Search

Research into pharmacokinetics plays an important role in the development process of new drugs. Accurately predicting human pharmacokinetic parameters from preclinical data can increase the success rate of clinical trials. Since clearance (CL) which indicates the capacity of the entire body to process a drug is one of the most important parameters, many methods have been developed. However, there are still rooms to be improved for practical use in drug discovery research; "improving CL prediction accuracy" and "understanding the chemical structure of compounds in terms of pharmacokinetics". To improve those, this research proposes a multimodal learning method based on deep learning that takes not only the chemical structure of a drug but also rat CL as inputs. Good results were obtained compared with the conventional animal scale-up method; the geometric mean fold error was 2.68 and the proportion of compounds with prediction errors of 2-fold or less was 48.5%. Furthermore, it was found to be possible to infer the partial structure useful for CL prediction by a structure contributing factor inference method. The validity of these results of structural interpretation of metabolic stability was confirmed by chemists.

Typical angioid streaks were found on routine ophthalmologic examination in a 42-year-old female with yellowish, coalescing papules on her neck without any symptoms. Biopsy of the cutaneous lesion showed degeneration and fragmentation of the elastic fibers and many basophilic-stained calcifications in mid-dermis, which are consistent with pseudoxanthoma elasticum. Twenty-four-hour Holter electrocardiography (ECG) showed sinus arrest for 2.5 seconds, and an electrophysiological study revealed sinus nodal dysfunction (sick sinus syndrome), whereas all of the coronary arteries were intact, despite a treadmill stress ECG test showing significant ST depressions. The association of pseudoxanthoma elasticum and sick sinus syndrome is very rare. One possible explanation for this association here is that the degeneration of elastic fiber in endomysium of the sino-atrial node may have affected heart conduction systems, resulting in sick sinus syndrome.

The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process.

We examined the relation of serum lipids and apolipoprotein E genotype to colorectal adenomas among 205 cases and 220 controls with normal colonoscopy in Japanese men. With adjustment for body mass index, cigarette smoking, alcohol use, and other covaiates, odds ratios of proximal and distal adenomas associated with the presence of an allele varepsilon4 were 0.59 (95% confidence interval 0.23-1.45) and 0.99 (0.50-1.98), respectively. While serum total and LDL cholesterol were unrelated to both proximal and distal adenomas, serum triglycerides were positively related to distal adenomas. The findings suggest that altered lipid metabolism may be differentially associated with tumorigenesis in the proximal and distal colorectum.

A homozygous mutation at bp 677 in the gene for the methylenetetrahydrofolate reductase (MTHFR) was previously shown to be associated with a decreased risk of colorectal cancer. We examined the relation between the MTHFR genetic polymorphism and risk of colorectal adenoma in Japanese men using 205 cases of colorectal adenomas and 220 controls of normal total colonoscopy. The homozygous mutation was not measurably associated with colorectal adenomas. The findings corroborate the lack of an association between the MTHFR genotype and colorectal adenomas, but do not deny the possibility that the genotype may be involved in the late stage of colorectal carcinogenesis.

Obesity has been related to increased risk of colon cancer or adenomas, but the epidemiologic findings are not entirely consistent. We examined the relation of not only body mass index (BMI) but also waist-to-hip ratio (WHR) and weight gain to colon adenoma risk in men who received a preretirement health examination at the Japan Self Defense Forces (SDF) Fukuoka and Kumamoto Hospitals during the period from 1995 to 1996. In the series of 803 men at age 47-55 years, 189 cases of colon adenomas and 226 controls with normal total colonoscopy were identified. Weight at 10 years before was ascertained by referring to the recorded data. After allowance for hospital, rank in the SDF, smoking and alcohol use, weight gain over the past 10 years was significantly associated with increased risk of colon adenomas (odds ratio for > or = 6 kg versus < or =-2 kg = 2.2; 95% confidence interval 1.0-4.8). High BMI and high WHR were each associated with increased risk, but only WHR was related to the risk independently of weight gain. In particular, weight gain accompanied with a high WHR was associated with a significant increase in the risk. Men with high physical activity tended to have lower risk. Associations with obesity-related variables and physical activity were not materially differential as regards the location and size of adenoma. The findings indicate that weight gain in middle age leading to abdominal obesity increases the risk of colon adenomas, and consequently of colon cancer.

