Diagnostic radiography and adult acute myeloid leukaemia: an interview and medical chart review study.

BACKGROUND: Aetiology of acute myeloid leukaemia (AML) is not well understood, perhaps because of its distinct subtypes. High-dose ionising radiation is a known risk factor, but less is known about risk from low-dose exposure such as from diagnostic radiography. METHODS: Subjects were 412 matched case-control pairs. Ten-year subject histories of diagnostic radiography were based on interview and medical records. RESULTS: There was no convincing association between AML risk and ionising radiation exposure from diagnostic imaging procedures, either for AML overall or for any AML subtype. CONCLUSION: The association between diagnostic radiography and AML risk remains uncertain.

A pooled analysis of extremely low-frequency magnetic fields and childhood brain tumors.

Pooled analyses may provide etiologic insight about associations between exposure and disease. In contrast to childhood leukemia, no pooled analyses of childhood brain tumors and exposure to extremely low-frequency magnetic fields (ELF-MFs) have been conducted. The authors carried out a pooled analysis based on primary data (1960-2001) from 10 studies of ELF-MF exposure and childhood brain tumors to assess whether the combined results, adjusted for potential confounding, indicated an association. The odds ratios for childhood brain tumors in ELF-MF exposure categories of 0.1-<0.2 µT, 0.2-<0.4 µT, and ≥0.4 µT were 0.95 (95% confidence interval: 0.65, 1.41), 0.70 (95% CI: 0.40, 1.22), and 1.14 (95% CI: 0.61, 2.13), respectively, in comparison with exposure of <0.1 µT. Other analyses employing alternate cutpoints, further adjustment for confounders, exclusion of particular studies, stratification by type of measurement or type of residence, and a nonparametric estimate of the exposure-response relation did not reveal consistent evidence of increased childhood brain tumor risk associated with ELF-MF exposure. These results provide little evidence for an association between ELF-MF exposure and childhood brain tumors.

Brain tumors in children and occupational exposure of parents.

Ninety-two cases of brain tumor in children less than 10 years old were compared with 92 matched controls for parental occupational history. Cases were more likely than controls to show material occupations involving chemical exposure, paternal occupations involving solvents, and employment of father in the aircraft industry. These three factors were not affected by adjustment for the potential confounding variables examined in this study.

Risk factors for meningiomas in men in Los Angeles County.

A case-control study among men in Los Angeles County was conducted to investigate further the causes of intracranial meningiomas. Meningioma patients and a neighbor of each one were interviewed about past experiences that might be associated with tumor development. Analysis of information from the 105 matched pairs showed an association with meningioma occurrence for various factors relating to head trauma and head X-rays: 1) ever boxed as a sport [odds ratio (OR) = 2.0, P = 0.03], 2) had a serious head injury (OR = 1.9, P = 0.01), and 3) had X-ray treatment to the head before 20 years of age and/or had five or more full mouth dental X-ray series before 1945 (OR = 3.5, P = 0.02). Of the 105 subjects, 72 (69%) had a history of exposure to at least one of these factors.

Prior exposure to medical and dental x-rays related to tumors of the parotid gland.

Findings from this population-based study in Los Angeles County suggest, for the first time, that tumors of the parotid gland are related to prior exposure to diagnostic medical and dental radiography. Responses to interviews with 408 patients with a parotid tumor (269 benign tumors and 139 malignant tumors) were compared to responses of 408 neighborhood controls. Cumulative exposure of the parotid gland from diagnostic radiography was associated with a dose-related increase in risk of malignant tumors (P for trend less than .05; relative risk for exposure to greater than or equal to 50 rad = 3.4; 95% confidence interval = 1.02-11.46). Benign tumors showed a weaker positive association, and exposure before age 20 to a major diagnostic examination (full-mouth or panoramic dental radiography or medical radiography to the head) increased risk (relative risk = 1.8; confidence interval = 1.13-2.91). This study also confirmed the association of malignant tumors with prior radiation treatment to the head or neck; 28% of these tumors are attributable to exposure of the parotid gland from diagnostic and therapeutic radiation.

Case-control study of intracranial meningiomas in women in Los Angeles County, California.

