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  • Electronic Resource  (199)
  • 2000-2004  (199)
  • breast cancer  (140)
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  • Electronic Resource  (199)
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  • 1
    Electronic Resource
    Electronic Resource
    ras p21 isoprenylation inhibition induces flat colon tumors in Wistar rats (2000)
    Springer
    Diseases of the colon & rectum 43 (2000), S. 70-75 
    Details
    ISSN: 1530-0358
    Keywords: Pravastatin ; ras p21 isoprenylation ; Colon carcinogenesis ; Flat colon tumor ; Azoxymethane ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: The effect of pravastatin, an inhibitor ofras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associatedras p21 in colon tumors. CONCLUSIONS: These findings suggest that theras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02237247
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  • 2
    Electronic Resource
    Electronic Resource
    Development of the bones and synovial joints in the rat model of the VATER association (2000)
    Springer
    Journal of orthopaedic science 5 (2000), S. 390-396 
    Details
    ISSN: 1436-2023
    Keywords: Key words Adriamycin ; Rat ; Embryo ; VATER association ; Synovial joint ; Bones ; Limbs ; Vertebra ; Sirenomelia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The adriamycin-induced rat model of the Vertebral, Anorectal, Tracheo-Esophageal, Radial and Renal (VATER) association produces a variety of vertebral, rib, and limb abnormalities. This study was designed to document accurately the nature of these abnormalities and to determine whether synovial joints are affected. Fetuses from pregnant Sprague Dawley rats that had received intraperitoneal injections of 1.75 mg/kg of adriamycin on days 6–9 or 10–13 of gestation were harvested. Double-stained skeletal preparations and histological sections were examined for vertebral, rib, and limb anomalies. The incidence of anomalies was high in the group treated on gestational days (GD) 6–9, while it was low in the GD 10–13 group. The length and thickness of the long bones were reduced, with bowing and reduction in their endochondral ossification. Sirenomelia occurred in the group treated on GD 6–9, and was often associated with a short tail and anal atresia. The joint cavities, and intra-articular structures such as menisci and the cruciate ligaments developed normally from the mesenchymal interzone. These data indicate that adriamycin inhibits skeletal growth and differentiation without any interference in the differentiation of the mesenchymal interzone, thus producing normal synovial joints.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s007760050015
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  • 3
    Electronic Resource
    Electronic Resource
    Identification of High-Risk Breast Cancer Patients from Genetic Changes of Their Tumors (2000)
    Springer
    Surgery today 30 (2000), S. 516-522 
    Details
    ISSN: 1436-2813
    Keywords: Key Words: genetic changes ; prognostic factor ; breast cancer ; amplification ; loss of heterozygosity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: ERBB2 , INT2, and MYC genes, in 131 patients with breast carcinoma, 49 of whom had lymph node involvement, but none of whom had distant metastases. Among the several chromosome arms tested, LOH at 17q was correlated with lymph node metastasis. Amplification of the ERBB2, MYC, and INT2 genes was found more frequently in tumors from patients with lymph node metastases than in tumors from those without lymph node metastases. Univariate analysis demonstrated that LOH at 17q and INT2 amplification were factors influencing disease-free survival (DFS). A multivariate analysis was performed on 89 tumors that were able to be evaluated for both LOH at 17q and INT2 amplification, and the results showed that patients who had tumors with these genetic changes were more likely to have a poor prognosis. The findings of this study suggest that investigating genetic changes, in addition to conventional clinicopathologic factors, may contribute to defining groups of breast cancer patients with differences in prognosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005950070118
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  • 4
    Electronic Resource
    Electronic Resource
    Induction of adenocarcinoma containing myoepithelial cells in rat submandibular gland by 7,12-dimethylbenz(a)anthracene (2000)
    Springer
    Virchows Archiv 437 (2000), S. 314-324 
    Details
    ISSN: 1432-2307
    Keywords: Keywords 7 ; 12-dimethylbenz(a)anthracene ; Rat ; Submandibular gland ; Adenocarcinoma Myoepithelial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In an attempt to induce adenocarcinoma containing myoepithelial cells (MECs) in the rat submandibular gland, we injected 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in acetone into the glands of rat pups at the age of 10 days. In both male and female pups, the glands, including their developing terminal secretory units, contained far greater numbers of cells positive for proliferating cell nuclear antigen (PCNA) than did adult glands. A single administration of 1% DMBA (0.05 ml/130 g b.w.) did not produce adenocarcinoma, but did induce occasional sarcomas, such as rhabdomyosarcoma and fibrosarcoma, in 2 months. Most glands regenerated with minimal scar formation. Microscopically, these glands were atypical in that they contained increased numbers of PCNA-positive cells, underdeveloped granular ducts, and striated ducts surrounded by MECs positive for alpha smooth muscle actin (αSMA). Though these features were also observed in the regenerated glands after acetone injection, the number of PCNA-positive cells was relatively high in the glands of DMBA-treated females, especially in the terminal secretory unit. The second DMBA injection at 10 weeks of age produced adenocarcinoma made up of αSMA-positive MECs and keratin 19-positive duct cells. Such MEC-associated adenocarcinoma was induced in the glands of more than half the female but not the male animals. Replacement of either of the double DMBA treatments with acetone, or DMBA treatment, single or double, of adult glands did not produce adenocarcinoma, but did produce sarcoma and squamous cell carcinoma. These results suggest that (1) at least two genetic mutations are necessary for induction of adenocarcinoma with MECs in the rat submandibular gland, (2) the mutation is efficiently introduced to pup glands whose terminal secretory units exhibit extreme proliferative activity, and (3) the second mutation is difficult to introduce in male glands, whose proliferative activity is relatively low, and/or transformed cells need some female hormone after the mutation to propagate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280000223
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  • 5
    Electronic Resource
    Electronic Resource
    Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome (2000)
    Springer
    Annals of oncology 11 (2000), S. 307-313 
    Details
    ISSN: 1569-8041
    Keywords: BRCA1 ; breast cancer ; p53 ; survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The association between BRCA1 germ-linemutations and breast cancer prognosis is controversial. A historical cohortstudy was designed to determine the prognosis for women with axillary lymphnode negative hereditary breast cancer. Patients and methods:We tested pathology blocks from 118Ashkenazi Jewish women with axillary lymph node negative breast cancer for thepresence of the two common BRCA1 founder mutations, 185delAG and5382insC. Patients were followed up for a median of 76 months. SomaticTP53mutations were screened for by immunohistochemistry, and directsequencing was performed in the BRCA1-positive tumours. Results:Sixteen breast cancer blocks (13.6%) carried aBRCA1 mutation. Young age of onset, high nuclear grade, negativeestrogen receptor status and over-expression of p53 were highly associatedwith BRCA1-positive status (P-values all 〈0.01).BRCA1 mutation carriers had a higher mortality than non-carriers(five-year overall survival, 50% and 89.6%, respectively,P = 0.0001). Young age of onset, estrogen receptor negative status,nuclear grade 3, and over-expression of p53 also predicted a poor outcome. Coxmultivariate analyses showed that only germ-line BRCA1 mutationstatus was an independent prognostic factor for overall survival (P= 0.01). Among nuclear grade 3 tumours, the BRCA1 mutation carrierstatus was a significant prognostic factor of death (risk ratio 5.8,95% confidence interval: 1.5–22, P = 0.009). Sequencingof BRCA1-related breast cancers revealed one TP53missensemutation not previously reported in breast cancer. Conclusions:Using a historical cohort approach, we haveidentified BRCA1 mutation status as an independent prognostic factorfor node negative breast cancer among the Ashkenazi Jewish women. Thosemanaging women carrying a BRCA1 mutation may need take these findingsinto consideration. Additionally, our preliminary results, taken together withthe work of others suggest a different carcinogenic pathway inBRCA1-related breast cancer, compared to non-hereditary cases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008340723974
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  • 6
    Electronic Resource
    Electronic Resource
    The contribution of molecular markers to the prediction of response in the treatment of breast cancer: A review of the literature on HER-2, p53and BCL-2 (2000)
    Springer
    Annals of oncology 11 (2000), S. 647-663 
    Details
    ISSN: 1569-8041
    Keywords: BCL-2 ; breast cancer ; HER-2 ; p53 ; predictive factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The selection of therapies for breast cancer is todaybased on prognostic features (chemotherapy, radiotherapy), hormone receptorstatus (hormonal therapy) and HER-2 status (trastuzumab therapy). HER-2,p53and BCL-2are tumour-related proteins that have thepotential to further improve individualisation of patient management, bypredicting response to chemotherapy, hormonal therapy and radiotherapy. Materials and methods:This paper reviews the rationale for theuse of these proteins as predictive factors, as well as the publishedliterature addressing the use of each one to predict response to hormonaltherapy, chemotherapy and radiotherapy. Results:HER-2, p53and BCL-2remaininadequately assessed as predictive factors in breast cancer. HER-2 evaluationis required for the selection of patients for trastuzumab (Herceptin®)therapy, as trials of this therapy have been limited to HER-2 overexpressors.HER-2 overexpression may be predictive of resistance to hormonal therapy.Anthracyclines are effective therapy for breast cancer regardless of HER-2status, but patients whose tumours overexpress HER-2 appear to receive thegreatest relative benefit from this therapy. Studies of HER-2 as a predictorof response to CMF and to radiotherapy are inconclusive at this time. No datayet exist to support the use of p53or BCL-2as predictivefactors in the therapy of breast cancer. Conclusions:At this point in time, there is inadequate evidenceto support the use of HER-2, p53or BCL-2to guide theselection of hormonal therapy, chemotherapy or radiotherapy for breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008390429428
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  • 7
    Electronic Resource
    Electronic Resource
    Activity and toxicity of GI147211 in breast, colorectal and non-small-cell lung cancer patients: An EORTC–ECSG phase II clinical study (2000)
    Springer
    Annals of oncology 11 (2000), S. 793-797 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; camptothecins ; colorectal cancer ; GI147211 ; non-small-cell lung cancer ; topoisomerase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:GI147211 is a water-soluble synthetic analogue ofcamptothecin showing promising in vivoand in vitroantitumor activity and an acceptable toxicity profile. Patients and methods:Between April 1995 and November 1996, 67eligible patients with pretreated breast cancer (25 patients) andchemo-naïve colorectal (19 patients) and non-small-cell lung cancer (23patients) were entered into three multicentric, non-randomized phase IItrials. Treatment schedule consisted of intravenous GI147211 administered ata dose of 1.2 mg/m2/day for five consecutive days every threeweeks. Results:Hematological toxicity was common with grade 3–4neutropenia in 54% of patients and neutropenic fever together or notassociated with infection in 14.5% of patients. Grade 3–4thrombocytopenia and grade 2–4 anemia were observed in 20% andin 68% of patients, respectively. Non-hematological toxicity wasgenerally mild to moderate and consisted mainly of gastrointestinal toxicity,asthenia and alopecia. A dose-escalation to 1.5 mg/m2/d wasfeasible in 17 (25%) patients. The antitumor activity of GI147211 wasmoderate in breast cancer patients (3 partial responses (PRs), response rate(RR) 13%) and minimal in non-small cell lung cancer patients (2 PRs,RR 9%). No objective responses were obtained in colorectal patients. Conclusions:GI147211, at the dose and schedule employed in thisstudy, showed an acceptable safety profile but a modest antitumor activity inthe examined tumor types.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008373031714
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  • 8
    Electronic Resource
    Electronic Resource
    An Analysis of Unicellular Mass Transfer Using a Microfabricated Experimental Technique (2000)
    Springer
    Biomedical microdevices 2 (2000), S. 305-316 
    Details
    ISSN: 1572-8781
    Keywords: membranes ; breast cancer ; oncology ; cell column regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract Using microfabrication technology, we have developed a new experimental apparatus and technique which allow isolation of individual cells and which facilitate the study of kinetic volume changes and membrane permeability. The key component of the apparatus is a microdiffusion chamber which was constructed using silicon microfabrication technology and standard photolithography. The central unit of the chamber is a 1 μ m thick silicon nitride membrane with a center hole on the order of 2–3 μ m in diameter. The device is novel in its analysis of a single cell, instead of the traditional array of cells, and its avoidance of the damage artifacts and computational difficulties which are inherent in other, commonly used methods of cellular analysis. The device is used in conjunction with a predictive computer model which simulates the response of the entire membrane or a portion of the membrane to various permeant and impermeant concentrations. This study introduces the apparatus and the model, and illustrates the effectiveness of the new procedure by determining several membrane permeability coefficients for HBL-100 (healthy human breast line). The empirical data and theoretical data were combined to yield a water permability (L p) of 1.1 ± 0.5μ m/(min-atm) (mean ± 1 standard deviation) (N= 5) during the uncoupled transport of water at 22 ±C. In the presence of 6 M glycerol, the water permeability (L p), permeability coefficient (P S), and the reflection coefficient (σS) were determined to be 2.0 ± 0.63 μ m/(min-atm), 2.7E-5 ± 6.1E-6 cm-sec-1, and 0.76 ± 0.5 (N = 6). No previous values of these coefficients could be found for HBL-100 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009959323022
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  • 9
    Electronic Resource
    Electronic Resource
    Comparative study of clinical, pathological and biological characteristics of symptomatic versus asymptomatic breast cancers (2000)
    Springer
    Annals of oncology 11 (2000), S. 581-586 
    Details
    ISSN: 1569-8041
    Keywords: biological/pathological characteristics ; breast cancer ; prognosis ; progression ; symptomatic/asymptomatic patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:It is well known that mammographic screening reducesbreast cancer mortality. One possible explanation for this effect is thatscreening makes it possible to detect smaller breast cancers with fewerinvolved nodes, but another hypothesis is that some screening-detected tumorsare in a pathologically and biologically different phase of evolution fromthose that are detected clinically. The aim of the present study was tocompare the biological, pathological and clinical characteristics ofsymptomatic vs. asymptomatic breast cancers. Patients and methods:The study considers a series of 1916consecutive patients who underwent surgery for stage I and II infiltratingbreast cancer at Verona hospitals after having undergone ultrasound andmammography (at least one of which was positive). They were divided into twogroups on the basis of why they decided to undergo the imaging examinations:group A refers to the 1247 patients with a palpable lump, and group B to the616 who were asymptomatic. Results:The patients in group A were older, and had larger tumorsand a higher percentage of positive nodes than those in group B; they also hadsignificantly higher grade tumors, higher Ki-67 levels, and a higherpercentage of ER and PgR negative and c-erbB-2 positive tumors (allof the P-values were significant). A logistic regression analysisadjusted for tumor diameter and age showed a reduction in the significance ofeach of the considered variables, but all of them remained significantlyassociated with the modality of diagnosis except ER, PgR andc-erbB-2. Conclusions:Our results suggest that asymptomatic tumors arebiologically different from their clinically presenting counterparts, thusconfirming the hypothesis that progression towards greater malignancy mayoccur during the natural history of breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008320317114
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  • 10
    Electronic Resource
    Electronic Resource
    Combined 4-hydroxy-ifosfamide and vinorelbine treatment in established and primary human breast cell cultures (2000)
    Springer
    Annals of oncology 11 (2000), S. 587-594 
    Details
    ISSN: 1569-8041
    Keywords: 4-OH-IF ; breast cancer ; drug combination ; human cell lines ; primary cultures ; VNB
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Vinorelbine and ifosfamide are active drugs againstbreast cancer, but the best treatment schedule has yet to be defined bypreclinical or clinical studies. The antitumor activity of4-hydroxy-ifosfamide (4-OH-IF), the active form of ifosfamide, and vinorelbine(VNB) and their interaction were investigated in two established breast cancercell lines (MCF-7 and BRC-230) and in 10 primary breast cancer cultures. Materials and methods:Cytotoxic activity was evaluated by ahighly efficient clonogenic assay (HECA). The median-effect principle wasapplied to evaluate synergistic and antagonistic interactions and thecorresponding combination index values were calculated. Cell cycleperturbations were analysed by flow cytometry. Results:In MCF-7 and BRC-230 cell lines the sequence VNB for 4hours followed by 4-OH-IF for 24 hours produced an antagonistic effect.Conversely, the inverse sequential scheme, 4-OH-IF → VNB providedsynergistic effects on both cell lines. The synergism was associated with astrong block in the G2-M phase. Synergistic activity of 4-OH-IF → VNBsequence was confirmed in 7 of 10 primary breast cancercultures. Conclusions:In conclusion, the sequence 4-OH-IF → VNBappeared to be the most effective scheme both in established cell lines andin primary breast cancer cultures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008340902093
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  • 11
    Electronic Resource
    Electronic Resource
    Delayed adjuvant tamoxifen: Ten-year results of a collaborative randomized controlled trial in early breast cancer (TAM-02 trial) (2000)
    Springer
    Annals of oncology 11 (2000), S. 515-519 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant treatment ; breast cancer ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aim:Immediate adjuvant tamoxifen reduces disease recurrence andimproves survival in patients with early breast cancer. However, is it toolate to administer tamoxifen to patients who have already undergone treatment,but were unable to benefit from this adjuvant therapy? The French NationalCancer Centers (FNCLCC) have investigated the efficacy of delayed tamoxifenadministration in a randomized controlled trial. Patients and methods:From September 1986 to October 1989, womenwith primary breast cancer, who had undergone surgery, radiotherapy, and/orreceived adjuvant chemotherapy but not hormone therapy more than two yearsearlier, were randomized to receive either 30 mg/day tamoxifen or notreatment. The 10-year disease-free and overall survival rates of the twogroups of patients and of various subgroups were determined according to theKaplan–Meyer method and compared by the log-rank test. Results:This intention-to-treat analysis comprised 250 women inthe tamoxifen group and 244 in the control group. Patient characteristics(age, T stage, number of positive nodes, receptor status, and interval sincetumor treatment) were comparable in both groups. Delayed adjuvant tamoxifensignificantly improved overall survival only in node-positive patients and inpatients with estrogen receptor-positive (ER+) or progesteronereceptor-positive (PR+) tumors. Disease-free survival, however, wassignificantly improved in the global population and in several patientsubgroups (node-positive, ER+, PR+). Patients in whom the interval betweenprimary treatment and delayed adjuvant tamoxifen was greater than five yearsalso had significantly improved disease-free survival. Conclusions:Overall and disease-free survival results indicatethat delayed adjuvant tamoxifen administration (30 mg/day) is justified inwomen with early breast cancer, even if this treatment is initiated two ormore years after primary treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008321415065
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  • 12
    Electronic Resource
    Electronic Resource
    Tumor lysis syndrome following hemi-body irradiation for metastatic breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 1349-1351 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; radiotherapy ; tumor lysis syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tumor lysis syndrome (TLS) is a rare serious acute complication of cancertherapy, reported mainly following chemotherapy in patients with large tumorload and chemosensitive disease. These are mainly patients with non-Hodgkin'slymphoma, leukemia and rarely in solid tumors. It is less frequently describedafter radiotherapy for lymphoid and hematological malignancies. TLS followingradiotherapy for solid tumors is a very rare complication. In thisreport/review we describe a seventy-three-year-old male patient withprogressive metastatic carcinoma of the breast to the lungs, liver and bone.He was referred for radiotherapy because of generalized bony pains. Thepatient was planned for sequential hemi-body irradiation starting with themore symptomatic upper half body. After premedication, he was given 8.5 Gy tothe mid point at the maximum chest separation with anterior lung attenuatorlimiting uncorrected lung dose to 6.15 Gy. A further 3.5 Gy electron boost tothe fungating breast tumor was given to the 100%. Forty-eight hours after irradiation he developed hyperkalemia,hyperphosphatemia, hyperuricemia, hypocalcemia and renal failure. Theseclinical and biochemical changes are typical of tumor lysis syndrome (TLS).Despite hydration, and treating the hyperuricemia, the patient developed comaand died eight days after irradiation. The prophylaxis and management of TLS and in high-risk patients aredescribed to avoid this frequently fatal complication.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008347226743
