Po-Huang Chyou

Helicobacter pylori Infection and Gastric Carcinoma among Japanese Americans in Hawaii

BACKGROUND Helicobacter pylori are gram-negative spiral bacteria that are associated with chronic gastritis, a known precursor of gastric carcinoma. Persons at high risk for gastric carcinoma have been shown to have a high prevalence of H. pylori infection. METHODS We studied the relation of H. pylori infection and gastric carcinoma in a cohort of Japanese American men living in Hawaii. The 5908 men were enrolled and examined from 1967 to 1970. By 1989, 109 cases of pathologically confirmed gastric carcinoma had been identified. The store serum of each patient with gastric carcinoma and of each matched control subject were tested for the presence of serum IgG antibody to H. pylori. RESULTS Ninety-four percent of the men with gastric carcinoma and 76 percent of the matched control subjects had a positive test for H. pylori antibodies, for an odds ratio of 6.0 (95 percent confidence interval, 2.1 to 17.3). As the level of antibody to H. pylori increased, there was a progressive increase in the risk of gastric carcinoma (P for trend = 0.0009). The association was strong even for men in whom the diagnosis was made 10 or more years after the serum sample was obtained (odds ratio, 10.5; 95 percent confidence interval, 2.5 to 44.8). CONCLUSIONS Infection with H. pylori is strongly associated with an increased risk of gastric carcinoma. However, most persons infected with H. pylori will never have gastric carcinoma. Therefore, other factors that increase the risk of gastric carcinoma among persons infected with H. pylori need to be identified.

