Immunopathophysiological aspects of an emerging neonatal infectious disease induced by a bacterial superantigen.

We recently discovered an emerging neonatal infectious disease, neonatal toxic shock syndrome-like (TSS-like) exanthematous disease (NTED), which is induced by a superantigen, TSS toxin-1 (TSST-1), produced by methicillin-resistant Staphylococcus aureus (MRSA). Here, we analyzed the activation and the response of TSST-1-reactive Vss2(+) T cells in NTED patients during the acute and recovery phases and in asymptomatic infants exposed to MRSA. In the acute phase, Vss2(+) T cells were anergic to stimulation with TSST-1 and underwent marked expansion, but by 2 months after disease onset, their numbers had declined to about 10% of the control level. Although the percentage of Vss2(+) T cells in the ten asymptomatic neonatal MRSA carriers was within the control range, these individuals could be divided into two groups on the basis of Vss2(+) T-cell activation. Vss2(+)CD4(+) T cells from three of these infants (Group 1) highly expressed CD45RO and were anergic to TSST-1, whereas in the other seven asymptomatic neonatal MRSA carriers (Group 2), these cells expressed CD45RO at the control level and were highly responsive to stimulation with TSST-1. The serum anti-TSST-1 IgG Ab titer was negligible in the four NTED patients in the acute phase and the three asymptomatic neonatal MRSA carriers in Group 1, but it was high in the seven asymptomatic carriers in Group 2. We suggest that maternally derived anti-TSST-1 IgGs helps to suppress T-cell activation by TSST-1 and protects infants from developing NTED.

Inhibition of growth of human lung adenocarcinoma cell lines by anti-transforming growth factor-alpha monoclonal antibody.

We previously reported that two human lung adenocarcinoma cell lines (A-549 and PC-9) produce human transforming growth factor-alpha (hTGF-alpha) and express its receptors. In the present study an exogenously added monoclonal antibody against recombinant hTGF-alpha inhibited growth of these cell lines in vitro. This result indicated that endogenous hTGF-alpha produced by the cancer cells can function as an autocrine growth factor.

Effect of urine on clonal growth of human bladder cancer cell lines.

Human urine contains growth factors; their physiological roles have not been established. The effect of normal human urine was examined in vitro on clonal growth of human bladder cancer cell lines. Clonal growth of HT-1376, HT-1197, and T24 was enhanced by five different fresh human urine samples from young men. Colony stimulating activity was detected in fractions with a molecular weight greater than 5000 by ultrafiltration. Sephadex G-50 gel chromatography identified two peaks of colony stimulative activity in HT-1376 with molecular weights of approximately 6000 and greater than 12,400, respectively; these two peaks also possessed immunoreactive epidermal growth factor (EGF) and NRK-49F transforming activities. The three bladder cancer cell lines possessed large quantities of EGF specific binding sites and exogenous EGF stimulated colony formation; EGF concentrations in human urine were found to be remarkably higher than those of exogenously added EGF which stimulated clonal growth of bladder cancer cell lines. Moreover, it was demonstrated that fresh urine samples (5%) incubated with anti-human EGF monoclonal antibody (KEM-10) neutralized completely the colony stimulating effects in HT-1376. These results indicate that fresh human urine stimulates clonal growth in human bladder cancer cell lines and that a major part of the activity is represented by urinary EGF. The data promote urinary EGF as a progressive agent of human bladder cancer.

cDNA cloning of a mouse pituitary adenylate cyclase-activating polypeptide receptor.

A cDNA clone for mouse pituitary adenylate cyclase-activating polypeptide (PACAP) receptor (PACAP-R) was obtained from the brain using reverse transcription-polymerase chain reaction (RT-PCR). The recombinant PACAP receptor expressed in COS cells bound PACAP with about 1000-times higher affinity than vasoactive intestinal polypeptide (VIP), and PACAP stimulated adenylate cyclase through the cloned PACAP receptor. The mouse PACAP receptor consists of 496 amino acids, contains seven transmembrane segments and has 98.4%, 93.0%, and 92.5% identity with the rat, bovine, and human PACAP-R, respectively.

Fatherhood and distal adenomas of the large bowel: a study of male self-defense officials in Japan.

