens for future treatment of SCLC is warranted.

Aged↗
PubMed1996

Plasminogen activator inhibitor type-2 (PAI-2) in human keratinocytes regulates pericellular urokinase-type plasminogen activator.

Plasminogen activation is observed in the human epidermis during reepithelialization of epidermal defects and under certain pathological conditions. The activation reaction depends on keratinocyte-associated plasminogen activators (PAs), which convert the ubiquitous proenzyme plasminogen into the active trypsin-like serine proteinase plasmin. The PAs are controlled by PA inhibitors (PAIs), of which two major types are known: PAI-1 and PAI-2. In vitro and in vivo keratinocytes express both PAIs. In the current study, we have addressed the possible function of PAI-2 in regulating extracellular PA activity in cultured normal human epidermal keratinocytes (NHEK), the human keratinocyte cell line (HaCaT), and a Ha-ras transfected HaCaT variant (HaRas). PAI-2 was detected intracellularly in all three cell types. Whereas only the NHEK and the HaCaT cells secreted detectable levels of PAI-2 into the culture medium, all three cell types released urokinase-type PA (uPA) into the supernatants. When comparing HaCaT and HaRas cells, we found that the cell lines secreted comparable levels of uPA antigen, whereas the levels of uPA activity were low in the presence of PAI-2, indicating that PAI-2 serves to regulate uPA activity. This assumption was supported by the findings that PAI-2 formed complexes with secreted uPA and that uPA/PAI-2 complexes were present at the surface of the PAI-2-secreting HaCaT cells but not at the surface of PAI-2 nonsecreting HaRas cells. Finally, PAI-2 was found to counteract the uPA-dependent and plasmin-mediated detachment of cultured HaCaT cells. Taken together, our findings indicate that secreted PAI-2 serves to regulate the activity of extracellular uPA in keratinocytes.

Aprotinin↗
PubMed1996

Psychiatric disorders in candidates for surgery for epilepsy.

OBJECTIVE: To provide a descriptive analysis of the prevalence and pattern of psychiatric morbidity among 300 consecutive epileptic patients refractive to treatment and admitted during a six year period for evaluation of their candidature for surgery. METHODS: Patients underwent detailed observation of their seizure and standardised psychiatric assessment. Patients were considered to be refractory to treatment if they continued to manifest seizures with an average frequency of at least once every month even with polytherapy using up to three different anti-convulsants for a period of at least two years. Of the 300 patients, 231 had a temporal lobe focus, 43 had a non-temporal lobe focus, and 26 patients had a generalised and multifocal seizure onset. RESULTS AND CONCLUSIONS: With the DSM-III-R criteria 142 (47.3%) patients emerged as psychiatric cases. A principal axis I diagnosis was made in 88 (29.3%), and an axis II diagnosis (personality disorder) in another 54 (18.0%) patients. The most common axis I diagnosis was anxiety disorders (10.7%). A schizophrenia-like psychosis was seen in 13 (4.3%). Most patients with personality disorders showed dependent and avoidant personality traits. There was a significantly higher psychotic subscore on the present state examination in the temporal than with the non-temporal group of patients. These findings were not significant when compared with patients with a generalised and multifocal seizure disorder. There were no significant findings between the different seizure focus groups on the neurotic subscores. The findings with regard to laterality of seizure focus and the neurotic or psychotic subscores were not significant.

Adult↗
PubMed1995

Intracellular localization, vesicular accumulation and kinetics of daunorubicin in sensitive and multidrug-resistant gastric carcinoma EPG85-257 cells.