Helicobacter pylori Infection and the Risk for Duodenal and Gastric Ulceration

Infection with Helicobacter pylori probably increases the risk for developing duodenal and gastric ulcer disease. Previous studies have shown that 75% to 100% of patients with duodenal ulcer and 35% to 86% of patients with gastric ulcer have evidence of an H. pylori infection [1]. The finding that eradication of H. pylori in patients with duodenal ulcer is associated with a statistically significant decrease in the recurrence rate of the disease further supports the association [2-5]. However, these observations may just reflect the frequent coexistence of duodenal ulcer with antral gastritis [6], which has been shown to be caused by H. pylori [7, 8]. Wormsley [9] has noted that the Henle-Koch postulates have not been satisfied for causation of duodenal ulcer by H. pylori because the organism has not been shown to produce the disease. The evidence is weaker that H. pylori causes gastric ulcer because only a single study with 26 patients has shown that antimicrobial therapy directed against H. pylori decreased the gastric ulcer recurrence rate [5]. None of the previous studies evaluated patients with duodenal or gastric ulcers before they were diagnosed or hospitalized with their disease. The usual temporal sequence is that patients with peptic ulcer disease are examined to detect H. pylori infection at the time the diagnosis is made or after they have had treatment to eradicate the organism. Consequently, peptic ulceration could possibly predispose persons to colonization by H. pylori [9]. We did a prospective study in a large population-based cohort using serum specimens that were obtained from study participants before they were diagnosed with peptic ulcer. We tried to determine whether H. pylori infection, as shown by the presence of specific IgG antibodies, is a risk factor for the subsequent development of either duodenal or gastric ulceration. Methods Study Population Japanese-American men born from 1900 to 1919, who were identified by the Honolulu Heart Program in 1965 by using the comprehensive 1942 Selective Service draft registration files [10], composed the study population. Of 11 148 eligible men, 8006 (72%) were interviewed and examined from 1965 to 1968, 180 (2%) died before they could be examined, and 2962 (26%) did not participate in the program. Study participants ranged in age from 45 to 68 years. The data collected included birthplace, marital status, history of alcohol use, blood pressure, and body mass index (the weight in kilograms divided by the square of the height in meters). Serum cholesterol values were determined by the Auto Analyzer N-24A method, and serum glucose values were determined by the Auto Analyzer N-2B method 1 hour after a 50-g glucose load had been given [11]. A total of 7498 (94%) men returned for a second examination between 1967 and 1970, and a serum specimen was obtained at this time. Serum specimens for a 20% random sample of the men were sent to the U.S. Public Health Service Hospital in San Francisco, whereas specimens for the remaining 5924 men were stored at 20C at the study site. Four hundred eighty-one patients with previous gastrectomy or a previous diagnosis of peptic ulcer disease were excluded from the study. The average age of the remaining 5443 patients at the time of their second examination was 56.6 years. Surveillance Methods Surveillance of the cohort to identify incident patients with peptic ulcer was done by a continuous review of discharge records of all general hospitals on Oahu. Based on a 19-year follow-up survey of the study patients from the time of their examination in 1965 to 1968, only 1.3% of the men could not be located on Oahu. Thus, surveillance was nearly complete. Two hundred fifty-eight patients were hospitalized with peptic ulcer disease from 1968 to 1989. One hundred sixty (62%) patients had their diagnosis confirmed by examination of tissue obtained by either surgery or biopsy, 36 (14%) were diagnosed by radiologic examination, and 62 (24%) were clinically diagnosed based on the endoscopic or surgical report of the presence of an ulcer. One hundred sixty-nine incident patients had gastric ulcer, 73 had duodenal ulcer, and 16 had gastric and duodenal ulcers. Seventeen of the 169 patients with gastric ulcer, 6 of the 73 patients with duodenal ulcer, and 2 of the 16 patients with gastric and duodenal ulcers were removed from study because they had an insufficient amount of serum in the freezer repository. Selection of Controls Each of the remaining patients was matched with one control from the study cohort based on age at examination (47 to 70 years) and date of serum collection. If a potential control had a diagnosis of gastric cancer before or after the serum was obtained, he was excluded from the study. As a consequence, 160 patients (3.1%) were removed from the control pool of 5185 men because of the reported association between H. pylori infection and gastric cancer [12, 13]. Of the remaining 5025 men, 336 (6.7%) were excluded because they previously had cardiovascular disease or other cancer, and 1532 (30.5%) were excluded because they were diagnosed with cardiovascular disease or other cancer after their serum collection. This exclusion was done because the serum specimens from these patients are going to be used for other studies. A total of 3157 patients remained in the pool of controls from which 233 (7.4%) were matched to incident case-patients with peptic ulcer. Each control participant was alive at the time of hospitalization of the matched case-patient, so that death was not a competing factor. Serologic Testing The presence of serum IgG antibodies to H. pylori was determined by enzyme-linked immunosorbent assay (ELISA), using the Pyloristat kit (Whittaker Bioproducts, Inc., Walkersville, Maryland). As validated by the manufacturer, the results of this assay closely mirror those of a previously described IgG ELISA [13-18]. In brief, serum specimens from patients were diluted 1:20 for use in the kit, and IgG levels of sera were determined according to the manufacturers instructions. The serum specimens were coded so that the laboratory technician could not distinguish case-patients from controls. A ratio of 1.00 or greater was considered positive, a ratio of less than 0.80 was considered negative, and a ratio of 0.80 to 0.99 was considered equivocal, as calibrated in the kit. Two patients with gastric ulcer and two patients with duodenal ulcer or their controls had equivocal values, so they were excluded from the study. Statistical Analysis A matched casecontrol study design was used to identify the patients and controls for serum tests. As a result, odds ratios, based on the results of the H. pylori IgG antibody test, were determined using conditional logistic regression methods [19]. When odds ratios were indeterminable, approximate confidence intervals (CIs) were determined by the method of Breslow and Day [19]. Tests for trend in the logit of risk were derived from conditional logistic regression models by using grouped H. pylori test results (coded as 1, 2, 3, and 4). All conditional logistic regression models were fitted using iterative maximum likelihood methods and a special application of the proportional hazards regression model [20]. Results The characteristics of the 229 patients with peptic ulcer and of their matched controls are presented in Table 1. The two groups of men were similar with respect to demographic characteristics and laboratory values. Table 1. Characteristics of Patients with Peptic Ulcer and of Controls The mean age at diagnosis was 67.5 years (range, 52.7 to 87.2 years) for the 150 patients with gastric ulcer, 64.5 years (49.4 to 80.0 years) for the 65 patients with duodenal ulcer, and 63.5 years (52.4 to 83.1 years) for the 14 patients with gastric and duodenal ulcers. Table 2 shows the association between the H. pylori test result and peptic ulcer by specific type. Ninety-three percent (139 of 150) of the patients with gastric ulcer and 78% (117 of 150) of the matched controls had a positive H. pylori-specific IgG antibody level, yielding an odds ratio of 3.2 (P = 0.001). (The odds ratio is determined by dividing 32 pairs by 10 -/+ pairs.) Ninety-two percent of the case-patients with duodenal ulcer and 78% of the matched controls had a positive test result, yielding an odds ratio of 4.0 (P = 0.03). If a patient had either a gastric or duodenal ulcer, then the odds ratio was 3.4 (P = 0.0001). Only 14 patients had both gastric and duodenal ulcers. The odds ratio was 1.3 (P > 0.2), based on these patients. Table 2. Odds Ratio for the Association between Helicobacter pylori Seropositivity and Type of Peptic Ulcer Because some of the hospitalized patients with peptic ulcer may have developed their ulcers after the use of adrenocorticosteroids or nonsteroidal anti-inflammatory drugs, we systematically reviewed the hospital records of the patients. A similar review could not be done for the controls because they were not hospitalized. We found that 18 of the 150 patients with gastric ulcer and 9 of the 65 patients with duodenal ulcer had taken these medications at the time of hospitalization. If these patients and their matched controls were excluded, the odds ratio would have been 3.3 (95% CI, 1.6 to 7.0) for gastric ulcer, 3.3 (CI, 0.9 to 12.1) for duodenal ulcer, and 3.3 (CI, 1.7 to 6.4) for either gastric or duodenal ulcer. Of the 215 patients with either gastric or duodenal ulcer, 100 also had a hospital-based diagnosis of cardiovascular disease or cancer. If these patients were excluded from the study, as were controls with these diseases, 115 patients with gastric or duodenal ulcer would have remained in the study. Ninety-four percent of these case-patients and 77% of their controls had a positive test result for H. pylori antibody. The odds ratio for peptic ulcer was 4.3 (CI, 1.8 to 10.5) in this group of patients. When the patients with gastric ulcer who had positive antibody resu

