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Mutational loss of the human DNA repair gene MUTYH in the germline predisposes for colorectal polyposis and cancer, a recessively heritable disease called MUTYH-associated polyposis. The MUTYH gene shows heavy alternative splicing, but the transcripts relevant for biological function and cancer prevention have not been determined. This knowledge is required to assess the consequences that germline variants of unknown functional significance may have. We therefore quantified expression and investigated patterns of alternative splicing in control individuals, tissue samples, and carriers of two frequent germline alterations. MUTYH expression differed organ dependently, correlating with proliferative activity. Alternative first exons were used tissue specifically; transcripts for mitochondrial proteins predominated in muscle tissues, while ascending colon and testes showed the highest fractions of transcripts for nuclear proteins. Colon cancer cell lines produced predominant transcripts for nuclear protein. Exon skipping was frequent and governed by splice-site quality. Five transcripts were found to encode the biologically relevant products of the MUTYH gene. Carriers of the disease-causing mutation c.1187G>A (p.Gly396Asp) showed normal transcript composition, but the frequent single-nucleotide polymorphism rs3219468:G>C largely reduced one transcript species of MUTYH. Since this alteration decreases protein production of the gene, an increased cancer risk for compound heterozygous carriers is possible., (© 2012 Wiley Periodicals, Inc.)

Aim: Biallelic MutY human homologue (MUTYH) germline mutations predispose to recessively inherited adenomatous polyposis, designated MUTYH-associated polyposis (MAP), and colorectal cancer (CRC). The hotspot mutations p.Y179C and p.G396D account for the majority of pathogenic variants of MUTYH in Caucasians. Our aim was to evaluate the prevalence of MUTYH mutations in a prospective cohort of unselected patients with different colorectal diseases., Method: The hotspot mutations p.Y179C and p.G396D were genotyped in 352 consecutive patients undergoing colonoscopy at our tertiary referral centre. Exons 2-14 were sequenced in hotspot mutation carriers to exclude additional variants., Results: Overall, we identified five heterozygous p.Y179C mutations and three heterozygous p.G396D mutations in seven hotspot mutation carriers (risk allele frequencies 0.7% and 0.4%, respectively). Two of these hotspot mutation carriers harboured a heterozygous p.Q338H variant, which is of uncertain clinical significance, on the other allele. Three individuals were biallelic MUTYH variant carriers (p.Y179C/p.G382D: typical MAP; p.Y179C/p.Q338H: atypical MAP with late onset and lower polyp burden; p.G382D/p.Q338H: inflammatory bowel disease), and four subjects were monoallelic mutation carriers., Conclusion: MUTYH-associated disease, and hence genetic counselling and MUTYH genetic testing, should be considered in the clinical routine of an endoscopy unit, but the wide range of phenotypes represents a challenge for patient identification. The clinical significance of p.Q338H should be evaluated in future case-control studies because compound heterozygotes for pathogenic mutations and p.Q338H may be at increased risk for mild polyposis or CRC. In addition, MUTYH should be assessed as a potential susceptibility gene for the development of colitis-associated CRC in future., (© 2012 The Authors. Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.)

Gallstone disease is one of the most common gastroenterological diseases and represents a major burden for our heath care systems. Cholesterol gallstones, responsible for about 90% of stones, represent a multifactorial disease with an important genetic component. Most gallstone-carriers remain asymptomatic and hence in general, they not need any therapy. In contrast those with symptomatic (biliary colic) or complicated gallstone disease (cholecystitis, obstructive cholangitis, biliary pancreatitis) have to be treated interdisciplinary by surgeons and endoscopists. Laparoscopic cholecystectomy represents the causal therapy to avoid recurrent symptoms as well as the therapy of choice for cholecystitis as the most common complication of gallstone disease. Bile duct stones and the associated complications (cholangitis, biliary pancreatitis) are primarily treated endoscopically.

Objective: To assess the association between neighborhood-level racial residential segregation and stroke mortality using a spatially derived segregation index., Design: Cross-sectional study, Setting: Atlanta Metropolitan Statistical Area, Methods: The study population consisted of non-Hispanic Black and White residents of the Atlanta Metropolitan Statistical Area during the time period Jan 1, 2000 to December 31, 2006. Census tract-level stroke death rates for Blacks and Whites were modeled as a function of the segregation index while controlling for two neighborhood-level chronic stressors (poverty, low education)., Results: Racial segregation was positively associated with stroke mortality for both Blacks and Whites aged 35-64 years. Among Blacks and Whites aged 65 or older, segregation was negatively associated with stroke mortality after controlling for the two stressors, suggesting that they were pathways between segregation and stroke death rates., Conclusion: Future studies are needed to identify additional pathways between residential segregation and other health outcomes, and to collect data that support a life course approach to understanding the impact of residential segregation on health.

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 × 10(-18) ). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy., (2011 American Association for the Study of Liver Diseases.)

Purpose: Biallelic germ-line mutations in MUTYH have recently been found to predispose for MUTYH-associated polyposis (MAP). Affected patients present with a wide range of clinical phenotypes at the time of diagnosis, but there is little precise information about the natural course of this disease., Results: Fourteen years of colonoscopic surveillance of an MAP patient (compound heterozygous p.Y165C/p.G382D) showed that adenoma development was slow after initial diagnosis of a single colorectal carcinoma at the age of 44, but then the annual number of new adenomas increased substantially in the patient's early fifties., Conclusion: This course of the disease, with a strong subsequent acceleration of polyp development, may explain the wide range of polyp numbers counted in newly diagnosed MAP patients as a result of the time of observation. Therefore, MAP should also be considered in younger patients (35-55 years) with only few adenomas or colorectal cancer. The high frequency of medium and severe dysplasia in the patient's preferential small adenomas suggests accelerated progression from adenoma to carcinoma in MAP, but this observation must be confirmed by further studies.

