Volatile anaesthetics restore bradykinin and serotonin-induced coronary vasodilation after blocking nitric oxide synthase: lack of anaesthetic effects on KATP channels and prostaglandin pathways.

BACKGROUND AND OBJECTIVE: Volatile anaesthetic effects on altering tone after blocking nitric oxide synthase, cyclo-oxygenase-prostaglandin synthase and KATP channel pathways are controversial. We examined in isolated guinea pig hearts whether anaesthetics alter bradykinin and 5-hydroxytryptamine-induced effects on coronary flow and percentage oxygen extraction after blocking these pathways. METHODS: Before and during exposure to sevoflurane, halothane or isoflurane, hearts were infused with 10-13-10-8 M bradykinin, or 10-8-10-6 M 5-hydroxytryptamine (serotonin), with either L-NAME, indomethacin, or glibenclamide. Bradykinin or 5-hydroxytryptamine alone increased flow and decreased percentage oxygen extraction in a concentration-dependent manner; these effects were largely blocked by L-NAME (nitro-L-arginine methylester), which also decreased basal flow and increased basal percentage oxygen extraction. RESULTS: The anaesthetics restored bradykinin and 5-hydroxytryptamine-induced increases in flow or decreases in percentage oxygen extraction after inhibition by L-NAME. Indomethacin or glibenclamide alone had little effect on basal flow and percentage oxygen extraction. The anaesthetics restored bradykinin and 5-hydroxytryptamine-induced increases in flow or decreases in percentage oxygen extraction after inhibition by L-NAME. Indomethacin or glibenclamide alone had little effect on basal flow and percentage oxygen extraction. Drug-induced increases in flow and decreases in percentage oxygen extraction in the absence or presence of glibenclamide or indomethacin were not altered at either of the two concentrations of anaesthetics. CONCLUSIONS: Endothelium-dependent vasodilatation is not affected by blocking prostaglandin release or KATP channels in the intact heart even in the presence of an anaesthetic. However, the diminished responses to vasodilators after nitric oxide synthase inhibition is largely restored or enhanced by anaesthetics.

Evaluation of a motion fidelity criterion with visual scene changes.

An experiment examined how visual scene and platform motion variations affected a pilot's ability to perform altitude changes. Pilots controlled a helicopter model in the vertical axis and moved between two points 32-ft apart in a specified time. Four factors were varied: visual-scene spatial frequency, visual-scene background, motion-filter gain, and motion-filter natural frequency. Drawing alternating black and white stripes of varying widths between the two extreme altitude points varied visual-scene spatial frequency. The visual-scene background varied by either drawing the stripes to fill the entire field of view or by placing the stripes on a narrow pole with a natural sky and ground plane behind the pole. Both the motion-filter gain and natural frequency were varied in the motion platform command software. Five pilots evaluated all combinations of the visual and motion variations. The results showed that only the motion-filter natural frequency and visual-scene background affected pilot performance and their subjective ratings. No significant effects of spatial frequency or motion system gain were found for the values examined in this tracking task. A previous motion fidelity criterion was found to still be a reasonable predictor of motion fidelity.

tie-1 protein tyrosine kinase: a novel independent prognostic marker for gastric cancer.

Protein tyrosine kinases (PTKs) are a major class of proto-oncogenes that are involved in tumor progression. The purpose of this study was to establish a comprehensive PTK expression profile in gastric cancers, with the objective of identifying possible biomarkers for gastric cancer progression. We have designed degenerate primers according to the consensus catalytic motifs to amplify PTK molecules from gastric cancers by reverse transcriptase-PCR methods. The PTK expression profile was established by sequencing analysis of the cloned PCR products. We have identified 17 PTKs from a gastric adenocarcinoma. Two receptor PTKs, tie-1 and axl, were selected for in situ immunohistochemistry studies because of their higher expression level and their described roles in adhesion, invasion, and angiogenesis. Among the 97 gastric adenocarcinoma tissues examined, we observed positive immunohistochemical staining of tie-1 PTK in 69 and positive staining of axl kinase in 71 tissues. Statistical analysis with clinicopathological features indicates that tie-1 kinase expression is inversely correlated with patients' survival, whereas axl fails to show similar clinical significance. Our results illustrate the utility of tyrosine kinase gene family profiling in human gastric cancers and show that tie-1 tyrosine kinase may serve as a novel independent prognostic marker for gastric adenocarcinoma patients.

