Refining the nuclear localization signal within the Egr transcriptional coregulator NAB2.

NAB1 and 2 are coregulators for early growth response (Egr) transcription factors. The NAB1 nuclear localization signal (NLS) was previously described as a bipartite NLS of sequence R(X2 )K(X11 )KRXK. The sequence is conserved in NAB2 as K(X2 )R(X11 )KKXK; however, whether it functions as the NAB2 NLS has not been tested. We show that the KKXK motif in NAB2 is necessary and sufficient to mediate nuclear localization. Mutation of the KKXK motif to AAXA causes cytoplasmic localization of NAB2, while Lys/Arg-to-Ala mutations of the upstream K(X2 )R motif have no effect. Fusion of the KKXK motif to cytoplasmic protein eIF2Bε causes nuclear localization. Altogether, this study refines our knowledge of the NAB2 NLS, demonstrating that KKXK343-346 is necessary and sufficient for nuclear localization.

Role for Egr1 in the Transcriptional Program Associated with Neuronal Differentiation of PC12 Cells.

PC12 cells are a well-established model to study how differences in signal transduction duration can elicit distinct cell behaviors. Epidermal growth factor (EGF) activates transient ERK signaling in PC12 cells that lasts 30-60 min, which in turn promotes proliferation; nerve growth factor (NGF) activates more sustained ERK signaling that lasts 4-6 h, which in turns induces neuronal differentiation. Data presented here extend a previous study by Mullenbrock et al. (2011) that demonstrated that sustained ERK signaling in response to NGF induces preferential expression of a 69-member gene set compared to transient ERK signaling in response to EGF and that the transcription factors AP-1 and CREB play a major role in the preferential expression of several genes within the set. Here, we examined whether the Egr family of transcription factors also contributes to the preferential expression of the gene set in response to NGF. Our data demonstrate that NGF causes transient induction of all Egr family member transcripts, but a corresponding induction of protein was detected for only Egr1 and 2. Chromatin immunoprecipitation experiments provided clearest evidence that, after induction, Egr1 binds 12 of the 69 genes that are preferentially expressed during sustained ERK signaling. In addition, Egr1 expression and binding upstream of its target genes were both sustained in response to NGF versus EGF within the same timeframe that its targets are preferentially expressed. These data thus provide evidence that Egr1 contributes to the transcriptional program activated by sustained ERK signaling in response to NGF, specifically by contributing to the preferential expression of its target genes identified here.

The Psychohistory of Child Maltreatment Among Antebellum Slaveholders: Part II.

In the psychohistory of the antebellum South, the extent of child abuse in slaveholder families is important for understanding how members of the southern elite were reared and the extent to which they were infected with the toxic residue of their elders' passions and rages. It is argued that the Old South was a developing region, rather than an already developed one. Consequently, the rate of child abuse that is characteristic of contemporary postindustrial societies is not the proper paradigm for conceptualizing the abuse rate in slaveholder families. It is proposed instead that the rate of child abuse in contemporary developing societies is a better fit for estimating abuse in the antebellum South. Societal and familial variables impinging on the abuse of slaveholder children­corporal punishment, alcohol consumption, hyper-masculinity, a traumatogenic culture of violence, wife abuse, maternal ambivalence and neglect, miscegenation and incest are discussed, as is the likelihood of maltreatment by slaves. Using a study of child abuse across 28 nations, tentative rates of abuse are proposed.

The Psychohistory of Child Maltreatment Among Antebellum Slaveholders.

Examining the inner workings of the slaveholder family, including slave caretakers, this article probes the psychodynamics of slaveholder development to assess the extent of child abuse in the Old South. Childcare was haphazard and premised on paternal absence, maternal ambivalence, and the exigencies of slave surrogacy. Corporal punishment, sanctified by southern religion, was the rule. The likelihood of slave negligence and retaliatory attacks against slaveholder children are addressed. Childrearing practices such as swaddling, aunt adoption, and maternal incest are considered, as well as the possible usage of a West African cleansing ritual. The article classifies planter families within the Ambivalent Mode of parent-child relations and suggests the restaging of childhood trauma as the underlying dynamic in the march to civil war.