Introduction: New York City has one of the highest reported death rates from coronary heart disease in the United States. We sought to measure the accuracy of this rate by examining death certificates., Methods: We conducted a cross-sectional validation study by using a random sample of death certificates that recorded in-hospital deaths in New York City from January through June 2003, stratified by neighborhoods with low, medium, and high coronary heart disease death rates. We abstracted data from hospital records, and an independent, blinded medical team reviewed these data to validate cause of death. We computed a comparability ratio (coronary heart disease deaths recorded on death certificates divided by validated coronary heart disease deaths) to quantify agreement between death certificate determination and clinical judgment., Results: Of 491 sampled death certificates for in-hospital deaths, medical charts were abstracted and reviewed by the expert panel for 444 (90%). The comparability ratio for coronary heart disease deaths among decedents aged 35 to 74 years was 1.51, indicating that death certificates overestimated coronary heart disease deaths in this age group by 51%. The comparability ratio increased with age to 1.94 for decedents aged 75 to 84 years and to 2.37 for decedents aged 85 years or older., Conclusion: Coronary heart disease appears to be substantially overreported as a cause of death in New York City among in-hospital deaths.

Objectives: This study was designed to document local-level geographic disparities in heart failure (HF) hospitalization rates among Medicare beneficiaries., Background: Although the burden of HF is well documented at the national level, little is known about the geographic disparities in HF., Methods: The study population consisted of fee-for-service Medicare beneficiaries >or=65 years of age who resided in the U.S., Puerto Rico, or the U.S. Virgin Islands during the years 2000 to 2006. Using hospital claims data for Medicare beneficiaries, we calculated spatially smoothed and age-adjusted average annual county-level HF hospitalization rates per 1,000 Medicare beneficiaries for the total population and by racial/ethnic group (blacks, Hispanics, and whites) for the years 2000 to 2006. A HF hospitalization was defined as a short-stay hospital claim with a principal (first-listed) discharge diagnosis of HF using the International Classification of Diseases-9th Revision-Clinical Modification code 428., Results: The average annual age-adjusted HF hospitalization rate per 1,000 Medicare beneficiaries was 21.5 per 1,000, and ranged from 7 to 61 per 1,000 among counties in the U.S. For the total study population, a clear East-West gradient was evident, with the highest rates located primarily along the lower Mississippi River Valley and the Ohio River Valley, including the Appalachian region. Similar patterns were observed for blacks and whites, although the pattern for Hispanics differed., Conclusions: The evidence of substantial geographic disparities in HF hospitalizations among Medicare beneficiaries is important information for health professionals to incorporate as they design prevention and treatment policies and programs tailored to the needs of their communities., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Potent 5-HT(2A) inverse-agonists containing phenyl-pyrazole ureas with an amino side chain were identified. Optimization of this series resulted in selective compounds that proved effective in modulating 5HT-induced amplification of ADP-stimulated human platelet aggregation.

Objective: To examine the potential for rejuvenation of aged periosteum by local injection of transforming growth factor-beta1 (TGF-beta1) and insulin-like growth factor-1 (IGF-1) alone or in combination to induce cambium cell proliferation and enhance in vitro periosteal cartilage formation., Methods: A total of 367 New Zealand white rabbits (6, 12, and 24+ month-old) received subperiosteal injections of TGF-beta1 and/or IGF-1 percutaneously. After 1, 3, 5, or 7 days, the rabbits were sacrificed and cambium cellularity or in vitro cartilage forming capacity was determined., Results: A significant increase in cambium cellularity and thickness, and in vitro cartilage formation was observed after injection of TGF-beta1 alone or in combination with IGF-1. In 12 month-old rabbits, mean cambium cellularity increased 5-fold from 49 to 237 cells/mm and in vitro cartilage production increased 12-fold from 0.8 to 9.7 mg 7 days after TGF-beta1 (200 ng) injection compared to vehicle controls (P<0.0001). A correlation was observed between cambium cellularity and in vitro cartilage production (R2=0.98). An added benefit of IGF-1 plus TGF-beta1 on in vitro cartilage production compared to TGF-beta1 alone was observed in the 2 year-old rabbits. IGF-1 alone generally had no effect on either cambium cellularity or in vitro cartilage production in any of the age groups., Conclusions: These results clearly demonstrate that it is possible to increase cambium cellularity and in vitro cartilage production in aged rabbit periosteum, to levels comparable to younger rabbits, using local injection of TGF-beta1 alone or in combination with IGF-1, thereby rejuvenating aged periosteum.

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH- or FH-deficient cells, HIF activation is due to HIF1alpha stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIFalpha prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, alpha-ketoglutarate. We designed and synthesized cell-permeating alpha-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate- or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular alpha-ketoglutarate. Introduction of alpha-ketoglutarate derivatives restores normal PHD activity and HIF1alpha levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.

The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided N-(cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride 28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the alpha2A receptors.

Abstract Twelve adult clients described the role of religion and spirituality in their lives and in therapy as a whole, as well as their specific experiences of discussing religious-spiritual topics in individual outpatient psychotherapy with nonreligiously affiliated therapists. Data were analyzed using Consensual Qualitative Research (CQR; Hill, Thompson, & Williams, 1997 ). Results indicated that clients were regularly involved in religious-spiritual activities, usually did not know the religious-spiritual orientation of their therapists, but often found them open to such discussions. Specific helpful discussions of religion-spirituality were often begun by clients in the 1st year of therapy, were related to clients' presenting concerns, were facilitated by therapists' openness, and yielded positive effects. Specific unhelpful discussions were raised equally by clients and therapists early in therapy, made clients feel judged, and evoked negative effects. Implications for practice and research are addressed.

