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Biomedical subjects

E Weber

Publications and source records attributed to E Weber.

At least 109 records · Page 6Linked to original sources
PubMed1997

Synthesis of racemic 6,7,8,9-tetrahydro-3-hydroxy-1H-1-benzazepine-2,5-diones as antagonists of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors.

The synthesis and pharmacological properties of several racemic 6,7,8,9-tetrahydro-3-hydroxy-1H-1-benzazepine-2,5-diones (THHBADs) are described. Synthesis was accomplished via a Schmidt reaction with 5,6,7,8-tetrahydro-2-methoxynaphthalene-1,4-diones (THMNDs) followed by demethylation. THMNDs were prepared via a Diels-Alder reaction with 2-methoxybenzoquinone (5) or 2-bromo-5-methoxybenzoquinone (14) and substituted 1,3-butadienes. The pharmacology of THHBADs was characterized by electrical recordings in Xenopus oocytes expressing rat brain NMDA and AMPA receptors. THHBADs are antagonists of NMDA and AMPA receptors with functional potency being dependent upon the substitution pattern on the tetrahydrobenzene moiety. The 7,8-dichloro-6-methyl (18a) and 7,8-dichloro-6-ethyl (18b) analogs are the most potent THHBADs prepared and have apparent antagonist dissociation constants (Kb values) of 0.0041 and 0.0028 microM, respectively, for NMDA receptors and 0.51 and 0.72 microM, respectively, for AMPA receptors.

Animals↗
PubMed1997

CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells.

P-selectin (CD62P) is a Ca2+-dependent endogenous lectin that can be expressed by vascular endothelium and platelets. The major ligand for P-selectin on leukocytes is P-selectin glycoprotein ligand-1 (PSGL-1). P-selectin can also bind to carcinoma cells, but the nature of the ligand(s) on these cells is unknown. Here we investigated the P-selectin binding to a breast and a small cell lung carcinoma cell line that are negative for PSGL-1. We report that CD24, a mucin-type glycosylphosphatidylinositol-linked cell surface molecule on human neutrophils, pre B lymphocytes, and many tumors can promote binding to P-selectin. Latex beads coated with purified CD24 from the two carcinoma cell lines but also neutrophils could bind specifically to P-selectin-IgG. The binding was dependent on divalent cations and was abolished by treatment with O-sialoglycoprotein endopeptidase but not endoglycosidase F or sialidase. The beads were stained with a monoclonal antibody (MoAb) to CD57 (HNK-1 carbohydrate epitope) but did not react with MoAbs against the sialylLe(x/a) epitope. The carcinoma cells and CD24-beads derived from these cells could bind to activated platelets or P-selectin transfected Chinese hamster ovary cells (P-CHO) in a P-selectin-dependent manner and this binding was blocked by soluble CD24. Transfection of human adenocarcinoma cells with CD24 enhanced the P-selectin-dependent binding to activated platelets. Treatment of the carcinoma cells or the CD24 transfectant with phosphatidylinositol-specific phospholipase C reduced CD24 expression and P-selectin-IgG binding concomitantly. These results establish a role of CD24 as a novel ligand for P-selectin on tumor cells. The CD24/P-selectin binding pathway could be important in the dissimination of tumor cells by facilitating the interaction with platelets or endothelial cells.

Amino Acid Sequence↗
PubMed1997

Structure-activity relationships of alkyl- and alkoxy-substituted 1,4-dihydroquinoxaline-2,3-diones: potent and systemically active antagonists for the glycine site of the NMDA receptor.

