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Biomedical subjects

G Laurent

Publications and source records attributed to G Laurent.

At least 163 records · Page 9Linked to original sources
PubMed1994

Potentiation of gentamicin nephrotoxicity in the rat by infusion of aprotinin.

The present study was undertaken to examine a possible effect of aprotinin, a 6.5-kDa polypeptide with an inhibitory effect on proteolysis, on aminoglycoside nephrotoxicity. Experimental animals (female Sprague-Dawley rats, 175-200 g body wt) were treated for 4 days with 40 mg/kg gentamicin given ip at 12-hr intervals. Aprotinin (40,000 kIU per animal) was infused i.v. over a period of 8 days, using subcutaneously implanted miniosmotic pumps. In protocol A, infusion pumps were placed 4 days before starting gentamicin treatment. In protocol B, pumps were implanted 15-18 hr prior to first gentamicin administration. In addition to rats exposed to both gentamicin and aprotinin (GAP), animals were treated with gentamicin ip+saline i.v. (G), saline ip+aprotinin i.v. (AP), or received only saline by both routes of administration (C). All rats were terminated 4 days after the end of gentamicin dosing. One hour before sacrifice, 200 microCi of [3H]thymidine was given ip to each animal in order to monitor cell turnover in renal tissue. The kidneys were analyzed with respect to (i) histopathological alterations and renal dysfunction, (ii) aminoglycoside tissue accumulation, and (iii) tubular regeneration (measurement of cell proliferation). In animals receiving aprotinin alone, histological examination of renal cortex on paraffin sections disclosed mild tubular injury with focal cell necrosis. In plastic-embedded tissue, proximal tubule epithelium was characterized by the presence of numerous inclusions densely stained with toluidine blue. At the ultrastructural level, these inclusions appeared filled with amorphous electron-dense material. In gentamicin-treated animals, cortical drug accumulation reached values higher than 0.3 mg/g renal tissue, but a significant 30-40% decrease of gentamicin accumulation was noted in GAP groups, compared to G groups. Histological examination of renal cortex (paraffin sections) revealed the development of acute tubular necrosis in both G and GAP groups. Tubular injury was accompanied by mild renal dysfunction, as shown by the level of serum creatinine which was increased almost 3-fold in the G group, compared to C and AP groups. Aprotinin infusion produced a further increase of serum creatinine, particularly in protocol A where it was 72% higher for the GAP group than for the G group. In both G and GAP groups, postnecrotic tubular regeneration was evidenced by determining the rate of DNA synthesis and the frequency of S-phase cells in renal cortex. Both methods gave consistent results and showed a 8- to 13-fold increase of cell proliferation in groups receiving gentamicin alone, compared to C groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Distinct rhythmic locomotor patterns can be generated by a simple adaptive neural circuit: biology, simulation, and VLSI implementation.

Rhythmic motor patterns can be induced in leg motor neurons of isolated locust thoracic ganglia by bath application of pilocarpine. We observed that the relative phases of levators and depressors differed in the three thoracic ganglia. Assuming that the central pattern generating circuits underlying these three segmental rhythms are probably very similar, we developed a simple model circuit that can produce any one of the three activity patterns and characteristic phase relationships by modifying a single synaptic weight. We show results of a computer simulation of this circuit using the neuronal simulator NeuraLOG/Spike. We built and tested an analog VLSI circuit implementation of this model circuit that exhibits the same range of "behaviors" as the computer simulation. This multidisciplinary strategy will be useful to explore the dynamics of central pattern generating networks coupled to physical actuators, and ultimately should allow the design of biologically realistic walking robots.

Adaptation, Physiological↗
PubMed1994

Optimization of immunohistochemical detection of P-glycoprotein in chronic lymphoid disorders.

