Seishiro Marukawa

Role of interleukin 18 in nitric oxide production and pancreatic damage during acute pancreatitis.

The release of the immunomodulator, interleukin 18 (IL-18) into sera early in acute pancreatitis (AP) corresponds to disease severity. IL-18 induces nitric oxide (NO), which is involved in the pathophysiology of pancreatitis. The objective of this study was to clarify the role of IL-18 in pathogenesis and NO production during early AP using recombinant mouse (rm) IL-18 protein and IL-18 gene knockout (KO) mice. After pretreatment with phosphate-buffered saline or rmIL-18, wild-type (WT) or KO mice were injected intraperitoneally with phosphate-buffered saline (sham) or cerulein (AP) hourly for 3 h. Blood, pancreas, spleen, and liver were collected until 24 h after the first dose. Main outcome measures were serum IL-18, amylase and lipase levels, histological evaluation of the pancreas with parenchyma vacuolization of acinar cells, mRNA expression of inducible NO synthase (iNOS) in the pancreas, and spleen, liver, and plasma NO metabolite level. Serum IL-18 was significantly increased immediately after induction of AP in WT mice. Serum amylase, lipase, and the numbers of acinar cells with parenchyma vacuolization were significantly higher in the group AP/KO than in the group AP/WT, but these parameters were improved by dose-dependent pretreatment with rmIL-18 administration in both groups. Pancreatic iNOS gene expression and plasma NO metabolites were significantly increased by 6 h after the initiation of AP, but were significantly lower in the group AP/KO than in the AP/WT mice. Pretreatment with rmIL-18 also significantly increased these levels in both groups. Splenic and hepatic iNOS expression was not changed after the initiation of AP in WT mice, whereas pretreatment with rmIL-18 also increased these levels. Administration of aminoguanidine, a selective iNOS inhibitor, before AP induction abolished the protective effect of pretreatment with rmIL-18 on pancreatic injury. IL-18 appears to protect the pancreas during early induced-induced AP in mice, probably through induction of NO release from an iNOS source. IL-18 may be a target for new AP therapeutics.

Plasma nitrotyrosine concentration relates to prognosis in human septic shock.

Interrelation of plasma nitrotyrosine (NT) concentrations in patients of septic shock and their prognosis was examined. Blood samples were obtained from 12 patients during the first episode of septic shock at hospitalization, and their plasma NT concentrations were measured. Five patients died within five days after hospitalization, but seven patients recovered. Plasma NT concentrations (means ± SE) of the non-survivors and survivors were 0.68 ± 0.13 nmol/mL (n = 7), and 0.21 ± 0.05 nmol/mL (n = 5), respectively, the former being significantly higher than the latter. The present results suggest that plasma concentration of NT relates to prognosis in human septic shock, although further studies with a larger patient population are necessary for confirmation of the suggestion.

Interleukin-18 Induces Acute Biphasic Reduction in the Levels of Circulating Leukocytes in Mice

ABSTRACT We investigated the acute hematological changes caused by interleukin-18 (IL-18) in mice. Intraperitoneal administration of IL-18 (2 μg/mouse) resulted in biphasic decreases in the number of leukocytes in the blood. The first phase of decrease occurred within 2 h of IL-18 administration and was followed by a transient increase at 5 h. The second phase of decrease occurred at around 6 h, reaching a nadir which lasted for more than 24 h. In mice deficient in inducible nitric oxide (NO) synthase, the first phase of reduction of leukocytes did not occur although the second phase of decrease was observed. In mice deficient in gamma interferon (IFN-γ) or in mice depleted of natural killer cells and incapable of producing IFN-γ, IL-18 had no effect on the number of circulating leukocytes. Levels of nitrite and/or nitrate in the serum were elevated within 2 h after administration of IL-18, reaching a peak at 4 h and then decreasing gradually to the basal level over a 24-h period of time. On the other hand, serum IFN-γ levels changed in a biphasic manner, reaching a peak at 2 h after IL-18 administration, followed by a decrease in the basal level and a second increase at 6 h. Levels of IL-18 receptor mRNAs also showed biphasic changes in correlation with the changes in serum IFN-γ levels. These results suggest that the changes in the leukocyte number following IL-18 administration are mediated by NO and IFN-γ, with NO being involved in the first phase of reduction and IFN-γ being involved in both phases.

Vasorelaxant effects of oxpentifylline and theophylline on rat isolated aorta.