Voluntary wheel-running attenuates insulin and weight gain and affects anxiety-like behaviors in C57BL6/J mice exposed to a high-fat diet.

It is widely accepted that lifestyle plays a crucial role on the quality of life in individuals, particularly in western societies where poor diet is correlated to alterations in behavior and the increased possibility of developing type-2 diabetes. While exercising is known to produce improvements to overall health, there is conflicting evidence on how much of an effect exercise has staving off the development of type-2 diabetes or counteracting the effects of diet on anxiety. Thus, this study investigated the effects of voluntary wheel-running access on the progression of diabetes-like symptoms and open field and light-dark box behaviors in C57BL/6J mice fed a high-fat diet. C57BL/6J mice were placed into either running-wheel cages or cages without a running-wheel, given either regular chow or a high-fat diet, and their body mass, food consumption, glucose tolerance, insulin and c-peptide levels were measured. Mice were also exposed to the open field and light-dark box tests for anxiety-like behaviors. Access to a running-wheel partially attenuated the obesity and hyperinsulinemia associated with high-fat diet consumption in these mice, but did not affect glucose tolerance or c-peptide levels. Wheel-running strongly increased anxiety-like and decreased explorative-like behaviors in the open field and light-dark box, while high-fat diet consumption produced smaller increases in anxiety. These results suggest that voluntary wheel-running can assuage some, but not all, of the physiological problems associated with high-fat diet consumption, and can modify anxiety-like behaviors regardless of diet consumed.

Psychohistory and Family Among Antebellum Slaveholders.

This article examines the macroscopic reasons for maternal rage and its injection into slaveholder children in the antebellum South. It is argued that the misogyny that infected antebellum life metastasized in southern mistresses and affected the way they felt about themselves and their children. As mothers, they were casual parents, concerned with molding the character of their charges, rearing warriors and proper ladies, but uninterested in caring for them and helping them realize their own aspirations. It is argued that the misanthropic rage that they injected into their children constituted the poison that each generation of slaveholders had to ventilate into poison containers, slaves, as a homeostatic means of psycho-emotional survival. This intergenerational process of poison injection--from father to mother, from mother to child, from child to slave, constituted the process that insured the perpetuation of the psychic structure necessary for the continuation of slavery from generation to generation.

The Psychohistory of Climate Change: A Clear and Present Danger.

The inability of contemporary society to transition from fossil fuels to green energy was engineered by the oil industry, which has worked for decades to stifle the emergence of ecological awareness. Climate change presents a clear and present danger to our society. The present dilemma is the result of the psychopathic corporate system, that pillages the earth for profit (extractivism), evades the real costs of production (externalizing costs), and pursues only self-interest (the best interests of the corporation). The well-being of the environment is thereby sacrificed for profit and our collective future is jeopardized. The corporate practice of creative destruction has gained such Thanatos-like momentum that it threatens the earth in its obsession with profit. Conservatives, under the sway of the unreality principle, dismiss climate change and block efforts to solve climate issues. For them, science is wish fulfillment based on denial. Their willingness to endanger the world results from their authoritarian upbringing. The corporal punishment they endured as children left a residue of rage­the impulse to destroy life­that underlies corporate rationality's assault on the environment. Fearing death, they inflict death in a perverse ritual to feel alive. Compensating for the narcissistic wounds of childhood through the formation of a grandiose self, they are identified with the omnipotent parent, and alternate between suicidal impulse and escape via godlike technology. Conservative attacks on women highlight the residual wounds of relatedness to their dragon mothers, just as their relatedness to the environment involves a restaging of their encounters with their breast and toilet mothers. Solving environmental problems, however, will require more than overcoming conservative intransigence. The concept of ecological debt accentuates the importance of consumer choice for the environment. The United Nations Human Development Report 2015 regarding CO2 emissions demonstrates the massive environmental debt of Northern Hemisphere societies and suggests the magnitude of the transformation necessary to resolve the problem of climate change.