A series of 4-(dimethylamino)quinazoline based antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. This series was derived from a lead compound, AR129330, identified by HTS of a GPCR-directed library using a functional assay with a constitutively activated (CART) form of the receptor. The preliminary optimization resulted in the identification of compounds 20, 21, and 23.

Objective: To conceptualize and measure community contextual influences on population health and health disparities., Data Sources: We use traditional and nontraditional secondary sources of data comprising a comprehensive array of community characteristics., Study Design: Using a consultative process, we identify 12 overarching dimensions of contextual characteristics that may affect community health, as well as specific subcomponents relating to each dimension., Data Collection: An extensive geocoded library of data indicators relating to each dimension and subcomponent for metropolitan areas in the United States is assembled., Principal Findings: We describe the development of community contextual health profiles, present the rationale supporting each of the profile dimensions, and provide examples of relevant data sources., Conclusions: Our conceptual framework for community contextual characteristics, including a specified set of dimensions and components, can provide practical ways to monitor health-related aspects of the economic, social, and physical environments in which people live. We suggest several guiding principles useful for understanding how aspects of contextual characteristics can affect health and health disparities.

Objectives: This study examines the prevalence of lower extremity arterial disease (LEAD) and its association with cardiovascular disease (CVD) risk factors., Methods: Linear and logistic regression were used to analyze cross-sectional data from 1333 Chippewa and Menominee Indians., Results: Approximately 6.4% of participants (6.9% of men, 6.1% of women) had LEAD. Among women, LEAD was associated with lower high-density lipoprotein cholesterol; higher levels of diastolic blood pressure, creatinine, and triglycerides; and current smoking, diabetes, microalbuminuria, prior myocardial infarction, and stroke (P < or = .05). Among men, LEAD was associated with higher levels of creatinine (P < or = .05)., Conclusions: Use of the ankle-brachial index to assess LEAD is a noninvasive and inexpensive measurement that can be used by clinicians to identify persons at increased risk of developing CVD, and may provide opportunities to prevent CVD.

In this paper, we examine geographic and racial/ethnic differences in heart disease and stroke mortality in the Appalachian region. Initial comparisons are made between national rates for heart disease and stroke mortality and those for the Appalachian region. County-level analyses were performed to examine the relative mortality experience of populations in Appalachian counties compared to other counties in the United States and to assess the degree of geographic disparity in mortality from heart disease and stroke among these race/ethnic and gender groups within Appalachia. The Appalachian region exhibits higher rates of both heart disease and stroke mortality for all race/ethnic, gender, and age groups examined. We found that many counties in the Appalachian region endure a considerable burden of the national excess in both heart disease and stroke mortality, and these counties tend to be aggregated in particular areas as opposed to being dispersed regionwide. Finally, we compare 2 groups of counties in Appalachia based on the designation as an "economically distressed county," defined by the Appalachian Regional Commission. As a group, distressed counties in Appalachia exhibit higher rates of both heart disease and stroke mortality than the rest of Appalachia.

Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each pool) of total RNA from left-sided sporadic colorectal carcinomas. We compared normal tissue to carcinoma tissue from Dukes' stages A-D (noninvasive to distant metastasis) and identified 908 known genes and 4,155 ESTs that changed remarkably from normal to tumor tissue. Based on intensive filtering 226 known genes and 157 ESTs were found to be highly relevant for CRC. The alteration of known genes was confirmed in >70% of the cases by array analysis of 25 single samples. Two-way hierarchical average linkage cluster analysis clustered normal tissue together with Dukes' A, clustered Dukes' B with Dukes' C, and clustered Dukes' D separately. Real-time PCR of 10 known genes and 5 ESTs demonstrated excellent reproducibility of the array-based findings. The most frequently altered genes belonged to functional categories of metabolism (22%), transcription and translation (11%), and cellular processes (9%). Fifteen nuclear encoded mitochondrial proteins were all down-regulated in CRC. We identified several chromosomal locations with clusters of either potential oncogenes or potential tumor suppressors. Some of these, such as aminopeptidase N/CD13 and sigma B3 protein on chromosome 15q25, coincided with a high frequency of loss of heterozygosity. The genes and ESTs presented in this study encode new potential tumor markers as well as potential novel therapeutic targets for prevention or therapy of CRC.

High-throughput screening of in-house compound libraries led to the discovery of a novel antibacterial agent, compound 1 (MIC: 12-25 microM against S. pyogenes). In an effort to improve the activity of this active compound, a series of 2-substituted quinazolines was synthesized and evaluated in several antibacterial assays. One such compound (22) displayed improved broad-spectrum antibacterial activity against a variety of bacterial strains. This molecule also inhibited transcription/translation of bacterial RNA, suggesting a mechanism for its antibiotic effects. Structure-activity relationship studies of 22 led to the synthesis of another 24 compounds. Although some of these molecules were found to be active in bacterial growth assays, none were as potent as 22. Compound 22 was tested for its ability to cure a systemic K. pneumonia infection in the mouse and displayed moderate effects compared with a control antibiotic, gentamycin.

Purpose: Few data are available to examine coronary heart disease (CHD) mortality trends by social class in the United States, in contrast to ample data and well-documented social class disparities in CHD in Europe. In addition, previous analyses of U.S. national data indicated that the rate of decline in CHD mortality slowed substantially for blacks in the 1980s. Using a recently published method for calculating mortality rates by social class, we examined trends in CHD mortality for black men and white men aged 35-54 in North Carolina from 1984 to 1993., Methods: Men were assigned to one of four social classes: primary white collar (I), secondary white collar (II), primary blue collar (III), or secondary blue collar (IV), based on usual occupation as recorded on the death certificate. Population denominators for each social class were constructed using data from census Public Use Microdata Sample files. Average annual percent change in mortality rates for each race-social class group was derived from linear regression of the log-transformed age-adjusted rates., Results: For black men, CHD mortality increased by 18% in social class II, by 2% in social class III, and by 6% in social class IV over the 10-year study period. In contrast, CHD mortality decreased by 33% for black men in social class I (the highest class). CHD mortality declined for all white men, with the greatest decline in social class I and the least decline in social class IV., Conclusions: These results suggest that CHD prevention efforts have not benefited black men of lower social class, and that public health programs need to be targeted to these men.