In the human gastric carcinoma cell line EPG85-257P (parent) induction of resistance to daunorubicin (DAU) was achieved by selection with stepwise increased concentrations of the drug. The new variant was named EPG85-257DAU and was shown to overexpress the mdr1 gene product 170 kDa P-glycoprotein (P-Gp) as demonstrated by immunocytochemistry and mdr1-specific RT-PCR. To investigate the intracellular pathway of DAU the subcellular distribution of this autofluorescent drug was studied in the resistant cells and compared to its chemosensitive counterpart EPG85-257P. When sensitive cells were exposed to DAU the drug rapidly accumulated in the nucleus until cell death. No redistribution of DAU to the cytoplasm was observed. In resistant cells exposed to the drug DAU also accumulated in the nucleus but to a lesser extent than in parent cells. Following exposure, nuclear fluorescence was observed to decrease over a time period of up to 48 h. Six hours after DAU exposure formation of fluorescent vesicle formation started in the perinuclear region and increased continuously. After 48 h nuclear fluorescence was no longer detectable and DAU was located exclusively in vesicles. During this period the vesicles moved from the region of origin to the cell periphery. A pulse chase experiment showed, that vesicles may contain DAU derived from the nucleus. Treatment of EPG85-257DAU cells with DAU in conjunction with the chemosensitizer cyclosporin A (CsA) increased nuclear fluorescence without impairing vesicle formation. Disruption of microtubules by nocodazole led to an accumulation of vesicles in the perinuclear region indicating that microtubules are involved in vesicular transport. Treatment of EPG85-257DAU cells with the actin disruptor cytochalasin B led to accumulation of vesicles in the cell periphery indicating that actin may be involved in exocytosis. Uptake and efflux of DAU and rhodamin (RH) were determined in sensitive and resistant cells using a fluorescence activated cell sorter. Uptake of both compounds was distinctly lower in resistant than in sensitive cells. When resistant cells preloaded for 2 h with RH subsequently were incubated in drug free medium the substance was rapidly released indicating transmembrane transport by P-Gp. In contrast, despite expression of P-Gp in resistant cells no considerable release of DAU was observed for up to 2 h under the same experimental protocol. This indicates that in resistant cells intracellular DAU at least in part may be inaccessible for P-Gp and that vesicular drug transport appears to contribute to DAU resistance by removing intracellular DAU via exocytosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Cell surface-bound urokinase-type plasminogen activator facilitates infiltration of freshly isolated granulocytes into fibrin matrix.

Human cell lines of myelo/monocytic origin express the cellular receptor for urokinase-type plasminogen activator (uPA-R). The receptor localizes urokinase-type plasminogen activator (uPA) to the surface of the cell, where it can convert plasminogen to the active serine proteinase plasmin. Plasmin may subsequently account for proteolysis of pericellular proteins. We demonstrated the expression of the uPA-R by freshly isolated neutrophilic granulocytes by using a specific mAb. In freshly isolated granulocytes we detected only a weak occupation of the uPA-R; further uPA binding by granulocytes was saturable and proceeded in a dose-dependent manner. Receptor-bound uPA retained its enzymatic activity. Saturation of isolated granulocytes with exogenous uPA enhanced cellular infiltration into a fibrin matrix in vitro. uPA-dependent infiltration was inhibited by an anti-catalytic monoclonal anti-uPA antibody. The findings show that circulating neutrophilic granulocytes express the cell surface uPA-R and suggest that surface-binding of uPA may facilitate the infiltration of granulocytes into a fibrin clot, a process that might add to thrombolysis in vivo.

Cell Movement↗
PubMed1995

Plasminogen activation by human keratinocytes: molecular pathways and cell-biological consequences.

