Dementia in stroke.
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Cerebrovascular Disorders↗
Biomedical subjects
C Lucas
Publications and source records attributed to C Lucas.
Effect of lymphocytes on hormonal secretion by autologous thyrocytes cultured in monolayers.
We studied the lymphocyte-induced alterations in hormonal metabolism and the production of tumour necrosis factor alpha (TNF-alpha) during coculture of thyrocytes and autologous lymphocytes from 20 patients with Graves' disease and from five normal subjects. Thyroglobulin (Tg) mRNA was assessed by slot-blot analysis under TSH stimulation. Tg, tri-iodothyronine (T3) and cAMP secretion in the presence of TSH were measured by RIA after 3 or 5 days of coculture. TNF-alpha levels produced after 5 days incubation were also assayed in lymphocyte culture and coculture media. Lymphocytes isolated from peripheral blood (PBLs) altered the production of Tg, T3 and cAMP in autologous thyrocytes. Intrathyroidal lymphocytes (ITLs) decreased Tg and cAMP secretion but had no effect on T3 secretion. The reductions in Tg and cAMP levels obtained with mechanically isolated ITLs (M-ITLs) were generally higher than those obtained with ITLs isolated by dispase (D-ITLs). No difference was seen between Graves' disease and normal cocultures. PBLs secreted large concentrations of TNF-alpha, larger than those obtained with M-ITLs whereas D-ITLs produced low amounts of this cytokine. In coculture, TNF-alpha levels were lower than those observed in lymphocyte culture. Significant correlations were obtained between TNF-alpha levels and the decrease in Tg, T3 and cAMP concentrations. The percentage of T lymphocytes was higher in PBLs and D-ITLs than in M-ITLs. B lymphocytes levels were higher in ITLs, especially M-ITLs, than in PBLs. TNF-alpha production by B lymphocytes was maximal in M-ITLs. In conclusion, lymphocytes induced a decrease in hormonal thyroid metabolism when cocultured with autologous thyrocytes. These perturbations may be attributed, at least partly, to TNF-alpha secreted by lymphocytes. TNF-alpha interacts via the adenylate cyclase pathway of TSH signal transduction.
Adult↗
Atrophy of the supraspinatus belly. Assessment by MRI in 55 patients with rotator cuff pathology.
A study of 5 fresh cadaveric shoulders demonstrated that an oblique-sagittal plane which crosses the scapula through the medial border of the coracoid process offers a view of the supraspinatus fossa mostly limited by bone. This view could easily be reproduced by MRI and we called it the Y-shaped view. It allowed a reliable measurement of supraspinatus muscle atrophy by the calculation of the occupation ratio (R) which is the ratio between the surface of the cross-section of the muscle belly and that of the fossa. This ratio was calculated in a prospective study based on 55 shoulders divided into 3 groups with different rotator cuff status: group I, 15 controls; group II, 10 degenerative cuffs, without tears; group III, 30 operated tears. There was no difference between groups I (mean ratio 0.7) and II (mean ratio 0.62), but the ratio was decreased in group III (mean ratio 0.44), in which the extent of the tear in both the sagittal and coronal planes aggravated the muscle atrophy. We propose a three-stage classification to improve indications for rotator cuff tear treatment.
Adolescent↗
Carotid pseudovalvular fold: a case diagnosed by angiography and helical cervical tomography.
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Adult↗
Cranial nerve palsies due to internal carotid artery dissection: seven cases.
Cranial nerve palsies are rare complications of internal carotid artery (ICA) dissections. The aim of this study is to evaluate the incidence of cranial nerve palsies in consecutive patients with ICA dissection and to describe clinical and radiological characteristics and their evolution over time. This study was conducted in 52 consecutive patients with dissection of the ICA. We have analyzed clinical data of patients with cranial nerve palsy as complication of ICA dissection. We defined ICA dissection as angiographic evidence of a string sign, double lumen, or internal flaps or visualization on magnetic resonance imaging (MRI) or computed tomographic scans of an enlarged arterial wall due to the hematoma. Of 52 consecutive patients with ICA dissection 7 had cranial nerve palsies: 2 had an involvement of the Vth cranial nerve and 5 had lower cranial nerve palsies. Five patients totally recovered while 2 did not after a 2 to 10-month period. The frequency of cranial nerve palsies associated with ICA dissection is higher in our study than in those of the literature. Many patients presenting with cranial nerve palsies due to ICA dissection without any ischemic event are probably not referred to stroke units. Angiography is less sensitive than cervical MRI to detect such patients. Cranial nerve palsies could either be due to compression by the enlarged ICA wall or an ischemia of the nerve.
