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Biomedical subjects

C Lucas

Publications and source records attributed to C Lucas.

At least 145 records · Page 8Linked to original sources
PubMed1995

Thyroid cell survival in coculture with autologous peripheral or intrathyroidal lymphocytes.

OBJECTIVE: We have studied lymphocyte induced cytotoxicity and the production of interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) during coculture of thyrocytes and autologous lymphocytes from patients with Graves' disease and from normal subjects. PATIENTS: Thyroid tissues and lymphocytes were obtained from 28 patients with Graves' disease and from 9 control subjects. MEASUREMENTS: Lymphocyte induced cytotoxicity was evaluated on autologous thyrocytes using 5 metabolic tests: the MTT assay, the neutral red uptake, lactate dehydrogenase measurement and glutathione assay. IFN-gamma and TNF-alpha measurements were performed after 1, 5 or 7 days' coculture. RESULTS: The lymphocytes isolated from peripheral blood (PB lymphocytes) altered the morphology and the metabolism of autologous thyrocytes. The intrathyroidal lymphocytes isolated after Dispase digestion were not toxic whereas mechanically isolated lymphocytes exerted a little toxicity. No difference was seen between Graves' disease and normal cells. The supernatants from cocultures had higher IFN-gamma levels than those from lymphocyte cultures. In coculture, PB lymphocytes secreted more IFN-gamma and TNF-alpha than intrathyroidal lymphocytes. The PB lymphocyte induced cytotoxicity was not due to IFN-gamma and TNF-alpha alone. CONCLUSION: Peripheral blood lymphocytes are cytotoxic in vitro to autologous thyrocytes whereas intrathyroidal lymphocytes exert little or no cytotoxicity according to their isolation method. The mechanisms of lymphocyte induced toxicity remain to be explained.

Adult↗
PubMed1995

Blood flow velocity profiles in pulmonary branch arteries in lambs.

We studied the detailed profiles of blood flow in the right and left pulmonary arteries using 20 MHz pulsed Doppler ultrasound equipment in a lamb model. Fourteen lambs aged four to six weeks were selected. In six lambs, monocrotaline pyrrole was injected parenterally to create pulmonary hypertension (PH group). Eight other lambs served as unaltered controls (control group). The blood flow velocities were sampled in 1mm increments along the anterior-posterior axis of the branch arteries. The maximum velocity of the forward flow in the left pulmonary artery was higher than that in the right pulmonary artery in the control group (71.7 +/- 15.9 cm/s vs 60.2 +/- 13.5; p < 0.05). The fastest backward flow was located at the posterior position of the vessel in the right pulmonary artery in the control group (71.7 +/- 15.9 cm/s vs 60.2 +/- 13.5; p < 0.05). The fastest backward flow was located at the posterior position of the vessel in the right pulmonary artery in the control group. No significant bias in location was shown in the left pulmonary artery. Using indices of P90, acceleration time, P90*AcT, the velocity waveforms in the PH group were compared with those in the control group. In the left pulmonary artery, every index in the control group showed a significantly greater value that in the PH group. On the other hand, no significant differences were found between either group in the right pulmonary artery.

Animals↗
PubMed1995

Early predictors of death and disability after acute cerebral ischemic event.

BACKGROUND AND PURPOSE: Many clinical trials are currently being conducted to evaluate the ability of neuroprotectors and thrombolytic agents to improve survival and functional outcome after ischemic stroke. Such trials require early predictors of survival and disability for ethical and methodological reasons. The aim of the study was to determine which variables, of those easily assessable during the first 24 hours after stroke onset, would be predictors of 8-day mortality rate and 3-month clinical outcome. METHODS: One hundred fifty-two consecutive patients with an acute ischemic event were evaluated within 24 hours after symptom onset. We determined (1) the 8-day mortality rate and (2) the 3-month functional outcome (Glasgow Outcome Scale). The following potential predictors of outcome were tested by means of a stepwise logistic regression analysis: age, sex, body mass index, atrial fibrillation, previous stroke, existence of headache, Orgogozo score, level of consciousness, swallowing disturbances, hemianopia, pulse rate, mean blood pressure, hematocrit, glycemia, and computed tomographic scan data (cerebral atrophy score, hyperdense middle cerebral artery sign, number of silent infarcts, leukoaraiosis score). RESULTS: The multivariate analysis revealed that the 8-day mortality rate depended only on the level of consciousness at admission (P = .0001); death or dependence at month 3 (scores 3 to 5 on the Glasgow Outcome Scale) depended on the severity of the clinical deficits (P = .0001), previous stroke (P = .0018), and age (P = .0237). CONCLUSIONS: In future drug trials, the distribution of patients between "active treatment" and "placebo" groups should be balanced regarding the severity of clinical deficits, history of stroke, and age.

