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Biomedical subjects

J Robert

Publications and source records attributed to J Robert.

At least 235 records · Page 13Linked to original sources
PubMed1994

[Structure and function of P-glycoprotein].

P-glycoprotein is a membrane ATPase transporter responsible for multidrug resistance. Its primary structure is known from cDNA sequencing, but its tri-dimension structure remains hypothetical. Its physiological role in detoxification, as well as its involvement in anticancer drug transport, are no longer questioned, but its molecular mechanism of action remains unknown. It appears likely that it extrudes the drugs laterally, in the plane of the membrane, that several distinct drug or modulator binding sites exist, that its activity is regulated by phosphorylation. Purification and reconstitution of P-glycoprotein will probably allow to better understand its mechanism of action.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Potential toxic effects of superselective injection of amobarbital sodium on microvasculature: a study in an animal model.

PURPOSE: To determine whether microvascular damage occurs from superselective intraarterial injection of amobarbital sodium using the swine endovascular embolization model. METHODS: Thirty-four swine underwent percutaneous femoral puncture for superselective catheterization of the proximal artery of the rete. Varying concentrations of amobarbital sodium were prepared (12.5 to 100 mg/mL solution) in either normal saline or sterile water (105 mOsm/L to 1138 mOsm/L) of which one concentration was infused slowly into one ipsilateral rete. Control infusions were also performed. Histopathologic changes were evaluated at 30 minutes and 10 days after infusion, using standard light and electron microscopy techniques. RESULTS: Moderate vasospasm occurred only in three swine at 100 mg/mL amobarbital sodium in normal saline. Light microscopy showed no significant histologic changes in the retia at any of the tested concentrations of amobarbital sodium. Electron microscopy showed ultrastructural alterations in the intima only at the higher amobarbital sodium concentrations. CONCLUSIONS: Concerns for inducing significant damage to cerebral microvasculature by superselective injection of amobarbital sodium at the usually recommended concentrations and doses are probably not justified.

Amobarbital↗
PubMed1994

An experimental arteriovenous malformation model in swine: anatomic basis and construction technique.

We assessed the feasibility of creating an experimental arteriovenous malformation model in swine by diverting and increasing blood flow through bilateral retia mirabilia. This was achieved by surgical formation of a large right-sided carotid-jugular fistula, in combination with endovascular occlusion of several neck arteries ipsilateral to the fistula. Using this technique, 11 of 13 swine demonstrated an acute-phase angiographic simulation of an arteriovenous malformation. There was rapid circulatory diversion from the left ascending pharyngeal artery ("feeder"), across both retia ("nidus"), and fast retrograde flow into the right ascending pharyngeal and common carotid arteries ("draining vein") toward the fistula. The relevant vascular anatomy of the swine head and neck is outlined, and steps in the construction of this arteriovenous malformation model are detailed.

Anastomosis, Surgical↗
PubMed1994

Experimental models of bifurcation and terminal aneurysms: construction techniques in swine.

We report our preliminary experience in the surgical construction of five experimental bifurcation and terminal aneurysm models in swine. We used unilateral neck vessels to construct models in which the relative directions and sizes of the parent and daughter arteries could be varied by surgery, resulting in aneurysms with high morphologic similarity to human intracranial lesions. Steps in the construction of each model are detailed.

Anastomosis, Surgical↗
PubMed1994

An in vivo arteriovenous malformation model in swine: preliminary feasibility and natural history study.

PURPOSE: To assess the feasibility, natural history, and preliminary physiologic validation of creating an in vivo arteriovenous malformation model in swine. METHODS: A transorbital puncture technique into the cavernous sinus was used to create an arteriovenous communication between the rostral rete and the cavernous sinus in eight swine. Short-term patency and hemodynamic behavior were assessed clinically and by serial angiography. Acute phase physiologic characterization of four models was also performed, using intravascular pressure and Doppler blood flow velocity measurements. RESULTS: Large arteriovenous shunts between the rostral rete and cavernous sinus were consistently produced, which mimicked the angiographic features of cerebral arteriovenous malformations in humans. Classic changes in intraarterial and intravenous pressures and blood flow velocities were also observed. Early pathophysiologic evolution occurred in two animals, consisting of recruitment of previously unseen collateral vessels. Spontaneous occlusion of the arteriovenous shunt occurred in most animals within 7 days because of a rigorous fibroblastic response. CONCLUSIONS: A simple technique for creating an arteriovenous malformation model in swine is now possible and is promising for future studies.