Adult↗
[Expression of the MDR1 gene in five human cell lines of medullary thyroid cancer and reversion of the resistance to doxorubicine by ciclosporin A and verapamil].
Medullary thyroid carcinoma (MTC) is frequently resistant to chemotherapy. Multidrug resistance (MDR) is one of the involved mechanisms. In this work we have studied the MDR1 gene expression in five MTC human cell lines that we have isolated and we have compared this expression to that of normal thyroid tissue. We have also tried to reverse the resistance to doxorubicin with verapamil (VRP) and ciclosporin A (CSA). MDR1 ARNm expression was studied and quantified by polymerase chain reaction (PCR) in normal and pathological thyroid tissues. The doxorubicin-induced cytotoxicity was evaluated with the 3,-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptake and with total glutathione (GSH) or intracellular lactate dehydrogenase (LDH) measurements. We found an increase of MDR1 ARNm in MTC as compared with normal tissues. Doxorubicin was cytotoxic after a 48-h coincubation with the cells. Three microM CSA and 10 microM VRP reversed the doxorubicin resistance only after a 48-h coincubation, generally followed with a 24 h-post-incubation. In these conditions, the GSH levels were decreased only by VRP in all the five cell lines. In conclusion, a chemoresistance related to the MDR1 gene overexpression was found in the five human MTC lines tested. VRP and CSA reversed the resistance to doxorubicin in all the MTC cell lines tested.
Antineoplastic Agents↗
[Modulation of cisplatin cytotoxicity by amphotericin B in six human cell lines of medullary thyroid cancer].
Medullary thyroid carcinoma (MTC) is frequently resistant to chemotherapy. In this work, we have studied the effect of cisdiamminedichloroplatinum (II) (CDDP) in six MTC human cell lines and we have tried to reverse the resistance to CDDP with amphotericin B (AmB). We also studied the metabolism of glutathione (GSH) and the presence of the glutathione-sulfotransferase pi (GST pi) mRNA in the MTC cell lines. The cisplatin-induced cytotoxicity was evaluated with the 3-4,5 dimethylthiazol-2,5 diphenyl tetrazolium bromide (MTT) test, the neutral red (NR) uptake and with total GSH measurement in six cell lines, TT cell line and five cell lines that we isolated. The cultures were performed with or without AmB (5 micrograms/mL). Intracellular GSH was measured in TMC cells and compared to the levels obtained in six normal thyroid tissues. The expression of GST pi mRNA was evaluated by Northern blotting in the different cell lines. A CDDP-induced cytotoxicity was obtained in the six cell lines at doses inhibiting 50% of the cellular proliferation (IC50) varying from 6 to 40 micrograms according to the tests and the cells tested. A low concentration of AmB (5 micrograms/mL) potentiated the cisplatin toxicity after a 48-h coincubation of TMC in all cases. GSH levels in TMC cell lines were identical to those found in normal cells. GST pi mRNA was detected in all the TMC lines, except in TT cell line. In conclusion, CDDP was toxic for all the TMC cell lines and AmB potentiated this antitumoral effect. On the contrary, GSH and GST pi do not seem to be involved in the mechanisms of the resistance in these cell lines.
Amphotericin B↗
[Antigenic retrieval using a pressure cooker].
This technical note describes antigen retrieval procedures using a pressure cooker. These procedures are perfectly adapted to routine immunohistochemistry and improve the overall quality of immunostaining.
Antigens↗
Influence of S9788, a new modulator of multidrug resistance, on the cellular accumulation and subcellular distribution of daunorubicin in P-glycoprotein-expressing MCF7 human breast adenocarcinoma cells.