Acute Disease↗
PubMed1995

[Magnetic resonance imaging in vascular dementia].

The heterogeneity of vascular dementia depends on the cause, size, location and nature of the vascular lesions (36, 62). Magnetic resonance imaging (MRI) techniques are of major interest to detect the vascular origin of dementia: the lack of focal lesions or leukoencephalopathy excludes the vascular origin of dementia (36). Occlusions of large extra-cerebral arteries usually lead to cortical or large subcortical infarcts or both (28). Dementia may be due to multiple infarcts or to a single infarct located in a strategic area (47). Lacunar infarcts are due to the occlusion of one single deep perforator with a thickening of the arterial wall due to lipohyalinosis (25), usually in a patient with arterial hypertension; lacunes are located in a territory supplied by the deep perforators. They appear as hyperintense in T2-weighted sequences and hypo-intense in T1-weighted sequences. Old small hemorrhages have the same appearance than infarcts on CT-scans but their center appears hypo-intense in T2-weighted sequences. In normal subjects, age and arterial hypertension are risk factors for hemispheric white matter hyperintensities (59, 60). Their vascular origin is likely because of the evidence of lesions of the wall of deep perforators (17, 21), their association with lacunes (17, 21, 30, 37) or deep hemorrhages (30, 32, 37), and their frequency in amyloid angiopathy (26). Their prevalence is higher in vascular dementia than in Alzheimer's disease (59). They sometimes fulfill criteria for Binswanger's disease (5). Even after exclusion of predisposing factors they remain frequent in healthy subjects over 50 years (39, 56); however, whether they herald subsequent dementia remains unsettled.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗
PubMed1994

Methods for the analysis of the new vinca alkaloid derivative, S 12363, in plasma by high-performance liquid chromatography with fluorescence detection.

Two sensitive analytical methods for the analysis of S 12363 in plasma are described. A highly sensitive procedure for human and dog plasma using cyanopropyl solid-phase extraction with ion pairing chromatography and fluorescence detection, has a limit of quantification of 0.1 ng ml-1. The technique has an overall precision and accuracy of 4.8 and 5.4% respectively over the concentration range 0.1-20 ng ml-1. A second, less sensitive, assay specifically adapted for rodent plasma, uses benzene sulphonyl cation-exchange solid-phase extraction followed by reversed-phase chromatography, with post-column fluorescence enhancement. This method has a limit of quantitation of 1.0 ng ml-1, with overall accuracy and precision of 7.2 and 11.6% respectively, over the concentration range 1.0-20.0 ng ml-1. Both assays have been successfully applied to dog and mouse toxicokinetic studies.

Animals↗
PubMed1994

One-year outcome for patients with a chief complaint of dizziness.

