Fatty acid induced insulin resistance in rat-1 fibroblasts overexpressing human insulin receptors: impaired insulin-stimulated mitogen-activated protein kinase activity

Saturated fatty acids cause insulin resistance but the underlying molecular mechanism is still unknown. We examined the effect of saturated nonesterified fatty acids on insulin binding and action in transfected Rat-1 fibroblasts, which over-expressed human insulin receptors. Incubation with 1.0 mmol/l palmitate for 1-4 h did not affect insulin binding, insulin receptor autophosphorylation, insulin-stimulated tyrosine kinase activity toward poly(Glu4:Tyr1), pp185 and Shc phosphorylation and PI3-kinase activity in these cells. However, the dose response curve of insulin-stimulated glucose transport was right-shifted. Palmitate inhibited the maximally insulin-stimulated mitogen activated protein (MAP) kinase activity toward synthetic peptide to 7% that of control. The palmitate treatment influenced neither cytosolic protein kinase A activity nor cAMP levels. These results suggested that 1) palmitate did not inhibit the early steps of insulin action from insulin binding to pp185 or Shc phosphorylation but inhibited insulin-stimulated MAP kinase, and that 2) palmitate decreased insulin sensitivity as manifested by inhibited insulin-stimulated glucose uptake. In conclusion, the mechanism of saturated non-esterified fatty acid induced insulin resistance in glucose uptake may reside at post PI3-kinase or Shc steps, including the level of MAP kinase activation.     

Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with noncyclic gastrin receptor antagonistic moieties

In order to study structure-activity relationships of dual histamine H2 and gastrin receptor antagonists as well as to improve their low oral absorbability, their prototype benzodiazepine gastrin receptor antagonistic moieties were altered to a conformationally flexible noncyclic dipeptide equivalent. This skeletal modification significantly potentiated the binding affinity of hybrid compounds for the histamine H2 receptor, whereas their affinity for the gastrin receptor and receptor selectivity over the CCK-A receptor varied widely with the substituents on the gastrin moiety. Among them, [3-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl]p ropyl carbamic acid 3-[3-([(3-methoxyphenyl)[(methylphenylcarbamyl)methyl]carbamoyl]me thyl)ureido]benzyl ester (7a) showed the highest dual histamine H2 and gastrin receptor antagonistic activities. It also displayed distinct gastric acid antisecretory activity in vivo for two assays, namely, Schild's rat method by i.d. administration and the rat pylorus ligation method by oral administration. With the latter case, dose-response relationships were observed for the first time, suggesting its substantially improved oral absorbability. However, 7a did not display distinct in vivo gastric acid antisecretory activity for the assay with Heidenhain pouch dogs.     

Differential effects of ursodeoxycholic acid and ursocholic acid on the formation of biliary cholesterol crystals in mice

The preventive effect of 3α,7β,12α-trihydroxy-5β-cholanoic acid (ursocholic acid) and ursodeoxycholic acid on the formation of biliary cholesterol crystals was studied in mice. Cholesterol crystals developed with 80% incidence after feeding for five weeks a lithogenic diet containing 0.5% cholesterol and 0.25% sodium cholate. When 0.25% ursocholic acid or ursodeoxycholic acid was added to the lithogenic diet, the incidence as well as the grade (severity) of the gallstones were reduced. Plasma and liver cholesterol levels were decreased by ursodeoxycholic acid but not by ursocholic acid. Gallbladder cholesterol and phospholipid levels were decreased by both bile acids. The biliary bile acid level was decreased by ursocholic acid but not by ursodeoxycholic acid. After feeding ursocholic acid, its level in the bile was about 25% and the levels of cholic acid and β-muricholic acid decreased. Fecal sterol excretion was not changed by ursocholic acid, but was increased by ursodeoxycholic acid. After feeding ursocholic acid, fecal excretion of deoxycholic acid, cholic acid, and ursocholic acid increased. No differences were found between mice, with or without gallstones, in plasma and liver cholesterol levels, biliary phospholipid and bile acid levels, fecal sterol and bile acid levels, and biliary and fecal bile acid composition. The results suggest that the lower incidence of crystal formation after treatment with ursocholic acid is probably by a different mechanism than with ursodeoxycholic acid. In the mouse model, ursodeoxycholic acid exerts its effect at least partially, by decreasing cholesterol absorption. Ursocholic acid is well absorbed and excreted into bile and transformed into deoxycholic acid by the intestinal microflora in mice.     

The Second Generation of the Laboratory Information System and the Laboratory Automation System in Osaka City University Hospital

The first total clinical laboratory system (TCLA) in the Osaka City University Hospital was introduced in 1993. After six years of operation, it was recently replaced by a new system. The goals of this replacement were as follows: 1. Improve the analytical performance. 2. Make the system operate more efficiently. 3. Improve the quality of laboratory analyses. We successfully reduced the labor required to operate the laboratory; made the laboratory reports quicker; reduced the number of retraction and revalidation of the results; and minimized the system downtime.     