The natural variant of the cytochrome P450 enzyme CYP2D6.1, CYP2D6.17, is most common in African populations, has three amino acid substitutions (T107I, R296C, and S486T) compared to the wild-type, and is known to have a different ligand preference from CYP2D6.1. It is becoming increasingly important to understand differences in the metabolism of medicines in different ethnic groups in order to assess the relevance of clinical data from different countries. This study investigated differences in the inhibition profiles of drugs for CYP2D6 with respect to gene polymorphisms. Firstly, we used computer docking with six drugs to several CYP2D6.1 structures, sampled from the trajectory of MD simulations, and calculated MM-GB/SA scores representing binding free energies. We then used regression analysis to predict the potency with which drugs inhibited CYP2D6.1 based on MM-GB/SA scores. The pKi-values obtained were in good agreement with experimental values measured for the six drugs (r(2) = 0.81). We carried out the same analysis for CYP2D6.17 and the pKi-values calculated were also in good agreement with experimental values (r(2) = 0.92). Finally, we were able to successfully explain the different abilities of CYP2D6.1 and CYP2D6.17 to metabolize drugs in different ethnic groups with reference to their 3D-structures.

Summary: Cytochrome P450 3A4 (CYP3A4) is a member of the CYP family and is an important enzyme in drug metabolism. A compound that inhibits CYP3A4 activity could also affect the pharmacokinetics of other substrates, resulting in drug–drug interactions (DDIs) that could cause side effects. Pharmacokinetic data from drug-development studies in rats often determine the dosage used in human clinical trials. It is therefore useful to understand differences in metabolism in different species at an early stage in drug development. Human and rat CYP3A enzymes show different inhibition profiles with different drugs, although the mechanisms involved are not yet clear. Here we built three-dimensional quantitative structure–activity relationship (3D-QSAR) models using structure-based comparative molecular field analysis (CoMFA), to predict the direct inhibitory activity of ligands for human CYP3A4 and rat CYP3A1, based on computer-ligand docking. The alignment of the ligand docking poses suggested that key amino acid–ligand interactions (e.g., Thr309 in CYP3A4 and Pro310 in CYP3A1) characterized the different potencies with which the ligands inhibited CYP3A4 and CYP3A1. The 3D-QSAR models for human and rat CYP3A family inhibitors predicted the potency of inhibitors and could be useful for assessing DDIs at an early stage in drug discovery.

The authors evaluated elements of the coagulation and fibrinolytic systems in 18 male patients with intermittent claudication vs 19 men matched for risk factors who served as controls. Prothrombin time and activated partial thromboplastin time did not significantly differ in the patients and the controls. The plasminogen level in the two groups was not significantly different. The level of lipoprotein(a) was significantly higher in the patients than in the controls. The levels of antigen and the activity of protein C did not differ significantly between the two groups. The thrombomodulin level was significantly higher in the patients than in the controls. There were no significant differences between the two groups in the levels of α2-macroglobulin, C1-inactivator, or antithrombin III. The levels of fibrinogen and α-antitrypsin were significantly higher in the patients vs the controls. Significantly lower levels of α2-plasmin inhibitor and higher levels of α2-plasmin inhibitor/plasmin complex and thrombin/antithrombin III complex were found in the patients vs the controls. These findings suggest that the levels of thrombin/antithrombin III complex, α2- plasmin inhibitor/plasmin complex, and thrombomodulin may perhaps serve as indica tors for injury to the peripheral endothelium and that the coagulation and fibrinolytic systems may be activated in patients with intermittent claudication.