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  • 13
    Electronic Resource
    Electronic Resource
    ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 1545-1550 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; erbB2 ; HER-2/neu ; tamoxifen ; therapy resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aim:We aimed to study the importance of erbB2 status in earlystage postmenopausal breast cancer for patients who participated in a trialof five vs. two years of adjuvant tamoxifen. Patients and methods:We analysed the erbB2 status of the tumoursfrom 577 patients participating in the trial, either by a DNA amplificationassay (n = 181) or by measurement of the protein level with flowcytometry (n = 396). Results:ErbB2 was overexpressed or gene amplified in 102 of thepatients (18%). Overall, erbB2-positive patients had a significantlylower recurrence-free probability than others, 62% at five years ascompared to 83%, and showed a significantly decreased breast cancersurvival rate (P = 0.0007). ErbB2 status was significantlyassociated with recurrence and death in Cox multivariate analysis, adjustingfor nodal status, tumour size and estrogen receptor status. The relative riskof recurrence (RR) for five vs. two years of tamoxifen was analysed inrelation to erbB2 status for patients still disease-free two years aftersurgery. Whereas erbB2-negative patients showed significant benefit fromprolonged treatment (RR = 0.62, 95% confidence interval (95%CI): 0.42–0.93), no benefit was evident for erbB2-positive patients (RR= 1.1, 95% CI: 0.41–3.2). When the same analysis was restrictedto ER-positive patients a similar difference in relative hazard was obtainedbut the difference was not strictly significant (P = 0.065). Conclusions:For early stage breast cancer patients treated withadjuvant tamoxifen, overexpression of erbB2 is an independent marker of poorprognosis. The results suggest that overexpression decreases the benefit fromprolonged tamoxifen treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008313310474
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  • 14
    Electronic Resource
    Electronic Resource
    Dose-finding study of oral idarubicin and cyclophosphamide in first-line treatment of elderly patients with metastatic breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 229-230 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; cyclophosphamide ; elderly ; idarubicin ; oral chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008384820279
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  • 15
    Electronic Resource
    Electronic Resource
    A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 169-175 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant therapy ; breast cancer ; docetaxel ; feasibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background and purpose:Docetaxel is an active agent in thetreatment of metastatic breast cancer. We evaluated the feasibility ofdocetaxel-based sequential and combination regimens as adjuvant therapies forpatients with node-positive breast cancer. Patients and methods:Three consecutive groups of patients withnode-positive breast cancer or locally-advanced disease, aged ≤70 years,received one of the following regimens: a) sequential A → T → CMF:doxorubicin 75 mg/m2 q 3 weeks × 3, followed by docetaxel 100mg/m2 q 3 weeks × 3, followed by i.v. CMF days 1 + 8 q 4weeks × 3; b) sequential accelerated A → T → CMF: A and T wereadministered at the same doses q 2 weeks; c) combination therapy: doxorubicin50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks × 4,followed by CMF × 4. When indicated, radiotherapy was administeredduring or after CMF, and tamoxifen started after the end of CMF. Results:Seventy-nine patients have been treated. Median age was48 years. A 30% rate of early treatment discontinuation was observedin patients receiving the sequential accelerated therapy (23% duringA → T), due principally to severe skin toxicity. Median relativedose-intensity was 100% in the three treatment arms. The incidence ofG3–G4 major toxicities by treated patients, was as follows: skintoxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%;b: 20%; c: 3%. The incidence of neutropenic fever was a:30%; b: 13%; c: 48%. After a median follow-up of 18months, no late toxicity has been reported. Conclusions:The accelerated sequential A → T → CMFtreatment is not feasible due to an excess of skin toxicity. The sequentialnon accelerated and the combination regimens are feasible and under evaluationin a phase III trial of adjuvant therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008345432342
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  • 16
    Electronic Resource
    Electronic Resource
    Myocardial enzyme activities in plasma after whole-heart irradiation in rats (2000)
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 27-32 
    Details
    ISSN: 1432-1335
    Keywords: Key words Heart irradiation ; Plasma enzyme levels ; Myocardial enzyme levels ; Rat ; AbbreviationsCK creatine kinase ; LDH lactate de-hydrogenase ; AST aspartate aminotransferase ; ALT alanine aminotransferase ; α-HBDHα-hydroxybutyrate dehydrogenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after radiotherapy. Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and α-hydroxybutyrate dehydrogenase (α-HBDH) were determined in the plasma and left ventricular myocardium of rats following local heart irradiation with a single dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and to reduce survival times of the animals. Cardiac enzyme assays were performed directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH, AST and α-HBDH levels were increased between 2 h and 24 h after irradiation. Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between 24 h and 16 days after radiation, did not differ between irradiated and control animals, although acute (first 12 h) reductions were observed in the irradiated group. The elevated enzyme levels in plasma appeared to correlate with the acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20 Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that fractionated radiation, as applied clinically for treatment of solid tumors, will induce plasma enzyme elevations that are large enough to indicate the extent of cardiac damage occurring acutely or chronically.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008461
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  • 17
    Electronic Resource
    Electronic Resource
    Decreased expression of vascular endothelial growth factor in glomeruli of puromycin aminonucleoside nephrosis (2000)
    Springer
    Clinical and experimental nephrology 4 (2000), S. 29-33 
    Details
    ISSN: 1437-7799
    Keywords: Key words VEGF ; Glomeruli ; Ribonuclease protection assay ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Vascular endothelial growth factor (VEGF) is a selective endothelial growth factor which potently enhances microvascular permeability. In the kidney, VEGF mRNA is known to be highly expressed in visceral epithelial cells in glomeruli. However, the physiological role of VEGF in glomerular function and its involvement in the pathogenesis of proteinuria are not clear. The present studies were designed to determine whether altered expression of VEGF mRNA was observed in the course of puromycin aminonucleoside (PAN) nephrosis in rats (a model of human minimal change nephrosis). Methods. The message level of VEGF in isolated glomeruli of PAN nephrosis rats was measured using a ribonuclease protection assay. Results. VEGF expression began to decrease 4 days after PAN injection and could not be detected in the nephrotic stage of PAN nephrosis (on days 8 and 16). In the remission of stage of PAN nephrosis (on day 28), mRNA was restored to the control level. Conclusions. According to our results, a functional defect in the VEGF expression of visceral epithelial cells was observed in PAN nephrosis. VEGF could be a functional marker of visceral epithelial cells, and the loss of normal expression of VEGF after damage to visceral epithelial cells could affect glomerular endothelial cell function in PAN nephrosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s101570050058
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  • 18
    Electronic Resource
    Electronic Resource
    Apoptosis in murine duodenum during embryonic development (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 485-487 
    Details
    ISSN: 1437-9813
    Keywords: Key words Duodenum ; Apoptosis ; Fetus ; Rat ; Duodenal atresia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Duodenum is thought to go through a solid-core stage followed by recanalization during its development. This study investigates the role of apoptosis in normal duodenal development, especially during widening of the lumen, and hence, the possible role of apoptosis in duodenal atresia (DA). Twenty-four time-mated Sprague-Dawley rats were killed from day 13 to day 20 of gestation. Duodenums of 3 fetuses were chosen randomly from each rat and processed. Apoptosis was determined by the terminal deoxytransferase-mediated biotin dUTP nick-end labeling (TUNEL) technique (ApopTag). Apoptosis count and cross-sectional areas were measured with an image analyzer (MetaMorph). The number of apoptotic cells per unit area duodenum peaked on day 15 for the mucosal/submucosal layer and on day 14 for the muscular/mesenchymal layer. The maximal number of apoptotic cells per cross-section of duodenum was between 7 and 8. The cross-sectional areas of the duodenal wall and lumen increased exponentially between day 17 and day 19 while duodenal-wall thickness remained relatively constant throughout duodenal development. The localization, timing, and intensity of apoptosis do not suggest that apoptosis is responsible for the widening of the duodenal lumen; enlargement of the lumen is related to the increase in duodenal circumference. Apoptosis thus may not be involved in the pathogenesis of DA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003830000408
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  • 19
    Electronic Resource
    Electronic Resource
    Organ-specific distribution of major histocompatibility antigens in rats (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 285-292 
    Details
    ISSN: 1437-9813
    Keywords: Key words Major histocompatibility complex (MHC) ; Rat ; Immunohistochemistry ; Distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study systematically investigated the expression and distribution of the major histocompatibility complex (MHC) classes I and II in the rat. About 150 native tissue probes from eight adult Lewis rats were taken, representative for most organs, tissues, and the vascular system. MHC expression was analyzed by two monoclonal antibodies (mAb) generated against the non-polymorphic determinants of rat MHC class I (Ox-18) and class II (Ox-6). Immunoreactivities were compared to those of different endothelial (HIS52, TLD-3A12, Ox-43, REHA-1 antigen), histiocytic (ED1, ED2), B-cell (RLN-9D3), and T-cell (MRC Ox-52) markers. A nonspecific mAb (MR12/53) served as a negative control. Pretested concentrations on various tissues and the alkaline phosphatase-anti-alkaline phosphatase technique allowed semiquantitative evaluation of serial cryostat tissue sections. MHC class I expression was detected on most immunocompetent cells. Endothelial cells were stained heterogeneously along the vascular system and the organ-specific microcirculation. Furthermore, some organs showed staining of parenchymal cells. MHC class II was found on all immunocompetent cells positive for the B-cell marker and about 15% of cells positive for the histiocytic markers. Besides the well-known expression of MHC class II in the outer zone of the renal proximal tubule, further organ-specific cell forms were found positive. In conclusion, the present study outlines tissue-specific distribution of MHC I/II and implies that each organ carries a variable immunologic burden that needs to be considered for any transplantation model.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003830050746
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  • 20
    Electronic Resource
    Electronic Resource
    Proliferation, zonal maturation, and steroid production of fetal adrenal transplants in adrenalectomized rats (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 293-296 
    Details
    ISSN: 1437-9813
    Keywords: Key words Fetal transplantation ; Proliferation ; Adrenal glands ; Addisonian crisis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study investigated the histologic maturation, proliferative capacity, and steroid production of fetal adrenal transplants (Tx) in adrenalectomized rats. A pair of fetal adrenal glands (18–20 days of gestation) was transplanted into the omentum of syngeneic Lewis rats (n=45). Four weeks later, in 5 animals the grafts were excised for morphologic evaluation. Proliferation was investigated by immunohistochemical staining for KI-67 protein and quantified by the proliferation index (PI = positive cells/100 counts). All other hosts (Tx; n = 40) underwent bilateral adrenalectomy (AE) to induce Addisonian crisis. Postoperatively, survival and concentrations of potassium, sodium, aldosterone, and corticosterone were recorded for 6 months. These data were compared to controls (C = only AE; n = 30) and a sham group (S; n = 10). At the end of the study period all surviving hosts were killed for histologic examination of grafts. At 4 weeks post-Tx the adrenal grafts demonstrated a distinct zona glomerulosa and frequent proliferation with a PI of 0.084, comparable to normal control (0.092). Following AE survival was significantly prolonged in Tx (86% vs 12% of C, P 〈 0.05). Control animals developed severe hyponatremia and hyperkalemia, whereas in Tx only transient signs of Addisonian crisis were recorded. Levels of aldosterone dropped within 7 days in the Tx and C groups, but returned to normal for Tx within 8 weeks. Corticosterone levels of Tx animals fell to 25% within week, but steadily increased to 70% by the end of the study. At 6 months, grafts revealed a mature adrenocortical structure with little proliferative activity, which was comparable to controls. In a syngeneic rat model fetal adrenal transplants thus mature and proliferate to provide sufficient steroid production for adrenalectomized hosts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003830050747
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  • 21
    Electronic Resource
    Electronic Resource
    Antenatal dexamethasone administration inhibits smooth-muscle-cell DNA synthesis in pulmonary-arterial media in nitrofen-induced congenital diaphragmatic hernia in rats (2000)
    Springer
    Pediatric surgery international 16 (2000), S. 414-416 
    Details
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Hypoplastic lung ; Bromodeoxyuridine (BrdU) ; Antenatal glucocorticoids ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this study was to investigate the effect of antenatal glucocorticoid therapy on smooth-muscle-cell (SMC) DNA synthesis in the pulmonary arteries (PA) in a nitrofen-induced congenital diaphragmatic hernia (CDH) rat model following nitrofen administration on day 9.5 of gestation. Antenatal dexamethasone (DEX) was given intraperitoneally on days 18.5 and 19.5 of gestation. Bromodeoxyuridine (BrdU) was injected via a jugular vein into the dam 1 h before the fetuses were killed by cesarean section at term. The fetuses were divided into three groups: group I (n = 10): normal controls; group II (n = 10): nitrofen-induced CDH; group III (n = 10): nitrofen-induced CDH with antenatal DEX treatment. Immunostaining of the lungs with anti-BrdU antibody was obtained by a standard avidin-biotin complex method. The number of immunopositive cells in the PA media and adventitia were counted using an image analyzer and analyzed statistically. The number of BrdU-immunopositive cells in the media was significantly increased in group II (16.83 ± 3.01) compared to groups I (9.16 ± 2.20) and III (6.83 ± 1.70) (P 〈 0.01). There was no significant difference between groups I and III. The number of BrdU-immunopositive cells in the adventitia was not significantly different between the three groups. Antenatal DEX treatment inhibits SMC DNA synthesis in PA media in CDH lungs. This may be a possible mechanism by which antenatal DEX prevents structural PA changes in nitrofen-induced CDH in rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003839900336
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  • 22
    Electronic Resource
    Electronic Resource
    Long-term small bowel allograft function induced by short-term FK 506 application is associated with split tolerance (2000)
    Springer
    Transplant international 13 (2000), S. S532 
    Details
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Split tolerance ; FK 506 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Functional long-term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high-dose FK 506 has been shown to induce stable long-term graft function. In order to examine whether this long-term function is associated with donor-specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One-step orthotopic SBT was performed in the allogeneic Brown Norway (BN)-to-Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0–5 in the rejection model and from days 0–9 in the long-term functional model. Mean survival time in the rejection model was 98 ± 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long-term functional model survived long term ( 〉 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor-specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely ( 〉 70 days). In vitro, mixed leukocyte reactivity of CD4 + T cells was similarly strong against donor (BN) antigens as against third-party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor-specific heart allografts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050396
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  • 23
    Electronic Resource
    Electronic Resource
    Heart valve dysfunction resulting from cellular rejection in a novel heterotopic transplantation rat model (2000)
    Springer
    Transplant international 13 (2000), S. S528 
    Details
    ISSN: 1432-2277
    Keywords: Key words Implantation model ; Aortic valves ; Valve dysfunction ; Rejection ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Structural failure of heart valve allografts may be related to technical factors or immunological reactions. To circumvent nonimmunological factors a new rat implantation model was developed to study whether alloreactivity results in histopathological changes and valve dysfunction. Syngeneic (WAG-WAG, DA-DA) and allogeneic (WAG-BN, WAG-DA) transplantation was carried out using this new technique, and the function of explanted valves was assessed 21 days later by retrograde comptence testing. Additionally, grafts were examined using standard histological and immunohistochemical techniques. There was no leakage during retrograde injection in nine of tem syngeneic and two of ten allogeneic grafts. Microscopically, syngeneic valves appeared normal without fibrosis or intimal thickening, although CD8+ lymphocytes and macrophages were found in necrotic myocardial rim and adventitia. In contrast, allogeneic valves were deformed and noncellular, with extensive infiltration of CD4+, CD8+ and CD68+ cells in adventitia and media. Absence of fibrosis and intimal thickening in syngeneic transplanted valves indicated circumvention of nonimmunological factors. Allogeneic valve transplantation induces cellular infiltration in the graft with subsequent graft failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050395
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  • 24
    Electronic Resource
    Electronic Resource
    Hypoxia-reoxygenation differentially stimulates stress-activated protein kinases in primary-cultured rat hepatocytes (2000)
    Springer
    Transplant international 13 (2000), S. S597 
    Details
    ISSN: 1432-2277
    Keywords: Key words Hypoxia-reoxygenation ; JNK1/SAPK1 ; Rat ; Hepatocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Organ injury after ischemia and reperfusion (I/R) remains one of the most important limiting factors in liver surgery and transplantation. Oxygen-free radical (OFR) generation is considered a major cause of this damage. JNK1/SAPK1, a member of MAPK family, regulates cell adaptation to stressful conditions. The aim of this study was to determine if hypoxia-reoxygenation (H/R) can activate JNK1/SAPK1 and if OFR are involved in this activation. Primary cultured rat hepatocytes isolated from other liver cells and blood flow were submitted to warm and cold H/R phases mimicking surgical and transplant conditions. JNK1/SAPK1 was activated by both warm and cold H/R. Deferoxamine (1 mM), di-phenyleneiodonium (50 μM) and N-acetylcysteine (10 mM) significantly inhibited this kinase activation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050410
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  • 25
    Electronic Resource
    Electronic Resource
    Real-time monitoring of nitric oxide in ischemia-reperfusion rat kidney (2000)
    Springer
    Urological research 28 (2000), S. 141-146 
    Details
    ISSN: 1434-0879
    Keywords: Key words Kidney ; Nitric oxide ; Ischemia-reperfusion injury ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study we attempted to clarify the release of nitric oxide (NO) and its role in the ischemia-reperfusion rat kidney. After right nephrectomy, male Wistar rats were divided into four groups: one sham operated and three groups who underwent ischemia (30 min) and reperfusion of the left renal artery. Thirty minutes prior to ischemia-reperfusion, two groups were injected intraperitoneally with 10 and 30 mg/kg of NG-nitro-l-arginine methylester (L-NAME). Real-time monitoring of blood flow and NO release in the rat kidney was measured with a laser Doppler flowmeter and an NO-selective electrode, respectively. Serum creatinine and blood urea nitrogen (BUN) levels were measured 1 and 7 days after the induction of ischemia-reperfusion. Clamping of the renal artery decreased blood flow to 1–5% of the basal level measured before clamping. After removal of the clip, the blood flow of the 30 mg/kg L-NAME rats was significantly lower than that of the controls. Immediately following the clipping of the renal artery, NO release rapidly increased. After removing the clip, NO release immediately returned to three-quarters of the basal level. Serum creatinine and BUN levels of the ischemia-reperfusion rats were slightly but not significantly higher and those of 30 mg L-NAME rats were significantly higher than those of the control or ischemia-reperfusion rats 1 day and 7 days after ischemia-reperfusion. Our data suggest that NO acts as a cytoprotective agent in ischemia-reperfusion injury of the rat kidney.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002400050153
