Enhancement of morphine clearance following intravenous administration by oral activated charcoal in rabbits

A single dose of activated charcoal (10 g) significantly reduced the half-life of elimination (1.02 +/- 0.10 and 0.70 +/- 0.04 h for the control and treated groups, respectively) and mean residence time (1.01 +/- 0.12 and 0.76 +/- 0.05 h for the control and treated groups, respectively) of morphine in rabbits. A 40% increase in the systemic clearance (85.73 +/- 7.72 and 122.64 +/- 16.32 mL min-1 kg-1 for the control and treated groups, respectively) and a 30% decrease in AUC (204.38 +/- 22.20 and 140.03 +/- 19.32 micrograms h L-1 in the control and treated groups, respectively) were also noted. Charcoal administration did not significantly alter the volume of distribution (Varea and Vss) or the apparent distribution half-life. A two-compartment model adequately described morphine kinetics in control and treated rabbits; charcoal administration produced a significant increase in the tissue compartment rate constant (K21). This finding indicates that activated charcoal not only enhances the systemic elimination of morphine, but also accelerates the rate of transfer of morphine from the tissue compartment to the central compartment.     

Gastric cancer heterogeneity

This study was carried out on 222 samples from 37 gastric carcinomas to assess the incidence of multiple stem lines in primary tumors and metastasis as reflected by multiple DNA stem lines and their relationship to epidermal growth factor (EGF) receptor expression, histologic grade, tumor size, and degree of wall infiltration. Fifteen primary tumors (40.5%) were homogeneously diploid/peridiploid whereas 22 (59.5%) were aneuploid. In the lymph node metastasis, seven patients (29.2%) had an homogeneous diploid/peridiploid pattern in all metastatic lymph nodes. On the other hand, 17 (70.8%) had at least one aneuploid peak in the lymph node metastasis. DNA content heterogeneity was seen in 12 (33%) of primary tumors whereas 14 (66.6%) of 21 patients had multiple cell clones in the metastasis. Therefore, 12 patients had a metastatic clone which was not observed in the primary tumor. DNA content heterogeneity was seen even in tumors with submucosal invasion suggesting that this phenomenon is also present at earlier stages. No correlation between the histologic grade and the DNA distribution was observed. Furthermore, histologic heterogeneity was independent of DNA content heterogeneity. The EGF receptor expression was observed in six of the 23 patients in whom this analysis was done. The EGF receptor expression was constant in all samples which were studied and even samples with a different DNA content and histologic grade were stables for the EGF receptor expression.     

Neuroendocrine and juvenile hormone effects on fat body protein synthesis during the reproductive cycle in female Blaberus discoidalis cockroaches

Ovarian protein content and fat body protein synthesis were measured during the first gonotrophic cycle in virgin female Blaberus discoidalis cockroaches. Protein synthesis was measured for in vitro fat bodies from animals treated with combinations of a juvenile hormone analog (JHA = methoprene) and corpora cardiaca (CC) extracts. Ovarian protein content began to increase on Day 5 of adult life and reached its maximum at Days 20-22. Synthesis of proteins secreted by the in vitro fat body increased by 12-fold between emergence and its maximum on Day 18, then declined to nearly its original level by Day 33. Synthesis of nonsecreted, fat body proteins increased by 4-fold between emergence and a maximum on Day 21, then declined. CC extracts and JHA were administered to decapitated females to determine their regulative effects on fat body protein synthesis. The synthesis by the fat body of nonsecreted proteins was increased by both JHA and CC extracts. In contrast, synthesis of secreted proteins increased only in the presence of JHA. CC extracts, alone, had no effects on the synthesis of secreted proteins, but administration of CC extracts in combination with JHA increased the synthesis of the secreted proteins by 55% above that observed with JHA alone. SDS-PAGE of proteins secreted into the medium by the in vitro fat body demonstrated that JHA stimulated the synthesis of specific polypeptides, whereas CC extracts did not affect the synthesis of specific-secreted polypeptides. These results suggest that JH regulates specific protein synthesis by the fat body of B. discoidalis; neurohormones elevate the general capacity of the fat body for protein synthesis and amplify the specific effects of JH.     

