Times Greater Risk Research Articles

Abstract 264: High Serum Lp(a) Levels Are Associated With Subclinical 3-Vessel and Left Main Coronary Disease, Severe Stenoses and Plaque Volume in Apparently Healthy African Americans

Background: Serum Lp(a) is a CAD risk factor in European Americans (EA). Levels are 2-3 fold higher in African Americans (AA) but associations with CAD are inconsistent, including coronary calcium. The relationship of race-specific levels of Lp(a) with the extent and severity of subclinical total coronary plaque (TCP) has not been described. Methods: We screened 418 apparently healthy individuals for risk factors and coronary plaque using advanced CTA. TCP volumes (mm3) were quantified using a validated automated method. Lp(a) was measured by ELISA. The association of Lp(a) with plaque was investigated by race. Multivariable modeling was performed with adjustment for traditional CAD risk factors, including LDL-C, and intrafamilial correlations. Results: Mean age was 51±11 years; 57% female; 34% AA. Lp(a) was higher in AA than in EA (median 38 [18,65] vs 17 [10,33], p<0.0001). Plaque was present in 45% of AA and 47% of EA. In those with plaque continuous Lp(a) levels were associated with plaque volume in AA (β=8.83, p<0.0001) but not EA (β=1.49, p=0.45). Lp(a) was strongly associated with plaque extent and severity (Table), and with TCP volume in AA (adjusted p=0.01) but not in EA (p=0.10). In AA, Lp(a)≥60 mg/dL (top quintile) was independently associated with a 3.7 times greater risk of 3-vessel and/or LM disease (95% CI:1.4-10.3), a 6.6 times greater risk of having a stenosis ≥50% (95% CI:1.4-38.4, p=0.02), and higher TCP (median 438 [203,1247] vs 142 [73,262], p=0.001). Conclusion: High Lp(a) is strongly associated with coronary plaque extent, severity, and volume in apparently healthy AA. High levels of Lp(a) may be particularly important in the pathogenesis of CAD in AA.

Transporting pharmacogenomics into clinical practice

A very interesting and concise study by Clarke et al. in this month’s issue of the Journal highlights important principles about the genetic determinants of drug disposition and toxicity, and the impact of underlying liver disease on adverse events from medications. The findings provide an opportunity to consider the current state of our knowledge about how genetic variations affect drug metabolism (i.e., pharmacogenomics), and to highlight efforts being developed to integrate genetic information into the clinical care of patients. The Clarke study is the most recent work in a series of publications by the authors examining the behavior of the hepatic uptake transporter organic ion transporting polypeptide-1B1 (OATP1B1) in drug disposition. This well-characterized membrane transporter regulates the uptake of organic compounds from the circulation into the hepatocyte where they can be metabolized. OATP1B1 has a large number of genetic variants, or single nucleotide polymorphisms (SNPs), that confer widely variable uptake activity by the transporter [1]; variants that confer reduced uptake lead to slower clearance of substrates, and therefore higher blood levels. That is exactly the case with several single nucleotide polymorphisms (SNPs) that have been linked to increased risk of myopathy associated with statin drugs used to treat hypercholesterolemia [1–3]. While statins are remarkably safe in general, individuals with these variants can be at up to 20 times greater risk of myopathy. Moreover, because these transporters have hundreds of substrates, altered activity can also lead to many adverse drug-drug interactions, in addition to altering the pharmacokinetics of individual drugs [1]. As hepatologists know well, many patients with hypercholesterolemia who are treated with statins are also obese and have metabolic syndrome complicated by non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). These conditions introduce the confounding effect of underlying fatty liver disease, which may further alter hepatic drug metabolism [4–6]. Additionally, the increased adiposemass in these patients can lead to accumulation of lipophilic drugs in fat cells and hepatocytes. The Clarke study examines how these two important variables, namely the genetic regulation of OATP1B1 activity and