Animals↗
PubMed1994

Combined stent implantation and endosaccular coil placement for treatment of experimental wide-necked aneurysms: a feasibility study in swine.

PURPOSE: To assess the feasibility of combining stent implantation in the parent artery with endosaccular coil placement for the treatment of experimentally created wide-necked aneurysms. METHODS: Wide-necked aneurysms were surgically created on the common carotid artery in 12 swine. A metal stent was endovascularly implanted across each aneurysm neck and its effect documented anigiographically. If the aneurysm remained patent, a microcatheter was introduced into the aneurysm through the stent mesh. Electrically detachable coils were delivered into the aneurysm sac to produce thrombosis. RESULTS: After stent implantation, one carotid artery thrombosed and two aneurysms spontaneously occluded. In the other 9 cases, coils were deposited through the stent to occlude the aneurysm. Complete aneurysm packing was possible in all 9 cases. The presence of the stent allowed placement of small coils near the aneurysm neck, thus contributing to the safe occlusion of small remnants in the final stages of aneurysm packing. CONCLUSION: The combination of stent implantation and coil placement is feasible in the treatment of experimental wide-necked saccular aneurysms. The stent maintains patency of the parent artery while allowing aneurysm occlusion by endosaccular coil placement through the stent's mesh. Occlusion of small aneurysm remnants is possible with no fear of coil hernation or migration into the parent artery. Long-term studies will be necessary before application to treatment of selected intracranial aneurysms.

Aneurysm↗
PubMed1994

Technical feasibility and histopathologic studies of ethylene vinyl copolymer (EVAL) using a swine endovascular embolization model.

PURPOSE: To study the safety, technical efficacy, and histopathology of the ethylene vinyl alcohol copolymer (EVAL) embolic mixture in an animal model. METHODS: Microcatheterization of the rete was performed in 29 swine. The clinical, angiographic, and histopathologic consequences of superselective injection of the two principal embolic mixture components (EVAL and dimethyl sulfoxide [DMSO]) were evaluated. Necropsy and standard histologic preparation were used for pathologic analysis. RESULTS: Significant technical difficulties and adverse outcomes occurred. The EVAL mixture was difficult to see under fluoroscopy and prematurely polymerized during one embolization, resulting in catheter occlusion. However, polymerized EVAL did not adhere to the catheter. DMSO damaged the plastic hubs of the microcatheters. Infusions of DMSO always caused immediate, moderate to severe vasospasm and frequently caused either subarachnoid hemorrhage or stroke. Histopathologic findings of both DMSO and DMSO plus EVAL were similar, producing variable endothelial denuding, thrombosis, and disruption of internal elastic lamina in the acute stage. An intense, mixed inflammatory response, organized thrombus, and transmural necrosis with extravasation were seen in the subacute and chronic stages. CONCLUSIONS: Despite having some desirable features as an embolic agent, significant problems were encountered with EVAL; the most important of which is that one of the principal components of the embolic mixture, DMSO, seems to be very angiotoxic.

Animals↗
PubMed1994

Technical feasibility and performance studies of a Doppler guide wire for potential neuroendovascular applications.

PURPOSE: To conduct technical feasibility and performance studies on a new Doppler-tipped, 0.014-inch micro-guide wire for potential neuroendovascular applications. METHODS: In vivo microcatheterizations of brachiocephalic arteries were performed in two swine using the 0.014-inch Doppler guide wire and a commonly used microcatheter. A standardized, bench-top method of evaluating basic mechanical properties of micro-guide wires was also used to compare the 0.014-inch Doppler guide wire with a commonly used micro-guide wire. RESULTS: The 0.014-inch Doppler guide wire had similar steerability, tractability, torque control, and distal tip flexibility to the commonly used micro-guide wire in the in vivo simulations. Frequent micro-guide wire exchanges were possible without loss of superselective positioning of the microcatheter. Bench-top testing showed the 0.014-inch Doppler guide wire to have comparable distal tip flexibility and stiffness to the commonly used micro-guide wire. CONCLUSION: The comparable subjective and objective mechanical properties of the 0.014-inch Doppler guide wire to that of a commonly used micro-guide wire further establishes the possibility of clinical implementation of the device.

Animals↗
PubMed1994

Use of a Doppler guide wire for intravascular blood flow measurements: a validation study for potential neurologic endovascular applications.

