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E Weber

Publications and source records attributed to E Weber.

At least 91 records · Page 5Linked to original sources
PubMed1998

Cysteine proteinase inhibitor cystatin A in breast cancer.

Cystatin A (acid cysteine proteinase inhibitor; ACPI) is a natural inhibitor of cysteine proteinases. It has been suggested that an inverse correlation exists between cystatin A and malignant progression. We wanted to assess the biological and clinical significance of cystatin A in infiltrative breast carcinoma by immunohistochemical staining. Formalin-fixed paraffin-embedded material from 440 cases treated during the years 1988-1991 was used in the study. After exclusion of patients with disseminated disease at diagnosis, previous contralateral breast carcinoma, and absence of follow-up data, 384 patients could be included in the survival analysis. For immunohistochemical analysis of cystatin A, we used monoclonal cystatin A antibody WR-23/2/3/3, the binding of which was detected by the avidin-biotin-peroxidase method. Immunohistochemical analysis of Bcl-2 and p53 was also done, and mitotic activity was evaluated. Positive staining for cystatin A was found in 52 of 440 cases. The staining was irregular but showed irrefutably positive areas within neoplastic tissue. Most of the positive tumors were of the ductal infiltrative type, but two were mucinous carcinomas, one medullary and one squamous cell carcinoma. No lobular carcinomas showed positive staining. Focal cystatin A positivity was seen in myoepithelial cells of benign ducts. Occasional apoptotic bodies within the neoplasm showed strong positivity for cystatin A. Tumors positive for cystatin A were of larger size and had higher mitotic activity than cystatin A-negative tumors. Cystatin A was associated with negative Bcl-2 staining, but there was no statistically significant association between axillary lymph node status or p53 immunostaining. The risk for breast cancer-related death was significantly higher in patients with cystatin A-positive tumors than in those with cystatin A-negative ones. The risk increase was significant also in lymph node-negative patients. After adjusting for the effect of tumor size, histological grade, and lymph node status, cystatin A-positive patients still had a higher risk of death. Patients with cystatin A and p53 coexpression had a higher risk of death than the other patients. The findings reveal a new variant of aggressive breast cancer. This type of carcinoma may develop during tumor progression through genetic instability that allows cystatin A expression and gives growth advantage to a clone of tumor cells.

Adenocarcinoma, Mucinous↗
PubMed1998

Activated Raf-1 causes growth arrest in human small cell lung cancer cells.

Small cell lung cancer (SCLC) accounts for 25% of all lung cancers, and is almost uniformly fatal. Unlike other lung cancers, ras mutations have not been reported in SCLC, suggesting that activation of ras-associated signal transduction pathways such as the raf-MEK mitogen-activated protein kinases (MAPK) are associated with biological consequences that are unique from other cancers. The biological effects of raf activation in small cell lung cancer cells was determined by transfecting NCI-H209 or NCI-H510 SCLC cells with a gene encoding a fusion protein consisting of an oncogenic form of human Raf-1 and the hormone binding domain of the estrogen receptor (DeltaRaf-1:ER), which can be activated with estradiol. DeltaRaf-1:ER activation resulted in phosphorylation of MAPK. Activation of this pathway caused a dramatic loss of soft agar cloning ability, suppression of growth capacity, associated with cell accumulation in G1 and G2, and S phase depletion. Raf activation in these SCLC cells was accompanied by a marked induction of the cyclin-dependent kinase (cdk) inhibitor p27(kip1), and a decrease in cdk2 protein kinase activities. Each of these events can be inhibited by pretreatment with the MEK inhibitor PD098059. These data demonstrate that MAPK activation by DeltaRaf-1:ER can activate growth inhibitory pathways leading to cell cycle arrest. These data suggest that raf/MEK/ MAPK pathway activation, rather than inhibition, may be a therapeutic target in SCLC and other neuroendocrine tumors.

