Microanatomy of the rat diaphragm with special reference to the lymphatics and mesothelial stomata

The three-dimensional microstructure of the rat diaphragm was studied in order to reveal morphological bases which permit peritoneal fluids to pass across the diaphragm to enter the pleural cavity. The methods used include scanning electron microscopy of either intact or alkali-treated tissues, enzyme-histochemistry, and confocal laser scanning microscopy (CLSM). The peritoneal and pleural surfaces of the diaphragm are covered with mesothelial cells studded with numerous microvilli. There are many round gaps between mesothelial cells on the peritoneal side of the diaphragm. The subperitoneal connective tissue contains voluminous, irregularly shaped lymphatics which extended many funnel-shaped projections of the endothelia towards the pored region of the mesothelium. On coming into contact with the mesothelium, many of the lymphatic projections are perforated at their ends, thus giving rise to stomata connecting the peritoneal cavity and lymphatic lumen. Some projections ended blindly while plugging the mesothelial pores, thereby making visible some intercellular gaps in this contact. The subperitoneal sheet of collagen fiber network possesses clusters of pores which tightly fit the passage of the lymphatic projections. CLSM of the diaphragm after intraperitoneal injection of FITC-dextran has demonstrated the tracer both in the lymphatic lumen and in the connective tissue spaces. The tracer has also been detected in the lymphatics located in the subpleural connective tissue space. These results indicate that peritoneal fluid is allowed to flow into the lymphatics directly through the stomata and indirectly through the intercellular gaps between endothelia and mesothelial cells, and then drain into the subpleural lymphatics. Discussions were made on the probable mechanisms by which a hydrothorax may occur during continuous ambulatory peritoneal dialysis.     

Evaluation of the pressure transfer system in the intracranial cavity by coherency

Coherency provides a method to evaluate model linearity. The characteristics of pressure wave transmission in the intracranial cavity were studied by coherency in 16 cats with hydrostatic pressure loading to assess the linearity of the system, which is an assumption for use of the transfer function. Linearity was observed in only the fundamental waves of the respiration-induced component and the cardiac-induced component of intracranial pressure oscillation, and in the second harmonic wave of the latter. Linearity at the other frequencies was close to zero. The pressure transfer system in the intracranial cavity was basically a non-linear system. As intracranial pressure rose, the increase in the pressure transfer efficiency was largest in the low-frequency domain and smallest in the high-frequency domain, indicating that the cerebral blood vessels are characterized by inferior transmission of high frequency due to increased intracranial pressure. In addition, the correlation between the coherencies of the cardiac-induced fundamental wave component and intracranial pressure, and between those of the cardiac-induced second harmonic wave component and intracranial pressure, showed that the slope of the straight line was greater between 45 and 70 mmHg than between 10 and 45 mmHg. This suggests that there is a break point, located between 45 and 70 mmHg, where the increase in the coherency values is accelerated, caused by an increase in the intracranial elastance, as well as an increase in the cerebrovascular compliance due to the reduced vascular transmural pressure.     

Coagula tamponade as a complication of open heart surgery: the clinical significance and diagnostic value of transesophageal echocardiography]

The pathogenesis of low cardiac output failure (LOF) immediately after open heart surgery was studied in 41 patients with LOF and 15 control patients without LOF using echocardiography. In 35 patients, transesophageal echocardiography was also performed. Left ventricular (LV) contraction was impaired in 28 of the 41 LOF patients, in whom LV fractional shortening was less than 25%. In the other 13 LOF patients, however, it was greater than 25%. In 12 of these 13 patients, transesophageal echocardiography revealed that accumulating pericardial coagula were localized in the right side of the heart, deforming the right atrial and ventricular chambers. The LV end-diastolic diameter was significantly less than the control, indicating that the pericardial coagula disrupted the distension of the heart. Emergent coagulotomy was performed in 5 patients, and hemodynamic conditions were improved. In spite of "cardiac tamponade", the wall motion and pressure tracings of the right atrium and right ventricle in these patients differed from those in fluid tamponade. Therefore, this condition should be designated "coagula tamponade." In the other 22 patients in whom transesophageal echocardiography was employed, no coagula were observed. Since pericardial coagula can hardly be detected by transthoracic echocardiography, transesophageal echocardiography is indispensable for diagnosing pericardial coagula noted immediately after open heart surgery.     

Proliferative activity in primary ovarian carcinoid tumors.

The proliferative potential of six primary ovarian carcinoids with different clinical outcome and histogenetic origin was examined immunohistochemically. The results showed that two cases with extremely high level of proliferative activity were associated with metastatic spread. In the remaining tumors, the examined factor was found to be at low level comparable with excellent prognosis of typical carcinoids in other locations. The preliminary results showed a possibility of a prognosis prediction according to typing of the ovarian carcinoids into two categories, i.e., tumors of low and intermediate malignancy. Topoisomerase II-alpha and Ki-67 are suitable markers giving valuable information about this phenomenon.     