PURPOSE: To conduct a validation study of a Doppler guide wire for potential neuroendovascular applications. METHODS: A 12-MHz, 0.018-inch Doppler guide wire was evaluated in eight swine under various blood flow conditions using two types of in vivo cerebrovascular models (physiologic and arteriovenous shunting). Flow conditions were mechanically and pharmacologically altered. Doppler average peak velocity was compared with volumetric blood flow, and flow profile corrections were calculated and analyzed. Qualitative aspects of the Doppler guide wire spectra were also assessed. RESULTS: Plots of average peak velocity versus volumetric blood flow showed excellent linear relationships (r2 > 0.94), which were maintained at high flow conditions (average peak velocity, 99 to 236 cm/sec; volumetric blood flow, 392 to 889 mL/min). Values of flow profile correction varied from 0.43 to 0.94 and showed no consistent relationship to changes in volumetric blood flow. CONCLUSIONS: The excellent correlation between average peak velocity and volumetric blood flow over a wide range of blood flow conditions and the additional qualitative information of the Doppler guide wire spectra establish a foundation for clinical implementation. The unpredictable variations of flow profile corrections remain obstacles for calculating volumetric blood flow based on Doppler guide wire average peak velocity.

Animals↗
PubMed1993

Differential over-expression of mdr1 genes in multidrug-resistant rat glioblastoma cell lines selected with doxorubicin or vincristine.

We have compared the pharmacological and molecular characteristics of 2 cell lines derived from the C6 rat glioblastoma, and selected for resistance either to doxorubicin (C6 0.5 line) or to vincristine (C6 IV line). Each line displays a preferential 400-fold resistance towards the drug used for selection, the C6 IV line being especially weakly resistant to doxorubicin (13-fold). Verapamil completely restored doxorubicin sensitivity in the C6 IV line as well as vincristine resistance in the C6 0.5 line, but could not completely reverse doxorubicin resistance in the C6 0.5 line or vincristine resistance in the C6 IV line. This suggests that specific mechanisms of resistance against each drug were added to a common P-glycoprotein-mediated multidrug-resistance mechanism. Doxorubicin efflux was total within 2 hr in the C6 IV line, whereas it remained 8 to 10% of drug in the C6 0.5 line 4 hr after drug removal, despite a more rapid efflux of the drug in the first 30 min. This 2-compartment behavior could be related to a special sub-cellular distribution of doxorubicin in C6 0.5 cells. Northern and Western blot analysis of the mdrI gene and of the P-glycoprotein expressed by the 2 resistant cell lines made it possible to quantify their degree of over-expression; when compared with the C6 wild strain, the C6 0.5 line over-expressed both the mdrI gene and the P-glycoprotein to a slightly higher level than the C6 IV line. Northern and Western blot analysis also suggested that C6 0.5 cell preferentially over-expressed the mdrIa gene, whereas the C6 IV cells preferentially over-expressed the mdrIb gene. This differential over-expression was confirmed after polymerase-chain-reaction amplification of the cDNA sequences transcribed from total RNA extracted from the 2 lines. It can be concluded therefore that the mdrIa gene product is more efficient than the mdrIb gene product in extruding anti-cancer drugs from the cells; and that the mdrIb gene product might preferentially extrude vincristine rather than doxorubicin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Doxorubicin-induced oxygen free radical formation in sensitive and doxorubicin-resistant variants of rat glioblastoma cell lines [corrected and republished erratum originally printed in FEBS Lett 1993 May 17;322(3):295-8].

We have studied the formation of hydroxyl radical (OH.) induced by doxorubicin in a series of doxorubicin- or vincristine-selected variants of C6 rat glioblastoma cells in culture by electron-spin resonance spectroscopy using 5,5'-dimethyl-1-pyrroline-1-oxide as a spin trap. Wild-type cells, sensitive to doxorubicin, exhibited in the presence of this drug a concentration-dependent OH. formation which could be inhibited by preincubation with superoxide dismutase, catalase or an antibody against cytochrome P450-reductase. In highly doxorubicin-resistant cells, OH. formation was reduced to about 20% of the level obtained in sensitive cells. In cells presenting a very low level of resistance to doxorubicin or in cells selected with vincristine, both presenting a pure multidrug-resistant phenotype, OH. formation was identical to that obtained in sensitive cells. In cells of intermediate resistance or in revertant cells, intermediate levels of OH. formation were obtained. Protection against OH. formation and action can be identified at the levels of superoxide dismutase and glutathione peroxidase activities, which are both enhanced in the resistant cells.

Animals↗
PubMed1993

[Value of computerized tomography in acute diverticulitis of the left colon].