Adenovirus E1A Proteins↗
PubMed1998

Tolerance develops to the antinociceptive and motor impairing effects of ACEA-1416, a NMDA receptor antagonist, in the formalin and rotarod test in mice.

Antinociception, disturbances of motor coordination and development of tolerance to these effects were examined following acute and chronic administration of ACEA-1416, a NMDA receptor/glycine site antagonist, in Swiss Webster mice using the formalin and rotarod tests. In the formalin test, mice were injected with either the vehicle (Tris, 0.05 M) or ACEA-1416 (1-10 mg kg-1). Fifteen or 60 min later, mice were injected with formalin and observed for nociceptive responses (licking and/or biting of the injected paw). In the vehicle-treated control mice a biphasic nociceptive response was observed at 0-5 min (early phase) and from 15 to 50 min (late phase) after formalin injections. ACEA-1416 showed a dose-dependent attenuation of the nociceptive responses in both phases of the formalin test. In the rotarod test, mice were injected with ACEA-1416, placed on a rotating bar at 6 rpm for 2 min and examined for motor impairments. ACEA-1416 produced disturbances of motor coordination in a dose-dependent manner. For tolerance studies, mice were injected once daily with either the vehicle or ACEA-1416 (30 mg kg-1) and tested for antinociception and motor impairment on day 5, 10 and 20. A time-dependent decrease in the antinociceptive effect of the drug was observed in the early but not in the late phase of the formalin test. Tolerance also developed to the motor impairing effect of the drug. Taken together, these data suggest that chronic inhibition of NMDA receptors by ACEA-1416 differentially affected the antinociceptive effect of the drug in the early and late phase of the formalin test. Furthermore, the antinociceptive and motor impairing effects of the drug can be separated.

Analgesics↗
PubMed1998

ACEA-1328, an NMDA receptor antagonist, increases the potency of morphine and U50,488H in the tail flick test in mice.

The effect of 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was examined on opioid-induced antinociception in the tail flick test. Swiss Webster mice were injected with ACEA-1328 either alone or in combination with morphine or (+/-)-trans-U-50488 methanesulfonate (U50,488H), a mu- and a kappa-opioid receptor agonist, respectively, and tested for antinociception. Systemic administration of ACEA-1328 alone increased the tail flick latencies with an ED50 of approximately 45 mg kg-1. Concurrent administration of ACEA-1328 with morphine, or U50,488H, at doses that did not affect tail flick latencies, potentiated the antinociceptive effect of the opioid analgesics and vice versa. Naloxone, an opioid receptor antagonist, while not modifying the effect of ACEA-1328, did block the augmentation, suggesting that opioid receptors might be involved in the latter effect. 5-Aza-7-chloro-4-hydroxy-3-(m-phenoxyphenyl)quinoline-2(1H)-one (ACEA-0762), a selective NMDA receptor/glycine site antagonist, also showed enhancement of the antinociceptive effect of morphine and U50,488H. However, concurrent administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzol[f]quinoxaline (NBQX), a selective non-NMDA receptor antagonist, with morphine did not alter the antinociceptive potency of the opioid analgesic. Overall, the data suggest that ACEA-1328 may increase the potency of the opioid analgesics by antagonising the glycine site associated with the NMDA receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

Endoscopic sclerotherapy with fibrin glue as compared with polidocanol to prevent early esophageal variceal rebleeding.

