Segregation analysis of esophageal cancer in 221 high-risk Chinese families.

BACKGROUND: Until recently, environmental factors were considered of greatest importance in the etiology of esophageal cancer. Recent studies, however, have suggested that genetic factors also have a role. PURPOSE: Since no formal genetic study of this cancer has been previously reported, we carried out a statistical analysis to determine how important genetic factors are in the etiology of esophageal cancer in high-incidence areas of North China. METHODS: Using a logistic regressive model, we performed a segregation analysis on 221 high-risk nuclear families from the Yaocun Commune, Linxian, Henan Province of China, with at least one affected family member and with all offspring aged 40 years or older. Three models, the mendelian, the environmental, and the no-transmission models, were each compared with the general-transmission model that incorporated both genetic and environmental factors. RESULTS: According to Akaike's Information Criterion, the mendelian model provided the best fit for the data. By the chi-square test, the mendelian inheritance model was not rejected, but the environmental and the no-transmission models were both rejected. CONCLUSION: The segregation analysis indicated an autosomal recessive mendelian inheritance, with the alleged mendelian gene present at a frequency of 19%, causing 4% of this population to be predisposed to develop esophageal cancer. Large, unmeasured, residual familial factors, however, were also significant. IMPLICATIONS: Both an autosomal recessive gene and unexplained environmental factors appear to be important in the etiology of esophageal cancer in the subpopulation studied.

Body fat distribution and breast cancer in the Framingham Study.

We examined the relation between central body fat distribution and breast cancer in a prospective cohort of women who participated in the Framingham Study. At the baseline examination in 1948, a total of 2,201 women aged 30-62 years were analyzed. An index of central to peripheral body fat (the central adiposity ratio) was calculated from the sum of the trunkal skinfolds (chest, subscapular, and abdominal) divided by the sum of the extremity skinfolds (triceps and thigh). These skinfolds were measured at the fourth examination in 1954. The cohort was followed for up to 28 years and yielded 106 cases of breast cancer. When divided into quartiles based on the central adiposity ratio, only women in the fourth quartile (those with the highest central to peripheral body fat distribution) demonstrated an increased risk for breast cancer. The age- and adiposity-adjusted relative risk estimate for having an increased central adiposity ratio (fourth quartile) compared to lower central adiposity ratios was 1.8 (95% confidence interval, 1.2-2.6). Adjustment for potential confounders of height, parity, and education did not appreciably alter this estimate (1.7, 1.1-2.5). There was no association between degree of adiposity, as measured by the sum of the five skinfolds or by body mass index (weight in kg divided by height in m2), and subsequent breast cancer. The results of this study suggest that increased central to peripheral body fat distribution predicts breast cancer risk independently of the degree of adiposity and may be a more specific marker of a premalignant hormonal pattern than degree of adiposity.

Is alcohol consumption related to breast cancer? Results from the Framingham Heart Study.

We studied the relation between alcohol consumption and breast cancer among women in the Framingham Heart Study cohort. A total of 2,636 women aged 31-64 years provided information on alcohol consumption at the second biennial examination. They were followed for up to 32 years; during this period, breast cancer was diagnosed in 143 of these women. Alcohol intake was also assessed at 10 and 20 years of follow-up and every 2 years thereafter. In analyses using only baseline alcohol intake, the multiple risk factor-adjusted relative risk (RR) estimate of breast cancer for any drinking, compared with nondrinking, was 0.8 [95% confidence interval (CI), 0.5-1.1]. For three levels of alcohol intake (0.1-1.4 g/day, 1.5-4.9 g/day, and greater than or equal to 5.0 g/day), the baseline analyses yielded RRs (vs. nondrinking) of 1.0 (CI, 0.6-1.5), 0.7 (CI, 0.4-1.1), and 0.6 (CI, 0.4-1.0), respectively. In analyses incorporating repeated measures of alcohol, the comparable RRs were 0.9 (CI, 0.6-1.2) for any drinking (vs. nondrinking) and 0.7 (CI, 0.4-1.4), 1.1 (CI, 0.7-1.8), and 0.8 (CI, 0.5-1.2), respectively, for the three levels of intake (vs. nondrinking). Alcohol consumption was not associated with an increased risk of breast cancer in this cohort.

Site-specific analysis of total serum cholesterol and incident cancer in the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study.