We evaluated left anterior descending coronary artery stenosis by transesophageal echocardiography using the acute hemodynamic effects produced by administration of nitroglycerin (NTG) spray in 11 patients with stenosis and 8 subjects without stenosis (normal group). Before administration of NTG, there were no differences in systolic and diastolic blood pressure, heart rate, the diameter of the left main trunk, systolic flow velocity (SFV), diastolic flow velocity (DFV), or the ratio of diastolic flow velocity to systolic flow velocity (DFV:SFV) between the normal and stenosis groups. NTG administration significantly reduced systolic and diastolic blood pressures and significantly increased heart rate and the diameter of the left main trunk in each group. The increase in diameter of the left main trunk was significantly greater in the normal group compared with the stenosis group, despite the lack of significant differences in NTG-induced changes in blood pressure and heart rate between the two groups. NTG significantly increased peak SFV and DFV in both groups. The average NTG-induced change in SFV was similar in both groups, but the increase in DFV was significantly greater in the stenosis group compared with the normal group. Consequently, the DFV:SFV decreased significantly after NTG administration in the normal group but not in the stenosis group. The change in DFV:SFV was significantly different between the two groups. Our results suggest that NTG spray is potentially useful for enhancing the diagnostic utility of transesophageal echocardiography for stenosis of the left descending coronary artery.

The association of the severity of coronary atherosclerosis with hypertension and dyslipidemia, independent of other known coronary risk factors, was examined in 313 men and 155 women who underwent coronary angiography. The severity of coronary atherosclerosis was quantified using Gensini's scoring system. The following criteria were used to define dyslipidemia : hypercholesterolemia (total serum cholesterol concentration ≥220 mg/dl), hypertriglyceridemia (serum triglyceride concentration ≥150 mg/dl), and low HDL-cholesterolemia (serum HDL-cholesterol concentration

We studied the relationship of cigarette smoking to the severity of coronary and thoracic aortic atherosclerosis in 116 men who received coronary angiography and transesophageal echocardiography. Severity of coronary atherosclerosis was assessed in terms of Gensini's score (GS), and that of thoracic aortic atherosclerosis was assessed by the average sclerotic length (ASL) and average sclerotic area (ASA). The plasma fibrinogen levels were significantly positively correlated with smoking, and fasting blood sugar levels tended to be positively associated with smoking. GS was inversely associated with serum levels of high density lipoprotein (HDL) cholesterol. ASL and ASA were positively associated with age, fasting blood sugar levels and plasma fibrinogen levels, and these associations were statistically significant. Analysis of covariance was used to examine the net association between cigarette smoking and GS, ASL or ASA controlling for age, total cholesterol, HDL cholesterol, fasting blood sugar and plasma fibrinogen. We found that GS, ASL, and ASA were all significantly increased with increasing number of cigarette years. Additional adjustment for other risk factors (triglyceride, uric acid, body mass index, alcohol use and hypertension) also showed a strong independent contribution of smoking to GS, ASL and ASA. We concluded that the cumulative exposure to cigarette smoking was an independent indicator of the severity of coronary atherosclerosis as well as thoracic aortic atherosclerosis.

Toshio Sano1, Toshihiro Yoshihara1, Koichi Handa2, Masa H. Sato3, Toshiyuki Nagata1 and Seiichiro Hasezawa2,4 1Faculty of Bioscience and Applied Chemistry, Hosei University 2Graduate School of Frontier Sciences, The University of Tokyo 3Graduate School of Life and Environmental Sciences, Kyoto Prefectural University 4Advanced Measurement and Analysis, Japan Science and Technology Agency (JST) Japan

We examined activities or levels of plasmin and thrombin inhibitors in essentially untreated patients with angiographically documented coronary artery spasm. The patients received the ergonovine malate provocation test and were classified into two groups: (a) those with significant coronary artery spasm that produced reduction of the internal luminal diameter of 50% or greater with chest pain and change of electrocardiography ( n = 18), and (b) those without coronary artery spasm ( n = 17). There was no significant differences in α 1 -antitrypsin and α 2 -macroglobulin levels, and C 1 -inactivator activity between the control and patients with coronary artery spasm. On the other hand, the lower antithrombin III and α 2 -plasmin inhibitor activities were noted in patients with coronary artery spasm than the control. Thrombin/antithrombin III complex and α 2 -plasmin inhibitor/plasmin complex levels were significantly higher in coronary artery spasm patients. These results suggest that the coagulation and fibrinolytic systems may maintain their equilibrium in untreated patients with coronary artery spasm.