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  • 26
    Electronic Resource
    Electronic Resource
    Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats (2000)
    Springer
    Urological research 28 (2000), S. 75-81 
    Details
    ISSN: 1434-0879
    Keywords: Key words Castration ; Epidermal growth factor ; Insulin-like growth factor I ; Prostate ; Testosterone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated Wistar rats were treated with growth factors (EGF 35 μg/rat per day; IGF-I 350 μg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P 〈 0.05), whereas treatment with IGF-I did not affect the prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration. Compared with testosterone, the effects of EGF treatment on the prostate involution were moderate, and the effects of EGF were not related to cellular proliferation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002400050141
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  • 27
    Electronic Resource
    Electronic Resource
    Effect of aging on bladder function and the response to outlet obstruction in female rats (2000)
    Springer
    Urological research 28 (2000), S. 33-37 
    Details
    ISSN: 1434-0879
    Keywords: Key words Bladder ; Rat ; Aging ; Obstruction ; Cystometrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bladder dysfunction in the aging population is a significant problem. However the concomitant presence of other diseases in many patients can make it difficult to distinguish between changes in bladder function and other influences. The present study was designed to study, in aging rats, bladder function and the effect of partial bladder outlet obstruction (BOO) on bladder function. Cystometrics were performed in awake, female Fischer 344 rats of four age groups (6, 12, 18 and 24 months) following subcutaneous implantation of a mediport catheter. Cystometric evaluations were carried out in control rats or those subject to three weeks of BOO. Bladder compliance significantly decreased with aging, which reflected an increase in threshold pressure without changes in bladder capacity. Partial BOO caused development of severe bladder instability. Following BOO, bladder capacity and compliance were significantly increased in all age groups. Threshold pressure was lower in obstructed animals, except for 6-month rats. Younger animals were able to generate a higher contraction pressure to compensate for the BOO, whereas older animals did not. Using an awake model of cystometric measurement, we have demonstrated that aging, by itself can affect bladder function. Furthermore, aged animals respond differently to BOO than younger animals. These results demonstrate that both aging and disease can contribute to bladder dysfunction, and suggest that treatment of bladder dysfunction may require a combination of therapies targeted to multiple etiologies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002400050007
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  • 28
    Electronic Resource
    Electronic Resource
    Morphological analysis of peripheral nerve regenerated by means of vein grafts filled with fresh skeletal muscle (2000)
    Springer
    Anatomy and embryology 201 (2000), S. 475-482 
    Details
    ISSN: 1432-0568
    Keywords: Key words Nerve repair ; Nerve fiber regeneration ; Sciatic nerve ; Muscle-vein-combined graft ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Clinical data have shown that a vein segment filled with fresh skeletal muscle can be considered a good autologous grafting conduit for the repair of peripheral nerve lesions. In this study, the long-term morphological organization of rat sciatic nerve fibers regenerated along a muscle-vein-combined graft conduit is further analysed by light and electron microscopy. Regenerated nerve fibers were organized into fascicles of various sizes that were clearly delimited by perineurial-like shells made by long and thin cytoplasmic processes of perineurial-like bipolar cells and by densely packed collagen fibrils. Grafted skeletal muscle fibers were still detectable among nerve fiber fascicles. However, in spite of the persistence of skeletal muscle along the graft, regenerated nerve fibers showed a good morphological pattern of regeneration, providing further evidence that the muscle-vein-combined grafting technique represents an effective surgical alternative to the classical fresh nerve autograft for the repair of peripheral nerve defects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004290050334
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  • 29
    Electronic Resource
    Electronic Resource
    Immunocytochemical distribution of the GABAB receptor splice variants GABAB R1a and R1b in the rat CNS and dorsal root ganglia (2000)
    Springer
    Anatomy and embryology 201 (2000), S. 1-13 
    Details
    ISSN: 1432-0568
    Keywords: Key words GABAB receptor ; CNS ; Dorsal root ganglia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The anatomical distribution of the GABAB receptor (GBR) splice variants GBR1a and 1b in the CNS has not previously been studied. In the present study, distribution of the splice variants was mapped using immunohistochemistry. Polyclonal antibodies against splice variant unique epitopes were raised in rabbits. Affinity purified antibodies were used according to routine immunohistochemical procedures in sections from the rat CNS or dorsal root ganglia (DRG). The staining intensity was high in the cerebral cortex but lower in basal ganglia and the hippocampus. In the cerebellum, there was a marked difference in the distribution of GBR1a- and 1b-like immunoreactivity (LI). GBR1a-LI was preferentially localised in the granule cell layer whilst GBR1b-LI was mostly found in Purkinje cells and in the molecular layer. Cell bodies of the deep cerebellar nuclei stained for the GBR1a antibody while terminals surrounding the cell bodies were strongly labelled with the GBR1b antibody. A similar pre- vs postsynaptic pattern was seen in several nuclei ventral or caudal to the cerebellum (e.g. the cochlear nucleus, the facial nucleus, the spinal cord) but not in regions rostral to the cerebellum. In the spinal cord, strong labelling for both antibodies was seen in the dorsal horn. The GBR1b but not the GBR1a antibody stained tanycytes in the epithelium of the 3rd ventricle and in the central canal at the brain stem level. DRG neurons were positive for both the GBR1a and 1b antibody, but the former stained the cells much more intensely. Satellite cells were labelled with the GBR1b antibody. The most important aspect of these findings is that in some nuclei, GBR1b may mediate inhibition of transmitter release while in the same regions, GBR1a may mediate postsynaptic inhibition. Further, the observations support previous findings that GBR1b is the predominant splice variant in Purkinje cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008224
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  • 30
    Electronic Resource
    Electronic Resource
    NK1, NK2 and NK3 tachykinin receptor localization and tachykinin distribution in the ileum of the mouse (2000)
    Springer
    Anatomy and embryology 202 (2000), S. 247-255 
    Details
    ISSN: 1432-0568
    Keywords: Key words Enteric neurons ; Interstitial cells of Cajal ; Smooth muscle cells ; Guinea-pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Tachykinin receptors NK1r, NK2r and NK3r bind tachykinins with different affinities and share pharmacological and molecular differences among animal species. NK1r, NK2r, NK3r and tachykinin (SP/NKA) distribution was studied by immunohistochemistry in the ileum of mouse since no data are available for this species. The results were then compared to those obtained in the rat and guinea pig either by us or by others to ascertain interspecies similarities and/or differences. NK1r- and NK3r-immunoreactivity (IR) were detected in neurons and NK1r-IR in the interstitial cells of Cajal at the deep muscular plexus. At variance with rat and guinea pig, NK1r-IR was also found in the myoid cells of the villi, while NK2r-IR was never detected in nerve varicosities. This latter datum suggests that the NK2r does not play a presynaptic role in the mouse. Unexpectedly, a high NK2r-IR and the presence of NK3r-IR were observed at the inner portion of the circular muscle layer in the mouse as well as in the rat and guinea pig, demonstrating a subregional distribution of these receptors. Tachykinin distribution did not show noticeable species-related differences. The present findings show species-related differences in the tachykinin receptor distribution that might be related to a different tachykinin controlof intestinal motility.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004290000106
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  • 31
    Electronic Resource
    Electronic Resource
    Systemic hypothermia following spinal cord compression injury in the rat: an immunohistochemical study on MAP 2 with special reference to dendrite changes (2000)
    Springer
    Acta neuropathologica 100 (2000), S. 546-552 
    Details
    ISSN: 1432-0533
    Keywords: Key words Hypothermia ; Immunohistochemistry ; Microtubule-associated protein 2 (MAP2) ; Rat ; Spinal cord injury
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Systemic hypothermia has been shown to exert neuroprotective effects in experimental ischemic CNS models caused by vascular occlusions. The present study addresses the question as to whether systemic hypothermia has similar neuroprotective qualities following severe spinal cord compression trauma using microtubule-associated protein 2 (MAP2) immunohistochemistry combined with the avidin-biotin-peroxidase complex method as marker to identify neuronal and dendritic lesions. Fifteen rats were randomized into three equally sized groups. One group sustained thoracic laminectomy, the others severe spinal cord compression trauma of the T8-9 segment. The control group contained laminectomized animals submitted to a hypothermic procedure in which the esophageal temperature was reduced from 38 °C to 30 °C. The two trauma groups were either submitted to the same hypothermic procedure or kept normothermic during the corresponding time. All animals were sacrificed 24 h following the surgical procedure. The MAP2 immunostaining in the normothermic trauma group indicated marked reductions in MAP2 antigen in the cranial and caudal peri-injury zones (T7 and T10, respectively). This reduction was much less pronounced in the hypothermic trauma group. In fact, the MAP2 antigen was present in almost equally sized areas in both the hypothermic groups independent of previous laminectomy alone or the addition of trauma. Our study thus indicates that hypothermia has a neuroprotective effect on dendrites of rat spinal cords subjected to compression trauma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010000206
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  • 32
    Electronic Resource
    Electronic Resource
    Changes of Fas and Fas ligand immunoreactivity after compression trauma to rat spinal cord (2000)
    Springer
    Acta neuropathologica 100 (2000), S. 75-81 
    Details
    ISSN: 1432-0533
    Keywords: Key words Fas ; Fas ligand ; Rat ; Spinal cord ; Trauma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This immunohistochemical study evaluated Fas and Fas ligand (FasL) in the rat nervous system and their changes in the spinal cord subjected to compression. Normal spinal cord showed a low level of Fas and FasL immunoreactivity in the white matter except in the corticospinal tracts. Fas and FasL immunoreactivity seemed to be located in axons and their myelin sheaths. Other regions of the nervous system did not show immunoreactivity to Fas and FasL. Moderate and severe compression injury of the spinal cord resulted in a reduction of Fas and FasL immunoreactivity in the white matter of injured T8–9 segments at 4 h and a complete loss at 1 day after trauma. This was seen even in the remaining white matter. In contrast, increased immunoreactivity to Fas and FasL was present in the cranial T7, caudal T10 (moderate injury) and T12 (severe injury) segments at day 4 with most intense staining were seen at day 9 after trauma. Increased Fas and FasL immunoreactivity may have pathophysiological implications for the development of secondary injuries after trauma to the spinal cord. Fas-FasL interactions may for instance be involved in apoptosis of oligodendrocytes which occurs as a delayed phenomenon after trauma to the spinal cord. The integrity of myelin sheaths may in this way be jeopardized by apoptosis of oligodendrocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010051195
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    Maximum tolerated doses of methotrexate and 7-hydroxy-methotrexate in a model of acute toxicity in rats (2000)
    Springer
    Cancer chemotherapy and pharmacology 46 (2000), S. 69-73 
    Details
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxymethotrexate ; Methotrexate ; Maximum tolerated dose ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD50 for reasons of animal welfare. Methods: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8–11.3 g/kg MTX and 0.1–1.2 g/kg 7-OH-MTX. Results: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. Conclusions: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800000111
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    A polymorphism of the rat T-cell receptor β-chain variable gene 13 (BV13S1) correlates with the frequency of BV13S1-positive CD4 cells (2000)
    Springer
    Immunogenetics 51 (2000), S. 296-305 
    Details
    ISSN: 1432-1211
    Keywords: Key words Vβ13 ; CD4/CD8 ratio ; Rat ; Tcrb ; Polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Three rat BV13S1 alleles (T-cell receptor β-chain variable gene 13) were characterized by new BV13S1-allele specific monoclonal antibodies (18B1 and 17D5) and sequence analysis of expressed and genomic BV13S1. Two alleles were functional and designated BV13S1A1 present in strains LEW, BUF, PVG, and BV13S1A2 present in BN and WF. Their products differed by six amino acids, two of them in complementarity-determing region (CDR)1 and one in CDR2. A third nonfunctional allele, BV13S1A3P, was found in strains F344 and DA. Apart from a single nucleotide insertion, it was identical to BV13S1A2. All 12 rat strains tested showed association of TCRBC1 with BV8S2/4 alleles but not with the BV13S1 alleles, which may reflect a different gene order of the rat BV compared to mouse. BV13S1A1-encoded T-cell receptors (TCRs) which bind both monoclonal antibody (mAb) 18B1 and mAb 17D5 are over-represented in the CD4 lymphocyte subset. BV13S1A2-encoded TCRs which are stained by mAb 18B1 but not by mAb 17D5 show a slight CD8-biased expression. Preferential usage of BV13S1A1-positive TCRs by CD4 but not by CD8 cells in (LEW×WF)F1 hybrids and cosegregation of BV13SA1 and increased frequency of BV13S1 TCR-positive CD4 cells in a (LEW×BN)×BN backcross suggest structural differences of the two allelic products as the reason for their contrasting CD4/CD8 subset bias.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002510050623
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    Electronic Resource
    Constitutive NF-κB activity is modulated via neuron-astroglia interaction (2000)
    Springer
    Experimental brain research 130 (2000), S. 100-104 
    Details
    ISSN: 1432-1106
    Keywords: Key words NF-κB ; p65 ; Hippocampal neurons ; Glia ; Astrocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  NF-κB is found in many neuronal cell types in different states of activity. This study aimed to define which conditions induce constitutive NF-κB activity in cultured hippocampal neurons using activity-specific antibody staining. In co-culture with astroglia, hippocampal neurons were devoid of activated NF-κB. In these co-cultures, NF-κB could not be activated via kainate or glutamate. In contrast, separating neurons from the glial compartment resulted in a time-dependent increase of activated neuronal NF-κB. In this line, activation of NF-κB by kainate or glutamate is very effective in freshly separated cultures, but inhibited when the cultures are reassembled after stimulation. These findings suggests that a neuronal-glial interaction may regulate gene expression via NF-κB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002210050011
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    Localization of endothelin receptors in bleomycin-induced pulmonary fibrosis in the rat (2000)
    Springer
    Histochemistry and cell biology 122 (2000), S. 507-517 
    Details
    ISSN: 1432-119X
    Keywords: Endothelin-A receptor ; Endothelin-B receptor ; Rat ; Pulmonary fibrosis ; Immunohistochemistry ; Quantitative PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: AbstractPulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ETB receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ETA and ETB receptor mRNA, and ETA receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ETA nor ETB receptor mRNA which were also not induced by bleomycin. We conclude that, while ETB receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ETA receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s00418-004-0708-7
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    Resistance to growth hormone and insulin-like growth factor-I in acidotic rats (2000)
    Springer
    Pediatric nephrology 14 (2000), S. 720-725 
    Details
    ISSN: 1432-198X
    Keywords: Key words Metabolic acidosis ; Growth ; Growth hormone ; Insulin-like growth factor-I ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Growth impairment induced by chronic metabolic acidosis is associated with an abnormal growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. To examine the potentially beneficial effects of IGF-I on acidosis-induced growth impairment and the influence of GH and IGF-I treatment on the GH/IGF-I axis, three groups of acidotic young rats (untreated, AC, n=12; treated with recombinant human GH, GH, n=8; treated with recombinant human IGF-I, IGF-I, n=8) were studied, and compared with nonacidotic rats fed ad libitum (C, n=9)) or pair-fed with the AC group (PF, n=12). After 14 days of acidosis and 7 days of treatment, growth rate, hepatic abundance of 4.7-kilobase (kb) and 1.2-kb GH receptor transcripts and 7.5-kb and 1.8- to 0.8-kb IGF-I transcripts, serum GH-binding protein (GHBP), and IGF-I concentrations (mean±SEM) were analyzed. Significant decreases of 4.7-kb GH receptor [26±2 vs. 49±6 arbitrary densitometry units (ADU)] and 7.5 kb IGF-I (41±3 vs. 104±10 ADU) transcripts and low serum GHBP (25±1 vs. 32±1 ng/ml) and IGF-I (279±50 vs. 366±6 nmol/l) levels were found in the AC compared with the C rats. The majority of these alterations were also observed in PF rats. Compared with acidotic untreated rats, GH and IGF-I therapy produced no improvement in growth rate. GH treatment normalized the levels of IGF-I mRNA, aggravated the acidosis-related inhibition of the GH receptor gene, and did not modify the serum levels of GHBP and IGF-I. In contrast, IGF-I administration depressed the hepatic expression of all GH and IGF-I transcripts and normalized serum IGF-I concentrations. Our results confirm that sustained metabolic acidosis alters the GH/IGF-I axis, in part because of associated malnutrition, and induced growth retardation that is resistant to GH therapy. Our study also shows that administration of IGF-I does not accelerate the growth of acidotic rats, suggesting a peripheral mechanism, at the level of target tissues, is responsible for the resistance to the growth-promoting actions of GH and IGF-I.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00013425
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    Electronic Resource
    Apoptosis parallels ceramide content in the developing rat kidney (2000)
    Springer
    Pediatric nephrology 15 (2000), S. 188-191 
    Details
    ISSN: 1432-198X
    Keywords: Key words Apoptosis ; Ceramide ; Development ; Kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ceramide is emerging as an important hydrophobic sphingolipid involved in cell differentiation and apoptosis. Since apoptosis plays a significant role in cellular remodeling during renal morphogenesis, we measured ceramide content and apoptosis in the fetal (18 days gestation), neonatal (3, 7, and 14 days postnatal), and adult rat kidney. In addition, to determine whether developmental changes in ceramide content are tissue-specific, we compared renal ceramide content with that in lung and liver. Ceramide was measured by the diacylglycerol kinase assay, and apoptosis was determined by the TUNEL technique. Renal ceramide content fell over 100-fold from the fetus to the 7th postnatal day. Renal apoptosis paralleled ceramide content, with a greater than 300-fold decrease in apoptosis from fetal to adult life. Ceramide content of the lung and liver was significantly less than that of the kidney, and changed less with maturation. We conclude that maturational changes in ceramide content are tissue-specific, and that the high rate of apoptosis in the developing kidney may be related to the elevated ceramide content.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004670000444
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    Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex (2000)
    Springer
    Psychopharmacology 151 (2000), S. 166-174 
    Details
    ISSN: 1432-2072
    Keywords: Keywords Novelty ; Context ; Environment ; Stress ; 6-OHDA ; Rotational behavior ; Striatum ; Nucleus accumbens shell ; Caudate ; Amphetamine ; Dopamine ; Glutamate ; Aspartate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900359
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  • 40
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    Electronic Resource
    Human interferon-α increases immobility in the forced swimming test in rats (2000)
    Springer
    Psychopharmacology 148 (2000), S. 106-110 
    Details
    ISSN: 1432-2072
    Keywords: Key words Interferon ; Depression ; Forced swimming test ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Objectives: We examined the immobility of the forced swimming test induced in an animal model by human interferon (IFN), which has often been reported to induce depression in clinical use. Methods: In the present study, we examined the effects of human IFNs on results of the forced swimming test in rats. Results: Single intravenous (IV) administration of human IFN-α (6×104 IU/kg), but not of human IFN-β or -γ, significantly increased immobility time in the forced swimming test in rats. Repeated administration of human IFN-α (6×103 IU/kg) also significantly increased the immobility time. On the other hand, none of the rat IFNs (rat IFN-α, -β and -γ, 6×104 IU/kg, IV) changed the immobility time. Neither human IFNs nor rat IFNs changed the locomotor activity of rats. Conclusions: These findings suggest that human IFN-α has a greater potential for inducing increase of the immobility in the rat forced swimming test than human IFN-β and -γ, and that the effect of human IFN-α might not be mediated through IFN-α/β receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050031