This prospective study focuses on the prediction of late outcome after acute left colonic diverticulitis successfully treated conservatively and in which the diagnosis was confirmed radiologically (computed tomography [CT] and gastrografin enema [GE]). Acute diverticulitis was diagnosed in 226 patients. Sixty-six patients (29%) were operated on during their first hospitalization, and 2 of them died (3% mortality). The remaining 160 patients, successfully treated conservatively, had a CT and a GE within 72 hours of admission and entered this study. Signs of severity on CT included the presence of abscess(es) and/or extraluminal air and/or extraluminal hydrosoluble contrast (Gastrografin). Follow-up averaged 25 months (range 1 month to 5.3 years). Twenty-seven of these 160 patients (17%) had a poor outcome (persistent diverticulitis in 12, colonic stenosis in 6, recurrences in 7, residual parasigmoid abscess and colovesical fistula in one each). When comparing these 27 patients with the 133 others it appeared that: (1) men up to 50 years of age were significantly more prone to develop such complications (p = 0.003); (2) the probability of developing a complication was significantly greater when the initial CT had revealed an abscess and/or extraluminal air and/or extraluminal Gastrografin (p = 0.005). These results support the view that elective colectomy can reasonably be proposed after a first attack of acute left diverticulitis treated conservatively in men up to 50 years of age, and/or in patients whose initial CT revealed findings of severe diverticulitis.

Age Factors↗
PubMed1993

Aspects of the cellular pharmacology of N-l-leucyldoxorubicin in human tumor cell lines.

We have compared the cytotoxicity, incorporation and metabolism of doxorubicin (dox) and N-l-leucyldoxorubicin (leu-dox) in two human tumor cell lines in culture, the MCF-7 breast cancer line and the K562 leukemia line, and their dox-resistant counterparts. Dox was 3-4-fold more cytotoxic than leu-dox in the MCF-7 lines, and 7-10-fold in the K562 lines. This could be explained by differences in cell incorporation of the drugs, which differs by the same proportion as the cytotoxicities in the various cell lines, rather than by differences in biotransformation of leu-dox into dox, which is similar in all of the cell lines.

Breast Neoplasms↗
PubMed1993

Doxorubicin-induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin.

Doxorubicin-induced lipid peroxidation was evaluated in four human or murine cell strains in culture and in their doxorubicin-resistant variants, by the quantification of malondialdehyde produced after a 2-h incubation of cells with the drug. Significantly increased malondialdehyde levels were obtained 24 h after doxorubicin treatment in three of the wild-type cell lines with doses as low as 0.05-0.1 micrograms/ml, which is within an order of magnitude of the concentration of the drug which inhibits cell growth by 50%. This production of malondialdehyde was abolished in two doxorubicin-resistant strains, even with high doses of drug (100-300 micrograms/ml), but was maintained in the third resistant line. No malondialdehyde production was observed in the fourth cell line, sensitive or resistant. It is remarkable that an enhancement of selenium-dependent and non-selenium-dependent glutathione peroxidase activities was exhibited during the acquisition of resistance to doxorubicin in the two first lines, but not in the third, whereas a constitutively high non-selenium-dependent glutathione peroxidase activity existed in the doxorubicin-sensitive and doxorubicin-resistant variants of the fourth cell line. Gene expression of selenium-dependent glutathione peroxidase and of glutathione S-transferase pi, which is known partially to bear a non-selenium-dependent glutathione peroxidase activity, were correlated with the corresponding enzyme activities. It appears, therefore, that the already known enhancement of glutathione peroxidase activity and expression in doxorubicin-resistant cell lines has a quantifiable consequence upon doxorubicin-induced lipid peroxidation and may have consequences in the mechanism of resistance to this drug.

Animals↗
PubMed1993

Pathophysiology, recognition and management of pneumoretroperitoneum.

The medical records of 15 patients found to have pneumoretroperitoneum in a 10-year period were reviewed. The cause of retroperitoneal emphysema was infection in six patients, trauma in five and iatrogenic in four. Emphysema was confined to the retroperitoneum in 11 patients, and extended to the mediastinum in four and to the soft tissue of the neck in three. Failure to diagnose pneumoretroperitoneum resulted in delayed intervention in two patients. One patient with pneumoretroperitoneum and pneumoperitoneum secondary to a lung lesion underwent unnecessary laparotomy. Outcome was favourable in these three patients. The presence of air in the retroperitoneum is not dangerous but its early recognition and detection of the source are important as septic conditions may be involved.

Adolescent↗