We studied the relation of total serum cholesterol to all cancer and site-specific cancer incidence in a cohort based on a probability sample of the United States population. A total of 5125 men (yielding 459 cancers) and 7363 women (398 cancers) were initially examined in 1971-75 and followed a median of 10 yr. An examination of age-adjusted incidence rates by cholesterol level showed an inverse association between cholesterol and all cancer; lung, colorectal, pancreatic, and bladder cancers; and leukemia. In women a weak inverse relation (reflecting an elevated rate among those only in the lowest cholesterol quintile) was apparent for all cancer; more prominent inverse associations were seen for cancers of the lung, pancreas, bladder, cervix, and for leukemia. A more detailed analysis of cholesterol and colorectal cancer revealed little association in both men and women. For an aggregate group of smoking-related cancers, the inverse relation was especially prominent: the multivariate relative risk estimates for subjects in the lowest cholesterol quintile, compared to those in the highest quintile, were 2.1 (1.1-3.8) and 3.3 (1.4-7.8) for men and women, respectively. The inverse association was present for smoking-related cancers diagnosed 6 or more yr after cholesterol determination in both men and women, suggesting that this association cannot be simply dismissed as a preclinical cancer effect. Further investigation of the cholesterol-cancer question, particularly the relation between cholesterol and smoking-related cancers, may provide useful etiological leads.

Mast cells in human periodontal disease.

Recently, mast cells have been shown to produce cytokines which can direct the development of T-cell subsets. The aim of the present study was to determine the relationship between mast cells and the Th1/Th2 response in human periodontal disease. Tryptase+ mast cell numbers were decreased in chronic periodontitis tissues compared with healthy/gingivitis lesions. Lower numbers of c-kit+ cells, which remained constant regardless of clinical status, indicate that there may be no increased migration of mast cells into periodontal disease lesions. While there were no differences in IgG2+ or IgG4+ cell numbers in healthy/gingivitis samples, there was an increase in IgG4+ cells compared with IgG2+ cells in periodontitis lesions, numbers increasing with disease severity. This suggests a predominance of Th2 cells in periodontitis, although mast cells may not be the source of Th2-inducing cytokines.

P. gingivalis-specific T-cell lines produce Th1 and Th2 cytokines.

Cytokines produced by T-cells in periodontal lesions may determine the nature of the adaptive immune response. Since different antigen-presenting cells (APC) may direct the Th1/Th2 response, P. gingivalis-specific T-cell lines were established by different APC subpopulations, and their cytokine profiles were determined. Peripheral blood mononuclear cells induced similar percentages of IL-4+ and IFN-gamma+ T-cells and lower percentages of IL-10+ T-cells. Epstein-Barr virus-transformed B-cells (LCL) induced higher percentages of IL-4+ cells than IFN-gamma+ cells, with lower percentages of IL-10+ cells. Peripheral blood mononuclear cells induced a higher percent of IFN-gamma+ CD8 cells than LCL (p = 0.004). Purified B-cells, monocytes, and dendritic cells induced similar percentages of IL-4+ and IFN-gamma+ cells, although again, the percentage of IL-10+ cells was lower. The results of the present study have demonstrated that, as measured by FACS analysis of intracytoplasmic cytokines, P. gingivalis-specific T-cells produce both Th1 and Th2 cytokines, regardless of the APC population.

The Oncormed approach to genetic testing.

This report describes a commercial laboratory's novel approach to providing genetic testing services to detect BRCA1 mutations in persons with hereditary breast/ovarian cancer. The approach involves the use of institutional review board (IRB)-approved protocols as a paradigm for conducting genetic testing in a commercial setting. We discuss the rationale for this approach and the key elements of the protocol. In addition, we provide data on the first 6 months of implementation of the protocol in 32 clinical sites. A phased testing approach was used, consisting of an allele-specific oligonucleotide assay for the 8 most common BRCA1 mutations, a protein truncation test of exon 11, and direct sequencing of the remaining regions of the gene. Data are presented on the yield of mutation carriers by category of family history and by stage of analysis.

A prospective study of reproductive, familial and socioeconomic risk factors for breast cancer using NHANES I data.