To optimize the immunohistochemical detection of the multidrug resistance (MDR)-associated P-glycoprotein (P-gp) in chronic lymphoid disorders, the authors compared the sensitivity of three different monoclonal antibodies (MoAb) directed against P-gp (C219, JSB-1, and MRK 16) by using the APAAP technique on four tissue preparations obtained from lymphoid tumors: Cryostat sections, ModAMEX processed sections, frozen cytospin preparations, and fresh cytospin preparations. Tumor samples were obtained from patients with previously treated chronic lymphocytic leukemia (6 cases) or non-Hodgkin's malignant lymphoma (4 cases). Lymph nodes (n = 9), spleen (n = 3), and blood (n = 5) were analyzed. JSB-1 MoAb detected P-gp in 4 of 12 cases (33.3%) on either frozen sections or ModAMEX processed sections, and in 6 of 17 cases (35.3%) on frozen cytospin preparations. The sensitivity of JSB-1 was significantly improved when fresh cytospin preparations were used with an incidence of P-gp positive samples as high as 70.6% (P < .05). C219 MoAb was unreactive with lymphoid cells whatever the technique used, whereas this antibody stained stromal cells. MRK 16 MoAb was equally reactive to JSB-1 on fresh cytospin preparations, but unreactive when the other preparations were used. The specificity of JSB1 MoAb was confirmed by both Western blot analysis and Rhodamine 123 efflux assay. The authors used JSB-1 MoAb on fresh cytospin smears prepared from 28 CLL patients. Overall incidence of P-gp positive cases was 39.2%. Univariate analysis showed that P-gp expression was correlated with prior therapy, refractoriness to treatment, Rai stratification, and time of tissue storage after diagnosis. The authors recommend the use of JSB-1 on fresh cytospin preparations for the immunocytochemical detection of P-gp in chronic lymphoid disorders.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Epstein-Barr virus in familial Hodgkin's disease.

Hodgkin's disease (HD) has been found to be linked to Epstein-Barr virus (EBV). Familial HD (FHD) may be related to a possible unknown agent. We have determined whether EBV small RNAs (EBERs) were found in Reed-Sternberg cells from FHD. Five families were studied for histological subtype and EBER presence. There was a striking similarity in FHD subtypes of each family and 3/11 (27%) of the cases were EBER positive. In conclusion, EBV EBERs are only infrequently found in FHD and other factors including viruses different from EBV should be further investigated in FHD.

Female↗
PubMed1994

bcl-2 proto-oncogene and Epstein-Barr virus latent membrane protein-1 expression in AIDS-related lymphoma.

The expression of bcl-2 protein and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) was investigated in 18 cases of lymphoma occurring in the acquired immunodeficiency syndrome (AIDS). EBV small RNAs were detectable in tumour cells in all cases by in situ hybridization with EBER oligonucleotides. LMP-1 expression was detected in 61% of the cases, and 55% were positive for bcl-2. Dual expression of LMP-1 and bcl-2 was found in 8/18 (44%) cases, while five cases (28%) expressed either LMP-1 or bcl-2 and five expressed neither. Thus, there was an inconsistent relationship between the presence of EBV and the expression of bcl-2. One LMP-1 negative case was found to express bcl-2 in reactive lymphocytes but not in lymphoma cells. No clinical features were found to correlate statistically with LMP-1 or bcl-2 expression in the tumour cells. However, CD4 counts at diagnosis were significantly lower in bcl-2 positive cases (P < 0.05). The respective roles of EBV LMP-1 and the expression of bcl-2 in lymphogenesis in AIDS patients remains complex and is not yet fully understood.

Adult↗
PubMed1994

Rhythmic modulation of the responsiveness of locust sensory local interneurons by walking pattern generating networks.