We report on a series of alkyl- and alkoxy-substituted 1,4-dihydroquinoxaline-2,3-diones (QXs), prepared as a continuation of our structure-activity relationship (SAR) study of QXs as antagonists for the glycine site of the N-methyl-D-aspartate (NMDA) receptor. The in vitro potency of these antagonists was determined by displacement of the glycine site radioligand [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) in rat brain cortical membranes. In general, methyl is a good replacement for chloro or bromo in the 6-position, and alkoxy-substituted QXs have lower potencies than alkyl- or halogen-substituted QXs. Ethyl-substituted QXs are generally less potent than methyl-substituted QXs, especially in the 6-position of 5,6,7-trisubstituted QXs. Fusion of a ring system at the 6,7-positions results in QXs with low potency. Several methyl-substituted QXs are potent glycine site antagonists that have surprisingly high in vivo activity in the maximal electroshock (MES) test in mice. Among these, 7-chloro-6-methyl-5-nitro QX (14g) (IC50 = 5 nM) and 7-bromo-6-methyl-5-nitro QX (14f) (IC50 = 9 nM) are comparable in potency to 6,7-dichloro-5-nitro QX (2) (ACEA 1021) as glycine site antagonists. QX 14g has an ED50 value of 1.2 mg/kg iv in the mouse MES assay. Interestingly, alkyl QXs with log P values of 0.5 or less tend to be more bioavailable than QXs with higher log P values. QX 14g has 440-fold selectivity for NMDA vs alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as determined electrophysiologically under steady-state conditions in oocytes expressing rat cerebral cortex poly(A)+ RNA. Overall, 14g was found to have the best combination of in vitro and in vivo potency of all the compounds tested in this and previous studies on the QX series.

Animals↗
PubMed1997

The N-methyl-D-aspartate (NMDA) receptor glycine site antagonist ACEA 1021 does not produce pathological changes in rat brain.

ACEA 1021 is a potent, selective N-methyl-D-aspartate (NMDA) receptor glycine site antagonist under clinical evaluation as a neuroprotectant for stroke and head trauma. The potential of ACEA 1021 to produce morphologic changes in cerebrocortical neurons of the rat was assessed since it is known that noncompetitive (e.g., MK-801) and competitive (e.g., CGS 19755)NMDA receptor antagonists produce neuronal vacuolization and necrosis in the rat posterior cingulate/retrosplenial cortex. Male and female adult rats were treated intravenously with either vehicle (Tris) or 10 mg/kg or 50 mg/kg ACEA 1021. MK-801 (5 mg/kg, s.c.) served as positive control. Whereas MK-801 produced characteristic neuronal vacuolization and necrosis in the posterior cingulate/retrosplenial cortex, neither dose of ACEA 1021 had any effect on neuronal morphology. The absence of neuropathological changes in rats supports the further clinical evaluation of ACEA 1021 for stroke and head trauma, and suggests that glycine site antagonists may be devoid of neurotoxic potential.

Animals↗
PubMed1997

The structure of superficial lymphatics in the human thigh: precollectors.

BACKGROUND: Little is known about the morphology of precollectors, the lymphatic vessels connecting the absorbing and the collecting vessels, which are regarded as the initial drainage routes of lymph. The aim of this study was to describe the structural features of human precollectors. METHODS: Samples of fat from around the saphenous veins were obtained from patients undergoing varicotomy, and serial sections were observed under light and transmission electron microscopy. Tridimensional reconstructions were also obtained by computer analysis. RESULTS: Precollectors were characterized by an irregular and discontinuous arrangement of smooth muscle cells in their wall. This arrangement was unrelated to the site of valves. When present, muscular elements were arranged helicoidally, as shown in tridimensional reconstructions. Under transmission electron microscopy, the endothelium of precollectors was similar to that of absorbing lymphatic vessels, irrespective of the presence of smooth muscle cells, and was thin, rich in pinocytotic vesicles, supported by a discontinous basal lamina, and connected by anchoring filaments to the surrounding connective tissue. Myoendothelial contacts were frequent. Valves were similar to those of collecting vessels, except for the presence of numerous zonulae adherentes connecting the characteristic "tip cells" of the free edge. CONCLUSIONS: Human thigh precollectors are characterized by the alternation of portions with a well-developed muscular coat and portions with an absorbing structure. These morphological features suggest that the precollectors contribute to fluid absorption and lymph propulsion. The frequent myoendothelial contacts suggest that smooth muscle contraction is regulated locally.

Aged↗
PubMed1997

Concentrations of lysosomal cysteine proteases are decreased in renal cell carcinoma compared with normal kidney.