Risk factors for breast cancer in a cohort of women who participated in the first National Health and Nutrition Examination Survey (NHANES) and its followup epidemiologic survey were examined. The analytic cohort consisted of 122 breast cancer cases and 7,304 noncases, with a median followup time of 10 years. We found no appreciable increase in risk among women who reported their onset of menarche as occurring before the age of 13 compared with those reporting onset at ages 13 and older. Breast cancer risk was progressively elevated with increasing age at first live birth (test for trend, P less than 0.007). The number of children born to a woman did not influence risk, but the data suggested an increased risk for nulliparous women. A family history of breast cancer in a first-degree relative was the strongest predictor of risk for this cohort of women, with relative risks of 2.2 and 2.4 associated with a mother or sister affected with breast cancer, compared with women having no family history. The age of natural menopause had little influence on breast cancer risk, and the data suggested a slight protective effect of early surgical menopause. Higher education (compared with less than a high school education) was associated with an increased risk in this cohort of women (relative risk (RR) = 2.1; 95 percent confidence interval (CI) = 0.9-5.1). These results (a) confirm the importance of some well-recognized risk factors for breast cancer in a cohort of women, followed prospectively for 10 years, and perhaps more importantly, (b) uniquely provide risk estimates on a probability sample of women in the United States.

Exercise response during wall-pulley versus bicycle ergometer work.

The purpose of this study was to test the significance of differences between cardiopulmonary responses to wall-pulley arm exercise and to bicycle ergometer leg exercise. The heart rate responses were greater for arm exercise than for leg exercise at comparable external work rates or energy cost levels. The systolic blood pressure responses and myocardial oxygen cost were greater for arm exercise at given external work loads, but not a comparable energy cost levels. The clinical and theoretical significance of these results is discussed.

Relationship between Hip Extension Range of Motion and Postural Alignment.

The purpose of this study was to examine the relationships between hip extension range of motion (ROM) and three determinants of postural alignment: standing pelvic tilt, standing lumbar lordosis, and abdominal muscle performance. The subjects were 25 healthy adults ranging in age from 21 to 49 years. The Pearson product-moment correlation of hip extension ROM with pelvic tilt was -0.04, with lumbar lordosis -0.09, and with abdominal muscle performance 0.09. These results indicate that these variables are not related. This study demonstrates that the hypothetical correlation among these clinical parameters needs to be reassessed. J Orthop Sports Phys Ther 1990;12(6):243-247.

Phosphorylated p68 RNA helicase activates Snail1 transcription by promoting HDAC1 dissociation from the Snail1 promoter.

The nuclear p68 RNA helicase is a prototypical member of the DEAD-box family of RNA helicases. p68 RNA helicase has been implicated in cell proliferation and early organ development and maturation. However, the functional role of p68 RNA helicase in these biological processes at the molecular level is not well understood. We previously reported that tyrosine phosphorylation of p68 RNA helicase mediates the effects of platelet-derived growth factor (PDGF) in induction of epithelial mesenchymal transition by promoting ß-catenin nuclear translocation. Here, we report that phosphorylation of p68 RNA helicase at Y593 upregulates transcription of the Snail1 gene. The phosphorylated p68 activates transcription of the Snail1 gene by promoting histone deacetylase (HDAC)1 dissociation from the Snail1 promoter. Our results showed that p68 interacted with the nuclear remodeling and deacetylation complex MBD3:Mi-2/NuRD. Thus, our data suggested that a DEAD-box RNA unwindase could potentially regulate gene expression by functioning as a protein 'displacer' to modulate protein-protein interactions at the chromatin-remodeling complex.

Inflammation, heat shock proteins and periodontal pathogens in atherosclerosis: an immunohistologic study.

BACKGROUND: Inflammation is a significant component of atherosclerosis lesions. Bacteria, including periodontopathogens, have been demonstrated in atherosclerotic plaques and cross-reactivity of the immune response to bacterial GroEL with human heat shock protein 60 has been suggested as a link between infections and atherosclerosis. METHODS: In this study, the nature of the inflammatory infiltrate and the presence of human heat shock protein 60 and GroEL were examined in 31 carotid endarterectomy specimens. Additionally, monoclonal antibodies were used to detect the presence of six bacteria, including those implicated in periodontal disease. RESULTS: The inflammatory cell infiltrate of the lesions was dominated by CD14(+) macrophages and CD4(+) T cells. Most cells of the infiltrate as well as the endothelium were HLA-DR(+), indicating activation; however, there was an absence of CD25 expression, demonstrating that the activated T cells were not proliferating. Few CD1a(+) and CD83(+) cells were noted. Human heat shock protein 60 expression was evident on endothelial cells and cells with the appearance of smooth muscle cells and lymphocytes. GroEL and bacteria were detected within intimal cells. Chlamydia pneumoniae, Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, Prevotella intermedia, and Actinobacillus actinomycetemcomitans were found in 21%, 52%, 34%, 34%, 41%, and 17% of arteries, respectively. CONCLUSION: These results give evidence for a specific immune response associated with atherosclerosis. Whether bacteria initiate the observed inflammation in atherosclerotic lesions is not clear; however, the present study shows that maintenance of inflammation may be enhanced by the presence of periodontopathic bacteria.