BACKGROUND/AIMS: Endoscopic sclerotherapy is of proven benefit for patients after esophageal variceal bleeding, but is associated with substantial local and systemic complications. Since fibrin glue is a promising agent for endoscopic sclerotherapy of esophageal varices, we compared its safety and efficacy in patients after esophageal variceal bleeding. PATIENTS AND METHODS: In a randomized, controlled trial, 36 patients with an acute episode of variceal bleeding were endoscopically treated with either polidocanol (18 patients) or fibrin glue (18 patients) by intravariceal injections within 12 h of admission. Tissue compatibility, incidence of various complications, episodes of rebleeding and overall survival rates were investigated. RESULTS: Rebleeding, especially from enrollment to day 28, was less common in the fibrin group (p=0.046), and all patients treated with fibrin glue survived for more than 28 days, whereas five patients treated with polidocanol died within this period. The incidence of sclerotherapy-induced ulcers was significantly lower in the fibrin group than in the polidocanol group (p=0.001), and major complications such as perforation or ulcer bleeding were observed only in the polidocanol group. There were no complications in any group due to activation of systemic coagulation, fibrinolysis or clinically relevant pulmonary embolization. CONCLUSIONS: We conclude that fibrin glue is an efficient and safe agent for endoscopic sclerotherapy of bleeding esophageal varices, especially in the immediate posthemorrhagic period.

Aged↗
PubMed1998

Relationships between gastric emptying and intestinal absorption of nutrients and energy in mini pigs.

Little is known about the relationship between gastric emptying of nutrients regulated by feedback mechanisms and the absorptive capacity of the gut. Therefore, we wanted to elucidate these interrelationships. A 150-cm jejunal segment was perfused (1-8 kcal/min) with three different nutrient solutions (either 60% of energy as carbohydrate, or 60% as protein, or 33.3% of each nutrient). In separate experiments, gastric emptying was measured after administration of three different meals with the same nutrient composition as the perfusion solutions. The jejunal absorption of carbohydrate, protein, fat, and energy demonstrated saturation kinetics. The kinetics differed among the three nutrients; carbohydrates were absorbed at higher rates than fat and protein. Interactions among the nutrients altered the kinetics providing a constant absorption of energy. After meals, the stomach emptied equal amounts of energy despite large variations in meal composition. The available intestinal absorptive capacity for protein was utilized by 96%, whereas that for carbohydrate, fat and energy were utilized only by 46-62%. Besides reserves in the absorptive capacity, the intestine provided reserves in total length available for absorption. The results indicate a close relationship between the energy-dependent absorption of nutrients and the energy-dependent feedback inhibition of gastric emptying.

Animals↗
PubMed1998

Cerebrospinal fluid shunt infections in infants and children in Mobile, Alabama.

Cerebrospinal fluid shunt systems are used to treat hydrocephalus in infants and children; unfortunately, some shunt systems become infected. We sought to define the epidemiology of shunt infections and shunt survival prior to infection at our institution. We identified 268 shunt procedures performed from January 1990 to June 1996 in 145 patients. There were 29 episodes of shunt infection for an incidence of 10.8% per procedure and 13.1% per patient. Staphylococcus epidermidis was the most common isolate recovered. The probability of shunt infection was highest during the first 8 weeks after a shunt procedure and subsequent infection was less likely after 28 weeks.

Adolescent↗
PubMed1998

Effects of intrathecal NMDA and non-NMDA antagonists on acute thermal nociception and their interaction with morphine.

BACKGROUND: N-methyl-D-aspartate (NDMA) antagonists have minimal effects on acute nociception but block facilitated states of processing. In contrast, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists decrease acute noxious responses. Morphine (a mu-opioid agonist) can also decrease acute nociceptive processing. The authors hypothesized that the interaction between morphine and AMPA receptor antagonists would be synergistic, whereas morphine and NMDA antagonists show no such interaction in acute nociception. METHODS: Sprague-Dawley rats (weight, 250-300 g) were implanted with chronic lumbar intrathecal catheters and were assigned to receive one of several doses of morphine--ACEA 1021 (NMDA glycine site antagonist), ACEA 2085 (AMPA antagonist), AP-5 (NMDA antagonist), saline or vehicle--and were tested for their effect on the response latency using a 52.5 degrees C hot plate. The combinations of morphine and other agents also were tested. RESULTS: Intrathecal morphine (ED50:2 microg/95% confidence interval, 1-4 microg) and ACEA 2085 (6 ng/2-15 ng), but not AP-5 or ACEA 1021, yielded a dose-dependent increase in the thermal escape latency. A systematic isobolographic analysis was carried out between intrathecal morphine and ACEA 2085 using the ED50 dose ratio of 357:1. A potent synergy was observed with decreased side effects. Morphine dose-response curves were carried out for morphine and fixed doses of ACEA 1021 (12 microg) or AP-5 (10 microg). No synergistic interactions were noted. CONCLUSIONS: Spinal mu-receptor activation and AMPA receptor antagonism showed a synergistic antinociception in response to an acute thermal stimulus. NMDA or NMDA glycine site antagonism had no effect alone nor did they display synergy with morphine. These results suggest an important direction for development of acute pain strategies may focus on the AMPA receptor.