Renal cell carcinoma contains significantly lower concentrations of the lysosomal cysteine proteases, cathepsins B, C, H, L and S, than does normal kidney, as shown by several methods, such as activity determination, enzyme-linked immunosorbent assay, immunoblotting and immunohistochemistry. The same low levels of enzyme activity and concentration have been determined in renal cell carcinoma metastases in the lung. Our results on the decreased concentration of cysteine peptidases at the protein level would seem to conflict with earlier results on an increased concentration of the cathepsin L mRNA in renal cell carcinoma.

Carcinoma, Renal Cell↗
PubMed1997

Immunohistochemical and clinical evaluation of cathepsin expression in soft tissue sarcomas.

Lysosomal proteases are known to enhance the spread of epithelial tumour cells, but little is known of the possible role of proteases in the growth of soft tissue sarcomas (STS). We investigated the expression of cathepsins D, B, S, H, L and procathepsin L in frozen sections of 34 STS from 34 patients by immunohistochemistry (IHC). Cathepsins D, B and H were relatively highly expressed in STS (77-91%). The expression rate of cathepsins S and L and of procathepsin L was lower (40-66%). Cathepsin S and L expression showed a moderate (P = 0.078 and P = 0.019) and procathepsin L a strong (P = 0.00001) correlation with the survival rate of STS patients. Cathepsin S expression is also correlated with the local recurrence rate (P < 0.01). Lysosomal proteases may play a role in STS progression, and cathepsin expression may also have significance as a prognostic factor in STS.

Adult↗
PubMed1997

Correction of erythrocyte shape abnormalities in familial hypercholesterolemia after LDL-apheresis: does it influence cerebral hemodynamics?

It is well known that red blood cells incubated in low-density lipoprotein (LDL)-rich medium show shape abnormalities that revert to normal after reincubation in normal plasma. Patients with homozygous familial hypercholesterolemia (HFH) have an increased percentage of abnormally-shaped erythrocytes (mostly stomatocytes, knisocytes, and crenated cells) compared to normocholesterolemic controls: 7.73+/-0.96 versus 3.52+/-0.52 (mean+/-SEM; P = 0.001). To confirm the role of high LDL concentration in inducing red cell shape abnormalities we determined the percentage of abnormally shaped erythrocytes in seven HFH patients 1 day after the procedure of LDL-apheresis with a 40% cholesterol decrease. A reduction in kniscocytes, stomatocytes, and crenated cells was observed in the patients treated by LDL-apheresis (P < 0.01). To investigate the possible benefit of a reduction in erythrocyte shape abnormality on cerebral hemodynamics, cerebral flow velocity, as evaluated by transcranial Doppler, was evaluated concomitantly and found to be remarkably increased after apheresis (P < 0.01). No significant change in hematocrit, plasma viscosity, blood viscosity, mean pressure, or cardiac output was detected, 1 day after apheresis. An inverse correlation was demonstrated (r = 0.55; P = 0.04) between changes in the percentage of knisocytes+stomatocytes +crenated cells and percent changes in middle cerebral artery peak systolic velocity. The correction of erythrocyte shape abnormalities after LDL-apheresis might be related to dramatic changes in plasma phospholipid concentration and proportion occurring after this procedure in HFH patients. The reduction of erythrocyte shape abnormalities could contribute, together with other hemorheological factors, to the improvement of cerebral hemodynamics after LDL-apheresis.

Blood Component Removal↗
PubMed1997

Auditory sustained attention is a marker of unilateral spatial neglect.

The relationships between performance on a non-spatially-lateralized measure of sustained attention and spatial bias on tests sensitive to unilateral neglect were considered in a group of 44 patients with right hemisphere lesions following stroke. As predicted from earlier studies showing a strong association between unilateral spatial neglect and sustained attention, performance on a brief and monotonous tone-counting measure formed a significant predictor of spatial bias across a variety of measures of unilateral visual neglect. This study provides further evidence for a very close link between two attentional systems hitherto regarded as being quite separate, namely a spatial attention system implicated in unilateral neglect and a sustained attention system. A close connection between these two systems was predicted by Posner, who argued that the right hemisphere-dominant sustained attention system provides a strong modulatory influence on the functioning of the lateralized posterior attention system.

Acoustic Stimulation↗
PubMed1997

Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice.

