Induction of Cytotoxic Cell Activities by a Novel Cyclic Disulfide Compound, SA3443 in vivo

(4R)-Hexahydro-7, 7-dimethyl-6-oxo-1, 2, 5-dithiazocine-4-carboxylic acid (SA3443) is a newly synthesized cyclic disulfide compound which offers potential hepatoprotective properties.

The effect of SA3443 on the induction of natural killer (NK) and cytotoxic T lymphocyte (CTL) activities was investigated. NK activity in BALB/c mice splenic cells was investigated using YAC-1 cells as target cells. SA3443, at a dose range of 30-300 mg/kg/day, augmented NK activity significantly when administered orally once daily for 4 days before the assay. Alloantigen-specific CTL activity in splenic cells from BALB/c mice was detected 9 days after sensitization with C57BL/6 mice splenic cells. SA3443, at a dose of 100 mg/kg/day, augmented CTL activity significantly when administered orally, once daily for 4 days beginning after the sensitization and for 2 days before the assay, while a high dose of SA3443, at 300mg/kg, suppressed CTL activity.

From these results, it is thought that SA3443 may assist in the elimination of hepatitis viruses from the liver in patients with chronic active hepatitis, by the activation of NK and/or CTL activities.     

Induction of metallothionein synthesis by menadione or carbon tetrachloride is independent of free radical production.

The relationship between induction of hepatic metallothionein (MT) synthesis and lipid peroxidation by free radical production following an injection of menadione or carbon tetrachloride (CCl4) in mice was studied. The hepatic concentration of MT was increased by menadione significantly at 25 mg/kg or higher. A significant increase in thiobarbituric acid (TBA) value, indicative of lipid peroxidation, was observed in the liver at menadione doses of 62.5 mg/kg or higher. Both the MT and the TBA value in the liver were significantly increased at the low dose of CCl4. The concentration of MT was increased significantly 4-8 hr after administrations of these compounds. The increase of TBA value over time was similar to that of MT concentration after administration of CCl4, but not after administration of menadione. The MT concentration in the menadione group was higher than that in the CCl4 group, and the TBA level in the menadione group was lower than that in the CCl4 group. Pretreatment with vitamin E caused a significant reduction in the TBA value, but did not affect the MT level in the liver. The concentration of MT did not significantly correlate with the TBA value in either the menadione or the CCl4 group. Pretreatment with phenobarbital, which promotes free radical production, did not influence induction of MT synthesis following an injection of menadione or CCl4. Neither L-buthionine sulfoximine nor 2-cyclo-hexen-1-one, which decreases hepatic glutathione, influenced the induction of MT by menadione. These data suggest that induction of MT synthesis by menadione or CCl4 is independent of free radical production in the liver.     

Two cases of leiomyoma of the kidney]

Renal leiomyomas large enough to be clinically diagnosed are extremely rare. We review 30 cases of clinically diagnosed renal leiomyoma from the literature in Japan, including our 2 new cases. Case 1: In a 52-year-old man with no symptoms a renal mass was found accidentally on an ultrasonogram. CT scan showed a mass with a cystic area at the upper pole of the right kidney. Angiogram showed a hypovascular mass. Case 2: CT scan revealed a cystic mass and angiogram showed an avascular mass at the upper pole of the left kidney in a 19-year-old man having gross hematuria and left flank pain. Transperitoneal nephrectomy was done in both cases. Histologically each tumor was composed of monotonous proliferation of spindle shaped cells without atypia, which showed intense immunoreactivity for alpha-smooth muscle actin. The diagnosis of benign leiomyoma was made in each case. In a review of 30 cases, we found that renal leiomyomas occur most often in female (77%), between decades 2 and 5 of life (median: 46 years). On the angiogram it appears most often as an avascular or hypovascular mass. CT scan shows cystic or mixed solid/cystic or solid lesion, occasionally with calcification. Preoperative diagnosis is extremely difficult to be made. Histologically, fibroma, angiomyolipoma, congenital mesoblastic nephroma and leiomyosarcoma should be differentiated.     