Obesity and the risk of stillbirth: a population-based cohort study

Obesity is a known risk factor for stillbirth. However, this relationship has not been characterized fully. We attempted to further examine this relationship with a focus on delivery near and at term. We designed a retrospective cohort study of singleton nonanomalous live births and stillbirths in the states of Washington and Texas to examine the associations of maternal prepregnancy body mass index (BMI) and risk of stillbirth. Confounder-adjusted hazard ratio of stillbirth in relation to BMI was estimated through Cox proportional hazards regression model. The hazard ratio was used to estimate the population-attributable risk. We also estimated the fetuses who were at risk for stillbirth based on gestational age. Among 2,868,482 singleton births, the overall stillbirth risk was 3.1 per 1000 births (n = 9030). Compared with normal-weight women, the hazard ratio for stillbirth was 1.36 for overweight women, 1.71 for class I obese women, 2.00 for class II obese women, 2.48 for class III obese women, and 3.16 for women with a BMI of ≥50 kg/m(2). The fetuses who are at risk for stillbirth increased after 39 weeks' gestation for each obesity class; however, the risk increased more rapidly with increasing BMI. Women with a BMI of ≥50 kg/m(2) were at 5.7 times greater risk than normal weight women at 39 weeks' gestation and 13.6 times greater at 41 weeks' gestation. Obesity was associated with nearly 25% of stillbirth that occurred between 37 and 42 weeks' gestation. There is a pronounced increase in the risk of stillbirth with increasing BMI; the association is strongest at early- and late-term gestation periods. Extreme maternal obesity is a significant risk factor for stillbirth.

Psychiatric symptoms are not an independent mortality risk factor in community-living elderly people

Mortality risk factors have attracted great research interest in recent years. Physical illness is strongly associated with mortality risk in elderly people. Furthermore, a relationship between mortality risk and psychiatric disease in the elderly has gained research interest. This is a prospective longitudinal multicenter study. A sample of 324 participants was selected as a representative sample of community members aged 65 years and older and living in Huesca (Spain). The following information was collected: affiliation data, severity of physical illness, psychosocial, and psychiatric factors. Statistical analyses were completed with a multivariate analysis in order to control possible confounding variables related to mortality. Of the initially selected sample, 293 participants were assessed. Sixty-four participants died (21.8%, 95% CI [16.9%, 26.7%]), 5.3% annual rate, and 46.1% showed symptomatology of mental disorders. Older people have eight times greater risk of mortality. The risk increased 53 times in patients affected by several physical illness. No relationship between cognitive dysfunction and depressive symptomatology was observed. In fact, physical condition was associated with depression, and the percentage of participants with depressive symptoms increased according to the severity of physical illness. Severity of physical illness and age are independently and directly associated with mortality in the elderly people. Therefore, severity of physical illness seems to be a crucial factor in the bi-directional association between mortality and depression, acting as a risk factor independently for both. So the relationship between depression and mortality can be affected by the severity of physical illness.

Abstract W P225: The Relationship between Leukocytosis and Time to Neurodeterioration

Background: Previous research has illustrated how leukocytosis after acute ischemic stoke (AIS) is related to poor functional outcome. A main predictor of poor functional outcome is neurodeterioration (ND). We sought to explore the relationship between leukocytosis and time to ND to identify a risk factor for a process that predicts poor functional outcome. Methods: Patients admitted to our stroke center (07/08-06/12) were retrospectively assessed. Leukocytosis was defined as WBC >11,000, ND was characterized as ≥ 2 point increase in NIHSS scale and poor functional outcome was classified as modified Rankin Scale (mRS) of 3-6. Patients were grouped into 2 categories: (1) the leukocytosis group- those who developed leukocytosis ≥24 hours after admission and those who presented with leukocytosis and remained at 24 hours and, (2) the non-leukocytosis group- those that did not have leukocytosis and those where the leukocytosis resolved within 24 hours of admission. Results: A cohort of AIS patients (N=476) with median age 64 years, 43% female and 69% Black were assessed. Of the patients with ND (27%), median time to ND was 43 hours. In the leukocytosis group (N=84), 42 (50.6%) of them developed ND. In the non-leukocytosis group (N=312), 75 (24.5%) developed ND. Leukocytosis within 24 hours of admission is predictive of earlier time to ND (p<0.0001; Figure 1). Adjusting for age, stroke severity, glucose, tPA and infection, the leukocytosis group had a 2 times greater risk for developing ND (HR 2.49, 95%CI 1.61-3.84, p<0.0001). Conclusion: Having leukocytosis persist from admission to 24 hours or developing leukocytosis within 24 hours of admission is a significant predictor of early ND, which often results in poor functional outcome. Identifying such a predictor can enable physicians to identify those at risk for ND and subsequent poor functional outcomes. Future studies are needed to identify if interventions targeting leukocytosis may improve outcome after stroke.

Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease

Comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) represents the fourth leading cause of morbidity and mortality worldwide, and women have a two times greater risk than men. Thus understanding the pathophysiology has widespread implications for attenuation and prevention of disease burden. We suggest that sex-dependent MDD-CVD comorbidity may result from alterations in fetal programming consequent to the prenatal maternal environments that produce excess glucocorticoids, which then drive sex-dependent developmental alterations of the fetal hypothalamic-pituitary-adrenal (HPA) axis circuitry impacting mood, stress regulation, autonomic nervous system (ANS), and the vasculature in adulthood. Evidence is consistent with the hypothesis that disruptions of pathways associated with gamma aminobutyric acid (GABA) in neuronal and vascular development and growth factors have critical roles in key developmental periods and adult responses to injury in heart and brain. Understanding the potential fetal origins of these sex differences will contribute to development of novel sex-dependent therapeutics.

Vasodilator Response in Exercise Induced Pulmonary Hypertension

Background: Micronutrient deficiency is an important factor to determine quality of patients’ diets. Micronutrient deficiency is known to be associated with adverse health outcome in patients with heart failure (HF). A strict low sodium diet is assumed to be related to inadequate food intake, resulting in poor nutritional status. However, there is limited research about the link of a strict low sodium diet to micronutrient deficiency. The purpose of this study was to determine whether a strict low sodium diet affects micronutrient deficiency. We hypothesized that less than 2g of daily sodium intake independently predict higher micronutrient deficiency. Methods: A total of 100 outpatients with HF (age 61612 years, 27% female, 50% New York Heart Association [NYHA] class III/IV) completed a 3-day food diary to estimate the total number of micronutrient deficiencies (range 0 to 15) and daily sodium intake. The Computer Aided Nutrition Analysis Program for Professionals was used to analyze the food diaries and determine dietary micronutrient deficiencies including phosphate, calcium, magnesium, niacin, zinc, folate, selenium, vitamin B1, B2, B6, B12, C, D, E and K. Patients were divided into 2 groups by the median split as 5 of a total number of micronutrient deficiencies; higher vs. lower micronutrient deficiency. Patients were divided into 4 groups by the level of daily sodium intake; ! 2g, 2 to 3g, 3 to 4g, and O 4g. Hierarchical logistic regression was used to determine the association of less than 2g of daily sodium intake with micronutrient deficiency. Results: The average sodium intake was 3.2 6 1.4 g/day. Fourteen patients had less than 2g of daily sodium intake. A half of patients had at least 5 micronutrient deficiencies (range 0-15). The most common micronutrient deficiencies were calcium, magnesium, and vitamin D. In univariate logistic regression, less than 2g of daily sodium intake independently predicted higher micronutrient deficiency (OR5 4.67, 95% CI5 1.04 20.94, p5 0.044). In hierarchical multivariate logistic regression, less than 2g of daily sodium intake was independently associated with an almost 9 times greater risk for higher micronutrient deficiency after controlling for age, gender, etiology, body mass index, NYHA class, ejection fraction, total comorbidity score, and use of diuretics (OR 5 9.08, 95% CI 5 1.06 20.5, p 5 0.027). Conclusion: This finding shows that patients with HF had poor nutritional intake if daily sodium intake was restricted to less than 2g. This result suggests clinically relevant evidence for raising concerns about a strict low sodium diet in patients with HF.

Risk factors of chronic hepatitis in antiretroviral-treated HIV infection, without hepatitis B or C viral infection

