Ultrastructural changes of the air–blood barrier in mice after intratracheal instillation of lipopolysaccharide and ultrafine carbon black particles

Epidemiological studies have indicated associations between exposure to increased concentrations of ambient ultrafine particles and adverse health effects especially in susceptible individuals. To ellucidate the mechanisms underlying the findings from epidemiological studies, mice pretreated with lipopolysaccharide (LPS) (acute lung injury model) were intratracheally instilled with ultrafine carbon black particles (UFCB), and the air–blood barrier was observed to examine the translocation pathway of UFCB from the lung into the systemic circulation. In addition, lung toxicity induced by the intratracheal instillation of LPS and UFCB was studied with the use of electron microscope. LPS treatment induced acute inflammatory changes with increased number of activated macrophages and neutrophils in the degenerated alveolar walls. UFCB were demonstrated on or in the denuded basement membrane in the air–blood barrier; these findings were associated with edematous changes and fragmentation of the cytoplasms of alveolar epithelial cell type 1, and the damages of alveolar epithelial cell type 1 were frequently observed in the close vicinity of the clumps of UFCB. These findings suggest that translocation of the exposed ultrafine particles may be enhanced in the lung tissues with acute inflammatory changes.     

Impact of positron emission tomography/computed tomography in the management of patients with epithelial ovarian carcinoma after treatment

Purpose  

The aims of this study were to compare the usefulness and reliability of integrated whole-body positron emission tomography/computed tomography (PET/CT) using ¹⁸F-fluorodeoxyglucose (FDG) with those of contrast-enhanced multidetector CT during regular follow-up in patients after initial treatment of ovarian cancer, to assess the impact of FDG–PET/CT on the confirmation of recurrence, restaging, and clinical management of patients, and to determine the incremental information provided by PET/CT.     

Hypotensive and hypertensive effects of acetaldehyde on blood pressure in rats

Intravenous injection of acetaldehyde produced hypotensive actions in pentobarbital-anaesthetised whole rats, but hypertensive actions in pithed rats. The hypotensive effects of acetaldehyde in whole rats were abolished by pre-treatment with yohimbine. In pithed rats, the hypertensive effects of acetaldehyde were significantly attenuated by prazosin and phentolamine, and in rats that had been pre-treated with reserpine. Our results suggest that the hypertensive actions of acetaldehyde in pithed rats are due to the release of catecholamines, which subsequently leads to vasoconstriction. In whole rats the hypotensive actions of acetaldehyde may be due to alpha2-adrenoceptor stimulation in the central nervous or peripheral system.     

Transfection-induced Tumor Necrosis Factor-α Increases the Susceptibility of Human Glioma Cells to Lysis by Lymphokine-activated Killer Cells: Continuous Expression of Intercellular Adhesion Molecule-1 on the Glioma Cells

To develop more effective adoptive immunotherapy, we transfected the human tumor necrosis factor-α (TNF-α) gene into human glioma cells (U251-SP), which were used as target cells. TNF-α is known to increase both the expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of glioma cells and the susceptibility of glioma cells to lymphokine-activated killer (LAK) cell cytolysis. We compared the expression of ICAM-1 induced by TNF-α generated by the TNF-α gene-transfected cells with that induced by exogenously added TNF-α. When the TNF-α gene was transfected into U251-SP cells, the expression of ICAM-1 was detected on the cell surface from 3 days after the transfection and continued until at least 9 days. In contrast, it was expressed only transiently in the case of exogenously added TNF-α. Also, the cytolytic activity of LAK cells induced by transfection-induced TNF-α was significantly stronger than that induced by exogenously added TNF-α. The increased susceptibility was quenched by anti-ICAM-1 monoclonal antibody. These data indicated that continuous expression of ICAM-1 induced by TNF-α gene transfection of glioma cells resulted in higher cytolytic activity of LAK cells.     

Reinforced Cytotoxicity of Lymphokine-activated Killer Cells toward Glioma Cells by Transfection of the Killer Cells with the γ-Interferon Gene

Lymphokine-activated killer (LAK) cells generated from peripheral blood lymphocytes incubated with recombinant interleukin-2 were transfected with the human γ-interferon (HuIFN-γ) gene by means of liposomes having a positive charge on their surface. The cells secreted significant amounts of HuIFN-γ (reaching more than 5 U/ml) into the culture medium. The HuIFN-γ produced by the cells induced intercellular adhesion molecule-1 (ICAM-1) and enhanced the expression of Fas antigen on the surface of human glioma cells. Also, LAK cells transfected with HuIFN-γ gene exhibited reinforcement of cytotoxicity toward human glioma cell lines (U251-MG and SK-MG-1). Furthermore, the reinforcement was significantly quenched by anti-ICAM-1 and/or anti-TNF-α monoclonal antibody.     