Psychohistory and Slavery: Preliminary Issues.

"Psychohistory and Slavery: Preliminary Issues," begins an examination of slavery in the antebellum South. The paper suggests that how slavery and the group-fantasy of white male supremacy were perpetuated among slaveholders is a question of fundamental importance for psychohistorians. The family and childrearing are the focus of attention. Given the ferocity of slavery, it is argued that the psychological and emotional consequences of this barbarism were not limited to the slaves themselves, but had significant impact on the slaveholders as well-their parenting, their children, and their children's parenting of the next generation. In each generation the trauma of slavery was injected into slaveholder children and became a fundamental component of elite Southern personality.

Development of an Algorithm to Classify Colonoscopy Indication from Coded Health Care Data.

INTRODUCTION: Electronic health data are potentially valuable resources for evaluating colonoscopy screening utilization and effectiveness. The ability to distinguish screening colonoscopies from exams performed for other purposes is critical for research that examines factors related to screening uptake and adherence, and the impact of screening on patient outcomes, but distinguishing between these indications in secondary health data proves challenging. The objective of this study is to develop a new and more accurate algorithm for identification of screening colonoscopies using electronic health data. METHODS: Data from a case-control study of colorectal cancer with adjudicated colonoscopy indication was used to develop logistic regression-based algorithms. The proposed algorithms predict the probability that a colonoscopy was indicated for screening, with variables selected for inclusion in the models using the Least Absolute Shrinkage and Selection Operator (LASSO). RESULTS: The algorithms had excellent classification accuracy in internal validation. The primary, restricted model had AUC= 0.94, sensitivity=0.91, and specificity=0.82. The secondary, extended model had AUC=0.96, sensitivity=0.88, and specificity=0.90. DISCUSSION: The LASSO approach enabled estimation of parsimonious algorithms that identified screening colonoscopies with high accuracy in our study population. External validation is needed to replicate these results and to explore the performance of these algorithms in other settings.

Prevalence of colonoscopy before age 50.

OBJECTIVE: Describe the prevalence of colonoscopy before age 50, when guidelines recommend initiation of colorectal cancer screening for average risk individuals. METHOD: We assembled administrative health records that captured receipt of colonoscopy between 40 and 49-years of age for a cohort of 204,758 50-year-old members of four US health plans and used backward recurrence time models to estimate trends in receipt of colonoscopy before age 50 and variation in early colonoscopy by age and sex. We also used self-reported receipt of colonoscopy from 27,157 40- to 49-year-old respondents to the 2010 National Health Interview Survey (NHIS) to estimate the association between early colonoscopy and sex, race/ethnicity, and geographic location based on logistic regression models that accounted for the complex NHIS sampling design. RESULTS: About 5% of the health plan cohort had a record of colonoscopy before age 50. Receipt of early colonoscopy increased significantly from 1999 to 2010 (test for linear trend, p<0.0001), was more likely among women than men (RR=1.9, 95% CI 1.14-1.24) and in the east coast health plan compared to west coast and Hawaii plans. The NHIS analysis found that early colonoscopy was more likely in Northeastern residents compared to residents in the West (odds ratio=1.75, 95% CI 1.28-2.39). CONCLUSION: Colonoscopy before age 50 is increasingly common.

Follow-up and clinical significance of unsatisfactory liquid-based Papanicolaou tests.