UNLABELLED: OBJECTIVE. To determine the one-year outcome for patients with a chief complaint of dizziness that had persisted at least two weeks. DESIGN: Prospective cohort study. SETTING: Federal teaching hospital. PATIENTS: 100 dizzy patients and 25 control subjects. MEASUREMENTS: The primary outcome was dizziness status (improved or not improved); the secondary outcomes were morbidity and health care utilization. RESULTS: The dizziness resolved for 18 patients, whereas the status improved for 37, stayed the same for 32, and worsened for 11, with two patients lost to follow-up. Thus, 55% of patients whose dizziness had not resolved two weeks after their initial visits improved over the subsequent 12 months. Logistic regression revealed four independent predictors of persistent dizziness at one-year follow-up: dizziness due to psychiatric causes, dysequilibrium, vertigo other than benign positional vertigo, vestibular neuronitis, or migraine (odds ratio, 6.3; 95% CI, 2.1-18.6); daily dizziness (odds ratio, 6.4; 95% CI, 2.0-21.0); dizziness worse with walking (odds ratio, 3.0; 95% CI, 1.1-9.0); and patient had initially feared a serious illness (odds ratio, 0.25; 95% CI, 0.10-0.74). These four factors could be used to classify patients as having either a high (82%), medium (47%), or low (0%) likelihood of improvement at one-year follow-up. One patient died from heart failure, and none developed a serious disease for which dizziness had been a harbinger. Dizziness was not associated with an increased number of clinic visits. CONCLUSIONS: Among patients with a chief complaint of dizziness who are still symptomatic at two-week follow-up, more than half improve within a year. Clinical factors identify patients at higher risk for persistent dizziness.

Cohort Studies↗
PubMed1994

ELISA for the neuropeptide degrading endopeptidase 3.4.24.11 in human serum and leukocytes.

We describe the development of a new ELISA for the detection of neural endopeptidase 3.4.24.11 (NEP). Neutral endopeptidase 3.4.24.11 was determined in preparations of human granulocytes, mononuclear cells (MNC), and in serum. Human recombinant NEP was used as reference. Specificity of the mAbs was tested using APAAP, FACS analysis, and Western blot analysis. Lysis of the blood cells was performed by incubating the cells with 0.4% Tween-20 and repeated freezing cycles. The minimal detectable dose for recombinant NEP was 15 pg/ml. The recovery was 94 +/- 9%. The NEP was detectable in 15 out of 20 serum samples of 20 volunteers (mean +/- SEM, 245 +/- 88 pg/ml, n = 20)) and in all granulocyte preparations (1176 +/- 138 pg/10(7) cells, n = 20)). The results were reproducible among replicates (CV = 3 +/- 1%, n = 40), dilutions (CV = 8 +/- 2%, n = 5), and assays (CV = 12 +/- 4%, n = 5). With this new ELISA, a simple and reproducible method for the measurement of NEP 3.4.24.11 is described.

Blotting, Western↗
PubMed1994

Pharmacokinetics and tissue distribution of recombinant human transforming growth factor beta 1 after topical and intravenous administration in male rats.

Recombinant human transforming growth factor beta (rhTGF-beta 1) enhances the healing process after topical application to various animal wound models. A detailed pharmacokinetic and tissue distribution study was performed to support the clinical development of rhTGF-beta 1 for wound healing indications. Rats received radioiodinated or unlabeled rhTGF-beta 1 as an intravenous (iv) bolus or as a topical formulation applied to a full thickness wound. Plasma concentrations of TGF-beta 1 were estimated from TCA-precipitable radioactivity or were measured by ELISA. Following iv administration, the initial half-life was rapid (< 11 min), regardless of whether radiolabeled or unlabeled rhTGF-beta 1 was used. The terminal half-life was long (163 min) when the test material was radioiodinated and administered as a trace dose and relatively short (< or = 61 min) when given at high doses and assayed by ELISA. Analysis of plasma radioactivity by SDS-PAGE revealed a time-dependent clearance of the 25-kDa parent molecule without a significant appearance of lower molecular weight radiolabeled metabolites. The majority of the radioactivity was associated with highly perfused organs, known iodide elimination pathways, and the thyroid at 1 and 8 hr after iv injection. After topical administration of a high dose (0.8 mg/kg), no immunoreactive TGF-beta 1 was detectable in plasma samples taken over a 48-hr period. However, trace amounts (< or = 0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of [125I]rhTGF-beta 1 (1 microgram/kg, 126 microCi/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1994

Multidrug resistance circumvention by a new triazinoaminopiperidine derivative S9788 in vitro: definition of the optimal schedule and comparison with verapamil.