1. Spiking local interneurons in the thoracic ganglia of the locust are known to process mechanosensory information from leg receptors and to contribute to postural reflexes. It is not clear, however, whether these interneurons are also involved in the control of leg movement during walking or whether their role in mediating local reflexes is phasically modulated by the walking pattern generating networks. To address these questions, intracellular recordings from spiking local interneurons in a midline population were made both in a "fictive walking" preparation reduced to isolated thoracic ganglia and in semi-intact locusts walking on a treadwheel. 2. In fictive walking (and therefore deafferented) preparations, rhythmic synaptic inputs were observed in 72% of the sampled local interneurons. These inputs resulted in a modulation of the interneurons' firing rate in phase with the centrally generated rhythm. A similar rhythmic drive was seen in spiking local interneurons recorded from semi-intact walking locusts. This drive persisted after amputation of the leg from which the interneurons received their sensory inputs. These results indicate that this population of interneurons receives inputs from central networks that participate in the generation of walking. 3. In fictive walking preparations where a hindleg was left attached to its segmental ganglion, individual local interneurons could be characterized physiologically by their receptive field properties. The central inputs were found to modulate the activity of members of all subclasses of interneurons (i.e., purely exteroceptive, purely proprioceptive, and with mixed receptive fields. The mode of modulation observed could oppose or assist the effect of sensory input expected to occur during normal walking.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Interactions between segmental leg central pattern generators during fictive rhythms in the locust.

1. Rhythmic activity of leg motor neurons could be evoked in isolated locust thoracic ganglia as well as in preparations of two or three connected thoracic ganglia superfused with the muscarinic agonist pilocarpine. Rhythms were always more regular and reliably elicited in single isolated ganglia. When the ganglia were connected, rhythmic activity of leg motor neurons was not usually simultaneously evoked in all six hemiganglia. Typically, some of the hemiganglia were rhythmically active, whereas others showed tonic or highly irregular activity. 2. Action potentials from leg motor neuron pools were recorded extracellularly from motor nerves and cross-correlated with the use of standard algorithms. The following correlations were observed between activities of motor neurons in different hemisegments. 1) Within a segment, trochanteral levators were coactive with contralateral trochanteral depressors. This correlation was strong in the metathoracic ganglion, and weaker in the pro- and mesothoracic ganglia. 2) Coupling between levators on opposite sides of the same segment was variable in the pro- and mesothoracic ganglia, because phase relationships between levators were different in each preparation and could also change during the course of an experiment. In the metathoracic ganglion, levators on opposite sides were never coactive. 3) Trochanteral levators were often active within a short latency of levator bursts in an ipsilateral adjacent hemiganglion. In addition, levators in one segment were often inhibited during levators bursts in the ipsilateral adjacent segment. 4) Trochanteral levators were strongly coupled to ipsilateral adjacent trochanteral depressors, for all three thoracic ganglia. 3. The phase relationships between motor neuron activities revealed by cross-correlation are discussed in the context of what is known about the mechanisms involved in the control of intersegmental coupling during legged locomotion.

Action Potentials↗
PubMed1994

Escalating dose of mitoxantrone with high-dose cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation.

PURPOSE: We conducted a dose-finding study of mitoxantrone (MITO) in combination with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) in refractory lymphoma undergoing autologous bone marrow transplantation (ABMT). The objective were to determine the following: (1) the maximum-tolerated dose of MITO, (2) the extramedullary toxicity of this regimen, (3) its antitumor activity, and (4) the pharmacokinetic characteristics of MITO at each dose level. PATIENTS AND METHODS: Escalating doses of MITO (15 to 90 mg/m2, single bolus infusion on day -8) followed by CBV were administered to 20 patients (mean age, 38.5 years) with refractory lymphoma. MITO concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: No toxic death occurred. The maximum-tolerated dose appears to be 75 mg/m2. Two of five patients treated with 90 mg/m2 developed severe organ toxicity, versus zero of 15 treated with doses up to 75 mg/m2. Duration of neutropenia was longer for patients treated with 90 mg/m2 (31.7 days) than for patients treated with doses up to 75 mg/m2 (22.1 days) (P < .05). A linear relationship was observed between administered dose of MITO and (1) plasma peak value, (2) area under the curve (AUC), and (3) plasma concentration on the day of marrow infusion (day 0). Hematologic toxicity was related to the terminal half-life (T1/2) of MITO, and day-0 plasma concentration. A high complete response (CR) rate was observed (60%), and eight of 11 (73%) patients treated with MITO > or = 60 mg/m2 achieved a CR. CONCLUSION: MITO (up to 75 mg/m2) and CBV can be administered with acceptable toxicity and a promising CR rate in this poor-risk population, justifying further phase II studies.

