Arginine methylation regulates the p53 response.

Activation of the p53 tumour suppressor protein in response to DNA damage leads to apoptosis or cell-cycle arrest. Enzymatic modifications are widely believed to affect and regulate p53 activity. We describe here a level of post-translational control that has an important functional consequence on the p53 response. We show that the protein arginine methyltransferase (PRMT) 5, as a co-factor in a DNA damage responsive co-activator complex that interacts with p53, is responsible for methylating p53. Arginine methylation is regulated during the p53 response and affects the target gene specificity of p53. Furthermore, PRMT5 depletion triggers p53-dependent apoptosis. Thus, methylation on arginine residues is an underlying mechanism of control during the p53 response.

TGFbeta induces apoptosis and EMT in primary mouse hepatocytes independently of p53, p21Cip1 or Rb status.

BACKGROUND: TGFbeta has pleiotropic effects that range from regulation of proliferation and apoptosis to morphological changes and epithelial-mesenchymal transition (EMT). Some evidence suggests that these effects may be interconnected. We have recently reported that P53, P21Cip1 and pRB, three critical regulators of the G1/S transition are variably involved in TGFbeta-induced cell cycle arrest in hepatocytes. As these proteins are also involved in the regulation of apoptosis in many circumstances, we investigated their contribution to other relevant TGFbeta-induced effects, namely apoptosis and EMT, and examined how the various processes were interrelated. METHODS: Primary mouse hepatocytes deficient in p53, p21 and/or Rb, singly or in combination were treated with TGFbeta for 24 to 96 hours. Apoptosis was quantified according to morphology and by immunostaining for cleaved-capsase 3. Epithelial and mesenchymal marker expression was studied using immunocytochemistry and real time PCR. RESULTS: We found that TGFbeta similarly induced morphological changes regardless of genotype and independently of proliferation index or sensitivity to inhibition of proliferation by TGFbeta. Morphological changes were accompanied by decrease in E-cadherin and increased Snail expression but the mesenchymal markers (N-cadherin, SMAalpha and Vimentin) studied remained unchanged. TGFbeta induced high levels of apoptosis in p53-/-, Rb-/-, p21cip1-/- and control hepatocytes although with slight differences in kinetics. This was unrelated to proliferation or changes in morphology and loss of cell-cell adhesion. However, hepatocytes deficient in both p53 and p21cip1were less sensitive to TGFbeta-induced apoptosis. CONCLUSION: Although p53, p21Cip1 and pRb are well known regulators of both proliferation and apoptosis in response to a multitude of stresses, we conclude that they are critical for TGFbeta-driven inhibition of hepatocytes proliferation, but only slightly modulate TGFbeta-induced apoptosis. This effect may depend on other parameters such as proliferation and the presence of other regulatory proteins as suggested by the consequences of p53, p21Cip1 double deficiency. Similarly, p53, p21Cip1 and pRB deficiency had no effect on the morphological changes and loss of cell adhesion which is thought to be critical for metastasis. This indicates that possible association of these genes with metastasis potential would be unlikely to involve TGFbeta-induced EMT.

Sodium dietary restriction, knowledge, beliefs, and decision-making behavior of older females.

PURPOSE: The purposes of this qualitative/descriptive study were to (a) explore experiences and decision-making behaviors associated with adoption of a sodium-restricted diet (SRD) among older women with hypertension or heart failure and (b) identify healthcare system and contextual factors that facilitate or impede adherence to SRD. DATA SOURCES: Participants were 33 single older women, aged 65-98 years, residing in three congregate living facilities in the high-risk "coronary valley" area of the United States. A semistructured interview format was employed with three focus groups. The audio-taped transcribed data were content analyzed for themes by the researchers with the assistance of ATLAS.Ti computer software. CONCLUSIONS: Predominant themes were lack of SRD education by healthcare providers, a desire for more information about sodium, including the use of alternative herbal seasonings, and large-print informational materials. Eating alone with no motivation to cook and share meals was a contextual barrier to healthy nutrition. IMPLICATIONS FOR PRACTICE: To prevent costly hospitalizations and rehospitalization from nonadherence to SRD, clinicians need to provide more structured SRD education supplemented with printed brochures. Exploring the client's nutritional social setting may improve SRD adherence.

Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFbeta cell cycle arrest.

BACKGROUND: TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest. RESULTS: Primary hepatocytes isolated from Rb-floxed mice were infected with an adenovirus expressing CRE-recombinase to delete the Rb gene. In control cells treatment with TGFbeta prevented cells to enter S phase via decreased cMYC activity, activation of P16INK4A and P21Cip and reduction of E2F activity. In Rb-null hepatocytes, cMYC activity decreased slightly but P16INK4A was not activated and the great majority of cells continued cycling. Rb is therefore central to TGFbeta-induced cell cycle arrest in hepatocytes. However some Rb-null hepatocytes remained sensitive to TGFbeta-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21Cip1 and P53 we investigated whether these proteins regulate pRb-independent signaling to cell cycle arrest by evaluating the consequences of disruption of p53 and p21Cip1. Hepatocytes deficient in p53 or p21Cip1 showed diminished growth inhibition by TGFbeta. Double deficiency had a similar impact showing that in cells containing functional pRb; P21Cip and P53 work through the same pathway to regulate G1/S in response to TGFbeta. In Rb-deficient cells however, p53 but not p21Cip deficiency had an additive effect highlighting a pRb-independent-P53-dependent effector pathway of inhibition of E2F activity. CONCLUSION: The present results show that otherwise genetically normal hepatocytes with disabled p53, p21Cip1 or Rb genes respond less well to the antiproliferative effects of TGFbeta. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRb function, and to a lesser extend P21Cip1 and P53 in hepatocytes may represent an additional new mechanism of escape from TGFbeta-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development.

Impact of anxiety and perceived control on in-hospital complications after acute myocardial infarction.

OBJECTIVES: We tested the hypothesis that perception of control moderates any relationship between anxiety and in-hospital complications (i.e., recurrent ischemia, reinfarction, sustained ventricular tachycardia or fibrillation, and cardiac death) in patients with acute myocardial infarction (AMI). BACKGROUND: Anxiety is common among patients with AMI, but whether it is associated with poorer outcomes is controversial. Conflicting findings about the relationship of anxiety with cardiac morbidity and mortality may result from failure to consider the moderating effect of perceived control. METHODS: This was a prospective examination of the association among anxiety, perceived control, and subsequent in-hospital complications among patients (N = 536) hospitalized for AMI. RESULTS: Patients' mean anxiety level was double that of the published mean norm. Patients with higher levels of perceived control had substantially lower anxiety (p = .001). A total of 145 (27%) patients experienced one or more in-hospital complications. Patients with higher levels of anxiety had significantly more episodes of ventricular tachycardia, ventricular fibrillation, and reinfarction and ischemia (p < .01 for all). In a multivariate hierarchical logistic regression model, left ventricular ejection fraction, history of myocardial infarction, anxiety score, and the interaction of anxiety and perceived control were significant predictors of complications. CONCLUSION: Anxiety during the in-hospital phase of AMI is associated with increased risk for in-hospital arrhythmic and ischemic complications that is independent of traditional sociodemographic and clinical risk factors. This relationship is moderated by level of perceived control such that the combination of high anxiety and low perceived control is associated with the highest risk of complications.

Comparison of anxiety between smokers and nonsmokers with acute myocardial infarction.