The current work was undertaken to investigate the importance of exposure sequence and duration in achieving the maximum reversal action of S9788 on doxorubicin (DOX) cytotoxicity against cells that exhibit the (MDR) multidrug resistance phenotype: the MCF7/DOX cell line. Accumulation and release of DOX were examined in this cell line. The reversal effect was compared with that obtained with verapamil. S9788 activity was schedule dependent: when comparing incubation with S9788 before or after treatment with DOX, the best reversal factor was obtained in the case of a post-treatment incubation (65.6 +/- 7.7 vs 20.8 +/- 7.0). S9788 was a more potent modulating agent than verapamil, whatever the schedule of exposure of the cells to the reversal agent. The reversal of resistance after short-term DOX exposures was caused not only by prolonged cellular accumulation of DOX, but also by its prolonged retention after transfer of cells to DOX-free medium. A relationship was noted between cellular exposure to DOX and the cytotoxic effect, and so the reversal of resistance induced by S9788 appears to be directly linked to the level of cell exposure to DOX. This work provided a rationale for improving the schedule of administration of S9788 in clinical trials.

Antineoplastic Agents↗
PubMed1994

Higher prevalence of atrial septal aneurysms in patients with ischemic stroke of unknown cause.

Atrial septal aneurysms (ASA) are frequent findings on transesophageal echocardiographies. Whether they are more frequent in patients with cerebral ischemia of unknown cause remains unclear. We investigated this question in 154 consecutive patients with an ischemic stroke or transient ischemic attack. The 16 patients with ASA were younger, less likely to have arterial hypertension and more likely to have a patent foramen ovale (PFO) or an unknown cause of stroke, but they did not differ for number and side of infarcts, other demographic data and vascular risk factors. Patients with ASA unassociated to PFO were also more likely to have an unknown cause of stroke. These findings lead to the hypothesis that ASA might be sources of cerebral emboli.

Adolescent↗
PubMed1993

Human pharmacokinetics of a new Vinca alkaloid S 12363 with use of a monoclonal antibody-based radio- or enzyme immunoassay.

S 12363 is a new Vinca alkaloid derivative, characterized by the grafting of an alpha-aminophosphonate, onto the Vinca nucleus, facilitating drug penetration and increasing intracellular drug retention. As a high cytotoxic activity had been demonstrated in in vitro and in vivo models recommended by the National Cancer Institute, a phase I trial was initiated in cancer patients. In order to quantify S 12363 systemic levels in humans, two monoclonal antibody-based immunoassays, RIA (radio-) and EIA (enzyme immunoassay) were developed. The gamma-emitting probe used in the RIA, 125I-(deacetyl-O4-vinblastine)-tyramine, bound very tightly to the monoclonal antibody (dissociation constant, Kd = 2.5 x 10(-11) M), demonstrating a high affinity mainly directed toward the catharantine nucleus (vindesine, vincristine, vinblastine, 100% cross-reactivity; vinorelbine, 0.3% cross-reactivity). In the EIA, a deacetyl O4-vinblastine/ovalbumine conjugate was used as the competing antigen. Its binding to the monoclonal antibody was revealed by an anti-mouse immunoglobulin G conjugated to biotin which interacts with streptavidin labeled with alkaline phosphatase. This method permitted obtaining nearly the same sensitivity and reproducibility with EIA as with RIA, their respective minimum quantitation limits being 0.100 and 0.040 ng/ml (106 and 42 pM) of S 12363 in plasma. These assays allowed the study of S 12363 systemic pharmacokinetics in cancer patients during a phase I trial up to 72 h after dosing. As determined by RIA, the S 12363 plasma profile was triphasic with a terminal half-life; t1/2 gamma = 49 +/- 16 h, a plasma clearance, CL = 0.14 +/- 0.04 liter/h/kg, and a volume of distribution at steady state, Vdss = 5.0 +/- 2.8 liter/kg. The pharmacokinetics of S 12363 is linearly related to dose when increased from 0.08 up to 0.84 mg/m2 in humans. Its plasma profile and pharmacokinetic parameters are close to those of other Vinca alkaloids with clearance and terminal half-life being intermediate between those of vinblastine and vincristine. Therapeutic doses are 4 to 10 times lower and should be a direct consequence of the higher uptake and retention by the cells of this new aminophosphonate Vinca alkaloid derivative.