Volatile anesthetics do not alter bradykinin-induced release of nitric oxide or L-citrulline in crystalloid perfused guinea pig hearts.

BACKGROUND: Nitric oxide (NO) and L-citrulline (L-cit) are released by endothelial NO synthase (eNOS) to induce vasodilation via guanylyl cyclase and cyclic guanosine monophosphate (cGMP). Volatile anesthetics directly reduce vascular muscle tone, but their effects on the eNOS cGMP pathway is controversial. The aim of this study was to examine the effects of anesthetics on bradykinin-induced increases in flow, NO, and L-cit in isolated hearts. METHODS: Guinea pig hearts were isolated, perfused at 55 mmHg with a crystalloid or erythrocyte perfusate at 37 degrees C, and heart rate, left ventricular pressure, coronary flow (CF), effluent pH, and oxygen tension were monitored. Effluent [NO] was measured by a Clark-type electrode (sensitivity > or = 1 nM = 3 pA) with a selectively permeable membrane. Effluent [L-cit] was measured by chromatography. Before, during, and after exposure to halothane, isoflurane, or sevoflurane, hearts were infused with as much as 100 nM bradykinin to induce increases in CF and effluent release of NO and L-cit. RESULTS: In crystalloid-perfused hearts, 10 nm bradykinin produced maximal concentration-dependent increases in CF (87+/-2%), [NO] (24+/-4 nM), NO release (128+/-18 pmol x g(-1) x min(-1)), and [L-cit] (58+/-8 nM). Isoflurane slightly increased CF but not NO. Anesthetics did not alter the bradykinin-induced CF, NO slope relationship, or change [L-cit]. In erythrocyte-perfused hearts, isoflurane also did not alter the bradykinin-induced increase in CF and decrease in percentage of oxygen extracted. CONCLUSIONS: This is the first study to simultaneously measure CF with bradykinin-induced changes in [NO] and [L-cit] in the presence of halothane, isoflurane, and sevoflurane in intact hearts. The study shows for the first time that volatile anesthetics do not alter the CF to NO relationship and suggests that NO production, NO release, and NO vasodilatory effects mediated by the eNOS cGMP pathway are not significantly affected by anesthetics in crystalloid or erythrocyte-perfused guinea pig hearts.

Hepatocyte growth factor and Met/HGF receptors in patients with gastric adenocarcinoma.

Overexpression and amplification of Met/HGF receptor has been detected in gastric cancer tissues and cell lines. In this study hepatocyte growth factor (HGF) and Met/HGF receptors were localized in 32 gastric cancer and adjacent normal gastric tissues by the avidin-biotin-peroxidase complex technique. HGF (87.5%) and Met/HGF receptors (68.8%) were demonstrated in gastric cancer tissues. A high positive rate of HGF (87.0%) and Met/ HGF receptors (82.6%) presented in intestinal type gastric cancer. HGF immunoreactivity in gastric cancer tissues was a significant and powerful prognostic indicator (relative risk 15.9; p=0.01). These data suggest that HGF and Met/HGF receptors are involved in the morphogenesis of intestinal type gastric cancer. HGF may have other mechanism that favor gastric cancer spread and independently affect survival.

Fulminant hepatic failure as the first manifestation of Wilson disease: a report of two cases.

Two cases of fulminant hepatic failure as a first manifestation of Wilson disease are reported. They were diagnosed as acute hemolytic anemia initially, and took a fatal course despite intensive medical therapy. The main object of this report is to emphasize that Wilson disease must be included in the differential diagnosis of fulminant hepatic failure in children. Liver transplantation is the only effective means of treatment in patients presenting with fulminant hepatic failure, but this procedure is difficult to perform because of insufficient organ donation in Taiwan. The best treatment for Wilson disease is prevention through diagnosis at a presymptomatic stage, and institution of life-long therapy with D. penicillamine.

Immunohistochemical study of arginase in cancer of the stomach.

