A causal model of blood enzyme data and visualization of tissue conditions

Quantitative diagnostics is an important field in which clinical data are converted into medical information. A variety of approaches to obtain medical diagnoses have been developed and multivariate statistical analysis supports the diagnostic process. Although many clinical data are affected by body conditions such as disease and functional failure, only a few models take this phenomenon into consideration. The correlation between laboratory test results can be understood as a causal relationship between body conditions and clinical test data variations. A multivariate statistical method, factor analysis, expresses a causal relationship between latent variables and observed variables. We developed a causal model for blood enzyme data using factor analysis. The latent variables were assumed to be organ specific regarding 9 enzyme data. This causal model expressed clinical knowledge within blood enzymes and allowed visualization of organ conditions. The visualization of laboratory data is useful to screen patient's pathological states.     

New lidocaine ester derivatives with a prolonged anesthetic effect

In order to find a new long acting local anesthetic, methyl, ethyl, and butyl ester derivatives of lidocaine were synthesized in our laboratory. The topical anesthetic activity was studied with the effects on corneal reflex in rabbits, and the duration of action with those on the action potential of rabbit vagus nerve was studied in vitro. All drugs showed adequate topical anesthetic activities. The onset time to induce a complete blockage of the action potential in the excised vagus nerve was 97.1 +/- 6.3 s for lidocaine, 289.3 +/- 29.0 s for methyl ester, 186.3 +/- 18.4 s for ethyl ester, and 85.3 +/- 9.0 s for butyl ester. The mean duration of action, which was assessed as the time to recover from the complete block to 30% of control amplitude in a drug-free medium, was 32.5 +/- 3.1 min for lidocaine, 39.9 +/- 11.3 min for methyl ester, 68.2 +/- 4.2 min for ethyl ester, and 108.7 +/- 12.3 min for butyl ester. The differences in the duration of action between the ester derivatives and the original lidocaine were all statistically significant. The duration of action of all drugs studied paralleled with their protein binding capacities. These findings indicate the possibility that the ester derivatives studied, especially butyl ester, can be used as a long acting local anesthetic.     

Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor,BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth

1. The aim of this study was to determine whether BAYw6228 (BAYw), a newly developed 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, could suppress an atherogenic process such as intimal thickening by a mechanism other than lowering the level of serum cholesterol.
2. First, we evaluated the in vitro effect of BAYw on the proliferation of vascular smooth muscle cells (SMC) from various species: Sprague-Dawley (SD) rats, New Zealand (NZ) white rabbits, intimal cells from Watanabe hereditary hyperlipidemic (WHHL) rabbit and SMC from the new-born human aorta. The increasing rate of total protein content of these cells was inhibited by the addition of BAYw in a dose-dependent fashion. In the presence of 2% foetal calf serum (FCS), the value of IC₅₀ was 1.0 μM in SD rats. 2.1 μM in NZ white rabbits, and 0.3 μM in WHHL rabbits. With human SMC, the value was 0.02 μM in the presence of 10% FCS and 0.2 μM with a mixture of growth factors.
3. Based on these above in vitro findings, we next examined the in vivo effect of the agent to determine whether it could suppress rabbit intimal thickening induced by balloon catheterization. A balloon catheter was inserted from a peripheral branch of the left external carotid artery to the aorta to denude the endothelium of the left common carotid artery in Japanese white rabbits. After 12 days they were divided into control and BAYw groups. The former were subcutaneously injected with saline and the latter with BAYw 1 mg kg⁻¹ day⁻¹. Two days after the beginning of treatment, a second balloon injury was performed to the previously injured left common carotid artery in both groups. After another two weeks, the left common carotid artery was removed and variously stained. Although the total serum cholesterol in the BAYw group was significantly lower than in the control (P<0.05), the difference was not enough to affect intimal thickening. In addition, the BAYw group had a smaller intima/media ratio than the control group, decreasing to 45% of control (P<0.05). By anti-α smooth muscle actin antibody staining, these intimal thickening areas were entirely occupied by SMCs, and their amount was attenuated by BAYw. By anti-rabbit macrophage antibody (RAM 11) staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared to control (P<0.01).
4. These results indicate that BAYw has an inhibitory effect on intimal thickening by attenuating intimal SMC proliferation and infiltration of macrophages, suggesting that BAYw could be effective in the prevention of the progression of atherosclerotic plaque-like restenosis after angioplasty.

     

FDG-PET for the evaluation of tumor viability after anticancer therapy

To evaluate positron emission tomography with¹⁸F-fluorodeoxy glucose (FDG-PET) as an diagnostic tool to determine tumor viability after anticancer therapy, fourteen patients were examined by FDG-PET after the end of the treatment. The lesions with residual viable tumor cells showed higher uptake of FDG than surrounding normal soft tissue. The lesions, in which tumor viability was lost or very low, showed higher uptake of FDG in four cases and similar uptake to normal soft tissue in three cases. The residual increased uptake of FDG was considered to be caused by remaining tumor cells and/or inflammatory reaction to anticancer treatment. FDG-PET after anticancer treatment should be interpreted by considering the reaction due to the treatment and the partial volume artifact of PET caused by the limited spatial resolution.     

Expandable metallic stent treatment for malignant colorectal strictures

Four patients were treated by placement of an expandable metallic stent (two Gianturco Z-stents, two Ultraflex stents) for malignant colorectal strictures. All four patients were able to defecate after stent placement. Stent migration was recognized in one patient. Two patients suffered from tenesmus after stent placement.     