Fish Intake May Limit the Increase in Risk of Coronary Heart Disease Morbidity and Mortality Among Heavy Smokers The Honolulu Heart Program

BACKGROUND Research has shown that fish consumption limits damage to the lungs caused by cigarette smoking, possibly by the effects of fish on arachidonic acid metabolism. We explored this fish-smoking interaction using coronary heart disease (CHD) incidence and mortality as the outcome. METHODS AND RESULTS The Honolulu Heart Program began in 1965 to follow a cohort of 8006 Japanese-American men aged 45 to 65 years who lived on Oahu, Hawaii, in 1965. Fish intake was measured at baseline by use of a questionnaire. For current smokers at baseline (n = 3310) who reported low fish intake (< 2 times/wk), age-adjusted 23-year CHD mortality rates increased with the number of cigarettes smoked per day (2.3, 3.1, and 6.9 per 1000 person-years for men who smoked < 20, 20 to 30, and > 30 cigarettes/d, respectively; trend test P < .0001). Among current smokers whose fish intake was high (> or = 2 times/wk), CHD mortality rates showed no relation with cigarettes/d (3.7, 3.2, and 3.7 per 1000 person-years for the corresponding levels of smoking). A Cox proportional hazards model based on current smokers, adjusted for age, years in Japan, calories/d, alcohol intake, physical activity index, years smoked, hypertension, and serum cholesterol, blood glucose, and uric acid levels, was examined. In the high-smoking group, the risk factor-adjusted relative risk (RR) for CHD mortality among those with high fish intake was half that of those with low fish consumption (RR = 0.5, 95% confidence interval = 0.28 to 0.91). A Cox model that adjusted for similar risk factors confirmed a significant interaction of cigarettes/d and fish intake (P < .01) on CHD mortality. Analyses for CHD incidence showed similar results. CONCLUSIONS Despite the findings of this investigation, the public health message for smokers continues to be to stop smoking. However, an interaction between fish intake and cigarette smoking is biologically plausible and deserves further investigation. The study of this phenomenon may shed light on the biological mechanisms by which cigarette smoking leads to CHD.

A prospective study of colon and rectal cancer among Hawaii Japanese men

The goals of this study were to assess the association of diet, alcohol, smoking, and other life-style factors with the risk of colon and rectal cancer and to examine the differences in the risk factors associated with each cancer site. Information on diet, alcohol, smoking, and other life-style factors was obtained from 7945 Japanese-American men who were living in Hawaii and examined from 1965 through 1968. After 174,514 person-years of observation, 330 incident cases of colon cancer and 123 incident cases of rectal cancer were diagnosed by histology. The risk of both colon and rectal cancer increased with age, alcohol intake, and pack-years of cigarette smoking. For colon cancer, there was also a direct association with body mass index and heart rate, while an inverse association was observed with serum cholesterol, intake of monounsaturated fatty acid, and percentage of calories from fat. For rectal cancer, the risk decreased with an increase in the intake of carbohydrates as percentage of calories. These findings suggest that some of the risk factors for colon cancer are different from those for rectal cancer.