A triazinoaminopiperidine derivative synthesized as a modulator of multidrug resistance, S9788, was investigated in the human breast adenocarcinoma MCF7DXR cell line expressing P-glycoprotein. In addition to being less sensitive to daunorubicin, the resistant cell line showed dramatic alterations in the subcellular distribution of daunorubicin, as observed via fluorescence microscopy and quantified via tritiated daunorubicin nuclear distribution analysis. Compared to verapamil and cyclosporin A at 2 and 5 mumol/liter, S9788 proved to be more potent in restoring the cellular accumulation and the subcellular distribution of daunorubicin in the resistant cells. Significant activity of S9788 was observed at 2 mumol/liter, which is clinically achievable, and S9788 restored the nuclear distribution of the drug to the level observed in the parental sensitive cell line. Consequently, the restoration of the cytotoxicity of daunorubicin by S9788 was nearly complete (> 90%) at 2 mumol/liter, wheras cyclosporin A reached this level of activity at 5 mumol/liter, and verapamil was always less active at both concentrations. These results suggest that the modulation of multidrug resistance by S9788 is not only related to the enhancement of the cellular accumulation but also especially by the restoration of the subcellular distribution of the drugs to their nuclear sites of action.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Characterization of a glycerol/H+ symport in the halotolerant yeast Pichia sorbitophila.
Pichia sorbitophila is a halotolerant yeast capable of surviving to extracellular NaCl concentrations up to 4 M in mineral medium when glucose or glycerol are the only carbon and energy sources. Evidence is presented here that glycerol, the main compatible solute this yeast accumulates so as to maintain osmotic balance, is actively co-transported with protons. This transport system was shown to be constitutive, not needing induction by either glycerol or salt, and was not repressible by glucose. In glucose- or glycerol-grown cells, a simple diffusion was detectable, and iterative calculations were performed to calculate kinetic parameters, in the presence and in the absence of NaCl. At 25 degrees C, pH 5.0, in glucose-grown cells these were: Km = 0.81 +/- 0.11 mM and Vmax = 634.2 +/- 164.8 mumol h-1 per g (glycerol); Km = 1.28 +/- 0.60 mM and Vmax = 558.6 +/- 100.6 mumol h-1 per g (protons). Correspondent stoichiometry was approximately 1, either for these conditions or in the presence of 1 M-NaCl. An increase in accumulation capacity was evident when different concentrations of NaCl were present. This capacity was shown to be dependent on delta pH and membrane potential, consistently with an electrogenic character. We suggest that the main role of this system is in osmoregulation, by keeping glycerol accumulated inside the cells, compensating for leakage, due to its liposoluble character.
Biological Transport↗
In vitro activity of S 9788 on a multidrug-resistant leukemic cell line and on normal hematopoietic cells-reversal of multidrug resistance by sera from phase I-treated patients.
The triazinoaminopiperidine derivative S 9788 is a new multidrug-resistance modulator that is currently being evaluated in phase I clinical trials. In this study, the reversal effect of S 9788 in comparison with verapamil was shown in vitro in human T-leukemic CCRF-CEM/VLB cells expressing the multidrug-resistance (MDR) phenotype. S 9788 increased in a dose-dependent manner the cytotoxic activity of doxorubicin or vinblastine, with complete reversal of resistance occurring at 2 microM for a concomitant continuous exposure (96 h) to the cytotoxic drugs. At respective concentrations equivalent to the IC10 value (the concentration inhibiting 10% of cell growth), S 9788 was 44 times more potent than verapamil in CCRF-CEM/VLB cells. S 9788 at 2 microM did not enhance the in vitro toxicity of doxorubicin or vinblastine in the human normal bone-marrow erythroid (BFU-E) and myeloid (CFU-GM) progenitors. The effect of exposure duration and concentrations on the synergistic action of modulator and cytotoxic agent closely depended on the cytotoxic agent studied. Post-incubations with S 9788 alone after a 1-h coadministration with vinblastine and S 9788 dramatically increased the reversal effect (4-41 times) in proportion to both the duration of postincubation and the concentration of S 9788. In contrast, for doxorubicin resistance, post-incubation with S 9788 alone induced a maximal 2-fold increase in the reversal effect that was not proportional to the post-incubation duration. In patients treated with S 9788 as a 30-min intravenous infusion during phase I trials, a good correlation was found between the serum levels of S 9788 and the ability to reverse MDR in CCRF-CEM/VLB cells. The reversal effect was dose-dependent and was effective beginning at a plasma concentration of 0.25 microM. These data form a basis for the design of phase II trials using a combination of a loading dose of S 9788 given before vinblastine or doxorubicin administration followed by a maintenance infusion of S 9788 alone for a period of 2-24 h.