Analgesia↗
PubMed1998

Reserve capacities of the small intestine for absorption of energy.

Previous in vitro studies showed that the small intestine has reserve capacities for absorption of nutrients. However, the size of the reserve capacity is controversial. Therefore, we measured the intestinal capacity for absorption of energy in relation to the postprandial gastric delivery of energy into the gut. In minipigs, a 150-cm length of jejunum was perfused (1-8 kcal/min) with four nutrient solutions containing 60% of energy as carbohydrate, protein, and fat, respectively, or containing 33.3% of each nutrient. In separate experiments, gastric delivery of energy to the jejunum was measured after oral administration of four meals with the same nutrient composition as the perfusion solutions. With all nutrient solutions, intestinal absorption of energy demonstrated saturation kinetics. The jejunal capacity for absorption of energy ranged from 0.66 to 0.94 kcal . m-1 . min-1. Despite large differences in nutrient composition of the four meals, equal amounts of energy (1.3 +/- 0.41 kcal/min) were delivered from the stomach to the jejunum. The absorption rates of energy after meals ranged from 0.40 to 0.58 kcal . m-1 . min-1. Therefore, only 58.8 +/- 2.7% of the jejunal capacity for absorption of energy was used. Additionally, the length of small intestine that would have been required for complete absorption was 42.9 +/- 3.7% of the total length. Results indicate that the feedback control of gastric emptying provides at least two types of intestinal reserve capacities: a reserve in absorption (1.7 fold) and a reserve in intestinal length (2.4 fold).

Analysis of Variance↗
PubMed1998

Sorting of non-glycosylated human procathepsin S in mammalian cells.

Cathepsin S, a lysosomal cysteine protease, is synthesized as inactive precursor. It is activated in the lysosomes by a proteolytic cleavage of the propeptide. HEK 293-cells which do not express cathepsin S were transfected with cDNA of either wild type human procathepsin S or a mutant procathepsin S in which Asn of the only glycosylation site in the proregion was replaced by Gln. The cells expressed glycosylated and non-glycosylated procathepsin S, respectively. Large amounts of the precursors were secreted into the culture media by both transfectants. Secreted wild type procathepsin S contained Man-6-phosphate in the oligosaccharide chain. Wild type procathepsin S was activated in the cells but no maturation occurred in the culture media. In vitro processing of glycosylated as well as of non-glycosylated procathepsin S gave fully active enzymes thus indicating that the oligosaccharide chain was not necessary for proper folding. A reuptake of the glycosylated and non-glycosylated procathepsin S by HEK 293-cells could be observed. Small amounts of mature cathepsin S were detected in the lysosomes of the mutant transfectants. Subcellular fractionation showed non-glycosylated procathepsin S in the membrane fraction. Non-glycosylated procathepsin S was bound to the plasma membrane at 2 degrees C, suggesting an additional sorting motif in the cathepsin S molecule besides the Man-6-phosphate residue.

Animals↗
PubMed1998

[Surgical treatment of proximal humerus fractures--international multicenter study].