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    Selective mu and delta, but not kappa, opiate receptor antagonists inhibit the habituation of novelty-induced hypoalgesia in the rat (2000)
    Springer
    Psychopharmacology 148 (2000), S. 99-105 
    Details
    ISSN: 1432-2072
    Keywords: Key words Opiate receptor ; Antinociception ; Habituation ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. Objectives: The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. Methods: In experiments 1–3, different groups of male, Wistar rats (275–300 g) were administered vehicle, 0.5, 1.0 or 2.0-nmol doses of the µ-selective antagonist Cys2-Tyr3-Orn5-Pen7-amide (CTOP), the δ-receptor selective antagonist naltrindole, or the κ-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5°C), once a day for eight consecutive days. Results: Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. Conclusions: These results support the involvement of the µ and δ, but not the κ, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050030
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    Electronic Resource
    Acute exposure to saccharin reduces morphine analgesia in the rat: evidence for involvement of N-methyl-d-aspartate and peripheral opioid receptors (2000)
    Springer
    Psychopharmacology 149 (2000), S. 56-62 
    Details
    ISSN: 1432-2072
    Keywords: Key words Morphine ; Opioid receptor ; NMDA ; Tolerance ; Rat ; Tail flick
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug’s peripheral effect, while learned tolerance involves activation of N-methyl-d-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. Objectives: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. Methods: Six experiments used the rat’s tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the non-competitive NMDA receptor antagonist MK-801 on this modulation of analgesia. Results: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment 1a), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. Conclusions: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900337
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    Electronic Resource
    Opiate withdrawal-induced place aversion lasts for up to 16 weeks (2000)
    Springer
    Psychopharmacology 149 (2000), S. 115-120 
    Details
    ISSN: 1432-2072
    Keywords: Key words Opiate ; Withdrawal ; Place aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Administration of low doses of opiate antagonists to morphine-dependent rats produces an aversive response as measured by a conditioned place aversion, but the time course of such a learned aversion is largely unknown. Objectives: The purpose of this experiment was to examine the time course for the expression of a place aversion to opiate withdrawal. Methods: Morphine-dependent rats were tested in a three-chamber place- aversion apparatus. The conditioning phase consisted of three pairings of either naloxone (15 µg/kg s.c.) or vehicle with two compartments, with the most similar time allotments during the preconditioning test. During the testing phase, rats were again allowed to explore the entire apparatus. Different groups were tested at 24 h, 1 week, 2 weeks, 4 weeks, 8 weeks, and 16 weeks post-conditioning (morphine-free tests). Results: A robust place aversion was recorded at every time point tested, including at 16 weeks. In previously published work, placebo-pelleted rats tested with naloxone at the same dose failed to show a place aversion and nondependent rats showed a stable lack of aversion at tests up to 56 days. Dependent animals without naloxone also failed to show a place aversion at any of those time points. Conclusions: In the absence of any active intervention, the place aversion produced by opiate withdrawal is very long lasting and provides a model for protracted abstinence that may be useful for delineating the neurobiological substrate for vulnerability to relapse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900358
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    Role of dopamine in prepulse inhibition of acoustic startle (2000)
    Springer
    Psychopharmacology 149 (2000), S. 181-188 
    Details
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Sensorimotor gating ; Schizophrenia ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. Objective: Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. Results: In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. Conclusions: In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130000369
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    Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat (2000)
    Springer
    Psychopharmacology 149 (2000), S. 366-376 
    Details
    ISSN: 1432-2072
    Keywords: Key words Prefrontal cortex ; Dopamine ; Anxiety ; Drug discrimination ; Pentylenetetrazol ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. Objectives: The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Methods: Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. Results: CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. Conclusions: The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ, suggesting a role for it in anxiety.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130000390
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  • 46
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    In vivo estimates of efficacy at 5-HT1A receptors: effects of EEDQ on the ability of agonists to produce lower-lip retraction in rats (2000)
    Springer
    Psychopharmacology 149 (2000), S. 377-387 
    Details
    ISSN: 1432-2072
    Keywords: Key words 5-HT1A agonist ; Intrinsic activity ; Efficacy ; Irreversible antagonism ; Lower-lip retraction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. Objectives: To characterize the intrinsic activity of serotonin (5-HT)1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT1A receptor-mediated responses. Methods: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retraction (LLR) in rats were studied. Results: In the absence of EEDQ, each 5-HT1A agonist produced full effects, the rank order of potency being: S 14506 〉 8-OH-DPAT 〉 buspirone 〉 ipsapirone. EEDQ decreased the number of 5-HT1A binding sites and shifted the dose–response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone 〈 buspirone ≈ 8-OH-DPAT 〈 S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA2 values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. Conclusions: The results suggest that the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1A receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130000374
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    Electronic Resource
    Electronic Resource
    Repeated dose (28 days) oral toxicity study of flutamide in rats, based on the draft protocol for the `Enhanced OECD Test Guideline 407' for screening for endocrine-disrupting chemicals (2000)
    Springer
    Archives of toxicology 74 (2000), S. 127-132 
    Details
    ISSN: 1432-0738
    Keywords: Key words Flutamide ; Androgen antagonist ; Rat ; Enhanced OECD Test Guideline 407 ; Endocrine disrupters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In association with the international validation project to establish a test protocol for the `Enhanced OECD Test Guideline 407', we performed a preliminary 28-day, repeated-dose toxicity study of flutamide, a non-steroidal androgen antagonist, and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine-disrupting chemicals (EDCs). Seven-week-old CD(SD)IGS rats were divided into four groups, each consisting of 10 males and 10 females, and administered flutamide once daily by oral gavage at doses of 0 (control), 0.25, 1 and 4 mg/kg body weight/day. Male rats were killed 1 day after the 28th administration. Female rats were killed on the day they entered the diestrus stage in the estrous cycle following the last treatment. Male rats receiving flutamide at dose levels of 1 and 4 mg/kg showed lobular atrophy of the mammary gland and a decrease in epididymal weight. In addition, 4 mg/kg flutamide-treated males exhibited raised serum testosterone and estradiol levels and decreased weight of the accessory sex glands. In females, a slight prolongation of the estrous cycle was also observed in the 4 mg/kg flutamide-treated group. No dose-related changes could be detected by haematology, serum biochemistry and sperm analysis. Thus, among the parameters tested in the present experimental system, the weight of endocrine-linked organs and their histopathological assessment, serum hormone levels, and estrous cycle stage allowed the detection of endocrine-related effects of flutamide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050664
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  • 48
    Electronic Resource
    Electronic Resource
    Changes in serum α2u-globulin levels in male rats given diethylstilbestrol and applicability to a screening test for endocrine-disrupting chemicals (2000)
    Springer
    Archives of toxicology 74 (2000), S. 48-53 
    Details
    ISSN: 1432-0738
    Keywords: Key wordsα2u-Globulin ; Diethylstilbestrol ; Endocrine disrupter ; Rat ; Screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract α2u-Globulin (AUG) is a major rat urinary protein, which has a molecular weight of 16 kDa (kidney type) or 19 kDa (native type). The biosynthesis of this protein is under multi-hormonal regulation. In this study, we investigated changes in serum AUG level and their association with changes in the reproductive organs of male rats after the administration of the estrogenic chemical, diethylstilbestrol (DES) at doses ranging from 0.01 mg/kg per day to 100 mg/kg per day by gavage for 14 days. Our aim was to establish basic data for the development of a new screening method for endocrine disrupting chemicals based on serum AUG levels. DES treatment decreased the weight of testes in a dose-dependent manner; and was accompanied by atrophic histopathological changes in testes. Testis weights were significantly decreased by the group given 1 mg/kg per day DES; however, histopathological abnormalities were found in the group given 0.1 mg/kg per day DES. In four of five animals in the group given 1 mg/kg per day there was no significant decrease in testis weight and only a slight or moderate degeneration of the pachytene spermatocytes. Despite these findings, serum AUG levels in this group decreased markedly, while the serum AUG level markedly decreased even in the animals with no histopathological change in the 1 mg/kg per day or 0.1 mg/kg per day groups with no histopathological change also showed decreased serum AUG level. These results suggest that the serum AUG level may be a sensitive parameter for detecting the activity of estrogenic chemicals in intact male rats. Although a uterotropic assay has been proposed for immature female or ovariectomized female rats and is currently undergoing validation studies internationally, there is no screening method for estrogenic chemicals in intact male animals. More data on AUG changes by treatment with other estrogenic chemicals are needed in order to determine the sensitivity and specificity of this response to estrogens. Nonetheless, an AUG-based screening test for estrogenic chemicals may be useful owing to its applicability to conventional toxicity studies and an apparently higher sensitivity of this parameter compared to organ weight change or histology of testis in intact male rats and applicability to conventional toxicity studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050651
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  • 49
    Electronic Resource
    Electronic Resource
    The T-type calcium channel blocker mibefradil reduced interstitial and perivascular fibrosis and improved hemodynamic parameters in myocardial infarction-induced cardiac failure in rats (2000)
    Springer
    Virchows Archiv 436 (2000), S. 147-157 
    Details
    ISSN: 1432-2307
    Keywords: Key words T-type calcium channel blockade ; Mibefradil ; Myocardial infarction ; Cardiac remodeling ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dtmax) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dtmax were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dtmax were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008215
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  • 50
    Electronic Resource
    Electronic Resource
    Sex differences in the discriminative stimulus effects of m-chlorophenylpiperazine and ethanol withdrawal (2000)
    Springer
    Psychopharmacology 149 (2000), S. 170-175 
    Details
    ISSN: 1432-2072
    Keywords: Key words  m-Chlorophenylpiperazine ; Drug discrimination ; Ethanol withdrawal ; Anxiety ; 17β-estradiol ; Sex difference ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. Objectives: This study examined sex differences in the anxiogenic stimu-li induced by a serotonin (5-HT)1b/2 agonist, meta- chlorophenylpiperazine (mCPP), prior to ethanol and during EW. Methods: Gonadectomized or sham-operated adult male and female rats and 17β-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0–1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. Results: Fewer sham female and β-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and β-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. Conclusions: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and β-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900353
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  • 51
    Electronic Resource
    Electronic Resource
    The dynamic infusion test in rats (2000)
    Springer
    Child's nervous system 16 (2000), S. 451-456 
    Details
    ISSN: 1433-0350
    Keywords: Keywords Intracranial pressure ; CSF dynamics ; Infusion test ; Rat ; H-Tx rat ; Outflow resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Although the hydrocephalic H-Tx rat is a widely used model, data on the cerebrospinal fluid (CSF) dynamics in hydrocephalic rats are rare or – as the pressure volume index (PVI) – not available. We used hydrocephalic and nonhydrocephalic H-Tx rats, a stock with a high percentage of inherited hydrocephalus, for the evaluation of such data. In addition, a new, simple mathematical algorithm (”dynamic infusion test”), which has not formerly been used in animal experiments, was used as a pathophysiological model of CSF dynamics. Compared with classical methods for evaluation of these data, the dynamic infusion test gives a deeper insight into the relation between ICP and CSF dynamics. It was found that the resistance to outflow (ROF) in hydrocephalic rats was at least twice that in nonhydrocephalic rats. The PVI measured was similar in hydrocephalic and nonhydrocephalic animals, but clearly higher than the values reported in the literature. This may be attributable to the fact that the classically used bolus test, in contrast to the ”dynamic infusion test”, is representative only for the CSF compartment which is directly exposed to the bolus application.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00007290
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  • 52
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    Electronic Resource
    Paclitaxel plus vinorelbine: An active regimen in metastatic breast cancer patients with prior anthracycline exposure (2000)
    Springer
    Annals of oncology 11 (2000), S. 85-89 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; combination therapy ; paclitaxel ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:To evaluate the anti-tumour activity and tolerance of thecombination of paclitaxel plus vinorelbine in metastatic breast cancer (MBC)patients previously treated with anthracyclines. Patients and methods:Fifty-six MBC patients who have had at leastone previous anthracycline-containing chemotherapy regimen were enrolled inthis phase II trial. Patients received paclitaxel (135 mg/m2 overone-hour infusion) and vinorelbine (30 mg/m2) both on day 1 of eachthree-week course of therapy (maximum eight courses or until diseaseprogression was evident). Results:Six complete and nineteen partial responses were observedamong the fifty-four assessable patients (response rate of 46%,95% CI: 33%–60%). Responses were observed in alldisease sites and in all subsets of patients. The response rates whenpaclitaxel plus vinorelbine were used as first, second and third-linechemotherapy for metastases were 67%, 41% and 35%,respectively. The response rate among anthracycline-refractory patients was46% (6 of 13). Median time to progression in the overall patient groupwas 28 weeks. The main toxicities (CTC grade 2 or more) were alopecia,myelosuppression and peripheral neuropathy (85%, 46% and19% of patients, respectively). Nine patients (17%) hadneutropenic fever in fifteen of the three hundred twenty-eight coursesadministered (5%). Conclusions:The combination of paclitaxel and vinorelbine on day1 every three weeks is active in MBC patients with prior anthracyclineexposure. The regimen is safe, well tolerated and convenient for the patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008374425246
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  • 53
    Electronic Resource
    Electronic Resource
    Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy (2000)
    Springer
    Annals of oncology 11 (2000), S. 1289-1294 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; cyclophosphamide ; fluorouracil ; mitoxantrone ; radiation therapy ; secondary leukemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The topoisomerase II-targeted drugs,epipodophyllotoxins and anthracyclines, have been shown to inducetherapy-related AML (t-AML) characterized by a short latency period afterchemotherapy, the absence of prior myelodysplastic syndrome and stereotypedchromosome aberrations. Few reports have been published on patients treatedwith the anthracenedione mitoxantrone which also targets topoisomerase II. Weobserved 10 cases of such t-AML over a 7-year-period in breast cancer patientstreated with mitoxantrone combined with fluorouracil, cyclophosphamide andregional radiotherapy, and in three cases with vindesine. Patients and methods:We retrospectively analyzed patientsreferred to our hospital for AML with a past history of polychemotherapy forbreast cancer, including mitoxantrone, either as adjuvant (8patients)/neoadjuvant (1 patient) therapy or for metastatic disease (1patient). We studied the probability of developing t-AML in a prospectiveseries of 350 patients treated with an adjuvant FNC regimen (mitoxantrone,fluorouracil, cyclophosphamide) and radiation therapy. Results:The median age was 45 years (range 35–67). t-AMLdeveloped 13–36 months (median 16) after beginning chemotherapy forbreast cancer, and 4–28 months (median 10.5) after ending treatment. Asdescribed in t-AML following treatment with epipodophyllotoxins oranthracyclines, we found a majority of FAB M4, M5 and M3 phenotypes (7 of 10),and characteristic karyotype abnormalities that also can be found in denovoAML: breakpoint on chromosome 11q23 (3 patients), inv(16)(p13q22)(2 patients), t(15;17)(q22;q11) (1 patient), t(8;21)(q22;q22) (1 patient) anddel(20q)(q11) (1 patient). The prognosis was poor. All patients died of AMLshortly after diagnosis. Since two patients had been enrolled in a prospectivetrial for the treatment of breast cancer which included 350 patients, theprobability of developing t-AML was calculated to be 0.7% from25–40 months, using the Kaplan–Meier method (95% confidenceinterval (95% CI): 0.1–4.5). Conclusions:The combination of mitoxantrone withcyclophosphamide, fluorouracil, and radiation therapy can induce t-AML, aswith other topoisomerase II-targeted drugs. Despite a low incidence, theprognosis appears to be poor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008375016038
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  • 54
    Electronic Resource
    Electronic Resource
    Breast cancer in women ≤35 years: Review of 1002 cases from a single institution (2000)
    Springer
    Annals of oncology 11 (2000), S. 1255-1262 
    Details
    ISSN: 1569-8041
    Keywords: age ≤35 years ; breast cancer ; single institution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Early-onset breast cancer may differ with respect toetiology, clinical features and outcome compared with breast cancer in olderwomen. To gain further insight, we retrospectively reviewed the clinicalfeatures and outcome of women ≤35 years with primary breast cancer seen atour institution over a 30-year period. Patients and methods:Charts were reviewed for women with operablebreast cancer diagnosed ≤35 years of age seen at the Princess MargaretHospital (PMH), Toronto from 1965–1994. Results:One thousand eighty-six women with non-metastaticinvasive breast cancer, aged 18.3–35.6 years (median 32.1 years) werereferred to PMH. Symptoms at presentation included: self-detected breast lump(83%), other breast symptom (10%), physician diagnosis(4%) and unknown (3%). Tumor size was known in 936 (〉2 cm in61%) and nodal status in 888 (lymph node positive in 52%).Modified radical mastectomy was performed in 568 (57%) andbreast-conservation surgery (BCS) in 422 (42%). Five hundred sixteen(51%) patients received adjuvant radiotherapy and five hundredthirty-four (53%) adjuvant systemic therapy. Two hundred ninety-three(29%) patients had a family history of breast cancer (FH).Contralateral breast cancer (CBC) occurred more frequently in women with FH(Prange 0.042–0.008). Local recurrence (LR) was 37% and73% at 10 years in those treated by BCS with and without radiotherapy,respectively. At 10 years, disease-free survival (DFS) was 30% andoverall patient survival 48%. Conclusions:In this cohort, breast cancer was usuallyself-diagnosed and tumors were 〉2 cm at presentation in approximatelytwo-thirds of cases, suggesting the possibilities of a delay in diagnosis,more aggressive tumors or both. Our results are compatible with the knownassociation of breast cancer FH with increased CBC. Our data also corroboratesthe suggestion that positive genetic testing in this age group should lead toconsideration of more aggressive ipsilateral and contralateral breastmanagement. In those receiving adjuvant irradiation after BCS, the LR rate washigh, but did not impact on overall survival.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008391401404
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  • 55
    Electronic Resource
    Electronic Resource
    Infusional ECarboF in patients with advanced breast cancer: A very active and well-tolerated out-patient regimen (2000)
    Springer
    Annals of oncology 11 (2000), S. 1557-1561 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; carboplatinum ; chemotherapy ; continuous 5-fluorouracil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We performed a trial using the combination of epirubicin 50mg/m2/day 1, carboplatinum AUC 5/day 1 and continuous5-fluorouracil (5-FU) 200 mg/m2/day (every 4 weeks for6 months) to confirm the efficacy and low toxicity profile of thisregimen in breast cancer. In 51 patients with metastatic(n = 33) or locally advanced (n = 18)breast cancer the overall response rate was 86% (95% confidenceinterval (95% CI): 73%–94%): 94% in locallyadvanced and 81% metastatic disease. Grade 3–4 toxicity was low:4% of patients presented with febrile neutropenia, 16% withsevere palmar-plantar syndrome, 10% with Port-a-cath thrombosis. This study confirms the high efficacy of infusional 5-FU-based regimens andjustifies further research into novel promising oral 5-FU derivatives.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008378220547