A placebo-controlled, double-blind crossover study was undertaken in 10 normal subjects to examine the effects of arotinolol (10 mg bid), a nonselective beta blocker with alpha-blocking activity, on exercise capacity and hormone levels during exercise after a 2-week treatment period. Maximal oxygen uptake (VO2 max) and blood lactic acid concentration (LA) were measured during progressive exercise testing. An exercise intensity equivalent to 4 mmol/l of LA was used for the constant workload exercise test. Humoral factors were measured after 20 minutes of constant workload exercise. The administration of arotinolol significantly decreased systolic blood pressure and heart rate at rest and during exercise, but diastolic blood pressure did not change. No significant difference was found between arotinolol and placebo with regard to VO2 max and maximal workload. Plasma renin activity (PRA), aldosterone (PAC), and norepinephrine (NE) levels at rest and during exercise did not differ between the two treatments. In contrast, plasma epinephrine (EN) levels at rest and during exercise were significantly greater with arotinolol. Atrial natriuretic peptide (ANP) at rest did not differ between the two treatments. However, exercise caused a significant increase in ANP after arotinolol treatment. These findings suggest that arotinolol decreases blood pressure and heart rate without affecting exercise capacity.

Thirty-three consecutive unselected patients with primary hypercholesterolemia received niceritrol 1.5 g daily for 12 weeks, with the effect of administering divided dose (twice daily (b.i.d.) and three times daily (t.i.d.)) evaluated. The serum concentrations of lipoprotein(a) (Lp(a)), lipids, the major apolipoproteins (apo), cholesteryl ester transfer activity and fibrinogen were determined before and after treatment. The b.i.d. and t.i.d. regimens each significantly reduced the serum levels of total cholesterol and triglyceride. The mean changes in serum lipids and lipoproteins did not differ significantly between the two groups. After 12 weeks of treatment, there was a significant decrease in total plasma cholesterol, triglyceride, low density lipoprotein cholesterol, apo A-II, apo B and fibrinogen and an increase in the high density lipoprotein cholesterol levels. Although the serum level of Lp(a) did not change in every patient, niceritrol significantly reduced the serum Lp(a) level in those with an initially high level of Lp(a) (greater than or equal to 20 mg/dl).

In a double-blind crossover study of 10 normal healthy subjects, we examined the effects of slow-release nifedipine (nifedipine-SR, 10 mg b.i.d) administration on exercise capacity, hormone levels during exercise, and quality of life (QOL) after a 2-week treatment. Two exercise tests, a progressive exercise test and a constant work-rate exercise test, were performed. Maximal oxygen uptake (VO2max) and blood lactate concentration were measured during the progressive exercise test and the exercise intensity corresponding to half lactate threshold (LT), LT, and 4 mmol/l of lactate concentration was determined. Subjects underwent 20 minutes of constant work-rate exercise at each work load, and blood lactate, plasma epinephrine, plasma norepinephrine, plasma renin activity, plasma aldosterone, atrial natriuretic peptide, plasma beta-endorphin, and met-enkephalin were measured. Taking nifedipine-SR had no effect on the responses of blood pressure, heart rate, VO2max, maximal work load, and LT compared to taking placebo. Blood lactate, plasma catecholamine, plasma renin activity, aldosterone, atrial natriuretic peptide, and beta-endorphin levels increased during exercise, and there was no difference between nifedipine-SR and placebo. Met-enkephalin did not increase with either treatment. In the QOL questionnaires, no differences were noted between the two treatments. These findings suggest nifedipine-SR to be a potentially useful drug in view of the lack of effect on exercise capacity, hormone release, and QOL.

