Beta-catenin is temporally regulated during normal liver development

BACKGROUND & AIMS: beta-Catenin, a key component of the Wnt pathway, plays an important role in unregulated liver growth in liver tumors, in regulated growth during liver regeneration, and in ex vivo embryonic liver cultures. METHODS: We used developing livers from several stages of gestational development to examine beta-catenin expression, protein-protein interactions, localization, and regulation in prenatal and postnatal livers. RESULTS: Microarray, Northern, and protein analyses showed peak expression of beta-catenin during early liver development at Embryonic day 10 (E10)-E12, followed by a decrease and a complete loss of normal beta-catenin (97-kilodalton species) after E16 through the remaining prenatal period. At the early stages, beta-catenin localized to the cytoplasm and nuclei of resident cells in addition to its normal membranous localization, which was seen at all later stages and in adult liver. Decreases in beta-catenin levels at E14 onward coincided with its decreased gene expression and increased degradation, as seen by an increase in serine 45/threonine 41-phosphorylated beta-catenin and its other negative regulators, such as axin, adenomatous polyposis coli gene product (APC), and glycogen synthase kinase-3 beta. Finally, we showed an intact association of E-cadherin and beta-catenin despite the loss of beta-catenin at E16-E18, owing to the presence of membrane-associated smaller-molecular-weight beta-catenin species. CONCLUSIONS: We also identified a stage-specific expression and regulation of beta-catenin during liver development that might be crucial for physiological liver development. Nuclear and cytoplasmic beta-catenin corresponded to cell proliferation in liver development. Finally, a smaller-molecular-weight species of beta-catenin might be maintaining normal interactions at the membrane.     

Evaluation of aldehyde dehydrogenase 1 promoter polymorphisms identified in human populations

BACKGROUND: Cytosolic aldehyde dehydrogenase, or ALDH1A1, functions in ethanol detoxification, metabolism of neurotransmitters, and synthesis of retinoic acid. Because the promoter region of a gene can influence gene expression, the ALDH1A1 promoter regions were studied to identify polymorphism, to assess their functional significance, and to determine whether they were associated with a risk for developing alcoholism. METHODS: Sequence analysis was performed in the promoter region by using Asian, Caucasian, and African American subjects. The resulting polymorphisms were assessed for frequency in Asian, Caucasian, Jewish, and African American populations and tested for associations with alcohol dependence in Asian and African American populations of alcoholics and controls. The functional significance of each polymorphism was determined through in vitro expression analysis by using HeLa and HepG2 cells. RESULTS: Two polymorphisms, a 17 base pair (bp) deletion (-416/-432) and a 3 bp insertion (-524), were discovered in the ALDH1A1 promoter region: ALDH1A1*2 and ALDH1A1*3, respectively. ALDH1A1*2 was observed at frequencies of 0.035, 0.023, 0.023, and 0.012 in the Asian, Caucasian, Jewish, and African American populations, respectively. ALDH1A1*3 was observed only in the African American population, at a frequency of 0.029. By using HeLa and HepG2 cells for in vitro expression, the activity of the luciferase reporter gene was significantly decreased after transient transfection of ALDH1A1*3-luciferase compared with the wild-type construct ALDH1A1*1-luciferase. In an African American population, a trend for higher frequencies of the ALDH1A1*2 and ALDH1A1*3 alleles was observed in a population of alcoholics (p = 0.03 and f = 0.12, respectively) compared with the control population. CONCLUSIONS: ALDH1A1*2 and ALDH1A1*3 may influence ALDH1A1 gene expression. Both ALDH1A1*2 and ALDH1A1*3 produce a trend in an African American population that may be indicative of an association with alcoholism; however, more samples are required to validate this observation. The underlying mechanisms contributing to these trends are still unknown.     

An updated review of quality-of-life questionnaires for urinary incontinence and overactive bladder: Which ones to use and why

Overactive bladder and stress urinary incontinence have a profound impact on patients’ health-related quality of life (HRQL). The purpose this paper is to update a previously published review of condition-specific HRQL measures validated among patients with symptoms of urinary incontinence or overactive bladder. For this update, MEDLINE (accessed via PubMed) and EMBASE literature searches were performed to identify articles or abstracts published since 2004 that focus on the development, psychometric validation, and use of relevant instruments. Target populations and psychometric properties (reliability, validity, responsiveness to change) of 22 questionnaires are summarized. A range of well-validated, condition-specific HRQL measures are available. Recommendations are provided regarding which measures to use in different situations. When choosing among instruments, psychometric evidence and the match of an instrument to the study population should be considered.     

Obesity, regional body fat distribution, and the metabolic syndrome in older men and women

BACKGROUND: The metabolic syndrome is a disorder that includes dyslipidemia, insulin resistance, and hypertension and is associated with an increased risk of diabetes and cardiovascular disease. We determined whether patterns of regional fat deposition are associated with metabolic syndrome in older adults. METHODS: A cross-sectional study was performed that included a random, population-based, volunteer sample of Medicare-eligible adults within the general communities of Pittsburgh, Pa, and Memphis, Tenn. The subjects consisted of 3035 men and women aged 70 to 79 years, of whom 41.7% were black. Metabolic syndrome was defined by Adult Treatment Panel III criteria, including serum triglyceride level, high-density lipoprotein cholesterol level, glucose level, blood pressure, and waist circumference. Visceral, subcutaneous abdominal, intermuscular, and subcutaneous thigh adipose tissue was measured by computed tomography. RESULTS: Visceral adipose tissue was associated with the metabolic syndrome in men who were of normal weight (odds ratio, 95% confidence interval: 2.1, 1.6-2.9), overweight (1.8, 1.5-2.1), and obese (1.2, 1.0-1.5), and in women who were of normal weight (3.3, 2.4-4.6), overweight (2.4, 2.0-3.0), and obese (1.7, 1.4-2.1), adjusting for race. Subcutaneous abdominal adipose tissue was associated with the metabolic syndrome only in normal-weight men (1.3, 1.1-1.7). Intermuscular adipose tissue was associated with the metabolic syndrome in normal-weight (2.3, 1.6-3.5) and overweight (1.2, 1.1-1.4) men. In contrast, subcutaneous thigh adipose tissue was inversely associated with the metabolic syndrome in obese men (0.9, 0.8-1.0) and women (0.9, 0.9-1.0). CONCLUSION: In addition to general obesity, the distribution of body fat is independently associated with the metabolic syndrome in older men and women, particularly among those of normal body weight.     