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  • 56
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    Electronic Resource
    Doxorubicin-based adjuvant chemotherapy in elderly breast cancer patients: The M.D. Anderson experience, with long-term follow-up (2000)
    Springer
    Annals of oncology 11 (2000), S. 1597-1601 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant chemotherapy ; breast cancer ; doxorubicin ; elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The purpose of this study was to evaluate the clinicaloutcome of doxorubicin-based adjuvant chemotherapy in elderly breast cancerpatients and to compare results in elderly patients with those in youngerpatients. Patients and methods:We retrospectively reviewed the records ofall patients aged 50 years or older treated in trials of doxorubicin-basedadjuvant chemotherapy between 1974 and 1988. Old age was not an exclusioncriterion for these trials. Patient characteristics, hematologic andnonhematologic side effects, patterns of recurrence, and causes of death weredetermined for patients aged 50–64 years and for patients aged 65 yearsor older, and results were compared between these two groups.Kaplan–Meier survival curves were plotted, and tested by the generalizedWilcoxon test. Results:A total of 390 patients aged 50 years or older weretreated with doxorubicin-based adjuvant chemotherapy during the study period.Of these, 325 were aged 50–64 years (group 1), and 65 were aged 65 yearsor older (group 2). The median follow-up period for group 1 was 185 months(range 29–272+ months), and the median follow-up period for group 2 was169 months (range 128–240+ months). There were no statisticallysignificant differences between the two groups with respect to performancestatus, hormone receptor profile, tumor size, nodal status, or type oflocoregional therapy. There also were no statistically significant differencesbetween the two groups in recurrence patterns, disease-free survival, oroverall survival. The granulocyte and platelet nadirs of cycles 1, 3, and 6were similar between the two groups. No cumulative hematologic side effectswere seen in either group. The occurrence of second malignancies was extremelylow in both groups. In both groups, the majority of deaths were due toprogression of disease. Conclusions:Adjuvant doxorubicin-based chemotherapy is welltolerated in elderly breast cancer patients who have good performance statusand normal cardiac ejection fraction. Adjuvant doxorubicin-based chemotherapyin these patients results in disease-free and overall survival rates similarto those seen in younger patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008315312795
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  • 57
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    Electronic Resource
    A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil®) in controlling hot flashes in breast cancer survivors (2000)
    Springer
    Annals of oncology 11 (2000), S. 17-22 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; hot flashes ; paroxetine ; serotonin uptake inhibitors ; survivors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Many breast cancer survivors suffer debilitating hotflashes. Estrogen, the drug of choice in perimenopausal women, is generallynot recommenced to breast cancer survivors. Nonhormonal treatments are mostlydisappointing. Anecdotal reports in our institution suggested that theselective serotonin-reuptake inhibitor, paroxetine hydrochloride, might beefficacious in alleviating hot flashes. Patients and methods:Thirty women with prior breast cancer whowere suffering at least two hot flashes a day entered a single institutionpilot trial to evaluate paroxetine's efficacy in reducing the frequency andseverity of hot flashes. After completing daily diaries for one week on notherapy, the women received open-label paroxetine, 10 mg daily for one week,followed by four weeks of paroxetine, 20 mg daily. The women completedhot-flash daily diaries throughout the study period, and a health-relatedsymptom-assessment questionnaire and a quality-of-life rating scale in thefirst and sixth week of the study. Results:Twenty-seven women completed the six-week study period.The mean reduction of hot flash frequency was 67% (95%confidence interval (95% CI): 56%–79%). The meanreduction in hot flash severity score was 75% (95% CI:66%–85%). There was a statistically significantimprovement in depression, sleep, anxiety, and quality of life scores.Furthermore, 25 (83%) of the study participants chose to continueparoxetine therapy at the end of study. The most common adverse effect wassomnolence, resulting in drug discontinuation in two women, and dose reductionin two women. One woman discontinued drug due to anxiety. Conclusions:Paroxetine hydrochloride is a promising new treatmentfor hot flashes in breast cancer survivors, and warrants further evaluationin a double-blind randomized placebo-controlled trial.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008382706068
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  • 58
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    Electronic Resource
    Socio-economic deprivation and stage of disease at presentation in women with breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 105-107 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; socio-economic status ; stage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:This study describes and compares the pathologicalprognostic factors and surgeon assessment of stage of breast cancer of womenliving in affluent and deprived areas to assess whether clinical stage atpresentation may explain the known poorer survival outcomes for deprivedwomen. Patients and methods:A population-based review of the caserecords of 417 women with breast cancer was carried out. Results:No difference in pathological criteria was found betweenthe 88% of women living in affluent and deprived areas for whom suchdata were available. Clinical assessment of the remaining 50 cases showed thatwomen living in deprived areas were more likely to present with locallyadvanced or metastatic disease. Conclusion:The poorer survival of women from deprived areas withbreast cancer may be explained by more deprived women presenting with advancedcancers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008385321476
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  • 59
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    Patient participation in medical decision-making: A French study in adjuvant radio-chemotherapy for early breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 39-45 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; choice ; decision-making process ; patient–physician relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Shared decision-making is increasingly advocated asan ideal model. However, very few studies have tested the feasibility ofgiving patients the opportunity to participate in the choice of treatment. Patients and methods:Women, with non-metastatic breast cancer,eligible for non-intensified adjuvant chemotherapy attending our hospital wereproposed two administrations of chemotherapy and radiotherapy: a sequentialand a concomitant one. Two patient-questionnaires were used to elicitmotivations for their choice and their degree of comfort with the process ofdecision-making and one questionnaire to test physicians' ability to predictpatients' choice. Results:Participation rate in the study was 75.3%(n = 64). Majority (64%) of patients chose the concomitanttreatment. Multivariate analysis revealed that patients with a lower level ofeducation, who discussed the choice with social circle, and who most fearedside-effects were more likely to choose the sequential treatment. Physicianswere able to predict patients' choice in 66% of cases. 89% ofpatients declared that they were "fully satisfied" with having participatedin the choice of treatment and 79% supported shared decision-making. Conclusions:Results are in favour of promoting activeparticipation of cancer-patients in medical decision-making. The adequatedegree of such participation remains however to be elicited and tested fortherapeutic choices implying more difficult trade-offs between quantity andquality of life.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008390027720
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  • 60
    Electronic Resource
    Electronic Resource
    Second cancers after adjuvant tamoxifen therapy for breast cancer in Japan (2000)
    Springer
    Annals of oncology 11 (2000), S. 1539-1544 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant therapy ; breast cancer ; second cancer ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Women treated with tamoxifen for breast cancer are atincreased risk of endometrial cancer. We conducted a retrospective cohortstudy to evaluate the risk of second primary cancers after adjuvant tamoxifentherapy for breast cancer in Japan. Patients and methods:The subjects of the study were 6148 womenwho had been diagnosed with stage I, II, or IIIA unilateral primary breastcancer and had received surgical treatment during the period from January 1982through December 1990 at nine institutions in Japan. The information on eachpatient was obtained from medical records or a prospectively compiled computerdatabase at each institution. Results:Of the 6148 women, 3588 (58.4%) were administeredtamoxifen as an adjuvant treatment and 2560 (41.6%) were notadministered. Median follow-up periods were 7.64 years for tamoxifen-treatedpatients and 8.10 years for non-tamoxifen-treated patients, respectively. Theduration of tamoxifen treatment was mostly two years or less (80.7%),and few patients received tamoxifen for more than five years. The cumulativeincidence rates of all second cancers at 10 years were 4.61% and4.09% among tamoxifen-treated and non-tamoxifen-treated patients(P = 0.62), respectively, and the incidence rate ratio (IRR) forall second cancers was 1.06 (95% confidence interval (CI):0.77–1.47) after adjustment of several covariates. The numbers ofendometrial cancers was 9 and 3 among tamoxifen-treated andnon-tamoxifen-treated patients, respectively, and the IRR was 2.37 (95%CI: 0.64–8.77, P = 0.20). Of the 12 patients who developedendometrial cancer, 4 died of cancer (for 3 of them, the cause of death wasbreast cancer), and the other 8 patients were alive as of March 1996. Stomachcancer was the most frequent second cancer and the IRR was 1.34 (95%CI: 0.76–2.38, P = 0.31). There was no substantialincrease in any other type of gastrointestinal cancer such as colorectal andliver cancers among tamoxifen-treated patients. Conclusions:The incidence and risk of second primary cancersassociated with tamoxifen therapy is low. The potential benefit of adjuvanttamoxifen therapy in breast cancer patients outweighs the risk of secondprimary cancers for Japanese breast cancer patients.
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    URL: http://dx.doi.org/10.1023/A:1008383804811
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  • 61
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    Front-line treatment of advanced breast cancer with docetaxel and epirubicin: A multicenter phase II study (2000)
    Springer
    Annals of oncology 11 (2000), S. 1249-1254 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; docetaxel ; epirubicin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:In a previous phase I trial we evaluated the toxicity anddetermined the maximum tolerated doses of the docetaxel (D)–epirubicin(Epi) combination. We conducted a multicenter phase II study to evaluate theefficacy and tolerability of this regimen as front-line treatment in womenwith advanced breast cancer (ABC). Patients and methods:Fifty-four women with ABC stage IIIB (4patients) or IV (50 patients) received front-line treatment with Epi 70mg/m2 on day 1 and D 90 mg/m2 on day 2. The median agewas 55 years, performance status (WHO) was 0–1 in 49 patients andvisceral disease was present in 45 (83%). Results:All patients were evaluable for toxicity and 50 forresponse. In an intent-to-treat analysis complete remission was observed in5(9%) patients, partial remission in 31 (57%) (overall responserate 66%, 95% confidence interval: 54%–79%),stable disease in 9 (17%) and disease progression in 9 (17%).After a median follow-up of 11.5 months, the median duration of responses was8 months, the median time to disease progression 11.5 months and the mediansurvival has not yet been reached. The probability of one-year survival was65%. Three hundred six cycles of treatment were administered (median6 cycles per patient). Grade 3 and 4 neutropenia was observed in 8(15%) and 31 (57%) patients, respectively, and febrileneutropenia in 19 (35%). Prophylactic rh-G-CSF was used in 45(83%) patients or 226 (74%) cycles. Other hematologic ornon-hematologic toxicities were usually mild. In five (9%) patients theleft ventricular ejection fraction (LVEF) was decreased by more than10% with the treatment. Two patients died during the treatment ofrespiratory failure without associated neutropenia. Conclusions:The combination of docetaxel–epirubicin is aneffective and well tolerated front-line treatment in patients with ABC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008351310818
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  • 62
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    p53 determination alongside classical prognostic factors in node-negative breast cancer: An evaluation at more than 10-year follow-up (2000)
    Springer
    Annals of oncology 11 (2000), S. 393-397 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; p53 ; prognostic factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:There is heterogeneity of methods and conflictingresults concerning the prognostic value of p53 in node-negativebreast cancer. The clinical value of a quantitative method for measuringtumoral p53 content still needs to be evaluated. Patients and methods: A long-term retrospective study wasconducted on 297 node-negative patients with a median follow-up greater than10 years (11 years, 101–172 months). Classic prognostic factors wereconsidered including age, tumor size, histoprognostic grade and estradiol (ER)and progesterone receptors (PR). In addition, the value of p53 determination (immunoluminometric assay in tumor cytosol) was assessed forthis long follow-up period. Results: p53 concentrations were significantly linked tothe histological grade (P = 0.001), to tumor size (P = 0.02)and ER status (P = 0.01). Higher p53 tumoral concentrationswere found in tumors with large size, pejorative histological grade andnegative ER status. In contrast, p53 tumoral concentrations were notinfluenced by menopausal or PR status. Multivariate Cox analysis demonstratesthat tumor size was the only significant predictor of disease-free survival(P = 0.049) with a risk factor at 1.38. As regards specific survival,univariate Cox analysis indicates that p53 taken as a continuousvariable is a significant predictor (P = 0.024) together withhistological grade, tumor size and ER status. In a multivariate Cox analysisthere were two significant and independent variables for predicting overallsurvival: tumor size (P = 0.031) and ER status (P = 0.015)with the highest risk factor (RR = 2.14). Conclusions:The present investigation points out that theprognostic power of p53 tumor determination evaluated at more than10 years median survival is not higher than the well-recognized classicprognostic factors in node-negative breast cancer. The present data highlightthe need to assess the prognostic value of potentially new biological factorsin node-negative breast cancer on cohorts of patients followed over periodsin excess of 10 years.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008359722254
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  • 63
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    A comparison of methods currently used in clinical practice to estimate familial breast cancer risks (2000)
    Springer
    Annals of oncology 11 (2000), S. 451-454 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; genetic counselling ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:With the identification of genes predisposing tohereditary breast cancer, the accurate and consistent estimation of a woman'srisk of developing breast cancer based on her family history is of paramountimportance if national service guidelines are to be developed. Patients and methods:The residual lifetime risk of developingbreast cancer was estimated for 200 women attending a breast cancer geneticassessment clinic by three different methods currently in use in the UK. Riskswere computed on the basis of the Cancer and Steroid Hormone (CASH) study dataand were classified as ‘low/moderate’ (〈20%) or ‘high’(〉20%). These risk categories are representative of those currentlyused to allocate surveillance and genetic testing. Risks were then comparedto estimates derived by other methods used in current clinical practice,including those of Houlston and Murday. Results:The CASH data-based method ascribed 27% to thehigh risk category, as compared to 53% for the combined Houlston andMurday methods. A method based on the number of affected relatives aloneascribed only 14% to the high risk category. Overall, 108 (54%)women were placed in the same risk category by all three methods. Conclusions:This study demonstrates that there is a significantdegree of variability between methods currently used to estimate breast cancerrisk which has serious implications for individual patient management, serviceprovision and multicentre studies evaluating the benefits of genetic testingfor breast cancer susceptibility.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008396129543
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  • 64
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    Gemcitabine and vinorelbine in pretreated advanced breast cancer: A pilot study (2000)
    Springer
    Annals of oncology 11 (2000), S. 495-496 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; gemcitabine ; metastases ; vinorelbine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:Gemcitabine (GEM) and vinorelbine (VNR) are both activeagainst advanced breast cancer (ABC), being able to induce a median ORR of25% and 40%, respectively. Because of their different mechanismof action and good tolerability, the combination of GEM and VNR has beentested in ABC. Patients and methods:Twenty-nine ABC patients pretreated withanthracycline-taxane were treated with GEM 1000 mg/m2 on day 1, 8,15, and VNR 25 mg/m2 on day 1 and 8 every twenty-eight days.Analysis of toxicity pattern, response rate, TTP and OS were carried out. Results:Twenty-nine patients were enrolled into the trial. TheORR was 48% (95% CI: 29–67): a CR was observed in threepatients (10%; 95% CI: 2–27), while eleven patients(38%; 95 CI: 21–58) achieved PR, eight (28%) had a SD, andseven (24%) progressed. Toxicity was mainly hematological and included:grade 3 leukopenia in 48% of cases without episodes of neutropenicfever, grade 3–4 thrombocytopenia in 10%, and grade 2 anemia in7%. Non-hematological toxicities were mild and rather infrequent. Conclusions:The GEM–VNR combination seems to be active inpretreated ABC with an acceptable toxicity pattern, and may well reppresentan interesting therapeutic choice after anthracycline/taxane regimens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008348704373
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  • 65
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    Psychosocial predictors of survival: Metastatic breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 469-474 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; Prognostic factors ; psychosocial factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Research interest in psychosocial predictors of theonset and course of cancer has been active since the 1950s. Recently wereported associations between psychological factors and survival in patientswith metastatic melanoma. We now report a replication of this study in asample of women with metastatic breast cancer. Patients and methods:Ninety-nine patients with metastatic breastcancer completed questionnaires measuring cognitive appraisal of threat,coping, psychological adjustment, perceived aim of treatment, social supportand quality of life, approximately four months after diagnosis. Survival wasmeasured from date of study entry to date of death or censored at the date oflast follow-up for surviving patients. Results:In a multivariate analysis, four factors independentlypredicted outcome. Patients with metastases in the liver, lung or pleurasurvived for a shorter duration (P 〈 0.001); older patients(P 〈 0.001) and those with a better appetite (P 〈0.05) also lived for a shorter time. Patients who minimised the impact ofcancer survived longer (a median of 29.1 vs. 23.9 months after study entry,P 〈 0.01). Conclusions:Minimisation was also significantly associated withoutcome in patients with metastatic melanoma who participated in anidentically designed study, reported elsewhere. This suggests thatminimisation may have a general impact on cancer progression and deservescloser scrutiny in other cancers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008396330433
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  • 66
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    Combination chemotherapy with navelbine and continuous infusion of 5-fluorouracil in metastatic, chemotherapy refractory breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 1041-1043 
    Details
    ISSN: 1569-8041
    Keywords: 5-FU ; breast cancer ; metastatic ; navelbine ; protracted continuous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:The protracted continuous infusion (PCI) of5-fluorouracil (5-FU) has proven in several studies an active and welltolerated treatment for advanced, pretreated breast cancer. Navelbine has alsoactivity in this setting. Patients and methods:Heavily pretreated patients with metastaticbreast carcinoma were eligible for the study. Treatment consisted of 5-FU 250mg/m2 given as a PCI by an elastomeric pump and navelbine 20mg/m2 on days 1 and 8, every four weeks. Eighty-three patients(median age 54 years; range 32–82 years) entered the study. The mediannumber of metastatic tumour sites was 2, with visceral involvement in 56patients. Apart from five patients with contraindications, all patients hadbeen pretreated with anthracyclines. Thirty-one patients had received taxanesand seventy-four bolus 5-FU. Results:A median of 5 cycles (range 1–14) per patient wasadministered. The median duration of 5-FU infusion was 17 weeks (range, 4-90).In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and24 partial remissions occurred (response rate, 45%). Median durationof response was 9 months. Toxicity was mild. Median survival was 20 months. Conclusions:PCI–5-FU combined with navelbine offers areasonable chance of tumour regression with modest side effects in patientswith heavily pretreated breast cancer.