Antineoplastic Agents↗
Binding of a new multidrug resistance modulator, S9788, to human plasma proteins and erythrocytes.
The interactions of S9788 with human plasma proteins have been investigated in vitro by an erythrocyte partitioning technique that allows an estimation of the plasma proteins and erythrocytes binding parameters. S9788 was 98% bound to plasma and blood. Lipoproteins bound S9788 with high affinities (binding constants of 0.645, 12.8 and 87.0 x 10(6) M-1 for HDL, LDL and VLDL, respectively) and accounted for more than 55% of the total circulating S9788. Albumin and alpha 1-acid glycoprotein also bound S9788 with lower binding constants of 0.022 and 0.245 x 10(6) M-1. S9788 was mainly distributed in the plasma blood compartment (75-80%) with blood-to-plasma concentrations ratio of 0.6 to 0.7. These results indicate that, in vivo, the fraction of blood S9788 available for tissue diffusion, i.e., the free drug fraction in blood, should depend on lipoprotein concentration in plasma.
Antineoplastic Agents↗
Phase I-II and pharmacokinetic study of a new fotemustine schedule in advanced non-small cell lung cancer.
UNLABELLED: Fotemustine, a new nitrosourea derivative has already demonstrated activity in non-small cell lung cancer (NSCLC). In order to improve its therapeutic index, we designed a protocol in which Fotemustine was delivered with dose escalation on 3 consecutive days as induction therapy followed by a 5-week rest period. Maintenance therapy consisted of 100 mg/m2 once every 3 weeks. Pharmacokinetic data were assessed during this Phase I-II study and reported here. PATIENTS AND METHODS: Nineteen patients with metastatic (17) or locally advanced (2) NSCLC were included in the present study. Ten of those with metastatic disease had brain metastases and 15 had previously received chemotherapy. Fotemustine was given at 50 mg/m2 on day 1-2-3 (group 1: four patients), 75 mg/m2 on day 1-2-3 (group 2: 16 patients including two who had already received 50 mg/m2) and 100 mg/m2 on day 1-2-3 (group 3: one patient). RESULTS: The maximal tolerated dose was 75 mg/m2 on day 1-2-3 (total cumulated dose 225 mg/m2). At this dose level, we observed 25% of Grade 3-4 neutropenia and 31% of Grade 3-4 thrombocytopenia. One patient died of pulmonary infection during aplasia. No other significant toxicity occurred. Of the 17 evaluable patients, one obtained a PR lasting 6 months in group 2 and 1 PR lasting 3 months in group 3. No significant difference was noted in the AUC between days 1, 2 or 3 in any of the seven patients in whom a pharmacokinetic study of Fotemustine was performed. CONCLUSION: Administered on 3 consecutive days, Fotemustine seems to be less effective and more toxic than other schedules tested in NSCLC. Despite the quality of the two responses observed, this protocol has been discontinued and the standard administration on days 1 and 8 remains the schedule of choice in NSCLC.
Adult↗
[Cadasil: a new familial disease responsible for cerebral infarction and dementia].
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Cerebral Arteries↗
Effect of adjuvants on immunogenicity of MN recombinant glycoprotein 120 in guinea pigs.
The immunogenicity of recombinant gp120 from the MN strain of HIV-1, a candidate HIV-1 vaccine, was evaluated in guinea pigs using adjuvant formulations with different physical and chemical properties. The adjuvants tested included Freund's adjuvant (FA), alum, and the novel adjuvant QS-21. These studies demonstrated that QS-21 provides a number of advantages compared to the two other adjuvants tested. QS-21 formulations accelerated the production of antibodies to MN rgp120 and elicited complete seroconversion after a single immunization. QS-21 shifted the antigen dose-response curve for antibody production by as much as three orders of magnitude, enabling a more economical use of antigen. Antibody titers to MN rgp120 and to the principal neutralizing determinant in the V3 domain were higher in animals receiving QS-21 formulations than in animals immunized with the other adjuvants, and correlated well with higher virus neutralization titers in an in vitro assay. These results support the testing of QS-21 in future clinical trials of candidate HIV-1 vaccines.