Abstract— The mechanism of the relaxation response of rat aorta to the phosphodiesterase inhibitors oxpentifylline and theophylline was studied. Oxpentifylline induced a greater vasorelaxation response in the intact strips than in those without endothelium. The endothelium‐dependent relaxation response to oxpentifylline was inhibited by nitro‐l‐arginine but not by indomethacin, and the endothelium‐independent relaxation response was potentiated by the combination with isoprenaline but not sodium nitroprusside. Theophylline induced a similar relaxation response in vascular strips with and without endothelium. The relaxation response to theophylline was not inhibited by indomethacin or nitro‐l‐arginine in intact strips, but was potentiated by combination with isoprenaline or sodium nitroprusside in the denuded strips. These results suggest that the two phosphodiesterase inhibitors oxpentifylline and theophylline induce vasorelaxation by different mechanisms. Oxpentifylline can induce both endothelium‐dependent relaxation, which is probably mediated by an endothelium‐derived relaxing factor, and endothelium‐independent relaxation, which may be due to an inhibitory action on phosphodiesterase of vascular smooth muscle. In contrast, theophylline can induce endothelium‐independent relaxation alone, without modulation by the endothelium.

Compression-only CPR training in elementary schools and student attitude toward CPR.

Little is known about the effectiveness of systematic cardiopulmonary resuscitation (CPR) training for elementary school children.

Mthanol: toxicity of the solvent in a commercial product should also be considered

Sir In general, the evaluation of toxicity relies on the toxicity of the main component in a poisoning case involving a commercial product. However, we usually pay little attention to the toxicity of the solvent used. Methanol finds widespread commercial use as a solvent.1 Here we report a case of death due to trichlorfon (O,O-dimethyl 2,2,2-trichloroi-hydroxyethylphosphonate; DEP) dissolved in methanol and phenobarbital ingestion with fatal levels of these components in the blood, and also a detected toxic level of methanol and its metabolite, formic acid.

Hyperpyrexia induced by a multiple antidepressants overdose.

A 23-year old male ingested an excessive amount of antidepressants that had been prescribed. Initially, he was hospitalized near his house. Subsequently, he was transferred to the emergency department (ED) in a university hospital, because of the difficulties in controlling his seizures. At the time of arrival in the ED, he was in cardiopulmonary arrest. His rectal temperature was 41.2°C (106.16°F). Resuscitation was unsuccessful. A number of empty packets of antidepressants were found in his house during the subsequent authorities’ investigation. At autopsy, no remarkable findings were observed except for severe pulmonary edema and congestion. No evidence of brain injury or infectious diseases such as meningitis, encephalitis or pneumonia was observed. Histological study of the skeletal muscle showed hypercontracted fiber appearing as ‘opaque fibres’ and multiple vacuolation (Figure 1). Drug screening testing using a TriageTM (Biosite Diagnostic Inc, San Diego, USA) panel was positive for benzodiazepines, barbiturates and tricyclic antidepressants, but negative for alcohol by gas chromatography. Figure 2 shows the chromatogram of femoral blood using a high performance liquid chromatography (HPLC) drug analysis system (Class VP system, Shimadzu, Kyoto Japan). Clomipramine, amoxapine, maprotiline, amitriptyline and milnacipran were confirmed by each retention time. The drug concentrations in the victim’s femoral blood and their fatal and therapeutic blood level are summarized in Table 1. Blood concentrations of clomipramine and amoxapine were at fatal levels, while the maprotiline and amitriptyline levels were toxic.2 Milnacipran, a newly developed serotonin-noradrenaline reuptake inhibitor, was found to be ten-fold higher than the therapeutic level.3 The positive benzodiazepines and barbiturates detected by the TriageTM screening

Proportional assist ventilation using a disturbance observer and predictive control

This paper presents a general control representation for medically-proposed methods of mechanical ventilation, and then proposes an improved configuration with a disturbance observer and with a predictive control block against an existing proportional assist ventilation (PAV) method. The trade-off relation between robust stability margin and responsibility has been shown using parSparinfin - 1 in Nyquist diagrams and time-response results with our mechanical ventilator SSV-200 connected to our lung simulator (LUNGOO). Also, a clinical issue of expiratory asynchrony is compared between two methods with the same test construction. The actual clinical tests for these performances will be expected with a next new version of our SSV. We also present on-line identification methods for patients airway resistance and respiratory compliance which are necessary for implementation of PAV. Animal test results and a few clinical test results of our techniques are also reported for these identification methods