To receive an overview of the presently used methods for the operative treatment of fractures of the proximal humerus a prospective controlled multicenter study was arranged. 146 fractures from 145 patients (76 females, 69 men) were assessed, documented with the AO standard sheets and radiographs and with a one year follow-up examination. Each of the nine clinics used his own treatment scheme. They applied: K-wires (27%) for adaptation and for intramedullary fixation; tension band wires (16%) or sutures (11%) alone or in combination with K-wires; osteosynthesis with screws alone (7%) or with plates (22%). In 17% the humeral-head was acutely replaced with a prosthesis. 11 fractures (8%) had to be reoperated because of instability or loss of fixation. 109 patients were available for clinical review, one patient could be questioned by letter and six patients had died after one year (follow-up 80%). In 38% of patients full limb function was restored, slight impairment persisted in 45% and 17% remained severely handicapped. 96 fractures (89%) were consolidated, 30% with a deformity. 35% of patients still were unable to work full time. The treatment of fractures of the proximal humerus is generally difficult. More over the various operative methods and problematic fracture classification make a differentiate statistical analysis impossible. Still many questions remain. For answers a new trial is mandatory. For this future series fixed guidelines for indications and operative treatment modalities are required to allow a meaningful comparison of results and a scoring system for evaluation of functional outcome is necessary.

Adult↗
PubMed1998

Glucose and maltodextrin in enteral diets have different effects on jejunal absorption of nutrients, sodium and water and on flow rate in mini pigs.

In four mini pigs a segment of the proximal jejunum was temporarily isolated and perfused with two enteral diets containing isocaloric amounts either of glucose or maltodextrin. With regard to total energy, the diets were composed of 60% carbohydrate, 20% protein and 20% fat. The perfusion rates were 1, 2, 4, 6, and 8 kcal/min. Absorption of glucose and fat from the maltodextrin diet was significantly greater than from the glucose diet, whereas absorption of protein was only slightly enhanced. A net water absorption occurred at perfusion of the isotonic solution with maltodextrin. Perfusing the hypertonic glucose diet, water was secreted. Therefore the flow rate increased from oligomer to monomer glucose source. With enhanced flow rate sodium secretion increased. However, the sodium concentration of the effluent was determined more by the transepithelial water movement than by the sodium secretion. The present results indicate that in enteral diets with interactions among different nutrients there is a 'kinetic advantage' in glucose absorption from maltodextrin compared to glucose. However, the reduced flow rate of the maltodextrin diet due to the lower osmolality contributed to the enhanced absorption.

Animals↗
PubMed1997

The inhibition of cathepsin S by its propeptide--specificity and mechanism of action.

The interaction of human recombinant full-length cathepsin S propeptide (amino acids 16-114) with mature cysteine proteinases was studied with respect to selectivity and pH dependence. The inhibitory capacity was tested towards mature human recombinant cathepsin S, purified cathepsin L from rat and Paramecium tetraurelia, rat cathepsin B, human cathepsin H, and papain. The propeptide of cathepsin S strongly inhibited cathepsin S (Ki = 0.27 nM) and the two cathepsin L species (Ki = 0.36 nM) at neutral pH. Papain, and to a minor extent cathepsin H, hydrolyzed the propeptide of cathepsin S, leading to competition with the hydrolysis of the fluorogenic substrates in the respective assays. Cathepsin B activity was nearly unaffected up to micromolar propeptide concentrations in the assay. The inhibition of cathepsin-L-like peptidases was diminished with decreasing pH, probably due to dramatic changes in the conformation of the propeptide. This assumption was supported by far-ultraviolet CD spectroscopy and by the finding of rapid hydrolysis of the cathepsin S propeptide by cathepsin L at pH values less than 5.5.

Animals↗
PubMed1997

5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors.

A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N-oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [3H]-(S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding to AMPA receptors, and [3H]kainate ([3H]KA) binding to KA receptors in rat brain membranes. 5-(N-Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and approximately 2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N-oxyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 microM at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A+) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5-(N-oxyaza)-QX (12e) have Kb values of 0.63 and 0.31 microM for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7-bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg i.v., respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (approximately -2.7). Separate studies indicate that QXs 12a and 12e are also active in vivo as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted-QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.

Animals↗