Effect of Atmospheric Humidity on the Fatigue Crack Propagation Behavior of Short Cracks in Silicon Nitride

The effect of the environment on crack-growth processes in silicon nitride was studied by investigating the static and fatigue crack-growth behavior of small surface cracks, as influenced by testing (i) in the ambient environment, (ii) in distilled water, (iii) under vacuum, and (iv) in toluene. A principal finding was that testing under cyclic conditions led to crack-growth rates that were much higher in air than in toluene, whereas testing under static conditions in air or toluene led to minor differences in the rate of static fatigue crack growth. This difference in sensitivity to the environment under static and cyclic loading conditions was attributed, in part, to a much-greater extent of microcracking at the surface ahead of the main crack in air under cyclic conditions, in comparison to that in other environments. This propensity for microcracking at the surface in air under cyclic conditions also was reflected in the aspect ratios of the crack shapes that developed.     

Comparison of two data interpretation programs in automated blood cell counters

Two data interpretation programs incorporated into two different automated blood cell counters were evaluated. The programs analysed size distribution histograms for screening for abnormal specimens. The messages given by the programs were ‘normal’, ‘abnormal’ and ‘suspect’. ‘Abnormal’ messages meant abnormalities in the values of the measured parameters. ‘Suspect’ messages were given when the histograms showed either a possibility of the existence of abnormal blood cells, or an abnormal level of such cells; re-examination by a manual method was necessary for such specimens. For reference, the manual differential was done. The false-negative rate for each kind of message was less than 10% and efficiency was about 90%. These programs were helpful in avoiding unnecessary manual observations in reducing the workload in a routine clinical laboratory.     

Strength Improvement Through Grain Refinement of Intermetallic Compound at Al/Fe Dissimilar Joint Interface by the Addition of Alloying Elements

Dissimilar material joining between Al alloys and steel may be effective in decreasing the weight of automobile bodies. In this study, dissimilar lap joining of Al alloys containing certain alloying elements, such as Ni, Cr, Mn, Ti, or Si, to interstitial-free steel was performed by tungsten inert gas arc brazing, and the effect of the alloying element on the joint strength associated with the Al-Fe intermetallic compound layer at the dissimilar interface was examined. The addition of an appropriate amount of an alloying element to the alloy increased the joint strength; the addition of Ni exhibited the most effective improvement. The additions of some elements changed the grain structure of the η-Fe₂Al₅ layer but not its chemical composition. This is the first study to clarify that smaller grain size of η-Fe₂Al₅ correlated to greater strength of the Al/Fe dissimilar joint.     

Sequence of a 42-kb mouse region containing the imprinted H19 locus: identification of a novel muscle-specific transcription unit showing biallelic expression

We have followed four patients with Bartter syndrome for a mean of 25.4 years (range 21.5-28.8 years) after diagnosis. All patients received non-steroidal anti-inflammatory drugs (NSAID). In all patients, various degrees of renal dysfunction were noted to be temporally associated with NSAID therapy. In two patients, renal dysfunction resolved after discontinuing NSAID therapy, while maintaining other chronic medications such as potassium-sparing diuretics. Renal dysfunction persisted after NSAID withdrawal in two patients. We report these cases as a warning that NSAID should be considered an important cause of either reversible or irreversible renal dysfunction in Bartter syndrome.     

Elevated serum soluble Fas ligand in natural killer cell proliferative disorders

We evaluated the serum level of soluble Fas ligand (sFasL) in patients with natural killer lymphocyte proliferative disorders (NK- LPD). The serum sFasL level was elevated in neoplastic groups of aggressive NK leukaemia, indolent NK leukaemia and NK lymphoma, all of which contained clonal EBV-DNA. In NK leukaemia the serum sFasL level was significantly higher than that found in others. However, it was not elevated in the patients with reactive NK-LPD and in one patient with NK leukaemia in remission. These findings indicate that the serum sFasL level is a useful indicator in evaluating disease activity.     

Doped Perovskite Oxide, PrMnO3, as a New Cathode for Solid-Oxide Fuel Cells that Decreases the Operating Temperature

Cathodic overpotentials of Ln_0.6Sr_0.4MnO₃ (Ln is La, Pr, Nd, Sm, Gd, Yb, and Y) were studied for a new cathode for solid-oxide fuel cells (SOFCs) with low overpotentials in a relatively-low-temperature region. Cathodic overpotentials strongly depended on the rare-earth cations in the A sites of the perovskite oxide. In particular, overpotentials of a Sr-doped PrMnO₃ cathode maintained low values despite decreased operating temperature. Consequently, almost the same power density of a SOFC with Ln_0.6Sr_0.4MnO₃ cathode was obtained at about 100 K lower operating temperature by using Sr-doped PrMnO₃ as the cathode.