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    URL: http://dx.doi.org/10.1023/A:1008333327500
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  • 67
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    Adjuvant chemotherapy in node negative breast cancer: Patterns of use and oncologists' preferences (2000)
    Springer
    Annals of oncology 11 (2000), S. 631-633 
    Details
    ISSN: 1569-8041
    Keywords: adjuvant chemotherapy ; attitudes ; breast cancer ; consensus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:A worldwide variation in policy is seen regardingadjuvant systemic treatment for node negative breast cancer (NNBC). After thefirst presentations of the 10-year EBCTCG results, a study was carried out inthe Netherlands to assess patterns of care and to obtain the views ofoncologists as to what constitutes a worthwhile benefit from treatment. Methods:A questionnaire regarding patterns of use of andpreferences for adjuvant chemotherapy in younger women was mailed to surgical,medical and radiation oncologists in the Netherlands. Results:Thirty-five percent stated that NNBC patients under 50in their hospital never received adjuvant chemotherapy. The majorityconsidered a 10-year survival gain of 6%–10% sufficientto warrant the use of chemotherapy in patients under 50. Surgical oncologistsrequired a larger benefit from treatment than radiotherapists and medicaloncologists. The more frequently oncologists treated patients in a researchcontext, the less benefit they required from treatment to make it worthwhile. Conclusions:Data such as these are valuable input into theprocess of guideline development, and may help discussion within theprofession as to what benefit offsets the burden of treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008379628579
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  • 68
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    Phase II study of docetaxel in patients with liver metastases from breast cancer (2000)
    Springer
    Annals of oncology 11 (2000), S. 541-546 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; clinical trial ; docetaxel ; hepatic metastases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Previous phase II studies of docetaxel have indicatedthat hepatic metastases from breast cancer respond well to first-linetreatment with docetaxel. The objective of this prospective, open label phaseII study therefore was specifically to evaluate the activity and safety ofdocetaxel in this indication. Patients and methods:The study recruited 47 women (mean age 50years, range 33–66 years) with hepatic metastases from breast cancer whofulfilled the eligibility criteria. After premedication with steroids,patients received a one-hour intravenous infusion of docetaxel 100mg/m2 at three-weekly intervals for up to eight cycles. Responseto treatment during medication was assessed after three, six and whereappropriate, eight cycles and every three month follow-up thereafter, untildisease progression or death. Results:The best overall response rate (ORR) for evaluablepatients was 64.3% (95% CI: 48.0%–78.5%).In terms of the primary efficacy parameters, the ORR at the sixth cycle oftreatment was 62% (95% CI: 45%–80%) with17% complete responses. The median duration of response was 139 days(95% CI: 111–216 days) and the median survival durationcalculated on an intent-to-treat basis was 335 days (227–568 days,95% CI). One (2%) toxic death was reported. Conclusions:Docetaxel is a highly effective cytotoxic agent inthe treatment of patients with liver metastases from breast cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008383707159
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  • 69
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    Sentinel node biopsy as a practical alternative to axillary lymph node dissection in breast cancer patients: An approach to its validity (2000)
    Springer
    Annals of oncology 11 (2000), S. 701-705 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; lymph nodes ; sentinel lymph node biopsy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Sentinel node biopsy (SNB) has been proposed as analternative to axillary lymph-node dissection (ALND) in breast cancer. Beforeimplementing SNB in our practice, we wished to test its validity by comparingit to the standard ALND, both in our hands and with other reported series. Patients and methods:One hundred thirty-two patients wereincluded prospectively. SNB and immediate ALND were performed. For SNB, atechnetium-colloid was used to produce preoperative lymphoscintigraphy andintraoperative gamma-probe search for the SN. Serial sectioning andimmunostains were used on the SN. A comprehensive review of the literature wasdone in order to run a meta-analysis of diagnostic tests using a summaryreceiver operating characteristic curve (SROC) to calculate the pooledparameters of sensitivity and associated 95% confidence interval(95% CI), including our own data. Results:Our technical success rate was 96%. Localsensitivity was 96%, with a 95% CI from85%–99%. Seven patients were upstaged by the SNB. Aliterature search identified 18 studies published from 1996–1999.Estimates of sensitivity ranged from 83%–100%. The pooleddata meta-analysis gave a global sensitivity of 91%, with a 95%CI from 89%–93%. The area under the global SROC curve was0.9967. Conclusions:The minimally invasive SNB was shown to be apractical alternative to ALND. We propose to use local as well as globalsensitivity and associated 95% CI to test the validity of SNB in theclinical setting. Due to limitations of ALND as the golden standard, SNB canin fact be considered a more accurate method for nodal staging.
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    URL: http://dx.doi.org/10.1023/A:1008377910967
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  • 70
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    Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study (2000)
    Springer
    Annals of oncology 11 (2000), S. 367-371 
    Details
    ISSN: 1569-8041
    Keywords: docetaxel + gemcitabine ; docetaxel + vinorelbine ; phase I ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose:The objective of this study was to determine thedocetaxel MTD when combined with gemcitabine or vinorelbine in advanced breastcancer patients who had received previous anthracycline-based chemotherapy foradvanced disease. Patients and methods:Advanced breast cancer patients aged between18 and 70 with ECOG PS 0–2 who had not responded to, or had relapsedafter, first-line anthracycline-based chemotherapy, were randomized to receiveeither gemcitabine 1000 mg/m2 or vinorelbine 25 mg/m2in combination with escalating doses of docetaxel (starting from 30mg/m2), all on days 1 and 8 every three weeks. Escalation wasstopped if 〉33% of patients treated at a given dose level showed DLTat the first cycle. Results:A total of 34 patients with locally advanced (8) ormetastatic disease (26) were treated, for a total of 94 cycles delivered.Nineteen patients received docetaxel in combination with gemcitabine and 15with vinorelbine. All patients had been pretreated with anthracyclines, and24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of40/m2 proved to be safe when combined on days 1 and 8 withgemcitabine, while a dose of 35 mg/m2 was tolerated in combinationwith vinorelbine. Overall, nine episodes of DLT, all of them neutropenia,occurred at the first cycle. Considering all 94 cyles, grades 3 or 4neutropenia and thrombocytopenia occurred in 15 (44%), and 7(20%) patients. Non-hematologic toxicity was mild, except for threecases of grade 2 peripheral neuropathy. All patients were assessed forresponse on an 'intent-to-treat' basis. Overall, five partial responses wererecorded (docetaxel + gemcitabine = 3 and docetaxel + vinorelbine = 2), fora 15% (95% CI: 5%–31%) overall responserate. Only 1 of 24 (4%) patients who had received weekly dose-densepaclitaxel responded to treatment. Conclusions:The weekly docetaxel administration in combinationwith either gemcitabine or vinorelbine is a well-tolerated treatment forheavily pretreated advanced breast cancer patients. This approach, althoughsometimes capable of achieving a major response, does not seem advisable inadvanced breast cancer patients refractory to both anthracyclines andpaclitaxel.
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    URL: http://dx.doi.org/10.1023/A:1008346708604
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  • 71
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    Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors (2000)
    Springer
    Annals of oncology 11 (2000), S. 1057-1059 
    Details
    ISSN: 1569-8041
    Keywords: breast cancer ; estrogen receptor ; progesterone receptor ; preoperative chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:We recently demonstrated that in premenopausalpatients with estrogen receptors (ER)-absent tumors, early initiation ofsystemic chemotherapy after primary surgery might improve outcome. These dataindicate a different responsiveness to chemotherapy for tumors not expressinghormone receptors. To test this hypothesis we evaluated the responsiveness topreoperative chemotherapy in patients with ER and progesterone receptors(PgR)-absent tumors. Patients and methods:Patients with biopsy-provenT2–T3, N0–2 breast cancertreated at a single institution from January 1995 to August 1999 withpreoperative chemotherapy were retrospectively evaluated. ER and PgR weredetermined immunohistochemically and classified for this purpose as absent(0% of the cells positive) or positive (≥1% of the cells). Results:On 117 evaluable patients 72 had an objective response(61%). A significant difference in response was observed for patientswith ER and PgR absent compared with those with ER and/or PgR-positive tumors(82% vs. 57%,P = 0.03 Fishers's exact test).Pathological complete remission rates were also significantly different in thetwo groups (23% vs. 7%, respectively; P = 0.04). Conclusions:The different degree of response according to hormonereceptors expression supports the hypothesis that tumors not expressing bothER and PgR might represent a different clinical entity in terms ofchemotherapy responsiveness.
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    URL: http://dx.doi.org/10.1023/A:1008334404825
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  • 72
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    Sensitization of amphetamine-induced wheel running suppression in rats: dose and context factors (2000)
    Springer
    Psychopharmacology 151 (2000), S. 219-225 
    Details
    ISSN: 1432-2072
    Keywords: Keywords Amphetamine ; Wheel running ; Behavioral sensitization ; Pharmacological sensitization ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study explored whether repeated injections of amphetamine (AMP), which increase general locomotion, also increase acute wheel running, a highly structured, rewarding, motor behavior not correlated with other locomotor activities. Objectives: The experiments determine how 1–5 mg/kg d-AMP affects wheel running and see if, over repeated injections, the AMP effects show context specific sensitization. Methods: In experiment 1, 2 mg/kg AMP or saline (SAL) was injected on days 1, 3, 6, 8, and 10 to male Sprague-Dawley rats with either limited or no wheel experience. 20 min after the injection animals were tested in an open field for 5 min and then in a running wheel for 1 h. Rats were injected with SAL or AMP on the days following testing. On days 13 and 15, animals were tested for conditioning (following SAL) and sensitization (following AMP). In experiment 2, the effects on wheel running of repeated 1, 2, or 5 mg/kg AMP were tested. Results: In experiment 1, AMP (2 mg/kg) elevated open field ambulation but suppressed wheel running. Limited wheel experience potentiated the AMP-induced suppression. At test, the suppression of running was found to be context specific. In experiment 2, 1 mg/kg did not affect running, while 2 and 5 mg/kg resulted in dose-dependent running suppression. Acquisition and test AMP dose both influenced the running suppression at test; context had a marginal influence. Conclusions: The degree of running suppression induced by repeated AMP is determined by both psychological (the injection context) and pharmacological (the acquisition dose) factors. This AMP-induced running suppression is consistent with the sensitization of stereotyped behavior.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130000446
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  • 73
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    Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids (2000)
    Springer
    Psychopharmacology 148 (2000), S. 136-145 
    Details
    ISSN: 1432-2072
    Keywords: Key words Fentanyl ; mu opioids ; Drug discrimination ; Training dose ; pA2 analysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms. Objectives: In vivo apparent pA2 analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl. Methods: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA2 analyses were used to evaluate receptor mechanisms of stimulus control. Results: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA2 values of 7.6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA2 values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. Conclusions: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization.
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    URL: http://dx.doi.org/10.1007/s002130050035
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  • 74
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    Discriminative stimulus properties of alprazolam (2000)
    Springer
    Psychopharmacology 148 (2000), S. 146-152 
    Details
    ISSN: 1432-2072
    Keywords: Key words Alprazolam ; Drug discrimination ; Benzodiazepines ; Antidepressant ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. Objective: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Methods: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40”-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. Results: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), N-methyl-β-carboline-3-carboxamide (FG-7142) and picrotoxin. Conclusions: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality.