A case-control study was conducted among women in Los Angeles County to investigate possible causes of intracranial meningiomas. Questionnaires sought information from patients and from a neighbor of each one on characteristics and past experiences that might be associated with the development of this disease. Information was obtained on 188 matched patient-neighbor pairs. Three primary factors appeared to be associated with meningioma occurrence: 1) a history of head trauma (odds ratio = 2.0, P = 0.01), 2) consumption of certain cured meats (odds ratio = 2.8, P less than 0.01), and 3) exposure to medical and dental diagnostic X-rays to the head. For diagnostic X-rays, the strongest association was with early exposure (less than 20 yr old) to full-mouth dental X-ray series (odds ratio = 4.0, P less than 0.01).

Childhood leukemia and parents' occupational and home exposures.

A case-control study of children of ages 10 years and under in Los Angeles County was conducted to investigate the causes of leukemia. The mothers and fathers of acute leukemia cases and their individually matched controls were interviewed regarding specific occupational and home exposures as well as other potential risk factors associated with leukemia. Analysis of the information from the 123 matched pairs showed an increased risk of leukemia for children whose fathers had occupational exposure after the birth of the child to chlorinated solvents [odds ratio (OR) = 3.5, P = .01], spray paint (OR = 2.0, P = .02), dyes or pigments (OR = 4.5, P = .03), methyl ethyl ketone (CAS: 78-93-3; OR = 3.0, P = .05), and cutting oil (OR = 1.7, P = .05) or whose fathers were exposed during the mother's pregnancy with the child to spray paint (OR = 2.2, P = .03). For all of these, the risk associated with frequent use was greater than for infrequent use. There was an increased risk of leukemia for the child if the father worked in industries manufacturing transportation equipment (mostly aircraft) (OR = 2.5, P = .03) or machinery (OR = 3.0, P = .02). An increased risk was found for children whose parents used pesticides in the home (OR = 3.8, P = .004) or garden (OR = 6.5, P = .007) or who burned incense in the home (OR = 2.7, P = .007). The risk was greater for frequent use. Risk of leukemia was related to mothers' employment in personal service industries (OR = 2.7, P = .04) but not to specified occupational exposures. Risk related to fathers' exposure to chlorinated solvents, employment in the transportation equipment-manufacturing industry, and parents' exposure to household or garden pesticides and incense remains statistically significant after adjusting for the other significant findings.

Dietary factors in oral and pharyngeal cancer.

A population-based case-control study of oral and pharyngeal cancer conducted in four areas of the United States provided information on a number of risk factors, including diet. Interviews were obtained from 871 oral cancer patients and 979 controls among whites, frequency matched for age and sex. Consumption frequency of 61 food items was assessed in the questionnaire; attention was given to foods that are sources of vitamins A and C and carotene. The major finding was an inverse relationship between fruit intake and risk of oral and pharyngeal cancer; individuals in the highest quartile of intake had about half the risk of those in the lowest quartile. Vitamin C, carotene, or fiber in fruit did not appear to account completely for this relationship, since these nutrients in vegetables did not provide similar protection. This finding suggests the influence of other constituents in fruits, although it is possible that cooking vegetables may have a nutrient-diminishing effect. Dietary intake of other nutrients, such as the B vitamins, vitamin E, folate, and iron, showed no consistent relationship to risk of oral and pharyngeal cancer. Coffee or other hot beverage consumption did not increase risk; intake of nitrite-containing meats or cooking practices, such as smoking, pickling, or charcoal grilling, also did not increase risk. All analyses were adjusted for the effects of tobacco and alcohol, strong risk factors for oral and pharyngeal cancer. Dietary findings among the few subjects who did not use tobacco or alcohol were similar to those for all subjects.

Racial differences in risk of oral and pharyngeal cancer: alcohol, tobacco, and other determinants.