Parity has been studied extensively as a risk factor for colorectal cancer but has not been definitively shown to be associated with altered risk. In a few studies, risk of colorectal cancer in childless men has been compared to risk in men with children, but results have not been consistent. We analyzed the association of fatherhood with risk of colorectal adenomas in male self-defense officials (ages 49-55) in Japan. The study participants received a preretirement health examination including flexible sigmoidoscopy at Self-Defense Forces hospitals in Japan from January 1991 through December 1992. The examinations identified 265 cases with rectal or sigmoid adenomas and 1480 controls with normal examinations up to 60 cm from the anus. Data on marital status, number of children, long-term work assignment away from wife and children, and other lifestyle variables were obtained by means of a self-administered questionnaire prior to physical examination. Multiple logistic regression analysis assessed the risk of adenomas in relation to number of children, marital status, long-term work assignment away from family, and military rank, with adjustment for cigarette smoking, alcohol intake, dietary variables, body mass index, and recreational physical activity. In this relatively homogeneous group, more than 98% of both cases and controls were currently married, and more than 93% had children. The adjusted odds ratio for the association of adenomas with fatherhood was 0.4 (95% confidence interval, 0.2-0.8). Marital status and work assignment away from the family were not associated with adenoma risk. These findings suggest that colorectal adenomas and perhaps cancer risk may be associated with childlessness in men.

Behavioral correlates of plasma sex hormones and their relationships with plasma lipids and lipoproteins in Japanese men.

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 HDL2 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 HDL2 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.

Blue dextran-mediated hemagglutination.

Blue dextran at low concentrations (0.1-1 ng/ml) agglutinated human, mouse, rabbit and rat erythrocytes. This agglutination was inhibited by 10% calf serum, 0.5 mg/ml bovine albumin and 0.2 M sodium thiocyanate, and less effectively by 1.5 M potassium chloride, but not by 30-50 mM magnesium sulfate.

Activation of the beta-catenin gene by interstitial deletions involving exon 3 as an early event in colorectal tumorigenesis.

beta-Catenin has been identified as an oncogene in several tumors including colorectal cancers. beta-Catenin gene is activated by interstitial deletions involving exon 3 in colorectal carcinomas of Japanese population, in contrast to amino acid substitutions detected among Caucasian population. The aim of this study was to examine the type and frequency of beta-catenin gene mutation during early stages of colorectal tumorigenesis. We screened 100 colorectal adenomas for somatic mutations in the beta-catenin gene by single-strand conformation polymorphism method, as well as polymerase chain reaction amplification. In cases with mutations, sequencing analyses and immunohistochemical staining were also performed. Somatic interstitial deletions of 272-413 bp, each of which included all parts of exon 3, were detected in three tumors. However, no adenoma carried missense mutations. We confirmed accumulation of aberrant beta-catenin protein in cytoplasm and nuclei of adenoma cells by immunohistochemical analysis. Our results suggested that activation of the beta-catenin gene by interstitial deletions involving exon 3 might be less frequent compared with frequent alterations of adenomatous polyposis coli (APC) gene, but could be an early event in colorectal tumorigenesis equivalent to APC gene alterations in the Japanese population.

Lifestyle and glucose tolerance: a cross-sectional study of Japanese men.

The relationship of smoking, alcohol use, body mass index, and physical activity to glucose tolerance was studied in 2407 male self-defense officials aged 49-56 years who received a health examination before retirement at the Self-Defense Forces Fukuoka Hospital from October 1986 to December 1990. Body mass index (BMI) was significantly, positively related to impaired glucose tolerance (IGT) and noninsulin-dependent diabetes mellitus (NIDDM); after adjustment for rank of the Self-Defense Forces, smoking, alcohol use, prior diagnosis of diabetes mellitus, and parental history of the disease, odds ratios (ORs) of IGT and NIDDM for the highest (> or = 25.5 kg/m2) versus lowest (< 21.6 kg/m2) quintile of BMI were 4.2 [95% confidence interval (CI) 2.6-6.8] and 4.6 (95% CI 2.3-9.3), respectively. Cigarette smoking was weakly, positively associated with IGT and strongly so with NIDDM; adjusted ORs of IGT and NIDDM for 800 cigarette-years or more versus never smoking were 1.6 (95% CI 1.1-2.5) and 4.1 (95% CI 1.8-9.3), respectively. The prevalence of IGT and NIDDM tended to be decreased among men with high physical activity as measured by the time spent for vigorous exercise in leisure time. There was virtually no association between alcohol consumption and either IGT or NIDDM. The findings suggest that obesity and cigarette smoking are important factors in the development of glucose intolerance in middle-aged Japanese men.