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    URL: http://dx.doi.org/10.1007/s002130050036
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    Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats (2000)
    Springer
    Psychopharmacology 148 (2000), S. 209-216 
    Details
    ISSN: 1432-2072
    Keywords: Key words Methamphetamine ; Drug-discrimination ; Dopamine ; Cocaine ; GBR-12909 ; Nomifensine ; Bupropion ; Chloro-PB ; Chloro-APB ; NPA ; 7-OH-DPAT ; SCH-23390 ; Spiperone ; cis-Flupenthixol ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Dopamine plays a major role in the behavioral effects of methamphetamine. Objective: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline. Methods: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1,D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine. Conclusions: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050044
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    Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine (2000)
    Springer
    Psychopharmacology 148 (2000), S. 234-242 
    Details
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Drug discrimination ; Self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed β2-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine’s acute subjective and reinforcing effects. Objective: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Methods: Adult male rats were trained to disciminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Results: Erysodine (0.3–10 mg/kg) and mecamylamine (0.1–1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32–32 mg/kg) and mecamylamine (0.32–3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for α4β2 nACHRs and its selectivity relative to α7 and α1β1γδ receptors, the present data support a critical role of β2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050047
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    The discriminative stimulus properties of the atypical antipsychotic olanzapine in rats (2000)
    Springer
    Psychopharmacology 148 (2000), S. 224-233 
    Details
    ISSN: 1432-2072
    Keywords: Key words Drug discrimination ; Olanzapine ; Clozapine ; Chlorpromazine ; Haloperidol ; Thioridazine ; Raclopride ; Risperidone ; Scopolamine ; Ritanserin ; Atypical antipsychotic ; Neuroleptic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Analysis of the preclinical behavioral effects of atypical antipsychotic agents will provide a better understanding of how they differ from typical antipsychotics and aid in the development of future atypical antipsychotic drugs. Objectives: The present study was designed to provide information about the discriminative stimulus properties of the atypical antipsychotic olanzapine. Methods: Rats were trained to discriminate the atypical antipsychotic olanzapine (either 0.5 mg/kg OLZ or 0.25 mg/kg OLZ, i.p.) from vehicle in a two- lever drug discrimination procedure. The atypical antipsychotic clozapine fully substituted for olanzapine in both the 0.5-mg/kg OLZ group (99.3% drug lever responding [DLR]) and the 0.25-mg/kg OLZ group (99.9% DLR). The typical antipsychotic chlorpromazine also substituted for olanzapine in both the 0.5-mg/kg OLZ group (87.5% DLR) and in the 0.25-mg/kg OLZ group (98.9% DLR); whereas, haloperidol displayed partial substitution for olanzapine in the 0.5-mg/kg OLZ group (56.1% DLR) and in the 0.25-mg/kg OLZ group (76.4% DLR). The 5.0-mg/kg dose of thioridazine produced olanzapine-appropriate responding in the 0.5-mg/kg OLZ group (99.6% DLR), but only partial substitution was seen with the 0.25-mg/kg OLZ training dose (64.0% DLR). The atypical antipsychotics raclopride (53.9% DLR) and risperidone (60.1% DLR) displayed only partial substitution in the 0.5-mg/kg OLZ group. Both the muscarinic cholinergic antagonist scopolamine (90.0% DLR) and the 5-HT2A/2C serotonergic antagonist ritanserin (86.0% DLR) fully substituted for olanzapine in the 0.5-mg/kg OLZ group. Conclusions: In contrast to previous discrimination studies with clozapine-trained rats, the typical antipsychotic agents chlorpromazine and thioridazine and the serotonin antagonist ritanserin substituted for olanzapine. These results demonstrate that there are differences in the mechanisms underlying the discriminative stimulus properties of clozapine and olanzapine. Specifically, olanzapine’s discriminative stimulus properties appear to be meditated in part by both cholinergic and serotonergic mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050046
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    The role of nicotinic and muscarinic acetylcholine receptors in attention (2000)
    Springer
    Psychopharmacology 148 (2000), S. 243-250 
    Details
    ISSN: 1432-2072
    Keywords: Key words Attention ; Scopolamine ; Mecamylamine ; Oxotremorine ; Physostigmine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. Methods: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Results: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01–0.03 mg/kg) and mecamylamine (0.5–1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non- selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Conclusions: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050048
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    Behavioral tolerance to the force differentiation effects of diazepam and midazolam in rats (2000)
    Springer
    Psychopharmacology 148 (2000), S. 327-335 
    Details
    ISSN: 1432-2072
    Keywords: Key words Benzodiazepine ; Operant ; Force ; Tolerance ; Chronic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Several benzodiazepines (BZs) have been shown to increase the peak force of operant responses at doses that increased, decreased, or had no effect on response rate, suggesting that operant response force may be a sensitive index of BZs’ effects rather than solely a correlate of rate-dependent effects. In addition, contingent tolerance to the rate-dependent effects of BZs has been reported, but the degree of contingent tolerance that develops when the critical variable of the task is force of the response has not been explored. Objectives: These experiments examined the effects of acute and repeated oral administration of diazepam (DZ) and midazolam (MZ) on a force-differentiation task to explore the importance of task requirements on the development of contingent tolerance. Methods: Two groups of rats were trained to press a force-sensing operandum, and responses having peak forces falling within fixed lower and upper limits [low force (8–10 g) or high force (40–50 g)] were reinforced with water. Acute effects of the oral administration of DZ (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg) and MZ (same doses) were determined for the discriminated-force task before and after a repeated-administration procedure. Results: When administered acutely, both drugs increased the peak force of responses in a dose-related manner and concomitantly reduced the proportion of reinforced responses, with MZ exhibiting greater potency. For the next 36 days, one group received drug before experimental sessions and the other group received drug after the experimental session. A second dose–effect determination demonstrated that rats chronically dosed with DZ or MZ pre-session displayed more contingent tolerance to alterations in peak force than rats that had received 36 drug injections post- session, where there was no opportunity to practice the force-discrimination response while under the drug state. Conclusions: These results suggest that perceptual motor difficulty of the task rather than effort may be an important variable in predicting the degree of contingent tolerance that develops. Additionally, these results suggest that both behavioral and pharmacological mechanisms are involved in the development of drug tolerance to the BZs.
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    URL: http://dx.doi.org/10.1007/s002130050059
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    Diazepam-like effects of a fish protein hydrolysate (Gabolysat PC60) on stress responsiveness of the rat pituitary-adrenal system and sympathoadrenal activity (2000)
    Springer
    Psychopharmacology 149 (2000), S. 34-40 
    Details
    ISSN: 1432-2072
    Keywords: Key words ACTH ; Corticosterone ; GABA ; Noradrenaline ; Adrenaline ; Stress ; Rat ; Diazepam
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Gabolysat PC60 is a fish protein hydrolysate with anxiolytic properties commonly used as a nutritional supplement. Objective: The diazepam-like effects of PC60 on stress responsiveness of the rat pituitary-adrenal system and on sympathoadrenal activity were studied. Methods: The activity of the pituitary-adrenal axis, measured by plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (B) of the sympathoadrenal complex, measured by circulating levels of noradrenaline (NA) and adrenaline (A), and the gamma aminobutyric acid (GABA) content in the hippocampus and the hypothalamus were investigated in male rats which received daily, by an intragastric feeding tube, for 5 days running either diazepam (1 mg/kg) or PC60 (300 or 1200 mg/kg). Controls received only solvent (carboxymethylcellulose 1%). Six hours after the last force-feeding, the rats were subjected to 3 min ether inhalation or 30 min restraint and killed by decapitation 30 min after ether stress or at the end of restraint. Results: Baseline plasma levels of ACTH, B, NA and A were not affected by either diazepam or PC60. Both ether- and restraint-induced release of ACTH, but not B, were similarly and drastically reduced by diazepam and PC60 (1200 mg/kg). Both diazepam and PC60 (1200 mg/kg) deleted restraint-induced NA and A increases. Both treatments also reduced the ether-induced rise of A. Basal levels of GABA were significantly increased in both the hippocampus and the hypothalamus in PC60-treated rats and only in the hippocampus in diazepam-treated ones. In controls, ether inhalation as well as restraint increased GABA content of these two brain structures. In contrast, such stress procedures performed in PC60-treated rats reduced GABA content slightly in the hippocampus but significantly in the hypothalamus. In diazepam-treated rats, GABA content of the hypothalamus was unaffected by stresses but that of the hippocampus was slightly decreased. Conclusions: Present data suggest diazepam-like effects of PC60 on stress responsiveness of the rat pituitary adrenal axis and the sympathoadrenal activity as well as GABA content of the hippocampus and the hypothalamus under resting and stress conditions. These effects of PC60 agree with anxiolytic properties of this nutritional supplement, previously reported in both rats and humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900338
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    The 5-HT1A receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT1A receptors (2000)
    Springer
    Psychopharmacology 149 (2000), S. 259-268 
    Details
    ISSN: 1432-2072
    Keywords: Key words 8-OH-DPAT ; WAY 100635 ; 5 ; 7-Dihydroxytryptamine ; Attention ; Impulsivity ; Pre- and postsynaptic 5-HT1A receptor ; Dorsal raphe ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Whilst several studies have investigated the role of serotonergic receptor subtypes in learning and memory, relatively few studies have examined their role in attentional processes. Objective: The present study investigated the role of pre- and postsynaptic 5-HT1A receptors on rats’ attentional performance in the five-choice serial reaction time task (5-CSRT). Methods: Hungry rats were trained in the 5-CSRT task to detect brief (0.5 s) flashes of light presented randomly in one of five locations with a fixed intertrial interval of 5 s paced by the rat. We studied the effects of 8-OH-DPAT, a 5-HT1A receptor agonist, at various subcutaneous (SC) doses (10–100 µg/kg) on measures of rats’ discriminative accuracy (the index of attentional functioning) and various behavioural indices of response control and motivation. Manipulations of basic task parameters, intracerebroventricular (ICV) injections of 5,7-dihydroxytryptamine (5,7-DHT) to deplete forebrain 5-HT and treatments with a selective 5-HT1A receptor antagonist WAY 100635 were made in order to determine the behavioural and neural specificity of the effects of 8-OH-DPAT. Results: A dose of 100 µg/kg, but not lower doses, significantly reduced choice accuracy and increased errors of omission, latencies to respond correctly and to collect food reward and premature responses. All these effects were completely blocked by WAY 100635, injected SC 5 min before 8-OH-DPAT at doses from 10–100 µg/kg. WAY 100635 by itself had no effect in the task. Dimming the visual stimuli to one-third of the usual brightness did not modify the effect of 8-OH-DPAT on choice accuracy. Prolonging the stimuli from 0.5 to 1.0 s reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the other effects on rats’ performance. An ICV injection of 150 µg 5,7-DHT, which depleted forebrain serotonin by 90%, reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the effects on errors of omission and latency to make correct responses. Similar effects were found by infusing 1.0 µg/0.5 µl WAY 100635 in the dorsal raphe 5 min before 8-OH-DPAT. 8-OH-DPAT increased the latency to collect the reinforcement; this effect was attenuated by ICV 5,7-DHT and completely antagonized by WAY 100635 in the dorsal raphe. Rats treated with 5,7-DHT or 8-OH-DPAT showed more premature responses and these effects were markedly reduced by the combined treatment. Conclusions: The results suggest that stimulation of presynaptic 5-HT1A receptors is involved in the ability of 8-OH-DPAT to cause attentional dysfunction and enhance impulsivity while slowing of responding and increase in errors of omission mainly depend on stimulation of postsynaptic 5-HT1A receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002139900368
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    Effects of cytomegalovirus infection and prolonged cold ischemia on chronic rejection of rat renal allografts (2000)
    Springer
    Transplant international 13 (2000), S. 54-63 
    Details
    ISSN: 1432-2277
    Keywords: Key words Kidney transplantation ; Rat ; Chronic rejection ; Cytomegalovirus ; Adhesion molecules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49 d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way.¶The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050009
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    Effect of anti-CD4 monoclonal antibody administration on rat small bowel allograft survival and circulating leukocyte populations (2000)
    Springer
    Transplant international 13 (2000), S. 211-217 
    Details
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Monoclonal antibody ; Rat ; Rejection ; Flow cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study assessed the effect of an anti-rat CD4 monoclonal antibody (OX38) on heterotopic small bowel allograft rejection. Fully allogeneic small bowel transplants were performed in the PVG-to-DA-rat strain combination. Animals received either i) short course (days –1, 0 and 1) of 1 mg/kg per day OX38, ii) short course of 5 mg/kg per day or iii) extended course (days –2, –1, 0, 1, 2 and twice weekly thereafter) of 1 mg/kg per day. Both the high dose (13 days) and extended low-dose (12 days) courses prolonged graft survival compared to untreated control animals (7 days). The low-dose, short-course treatment had no effect. Similar regimens were given to animals that did not receive transplants and in which peripheral blood CD4+ cell counts fell to between 20 and 55 % of pretreatment levels and 20–30 % of binding sites were blocked. In summary, anti-CD4 monoclonal antibody therapy delayed rejection of rat small bowel allografts; however, long-term survival was not achieved.
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    URL: http://dx.doi.org/10.1007/s001470050689
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    Regional Spinal Cord Blood Flow and Energy Metabolism in Rats after Laminectomy and Acute Compression Injury (2000)
    Springer
    European journal of trauma 26 (2000), S. 122-130 
    Details
    ISSN: 1615-3146
    Keywords: Key Words Spinal cord compression ; Autoradiography ; Blood flow ; ATP ; Glucose ; Lactate ; Bioluminescence ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Many data are available concerning spinal cord blood flow (SCBF) and metabolism on various models and timing after spinal cord injury, however, detailed information on their exact relationship in the same injury model is lacking. This relationship is a crucial factor in the understanding of the pathophysiology of spinal cord trauma. Rats were subjected to lumbar laminectomy or lumbar spinal cord compression trauma. 3 hours later, changes in SCBF were evaluated autoradiographically and changes in ATP, glucose and lactate levels were analyzed using substrate-specific bioluminescence techniques. Measurements were performed at the lesion site (segment L4), adjacent segments (L3 and L5) and at remote thoracic segments (Th8 to Th9). Laminectomy alone did not change SCBF, both in thoracic and lumbar segments. In contrast, ATP levels were significantly reduced and lactate levels were increased at the lesion site and in adjacent lumbar segments at 3 hours after laminectomy, whereas glucose levels were not significantly changed. In animal subjected to additional compression trauma, SCBF was significantly reduced in segments L3, L4 and L5 paralleled by a significant ATP reduction and lactate increase. Glucose levels did not differ significantly from controls 3 hours after compression injury. This metabolic profile was also reflected in the remote thoracic segments. In contrast, SCBF was not reduced in thoracic segments of traumatized animals. The observation that ATP was already significantly reduced and lactate increased in laminectomized segments and in remote thoracic regions after trauma signals that metabolic changes are sensitive indicators to spinal stress. The fact that posttraumatic metabolic profile differs from the pattern of hemodynamic and metabolic changes induced by ischemia, suggests posttraumatic mediators may be involved in the different regulation of the energy producing machinery.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s000680050010
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    Mechanomyograms recorded during evoked contractions of single motor units in the rat medial gastrocnemius muscle (2000)
    Springer
    European journal of applied physiology 83 (2000), S. 310-319 
    Details
    ISSN: 1439-6327
    Keywords: Key words Motor unit ; Mechanomyography ; Evoked contraction ; Medial gastrocnemius muscle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Acoustic phenomena accompanying contractions of single motor units (MUs) have previously received little attention. Therefore, in the present study, the mechanomyographic (MMG) signals during evoked contractions of single MUs have been recorded from the medial gastrocnemius muscle of the rat. A piezoelectric transducer immersed in a paraffin-oil pool was used for the measurement of these signals. Muscle fibre action potentials, tension and MMG were recorded in parallel during twitch (the weakest) and fused tetanic (the strongest) MU contractions. It was observed that the onset of the MMG signals was coincident with the beginning of the increase in tension for both the twitch and tetanus. Weaker MMG signals than those accompanying the beginning of the first phase of the fused tetanus were seen during the beginning of the relaxation after tetanic contraction. During contraction and relaxation, MMG signals were characterised by the reverse-direction of the first extreme phase, positive and negative, respectively. No MMG signals were observed when the tension was constant during the fused tetanus. The amplitude of MMG signals was correlated with both the tension increase and the velocity of tension increase during both the twitch and the fused tetanus. The strongest MUs (fast fatiguable) generated MMG signals of the highest amplitude. MMG signals were not detected for some of the weakest slow MUs (with tension increases of ≤2 mN). These results indicate a strong correlation between the MMG and the change of tension. Therefore, we believe that MMG signals are generated by muscle deformation that occurs during the contraction of MU muscle fibres. We conclude that the number of active muscle fibres, their topography, and their localisation in relation to the muscle surface (which is variable for different types of MUs) influence these MMG phenomena.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004210000261
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    Expression of bone sialoprotein and osteopontin in breast cancer bone metastases (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 253-260 
    Details
    ISSN: 1573-7276
    Keywords: bone sialoprotein ; osteopontin ; breast cancer ; metastasis ; bone metastases ; immunohistochemistry ; in situ hybridization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bone sialoprotein (BSP) and osteopontin (OPN) are prominent, mineral-associated proteins in the extracellular matrix of bone that have been implicated in the metastatic activity of cancer cells. The expression of BSP, which is normally restricted to mineralizing tissues, has been observed in cancers with a high propensity for forming bone metastases. To investigate the relationship between BSP expression and the formation of bone metastases we have conducted an initial study of the expression of BSP in 10 intraductal breast carcinoma bone metastases using immunostaining and in situ hybridization, and compared the expression with OPN. The metastases were characterized by the infiltration of tumour cells into bone with extensive bone resorption evident. Moderate to strong staining for BSP was observed in all (100%) carcinomas, which also expressed BSP mRNA as determined by in situ hybridization. Variable staining for BSP was also observed in the mineralized bone and expression of BSP mRNA could be observed in osteoblastic cells on the bone surface and in some osteocytes at sites of bone remodelling. Contrary to a previous report, BSP expression could be demonstrated by PCR in three breast cancer cell lines, MCF-7, T47-D and MDA-MB-231. Moreover, in sub-cutaneous tumours formed by MDA-MB-231 breast cancer cells injected into athymic mice, higher immunostaining for BSP was seen in large ulcerating tumours in which mineral deposits were formed. In contrast to BSP, staining for OPN in bone metastases was generally restricted to the interface between tumor cells and bone surface of the carcinomas. While OPN staining was also observed in the cytoplasm of osteoclasts, which showed strong hybridization to a digoxygenin-labelled OPN cRNA probe, expression of OPN was not clearly detectable in the tumour cells. These studies provide the first demonstration of BSP expression by tumour cells in bone metastases and support the concept that BSP may have a role in targeting metastatic cells to bone. Expression of OPN in bone metastases appears to be related to increased bone resorptive activity by osteoclasts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006754605901
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  • 87
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    Electronic Resource
    Keratinocyte growth factor-induced motility of breast cancer cells (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 573-580 
    Details
    ISSN: 1573-7276