BackgroundIncreasing rates of non-AIDS defining illnesses, and in particular liver diseases, have been found after the initiation of highly active antiretroviral therapy. However, there is little evidence concerning the risk factors for and clinical characteristics of liver disease in antiretroviral (ARV)-treated HIV infection, in the absence of hepatitis B or C viral co-infection.MethodsA nested case–control study of HIV infected volunteers, matched by starting date of anti-retroviral treatment, was conducted in a Thai cohort studied from Nov 2002 - July 2012. Cases were defined as those subjects with an elevated alanine aminotransferase (ALT ≥ 40 IU/L) at two consecutive visits six months apart, while controls were defined as individuals who never demonstrated two consecutive elevated ALT results and had a normal ALT result (< 40 IU/L) at their last visit. Both groups had normal ALT levels prior to ARV initiation. Clinical demographics and risk factors for chronic hepatitis including HIV-related illness, ARV treatment and metabolic diseases were collected and analyzed. Conditional logistic regression was used to determine risk factors for chronic hepatitis in HIV infection.ResultsA total of 124 matched pairs with HIV infection were followed over 3,195 person-years. The mean age (±SD) was 33.0 ± 7.3 years, with 41.1% of subjects being male. The incidence of chronic hepatitis was 5.4 per 100 person-years. The median time from initiation of ARV to chronic hepatitis was 1.3 years (IQR, 0.5-3.5). From univariate analysis; male sex, plasma HIV-1 RNA level > 5 log 10 copies/ml, metabolic syndrome at baseline visit, high BMI > 23 kg/m2, abnormal HDL cholesterol at time of ALT elevation and treatment experience with NNRTI plus boosted PI were selected (p value < 0.2) to the final model of multivariate analysis. Male sex had 3.1 times greater risk of chronic hepatitis than the females by multivariate analysis (adjusted OR, 95% CI: 3.1, 1.5-6.3, p =0.002). High BMI ≥ 23 kg/m2 was also associated with 2.4 times greater risk of chronic hepatitis (adjusted OR, 95% CI: 2.4, 1.2-4.8, p = 0.01).ConclusionsChronic hepatitis in ARV-treated HIV-infected patients is common and may lead to a major health care problem. Male sex and high BMI ≥ 23 kg/m2 carry higher risks for developing chronic hepatitis in this study. Therefore, these patients should be closely monitored for long-term hepatotoxicity.

Long-term survival of GSB III elbow prostheses and risk factors for revisions

Although replacement of the elbow joint is a complex procedure there is not much clinical evidence that contributes to surgical decision-making, mainly due to small clinical samples and short follow-up. Therefore, we performed a long-term analysis up to 30years after implantation of a GSB III total elbow prosthesis to quantify long-term outcome and to identify possible risk factors for implant revision. All patients who received a primary GSB III total elbow prosthesis between 1978 and 1998 were included. Information about patient characteristics, the latest known implant status and possible risk factors were collected, Kaplan-Meier survival curves plotted, and 10- and 20-year survival calculated. The cohort was stratified for known risk factors such as diagnosis, age, or gender and included in a Cox regression analysis. A total of 253 patients [mean age at operation 56.9years (range from 17.5 to 84years)] with 293 GSB III prostheses were included. The median follow-up was 9.1years (0months to 29.3years). Whereas 81 prostheses did not need revision during the observation period, 76 had been implanted in patients who died before any revision was required, and 75 had not been revised by the last known follow-up. 61 prostheses were revised. This corresponds to a 10-year survival rate of 0.8 (95% CI 0.74-0.85) and a 20-year rate of 0.67 (95% CI 0.57-0.76). Prostheses in patients with post-traumatic conditions survived significantly shorter than those in patients with rheumatoid arthritis; previous operations lead to a 2.8 times greater risk of revision (p=0.004). Neither age at implantation nor gender had a significant influence on prosthesis survival. The results indicate a good long-term prognosis for this design. The prognosis has to be adjusted for the underlying disease. Previous operations such as joint reconstruction significantly increase the risk of revision.

Mycobacterial disease in renal allograft recipients.

Implication for health policy/practice/research/medical education:Solid organ transplant recipients have impaired cell-mediated immunity, and are at increased risk of mycobacterial infection. Mycobacterium tuberculosis infection (TB) has a high mortality rate among this population. The diagnosis of tuberculosis in solid organ transplant recipients is a big challenge and needs rapid and accurate modalities. These patients have 3.8 time greater risk of developing extra-pulmonary TB than general population. High index of suspicion and applying with invasive diagnostic procedure are needed for diagnosis of TB in renal transplanted patients.