BACKGROUND: In the United States, Blacks have increasingly higher rates of oral and pharyngeal cancer (oral cancer) than Whites, but determinants of the racial disparity have not been clear. PURPOSE: The purpose of this study was to explore reasons for the higher incidence of oral cancer among Blacks than Whites. METHODS: We used data from a large, population-based case-control study of oral cancer risk factors conducted in four areas of the United States. On the basis of interviews that ascertained characteristics of 1065 oral cancer patients (871 Whites and 194 Blacks) and 1182 controls (979 Whites and 203 Blacks), we examined racial differences in exposure prevalences and relative risks for a number of known etiologic factors, including tobacco and alcohol consumption, diet, and socioeconomic and other variables. To evaluate the extent to which the major risk factors explained the excess risk of oral cancer among Blacks, population-attributable risks were calculated. RESULTS: Differences with respect to alcohol consumption, especially among current smokers, emerged as the most important explanatory variables. After adjusting for smoking, heavy drinking (> or = 30 drinks/week) resulted in a 17-fold increased risk among Blacks and a ninefold increase among Whites. Among drinkers, Blacks tended to drink more than Whites. Also, a higher (P = .01) percentage of Blacks (37%) than Whites (28%) were current smokers, although there were little or no racial differences in relative risks or patterns of use for other smoking variables, including number of cigarettes smoked per day, years of smoking, and age started smoking. From population-attributable risk calculations, we estimated that differences in alcohol and tobacco use account for the bulk of the higher incidence of oral cancer among Blacks in the United States and that, in the absence of alcohol and tobacco, the rates of this cancer according to race (Black, White) and gender would be nearly equal. With regard to other potential etiologic factors, protective effects provided by higher dietary intake of fruits and vitamin C were more pronounced for Whites, while Blacks more often tended to be in sociodemographic and medical or dental health categories associated with increased risk. CONCLUSIONS: These analyses provide evidence that various environmental or lifestyle determinants of oral cancer may contribute to the higher oral cancer rates in Blacks than in Whites in the United States, but that patterns and risks associated with alcohol consumption, particularly among current smokers, are the most important contributors to the excess risk in Blacks. IMPLICATIONS: These findings suggest that the key to prevention of oral and pharyngeal cancers among both Blacks and Whites is reduced intake of alcoholic beverages and, because of strong interactive effects, the cessation of smoking.

Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol.

BACKGROUND: The exceptionally high rate of second primary cancers among patients with oral and pharyngeal cancers is well recognized, yet there has been limited epidemiologic study of risk factors for second tumors. PURPOSE: To evaluate the relation of smoking and alcohol consumption to the development of second cancers among this high-risk patient group, we conducted a nested case-control study. METHODS: A total of 1090 patients enrolled in a 1984-1985 population-based, case-control study of oral cancer in four areas of the United States were followed through June 1989 for the occurrence of second primary cancers. Information on tobacco and alcohol consumption was obtained from the original interviews and was updated by follow-up interviews obtained for 80 case patients with second cancers and 189 sex-, study area-, and survival-matched cancer patients free of second cancers (control subjects). RESULTS: Tobacco smoking and alcohol drinking each contributed to risk of second cancers, with the effects of smoking more pronounced than those of alcohol. The odds ratios (ORs) for smoking (adjusted for alcohol) rose with duration and intensity of smoking and were strongest for tumors of the aerodigestive tract (oral cavity, pharynx, esophagus, larynx, and lungs), with ORs reaching 4.7 (95% confidence interval [CI] = 1.4-16) among smokers of 40 or more cigarettes per day for 20 or more years. Current smokers as of the baseline survey experienced a fourfold increased risk of a second aerodigestive tract cancer relative to nonsmokers and former smokers. No reduction in risk was associated with cessation of smoking or drinking at or after the index diagnosis, although the short median interval (27 months) between tumor diagnoses limited observation of the effects due to recent cessation. Risk was significantly reduced, however, 5 years after smoking cessation. Among drinkers, second cancer risk was greatest for beer intake, with an OR for a second aerodigestive tract cancer of 3.8 (95% CI = 1.2-12) for 15 or more beers per week. CONCLUSIONS: Oral and pharyngeal cancer patients with the highest intakes of tobacco and alcohol are the ones most prone to develop second primary cancers. IMPLICATIONS: Avoidance of tobacco smoking and alcohol drinking is the most desirable way not only to prevent primary oral cancers, but also to reduce risk of second cancers of the aerodigestive system.

Risk factors for gliomas and meningiomas in males in Los Angeles County.