Immunohistological analysis of Tannerella forsythia-induced lesions in a murine model.

Tannerella forsythia has been implicated as a defined periodontal pathogen. In the present study a mouse model was used to determine the phenotype of leukocytes in the lesions induced by subcutaneous injections of either live (group A) or nonviable (group B) T. forsythia. Control mice (group C) received the vehicle only. Lesions were excised at days 1, 2, 4, and 7. An avidin-biotin immunoperoxidase method was used to stain infiltrating CD4+ and CD8+ T cells, CD14+ macrophages, CD19+ B cells, and neutrophils. Hematoxylin and eosin sections demonstrated lesions with central necrotic cores surrounded by neutrophils, macrophages and lymphocytes in both group A and group B mice. Lesions from control mice exhibited no or only occasional solitary leukocytes. In both groups A and B, neutrophils were the dominant leukocyte in the lesion 1 day after injection, the numbers decreasing over the 7-day experimental period. There was a relatively low mean percent of CD4+ and CD8+ T cells in the lesions and, whereas the percent of CD8+ T cells remained constant, there was a significant increase in the percent of CD4+ T cells at day 7. This increase was more evident in group A mice. The mean percent of CD14+ macrophages and CD19+ B cells remained low over the experimental period, although there was a significantly higher mean percent of CD19+ B cells at day 1. In conclusion, the results showed that immunization of mice with live T. forsythia induced a stronger immune response than nonviable organisms. The inflammatory response presented as a nonspecific immune response with evidence of an adaptive (T-cell) response by day 7. Unlike Porphyromonas gingivalis, there was no inhibition of neutrophil migration.

Prospects for cancer prevention through genetics: family studies and population screening.

The ultimate goal of all genetic analyses, whether at the statistical or molecular level, is to identify individual genes and their function. The application of genetic epidemiological tools to common diseases, together with the recent implementation of recombinant DNA methodology, makes it feasible to identify, characterize, and even isolate genes involved in the major diseases of mankind. This paper outlines how the classical epidemiologic approach interfaces with the new DNA technologies. We review the progress of restriction fragment length polymorphism analyses in family studies and address their current and potential use in studies of unrelated individuals. In addition, we briefly discuss the role that oncogenes and inherited genetic alterations seem to play in the development of human cancers. The use of these techniques provides a framework for a better understanding of cancer etiology and may eventually help to define strategies for cancer prevention.

Segregation analysis of schizophrenia under a mixed genetic model.

Family data were collected on a multi-ethnic cohort of hospitalized schizophrenics in Hawaii in 1942. Results showed that prevalence rates for Orientals were significantly higher (p less than 0.001) than rates for Caucasians, Polynesians and others. Complex segregation analysis using a generalized mixed genetic model was performed on 507 sibships collected under both complete and incomplete selection. Likelihood ratio tests between the generalized model and two subhypotheses of a major gene effect and a polygenic effect revealed that neither subhypotheses could be rejected at the 5% level of significance. While neither hypothesis could be adequately supported by the likelihood ratio test, certain aspects of the findings suggest a preference for the multifactorial model in explaining the inheritance of schizophrenia in these data.

Infarct size and exercise capacity after myocardial infarction.

Estimation of infarct size from serum creatine phosphokinase elevations of 22 acute myocardial infarction (AMI) patients was compared to their functional exercise capacity determined on a bicyle ergometer. Eleven of these patients entered a controlled exercise program for 3-4 mo and were subsequently retested. Aerobic power of the exercise group increased significantly (mean +- SE 1.42 +- 0.5 met) and was also significantly greater than an unpaired control group tested the same number of months after infarct. Patients grouped 2.5-4.5 mo post-AMI demonstrated a correlation between aerobic power and estimated infarct size (r = -0.68, n = 15). This correlation was higher (r = -0.84, n = 11) after 3-4 mo of a controlled exercise program.