Adult↗
PubMed1994

Modification of immunoreactive EGF and EGF receptor after acute tubular necrosis induced by tobramycin or cisplatin.

Acute tubular necrosis induced by aminoglycoside antibiotics and various other nephrotoxins is followed by a regenerative process which leads to the restoration of damaged tubules. Several lines of evidence indicate that tubular regeneration is mediated by polypeptide growth factors such as epidermal growth factor (EGF). Previous studies devoted to cisplatin nephrotoxicity have shown that this agent causes tubular cystic degeneration possibly related to an impairment of renal tissue repair. Thus, we examined on a comparative basis the time course of the regenerative response subsequent to tubular damage induced by tobramycin or cisplatin, particular attention being paid to renal EGF and its receptor. Female Sprague-Dawley rats (160-180 g body weight) were treated during 4 consecutive days with daily doses of 200 mg/kg tobramycin i.p. (BID) or 2 mg/kg cisplatin (once a day). Sham-treated rats were given 0.9% NaCl i.p. following the same protocol. Groups of experimental animals (n = 5-10) were terminated at increasing time intervals (1, 4, 7, 14, 21, 60 days) after cessation of treatment. One hour prior to sacrifice, each individual received i.p. 200 mg/kg 5-bromo-2'-deoxyuridine (BrdU) for the immunohistochemical demonstration of cell proliferation. Blood was collected at the time of sacrifice in order to assess glomerular filtration rate by measuring serum creatinine and BUN levels. Kidneys were analyzed with respect to total EGF determined by RIA in renal tissue homogenates, and soluble EGF was assayed in extracts prepared by centrifugation. Renal tissue was processed for the immunohistochemical detection of S-phase cells, of EGF, of EGF receptors, and of the intermediate filament vimentin, the latter being used as a marker of epithelium dedifferentiation. In absence of nephrotoxic alterations, EGF was immunolocalized in distal tubules, whereas EGF receptor immunostaining was seen in proximal tubules cells. Vimentin immunostaining was confined to glomeruli and blood vessels. Tobramycin and cisplatin caused acute tubular necrosis in proximal convoluted tubules and proximal straight tubules, respectively. Tissue damage was accompanied by renal dysfunction reflected by an elevation of serum creatinine and BUN levels. Tubular necrosis was followed by a proliferative response indicative of tubular regeneration. Regenerative hyperplasia was associated with a reduction of total immunoreactive EGF due to a decrease of tissue-bound proEGF. Tubules undergoing regenerative repair were characterized by a disappearance of EGF receptors and the presence of immunoreactive vimentin. In tobramycin-treated rats, renal dysfunction lasted for 4-7 days and was fully reversible, as indicated by the return of serum markers to normal values.

Analysis of Variance↗
PubMed1994

[Pharmacological control of P-glycoprotein expression].