Clinical and Epidemiological Features of Early Lyme Disease and Human Granulocytic Ehrlichiosis in Wisconsin

To compare clinical features and assess risk factors for human granulocytic ehrlichiosis (HGE) and early Lyme disease, we enrolled patients in a case-control study during the 1996 and 1997 tick seasons. Clinical and demographic characteristics were assessed for patients with laboratory-confirmed cases of HGE or Lyme disease, and risk factors were compared with those of matched control subjects. We identified 83 persons with Lyme disease, 27 with HGE, and 11 with apparent coinfection. Unsuspected Ehrlichia infection was identified in 8 (13%) of 60 patients with Lyme disease. Patients with HGE were older and more likely to have fever, chills, or dyspnea than were those with Lyme disease only. Most patients with apparent coinfection did not have hematologic abnormalities. In the risk factor analysis, tickborne illness was independently associated with rural residence and camping. The clinical spectrum of HGE overlaps that of Lyme disease, and physicians in areas of endemicity should consider both diseases in treating patients with a compatible rash or febrile illness.

Prospective study of the association of alcohol with cancer of the upper aerodigestive tract and other sites.

The association of alcohol consumption with cancers of the upper aerodigestive tract, hepato-biliary-pancreatic system, urogenital organs (except for prostate), and lymphohematopoietic tissue was evaluated in a prospective study of 6,701 American men of Japanese ancestry living in Hawaii. Compared with cancer-free subjects, subjects who subsequently developed cancers of the upper aerodigestive tract (oral-pharynx, esophagus, and larynx), liver, biliary tract, and lymphohematopoietic tissue consumed significantly larger amounts of total alcohol-mainly in the form of beer. Subjects who developed oral-pharyngeal and esophageal cancer also consumed larger amounts of wine and spirits. Because the upper aerodigestive tract cancers were associated positively with cigarette smoking, age-adjusted relative risks (RR) were calculated, based on joint exposure to cigarette smoking and heavy alcohol intake (≥30 ml/day) in this population. A markedly increased risk was observed among subjects who were both heavy alcohol drinkers and smokers (RR=17.3, 95 percent confidence interval [CI]=6.7–44.2), compared with subjects who did not smoke and did not drink heavily. The risk for these cancers also was increased among heavy alcohol drinkers who were nonsmokers (RR=8.6, CI=2.1–36.0).

Cardiovascular Risk Factors and Hyalinization of Renal Arterioles at Autopsy The Honolulu Heart Program

Nephrosclerosis, commonly found in subjects with hypertension and diabetes, is marked by hyalinization of arterioles and fibroplasia of small arteries in the renal cortex. Cardiovascular risk factors that predicted subsequent hyalinization of renal arterioles at autopsy were identified, using data from the Honolulu Heart Program, a prospective epidemiological study of cardiovascular disease (CVD) in Japanese-American men. Among 8006 participants at baseline, 1381 died between 1965 and 1982; 285 of these had a protocol autopsy, and 150 had assessments of arteriolar hyalinization from renal tissue. Subjects were categorized into four groups on the basis of the number of hyalinized arterioles per square centimeter of renal tissue, and CVD risk factor levels and proportions were compared across these groups with the use of general linear models and logistic regression. Multivariate assessment using logistic regression demonstrated that diastolic blood pressure (DBP) and glucose level were positively associated and alcohol intake was negatively associated with an elevated degree of renal arteriolar hyalinization, independent of other CVD risk factors. The odds ratios for elevated hyalinization associated with a 10-mm Hg increase in DBP, a 20-mg/dL increase in glucose level, and a 30-mL/d increase in alcohol intake were 1.97 (95% confidence interval [CI] = 1.24-3.12), 1.23 (95% CI = 1.07-1.41), and 0.24 (95% CI = 0.11-0.55), respectively. Associations were similar when prevalent cases of CVD were excluded and when autopsy selection bias was taken into account. Renal arteriolar hyalinization was also more strongly associated with atherosclerosis in the larger cerebral vessels (Spearmans r = .59, P < .001) than in the coronary arteries (r = .16, P = .073) and aorta (r = .24, P = .022). Hyalinization was significantly related to cardiovascular-renal mortality, and this association was accounted for by other CVD risk factors. These findings suggest that blood pressure, glucose level, and alcohol intake are independent predictors of hyalinization in renal arterioles and that this type of renal vasculopathy may be a marker for atherosclerosis in other vascular regions, particularly the cerebral vessels. The protective association involving alcohol and the possibility that renal arteriolar hyalinization may be an indicator of cerebral atherosclerosis may warrant investigation in other populations.

