2-O-methylisohemigossylic acid lactone, a sesquiterpene, isolated from roots of mokumen (Gossampinus malabarica) induces cell death and morphological change indicative of apoptotic chromatin condensation in human promyelotic leukemia HL-60 cells

2-O-methylisohemigossylic acid lactone, a sesquiterpene, was purified from roots of mokumen (Gossampinus malabarica) and identified by Mass, and (1)H- and (13)-NMR. This sesquiterpene displayed strong growth inhibitory effect against human promyelotic leukemia HL-60 cells. Apoptotic morphological change of the nucleus, including chromatin condensation was induced in the HL-60 cells treated with the sesquiterpene. The fragmentation of DNA by the sesquiterpene to oligonucleosomal-sized fragments, a characteristic of apoptosis, was observed to be dose- and time-dependent in the HL-60 cells. Inhibitors of caspases suppressed the DNA fragmentation induced by the sesquiterpene. These findings suggest that growth inhibition by the sesquiterpene of HL-60 cells results from the induction of apoptosis by the sesqui-terpene, and that caspase cascade is involved in the induction of apoptosis by the compound in the HL-60 cells.     

Alpha 2-adrenergic modulation of pancreatic glucagon secretion in rats.

The present study was designed to clarify the mechanism of adrenergic modulation of pancreatic glucagon secretion in rats under physiological conditions by 1) epinephrine infusion alone or together with adrenergic blockers and 2) administration of adrenergic agonists. Intravenous infusion of epinephrine alone (1 microgram/kg/min, equal to 0.7 nmol/kg/min) caused a significant increase in glucagon secretion. Phentolamine (an alpha blocker) or yohimbine (an alpha 2 blocker) administration completely inhibited the increase of glucagon secretion caused by epinephrine infusion, but neither the administration of bunazosin (an alpha 1 blocker) nor beta blockers inhibited it. Infusion of clonidine (an alpha 2 agonist) caused significant increase of glucagon secretion even at a low dose of 0.5 nmol/kg/min, although infusion of neither an alpha 1 nor a beta 2 agonist caused it even at the high dose of 40.0 nmol/kg/min. It is concluded that the alpha 2 receptor mechanism plays the most important role in the adrenergic modulation of glucagon secretion in rats under physiological conditions.     

Differentiation of fibrinolysis and fibrinogenolysis by analysis of FDP fragments]

We previously analysed the fragments of fibrin/fibrinogen degradation products (FDP) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) combined with immunoblotting. In this report, we studied the semi-quantitative analysis of fibrinolysis (degradation of cross-linked fibrin) and fibrinogenolysis (degradation of fibrinogen and/or unstable fibrin) of patients' samples by our method. In vitro study of FDP made it clear that an appearance of D fragment confirmed fibrinogenolysis and an appearance of DD fragment and/or high molecular weight fragments which have higher molecular weight than DY or X fragment confirmed fibrinolysis. In addition, a study with mixtures of various concentrations of fibrin degradation products (FbDP) and fibrinogen degradation products (FgDP) demonstrated a dose dependent intensity of band by immunoblot method. These results show that our method is favorable for the semi-quantitative analysis of fibrinolysis and fibrinogenolysis. We applied the method to 6 samples from patients with disseminated intravascular coagulation (DIC). Consequently, fibrinogenolysis was observed in all of 6 samples, in which fibrinogenolysis was more enhanced than fibrinolysis in one sample, and an equivalent degree of fibrinolysis and fibrinogenolysis were observed in 3 of 6 samples. Although our method was probably devoid of the ability to distinguish FgDP from degradation products of unstable fibrin, these findings indicate that fibrinogenolysis is, at any rate, enhanced in the majority of patients with DIC, besides fibrinolysis.     

Long thoracic nerve paralysis associated with thoracic outlet syndrome

Two cases of long thoracic nerve palsy associated with thoracic outlet syndrome are reported. Both patients had abnormal posture, with low-set shoulders and winged scapulae. Clinically there was weakness of the serratus anterior muscle with partial denervotion on electromyography. The diagnosis of thoracic outlet syndrome was based on positive vascular tests and brachial plexus nerve compression symptoms induced by the vascular testing positions. An orthosis that held the shoulder in an elevated position was used in both cases. Complete recovery of shoulder function and relief of the symptoms was achieved in both cases at 8 and 13 months, respectively, after application of the orthosis.     

Efficacy of an echo contrast agent, SH/TA-508, in color doppler sonography of mass lesions in urology

We performed a clinical phase III study with a galactosebased ecoo contrast agent, SH/TA-508, to evaluate its efficacy, safety, and usefulness for mass lesions in urology. SH/TA-508 was prepared as a suspension containing stabilized micro-air bubbles by adding water for injection just before use. SH/TA-508 was administered into the antecubital vein at an initial dose of 300 mg/ml × 5 ml followed by higher doses of 400 mg/ml × 4 ml, 300 mg/ ml × 10 ml or 400 mg/ml × 8 ml when a sufficient effect was not obtained. Efficacy was evaluated by color Doppler signal enhancement, the duration of blood flow signal enhancement, and improvement of diagnostic capacity. Fifty-nine patients with mass lesions in the kidney, prostate, testis, adrenal gland, and bladder were enrolled in the study. Up to the third dose the cumulative efficacy rates (≥2+) of color Doppler signal enhancement and duration of blood flow signal enhancement were 92% and 87%, respectively. Consequently, diagnostic capacity in 76% of the patients was remarkably improved. A light transient angialgia occurred in one patient but no other clinically significant changes were observed. It was confirmed that SH/TA-508 is a safe echo contrast agent that offers satisfactory color Doppler signal enhancement in the urologic organs mentioned above.     