High levels of arginase have been detected in gastric adenocarcinoma. To examine the hypothesis that this is due to macrophage infiltration into the tumour, we localized the cellular distribution of arginase by immunohistochemical staining. We examined gastric adenocarcinomas and their corresponding normal tissues (n = 45), leiomyomas (n = 2), leiomyosarcomas (n = 3), human gastric adenocarcinoma cell lines (n = 3), and benign gastric ulcers (n = 4) by the avidin-biotin-peroxidase complex technique. Macrophages with strong arginase immunoreactivity were observed infiltrating both gastric normal and cancer tissues. No arginase immunoreactivity was observed in normal mucosal gland, muscular and serosal tissues or benign gastric ulcers. The immunoreactivity of arginase was positive but heterogeneous in most specimens of gastric adenocarcinoma (62.2%) and was absent from gastric intestinal metaplasia, leiomyomas and leiomyosarcomas. Among the 28 neoplasms with arginase immunoreactivity, scattered immunoreactivity was also noted in adjacent dysplastic glands in 12 (42.8%) specimens. Arginase immunoreactivity was observed in all three gastric cancer cell lines. Arginase is present in the cytoplasm but not in the nucleus. These data suggest that the high arginase levels in adenocarcinoma cancer tissues originate largely from cancer cells.

Regional distribution of neural cell adhesion molecule (N-CAM) and L1 in human and rodent hippocampus.

Cell surface adhesion molecules N-CAM and L1 are implicated in central nervous system (CNS) cell migration and axon outgrowth in in vitro and in vivo developmental studies. These molecules show a differential distribution during CNS development, thus suggesting that they subserve different roles in process outgrowth and tissue organization. A variety of N-CAM isoforms are known, and individual N-CAMs undergo posttranslational modification. Such changes and the potential for generating numerous molecules may mediate development of specific neural cell contacts and circuitry. We evaluated immunohistochemical staining of polyclonal antibodies to L1 and N-CAM, as well as monoclonal antibodies directed against embryonic N-CAM and the 140 and 180 kDa species of N-CAM in human, rat, and mouse hippocampus. Staining patterns in the three species were qualitatively similar, but staining in the mouse hippocampus was quantitatively greater for some epitopes. A distinctive pattern of staining was found, corresponding to the known anatomy of the structure. Total N-CAM staining was intense in the hilus and inner molecular layer (ML) of the dentate gyrus with lighter staining in the dentate outer ML. The mossy fiber tract (MFT), comprising axons traveling from the dentate granule cells to CA3 pyramidal cells, was strongly stained by polyclonal antibody to N-CAM. There was abundant staining of the stratum radiatum (SR) and stratum oriens (SO) of CA1, but stratum lacunosum moleculare (LM) showed very little staining. The monoclonal antibody 12F11, which recognizes the 140 and 180 kDa forms of N-CAM, intensely stained the MFT, hilus, and inner ML.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental expression of neural cell adhesion molecules in the mouse neocortex and olfactory bulb.

Polyclonal antibodies to N-CAM and L1 and monoclonal antibodies to epitopes of N-CAM (designated 12F11, 8A2, and 12F8) were used to investigate the spatial and temporal distribution of these neural cell adhesion molecules during the development of mouse cortex and olfactory bulb. The aim of the study was to correlate developmental events such as cell migration, dendritic and axonal outgrowth, and synaptogenesis with the appearance and disappearance of specific molecules involved in cell-cell interactions. Western transfer studies indicated that 12F8 antibody recognized polysialic acid found on embryonic N-CAM; 8A2 antibody primarily recognized the 140 kD component of N-CAM while the 12F11 antibody recognized the 180 and the 140 kD forms. The study demonstrates a high degree of cell surface molecular specialization of different compartments in developing neocortex and olfactory bulb. L1 is found on a variety of unmyelinated fiber tracts including thalamocortical fibers, olfactory nerve, and inner plexiform layer of the olfactory bulb. In contrast, N-CAM epitope recognized by 12F11 antibody is present on olfactory nerve fibers but appears later and is much weaker than L1 on thalamocortical fibers and is absent from the olfactory lobe inner plexiform layer. Dendritic regions are best labeled by 12F8 antibody; the epitope becomes faint in adult cortex but remains strongly expressed in olfactory bulb. This study reveals that widespread N-CAM expression in the central nervous system is constituted by a diversity of local expression of different molecular forms of N-CAM; their different anatomical distributions suggest they may each have unique roles.

Postnatal development of thalamic recipient neurons in the monkey striate cortex: II. Influence of afferent driving on spine acquisition and dendritic growth of layer 4C spiny stellate neurons.