Introduction: Leisure-time (LTPA), occupational, transportation, and household physical activity were evaluated among participants in the Inter-Tribal Heart Project (ITHP)., Methods: Age-stratified random samples of persons aged > or =25 years were drawn from three communities of Chippewa and Menominee Indians in Minnesota and Wisconsin. Participants (843 women and 501 men) completed an interviewer-administered questionnaire. Logistic regression analyses were performed to assess age-adjusted associations between no reported LTPA and potential correlates., Results: During leisure time, 12% of women and 17% of men were active 7-12 months in the past year; 33% of women and 21% of men reported no LTPA. During a typical workday for employed persons, approximately 90% of both genders walked > or =20 minutes, for carrying/lifting moderate to heavy objects the median value for men was 1 hour and women 0 hours. The median value of weekly household activity for men was 3 hours compared to 10 hours for women. Little transportation activity was reported by either gender. Age, household income, smoking, and poor/fair self-perceived health were associated with leisure-time inactivity in women (p < 0.05). Age, poor/fair self-perceived health, and smoking were associated with leisure-time inactivity in men (p < 0.05). Walking was the most prevalent activity in the population., Conclusions: Prevalence of leisure-time inactivity is higher than the national health objective of 15%, however, ITHP participants obtain a substantial amount of occupational and household activity that may lower risks of chronic diseases. Health promotion efforts to increase LTPA may lead not only to reduced chronic disease risk, but to additional benefits of enjoyment and improved psychological well-being.

Objective: To describe the 6-year probability of survival for older adults after their first hospitalization for heart failure., Setting: National Medicare hospital claims records for 1984 through 1986 and Medicare enrollment records from 1986 through 1992., Design: We identified a national cohort of 170 239 (9% black patients) Medicare patients, 67 years or older, with no evidence of heart failure in 1984 or 1985, who were hospitalized and discharged for the first time in 1986 with a principal diagnosis of heart failure. For groups defined by race, sex, age, Medicaid eligibility, and comorbid conditions, we compared the probability of survival with Cox proportional hazards regression., Results: Only 19% of black men, 16% of white men, 25% of black women, and 23% of white women survived 6 years. One third died within the first year. Men had lower median survival and 38% greater risk of mortality than did women (P<.05). White men had 10% greater risk of mortality than did black men (P<.05). Medicaid eligibility (white adults only) and diabetes were associated with increased mortality (P<.05)., Conclusions: The prognosis for older adults with heart failure underscores the importance of prevention strategies and early detection and treatment modalities that can prevent, improve, or reverse myocardial dysfunction, particularly for the growing number of adults who are at increased risk for developing heart failure because of hypertension, diabetes, or myocardial infarction.

We sought to examine the prevalence of self-reported multiple cardiovascular disease (CVD) risk factors (hypertension, high blood cholesterol, diabetes, overweight, and current smoking) among women in 1992 and 1995 in the United States using data from the Behavioral Risk Factor Surveillance System. In 1992, 37.5%, 34.4%, and 28.1% of women had zero, one, and two or more of the five risk factors, respectively. In 1995, the respective estimates were 35.5%, 34.3%, and 30%. In both years, the prevalence of two or more risk factors increased with age, decreased with educational level, was higher among black women (lowest among Hispanic women and women of other ethnic groups), and higher among women reporting cost as a barrier to healthcare. The percentage of women with two or more risk factors was higher in 1995 than in 1992 for 35 of 48 states, being statistically significant for 7 states. The percentage of women with at least two risk factors was not significantly lower in 1995 than in 1992 for any state. A higher percentage of women reported having multiple CVD risk factors in 1995 compared with 1992. A multifactorial approach to primary prevention and risk factor reduction should be encouraged to help reduce the prevalence and burden of CVD among women.

Background: Little is known about the causes and consequences of renal disease among American Indians in the Great Lakes region of the United States., Methods: We examined clinical correlates of albumin/creatinine ratios among 1368 participants in the three tribal communities of the Inter-Tribal Heart Project using univariate and multivariate analysis., Results: Compared to 1086 participants without albuminuria, the 240 with microalbuminuria (30 to 299 mg/g) and the 42 with macroalbuminuria (>300 mg/g) were more likely to report a history of a myocardial infarction (6.4%, 16.0%, and 23.8%, respectively, P < 0.001). Similarly, compared to patients without albuminuria, those with microalbuminuria and macroalbuminuria were more likely to report a history of stroke (2.3%, 8.4% and 26.2%, respectively, P < 0.001). In a multiple linear regression model, independent correlates of albumin excretion (P < 0.05) included: fasting blood sugar, treated diabetes, treated hypertension, higher systolic blood pressure, lower diastolic blood pressure, abnormal electrocardiogram, a history of stroke, the degree of American Indian heritage, and lower household income., Conclusions: Urinary albumin excretion is associated with cardiovascular disease outcomes and risk factors among American Indians of the Great Lakes region. Both heredity and socioeconomic status appear to play a role in the pathogenesis of renal injury in this population.