Human parvovirus-induced transient anemia and leukopenia after delivery]

A 30-year-old female at 27 weeks' gestation, was hospitalized on September 24 1990 because of the premature rupture of the amniotic sac. She underwent Caesarean section on the same day with 700 ml blood loss, but no blood transfusion was required. For several days after the operation, her hemoglobin level remained 7.8 g/dl and did not increase significantly in spite of parenteral iron therapy. On the 9th postoperative day, chills and pyrexia developed with leukopenia. Bone-marrow aspiration revealed severe erythroblastopenia with giant proerythroblasts, suggesting recent HPV infection, which was confirmed by the presence of anti-HPV IgM and HPV antigen by ELISA. The hemoglobin level gradually decreased to 6.0 g/dl by the 21st day, then began to increase rapidly. The serum of acute-phase containing HPV antigens inhibited BFU-E and CFU-E but not CFU-GM. The serum of convalescent-phase inhibited neither erythroid colony growth nor myeloid colony growth. These results indicate that the inhibitory effect of HPV in colony assay is highly specific for erythropoiesis and that HPV play a role in transient cessation of erythropoiesis. The reason, however, for leukopenia in HPV infection remained unclear. This case shows that HPV infection may induce severe hematological disorders even in normal person under erythropoietic stress.     

Imaging of thoracic aortic dissection

Acute thoracic aortic dissection has a high mortality if untreated, so the diagnosis must be rapidly made if mortality is to be lowered significantly. Multiple imaging techniques are often used. This retrospective study from 1988 to 1993 assesses the usefulness in diagnosis of chest X-rays, computed tomography (CT) scanning, aortography, magnetic resonance imaging (MRI), trans-thoracic (TTE) and trans-oesophageal (TOE) echocardiography. Forty-two patients with a final clinical diagnosis of dissection were studied. The diagnosis was confirmed in 16 (13 at surgery and three at autopsy). Three died with dissection given as the only cause for death. Chest X-ray abnormalities were seen in all 19 patients with surgery or death from dissection, with a widened mediastinum and/or dilated aorta being present in 17. In the group of 16 patients with surgery or autopsy proof, CT scans found dissections in 9 of 12 patients studied and correctly classified the type in only five. Aortography was performed in five, with accurate depiction of dissection and type in all. TTE found dissections in three of eight patients imaged by this method. MRI and TOE were performed each on two patients, with accurate depiction of dissection and type in each. Because of the relatively low sensitivity of CT scanning in defining aortic dissections Westmead Hospital is currently assessing the use of TOE as the prime imaging modality prior to surgical intervention.     

Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides.

We have investigated the use of a cationic lipid preparation to enhance antisense oligonucleotide activity in human umbilical vein endothelial cells. A liposomal preparation containing the cationic lipid N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) was found to increase by at least 1000-fold the potency of an antisense oligonucleotide (ISIS 1570) that hybridizes to the AUG translation initiation codon of human intercellular adhesion molecule-1. In the presence of 8 microM DOTMA, 6-15-fold more 35S-ISIS 1570 associated with cells, at oligonucleotide concentrations from 0.01 to 5 microM, than did in the absence of DOTMA. Both 35S-ISIS 1570 association with cells and antisense activity were increased as a function of DOTMA concentration and with increasing time of incubation with the cationic lipid. Fluorescein-labeled ISIS 1570 was used to assess the intracellular distribution of the oligonucleotide in the presence and absence of DOTMA. In the absence of DOTMA, the oligonucleotide localized to discrete structures in the cytoplasm of the cell, resulting in a punctate fluorescence pattern. In the presence of DOTMA, cellular fluorescence markedly increased and the oligonucleotide localized within the nucleus, as well as to discrete structures in the cytoplasm. Accumulation of the oligonucleotide in the nucleus in the presence of DOTMA was time and temperature dependent. Nuclear accumulation was inhibited by preincubation of the cells with monensin but not chloroquine, NH4Cl, nocodazole, colcemid, or brefeldin A. These data demonstrate that cationic lipids increase antisense activity by increasing the amount of oligonucleotide associated with cells and altering intracellular distribution of the oligonucleotide.