BACKGROUND: Increased anxiety correlates with increased complications after acute myocardial infarction. Anxiety levels and use of anxiolytic agents have not been compared between smokers and nonsmokers hospitalized because of acute myocardial infarction. OBJECTIVES: To compare anxiety level, sociodemographic factors, and clinical variables between smokers and nonsmokers hospitalized with acute myocardial infarction and to examine predictors of use of beta-blockers and anxiolytic agents among smokers and nonsmokers. METHODS: Secondary data analysis of a prospective multisite study on anxiety in 181 smokers and 351 nonsmokers with acute myocardial infarction. Anxiety was measured by using the State Trait Anxiety Inventory and the anxiety subscale of the Basic Symptom Inventory within 72 hours of admission. RESULTS: Smokers reported higher anxiety levels than nonsmokers reported on both anxiety scales. Female smokers reported the highest anxiety and peak pain levels of all, yet women were the least likely to receive anxiolytic agents. Smoking status was not a predictor for anxiety level when sex, peak pain, use of beta-blockers in the hospital, and age were controlled for. However, smokers were twice as likely as nonsmokers to receive an anxiolytic agent and 60% more likely to receive a beta-blocker in the emergency department, and smokers were 80% more likely than nonsmokers to receive an anxiolytic agent during hospitalization when these variables were controlled. CONCLUSIONS: Older female smokers are at risk for complications because they are older than their male counterparts and less likely to receive beta-blockers and antianxiety medications in the emergency department.

Counseling parents to quit smoking.

It is estimated that 20%-50% of adult smokers reside with children, and the majority of these smokers (70%) continue to smoke inside their homes despite the adverse health effects of second hand smoke (SHS) for their children (Centers for Disease Control and Prevention, 1997). Smoking is more prevalent among parents with lower incomes and less education (U.S. Surgeon General's Report, 2002a). Young persons, ages 20-40 in the family child-rearing stage, are more likely to be smokers. However, they usually have less time and financial resources for quitting smoking. To prevent the adverse health effects of SHS for children, pediatric nurses must provide parents with accurate information on affordable smoking cessation education resources. Evidenced-based smoking cessation guidelines, the cost and efficacy of prescription and over-the-counter (OTC) pharmacological aids, and essential counseling tips for parents are reviewed.

Additive effect of p53, p21 and Rb deletion in triple knockout primary hepatocytes.

Using Cre-Lox technology to inducibly delete Rb from wild-type, p21- and/or p53-deficient primary hepatocytes, we investigated the role of p53, p21 and pRb in the regulation of liver cell proliferation, polyploidization and death. These cellular decisions are critical to maintaining liver cell replacement in disease, and in determining the likelihood of carcinogenesis in chronic liver injury. Clearly, the present study shows a complex interplay between p53, p21 and pRb, which regulates the likelihood of hepatocytes stimulated from quiescence, to proliferate, undergo polyploidy or die. It reveals that these proteins act both in concert and independently, demonstrating that a small set of key cellular players is common to diverse cell decisions of fundamental importance to disease.

Smoking behavior and desire to quit among low-income female caregivers.

The purpose of this study was to examine smoking behavior and the desire to quit among low-income women. Two hundred and eight women caregivers were surveyed about their smoking status, exposure to environmental tobacco smoke in the home, and desire to quit smoking. Most of the smokers (74%) wanted to quit smoking. With a logistic regression model, the number of years smoked was the only significant predictor variable for the dependent variable of thoughts about quitting when age, years of smoking, number of children, marital status, number of smokers in the home, cigarettes smoked per day, and money spent per week on cigarettes were entered as independent variables. The fewer years smoked the more likely the women wanted to quit.

Counseling middle-aged women about physical activity using the stages of change.

PURPOSE: To discuss application of the Stages of Change theoretical framework and provide clinical tips on exercise adherence among midlife women. Included is a checklist to assist the nurse practitioner (NP) in effectively delivering the message. DATA SOURCES: Review of the current scientific literature on exercise adherence and the Stages of Change model. CONCLUSIONS: Middle-aged women comprise a unique population. Determining the woman's readiness for change using the Stages of Change model, NPs can routinely include appropriate exercise recommendations in their practices. IMPLICATIONS FOR PRACTICE: Nurse practitioners are in a unique position to promote healthy behaviors by counseling women in midlife about adopting an active lifestyle. Exercise counseling is an essential component of healthcare, especially among middle-aged women who are experiencing physical, emotional, and social changes.

How to help older adults quit smoking.

With the demographic trend toward an aging society, helping older smokers break a long-term nicotine addiction needs more attention. Clinicians should consider the subtle differences in the smoking patterns and the psychological meanings of smoking among older smokers when prescribing a successful smoking cessation modality. This article discusses the essential components of a smoking cessation program designed for these individuals.