We compare recent trends in ischemic heart disease (IHD) and stroke mortality in California among the 6 major sex-racial or -ethnic groups. Rates of age-specific and -adjusted mortality were calculated for persons aged 35 and older during the years 1985 to 1991. Log-linear regression modeling was performed to estimate the average annual percentage change in mortality. During 1985 through 1991, the mortality for IHD and stroke was generally highest for African Americans, intermediate for non-Hispanic whites, and lowest for Hispanics. Age-adjusted mortality for IHD declined significantly in all sex-racial or -ethnic groups except African-American women, and stroke rates declined significantly in all groups except African-American and Hispanic men. African Americans had excess IHD mortality relative to non-Hispanic whites until late in life, after which mortality of non-Hispanic whites was higher. Similarly, African Americans and Hispanics had excess stroke mortality relative to non-Hispanic whites early in life, whereas stroke mortality in non-Hispanic whites was higher at older ages. The lower IHD and stroke mortality among Hispanics was paradoxical, given the generally adverse risk profile and socioeconomic status observed among Hispanics. An alarmingly high prevalence of self-reported cardiovascular disease risk factors in 1994 to 1996, particularly hypertension, leisure-time sedentary lifestyle, and obesity, is a serious public health concern, with implications for future trends in cardiovascular disease mortality. Of particular concern was the growing disparities in stroke and IHD mortality among younger-aged African Americans relative to Hispanics and non-Hispanic whites.

Objective: This study aimed to examine the correspondence between seven established risk factors for coronary heart disease (CHD) and CHD mortality among the states in the United States. An ecologic analysis relating CHD risk factor prevalences to CHD mortality rates among 49 states was undertaken in 1991-1992., Methods: Approximately 68,000 men and women ages 45-74 were randomly sampled and interviewed by telephone in surveys conducted in 49 states in 1991 and 1992. From these interviews, we estimated state-specific prevalences of smoking, overweight, physical inactivity, hypertension, elevated cholesterol, diabetes, and alcohol abstinence. These seven CHD risk factors were also combined to create a CHD risk index for each state. The main outcome measures were mortality rates from CHD (ICD9 codes 410.0-414.9) in each of 49 states in 1991-1992 for men and women ages 45-74. The analysis was based on multiple linear regression and Spearman's rank-order correlations between the CHD risk factor prevalences, the combined CHD risk index, and the CHD mortality rates among the 49 states., Results: The prevalences of most of the CHD risk factors correlated with CHD mortality rates in the expected directions, and correlations were similar for men and women. The CHD risk index correlated strongly with CHD mortality for both men (r = 0.75) and women (r = 0.80)., Conclusion: About 60% of the variance in CHD mortality between the states in the United States (56% for men and 64% for women) is attributable to differences between the states in the prevalences of seven established risk factors for CHD. As state health agencies prioritize resources for chronic disease prevention programs, they should consider the potential benefits of increased efforts to reduce the prevalences of modifiable CHD risk factors in their populations to reduce CHD mortality.

Despite being a rather recalcitrant tool, the "Pap smear" is today the major cancer screening technology in the world. This paper examines how and why hetrogeneous actors chose to advocate the Pap smear as a screen for cervical cancer in the late 1940's, and to tinker both in and far beyond the diagnostic laboratory for over 50 years to make the Pap smear "fit" as a screening and clinical technology. Tinkerings included gendering the division of labour, attempting to automate reading of smears, juggling costs, exploring alternative screening technologies, pushing for regulation of laboratories, and settling for locally-negotiated orders of clinical accuracy instead of global standardization, still elusive today.

Background: We examined the association between clustering of risk factors and the risk for coronary heart disease, stroke, and all-cause mortality., Methods: Data from the First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study (N = 12,932) were used to estimate the relative risk for coronary heart disease (N = 2,255), stroke (N = 929), and death from any cause (N = 4,506) by the number of cardiovascular disease risk factors present. Risk factors included current smoking, overweight, hypertension, high blood cholesterol, and diabetes., Results: The proportions of respondents with 0, 1, 2, 3, or > or = 4 risk factors were 25.0, 32.8, 27.8, 12.3, and 2.1%, respectively. Relative risks for coronary heart disease associated with having 1, 2, 3, and > or = 4 risk factors were 1.6 (95% confidence interval [CI] 1.4, 1.9), 2.2 (95% CI 1.9, 2.6), 3.1 (95% CI 2.6, 3.6), and 5.0 (95% CI 3.9, 6.3), respectively. Relative risks for stroke associated with the same risk levels were 1.4 (95% CI 1.1, 1.8), 1.9 (95% CI 1.5, 2.4), 2.3 (95% CI 1.7, 3.0), and 4.3 (95% CI 3.0, 6.3), respectively. Similar results were observed for all-cause mortality., Conclusions: Risk for cardiovascular disease and all-cause mortality increased substantially with each additional risk factor. This supports the continued need for primary prevention of cardiovascular disease risk factors.

The aim of this study was to investigate whether the blockade of L-type Ca2+ channels with verapamil suppresses giant migrating contractions (GMCs) and therefore diarrhea during small intestinal inflammation. Small intestinal inflammation was induced by infection with the nematode Trichinella spiralis. T. spiralis infection alone significantly increased the frequency of GMCs and decreased the frequency of phase III activity in the small intestine for 9 days. The increased frequency of GMCs was associated with diarrhea. Immunohistochemical staining with specific antibodies indicated that the number of neutrophils and mast cells increased significantly in the jejunal lamina propria during T. spiralis infection. Only the neutrophils increased significantly in the muscularis externa of the jejunum. Myeloperoxidase (MPO) activity increased significantly in the jejunal and ileal lamina propria. Daily verapamil administration during T. spiralis infection significantly reduced the frequency of GMCs and diarrhea but had no further significant effect on the already reduced frequency of phase III activity. Verapamil administration, however, did not reduce MPO activity or immunocyte infiltration in the jejunum or ileum. We conclude that blockade of L-type Ca2+ channels selectively reduces the frequency of GMCs and therefore diarrhea during small intestinal inflammation. The decreased frequency of GMCs is not secondary to a reduction in the inflammatory response.