P428 New opportunities overcoming of the secondary inefficiencies of the anticytokine therapy in patients with inflammatory bowel disease

risk in a UK population, and to evaluate whether changes in 5-ASA formulation increase the risk of relapse. Methods: A retrospective cohort study was conducted using a UK pharmacy dispensing database. Adults who received continuous treatment with Asacol® (mesalazine) 400mg or 800mg oral tablets during a 6 month baseline period were followed for 18 months. Adherence was measured using the medication possession ratio (MPR); MPR 80 was classed as adherent. In this study, a doubling of MPR (peak MPR, indicating a doubling of 5-ASA dose) was used as a proxy for relapse. Switch was identified as a change to another oral 5-ASA. Relationships between adherence, switch and relapse were examined using cohort, nested case-control and subgroup analyses, controlled for age and gender. Results: 1,731 patient records were extracted, of which 568 patients received Asacol and had complete baseline and follow-up data (age, sex, interpretable MPR) for inclusion in the analysis (mean age 56 yrs, 51.2% male). There was a significant association between relapse and adherence during the follow-up period (RR 1.44, 95%CI 1.08 1.94; p = 0.014), indicating a relapse was more likely with lower adherence (mean MPR). In a subgroup of Asacol patients adherent in the baseline period (n = 276), switching medication was significantly associated with relapse in the follow-up period: 26.3% (62/236) who switched suffered relapses, compared to 7.5% (3/40) of those who did not switch (RR 3.5, 95%CI 1.16 10.62; p = 0.008). Conclusions: Non-adherence to mesalazine significantly increased the likelihood of relapse in this UK population. Moreover, in this study, adherent patients switched to another 5-ASA had a 3.5 times greater risk of relapse compared to nonswitched patients. This analysis represents the first evaluation of the impact of 5-ASA switch using a proxy for relapse in a nonclinical setting. These data may have substantial implications for disease management, but before making firm conclusions, further research is needed.

Mycobacterial Disease in Renal Allograft Recipients

Implication for health policy/practice/research/medical education:Solid organ transplant recipients have impaired cell-mediated immunity, and are at increased risk of mycobacterial infection. Mycobacterium tuberculosis infection (TB) has a high mortality rate among this population. The diagnosis of tuberculosis in solid organ transplant recipients is a big challenge and needs rapid and accurate modalities. These patients have 3.8 time greater risk of developing extra-pulmonary TB than general population. High index of suspicion and applying with invasive diagnostic procedure are needed for diagnosis of TB in renal transplanted patients.

New Anticoagulants Offer Options Beyond Warfarin to Reduce Stroke Risk

THE EMERGENCE OF NEW ANTICOagulation medications to treat nonvalvular atrial fibrillation and reduce stroke risk has been mostly welcomed by the medical community. But identifying patients who will receive the most benefit from a particular drug remains a challenge, and wider use may be limited until bleeding risks and other concerns associated with the drugs are better understood. The prevalence of atrial fibrillation, which can cause blood clotting, continues to increase in the United States, with 1 in 4 individuals now being projected to develop the condition in his or her lifetime. Patients with atrial fibrillation have 5 times greater risk of stroke and are estimated to constitute 15% of all stroke victims and 30% of those whose strokes occur after age 80 years. Since the 1940s, and until recently, the only anticoagulation treatment to reduce stroke risk from atrial fibrillation was warfarin, a vitamin K antagonist. Warfarin reduces stroke risk by about two-thirds, but it is a difficult drug to manage. The medication, which is supposed to be taken for the rest of the patient’s life, interacts with food and other drugs, necessitating frequent coagulation monitoring and dose adjustments. Too high a dose increases bleeding risks, such as intracranial hemorrhage, while too low a dose makes the drug ineffective as an anticoagulation agent. Maintaining warfarin’s dose levels in the proper therapeutic range is difficult, with many patients achieving the target range less than 60% of the time. As such, an estimated one-third of patients with atrial fibrillation at risk for stroke either are not given warfarin or discontinue it once started. But now alternatives to warfarin are available to reduce stroke risk in patients with atrial fibrillation. In 2010, the US Food and Drug Administration (FDA) approved dabigatran etexilite, a small-molecule direct thrombin inhibitor anticoagulation agent, for this purpose. In 2011, the FDA approved rivaroxaban, a small-molecule oral direct

Abstract A35: Metabolomic profiling and the biochemical basis of prostate cancer racial disparity.