Detailed job histories and information about other suspected risk factors were obtained during interviews with 272 men aged 25-69 with a primary brain tumor first diagnosed during 1980-1984 and with 272 individually matched neighbor controls. Separate analyses were conducted for the 202 glioma pairs and the 70 meningioma pairs. Meningioma, but not glioma, was related to having a serious head injury 20 or more years before diagnosis [odds ratio (OR) = 2.3; 95% confidence interval (CI) = 1.1-5.4], and a clear dose-response effect was observed relating meningioma risk to number of serious head injuries (P for trend = 0.01; OR for greater than or equal to 3 injuries = 6.2; CI = 1.2-31.7). Frequency of full-mouth dental X-ray examinations after age 25 related to both glioma (P for trend = 0.04) and meningioma risk (P for trend = 0.06). Glioma, but not meningioma risk, related to duration of prior employment in jobs likely to involve high exposure to electric and magnetic fields (P for trend = 0.05). This risk was greatest for astrocytoma (OR for employment in such jobs for greater than 5 years = 4.3; CI = 1.2-15.6). More glioma cases had worked in the rubber industry (discordant pairs 6/1) and more worked in hot processes using plastics (9/1). More meningioma cases had jobs that involved exposure to metal dusts and fumes (discordant pairs 13/5), and six of these cases and two controls worked as machinists. Finally, there was a protective effect among glioma pairs relating to frequency of use of vitamin C and other vitamin supplements (P for trend = 0.004); the OR for use at least twice a day was 0.4 (CI = 0.2-0.8).

N-Nitroso compounds and childhood brain tumors: a case-control study.

We questioned mothers of 209 young brain tumor patients and mothers of 209 controls about experiences of possible etiological relevance which they had during pregnancy or which their children had while growing up. Long-suspected brain tumor risk factors such as head trauma and X-rays appeared to be factors for relatively few cases. Increased risk was associated with maternal contact with nitrosamine-containing substances such as burning incense (odds ratio, 3.3; p = 0.005), sidestream cigarette smoke (odds ratio, 1.5; p = 0.03), and face makeup (odds ratio, 1.6; p = 0.02); with maternal use of diuretics (odds ratio, 2.0; p = 0.03) and antihistamines (odds ratio, 3.4; p = 0.002); and with the level of maternal consumption of cured meats (p = 0.008). These drugs contain nitrosatable amines and amides, and the cured meats contain nitrites, chemicals which are precursors of N-nitroso compounds. We propose a hypothesis that brain tumors in these young people are related to in utero exposure to N-nitroso compounds and their precursors, the most potent nervous system carcinogens known in experimental animals.

Risk factors for nodular sclerosis and other types of Hodgkin's disease.

The age-adjusted incidence rates of nodular sclerosis in Los Angeles County from 1972 to 1975 were 58% lower in Mexican-Americans and 42% lower in blacks than in other whites. They were the same for each sex among other whites and the curve of age-specific incidence peaked in young adulthood. The incidence of nodular sclerosis was directly associated with social class. In contrast, the rates for other histological varieties of Hodgkin's disease (lymphocyte predominance, mixed cellularity, lymphocyte depletion) were only 12% lower in Mexican-Americans but 34% lower in blacks. In other whites, the rates were 92% higher in men and increased gradually with age while there were no clear trends with social class. These characteristics support the hypothesis that, at least for purposes of etiology, the nodular sclerosis form of this disease should be considered a distinct entity. Self-administered questionnaire were completed by 218 of the 1972 to 1973 Hodgkin's disease patients and 218 individually matched neighbourhood controls. Significantly high risk ratios for Hodgkin's disease were found for prior appendectomy (risk ratios = 1.9, p = 0.01) and for past amphetamine use (risk ratios = 3.0, p = 0.01). The elevated risk associated with amphetamine use had been found in a previous study.

Increased cell division as a cause of human cancer.

Carcinogenesis research is increasingly focused on chemicals that are not genotoxic and yet, at high doses, can induce cancer, apparently by increasing cell proliferation. We hypothesize that increased cell division per se stimulated by external or internal factors is also associated with the development of many human cancers. Although this hypothesis is well substantiated in the experimental literature, it has not been generalized as an important mechanism for carcinogenesis in human populations. Under this increased cell division model, the pathogenesis of cancer may result from molecular genetic errors induced during the process of cell division and from altered growth control of malignant or premalignant cells. Molecular genetic analysis of human cancers has shown that tumor cells contain multiple genetic defects including mutations, translocations, and amplifications of oncogenes and are reduced to homozygosity for putative tumor suppressor genes; these phenomena all require cell division for their occurrence and fixation. Increased cell division increases the risk of such events occurring. An accumulation of a combination of such genetic errors leads to a neoplastic phenotype. Examples are discussed of human cancers in which increased cell division, which drives the accumulation of genetic errors and can lead to neoplastic transformation, is caused by hormones, drugs, infectious agents, chemicals, physical or mechanical trauma, and other chronic irritation.