Keratinocytes are the major cellular constituent of stratified epithelia. Defects in these epithelia are re-epithelialized by keratinocytes migrating from the edge of the defect into the wound. The cells form a monolayer with subsequent differentiation into a multilayered epithelium. It is thought that plasminogen activation by migrating keratinocytes is an important event during re-epithelialization. In the present report we summarize the studies on plasminogen activation by human keratinocytes in vitro and in vivo. Under the aspect of pericellular proteolysis the discussion is focused on the molecular mechanisms of plasminogen activation at the keratinocyte surface and on the cell-biological consequences of pericellular plasmin formation. We describe a cell surface-associated pathway of plasminogen activation which crucially depends on cell surface receptors for (pro)-uPA and plasmin(ogen). uPA bound to its receptor converts cell-bound plasminogen into the active protease plasmin. Compared to plasminogen activation in solution, activation at the keratinocyte cell surface is accelerated by a factor of approx. 7-10, and the plasmin generated and bound at the cell surface is protected against its specific inhibitor alpha 2-antiplasmin. Plasmin thus provided in the pericellular space leads to detachment of cultured keratinocytes from the growth substratum. Plasmin interferes with the adhesion of keratinocytes to fibrin, but not with the adhesion to collagen type I. By demonstrating that keratinocytes of the epithelial outgrowth in healing skin wounds express uPA and the uPA-R and that plasmin(ogen) is colocalized with uPA and/or uPA-R, indirect evidence is provided that this pathway may be operative in vivo. In view of previous findings that plasminogen activation is also observed under certain pathologic conditions in the epidermis, we conclude that plasminogen activation by keratinocytes is rather related to tissue damage and subsequent repair mechanisms than to a specific pathologic situation.

Fibrinolysin↗
PubMed1994

Secondary combined resistance to the multidrug-resistance-reversing activity of cyclosporin A in the cell line F4-6RADR-CsA.

Multidrug-resistant tumor cells can be resensitized by combined application of the selecting cytostatic drug and a chemosensitizer, such as cyclosporin A (CsA) or a calcium channel blocker. Since clinical trials on the circumvention of multidrug resistance (MDR) with chemosensitizers report disparate results, we investigated whether tumor cells of the MDR phenotype can develop additional resistance to the cytostatic chemosensitizer combination. Thus, the Adriamycin(ADR)-selected, P-glycoprotein-positive MDR Friend leukemia cell line F4-6RADR was exposed to stepwise increased concentrations of CsA at a constant level of 0.05 microgram/ml ADR. The initial CsA concentration (plus 0.05 microgram/ml ADR) to inhibit cell growth of F4-6RADR cells by 50% (IC50) was 0.04 microgram/ml. By continuous incubation for more than 6 months, the IC50 for CsA (at constant ADR) was elevated to 3.6 micrograms/ml (90-fold), thus generating the variant F4-6RADR-CsA. The F4-6RADR-CsA cells were cross-resistant for cyclosporin H (CsH), a non-immunosuppressive derivative of CsA. As shown by immunocytochemistry as well as by the polymerase chain reaction and by Western blotting including densitometry, P-glycoprotein was preserved in the F4-6RADR-CsA variant and was expressed at a 4-fold higher level than in F4-6RADR cells. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis could detect no new proteins in F4-6RADR-CsA as compared to F4-6RADR. Interestingly, resistance of F4-6RADR-CsA cells remained reversible for the calcium antagonists verapamil and dihydropyridine B859-35 (dexniguldipine-HCl), indicating that CsA and these compounds interfere with the P glycoprotein function by different pharmacodynamic mechanisms. Transport studies with [14C]ADR, performed in the presence and absence of chemosensitizers, confirmed the good correlation of P-glycoprotein function with the pattern of resistance found in proliferation assays. Cellular accumulation of [3H]cyclosporin was reduced to 71% of that of the F4-6 controls in F4-6RADR-CsA cells, but remained at the level of controls in F4-6RADR cells. Results indicate that increased amounts of the P-glycoprotein--besides other, perhaps more important mechanisms that are as yet unknown--partially mediate CsA resistance in F4-6RADR-CsA cells. We have designated this new form of resistance "secondary combined resistance" (SCR). The results suggest that at least some clinical cases of insensitivity to chemosensitizers or of relapse after reversing therapy could be explained by SCR, and that resensitizing treatment of tumor patients should be based on the consideration of several chemosensitizers of different pharmacodynamics.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

The influence of therapeutic self-disclosure on perceived marital intimacy.