In a placebo-controlled, randomized, crossover, double-blind study of 17 normal volunteers, we examined the effects of captopril on the concentration of opioid peptides during bicycle exercise and on quality of life after a 2-week treatment period. Two exercise tests (progressive exercise and constant work rate exercise) were performed. Maximum oxygen uptake and blood lactata concentrations were measured in progressive exercise tests. The exercise intensities corresponding to a 12 lactate threshold, a lactate threshold, and a 4 mmol/L lactate concentration were determined. Constant work rate exercise at selected work loads for 20 minutes was carried out to measure the concentrations of opioid peptides and other hormones. Quality of life was assessed after the 2-week treatment period. Captopril treatment had no effect on the exercise response of blood pressure, heart rate, maximum VO 2 , and maximum work loads. The plasma concentrations of lactate, epinephrine, norepinephrine, and aldosterone increased during exercise and captopril did not change them. β-Endorphin levels and plasma renin activity also increased during exercise, and the increases were greater with captopril treatment. Met-enkephalin and leu-enkephalin concentrations did not increase during exercise. According to responses in the quality of life questionnaires, administration of captopril improved the physiologic state more than the placebo did. These findings suggest that captopril may act on the central nervous system involving an increase in the β-endorphin level.

The relationship between cigarette smoking and blood pressure and serum lipids was studied in 1775 men aged 20-59 years, in non-drinkers and drinkers separately, controlling for body mass index and physical fitness (VO2max). While systolic blood pressure was not associated with cigarette smoking, diastolic blood pressure decreased with increasing levels of cigarette smoking in non-drinkers but not in drinkers. Total cholesterol was inversely associated with smoking cigarettes in drinkers and was not associated in non-drinkers. High density lipoprotein (HDL)-cholesterol decreased with an increasing degree of cigarette consumption in non-drinkers but not in drinkers. An increase in total cholesterol/HDL-cholesterol ratio and triglyceride levels was positively associated with smoking cigarettes regardless of drinking habit. The present study suggests that cigarette smoking is a cardiovascular risk factor, partly due to its effect of increasing the atherogenic index, but it remains to be consolidated whether chronic smoking has an effect of lowering diastolic blood pressure.

Glutathione S-transferases (GSTs) are a superfamily of detoxification enzymes that may play an important role in human carcinogenesis. While the genetic polymorphisms GSTM1 and GSTT1 have drawn particular interest in relation to cancer susceptibility, previous studies of colorectal cancer are inconsistent regarding their role. We examined the relation between GSTM1 and GSTT1 genotypes combined and colorectal adenomas, and the interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in Japanese men. Neither GSTM1 nor GSTT1 was related to colorectal adenomas, nor were the null genotypes of GSTM1 and GSTT1 combined. The lack of an association with GSTM1 and GSTT1 genotypes combined persisted even when the analysis was done separately for proximal and distal colorectal adenomas. A three- to fivefold significant increase in the odds of colorectal adenomas was observed among men with a high exposure to cigarette smoking across the genotype groups, and a statistically significant increasing trend was noted within each genotype group. The present findings do not support the role for GSTM1 and GSTT1 genotypes in the development of colorectal adenomas.

Acute pulmonary thromboembolism is a life-threatening disease and in almost all cases originates from deep venous thrombosis in the proximal deep venous system of the legs. In order to prevent further episodes of thromboembolism in 2 patients with acute pulmonary thromboembolism, we inserted an Antheor temporary vena cava filter after catheter-directed fragmentation and thrombolysis. No complications occurred during the insertion of the filters and our results suggest that this filter device may be clinically safe and effective for temporary protection against pulmonary thromboembolism. (Jpn Circ J 1998; 62: 462 - 464)

Losartan, an angiotensin II receptor antagonist with no bradykinin potentiating property, provides the opportunity to study the consequences of blocking angiotensin II. The objective of this study was to evaluate the antiarrhythmic responses of reperfusion arrhythmia to losartan in dogs. The effects of losartan on ventricular tachyarrhythmias induced during occlusion and reperfusion of the left anterior descending coronary artery were investigated in 30 dogs. The animals were randomized to receive either losartan (n = 15) or saline (n = 15). The VF inducing threshold was measured before occlusion and after reperfusion. Losartan (50 micrograms/kg per min) or saline was intravenously administered 5 minutes before occlusion and continued throughout the entire study period. The incidence of ventricular tachyarrhythmias during reperfusion was lower in the losartan group than in the control group (4/15 vs 6/15). There was no significant change in VF inducing threshold between the period before occlusion and during reperfusion in the losartan group [10.9 +/- 5.7 vs 11.1 +/- 5.7 mA, P = NS), whereas there was a significant decrease in the control group (15.5 +/- 4.4 vs 7.7 +/- 3.9 mA, P < 0.01). Blockade of the angiotensin II receptor has beneficial effects on reperfusion arrhythmias.