Serum lipids and gallstone disease. A study of self-defense officials in Japan.

Based on screening ultrasonography of the gallbladder in 2756 men who received a retirement health examination at the Self-Defense Forces Fukuoka Hospital, Japan, during the period of 1986 to 1990, we compared serum lipid levels among 61 men with gallstones, 38 who had the gallbladder removed previously, and 2494 with a normal gallbladder. In univariate analysis, men having gallstones and those who had had a cholecystectomy had lower concentrations of total and low-density-lipoprotein (LDL) cholesterol than did control subjects, although the differences were not statistically significant. After adjustment for body mass index, smoking, alcohol use, and glucose tolerance, inverse associations of cholecystectomy with total and LDL cholesterol levels were more pronounced and statistically significant. There was no appreciable difference in high-density-lipoprotein (HDL) cholesterol and triglycerides between control subjects and men either with gallstones or after cholecystectomy. The present study did not support a positive relation between gallstones and serum triglyceride levels and an inverse one to HDL cholesterol, which have been reported elsewhere. The findings on total and LDL cholesterol are consistent with some, but not all recent studies.

Relationship of cigarette smoking, alcohol use, and dietary habits with sigmoid colon adenomas.

The relationship between cigarette smoking, alcohol use, and dietary factors and the risk of adenomas of the sigmoid colon was examined in male self-defense officials who received a preretirement health examination at three Self-Defense Forces hospitals in Japan. In the comparison between 228 patients with sigmoid adenomas and 1484 control subjects with normal colonoscopy findings (> or = 60 cm from the anus), a clear dose-response relationship was observed between cigarette smoking and risk of adenoma. After adjustment for rank, body mass index, alcohol use, and physical activity as well as for hospital and survey season, the odds ratios (and 95% confidence intervals (CIs)) for the categories of 0, 1 to 399, 400 to 799, and 800 or more cigarette-years were 1.0, 2.1 (1.2 to 3.5), 2.8 (1.8 to 4.3), and 3.5 (2.1 to 5.8), respectively. Current alcohol drinkers tended to have an increased risk, but without a dose-response relation. Among four types of alcoholic beverages (shochu, sake, beer, and whiskey), only whiskey showed a weak association with risk of adenoma. None of the 13 dietary items studied (including meat and rice consumption) was measurably associated with adenoma risk. The present findings provide additional evidence that cigarette smoking is a risk factor for colon adenomas. It is inconclusive regarding alcohol intake's association with adenoma risk.

Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan.

PURPOSE: To examine the effect of coffee drinking on serum gamma-glutamyltransferase (GGT) level in relation to alcohol drinking, smoking, and degree of obesity in middle-aged Japanese men. METHODS: From 1986 to 1994, a total of 7,637 male officials of the Self-Defense Forces of Japan aged 48-59 years received a preretirement health examination. Coffee drinking was ascertained by a self-administered questionnaire, and serum GGT level was measured. After excluding 1,360 men with a possible pathologic condition influencing liver enzyme levels and 182 former alcohol drinkers, effect of coffee drinking on serum GGT was examined by a multiple linear regression model and analysis of variance adjusting for alcohol drinking, smoking, and body mass index (BMI). RESULTS: The adjusted percentage of difference in serum GGT was -4.3 (95% CI = -5.0; -3.5) per cup of coffee. The inverse coffee-GGT relation was most prominent among men drinking > or = 30 ml of ethanol and smoking > or = 15 cigarettes daily; and positive associations of alcohol and smoking with GGT were attenuated by coffee drinking, more clearly among men with BMI > or = 25.00 kg/m2. Adjusted percentages of difference in serum GGT were -2.6% (p = 0.0003) per cup of brewed coffee, and -5.1% (p = 0.0001) per cup of instant coffee, independently of each other. CONCLUSIONS: The present study suggests that coffee consumption may weaken GGT-induction by alcohol, and possibly by smoking. These effect modifications by coffee may differ according to the degree of obesity.

Physical activity, dietary habits and adenomatous polyps of the sigmoid colon: a study of self-defense officials in Japan.