Background: Despite the recent availability of new classes of heart failure medications, little is known about national patterns in the actual physician utilization of these drugs., Methods: In the National Ambulatory Medical Care Survey, 2912 US physicians reported on 16,968 office visits in 1991-1992 with patients aged > or = 65 years. National estimates were obtained from weighted results that accounted for the complex sampling design., Results: An estimated 8.3 million (2.6%) office visits with older adults involved heart failure. This included 9.3% of visits to cardiologists, 4.3% to internists, 3.5% to general and family physicians, and 0.6% to other physicians. The most frequently prescribed medications during visits with these patients were diuretics (69%), digitalis compounds (46%), angiotensin-converting enzyme inhibitors (30%), and nitrates (19%). Internists and general and family physicians prescribed angiotensin-converting enzyme inhibitors, digitalis compounds, and loop diuretics for patients with heart failure less often than did cardiologists., Conclusions: These are the first national surveillance estimates of physician practices in the management of heart failure. These data were collected during the same period in which heart failure clinical trial results were initially published, and they provide a baseline for monitoring the influence of recent clinical practice guidelines and professional education on changes in the management of heart failure by primary care physicians.

Objectives: Heart failure is a major health care burden among older adults, but information on recent trends has not been available. We compare rates, sociodemographic characteristics, and discharge outcomes of the initial hospitalization for heart failure in the Medicare populations of 1986 and 1993., Design: Information reported on the Medicare hospital claims record during initial hospitalization for heart failure was compared for patients aged 65 and older hospitalized in 1986 (N = 631,306) and those aged 65 and older hospitalized in 1993 (N = 803,506)., Results: Age-standardized hospitalization rates (per 1000 person-years) for any diagnosis of heart failure were higher in 1993 than in 1986 (white: 24.6 vs 22.4, black: 26.1 vs 22.4, respectively). Age-specific results suggested an earlier onset of heart failure in black adults. In 1993, compared with 1986, higher proportions of heart failure patients were discharged to another care facility (white: 23.9% vs 16.8%, black: 17.6% vs 10.5%, respectively) or to health service care at home (white: 11.3% vs 6.0%, black: 12.4% vs 6.5%, respectively). In contrast, in-hospital mortality was lower in 1993 than in 1986 (white: 10.4% vs 13.3%, black: 8.9% vs 11.1%, respectively)., Conclusion: The increased numbers of hospitalizations for heart failure and the likelihood that these patients will require advanced nursing care after discharge have important implications for future national health care expenditures and resources.

We compare the recent trends in ischemic heart disease mortality in California and the United States. Because California was among the first states to have declines in ischemic heart disease mortality, an examination of these recent trends may provide important clues for upcoming national trends. Age-adjusted and -specific ischemic heart disease mortality rates were calculated by sex for persons aged 35 and older during the years 1980 to 1991. Log-linear regression modeling was used to estimate the average annual percentage change in mortality. Between 1980 and 1991, the annual age-adjusted ischemic heart disease mortality declined less in California than in the United States for both women (1.9% versus 3.1%) and men (3.1% versus 3.5%). In California, it increased slightly between 1986 and 1990 for the oldest women and men. The slower rates of decline in mortality of this disease in California compared with the United States and the rising rates among the most elderly Californians suggest that careful attention should be paid to these trends in death rates of and risk factors for this disease in California.

Objective: To investigate the prevalence and selected correlates of leisure-time physical activity in a nationally representative sample of persons aged 65 years or older., Methods: Data from 2783 older male and 5018 older female respondents to the 1990 National Health Interview Survey were used. Regular physical activity was defined as participation in leisure-time physical activities 3 times or more per week for 30 minutes or more during the previous 2 weeks. Odds ratios (ORs) were estimated from multivariate logistic regression analysis., Results: Prevalence of regular physical activity was 37% among older men and 24% among older women. Correlates of regular physical activity included the perception of excellent to good health (men: OR, 1.5; 95% confidence interval [CI], 1.1-1.9; women: OR, 1.6; 95% CI, 1.3-1.9), correct exercise knowledge (men: OR, 2.4; 95% CI, 1.9-3.1; women: OR, 2.7; 95% CI, 2.2-3.4), no activity limitations (men: OR, 1.3; 95% CI, 1.0-1.6; women: OR, 1.7; 95% CI, 1.4-2.0) and not perceiving "a lot" of stress during the previous 2 weeks (men: OR, 1.7; 95% CI, 1.2-2.4; women: OR, 1.3; 95% CI, 1.0-1.6). Among those who had been told at least twice that they had high blood pressure, physician's advice to exercise was associated with regular physical activity (men: OR, 1.6; 95% CI, 1.2-2.3; women: OR, 1.5; 95% CI, 1.2-1.9). The 2 major activities among active older adults were walking (men, 69%; women, 75%) and gardening (men, 45%; women, 35%)., Conclusions: Prevalence of regular physical activity is low among older Americans. Identifying the correlates of physical activity will help to formulate strategies to increase physical activity in this age group.