Successful treatment of a huge meningeal hemangiopericytoma using Preoperative Autologous Transfusion and Hemodilutional Autologous Transfusion: case report

We report successful operations for a meningeal hemangiopericytoma using sufficient amounts of Preoperative Autologous Transfusion (PAT) and Hemodilutional Autologous Transfusion (HAT). A 23-year-old woman with amenorrhea and bilateral visual field disturbance was found to have a huge intracranial tumor. MRI showed a well-enhanced cystic mass in the left middle fossa, suprasellar, intrasellar, sphenoidal sinus, and cavernous sinus. Preoperatively, the tumor was thought to be a cystic pituitary tumor or meningioma. Surgical removal was planned in three steps. The first operation was carried out via the transsphenoidal approach. Total blood loss was 1348 ml and 2 MAP infusion were required to control bleeding. Histopathological diagnosis was hemangiopericytoma. After preparation of PAT 400 ml and HAT 800 ml, we carried out the second partial removal operation mainly via the interhemispheric approach. Total blood loss was 1829 ml and required autologous transfusion only. After preparation of PAT 1200 ml and HAT 400 ml, the last total removal operation was carried out mainly via the pterional and subtemporal approach. Total blood loss was 1813 ml and required autologous transfusion only. We needed 2 MAP infusion in the first operation, but were able to perform total removal successfully without homologous blood transfusion because a sufficient amount of PAT and HAT had been prepared preoperatively. Hemangiopericytoma required postoperative radiation therapy to avoid local recurrence. After successful removal of the tumor surgically, postoperative radiation therapy was able to be carried out efficiently.     

Pineal region tumor manifesting initially as hearing impairment

An 18-year-old male presented with a pineal region germinoma with hearing impairment as the chief complaint. Magnetic resonance image demonstrated a well-enhanced multi-cystic tumor extending into the upper fourth ventricle and wall of the bilateral lateral ventricles. Audiometry revealed bilateral mild hearing impairment in the low frequencies. Auditory brainstem response recording showed low amplitudes in all waves (IV-V/I ratio < 1) with prolong latencies (I-V and III-V) on the right but no discernable wave at 60 dB clicks on left. Hearing impairment and audiometric findings were improved after ventriculoperitoneal shunt operation. The hearing impairment appeared to be a mixed (conductive and sensorineural) type. The tumor was responsible for the sensorineural deafness because of invasion and compression of the central auditory structures. The inferior brachium was maximally compressed anterolaterally by the dilated bilateral lateral ventricles and posteromedially by the tumor. Hydrocephalus caused conductive deafness by halting or arresting the footplate of stapes movement, as a consequence of high-pressure transmission through the cochlear aqueduct.     

Molecular toxicological mechanism of the lethal interactions of the new antiviral drug,sorivudine, with 5-fluorouracil prodrugs and genetic deficiency of dihydropyrimidine dehydrogenase

In 1993, there were 18 acute deaths in Japanese patients who had the viral disease herpes zoster and were treated with the new antiviral drug sorivudine (SRV, 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil). All the dead patients had received a 5-fluorouracil (5-FU) prodrug as anticancer chemotherapy concomitant with SRV administration. Studies on toxicokinetics in rats and on hepatic dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme for 5-FU catabolism in rats and humans, strongly suggested that in the patients who received both SRV and the 5-FU prodrug, tissue levels of highly toxic 5-FU markedly increased as a result of irreversible inactivation of DPD in the presence of NADPH by 5-(2-bromovinyl)uracil (BVU), a metabolite formed from SRV by gut flora in rats and humans. Recombinant human (h) DPD was also irreversibly inactivated by [14C] BVU in the presence of NADPH. MALDI-TOF MS analysis of radioactive tryptic fragments from the radiolabeled and inactivated hDPD demonstrated that a Cys residue located at position 671 in the pyrimidine-binding domain of hDPD was modified with an allyl bromide type of reactive metabolite, dihydro-BVU. Thus artificial DPD deficiency caused by BVU from SRV led to patient deaths when coadministered with the 5-FU prodrug. Human population studies using healthy volunteers have demonstrated that there are poor and extensive 5-FU metabolizers who have very low and high DPD activities, respectively. Administration of a clinical dose of 5-FU or its prodrug to poor 5-FU metabolizers may cause death unless DPD activity is determined using their peripheral blood mononuclear cells prior to the administration of the anticancer drug.     

Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases

The phenolic active metabolites, cis-4-hydroxytamoxifen (cis-HO-TAM) and trans-4-hydroxytamoxifen (trans-HO-TAM), of the anti-breast-cancer drug, trans-tamoxifen (TAM), were geometrically selectively glucuronidated in the manner of cis>trans by microsomes and sulfated in the manner of trans>cis by cytosol from the liver of 10 human subjects (7 females and 3 males). There was a large individual difference in the microsomal glucuronidation of cis-HO-TAM, which correlated well with glucuronidation of 4-hydroxybiphenyl by human liver microsomes. However, there was only a slight correlation between the glucuronidation of cis-HO-TAM and trans-HO-TAM or 4-nitrophenol (NP). A small individual difference was observed for the human liver cytosolic sulfation of trans-HO-TAM, which correlated well with the sulfation of NP. Recombinant human UDP-glucuronosyltransferase (UGT)2B15 catalyzed the cis-selective glucuronidation of geometrical isomers of HO-TAM. UGTs1A1, 1A4, 1A9 and 2B7 had weak activity toward HO-TAMs with a much smaller cis-selectivity than did UGT2B15. UGTs1A3 and 1A6 had no detectable activity toward these substrates. Among the four known major sulfotransferases (SULTs) occurring in the human liver, SULT1A1 was strongly suggested to play the most important role in the hepatic cytosolic trans-selective sulfation of HO-TAM isomers. A good correlation was observed between the hepatic cytosolic sulfation of trans-HO-TAM and NP, a standard substrate for SULT1A1. SULT1E1 had slight activity toward the HO-TAMs. SULTs1A3 and 2A1 had no detectable activity toward HO-TAMs.