Physical activity and dietary habits were compared between 80 men with adenomatous polyps of the sigmoid colon and 1148 men with normal colonoscopy among male retiring self-defense officials. Physical activity as expressed in terms of time spent doing strenuous activities during leisure time was inversely related to the risk of adenomatous polyps. Controlling for rank, smoking, alcohol and body mass index (BMI), odds ratios for the categories of 0, 1-59, 60-119 and greater than or equal to 120 minutes per week were 1.0, 0.88, 0.70 and 0.44, respectively (trend p = 0.015). Among a limited range of foods and beverages, the consumption of rice, green tea and instant coffee tended to be associated with a decreased risk of adenomatous polyps. Although the associations observed with dietary habits still need to be substantiated, the findings on physical activity lend further evidence to the hypothesis that physical activity may be protective in the development of colon cancer.

Coffee consumption and serum aminotransferases in middle-aged Japanese men.

We investigated the relation between coffee drinking and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations among 7313 Japanese men receiving a health examination, excluding former alcohol drinkers and men with a history of chronic liver disease. Serum AST > 40 and/or ALT > 40 U/L was defined as liver inflammation. Adjustment was made for alcohol use, smoking, body mass index, serum marker for hepatitis virus infection, and other possible confounders. Adjusted odds ratios of liver inflammation were 1.00 (reference), 0.80, 0.69, and 0.61 for men drinking < 1, 1-2, 3-4, and > or = 5 cups of coffee daily, respectively. Among 6898 men without liver inflammation, serum AST and ALT were inversely associated with coffee consumption, and alcohol-related rise in AST was attenuated with coffee drinking. These findings suggest coffee may have an effect of suppressing the rise of serum aminotransferase, partly by inhibiting the alcohol-related elevation. Studies regarding biological mechanism are warranted.

Behavioural and biological correlates of serum uric acid: a study of self-defence officials in Japan.

BACKGROUND: In Japan epidemiological data on correlates of serum uric acid are sparse. METHODS: Behavioural and biological correlates of serum uric acid were investigated in 2487 men who received a retirement health examination at the Self-Defence Forces Fukuoka Hospital from October 1986 through 1990, excluding those under medication for hyperuricaemia, hypertension or hyperlipidaemia. RESULTS: Multiple regression analysis demonstrated that serum creatinine was the strongest correlate followed by serum triglycerides, body mass index and diastolic blood pressure; these four variables accounted for 16% of the overall variation in serum uric acid. Serum total cholesterol, alcohol intake and past smoking were positively associated with serum uric acid levels while diabetes mellitus and serum high density lipoprotein (HDL) cholesterol were negatively related to serum uric acid; these five variables additionally explained 2% of the variation. Although an independent impact was minimal, beer consumption was significantly associated with an elevated level of serum uric acid after allowing for the previously mentioned correlates. CONCLUSIONS: Serum creatinine and triglycerides are major correlates of serum uric acid in Japanese men. Our data add to the body of evidence suggesting that weight control, avoiding excessive drinking and adequate control of hypertension are beneficial in the prevention of hyperuricaemia.

Alcohol consumption and blood pressure: an extended study of self-defence officials in Japan.

BACKGROUND: It remains controversial whether the relation between alcohol intake and blood pressure is linear or non-linear. METHODS: The relation between alcohol intake and blood pressure was investigated in 2341 male self-defence officials who received a preretirement health examination at the Self-Defense Forces Fukuoka Hospital between October 1986 and December 1990. Average alcohol intake in the past year was ascertained by a self-administered questionnaire. The study excluded past drinkers, and allowed for smoking, body mass index and glucose tolerance. RESULTS: Blood pressure was higher at higher levels of alcohol intake across the range from 0 to 40-59 ml of alcohol per day, but was not progressively higher in men consuming > or = 60 ml per day. Blood pressure was significantly higher even among light drinkers (< 20 ml per day) compared to non-drinkers; adjusted mean differences were 3.1 mmHg (95% confidence interval (CI): 1.1-5.2) in systolic pressure and 2.1 mmHg (95% CI: 0.7-3.5) in diastolic pressure. CONCLUSIONS: Our findings do not support the existence of a threshold in the relation between alcohol and blood pressure.

Alcoholic beverages and adenomatous polyps of the sigmoid colon: a study of male self-defence officials in Japan.