THE HEART DISEASE MORTALITY RATES of the Chippewa and Menominee, who reside in the upper Midwest, are higher than the rates of most other tribes in the United States. Little is known, however, about the prevalence of hypertension, diabetes, and obesity among these communities. The Inter-Tribal Heart Project (ITHP) was designed to determine the prevalence of risk factors for heart disease and to implement community-based heart disease prevention programs. Age-stratified random samples of active users of the tribal-Indian Health Service (IHS) clinics, ages 25 and older, were drawn from three communities within the Bemidji Service Area. Between September 1992 and June 1994, 1396 people completed an extensive questionnaire and underwent a physical exam for heart disease risk factors. Preliminary data indicate mean blood pressure levels of 126 mmHg for systolic blood pressure (SBP) and 74.4 mmHg for diastolic blood pressure (DBP). Mean SBP and DBP were higher among men than women. Mean body mass index (BMI), which did not vary by gender, was 30.6 mmHg. The prevalence of hypertension was 33%; and diabetes, 33%. Men had a higher prevalence of hypertension than women, but there was little gender difference in the prevalence of diabetes. These preliminary data suggest that the prevalences of hypertension, diabetes, and obesity in these communities are higher than the recent estimates for the total United States. The next stage of the ITHP will focus on policies and programs to prevent and treat these conditions.

Background: Lower rates of invasive cardiac procedures have been reported for blacks and women than for white men. However, few studies have adjusted for differences in the type of hospital of admission, insurance status, and disease severity. SETTING, DESIGN, AND PARTICIPANTS: Data from the National Hospital Discharge Survey were used to investigate race and sex differences in rates of cardiac catheterization, percutaneous transluminal coronary angioplasty, and coronary artery bypass surgery among 10,348 persons hospitalized for acute myocardial infarction., Results: White men consistently had the highest procedure rates, followed by white women, black men, and black women. After matching for the hospital of admission and adjusting for age, in-hospital mortality, health insurance, and hospital transfer rates (with white men as the referent), the odds ratios for cardiac catheterization were 0.67 (95% confidence interval [CI], 0.51 to 0.87) for black men, 0.72 (95% CI, 0.63 to 0.83) for white women, and 0.50 (95% CI, 0.37 to 0.68) for black women. Similar race-sex differences were noted for percutaneous transluminal coronary angioplasty and coronary artery bypass surgery., Conclusions: Race and sex differentials in the rates of invasive cardiac procedures remained despite matching for the hospital of admission and controlling for other factors that influence procedure rates, suggesting that the race and sex of the patient influence the use of these procedures.

Background: Although coronary heart disease mortality has been decreasing, little is known about trends in morbidity from coronary heart disease. We evaluated trends in nonfatal coronary heart disease in the United States during 1980 through 1989., Methods: We analyzed data from the National Health Interview Survey, an ongoing survey of representative samples of the civilian, noninstitutionalized population of the United States. Survey respondents were determined to have coronary heart disease if they reported ever having a myocardial infarction or heart attack, angina pectoris, or coronary heart disease. Incidence was defined as initial onset of a coronary heart disease condition during the year preceding the interview date., Results: About 6 million people were estimated to be living with coronary heart disease. The age-standardized prevalence was relatively constant at about 25 per 1000. Among white men, however, prevalence increased significantly over the 10-year period. Among 75- to 84-year-old men, prevalence increased from 100 per 1000 in 1980 to 179 per 1000 in 1989. Among men and women 45 to 54 years old, prevalence decreased. Overall, the incidence rate of nonfatal coronary heart disease was relatively flat (at about 3 per 1000 per year after 1983). Among white women, the incidence rate increased from 1.4 to 2.8 per 1000, and by the end of the decade it nearly equaled the incidence rate among white men., Conclusions: Overall, the burden of nonfatal coronary heart disease remained fairly constant during the 1980s. The trends, however, were not uniform in all population groups. The apparent increasing incidence among women deserves continued monitoring. An encouraging trend is the decreasing prevalence in the younger age groups.

"Uniformly" modified phosphodiester or phosphorothioate oligonucleotides incorporating 2'-deoxy-2'-fluoroadenosine, -guanosine, -uridine, and -cytidine, reported herein for the first time, when hybridized with RNA afforded consistent additive enhancement of duplex stability without compromising base-pair specificity. CD spectra of the 2'-deoxy-2'-fluoro-modified oligonucleotides hybridized with RNA indicated that the duplex adopts a fully A-form conformation. The 2'-deoxy-2'-fluoro-modified oligonucleotides in phosphodiester form were not resistant to nucleases; however, the modified phosphorothioate oligonucleotides were highly nuclease resistant and retained exceptional binding affinity to the RNA targets. The stabilizing effects of the 2'-deoxy-2'-fluoro modifications on RNA-DNA duplexes were shown to be superior to those of the 2'-O-methylribo substitutions. RNA hybrid duplexes with uniformly 2'-deoxy-2'-fluoro-modified oligonucleotides did not support HeLa RNase H activity; however, incorporation of the modifications into "chimeric" oligonucleotides has been shown to activate mammalian RNase H. "Uniformly" modified 2'-deoxy-2'-fluoro phosphorothioate oligonucleotides afforded antisense molecules with (1) high binding affinity and selectivity for the RNA target and (2) stability toward nucleases.

Objectives: This study examines the association between increases in antihypertensive pharmacotherapy and declines in stroke mortality among 96 US groups stratified by race, sex, age, metropolitan status, and region from 1962 to 1980., Methods: Data on the prevalence of controlled hypertension and socioeconomic profiles were obtained from three successive national health surveys. Stroke mortality rates were calculated using data from the National Center for Health Statistics and the Bureau of the Census. The association between controlled hypertension trends and stroke mortality declines was assessed with weighted regression., Results: Prior to 1972, there was no association between trends in controlled hypertension and stroke mortality declines (beta = 0.04, P = .69). After 1972, groups with larger increases in controlled hypertension experienced slower rates of decline in stroke mortality (beta = 0.16, P = .003). Faster rates of decline were modestly but consistently related to improvements in socioeconomic indicators only for the post-1972 period., Conclusions: These results do not support the hypothesis that increased antihypertensive pharmacotherapy has been the primary determinant of recent declines in stroke mortality. Additional studies should address the association between declining stroke mortality and trends in socioeconomic resources, dietary patterns, and cigarette smoking.