This study uses Golgi-impregnated material to examine the effects of altering the nature of afferent driving on the maturation of spines and dendrites on thalamic recipient spiny stellate neurons in layers 4C alpha and beta of the monkey striate cortex. These two laminae receive input from different sets of thalamic afferents with different functional properties. The development of dendritic spine and dendritic branch populations on these neurons in experimental animals is compared to the same features on similar groups of neurons in a series of normal animals described in the preceding study (Lund and Holbach, '91). Three conditions of rearing were used to alter afferent driving from normal: complete darkness (with in some cases return to normal diurnal light-dark cycle), bilateral eye lid suture, and monocular eye lid suture. Some of the normal and dark-reared infant monkeys were examined behaviorally for visual capacity in an earlier study (Regal et al., '76). All conditions of abnormal afferent driving caused changes from the normal developmental patterns of spine and dendritic arbor growth in these first-order neurons of the cortex and each condition differed in the nature of change produced. Major findings of this study are: 1. Vigorous spine acquisition and dendritic growth occurs under all conditions of visual deprivation on alpha and beta neurons. Eventual spine and dendritic attrition occurs under at least conditions of bilateral or monocular lid suture to produce a rather constant adult morphology. We assume, therefore, that visually driven activity is a modulator or shaper of the developmental process for thalamic recipient neurons of visual cortex, rather than being an initiator, terminator, or driving force for their maturation. 2. An innate "clock," whose nature is unknown but is apparently not driven by visual input, initiates and terminates a period of growth of the thalamic recipient neurons between birth and 30-32 weeks of age. 3. Factors controlling dendritic arbor growth and retraction are different from those controlling spine synapse addition or attrition. 4. Whereas the alpha and beta neurons normally show quite different early growth patterns between birth and 30 weeks of age, when both eyes are simultaneously deprived of vision, an early temporal and numerical convergence occurs in patterns of spine population development on the two groups of neurons. This convergent pattern assumes a different form in dark-reared and lid-sutured animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of parenteral imipenem/cilastatin in patients on continuous ambulatory peritoneal dialysis.

We investigated the pharmacokinetics of two intravenous (iv) dose regimens of imipenem/cilastatin in Chinese patients on chronic ambulatory peritoneal dialysis (CAPD), who had an average creatinine clearance of 3.2 ml/min/1.73 m2. Doses of 0.5 and 1.0 g produced mean peak serum imipenem concentrations of 30 and 70 mg/l respectively, about 60% of cilastatin. Peritoneal dialysis fluid (PDF) imipenem concentrations reached 20-30% of the serum peak 4-5 h after iv injection, and the lowest maximum PDF concentrations were 2 mg/l after the 0.5 g dose and 14 mg/l after 1.0 g. Thus both regimes produced PDF imipenem concentrations above the MICs of susceptible pathogens. The half-life of imipenem was 6.4 h and the plasma clearance 66 ml/min; serum and PDF imipenem were in equilibration after about 5 h. Cilastatin had a prolonged half-life of 19 h and a plasma clearance of 10 ml/min, and accumulated in both serum and PDF. With a 0.5 g dose, the pharmacokinetics of imipenem/cilastatin suggest that the combination may prove an effective treatment for peritonitis associated with CAPD.

Pharmacokinetics and pharmacodynamics of subcutaneous and intraperitoneal administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis.

The single-dose pharmacokinetics of 50 U/kg body weight of recombinant human erythropoietin (rHuEPO) given by either the subcutaneous (s.c.) or the intraperitoneal (i.p.) route were studied in 20 anemic patients maintained on continuous ambulatory peritoneal dialysis. Their baseline hemoglobin levels were less than 9 g/dl. The absorption of rHuEPO via the i.p. route was limited. The serum erythropoietin (EPO) level was only slightly elevated from a baseline value of 27 +/- 3 mU/l to a plateau of 36 +/- 4 mU/l at 12-24 hours. In comparison, after s.c. injection, a peak EPO level of 81 +/- 13 mU/l was obtained after 24 hours. The areas under the concentration-time curve from 0-24 hour were 803 +/- 67 and 1492 +/- 165 mU/l.h for the i.p. and s.c. group respectively (p less than 0.003). The same two groups of patients were then given rHuEPO by either the s.c. or the i.p. route over a period of 16 weeks. In the s.c. group, the hemoglobin increased significantly from 6.9 +/- 0.3 g/dl to 9.8 +/- 0.6 g/dl (p less than 0.004). The mean rHuEPO dosage was 84 +/- 9 U/kg body wt/week. In the i.p. group, despite relatively higher rHuEPO dosage (133 +/- 7 u/kg body wt/week), the hemoglobin level did not increase significantly (7.0 +/- 0.4 g/dl to 8.0 +/- 0.4 g/dl, p = 0.09). Subcutaneous administration of rHuEPO is effective and convenient for patients maintained on continuous ambulatory peritoneal dialysis.