This study examines the effect of therapeutic changes in a couple's self-disclosure behavior and its impact on their perception of their marital intimacy. Twenty couples participated in 10 weekly sessions of structured self-disclosure. The Self-Disclosure Coding System was used to rate audiotapes of the second and ninth sessions. Two rates, blind to treatment condition, demonstrated high interrater reliability on measures of changes in: 1) amount of self-disclosure; 2) whether self-references were positive, negative, or neutral; 3) depth of disclosures; and 4) rate of self-reference. Spouses, who were rated as disclosing in greater depth and referring to themselves in a more positive manner, perceived increased intimacy in their marriages as a consequence of therapy. The role of self-disclosure between spouses as a specific technique in marital therapy merits further study.

Female↗
PubMed1993

In vitro prediction of cytostatic drug resistance in primary cell cultures of solid malignant tumours.

The in vitro monolayer proliferation assay (MP-assay) described here enables predictive determination of the efficacy of anticancer drugs considered for clinical application. The assay was designed (1) to achieve a high plating efficiency, (2) to adapt in vitro growth as close as possible to in vivo conditions, and (3) to prove that the cells in vitro correspond with the in vivo tumour cells they were derived from. From 452 freshly explanted or biopsied tumours, 321 (71%) proliferating cultures could be established. To prove malignant origin of the incubated cells each strain was characterised by DNA-cytophotometry for aneuploidy and by immunocytochemistry for marker proteins. Drug potency was determined by comparing the number of living cells in drug-treated cultures with non-treated controls. Drug concentrations in vitro corresponded with those achievable in tumour tissue and thus represented clinically relevant levels. Growth inhibition in vitro was correlated with in vivo tumour response. Two hundred in vitro/in vivo correlations were performed (50 retrospective, 150 prospective). Overall predictive accuracy of the MP-assay was 86%, with correct indication of resistance in 94.5% and of sensitivity in 75.8% (P < 0.001). The results show that the proposed assay is capable of estimating the response probability of cytostatic drugs in individual tumours and thus can contribute to reducing the applications of non-effective drugs and, within limitations, to improving the basis of drug selection.

Antineoplastic Agents↗
PubMed1993

Adrenal gland weight and suicide.

The purpose of this study is to determine if there is an anatomical correlate, namely adrenal hypertrophy, among people who have committed suicide. The adrenal weights and other relevant information were collected prospectively from 118 consecutive coroner's cases of sudden death in the province of Ontario. No statistically significant difference was found between the adrenal weights of those who had committed suicide, whether violent or non violent, and those dying suddenly of causes not self-inflicted. This was true irrespective of the age of the subjects, their sex or the centre at which the autopsy was performed. This finding does not support the findings of an earlier report of increased adrenal weight in successful suicides. The incidental finding of increased adrenal weight in all subjects is of some significance.

Adrenal Glands↗
PubMed1992

Sexual abuse and psychiatric symptoms in an epileptic population.

One hundred and seven consecutive patients attending the outpatient epilepsy clinic at a teaching general hospital were assessed by clinical interview for a history of sexual abuse. Questionnaires dealing with overall psychiatric symptomatology i.e., (SCL-90), (TSC-40) and depression (ZSRDS) were also used. The majority of subjects were single (60%), living at home (76.6%) and had an average age of 29 years. The mean duration of epilepsy was 18.8 years and the seizures were controlled with medication in 65.2% of patients. Ten (9.3%) of the subjects had been sexually abused. This frequency of sexual abuse is lower than in the general population and among psychiatric patients. The specific form of sexual abuse consisted of sexual intercourse (n = 4), fondling (n = 4) and oral sex (n = 2). The sexually abused subjects had significantly higher scores on the anxiety subscale of the SCL-90 and depression score on the ZSRDS than non-abused subjects.

Adolescent↗