BACKGROUND: To the authors' knowledge, few studies to date have examined adherence to recommended guidelines for follow-up and outcomes after an unsatisfactory Papanicolaou (Pap) test (UPT) with liquid-based technologies. METHODS: Within 4 US health plans, the median time to follow-up and the percentage of patients with follow-up testing by 120 days was calculated after a UPT. Multivariable analyses evaluated the association between clinical factors and follow-up testing. The authors compared the risk of a diagnosis of cervical intraepithelial neoplasia of type 2 or worse (CIN2+) after a UPT with the risk after a satisfactory Pap test while controlling for study site, test year, and other covariates. RESULTS: A total of 634,644 Pap tests performed between 2004 and 2010 were included in the current study. Of 1442 UPTs, 53.4% had follow-up testing within 120 days; follow-up differed across the health plans (P<.001) and was found to be higher among patients aged <50 years (57.2% vs 48.8%; P = .01) and those with positive human papillomavirus (HPV) results (84.6% vs 53.9; P <.01). The risk of CIN2+ was similar for patients with both unsatisfactory and satisfactory Pap tests. However, after a UPT, the variables of age <50 years, having no previous history of Pap testing, having a history of a previous abnormal Pap test, and positive HPV status were all found to be risk factors for CIN2+; a positive HPV test was found to be the strongest risk factor for developing CIN2+. A negative HPV test result was protective for a CIN2+ diagnosis. CONCLUSIONS: Various clinical factors associated with the risk of CIN2+ appear to influence the receipt of follow-up after a UPT. HPV test results in patients with UPTs might be used in follow-up strategies; specifically, a negative test result might reduce the urgency for repeat Pap testing.

Impact of hypertension on healthcare costs among children.

OBJECTIVES: Despite the significant prevalence of elevated blood pressure (BP) and body mass index (BMI) in children, few studies have assessed their combined impact on healthcare costs. This study estimates healthcare costs related to BP and BMI in children and adolescents. STUDY DESIGN: Prospective dynamic cohort study of 71,617 children aged 3 to 17 years with 208,800 child years of enrollment in integrated health systems in Colorado or Minnesota between January 1, 2007, and December 31, 2011. METHODS: Generalized linear models were used to calculate standardized annual estimates of total, inpatient, outpatient, and pharmacy costs, outpatient utilization, and receipt of diagnostic and evaluation tests associated with BP status and BMI status. Results: Total annual costs were significantly lower in children with normal BP ($736, SE = $15) and prehypertension ($945, SE = $10) than children with hypertension ($1972, SE = $74) (P <.001, each comparison), adjusting for BMI. Total annual cost for children below the 85th percentile of BMI ($822, SE = $8) was significantly lower than for children between the 85th and 95th percentiles ($954, SE = $45) and for children at or above the 95th percentile ($937, SE = $13) (P <.001, each), adjusting for HT. CONCLUSIONS: This study shows strong associations of prehypertension and hypertension, independent of BMI, with healthcare costs in children. Although BMI status was also statistically significantly associated with costs, the major influence on cost in this large cohort of children and adolescents was BP status. Costs related to elevated BMI may be systematically overestimated in studies that do not adjust for BP status.

Severe obesity in children: prevalence, persistence and relation to hypertension.

BACKGROUND: Newer approaches for classifying gradations of pediatric obesity by level of body mass index (BMI) percentage above the 95th percentile have recently been recommended in the management and tracking of obese children. Examining the prevalence and persistence of severe obesity using such methods along with the associations with other cardiovascular risk factors such as hypertension is important for characterizing the clinical significance of severe obesity classification methods. METHODS: This retrospective study was conducted in an integrated healthcare delivery system to characterize obesity and obesity severity in children and adolescents by level of body mass index (BMI) percentage above the 95th BMI percentile, to examine tracking of obesity status over 2-3 years, and to examine associations with blood pressure. Moderate obesity was defined by BMI 100-119% of the 95th percentile and severe obesity by BMI ≥120% × 95th percentile. Hypertension was defined by 3 consecutive blood pressures ≥95th percentile (for age, sex and height) on separate days and was examined in association with obesity severity. RESULTS: Among 117,618 children aged 6-17 years with measured blood pressure and BMI at a well-child visit during 2007-2010, the prevalence of obesity was 17.9% overall and was highest among Hispanics (28.9%) and blacks (20.5%) for boys, and blacks (23.3%) and Hispanics (21.5%) for girls. Severe obesity prevalence was 5.6% overall and was highest in 12-17 year old Hispanic boys (10.6%) and black girls (9.5%). Subsequent BMI obtained 2-3 years later also demonstrated strong tracking of severe obesity. Stratification of BMI by percentage above the 95th BMI percentile was associated with a graded increase in the risk of hypertension, with severe obesity contributing to a 2.7-fold greater odds of hypertension compared to moderate obesity. CONCLUSION: Severe obesity was found in 5.6% of this community-based pediatric population, varied by gender and race/ethnicity (highest among Hispanics and blacks) and showed strong evidence for persistence over several years. Increasing gradation of obesity was associated with higher risk for hypertension, with a nearly three-fold increased risk when comparing severe to moderate obesity, underscoring the heightened health risk associated with severe obesity in children and adolescents.