In contrast to the hypothesis that endogenous testosterone decreases plasma high-density lipoprotein (HDL) cholesterol levels, many, but not all, studies have reported a positive correlation between plasma total testosterone and HDL cholesterol. We examined behavioral correlates of plasma testosterone and estradiol and the relationships between these sex hormones and plasma lipoproteins, in middle-aged Japanese men. Plasma, lipids, including HDL subfractions, total and free testosterone, and total estradiol were determined with 313 men aged 50–54 years who received a preretirement health examination at the Self-Defence Forces Fukuoka Hospital from January to June in 1992. Body mass index and waist-hip ratio were also measured. Smoking habit, alcohol use, and physical activity were ascertained by a self-administered questionnaire. Obesity, especially waist-hip ratio, was a strong correlate of both total and free testosterone, but not of estradiol. Smoking was associated with elevated levels of testosterone without a dose-effect relation. Neither alcohol use nor physical activity was associated with total or free testosterone, but plasma estradiol levels were higher among current alcohol drinkers. HDL and HDL 2 cholesterol were unrelated to either total or free testosterone in the univariate analysis, but negatively associated with free, not total, testosterone after adjustment for obesity. HDL and HDL 2 cholesterol also were positively associated with estradiol regardless of adjustment for obesity and other covariates. These findings add to evidence for a hypothesis that high levels of endogenous testosterone and low estradiol levels may cause a decrease in plasma HDL cholesterol, thereby being linked with atherosclerosis in middle aged men.

The relation of serum glycoproteins and C-reactive protein (CRP) to severity of coronary atherosclerosis was examined in 133 men and 92 women undergoing coronary angiography. The following serum glycoproteins were determined: alpha 1-antitrypsin, alpha 1-acid glycoprotein, alpha 2-macroglobulin, ceruloplasmin, haptoglobin, fibrinogen, C4b binding protein, and lipoprotein (a) [Lp(a)]. Sex- and age-adjusted levels of alpha 1-antitrypsin, alpha 1-acid glycoproteins, alpha 2-macroglobulin, ceruloplasmin, Lp(a) and CRP were significantly associated with the severity of coronary atherosclerosis as determined by the Gensini score; these associations remained significant even after adjustment for body-mass index, smoking history, hypertension, and total cholesterol, except for Lp(a) (p = 0.075). These findings suggest that certain serum glycoproteins and CRP can serve as independent indicators for the progression of coronary atherosclerosis.

We describe a method for the rapid and non-radioactive examination of DNA samples for a mutation of cholesteryl ester transfer protein using a polymerase chain reaction-mediated site-directed mutagenesis. CETP deficiencies were studied in 554 Japanese subjects (370 men, 184 women) aged between 18 and 91 (mean 48.3 years). By this method, we detected one homozygote and 3 heterozygotes of the CETP deficiency.

The effects of nicorandil and diltiazem on serum lipid, apolipoprotein, and lipoprotein levels in 37 patients with ischemic heart disease were examined in a randomized, multicenter study. Nicorandil (n = 20, 10-40 mg/day, b.i.d.) and diltiazem (n = 17, 60-240 mg/day, b.i.d.) were administered for 12 weeks. Both nicorandil and diltiazem administration showed an effective antianginal effect. Diltiazem administration showed a significant hypotensive action. There were no significant changes in serum lipids, apolipoproteins, and lipoproteins for both nicorandil and diltiazem. There were no significant changes in body weight, uric acid, and fasting blood sugar levels during the test period for both drugs. These data show that nicorandil, like diltiazem, does not have any adverse effects on lipid metabolism and that it is a favorable drug to use as an agent for treating arteriosclerotic heart disease.