Abstract African American (AA) men have an approximately 60% higher incidence of prostate cancer and are at 2 times greater risk of dying of prostate cancer than European Americans (EA). Environmental and socio-economic factors as well as a number of genetic alterations have been previously interrogated as possible explanations for this disparity. Currently, little is known about the specific biological pathway differences in prostate cancer between AA and EA men that may help explain the greater burden borne by AA men with this disease. In this study, we seek to unravel and compare the prostate cancer metabolome of AA and EA men by employing state of the art metabolomic profiling and bioinformatic techniques. Based on the premise that metabolites are end products of enzyme action, we sought to identify a racially distinct biochemical signature for prostate cancer. Fifty-six prostate cancer tissue samples from AA and EA men and their adjacent benign tissues (i.e., matched normal/tumor pairs) were analyzed using an unbiased liquid chromatography-coupled mass spectrometry approach. Differential metabolites were mapped into pathways and combined with bioinformatics-based bioprocess mapping to categorize metabolic differences observed in cancers of AA and EA origin. Our data indicate a specific and largely mutually exclusive metabolic signature for AA and EA derived prostate cancers. These findings may have important clinical implications and, importantly, shed new light on the biological basis of prostate cancer racial disparity. Citation Format: Shaiju Kakkandan VareedKatrin Panzitt, Sumanta Basu, Vasanta Putluri, Tiffany Dorsey, Tiffany Wallace, Nagireddy Putluri, Sayeeduddin Mohammed, Michael Ittmann, Rick Kittles, George Michailidis, Stefan Ambs, Ganesh Palapattu, Arun Sreekumar. Metabolomic profiling and the biochemical basis of prostate cancer racial disparity. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A35.

Early Recognition of Pediatric Venous Thromboembolism: A Risk-Assessment Tool

The incidence of venous thromboembolism in children has increased dramatically, with most cases occurring in children with cancer, surgery, trauma, congenital heart disease, and systemic lupus erythematosus. Early assessment of risk factors present in children would minimize morbidity and mortality from these events. To evaluate the reliability and validity of a tool for assessing risk for venous thromboembolism in children. The tool was developed after a review of the literature with assessment of content validity by a multidisciplinary team of experts. Patients' charts were reviewed retrospectively to establish reliability and validity of the tool. A P value less than .05 was considered statistically significant. Thirty-five charts were assessed for tool validity and were found to be statistically significant for all 3 risk score assessment categories. Logistic regression was used to assess 1001 patients' charts for internal consistency, which was found to be high (χ(2)(5)[n = 1001] = 100.6, P < .001). Results indicated that most patients at risk for venous thromboembolism were between the ages of 13 and 17 years, with females having more than 7 times greater risk than males. Descriptive statistics show that the assessment tool displays strong reliability and validity. Results validated a significant relationship between the risk score and the incidence of venous thromboembolism. Findings suggest that use of the assessment tool could significantly reduce adverse outcomes associated with venous thromboembolism in children.

Abstract 4206: Identification of transcriptional regulatory motifs that control gene expression in premenopausal women with previous history of breast cancer

Abstract Background: Age is an important risk factor for Breast Cancer. Older women have a 50 times greater risk for breast cancer as compared to younger women (under the age of 30 years). Aging is associated with activation of specific transcription factor networks. We hypothesized that premature activation of these programs may predispose to cancer. The aims of this study were 1) to identify active transcription factor networks controlling the expression of specific cancer-related genes in the normal breast and 2) to analyze whether premature activation of this network is associated with neoplastic transformation. Methods: Fresh frozen normal breast tissue of women, under the age of 50 years, with and without history of breast cancer was obtained (ncancer=8, nnon cancer=4). Total RNA was extracted, cDNA annealed and Whole-genome DASL assay (Illumina Corp) was conducted to identify genes that correlated with cancer outcome in premenopausal women. Differential expression analysis was performed using Partek® software program to identify the up or down regulated genes in women with cancer compared to those without. Transcription factors affecting the regulation of genes in patients with cancer were predicted using MotifModeler program (Liu et al). The resulting data was confirmed using qPCR analysis. Results: Whole genome DASL analysis showed differential expression of 34 genes (p-value &amp;lt;0.01). MotifModeler analysis predicted 18 transcription factors as major regulators of gene expression in premenopausal women with previous history of breast cancer. JUNB and FOS were the most significantly altered in this comparison. qPCR pre-validated the over expression of JUNB and FOS in association with cancer development. Further validation studies in an independent cohort are ongoing using Formalin-fixed Paraffin-embedded (FFPE) samples. Conclusion: Gene expression analysis identified transcriptional features of cancer outcome. Differential expression of the JUNB and FOS family of proteins, which are part of AP-1 transcription factor complex, may be correlated with neoplastic transformation in premenopausal women. Breast Cancer Program of the IU Simon Cancer Center funded this project. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4206. doi:1538-7445.AM2012-4206