Calcium channel inhibitors, such as verapamil, have been identified as having the ability to modulate the multidrug-resistant (MDR) phenotype due to overexpression of P-glycoprotein (Pgp). We have studied the effect of verapamil on Pgp expression levels in a cell line originating from acute myeloblastic leukemia and resistant to adriamycin, K562/ADR. In this line, the addition of 15 microM verapamil in the culture medium gives a 3-fold decrease of Pgp expression after 72 hours of treatment. Similar results have been obtained for two other MDR cell lines, which suggest that this phenomenon is not specific of a single model. The level of mdr1 mRNAs is decreased in the presence of verapamil (with a maximum effect obtained at the 24th hour), which suggests that the mechanism of action of verapamil is transcriptional and/or post-transcriptional. We have also studied the effect of verapamil on the level of expression of mdr1 mRNAs in non-drug selected cells such as the HEL line (human acute myeloblastic leukemia) and the parental K562 line, which present a very low level of expression of Pgp, detectable only by PCR. In these lines, verapamil treatment has no effect on the level of expression of mdr1 mRNAs. The effect of verapamil is therefore restricted to drug-selected lines presenting high levels of Pgp expression. The impact of the negative regulation of Pgp expression on the MDR phenotype has been studied in the K562/ADR line. When the cells are treated for 72 h by verapamil, there is a decrease of resistance and an increase of intracellular accumulation of anticancer agents such as daunorubicin or vinblastine. Negative regulation of Pgp expression appears therefore as a possible strategy for MDR phenotype reversal. The effect of verapamil, whose molecular mechanism of action is being studied, could constitute a basis for this strategy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Antisense inhibition of myeloperoxidase increases the sensitivity of the HL-60 cell line to vincristine.

Myeloperoxidase (MPO), a heme-peroxidase found in the HL-60 myeloblastic cell line, is involved in vincristine (VCR) metabolism and the inactivation of this drug. We have examined whether decreased MPO activity correlated with increased sensitivity to VCR toxicity in myeloid leukemia cells. We have used MPO antisense RNA to reduce 60% of the MPO activity in the HL-60 cells. The MPO-deficient HL-60 cell line, C15, was significantly more sensitive to VCR than the parental MPO-positive cell line. Both cell lines were negative for P170-glycoprotein expression. Conversely, an MPO-positive C15 subclone was more resistant to VCR than the MPO-deficient C15 cell line. No significant differences in cytotoxic effects were observed between MPO-positive and MPO-deficient cells, following treatment with either daunorubicin or actinomycin D, two multidrug resistance-related drugs. These results strongly support an important role for MPO in VCR resistance in HL-60 cells. Antisense manipulation of the MPO content of myeloid cells could be of potential interest in leukemia treatment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

[Comparison of the functional survival in chronic renal insufficiency of Permcath jugular catheters according to their mode of insertion].

The functional survival of the same silicone double lumen catheter (DLC) was analyzed in relation with the mode of its insertion. Thirty-seven catheters were surgically inserted (34 in the right internal Jugular vein, 3 in the left internal Jugular vein), while 28 were percutaneously inserted (25 in the right internal Jugular vein, 3 in the left internal Jugular vein). The functional survival was calculated using Kaplan Meier method. Significant survival difference was looked for with log rank test. The maximum follow-up time was 62 months for surgically inserted DLC and 12 months for their percutaneous counterpart. There was no significant functional survival difference between the two groups at one year. At this term 86% of DLC were still in use. We conclude from our experience that the mode of insertion does not significantly modify the success rate of this type of blood access. The simplest and lightest method (i.e. percutaneous) should therefore be preferred.

Adult↗
PubMed1994

[Effect of catheter type on the functional survival of jugular access ports in chronic hemodialysis].

Silicone catheter (C) can be used in the hemodialysis setting as an alternative for the blood access. We analysed retrospectively the 3 types of the catheters used in 45 patients. 58 catheters were percutaneously inserted in the internal jugular vein (9 Bard (B)-Hickman; 17 Canaud (CD)-Vygon; 32 Permcath (PC)-Quinton). The indications were thrombosis or dysfunction of an arterio-venous fistula (A-V F) (52%), absence of a A-V F (21%), Thomas' shunt infection (8%), infection or extrusion of a previous catheter (19%). The functional survival curve of the C shows the best results for the PC and the worse with the B (Log-Rank test = 6,602, p < 0.037). The main cause of failure was the catheter's extrusion (3 of the 5 failures for the B; 4 of the 6 for the CD). None of the PC was extruded. Infection and inadequate blood flow were equally found in the 3 groups. In our experience, PC give the best results because of the quality of the cuff making a good attachment in the sub-cutaneous tunnel.