Lipoprotein(a) levels and apolipoprotein(a) isoforms related to life style risk factors

Lipoprotein(a) [Lp(a)] has been considered to be a predictor of premature coronary heart disease and other cardiovascular diseases. Lp(a) levels are largely genetically determined, but the detailed mechanism of Lp(a) elevation is uncertain. We examined the association between Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes as well as that of Lp(a) level and other various conditions. The subjects were 280 healthy Japanese (102 males and 178 females) aged 39 to 70 years who were living in a rural community in 1992. We obtained apo(a) phenotypes determined by SDS-PAGE as well as Lp(a) levels and other cardiovascular risk factors. We combined apo(a) phenotypes form 4 groups according to molecular weights (from high apo(a) molecular weight to low: I, II, III and IV). Lp(a) levels were associated with apo(a) phenotype-groups, that is, they were inversely associated with apo(a) molecular weight. Small apo(a) phenotypes were less frequent than large ones. The median Lp(a) level was higher in smoking (29.2 mg/dL) than in non-smoking subjects (18.5 mg/dL) in phenotype-group III. Adjusted means of total cholesterol and fibrinogen levels in apo(a) phenotype-group IV were the highest of all phenotype-groups. Age, apo(a) phenotype, smoking status, total cholesterol and fibrinogen were positively correlated with Lp(a) levels by multiple regression analysis. Lp(a) levels were found to be mainly associated with apo(a) phenotype, but varied broadly within the same apo(a) phenotype at various conditions, such as smoking status and high total cholesterol.     

Vinylamycin, a new depsipeptide antibiotic, from Streptomyces sp

A new depsipeptide antibiotic, vinylamycin, was isolated from the culture broth of an actinomycete strain. The producing organism, designated MI982-63F1, was identified as a member of Streptomyces. Vinylamycin was isolated from the culture broth by extraction with EtOAc and purified by crystallization from EtOAc. The structure of vinylamycin was determined by spectroscopic analysis and degradation studies. Vinylamycin showed antimicrobial activities against Gram-positive bacteria including MRSA.     

Important role of endothelium-derived hyperpolarizing factor in shear stress--induced endothelium-dependent relaxations in the rat mesenteric artery.

Shear stress is one of the most important stimulators for the release of endothelium-derived relaxing factors. Although shear stress-induced release of nitric oxide (NO) has been extensively investigated, it remains to be elucidated whether endothelium-derived hyperpolarizing factor (EDHF) contributes to the endothelium-dependent relaxations to shear stress. This study was designed to address this point in the isolated rat mesenteric artery. Large mesenteric arteries (400-500 microm) and resistance mesenteric arteries (150-250 microm) of the rat were precontracted with phenylephrine (at 80 mm Hg of perfusion pressure), and the changes in vessel diameter in response to variable flow (0-300 microl/min) were continuously examined. The relative contributions of vasodilator prostaglandins, NO, and EDHF were analyzed by the inhibitory effects of indomethacin (10(-5) M), N(G)-nitro-L-arginine (L-NNA, 10(-4) M), and KCl (40 mM), respectively. The shear stress-induced relaxations were totally endothelium dependent in both-sized blood vessels, and the contribution of NO was more prominent in large arteries than in resistance arteries, whereas that of EDHF was noted in both-sized blood vessels. Tetrabutylammonium (a nonselective inhibitor of K channels) almost abolished, whereas the combination of charybdotoxin (an inhibitor of both large- and intermediate-conductance Ca2+ -activated K channels) and apamin (an inhibitor of small-conductance Ca2+ -activated K channels) significantly inhibited the EDHF-mediated component of the shear stress-induced relaxations. These results indicate that EDHF plays an important role in shear stress-induced endothelium-dependent relaxations, where K channels, especially calcium-activated K channels, appear to be involved.     

Chronic hypertension induced by streptozotocin in rats

Summary An intravenous injection of 40 or 65 mg/kg streptozotocin induced not only diabetes but also severe hypertension in rats. Whereas the hyperglycemia developed fully within a few days after the injection of streptozotocin, the hypertension progressively advanced and reached maximum level several weeks after the treatment and lasted more than 20 weeks. Twenty mg/kg streptozotocin did not induce hyperglycemia but significantly increased blood pressure several weeks after the treatment. Arrest of growth, polyuria, glycosuria, hyperlipemia and lenticular cataracts developed in the animals treated with 40 or 65 mg/kg streptozotocin, but in none of the animals treated with 20 mg/kg. In histological examinations in the 24th week after the treatment, degranulation and necrosis in the pancreatic -cells, and vacuolization and deposition of PAS-positive materials in the renal proximal tubules were found in the animals treated with 40 or 65 mg/kg streptozotocin.     

Analysis of the potentiating action of NG-nitro-l-arginine on the contraction of the dog temporal artery elicited by transmural stimulation of noradrenergic nerves

Summary Dog temporal artery strips without endothelium responded to transmural electrical stimulation with a contraction which was potentiated by N^G-nitro-l-arginine (l-NNA). The noradrenaline-induced contraction and the release of 3H-noradrenaline were not affected. The stimulation-induced contraction was reversed to a relaxation by phentolamine. The relaxation was not influenced by timolol and atropine but inhibited by l-NNA; l-arginine abolished the inhibition. Transmural stimulation released NO_x from the arteries, the release being abolished by l-NNA. Potentiation by l-NNA of the neurally-induced contraction appears to be due to elimination of NO produced by non-adrenergic, non-cholinergic vasodilator nerve activation. Send offprint requests to N. Toda at the above address