A sheep survived for 48 days with the biventricular bypass type total artificial heart

A biventricular bypass type total artificial heart (BVB-TAH) utilizing two pusher-plate pumps was developed and implanted in a sheep for 48 days with excellent results. A Hall effect sensor was utilized to operate each pump independently with a full stroke at variable rates (VR). With this system, the animal's hemodynamics was kept physiologically, and all metabolic parameters except hemoglobin and hematocrit returned to normal three weeks after implantation. However, signs of infection appeared on the forty-second day, and consequently the animal fell into a state of shock. Even at that time the BVB-TAH maintained circulation by increasing pumping rate automatically. On the forty-eighth day, the animal could not stand and suffered from anuria; the experiment was then terminated after 1,140 h pumping. At autopsy, there was an enlarged heart with an atrophic change, 1,900 ml of pleural effusion, and 3,100ml of ascites fluid. Blood culture taken on the forty-seventh day yielded Acinetobacter calcoaceticus. The BVB-TAH operated in an independent VR mode maintained entire circulation, and has a capability of substituting the native heart function in any situation.     

Synergistic effect of 1,25-dihydroxyvitamin D3 and retinoic acid in inducing U937 cell differentiation.

We examined the effects of retinoic acid (RA), 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), and its synthetic analogue, 22-oxa-1,25-(OH)2D3, on differentiation of U937 cells by studying the cellular growth, surface marker expression and cytosolic free Ca2+ concentration ([Ca2+]i). RA inhibited cellular growth but did not induce expression of Mo2 (CD14), a monocyte/macrophage specific surface marker. To the contrary, 1,25-(OH)2D3 did not inhibit cellular growth, but increased CD 14-positive cells. Simultaneous addition of 1,25-(OH)2D3 and RA had no additive effect on cellular growth inhibition or CD14 expression. With regard to [Ca2+]i, however, 5 days' incubation with either of them increased the basal [Ca2+]i level and induced U937 cells to respond to formyl-methionyl-leucyl-phenylalanine (FMLP). When the cells were incubated with both 10(-6) M RA and 10(-8) M 1,25-(OH)2D3, basal [Ca2+]i was higher and FMLP caused a greater increase in [Ca2+]i than when only RA or 1,25-(OH)2D3 was added. These data suggest that RA and 1,25-(OH)2D3 induce monocytoid differentiation in U937 cells through different pathways and act synergistically in the differentiation process. The 22-oxa-1,25-(OH)2D3 induced CD14 expression, basal [Ca2+]i increase and [Ca2+]i response to FMLP, but did not cause cellular growth inhibition in U937 cells, and in these points, 22-oxa-1,25-(OH)2D3 exhibited no significantly different effects from 1,25-(OH)2D3. Thus, 22-oxa-1,25-(OH)2D3 has the same potent activity as 1,25-(OH)2D3 in inducing differentiation of U937 cells.     

Myocardial protective effect of lidocaine during experimental off-pump coronary artery bypass grafting.

Off-pump coronary artery bypass grafting (OPCABG) has recently gained popularity. During OPCABG, patients remain vulnerable to ischemic-reperfusion injury due to a temporary coronary occlusion without any active cardioprotection. Some strategies such as ischemic preconditioning (IP) and an intracoronary shunt have been applied with a view to minimizing the effects of ischemia, but the effects of these strategies remain controversial. This study was carried out to investigate the protective effect of lidocaine against myocardial ischemic-reperfusion injury. Twenty-one pigs were assigned to three groups, each consisting of seven pigs. In the control group, using a left internal thoracic artery (LITA) bypass circuit, the left anterior descending coronary artery (LAD) was occluded for 45 min followed by two hours of reperfusion. In the IP group, five min of occlusion followed by 15 min of reperfusion was performed. In the lidocaine group, 2 mg/kg of lidocaine was administered directly into the LAD just before the LAD occlusion. Infarct size expressed as a percentage of the area at risk was significantly smaller in the lidocaine group (2.7+/-4.2%) than in the control group (79.9+/-6.0%, p<0.001) or the IP group (57.0+/-25.9%, p<0.001). Lidocaine exhibited a potent myocardial protective effect in the present OPCABG model.     

Gyrate atrophy of the choroid and retina: 15 Japanese patients.

We examined 15 Japanese patients who had gyrate atrophy of the choroid and retina with hyperornithinaemia. Their visual acuities fell to 0.2 or worse in the second or third decade of life. Myopia developed late in the first decade, and the refractions decreased to -10 or -15 dioptres at age 20. Tunnel vision developed at approximately age 20. Our results suggested that the visual functions of Japanese patients were worse in the third decade or later than similarly affected Finnish patients.