Inhibition of spinal glutamate receptors induces antinociceptive effects in numerous animal models of pain. The present study compares the effects of intrathecally administered N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists on nociceptive responses in the tail flick test. Potency of antagonists at NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors was first measured by electrical assays in Xenopus oocytes expressing rat cerebral cortex poly(A)+ RNA. Subsequently, Swiss Webster mice were injected intrathecally with the antagonists and tested for antinociception. The drugs tested were: NBQX and GYKI-52466, selective AMPA receptor antagonists, ketamine, MK-801, R(+) HA-966 and ACEA-0762, selective NMDA receptor antagonists, and ACEA-1031, ACEA-1328 and ACEA-0593, NMDA receptor antagonists that also show inhibition of non-NMDA receptors. Selective NMDA receptor antagonists induced essentially no antinociceptive effects in the tail flick test. Antinociceptive activity generally correlated with inhibition of AMPA receptors. The exception was the non-competitive AMPA receptor antagonist GYKI-52466, which was unexpectedly weak. This may be due to inadequate dosing, because the compound has limited solubility, or may be due to differences in the non-NMDA receptor subtype-selectivity profile of GYKI-52466 as compared to competitive antagonists such as NBQX. Overall, our results suggest that inhibition of spinal non-NMDA receptors is the primary, and necessary, mechanism of antinociception by these drugs in the tail flick test in mice.

Animals↗
PubMed1997

Optimal conduct of the neuropathology evaluation of organophosphorus induced delayed neuropathy in hens.

Susceptibility of various areas of the nervous system to TOCP (triorthocresyl phosphate) induced delayed neuropathy was assessed in groups of seven hens respectively, intoxicated with a single oral does of 500 or 1000 mg/kg body weight. 18 hens were used as negative controls. About 3 weeks after the treatment the hens were submitted to fixation by whole body perfusion and their nervous system processed either to paraffin sections stained with Bodian's silver stain and luxol counterstain, or to semi-thin plastic sections stained with toluidine blue. The examined areas were the cerebellum, the spinal cord at upper cervical, thoracic and lumbar level, the sciatic nerve, and the posterior tibial nerve. The extent of nerve fiber degeneration was assessed independently by two pathologists using a semiquantitative scoring system. The most susceptible areas were the cerebellum and the tibial nerve, followed by the upper cervical spinal cord. Within the cerebellum the nerve fibers in the rostral lobules, especially IV and Va, were affected. Whereas the resolution of plastic section was superior to that of paraffin sections in the cerebellum (mid-longitudinal level) and the spinal cord (transverse level), in the peripheral nerves the lesions were best recognized in the longitudinal, paraffin sections. There was very good agreement between both pathologists with respect to detection and grading of lesions in the most susceptible areas, but poor agreement in the areas of low susceptibility, indicating the danger of false results when lesions are not very distinct. In the susceptible areas the lesions induced with 500 mg/kg were sufficiently prominent, indicating that this dose-level is acceptable as positive control. In the hen nervous system, examination of the most susceptible areas, especially the rostral cerebellar lobules, appears to be suitable for detection of any kind of organophosphorus induced, delayed neuropathy.

Animals↗
PubMed1997

Monoclonal antibodies against cathepsin L and procathepsin L of different species.

Mouse monoclonal antibodies directed against cathepsin L and procathepsin L have been generated. Mice were immunized with human procathepsin L purified from the cell culture medium of human nonsmall cell lung cancer cell line EPLC 32 M1. More than 400 hybridoma clones were screened by ELISA or Western blot and 50 were found to secrete antibodies which reacted with cathepsin L or its precursor. Twenty-six clones were selected for further characterization of the antibodies according to their reactivity in ELISA, Western blot, and immunocytochemistry against the mature enzyme or its latent precursor of man, rat, or mouse. Only those antibodies are described here, which do not cross-react with the closely related cathepsins B and S or their latent proenzymes.

Animals↗
PubMed1997

Rat strain and vendor differences in collateral anastomoses.