Aged↗
PubMed1994

Potential strategies for circumventing myeloperoxidase-catalyzed degradation of vinca alkaloids.

Myeloperoxidase (MPO) has recently been shown in an in vitro, cell-free system to catalyze the peroxidative degradation of vincristine (VCR). Oxidation of VCR involves a ring fission between positions 20' and 21', and is thought to be facilitated by the presence of an hydroxyl (-OH) group at position 20'. We report here two different approaches, both with potential clinical application, to decrease MPO-catalyzed vinca degradation. Firstly, we tested the hypothesis that -OH substitution at position 20' increases vinca susceptibility to peroxidation by comparing the relative extent of degradation of vinorelbine (Navelbine or NVB), which lacks a 20' hydroxyl substitution, with that of VCR. As anticipated, NVB was significantly less susceptible to MPO-catalyzed peroxidation than was VCR (p < 0.01). Secondly, we screened an array of compounds that are in current clinical use for their ability to inhibit MPO. Acetaminophen, N-acetylcysteine, propylthiouracil, D-penicillamine, mefenamic acid, dapsone, and methimazole all inhibited MPO at clinically achievable concentrations. Insofar as increased MPO activity has been observed in patients with acute myeloid leukemia, these findings suggest potential strategies for improving the activity of vinca alkaloids in this disease.

Antineoplastic Agents↗
PubMed1994

Odorant-induced oscillations in the mushroom bodies of the locust.

Kenyon cells are the intrinsic interneurons of the mushroom bodies in the insect brain, a center for olfactory and multimodal processing and associative learning. These neurons are small (3-8 microns soma diameter) and numerous (340,000 and 400,000 in the bee and cockroach brains, respectively). In Drosophila, Kenyon cells are the dominant site of expression of the dunce, DC0, and rutabaga gene products, enzymes in the cAMP cascade whose absence leads to specific defects in olfactory learning. In honeybees, the volume of the mushroom body neurophils may depend on the age or social status of the individual. Although the anatomy of these neurons has been known for nearly a century, their physiological properties and the principles of information processing in the circuits that they form are totally unknown. This article provides a first such characterization. The activity of Kenyon cells was recorded in vivo from locust brains with intracellular and local field potential electrodes during olfactory processing. Kenyon cells had a high input impedance (approximately 1 G omega at the soma). They produced action potentials upon depolarization, and consistently showed spike adaptation during long depolarizing current pulses. They generally displayed a low resting level of spike activity in the absence of sensory stimulation, despite a large background of spontaneous synaptic activity, and showed no intrinsic bursting behavior. Presentation of an airborne odor, but not air alone, to an antenna evoked spatially coherent field potential oscillations in the ipsilateral mushroom body, with a frequency of approximately 20 Hz. The frequency of these oscillations was independent of the nature of the odorant. Short bouts of oscillations sometimes occurred spontaneously, that is, in the absence of odorant stimulation. Autocorrelograms of the local field potentials in the absence of olfactory stimulation revealed small peaks at +/- 50 msec, suggesting an intrinsic tendency of the mushroom body networks to oscillate at 20 Hz. Such oscillatory behavior could not be seen from local field potential recordings in the antennal lobes, and may thus be generated in the mushroom body, or via feedback interactions with downstream neurons in the protocerebrum. During the odor-induced oscillations, the membrane potential of Kenyon cells oscillated around the resting level, under the influence of excitatory inputs phase-locked to the field activity. Each phasic wave of depolarization in a Kenyon cell could be amplified by intrinsic excitable properties of the dendritic membrane, and sometimes led to one action potential, whose timing was phase-locked to the population oscillations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