AIDS Vaccines↗
Development and characterization of murine monoclonal antibodies to the latency-associated peptide of transforming growth factor beta 1.
Transforming growth factor beta (TGF-beta) is a multifunctional peptide that controls proliferation, differentiation, and other functions in a variety of cell types. Transforming growth factor beta activities have been implicated in a variety of diseased states including arthritis, prostate cancer, and AIDS, and in the repair of tissue injury caused by trauma, burns, and surgery. We describe the development and characterization of novel murine monoclonal antibodies (MAbs) to the latency-associated peptide (LAP) of TGF-beta 1, and the subsequent development of an ELISA for the detection and quantitation of TGF-beta 1-LAP in buffer and serum matrices. Fusion of immune splenocytes with myeloma cells yielded 576 hybridomas, 110 of which were antibody secreting. Five were selected for extensive characterization. Clinically, the MAbs described here should be valuable for studying potentially abnormal production and/or function of the LAP, and its relationship to TGF-beta.
Animals↗
Cyclosporin A, verapamil and S9788 reverse doxorubicin resistance in a human medullary thyroid carcinoma cell line.
Multidrug resistance was investigated in TT cells, a human medullary thyroid carcinoma (MTC) cell line and in normal thyrocytes. MDR1 mRNA was revealed by polymerase chain reaction (PCR) analysis both in normal and neoplastic cells despite the absence of glycoprotein P (Pgp) by immunohistochemistry using JSB-1 monoclonal antibody. Glutathione-S-transferase mRNA was undetectable by Northern blotting in TT cells. Doxorubicin-induced cytotoxicity was evaluated in TT cells with MTT, lacticodehydrogenase (LDH), glutathione (GSH) assays and neutral red uptake. IC50 values obtained for MTT assays were higher than those obtained with the three other tests. Cyclosporin A (CSA) (3 microM), verapamil (10 microM) and S9788 (5 microM) partially reversed the resistance to doxorubicin after a 48 h co-incubation (followed by a 24 h post-incubation for the S9788). Under these conditions, GSH levels were altered by verapamil and S9788, whereas CSA decreased LDH activity. CSA and verapamil had no effect on MTT assay. In conclusion this MTC cell line exhibited over-expression of the MDR1 gene and its resistance to doxorubicin can be partially reversed by CSA, verapamil and S9788.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A prospective, randomized trial of a six-week ambulatory medicine rotation.
BACKGROUND: Medical schools are placing increased emphasis on training students in the ambulatory setting, but few studies show the benefit or academic risk of such innovation. The authors studied the effect of such a new rotation with a rigorous study design. METHOD: From a group of 166 third-year students at the Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine assigned in 1990-91 to do six weeks of their third-year medicine clerkship at Walter Reed Army Medical Center, 106 volunteers were randomized to six weeks either on the usual rotation on the general medicine wards (69 students) or to a new ambulatory rotation (37 students). Multiple pre- and postclerkship parameters were used to evaluate clerkship skills and knowledge; eventual internship choice was determined. RESULTS: The randomization was successful. Postclerkship performances were the same in (1) the medicine subject examination of the National Board of Medical Examiners, (2) a multiple-choice test in interpreting laboratory results, (3) blinded rating by an expert panel of the quality of final written histories and physical exams, (4) blinded rating by an expert panel of the students' written case analyses of their own patients, and (5) a written multiple-step examination of problem-solving ability. Any differences between groups favored the ambulatory group. An increase in choice of primary care internships among students randomized to the ambulatory rotation was not significant. CONCLUSION: It is possible to study innovative rotations using a prospective, randomized design. Substituting a six-week block ambulatory experience for a ward rotation did not decrease students' abilities to write up or analyze complex cases.
Ambulatory Care↗