    Keywords: breast cancer ; cell motility ; KGF ; metastasis ; MCF-7 ; T-47D ; ZR-75-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Endogenous growth factors and cytokines are known to have a major influence on the progression, motility and invasiveness of tumor cells. We have reported previously that conditioned media from mouse fibroblasts increases the motility of breast cancer cells. Further, we determined that keratinocyte growth factor (KGF) was an active factor from mouse fibroblasts responsible for most of the motility response in breast cancer cells. The present study examined the effect of human KGF on the motility of estrogen receptor (ER)-positive and ER-negative human breast cancer cell lines in culture using time-lapse videomicroscopy to quantify cell motility. In the present study we observed that recombinant human KGF enhanced several parameters of cellular motility in ER-positive cells but not in ER-negative cell lines. Further, we observed that the level of KGF receptor (KGFR) expression in ER-positive cells was much greater than in the ER-negative cell lines. The motility response to KGF was found to be both dose-and time-dependent. Of the three ER-positive breast cancer cell lines tested, MCF-7 cells were the most responsive to KGF stimulation. Finally, MCF-7 cells grown in estrogen-depleted media did not respond to KGF. These results suggest that KGF from stromal tissue surrounding a primary tumor mass can enhance tumor cell motility and may be an early signal in the progression of breast cancer cells to a more motile and metastatic phenotype. Thus, KGF, KGFR and/or the KGF signaling pathway may be important therapeutic targets for the treatment or prevention of breast cancer metastasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011997317994
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  • 88
    Electronic Resource
    Electronic Resource
    Analysis of mechanisms underlying BRMS1 suppression of metastasis (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 683-693 
    Details
    ISSN: 1573-7276
    Keywords: breast cancer ; chromosome 11q13 ; gap junctions ; metastasis suppressor gene ; motility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Introduction of normal, neomycin-tagged human chromosome 11 (neo11) reduces the metastatic capacity of MDA-MB-435 human breast carcinoma cells by 70–90% without affecting tumorigenicity. Differential display comparing MDA-MB-435 and neo11/435 led to the discovery of a human breast carcinoma metastasis suppressor gene, BRMS1, which maps to chromosome 11q13.1–q13.2. Stable transfectants of MDA-MB-435 and MDA-MB-231 breast carcinoma cells with BRMS1 cDNA still form progressively growing, locally invasive tumors when injected in mammary fat pads of athymic mice but exhibit significantly lower metastatic potential (50–90% inhibition) to lungs and regional lymph nodes. To begin elucidating the mechanism(s) of action, we measured the ability of BRMS1 to perturb individual steps of the metastatic cascade modeled in vitro. Consistent differences were not observed for adhesion to extracellular matrix components (laminin, fibronectin, type IV collagen, type I collagen, Matrigel); growth rates in vitro or in vivo; expression of matrix metalloproteinases, heparanase, or invasion. Likewise, BRMS1 expression did not up regulate expression of other metastasis suppressors, such as NM23, Kai1, KiSS1 or E-cadherin. Motility of BRMS1 transfectants was modestly inhibited (30–60%) compared to parental and vector-only transfectants. Ability to grow in soft agar was also decreased in MDA-MB-435 cells by 80–89%, but the decrease for MDA-MB-231 was less (13–15% reduction). Also, transfection and re-expression of BRMS1 restored the ability of human breast carcinoma cells to form functional homotypic gap junctions. Collectively, these data suggest that BRMS1 suppresses metastasis of human breast carcinoma by complex, atypical mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1013124725690
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  • 89
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    Electronic Resource
    Chemotherapy-induced Complete Regression of Choroidal Metastases and Subsequent Isolated Leptomeningeal Carcinomatosis in Advanced Breast Cancer: A Case Report and Literature Review (2000)
    Springer
    Journal of neuro-oncology 47 (2000), S. 161-165 
    Details
    ISSN: 1573-7373
    Keywords: choroidal metastasis ; leptomeningeal carcinomatosis ; breast cancer ; docetaxel ; mitoxantrone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Choroidal metastases from breast cancer represent an unusual metastatic presentation that has been traditionally treated with radiation therapy. Herein, we report a case of metastatic breast cancer presenting with pulmonary, cutaneous, lymph node and symptomatic choroidal metastases treated with systemic combination chemotherapy incorporating docetaxel and mitoxantrone without induction or consolidation radiation therapy to control visual symptoms from choroidal metastases. The patient experienced a durable complete remission in all metastatic sites that was maintained for 21 months since the initiation of chemotherapy, afterwhich she developed isolated leptomeningeal carcinomatosis managed successfully with intensive intrathecal methotrexate and whole brain irradiation leading to a new complete remission maintained until this report; 11 months after its presentation. This is the first case to our knowledge reporting complete regression of choroidal metastases with docetaxel-based chemotherapy as the only treatment modality and subsequent isolated leptomeningeal carcinomatosis recurrence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006449215047
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  • 90
    Electronic Resource
    Electronic Resource
    Biological Features of Premalignant Disease in the Human Breast (2000)
    Springer
    Journal of mammary gland biology and neoplasia 5 (2000), S. 351-364 
    Details
    ISSN: 1573-7039
    Keywords: Human ; breast cancer ; premalignant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Most human invasive breast cancers (IBCs)4 arise from preexisting benign lesions. There are many types of benign lesions in the human breast and only a few appear to have significant premalignant potential (atypical hyperplasias and in situ carcinomas). These lesions are relatively common and only a small proportion progress to IBC. They are currently defined by their histological features and their prognosis is imprecisely estimated from indirect evidence based on epidemiological studies. Although lesions within specific categories look alike, they must possess morphologically silent biological differences motivating some to remain stable and others to progress. Understanding the biological changes responsible for the development and progression of premalignant disease is a very active area of medical research. Progress in this area may provide new opportunities for breast cancer prevention by providing strategies to treat premalignant lesions before they develop or become cancerous. A large number of biological features have been evaluated in this setting during the past decade. This review discusses a few features that appear to be particularly important and have been studied in a relatively comprehensive manner.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009573710675
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  • 91
    Electronic Resource
    Electronic Resource
    Rat Models of Premalignant Breast Disease (2000)
    Springer
    Journal of mammary gland biology and neoplasia 5 (2000), S. 409-420 
    Details
    ISSN: 1573-7039
    Keywords: Pre-malignancy ; breast cancer ; experimental model ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract While a number of agents have been shown to induce mammary carcinogenesis in the rat, premalignant stages of the disease have been best characterized in chemically-induced models, specifically those initiated by either 7,12 dimethylbenz[α]anthracene (DMBA)4 or 1-methyl-1-nitrosourea (MNU). In general, it appears that epithelial cells in mammary terminal end buds or terminal ductules are the targets of carcinogenic initiation, and that a series of morphologically identifiable steps are involved in the development of mammary carcinoma. The premalignant steps include ductal hyperplasia of the usual type and carcinoma in situ of the cribriform or comedo type; atypical ductal hyperplasia has not been reported. Thus the histogenesis of lesions occurring in chemically induced mammary carcinogenesis in the rat is similar to that observed in the human; although, the spectrum of lesions observed in the rat is limited. Opportunities to investigate the biological and molecular characteristics of premalignant breast disease in the rat are presented.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009582012493
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  • 92
    Electronic Resource
    Electronic Resource
    The Basic Pathology of Human Breast Cancer (2000)
    Springer
    Journal of mammary gland biology and neoplasia 5 (2000), S. 139-163 
    Details
    ISSN: 1573-7039
    Keywords: breast cancer ; pathology atlas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This article illustrates the most common benign and malignant lesions in the breast, and is intended for the biologist working in the area of breast cancer and breast biology, not for the practicing pathologist. The atlas covers benign proliferative lesions, atypical lesions, variants of in situ cancer, the main types of invasive cancers, spindle cell lesions, and examples of vascular and lymphatic spread. Some entities are included to illustrate a point of particular relevance to the biology and histogenesis of the lesions. Some controversial diagnostic areas are considered, along with the relative risk of developing breast cancer associated with some of the proliferative lesions. The content of this atlas should be read in conjunction with the companion article by Howard and Gusterson in this issue. Their article covers the cellular origin of epithelial and stromal tumors and presents a description of some of the common benign proliferative lesions that are considered to be components of the normal spectrum of changes seen at postmortem or in biopsies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026439204849
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  • 93
    Electronic Resource
    Electronic Resource
    Historical and Epidemiologic Background of Human Premalignant Breast Disease (2000)
    Springer
    Journal of mammary gland biology and neoplasia 5 (2000), S. 341-349 
    Details
    ISSN: 1573-7039
    Keywords: Premalignancy ; risk ; breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Premalignant breast disease in humans is a concept that admits to a broad range of elements and possible determinants predicting the likelihood of developing breast cancer. Most of these elements are relative, such as the risk of breast cancer for women that is 130 times that of men and peaks at a younger age by about 10 years. Breast cancer is clearly a stochastic, multifactorial process that evolves over many years in which we must make predictions by likelihood. This review will present the most specially defined and reliably proven of these elements, highlighting anatomic and molecular factors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009521726605
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  • 94
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    Electronic Resource
    Modulation of Paired-Pulse Responses in the Dentate Gyrus: Effects of Normal Maturation and Vigilance State (2000)
    Springer
    Annals of biomedical engineering 28 (2000), S. 128-134 
    Details
    ISSN: 1573-9686
    Keywords: Hippocampus ; Vigilance states ; Paired-pulse ; Dentate gyrus ; Dentate granule cells ; Evoked response ; Rat ; In vivo studies ; Perforant path ; Maturation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract This study examined the effect of normal development and vigilance state on the modulation of dentate granule cell activity in the freely moving rat at 15, 30, and 90 days of age across three vigilance states: quiet waking, slow-wave sleep, and rapid eye movement sleep. Using paired-pulse stimulation, the paired-pulse index (PPI) was obtained for the dentate evoked field potentials elicited by the stimulation of the medial perforant path. Although significant differences in PPI values were observed during development, no significant vigilance state related changes were obtained. Preweaning infant rats, i.e., 15-day old, exhibited significantly less early (interpulse intervals, IPI= 20–50 ms) and late (IPI = 300–1000 ms) inhibition, and less facilitation (IPI = 50–150 ms) when compared to the 90-day old adult rats during all three vigilance states. PPI values obtained from the 30-day old group fell intermediate between the 15- and 90-day old animals. These changes in PPI values provide a quantitative measure of changes in the modulation of dentate granule cell excitability during normal maturation. They can now can be used to evaluate the impact of various insults, such as prenatal protein malnutrition or neonatal stress, on hippocampal development. © 2000 Biomedical Engineering Society. PAC00: 8717Nn, 8719La, 8719Nn
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1114/1.261
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  • 95
    Electronic Resource
    Electronic Resource
    Left Ventricular Contractility is Impaired Following Myocardial Infarction in the Pig and Rat: Assessment by the End Systolic Pressure–Volume Relation Using a Single-Beat Estimation Technique and Cine Magnetic Resonance Imaging (2000)
    Springer
    Annals of biomedical engineering 28 (2000), S. 484-494 
    Details
    ISSN: 1573-9686
    Keywords: Heart ; Left ventricle ; LV contractility ; ESPVR ; Pig ; Rat ; Magnetic resonance imaging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract The end systolic pressure–volume relation (ESPVR) has been shown to be a relatively load independent measure of left ventricular (LV) contractility. Recently, several single-beat ESPVR computation methods have been developed, enabling the quantification of LV contractility without the need to alter vascular loading conditions on the heart. Using a single-beat ESPVR method, which has been validated previously in humans and assumes that normalized elastance is constant between individuals of a species, we studied the effects of myocardial infarction on LV contractility in two species, the rat and the pig. In our studies, LV pressure was acquired invasively and LV volume determined noninvasively with magnetic resonance imaging, at one week postinfarction in pigs and at 12 weeks postinfarction in rats. Normalized systolic elastance curves in both animal species were not statistically different from that of humans. Also, the slope of the ESPVR $$\left( {E_{es} } \right)$$ decreased significantly following infarction in both species, while the volume-axis intercept $$\left( {V_0 } \right)$$ was unaffected. These results indicate that a single-beat ESPVR method can be used to measure the inotropic response of the heart to myocardial infarction, and that the basis for this method (i.e., constant normalized elastance) is applicable to a variety of mammalian species. © 2000 Biomedical Engineering Society. PAC00: 8719Uv, 8761Lh, 8719Hh, 8719Rr, 8719Ff
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1114/1.289
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  • 96
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    Electronic Resource
    Quantifying Coevolution of Nonstationary Biomedical Signals Using Time-Varying Phase Spectra (2000)
    Springer
    Annals of biomedical engineering 28 (2000), S. 1101-1115 
    Details
    ISSN: 1573-9686
    Keywords: Time–frequency analysis ; Coherence ; Cross correlation ; Nonstationary persistent signals ; Central pattern generator ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract We present a novel time-varying phase spectrum (TVPS) method to quantify the dynamics of coevolution of two persistent nonstationary coupled signals. Based on the TVPS, an instantaneous intersignal phase shift is defined within the primary frequency range in which the two signals are highly correlated. The TVPS is estimated using a fixed-window method or an adaptive-window method. In the latter method, the window length changes dynamically and automatically as a function of change in frequency of the signals. The effects of altering window types and lengths on the accuracy of the estimation of the primary phase shift is assessed by analyzing synthesized linear chirp signals with decaying amplitude and constant relative phase shift or decaying amplitude and changing relative phase shifts. The methods developed are also used for determining the evolution of the primary phase shift among ventral root activities during fictive locomotion in an in vitro rat spinal cord preparation. The analyses indicate that the TVPS method in conjunction with the determination of the primary frequency range, allows determination of both the evolution of the coupling strength and the evolution of the phase shift between two persistent nonstationary rhythmic signals in the joint time–frequency domain. An adaptive window reduces the estimation bias and the estimation variability. © 2000 Biomedical Engineering Society. PAC00: 0230-f, 8780Tq
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1114/1.1313775
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  • 97
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    Electronic Resource
    Framing of outcome and probability of recurrence: Breast cancer patients' choice of adjuvant chemotherapy (ACT) in hypothetical patient scenarios (2000)
    Springer
    Breast cancer research and treatment 60 (2000), S. 9-14 
    Details
    ISSN: 1573-7217
    Keywords: adjuvant chemotherapy ; breast cancer ; decision-making ; treatment preference ; decision board instrument
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose.To examine the effects of framing of outcome and probabilities of cancer occurrence on the treatment preference which breast cancer patients indicate for hypothetical patient scenarios. Methods.A modified version of the Decision Board Instrument (Levine et al. 1992) was administered to 35 breast cancer patients with past ACT experience. Patients expressed their choice regarding ACT for six scenarios which were characterized by either negative or positive framing of outcome and by one of the three levels of probability of recurrence (high, medium, low). Results.The framing had no influence on ACT choices over all three probability levels. The majority chose ACT for high and medium risk and one third switched from ACT to No ACT in the low-risk condition. This switch was statistically significant. Conclusion.Hypothetical treatment decisions against ACT occur only when the probability of recurrence is low and the benefit of ACT is small. This finding for patients with past experience of ACT is similar to those reported for other oncological patient groups still in treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006342316373
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  • 98
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    Electronic Resource
    Surgical treatment of hepatic metastases from breast cancer (2000)
    Springer
    Breast cancer research and treatment 59 (2000), S. 177-184 
    Details
    ISSN: 1573-7217
    Keywords: breast cancer ; metastasis ; liver metastasis ; surgical procedure ; hepatectomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have performed a retrospective study to evaluate whether surgical treatment is beneficial in patients with hepatic metastases from breast cancer. Between September 1985 and September 1998, 25 patients with hepatic metastases (14 solitary and 11 multiple), eight of whom had extrahepatic metastases, underwent hepatectomy. All of the detectable liver metastasis were resected in all of the cases. There were no severe postoperative complications. All but one of the patients received adjunctive polychemotherapy after the hepatectomy. After the hepatectomy, recurrent tumors were detected in 18 of the patients, being located in the liver in 12 (67%) of them. Overall, however, hepatectomy ensured that the liver was clinically recurrence-free for a median of 24 months (range 2–132 months). Eleven patients died of recurrent tumors, two died of other causes and the remaining 12 are currently alive. The 2- and 5-year cumulative survival rates after hepatectomy were 71% and 27%, respectively, and the median survival duration was 34.3±3.2 months, much better than the period of 8.5 months for another series of patients treated with standard or non-surgical therapies at our institution. The number and the size of hepatic metastases, the interval between treatment of the primary lesion and hepatectomy, and the existence of extrahepatic metastasis were not adverse prognostic factors. In conclusion, our data, although limited and highly selective, suggest that surgical treatment of hepatic metastases from breast cancer may prolong survival in certain subgroups of patients to a greater extent than standard or non-surgical therapies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006398401352
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  • 99
    Electronic Resource
    Electronic Resource
    Quantitative measurement of soluble cytokeratin fragments in tissue cytosol of 599 node negative breast cancer patients: a prognostic marker possibly associated with apoptosis (2000)
    Springer
    Breast cancer research and treatment 59 (2000), S. 211-221 
    Details
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; continuous variables statistical analysis ; cytokeratins ; multiple correspondence analysis ; prognosis ; tissue cytosol ; tissue polypeptide antigen (TPA)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Apoptosis is associated with caspase-mediated proteolysis of Type I (K18 and K19) cytokeratins. We previously showed a positive association between the levels of tissue polypeptide antigen (TPA), that recognizes cytokeratins K8, K18, and K19 fragments, and induced apoptosis in breast cancer cell lines. The aim of the present study was to evaluate the interrelationships between TPA, steroid receptors, and p53, and their joint prognostic role in node-negative breast cancer patients not treated with adjuvant therapies. Age and pT were also considered since they are known prognostic factors. Five hundred and ninety-nine cases with N- breast cancer were evaluated (median follow-up: 60 months). TPA was measured by an immunoradiometric assay and p53 by an immuno-chemiluminescent assay in tumor cytosol. Multiple correspondence analysis was used to study the associations among variables. Their prognostic role (univariate analysis) and their joint effect (multivariate analysis) on RFS were investigated with Cox regression models. TPA showed a direct association with ER and PgR. Higher p53 values were weakly associated to low values of ER, PgR, and TPA. Younger age was related to low and intermediate values of ER and PgR and to low p53 values, while older age was related to high values of ER. Multivariate analysis showed a significant prognostic impact for pT, age, ER, and TPA. Among the interactions considered clinically relevant, only that between ER and age was found. RFS estimated values were poorer in cases with lower than in those with higher TPA values, both in patients expected to have a poor (pT2, young age, low ER) and a better prognosis (pT1, older age, high ER). From the findings of the present study we can draw the following conclusions: The relationship of TPA with prognosis gives an additional contribution to pT, age, and steroid receptors in N- breast cancer; TPA may be considered the first marker of apoptosis measured with a fully standardized quantitative method in tumor cytosol and could be evaluated in prognostic indexes including markers related to different biological mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006318112776
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  • 100
    Electronic Resource
    Electronic Resource
    Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF-7 breast cancer cells (2000)
    Springer
    Breast cancer research and treatment 59 (2000), S. 231-244 
    Details
    ISSN: 1573-7217
    Keywords: reversal ; paclitaxel ; resistance ; P-glycoprotein ; breast cancer ; valspodar ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Paclitaxel (Taxol®) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated 〉6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006344200094
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