Major organ function under mechanical support: comparative studies of pulsatile and nonpulsatile circulation

We examined a major organ function during 3 h biventricular assisted circulation after acute myocardial infarction model in the pig. In left ventricular circulation, the outflow cannula was placed in the ascending aorta and an inflow cannula through the mitral valve in the left ventricle. A pump (pulsatile group, Zeon Medical, Inc., Tokyo, Japan and nonpulsatile group, Nikkiso HPM-15, Nikkiso, Inc., Tokyo, Japan) was connected to each cannula. In right ventricular circulation, the outflow cannula was placed in the pulmonary artery and an inflow cannula in the right ventricle. The right ventricular circulation was supported by a nonpulsatile pump (Nikkiso HPM-15). The items measured were the regional blood flows of the cortex and medulla in the kidney, white matter and gray mater in brain, and liver; renal arterial flow; carotid arterial flow; portal vein flow; common hepatic arterial flow; arterial ketone body ratio (AKBR); and lactate/pyrubic acid (L/P). In the pulsatile group, the renal cortical blood flow increased, and the medulla blood flow decreased. On the other hand, in the nonpulsatile group, both regional blood flows decreased. That means that in the pulsatile assisted group intrarenal redistribution improved rather than in the nonpulsatile assisted group. In addition the liver regional blood flow, AKBR, and L/P showed significant differences between the pulsatile and nonpulsatile groups. On the other hand, the white matter and gray matter regional blood flows and carotid arterial flow did not show significant differences between the groups. The results of our study indicated that pulsatile circulation produced superior circulation in the kidney and liver, and microcirculation on the cell level was superior as well in early treatment of acute heart failure.     

Specific IgG to gelatin in children with systemic immediate- and nonimmediate-type reactions to measles, mumps and rubella vaccines.

We examined anti-gelatin IgG in sera of children who suffered from systemic adverse reactions upon immunization with gelatin-containing live virus vaccines. In the group of 30 children who had immediate-type reactions and anti-gelatin IgE, 30 (100%) had anti-gelatin IgG and 29 (96%) had anti-gelatin IgG4. In another group of 75 children who had nonimmediate-type reactions and no anti-gelatin IgE, 22 (29%) had anti-gelatin IgG and six (8%) had IgG4. The IgG positivity well correlated with the lymphocyte proliferation assay positivity. In contrast, as a negative control, all 24 children who had no allergic reaction to live virus vaccines had no anti-gelatin IgG and IgG4. The results suggest that immune-response to gelatin may play a role in the pathogenesis of systemic nonimmediate-type reactions to the live virus vaccines.     

The modulatory effect of (+)-TAN-67 on the antinociceptive effects of the nociceptin/orphanin FQ in mice

To clarify the pharmacological properties of (+)2-Methyl-4aalpha-(3-hydroxyphenyl)-1, 2, 3, 4, 4a, 5, 12, 12aalpha-octahydro-quinolino[2, 3, 3-g]isoquinoline ((+)-TAN-67), the effect of (+)-TAN-67 on the antinociception induced by the intrathecal (i.t.) administration of nociceptin/orphanin FQ was studied in mice using the tail-flick test and the formalin test. I.t. administration of (+)-TAN-67, at doses of 1 to 10 ng, facilitated the tail-flick response in a dose-dependent manner in mice. In addition, i.t. administration of (+)-TAN-67 (1 to 10 ng) in mice produced a marked pain-like aversive responses. I.t. pretreatment with D-Pro(9)-[spiro-gamma-lactam]-Leu(10)-Trp(11)-physalaemin(1-11) (GR82334, 0.1-1.0 nmol), a potent and selective tachykinin NK(1) receptor antagonist, dose-dependently blocked the reduction of the tail-flick response induced by (+)-TAN-67. Furthermore, (+)-TAN-67-induced facilitation of the tail-flick response was abolished in capsaicin-treated mice. On the other hand, (+)-TAN-67-induced flinching responses were dose-dependently and significantly reduced by i.t. pretreatment with GR82334 (0.1-1.0 nmol). The duration of i.t. (+)-TAN-67-induced flinching responses was significantly reduced in capsaicin-treated mice as compared with naive mice. I.t. administration of nociceptin/orphanin FQ (1-10 nmol) dose-dependently increased the tail-flick latency. I.t. administration of nociceptin/orphanin FQ (0.1-1.0 nmol) significantly and dose-dependently reduced the first-phase nociceptive response, but not the second-phase nociceptive response. I.t. pretreatment with (+)-TAN-67 (0.3-3.0 microg) for 30 min dose-dependently attenuated the antinociception induced by i.t. nociceptin (10 nmol) in the tail-flick test. Furthermore, the antinociceptive effect of nociceptin/orphanin FQ (1 nmol, i.t.) on the first-phase response in the formalin test was dose-dependently attenuated by s.c. pretreatment with (+)-TAN-67 (0.3-3.0 microg). (+)-TAN-67 (0.3-3.0 microg, i.t.), by itself, did not facilitate the tail-flick response or produce apparent behavioral changes. It is possible that (+)-TAN-67 has an antagonistic effect on nociceptin/orphanin FQ-induced antinociception.