Abstract 5516: Race, age and advanced stage colorectal cancer survival

Abstract African Americans (AA) have worse stage-specific survival from colorectal cancer (CRC) compared to European Americans (EA), but the reasons for these differences are not well understood. To address this gap in understanding, and to examine racial differences in survival of patients with metastatic colorectal adenocarcinoma (mCRC) by age and prognostic tumor characteristics, we analyzed clinical data from Hollings Cancer Center (HCC) at the Medical University of South Carolina. Because metastatic disease has standard recommendations, a large racial difference in relative survival, and a documented change in chemotherapy usage in 2004, the dataset from HCC is ideal for this analysis. Data were collected by systematic medical record audits of patients diagnosed at HCC between June 2004 and June 2008 with follow-up through June of 2010. Analyses were designed to compare AA to EA by computing medical survival and hazard ratios (HR) and 95% CIs to model the hazard of death as a function of race, controlling for age, sex, and first-line chemotherapy treatment. We also assessed the interaction between race and age and race and clinicopathogic characteristics (i.e. histologic type, location, and grade) and their impact on survival. All tests of statistical significance were two-sided. Data from 82 (27 AA and 55 EA) patients with mCRC were evaluated. Overall survival between AA and EA differed by age, with the racial difference in survival most pronounced among younger (61 years - below the median) compared to older (≥ 61 years - above the median age) patients. Median survival among younger EA and AA was 31 months (95% CI 17-35 months) and 13 months (95% CI 6-17 months), respectively; among older patients, median survival for EA and AA was 22 months (95% CI 8-32 months) and 12 months (95% CI 3-α), respectively. In the younger group, AA had a 2.65 (95% CI 1.24-5.66) times greater risk of death than EA whereas in the older group there was no significant difference (HR 0.93 95% CI 0.39-2.21), a statistically significant interaction (p&amp;lt;0.03). Among the younger CRC cases, AA were more likely than EA to present with mucinous, lower-grade, and colonic carcinomas, even though the AA patients were more likely to die from non-mucinous (p for interaction = 0.04), rectal (p for interaction = 0.06), and higher-grade (p for interaction = 0.12) tumors. In conclusion, the overall poorer survival among AA was concentrated in the younger patients. Despite being less prevalent at diagnosis, the results also indicated that rectal location, non-mucinous histology, and higher tumor grade were associated with poorer survival among the young AA. The reasons for the overall racial disparity being concentrated in the younger patients in unexplained; future studies may consider the role of pathomolecular markers, medical comorbidities, and treatment-related factors to further elucidate etiologies of the disparities seen in younger AA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5516. doi:1538-7445.AM2012-5516

Amor and Psyche; a growing relationship?