Mouthwash use and oral conditions in the risk of oral and pharyngeal cancer.

Interviews with 866 patients with cancer of the oral cavity and pharynx and 1249 controls of similar age and sex from the general population in four areas of the United States revealed increased risks associated with the regular use of mouthwash. Risks of oral cancer were elevated by 40% among male and 60% among female mouthwash users, after adjusting for tobacco and alcohol consumption. Risks among both sexes generally increased in proportion to duration and frequency of mouthwash use. The increased risks were confined to users of mouthwash high in alcohol content, consistent with the elevated risks associated with drinking alcoholic beverages. Except for a higher prevalence of leukoplakia among cases, little relationship was found with oral or dental conditions, although denture wearing was reported more often by patients with cancer of the gums. These findings, together with other studies, provide further incentive for clarifying the association between mouthwash use and oral cancer.

Smoking and drinking in relation to oral and pharyngeal cancer.

A case-control study of oral and pharyngeal cancer conducted in four areas of the United States provided information on the tobacco and alcohol use of 1114 patients and 1268 population-based controls. Because of the large study size, it could be shown that the risks of these cancers among nondrinkers increased with amount smoked, and conversely that the risks among nonsmokers increased with the level of alcohol intake. Among consumers of both products, risks of oropharyngeal cancer tended to combine more in a multiplicative than additive fashion and were increased more than 35-fold among those who consumed two or more packs of cigarettes and more than four alcoholic drinks/day. Cigarette, cigar, and pipe smoking were separately implicated, although it was shown for the first time that risk was not as high among male lifelong filter cigarette smokers. Cessation of smoking was associated with a sharply reduced risk of this cancer, with no excess detected among those having quit for 10 or more years, suggesting that smoking affects primarily a late stage in the process of oropharyngeal carcinogenesis. The risks varied by type of alcoholic beverage, being higher among those consuming hard liquor or beer than wine. The relative risk patterns were generally similar among whites and blacks, and among males and females, and showed little difference when oral and pharyngeal cancers were analyzed separately. From calculations of attributable risk, we estimate that tobacco smoking and alcohol drinking combine to account for approximately three-fourths of all oral and pharyngeal cancers in the United States.

Childhood brain tumors and exposure to tobacco smoke.

Brain tumors are the second most common cancer in children after leukemia, yet the etiology of childhood brain tumors remains unknown. Tobacco smoke contains several dozen compounds that are known to be carcinogens. Among these are N-nitroso compound precursors, principally tobacco-specific nitrosamines. Although smoking has not been identified as a significant risk factor for the development of brain tumors in adults, fetuses and infants have incompletely formed blood-brain barriers that may allow the passage of carcinogenic tobacco metabolites into the central nervous system and initiate the formation of neural tumors. In this review, we present data from case-control and cohort studies published between 1971 and 1995 that examined the relationship between parental smoking during pregnancy and childhood brain tumors (CBTs). The majority of these studies found little association between CBTs and maternal smoking before or during pregnancy or between CBTs and maternal exposure to passive smoke during pregnancy.

Reproductive and hormonal risk factors for thyroid cancer in Los Angeles County females.

We conducted an individually matched case-control study (292 pairs) of female thyroid cancer patients to examine the role of reproductive history and exogenous hormones in this disease. Radiation treatment to the head or neck [28 cases and 2 controls exposed; odds ratio (OR), 14.0; 95% confidence interval (CI), 3.5-121.3] and certain benign thyroid diseases (including adolescent thyroid enlargement, goiter, and nodules or tumors) were strongly associated with thyroid cancer. Irregular menstruation increased risk (OR, 1.8; 95% CI, 0.9-3.7). Age at menarche and pregnancy history were not related to disease. Women with natural menopause and hysterectomized women without oophorectomy had no increase in risk, but disease risk was elevated in women with bilateral oophorectomy (OR, 6.5; 95% CI, 1.1-38.1). In general, use of oral contraceptives and other exogenous estrogens was not associated with thyroid cancer. However, risk increased with number of pregnancies in women using lactation suppressants (P = 0.03) and decreased with duration of breastfeeding (P = 0.04). These data provide only limited support for the hypothesis that reproductive and hormonal exposures are responsible for the marked excess of thyroid cancer risk in adult females.