Background: Regional, metropolitan, and socioeconomic factors related to the onset of decline of coronary heart disease (CHD) mortality among White women are reported. Such studies are important for planning population-level interventions., Methods: Mortality data for 1962 to 1978 were used, to estimate the year of onset of decline. Ecological analyses of socioeconomic data from the US census were used to emphasize structural and organizational aspects of changes in disease, rather than as a substitute for an individual-level design., Results: Onset of decline of CHD mortality among White women was estimated to have occurred by 1962 in 53% of 507 state economic areas (SEAs), ranging from 79% in the Northeast to 39% in the South. Metropolitan areas experienced earlier onset of decline than did nonmetropolitan areas. Average income, education, and occupational levels were highest in early onset areas and declined across onset categories., Conclusions: The results provide additional evidence for previously observed geographic and social patterns of CHD decline. Emphasis on structural economic factors determining the shape of the CHD epidemic curve does not detract from the medical importance of risk factors, but underscores the importance of community development to public health improvements. The results are consistent with the idea that the course of the CHD epidemic in the United States has been strongly influenced by socioeconomic development.

Study Objective: The aim was to examine the patterns of black-white differences in stroke mortality across communities with varying levels of occupational structure in the southern region of the United States, Design: Annual age adjusted race-sex specific rates for stroke mortality were calculated for the years 1979-1981 and related to socioeconomic conditions., Setting: The study involved 211 state economic areas comprising the southern region of the USA., Study Population: Data on stroke mortality for black and white men and women between the ages of 35 and 74 years living in the study area were acquired from the National Center for Health Statistics., Measurements and Main Results: Occupational structure was measured as the proportion of white collar workers in each state economic area, and is an indicator of the employment opportunities and related social and economic resources of a community. Stratified analyses and linear regression modelling indicate that communities of lower occupational structure have (a) higher levels of stroke mortality for all four race-sex groups (p less than 0.05) and (b) larger racial inequalities in stroke mortality (p less than 0.01). For men and women, the excess stroke mortality among blacks compared to whites is larger in communities of lower occupational structure., Conclusions: Consideration of occupational structure and related patterns of economic development is crucial for understanding the distribution of stroke mortality within and between racial groups, as well as for planning effective public health interventions. The larger racial inequalities in communities of lower occupational structure in the south suggest that aspects of the black experience which are conducive to high rates of stroke mortality are exacerbated in those communities. Public health interventions to reduce the racial and social inequalities in stroke mortality should recognise the social context within which nutritional, occupational, medical care, and environmental determinants of stroke are distributed.

A 60 base-pair region of a simian virus 40 DNA fragment was mutagenized to determine base-pairs that are critical for the fragment to bend. The site-directed mutagenesis saturated this region with all possible single base-pair substitutions. The mobility of each mutated fragment was measured by polyacrylamide electrophoresis at 4 degrees C and at 65 degrees C to assess the degree of bend. Four conclusions can be drawn. First, interruptions within the A tracts and changes in the phasing of the A tracts alter the degree of bend. Second, G tracts phased at a half-helical turn from an A tract are additive to the bend. Third, guanine residues in a nearest-neighbor contact with the A tracts modify the bend. Fourth, some mutations that do not obviously relate to the A tracts also alter the DNA bend and suggest clearly that base steps other than ApA are involved in sequence-directed DNA bends.

The association of passive smoking and cardiovascular disease (CVD) mortality was assessed in a cohort of 513 rural, married Black and White women who were disease-free and self-described as never-smokers at baseline in 1960. Over a 20-year period, 76 of 147 total deaths were attributed to CVD. Relative risk estimates adjusted for age, cholesterol, blood pressure, and body mass from proportional hazards models were 1.59 for CVD (95% CI = 0.99, 2.57) and 1.39 (CI = 0.99, 1.94) for all cause mortality among women with husbands who smoked cigarettes.

Synthetic DNA fragments were constructed to determine the effect of G tracts, in conjunction with periodically spaced A tracts, on DNA bends. Relative length measurements showed that the G tracts spaced at the half helical turn enhanced the DNA bend. When the G tract was interrupted with a thymine or shortened to one or two guanines, the relative lengths decreased. If the G tract was replaced with either an A tract or a T tract, the bend was cancelled. Replacement with a C tract decreased the relative length to that of a thymine interruption suggesting that bend enhancement due to G tracts requires A tracts on the same strand.

Substantial geographic variation of cardiovascular disease (CVD) mortality within the U.S. has been recognized for decades. Analyses reported here address the question of whether relative geographic inequality has increased or decreased during the period of rapidly declining CVD mortality 1962-1982. Trends in geographic inequality, as measured by the weighted coefficient of variation of State Economic Area rates, are analyzed for whites and blacks by sex for 10-year age groups 35-44 to 85 and over. The average annual percent change in the coefficient of variation for each demographic group is presented for all cause mortality, all CVD, stroke and ischemic heart disease. In general, geographic inequalities declined in total mortality for all except the youngest age group. This is consistent with reports of a strong convergence of age-adjusted cancer mortality in U.S. counties. By contrast, increasing geographic inequality dominates in the CVD categories, especially for whites in heart disease and stroke. At younger ages, increases in the coefficient of variation for all race-sex groups exceeded 1% per year in stroke and 2% per year in heart disease. These results suggest that factors influencing the percent decline of CVD mortality are not reaching communities of the U.S. equally. Since increases in relative inequality are strongest in the younger age groups, the pattern of inequality may be accentuated as these cohorts move into ages of higher mortality.