Adsorption of microorganism components by lixelle beads

We reported previously that Lixelle, which was used for beta-2 microglobulin (BMG) adsorption columns, could adsorb not only BMG but also inflammatory cytokines. We then were interested in the application of Lixelle to patients with systemic inflammatory response syndrome (SIRS) and tried to find out its ability to adsorb microorganism components in vitro using lipopolysaccharide (LPS) (E. coli: B8), endotoxin (ET) containing water, and peptidoglycan (PG: Micrococcus luteus). The initial concentrations of each solution were LPS (ET: 29,135 EU/L), contaminated water (ET: 3,523 EU/L), and PG (67.1 ng/ml) and 2.5 ml of each of the stock solutions and adjusted diluted solutions contained 0.5 ml of Lixelle beads. After shaking at 37 degrees C for 2 h, ET in the solutions was determined by the ET specific-limulus amebocyte lysate (ES-LAL) method and PG by the silkworm larbae plasma (SLP) method. The results revealed that even when ET concentrations in LPS and contaminated water were high, the samples containing Lixelle beads showed significant decreases. There was some adsorption of PG but no significant differences. Thus, Lixelle beads can adsorb not only BMG but also microorganism components such as ET and PG. These findings, together with the ability to adsorb inflammatory cytokines by Lixelle, show the possibility of application for the treatment of infectious SIRS.     

Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors.

BACKGROUND: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. PATIENTS AND METHODS: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). RESULTS: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C(max) was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days). CONCLUSIONS: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.     

Effect of cisplatin on calcium uptake by rat kidney cortical mitochondria

The effect of the nephrotoxic antineoplastic drug, cisplatin, on mitochondrial calcium uptake was examined in rat kidney cortical mitochondria. We treated rats with cisplatin (5 mg/kg, i.p.), and prepared and incubated the mitochondria. Uptake of calcium decreased after 24 h. The mitochondria contained platinum even 3 days after injection. Cisplatin (0.5 mM) added to incubation medium inhibited calcium uptake. Platinum accumulated in the mitochondria during incubation. Mitochondria accumulated less of another divalent cation, magnesium, in rats given cisplatin and in incubation medium with cisplatin added. The results suggest that cisplatin taken up into kidney cortical mitochondria inhibited divalent cation uptake there, which may contribute to cisplatin nephrotoxicity.     

Phenolic glycosides from berries of Pimenta dioica

Four new phenolic glycosides, (2-hydroxy-3-methoxy-5-allyl)phenyl beta- d-(6-O-E-sinapoyl)glucopyranoside (1), (1' R,5' R)-5-(5-carboxymethyl-2-oxocyclopentyl)-3 Z-pentenyl beta-D-(6-O-galloyl)glucopyranoside (2), (S)-alpha-terpinyl [alpha-L-(2-O-galloyl)arabinofuranosyl]-(1-->6)-beta-D-glucopyranoside (3), and (R)-alpha-terpinyl [alpha-L-(2-O-galloyl)arabinofuranosyl]-(1-->6)-beta-D-glucopyranoside (4), were isolated from the berries of Pimenta dioica together with eight known flavonoids. The structures of 1-4 were elucidated on the basis of MS and NMR data and enzymatic hydrolysis. All four glycosides showed radical-scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals.     

Developmentally regulated release of intraretinal neurotrophic factors in vitro

The effects of conditioned media either from aggregates or from explants of embryonic chick retinae and of recombinant neurotrophins were tested upon the survival in vitro of ganglion cells in dissociated cell cultures from the retina of newborn rats. Ganglion cells were identified by the detection of retrogradely transported horseradish peroxidase injected bilaterally into the superior colliculus. Conditioned media increased significantly the survival of ganglion cells after 2 days in culture, at a wide range of plating densities, and had no effect upon adhesion of rat retinal cells. Media conditioned by cell ensembles from chick retinae from embryonic day 8 (E8) to E16 had neurotrophic effects. Release of neurotrophic activity peaked at E10-E12, irrespective of the numbers of cells or total concentration of protein in the conditioned media. The active molecules were non-dialyzable and were released either in the presence or in the absence of fetal calf serum. The neurotrophic activity was abolished by trypsinization, and recovered by salting-out with 25–75% ammonium sulfate. NT-4, BDNF and, to a lesser extent, NT-3, increased the survival of ganglion cells in our assay, while NGF had no effect. The data show that chick retinal cells release soluble trophic proteins according to a developmentally regulated pattern. These neurotrophic factors may be involved in local competitive interactions that help control naturally occurring neuron death among ganglion cells of the vertebrate retina.