The drinking habits of 86 men with adenomatous polyps of the sigmoid colon were compared to those of 1184 men with normal colonoscopy among middle-aged male self-defence officials. After adjustment for rank, smoking history and rice consumption, total ethanol intake was positively associated with the risk of adenomatous polyps. The odds ratio (OR) was 2.4 (95% confidence interval (CI) 1.0-5.5) for men consuming at least 60 ml of ethanol per day. Among five alcoholic beverages (shochu, beer, sake, whiskey and wine), both sake and beer showed a dose-response relationship with the risk of adenomatous polyps although the association with beer was less striking. Shochu was the largest source of ethanol intake in the study population, but there was virtually no association between shochu consumption and adenomatous polyps. Men drinking wine had a significantly increased risk, but these men were too few to examine the relation in detail. The findings suggest that the consumption of specific alcoholic beverages rather than ethanol itself is associated with an increased risk of adenomatous polyps of the sigmoid colon.

Physiological control of a total artificial heart: conductance- and arterial pressure-based control.

To obtain a physiological response by a total artificial heart (TAH), while eliminating the hemodynamic abnormalities commonly observed with its use, we proposed the use of a conductance- and arterial pressure-based method (1/R control) to determine TAH cardiac output. In this study, we endeavored to make use of a variable more closely tied to central nervous system (CNS) efferents, systemic conductance, to provide the CNS with more direct control over the output of the TAH. The control equation that calculates the target cardiac output of the TAH was constructed on the basis of measurement of blood pressures and TAH flow. The 1/R control method was tested in TAH-recipient goats with an automatic method by using a microcomputer. In 1/R control animals, the typical TAH pathologies, such as mild arterial hypertension and substantial systemic venous hypertension, did not occur. Cardiac output varied according to daily activity level and exercise in a manner similar to that observed in natural heart goats. These results indicate that we have determined a control method for the TAH that avoids hemodynamic abnormalities exhibited by other TAH control systems and that exhibits physiological responses to exercise and daily activities under the conditions tested. The stability of the control and the complete lack of inappropriate excursions in cardiac output is suggestive of CNS involvement in stabilizing the system.

Interleukin 1 alpha, tumor necrosis factor alpha, and interferon gamma in psoriasis.

Although recent studies have suggested that a variety of cytokines released by keratinocytes and inflammatory leukocytes could contribute to induction or persistence of the inflammatory processes in psoriasis, it remains unclear how production of these cytokines is regulated in psoriatic patients. To elucidate the biologic relevance of these cytokines to the pathogenesis of psoriasis, we investigated serum levels of interleukin 1 alpha, tumor necrosis factor alpha, and interferon gamma in 21 patients with psoriasis vulgaris, together with 21 healthy controls. The mean serum levels of interleukin 1 alpha and tumor necrosis factor alpha were not significantly different from those in controls, while those of interferon gamma were significantly elevated in the patients with psoriasis. Serum levels of interleukin 1 alpha correlated negatively with clinical disease severity expressed as psoriasis area and severity index score and with duration of psoriasis. In contrast, interferon gamma levels were related, although not significantly, to disease severity. In addition, an inverse correlation was noted between the interleukin 1 alpha levels and interferon gamma levels. These results indicate that interleukin 1 alpha and interferon gamma may be relevant to the induction and perpetuation, respectively, of the inflammatory responses in psoriasis, and that these cytokines, which have similar biologic properties, may strictly regulate one another's production in vivo.

Lifestyles, glucose tolerance and blood pressure in male self-defence officials in northern Kyushu, Japan.

Evidence on determinants of BP is mostly derived from studies in western populations. The relationship of BP with lifestyle variables and glucose tolerance was studied in 1,302 male self-defence officials aged 49-56 years who received a health examination before retirement at the Self-Defense Forces Fukuoka Hospital from October 1986 to December 1988. Those with treated hypertension or diabetes mellitus and those with conditions affecting BP levels were excluded from the study. In multiple regression analysis, alcohol use, body mass index and glucose intolerance were strongly associated with elevated BP while there was an inverse relation between cigarette smoking and BP. Physical activity expressed as the time spent in vigorous exercise was not associated with either systolic or diastolic BP. These findings indicate that alcohol use, obesity and glucose intolerance are also important determinants of BP in male Japanese, and that cigarette smoking is a potential covariate in the study of BP.