Adolescent↗
PubMed1993

Transforming growth factor-beta primes macrophages to express inflammatory gene products in response to particulate stimuli by an autocrine/paracrine mechanism.

Macrophages maintain an essential role in orchestrating the host inflammatory response by selectively mobilizing portions of their large secretory repertoire in response to phagocytic as well as other stimuli. For example, after exposure to the inflammatory particulate stimulus zymosan (or its derivative beta 1,3-glucan), monocyte/macrophages synthesize and release lysosomal hydrolases, mobilize arachadonic acid, and secrete cytokines such as TNF-alpha and IL-8. However, the mechanisms by which particulate stimuli promote the selective synthesis and release of macrophage-derived inflammatory gene products are unknown. Given the previously reported potential of transforming growth factor-beta (TGF-beta) as an important mediator of the inflammatory response in vivo, we investigated the role of TGF-beta in the regulation of particulate-induced macrophage inflammatory gene expression. We determined that TGF-beta primed macrophages to synthesize lysosomal hydrolases and express platelet-derived growth factor-B mRNA transcripts in response to both submaximal doses of beta 1,3-glucan and the nonspecific phagocytic stimulus latex particles, which by themselves did not induce expression of either inflammatory gene product. The endogenous production of active TGF-beta was shown to regulate inflammatory gene expression by demonstrating that: 1) beta 1,3-glucan stimulated both TGF-beta mRNA expression and protein release into conditioned media; 2) supernatants from stimulated macrophages primed for lysosomal hydrolase synthesis, and this effect was blocked by anti-TGF-beta antibodies; and 3) anti-TGF-antibodies blocked beta 1,3-glucan-stimulated lysosomal hydrolase synthesis. Collectively, these data describe a novel function for TGF-beta as a priming agent for macrophage inflammatory gene expression and suggest a mechanism for local amplification of the inflammatory response.

Animals↗
PubMed1993

Method for the analysis of S9788, a drug to reverse resistance to anticancer agents, in animal plasma and human plasma and serum by high-performance liquid chromatography with ultraviolet detection.

An extraction method has been developed using benzene sulphonyl cation-exchange sample preparation cartridges and reversed-phase high-performance liquid chromatography with ultraviolet detection for the measurement of S9788, a drug to reverse resistance to anticancer agents, in plasma and serum. This includes a toxicokinetic assay which has a mean precision and accuracy of 11.7% and 7.9%, respectively, over the range 10-1000 ng ml-1 and a quantification limit of 10 ng ml-1 and a more sensitive pharmacokinetic procedure with a mean precision and accuracy of 5.0% and 7.9%, respectively, over the range 1-500 ng ml-1 and a quantification limit of 1 ng ml-1. The specificity of the procedure has been demonstrated by mass and ultraviolet spectrometry, and linearity, precision, accuracy, recovery and sensitivity have been established. The assays have been successfully applied to toxicokinetic and pharmacokinetic studies.

Animals↗
PubMed1993

An evaluation of mechanisms by which tolerance to organ-specific antigens is lost using a transgenic mouse model.

Patients with type I diabetes lose immunologic tolerance to beta cell Ag and produce anti-self (beta cell) antibodies. We have examined mechanisms by which this self tolerance is lost using transgenic mice in which islet cells express human CD4. These mice are immunologically tolerant to this human protein; the tolerance appears to be characterized by the presence of self reactive B cells and nonresponsive T cells. Autoantibodies can be induced by immunization with CD4 in CFA; this autoantibody response is accompanied by minor peri-islet inflammation but diabetes is not induced. Tolerance can also be broken by provision of an independent covalently linked T cell epitope. Although this mimic can lead to the appearance of an autoantibody response, the autoimmune response can not be maintained by the endogenous Ag. We have also demonstrated that an inflammatory lesion leading to death of the CD4-containing beta cells may not be sufficient to break tolerance. These results have implications for potential mechanisms relating to the appearance of autoantibodies in patients with type I diabetes.

Animals↗