Pulmonary function and exercise-associated changes with chronic low-level paraquat exposure

The present study was undertaken to test the hypothesis that chronic, low-level paraquat exposure causes restrictive lung function with gas transfer impairment. Three hundred thirty-eight Costa Rican farm workers from banana, coffee, and palm oil farms completed a questionnaire, spirometry, and a test of single-breath carbon monoxide diffusing capacity. Subjects 40 years of age or older, without other medical risk factors, completed maximal cardiopulmonary exercise tests. Most (66.6%) were paraquat handlers; 24.8% of handlers and 27.3% of nonhandlers reported current cigarette smoking. In linear regression models, cumulative paraquat exposure was not an independent predictor of VA, carbon monoxide diffusing capacity, peak oxygen uptake, FVC, or oxygen pulse peak. However, the ventilatory equivalent for CO(2), although within normal range, was significantly higher with increased cumulative paraquat exposure. Oxygen desaturation greater than 5% from rest to peak exercise had an odds ratio of 1.7 (95% confidence interval = 0.9-3.0) with the cumulative paraquat exposure index in models adjusted for age, weight, and smoking status. The association of paraquat exposure with ventilatory equivalent and oxygen desaturation suggests that paraquat may be associated with subclinical gas exchange abnormalities, but overall these findings are consistent with no clinically significant increases in interstitial thickening or restrictive lung disease among this population.     

Hemodynamics of increased pulse pressure in older women in the community-based Age, Gene/Environment Susceptibility-Reykjavik Study

Pulse pressure increases with advancing age particularly in women. As a result, women have a higher pulse pressure than men from midlife onward. Higher pulse pressure in older women as compared to men is often attributed to increased aortic wall stiffness and premature wave reflection. To evaluate this hypothesis, we measured central aortic input impedance, pulse wave velocity, and wave reflection in 408 older men and women (age range, 69 to 94 yr, mean 75 yr) participating in the community-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). Women as compared to men had higher pulse pressure (75.8+/-18.7 versus 69.5+/-16.8 mm Hg, P<0.001) and smaller aortic diameters (2.74+/-0.24 versus 2.97+/-0.28 cm, P<0.001). Augmentation index (AI) was higher (11.0+/-15.9 versus 7.9+/-12.9%, P=0.032) in women whereas proximal aortic elastance-wall thickness product (Eh) did not differ (P=0.61). In a stepwise model for pulse pressure that included age and sex and offered aortic diameter, Eh, mean pressure, AI, pulse wave velocity, height, weight, and body surface area as additional covariates, higher pulse pressure was associated with increased wall stiffness, smaller aortic diameter, higher mean pressure, and increased AI (Model R(2)=0.59, P<0.001). The sex difference in pulse pressure (6.6+/-1.7 mm Hg, P<0.001) persisted after Eh entered the model (6.9+/-1.5 mm Hg, P<0.001) but not after aortic diameter entered the model (-0.4+/-1.4 mm Hg, P=0.75). Thus, reduced aortic diameter and impaired matching between diameter and flow accounts for the sex difference in pulse pressure in an unselected community-based cohort of older people.     

Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study

OBJECTIVES: To examine the association between physical activity and inflammatory markers, with consideration for body fatness and antioxidant use. DESIGN: Cross-sectional study, using baseline data from the Health, Aging and Body Composition Study. SETTING: Metropolitan areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Black and white, well-functioning men and women (N=3,075), aged 70 to 79. MEASUREMENTS: Interviewer-administered questionnaires of previous-week household, walking, exercise, and occupational/volunteer physical activities. Analysis of covariance was used to examine the association between activity level and serum C-reactive protein (CRP), interleukin-6 (IL-6), and plasma tumor necrosis factor alpha (TNFalpha) with covariate adjustment. Antioxidant supplement use (multivitamin, vitamins E or C, beta carotene) was evaluated as an effect modifier of the association. RESULTS: Higher levels of exercise were associated with lower levels of CRP (P<.01), IL-6 (P<.001), and TNFalpha (P=.02) (e.g., CRP=1.95 mg/L for no exercise and 1.72 for >180 min/wk). Adjustment for body fatness attenuated the associations somewhat. Use of antioxidant supplements modified the CRP (P(interaction)=.01) and IL-6 (P(interaction)=.08) associations such that concentrations were low in those taking supplements (e.g., CRP=1.79-1.84 across exercise levels) and higher in nonsupplement users who did no exercise (2.03) than in those who did the most (1.72). Among nonexercisers, higher levels of other physical activity were related to lower levels of CRP (P<.01) and IL-6 (P=.02) but not TNFalpha (P=.36), even after accounting for body fat. CONCLUSION: Inflammatory markers are lower in older adults with higher levels of exercise and nonexercise activity and in antioxidant supplement users regardless of exercise level.