Diarrhea Incidence and Farm-Related Risk Factors for Escherichia coli O157:H7 and Campylobacter jejuni Antibodies among Rural Children

Serum samples were obtained from 215 farm-resident children and 396 non-farm-resident children living in a defined rural Wisconsin population. Antibodies to Campylobacter jejuni and Escherichia coli O157:H7 lipopolysaccharide (O157 LPS) immunoglobulin G were measured, and the incidence of clinic visits for diarrheal illness was determined. Risk factors were assessed in a telephone interview. There were 363 children (59%) with C. jejuni antibodies (seropositive for >or=2 immunoglobulin classes) and 86 (14%) with O157 LPS antibodies. Increasing age and farm residence were independently associated with C. jejuni seropositivity by multivariate analysis. O157 LPS antibodies were independently associated with increasing age, female sex, manure contact, and sheep contact. The incidence of clinically recognized diarrhea was similar among children with and without antibodies to C. jejuni and O157 LPS, but the clinic visit rate for diarrhea was 46% lower among farm-resident children. These results are consistent with reduced occurrence of clinical illness from repeated antigenic stimulation in a farm environment.

Virulence Genes and Genotypic Associations in Nasal Carriage, Community-Associated Methicillin-Susceptible and Methicillin-Resistant USA400 Staphylococcus aureus Isolates

ABSTRACT It is not well understood why strains of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), a major cause of skin and soft tissue infections, became successful so quickly, overtaking the place of methicillin-sensitive S. aureus (MSSA) in many communities. To evaluate the genetic basis of differences in their virulence traits, 293 S. aureus isolates consisting of three cohorts, genotypically defined clinical CA-MRSA (n = 77), clinical MSSA (n = 103), and nasal carriage MSSA (n = 113), collected over a 19-year period in two Midwestern states in the United States, were (i) extensively genotyped and (ii) screened for 40 known virulence genes which included those for enterotoxins, leukocidins, hemolysins, and surface proteins and several newly identified putative toxin genes from the USA400 lineage of CA-MRSA. Genotypically, nasal carriage and clinical MSSA isolates were much more diverse than was the CA-MRSA group, which was found to be of USA400 lineage only. Virulence gene profiles of the three groups showed that CA-MRSA strains harbored significantly higher percentages (≥95%; P value, <0.05) of the sea, sec, sec4, seg2, seh, sek, sel, sel2, ear, ssl1, lpl10, lukSF-PV, lukD, lukE, and clfA genes than did the carriage and the clinical MSSA group (range, 0% to 58%). Genes of the enterotoxin gene cluster, seg, sei, sem, sen, and seo, were present in the clinical and carriage isolates but not in the CA-MRSA group. These results suggest that the presence of additional virulence factors in USA400 CA-MRSA strains compared to the nasal carriage and clinical MSSA strains probably contributed to their enhanced virulence.

Obesity, alcohol consumption, smoking, and mortality.

PURPOSE The goals of this study were to assess prospectively the impact of obesity, alcohol use, and smoking on total mortality and to test the etiologic hypothesis that subjects with two or more of these risk factors may experience an elevated risk of overall mortality. METHODS Information on body mass index (BMI), alcohol intake, cigarette smoking, and other life-style factors was obtained from a cohort of 8006 Japanese-American men living in Hawaii. They were between 45 and 68 years of age at the initial examination (1965-1968). After 22 years of follow-up that included nearly 159,000 person-years of observation, 2667 deaths from all causes were identified. RESULTS There was a significant quadratic (J-shaped) relation between BMI and overall mortality. A weaker J-shaped pattern in risk was also present for the intake of alcohol. A strong positive association was observed with pack-years of cigarette smoking. A synergistic interaction between BMI and alcohol was statistically significant (P = 0.0017). Specifically, men who had the lowest body mass (BMI < 21.21 kg/m2) and drank moderately to heavily (> or = 25 oz/mo) experienced a 63% excess risk (relative risk, 1.63; 95% confidence interval; 1.33 - 1.99) compared to a reference group composed of men who had intermediate body mass (BMI, 21.21 - 26.30 kg/m2) and drank occasionally to lightly (0.01 - 24.99 oz/mo). The increase in risk due to the interactive effect of low BMI and high alcohol intake was stronger (and statistically significant) than when each of these risk factors was considered separately (excess risk, 28% and 2%, respectively). There was no significant interaction for BMI and cigarette smoking, for alcohol and cigarette smoking, or for the three factors combined. CONCLUSIONS The most important finding of this study was that, in addition to confirming that cigarette smoking could shorten life, extreme (high or low) BMI values and high alcohol consumption are each potentially harmful to health, but even more so if moderate or heavy drinking is concomitant with low body mass, a possible indicator for low intake of nutrients.