Farm and animal exposures and pediatric brain tumors: results from the United States West Coast Childhood Brain Tumor Study.

Nineteen counties from San Francisco and Los Angeles, California and Seattle, Washington were the United States sites for a large population-based case-control study of childhood brain tumors (CBTs), sponsored by the National Cancer Institute. CBT patients who were < 20 years of age and were diagnosed between 1984 and 1991 were reported to each region's cancer registry. The 801 control subjects were obtained by random digit dial and were frequency-matched to the 540 CBT patients in San Francisco and Seattle (one patient to two controls) and in Los Angeles (one patient to one control). Data collected by in-person interview with subjects' mothers were analyzed to investigate an association between risk for CBTs and life on a farm, exposure to farm animals (dairy cattle, beef cattle, pigs, sheep/goats, poultry, and horses), and some cat and non-farm horse exposures. Elevated risks for CBTs were observed in association with mothers' exposure to pigs [odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.2-12] and horses (OR = 2.2, 95% CI = 1.0-4.8) on a farm during the index pregnancy. Children diagnosed with primitive neuroectodermal tumors showed elevated risks for CBTs with personal and maternal prenatal exposure to pigs (child, OR = 4.0, 95% CI = 1.2-13; mother, OR = 11.9, 95% CI = 2.8-51) and poultry (child, OR = 3.0, 95% CI = 1.1-8.0; mother, OR = 4.0, 95% CI = 1.2-14). No other animal exposures of children or mothers were found to be consistently related to CBTs. Children diagnosed with primitive neuroectodermal tumors who were on a farm for > 1 year and were first on a farm when they were < 6 months of age also had increased risk for CBTs (OR = 3.9, 95% CI = 1.2-13). A somewhat increased risk for CBTs was found for children of mothers who ever had worked on livestock farms compared with mothers who never had worked on a farm (OR = 7.4, 95% CI = 0.86-64, based on five case mothers and one control mother who worked on livestock farms during the 5 years preceding the birth of the index child). The associations are consistent with those of two previous studies in Norway (P. Kristensen et al., Int. J. Cancer, 65: 39-50, 1996) and the United States and Canada (G. R. Bunin et al., Cancer Epidemiol. Biomark. Prev., 3: 197-204, 1994) that investigated the role of farm-related exposures in the etiology of CBTs.

Spinal meningiomas in women in Los Angeles County: investigation of an etiological hypothesis.

A series of 3 studies explored the hypothesis that the preponderance of spinal meningiomas among postmenopausal women relates to their higher prevalence of spinal osteoporosis: (a) medical records showed that meningiomas in women, unlike other spinal tumors, usually arise in the mid thoracic spine where osteoporotic vertebral fractures predominate; (b) radiographic evidence of osteoporosis was seen commonly with meningiomas but not with other spinal tumors; and (c) age-adjusted multivariate analysis of data from an interview study of 81 women with spinal meningioma and 155 random digit dial controls showed 6 factors related to risk. Four factors were protective: (a) current use (at diagnosis) of estrogen replacement therapy [odds ratio (OR) = 0.2; 95% confidence interval (CI) = 0.1-0.6]; (b) past use of oral contraceptives (P trend < 0.01); (c) past participation in sports (OR = 0.5; CI = 0.2-0.9); and (d) premenopausal status (OR = 0.2; CI = 0.1-0.7). Risk increased among women who had ever smoked cigarettes (OR = 1.7; CI = 0.9-3.1) or had a history of high dose radiography (> 500 mrad exposure to active marrow/examination; includes upper or lower gastrointestinal series and/or cardiac angiography; OR = 2.9, and CI = 1.6-5.3), although no association was seen with prior radiotherapy. Other results that did not support the hypothesis include findings that cases and controls were similar in mean body weight and in the proportion who had postmenopausal fractures or height loss. In conclusion, these studies lend some support to our hypothesis, but other known meningioma risk factors such as ionizing radiation also appear important.(ABSTRACT TRUNCATED AT 250 WORDS)