The relation between alcohol and nonfatal acute myocardial infarction (AMI) was examined in a case-control study of 89 male patients and 271 control subjects in Fukuoka, Japan. Patients admitted for the first AMI at 2 hospitals in Fukuoka City were aged 40 to 69 years, and control subjects were recruited based on the telephone directory of the city. Information on alcohol drinking and potential coronary risk factors was obtained by using a self-administered questionnaire, and past drinkers were separated from lifelong abstainers in the analysis. After adjustment for age, occupation, cigarette smoking, strenuous exercise, body mass index, hypertension, diabetes mellitus and parental heart disease, the risk of AMI was progressively less with increasing levels of alcohol consumption. With those who never drank as a referent, adjusted odds ratios for current drinkers consuming less than 30, 30 to 59, and greater than or equal to 60 ml/day of alcohol were 1.11 (95% confidence interval 0.51 to 2.42), 0.31 (0.11 to 0.83), and 0.13 (0.05 to 0.36), respectively. These findings add to the body of data showing that alcohol drinkers are less likely to have AMI.

The relation of alcohol consumption to serum lipids and the severity of coronary atherosclerosis was examined in 212 men undergoing coronary angiography. The severity of coronary atherosclerosis was assessed in terms of the presence of greater than or equal to 75% diameter stenosis and the Gensini severity score. Alcohol consumption was divided into 4 categories: none (0 ml alcohol/week), light (1 to 100 ml alcohol/week), moderate (101 to 300 ml alcohol/week) and heavy (greater than or equal to 301 ml alcohol/week). Alcohol consumption was positively related to high-density lipoprotein cholesterol and inversely related to total cholesterol, but was not associated with triglyceride. After adjustment for these serum lipids as well as for cigarette smoking and systemic hypertension, the risk of coronary stenosis was significantly decreased in the moderate drinkers. A decreased risk among moderate drinkers also was noted in terms of Gensini's severity score. These findings suggest that moderate alcohol consumption may protect against severe coronary atherosclerosis.

The thermal reactions of methoxy- and ethoxycycloheptatrienes at several temperatures from 300 to 800°C were studied. 7-Alkoxycycloheptatriene (1) isomerized to the 1-isomer (3) at 450°C in quantitative yield, and rearranged to aromatic compounds (5–8) at temperatures higher than 450°C. These findings were not consistent with the observation of Harrison et al. that the dissociation of the O–CH3 bond in la occurred at 400°C to give the hydroxytropylium radical (11).

Acute pulmonary thromboembolism frequently occurs in patients on pro tracted bed rest and by itself can cause acute right ventricular failure. The authors report findings in a patient with this disorder treated successfully by balloon angioplasty.

Higher plants respond to environmental stresses by a sequence of reactions which include the reduction of growth by affecting cell division. It has been shown that calcium ions plays a role as a second messenger in mediating various defence responses under environmental stresses. In this study, the role of calcium ions on cell cycle progression under abiotic stresses has been examined in tobacco BY-2 suspension culture cells. Using synchronized BY-2 cells expressing the endogenous calcium sensor aequorin as experimental system, we could show that oxidative and hypoosmotic stress both induce an increase of intracellular calcium and cause a delay of the cell cycle. The inhibitory effect of these abiotic stress stimuli on cell cycle progression could be mimicked by increasing the intracellular calcium concentration via application of an external electrical field. Likewise, depletion of calcium ions in the culture medium suppressed the effect of the stimuli tested. These results demonstrate that calcium signalling is involved in the regulation of cell cycle progression in response to abiotic stress.

The relationship between plasma fibrinogen levels and the severity of coronary atherosclerosis was examined in 229 patients, aged 25–82 years (162 men and 67 women), undergoing coronary angiography. Severity of coronary atherosclerosis was assessed in terms of the number of vessels with a 75% or greater stenosis and Gensini's severity score. Fibrinogen levels increased progressively with the severity of coronary atherosclerosis, determined by both the number of involved vessels and Gensini's severity score in men, and the relationships were statistically significant. Similar patterns were noted among women, but the trends were not statistically significant. The association was evident even after adjustment for age, hypertension, total cholesterol, cigarette smoking, alcohol intake, high density lipoprotein cholesterol and body mass index. These results provide evidence that in the Japanese also plasma fibrinogen levels can serve as an independent indicator of the progression of coronary atherosclerosis.