Recently we observed inter- and intrastrain differences in cortical infarct volumes after middle cerebral artery (MCA) occlusion. Variations in the anastomoses providing collateral blood supply could account for different lesion sizes. Our objectives were to compare number and internal diameters of the MCA-anterior cerebral artery (MCA-ACA) anastomoses and to determine if the lesion extended beyond branches of the MCA territory into the field of the ACA in the rat strains/lines. Sprague-Dawley rats and Wistar rats from Simonsen Laboratories (SLSD and SLWIS) and Sprague-Dawley rats from Taconic Laboratories (TLSD) and Charles River Laboratories (CRSD) were anesthetized and injected with papaverine and Vultex (white latex) for arterial visualization. Some rats were also subjected to MCA occlusion. Significantly fewer anastomoses were present in SLSD and SLWIS than in CRSD and TLSD (p < 0.05). The mean internal diameters of the anastomoses were not significantly different between the strains/lines (p < 0.05). After MCA occlusion, significantly more (p < 0.05) TLSD and CRSD than SLSD had lesions extending from the MCA field beneath the anastomoses and into the region supplied by the ACA. Neither the number, luminal diameter, nor density of MCA-ACA anastomoses appears to be the limiting factor that differentiates lesion size following MCA occlusion in these particular rat strains/lines. Therefore, factors other than anatomical variations probably account for different lesion sizes.

Animals↗
PubMed1997

[Fixation of femoral shaft fractures from a Swiss viewpoint. An international prospective controlled study by the Study Group for Osteosynthesis Problems].

A prospective, controlled study of fixation for femoral shaft fractures was undertaken by the Documentation Centre of the Association for the Study of Internal Fixation (AO/ASIF) at 7 Swiss and 5 foreign clinics in Europe, South America and Asia. 283 fractures in 272 patients were evaluated. 17% of all patients suffered a polytrauma. Only two fractures (1%) were treated conservatively. Ten percent of all fractures were stabilised by external fixation, 35% were plated and 54% were treated by reamed intramedullary nailing. An ARDS and deep venous thrombosis occurred in 1% respectively. The local infection rate was 2%. Seven patients (2.5%) died perioperatively. 32 fractures (12%) were reoperated. At follow-up 86% of all fractures appeared consolidated on radiography. Full limb function was restored in 61% of all patients, slight impairment persisted in 32% and 6% of all patients remained severely handicapped. The average age of the female patients was significantly higher in Europe. Wide differences existed in the administration of prophylactic antibiotics and antithrombotic drugs. In some centers antithrombotic drugs were not part of the treatment scheme. Femoral shaft fractures were treated with high priority in Switzerland. Patients profited from short transport ways and from the routine use of high end material. Most operations in Switzerland were performed by registrars. Their assessment of stability of the fixation was high, as 90% of all patients were allowed to bear weight postoperatively. There is an international consensus on the need for surgical stabilisation of femoral shaft fractures. However divergent views on surgical management and perioperative care remain.

Adult↗
PubMed1997

Vasa vasorum of superficial collecting lymphatics of human thigh.

Collecting lymphatics were obtained from human thigh fat for light microscopy and tridimensional reconstruction at time of operation for varicose veins. No patient had lymphedema and routine sections showed no inflammation or notable pathologic alteration of the surrounding soft tissue. Abundant vasa vasorum was observed around the musculature of superficial collecting lymphatics of human thigh. Within intervalvular portions of the lymphatic collectors where the muscle coat was thicker and more compact, the vasa vasorum penetrated between smooth muscle cells and was in contact with the endothelium. In valvular portions of the collecting lymphatics where the muscle layer was thinner and more fragmented, there were fewer vasa vasorum. Tri-dimensional reconstructions of the collecting lymphatic wall showed two communicating plexi of vasa vasorum--one outside and the other inside the muscle layer. Arteries and veins of similar size did not have such an abundant vasa vasorum. The explanation for this difference may relate to the fact that a relatively low oxygen and nutrient content of lymph is insufficient to nourish the collecting lymphatic. Moreover, diffusion of nutrients from the external plexus is likely also impeded by the thickness and density of the muscle layer. The vasa vasorum deep in the muscular layer and in the subendothelial space probably sustain adequate nutrition and oxygenation to the collecting lymphatic.

Adipose Tissue↗