Approaches for classifying the indications for colonoscopy using detailed clinical data.

BACKGROUND: Accurate indication classification is critical for obtaining unbiased estimates of colonoscopy effectiveness and quality improvement efforts, but there is a dearth of published systematic classification approaches. The objective of this study was to evaluate the effects of data-source and adjudication on indication classification and on estimates of the effectiveness of screening colonoscopy on late-stage colorectal cancer diagnosis risk. METHODS: This was an observational study in members of four U.S. health plans. Eligible persons (n = 1039) were age 55-85 and had been enrolled for 5 years or longer in their health plans during 2006-2008. Patients were selected based on late-stage colorectal cancer diagnosis in a case-control design; each case patient was matched to 1-2 controls by study site, age, sex, and health plan enrollment duration. Reasons for colonoscopies received in the 10-year period before the reference date were collected from three medical records sources (progress notes; referral notes; procedure reports) and categorized using an algorithm, with committee adjudication of some tests. We evaluated indication classification concordance before and after adjudication and used logistic regressions with the Wald Chi-square test to compare estimates of the effects of screening colonoscopy on late-stage colorectal cancer diagnosis risk for each of our data sources to the adjudicated indication. RESULTS: Classification agreement between each data-source and adjudication was 78.8-94.0% (weighted kappa = 0.53-0.72); the highest agreement (weighted kappa = 0.86-0.88) was when information from all data sources was considered together. The choice of data-source influenced the association between screening colonoscopy and late-stage colorectal cancer diagnosis; estimates based on progress notes were closest to those based on the adjudicated indication (% difference in regression coefficients = 2.4%, p-value = 0.98), as compared to estimates from only referral notes (% difference in coefficients = 34.9%, p-value = 0.12) or procedure reports (% difference in coefficients = 27.4%, p-value = 0.23). CONCLUSION: There was no single gold-standard source of information in medical records. The estimates of colonoscopy effectiveness from progress notes alone were the closest to estimates using adjudicated indications. Thus, the details in the medical records are necessary for accurate indication classification.

Body mass and weight change in adults in relation to mortality risk.

Using data from the National Institutes of Health-AARP Diet and Health Study, we evaluated the influence of adulthood weight history on mortality risk. The National Institutes of Health-AARP Diet and Health Study is an observational cohort study of US men and women who were aged 50-71 years at entry in 1995-1996. This analysis focused on 109,947 subjects who had never smoked and were younger than age 70 years. We estimated hazard ratios of total and cause-specific mortality for recalled body mass index (BMI; weight (kg)/height (m)(2)) at ages 18, 35, and 50 years; weight change across 3 adult age intervals; and the effect of first attaining an elevated BMI at 4 successive ages. During 12.5 years' follow-up through 2009, 12,017 deaths occurred. BMI at all ages was positively related to mortality. Weight gain was positively related to mortality, with stronger associations for gain between ages 18 and 35 years and ages 35 and 50 years than between ages 50 and 69 years. Mortality risks were higher in persons who attained or exceeded a BMI of 25.0 at a younger age than in persons who reached that threshold later in adulthood, and risks were lowest in persons who maintained a BMI below 25.0. Heavier initial BMI and weight gain in early to middle adulthood strongly predicted mortality risk in persons aged 50-69 years.