Two interesting studies on the brain-heart connection were recently presented. At the 12th Annual Spring Meeting on Cardiovascular Nursing of the European Society of Cardiology (ESC) in Copenhagen, Denmark (16/17 March, 2012), Nikki Damen, a PhD student at Tilburg University, reported that patients who are depressed after coronary artery stenting have a worse prognosis. The authors reported that in patients with coronary stents depression was associated with a 1.5 times greater risk of death during a seven-year study period. The study included 1234 coronary artery disease patients in the Netherlands (mean age 62 years), who underwent assessment for depression six months after receiving a coronary stent. Depression was diagnosed in 324 (26 %) of the patients. After seven years follow-up, 187 of the patients had died, of whom 23 % of the patients with depression and 12 % of the patients without depression. The researchers found that gender and age were factors in the increased risk, with men and older patients significantly more likely to die during the study. However, the use of cholesterol-lowering statins was associated with a reduced risk of death among study participants. The intriguing Tilburg study awaits further publication. One possible reason for the increased risk of earlier death is that depressed patients may have less healthy lifestyles in terms of smoking, drinking alcohol, exercise and diet. It could also be that depression alters the activity of the sympathetic nervous system, resulting in increased blood pressure and heart rate. Finally it was proposed that these patients may also be less likely to take their medication. The authors therefore suggested that more research is needed to determine how to screen for depression in cardiovascular patients, and then how to provide adequate treatment. However, the pertinent question here is: which treatment? In this context, a recent paper from a Finnish group published by Honkola et al. [1] in the European Heart Journal showed that the use of psychotropic drugs, especially the combined use of antipsychotic and antidepressant drugs, was strongly associated with an increased risk of sudden cardiac death at the time of an acute coronary event. In a case–control study addressing a consecutive series of 1814 victims of sudden cardiac death (mean age 65 years), the authors compared the use of psychotropic medication between victims of sudden cardiac death and survivors of an acute coronary event. In particular it was shown that combined use of phenothiazines and any antidepressant was associated with a very high risk of sudden cardiac death (odds ratio 18.3; p < 0.001). One of the reasons may be the pro-arrhythmic effects of psychotropic drugs, resulting in prolonged QT intervals and torsades des pointes. This work coming from the University of Oulu, Finland, may elucidate the observed phenomenon that psychiatric patients have an excess rate of unexplained sudden death. In an accompanying Editorial, Josep Brugada [2] wonders whether this is a population at higher risk for sudden cardiac death who should be screened and treated accordingly, or is the treatment they receive the reason for the excess mortality, and thus the drugs administered to them should be carefully selected based on the probability of a proarrhythmic effect of the therapy? We are thus dealing with a two-edged sword. On one hand, cardiac patients with psychiatric disorders, in particular depression, are at increased risk of coronary events; on the other hand, psychotropic drugs administered to these patients can be pro-arrhythmic, especially in patients prone to myocardial ischaemia. Psychiatrists and cardiologists should work closely together to identify the optimal medication in cardiac patients with psychiatric disorders, in particular depression [3] Amor and Psyche should support each other, also in gloomy times [4, 5].

Low papaya consumption increases risk for low high‐density lipoprotein cholesterol in Mexican college applicants

Raising high‐density lipoprotein cholesterol (HDL‐C) via nutrition intervention is a challenge. Papaya fruit contains Carica papaya lipase, which may influence lipid metabolism. Our objective was to determine whether individuals consuming less papaya were at greater risk for low HDL‐C or other dyslipidemias. We focused on a subset of 339 Mexican college applicants (50.7% females) aged 18–25 years with complete data on a Mexican‐adapted Willett food frequency questionnaire and blood lipid profiles. Overall prevalence of low HDL‐C was 48.4%. Subjects were split into two consumption groups: &lt;3 or &gt;3 weekly papaya servings (mean intake 0.38 vs. 4.3 servings/week, P&lt;0.0001). There were no differences in blood lipid profiles between the two groups; however, females who consumed less than 3 servings of papaya per week were at 1.52 times greater risk (95%CI: 0.99–2.32, P=0.05) of having low HDL‐C after adjustment for age and family history of cardiovascular disease and diabetes. These findings were not observed in males. We did not observe risk for other at‐risk blood lipid measures. Consumption of at least 3 servings of papaya per week may prevent low HDL‐C in female Mexican college applicants.Grant Funding Source: This study was sponsored by C09‐PIFI‐030606 (UASLP); UIUC Center for Health Aging and Disability grant; and USDA NIFA Hatch Projects.

Bioperformance evaluation of various summer pasture and winter feeding strategies for cow-calf production

Legesse, G., Small, J. A., Scott, S. L., Kebreab, E., Crow, G. H., Block, H. C., Robins, C. D., Khakbazan, M. and McCaughey, W. P. 2012. Bioperformance evaluation of various summer pasture and winter feeding strategies for cow-calf production. Can. J. Anim. Sci. 92: 89–102. Bioperformance of two summer pasture and four winter feeding cow-calf production strategies in the western Canadian Parkland was evaluated. Diet composition and animal data were collected over 5 production years. Each production year began with fixed-time artificial insemination (TAI) of cows and turnout of cow-calf pairs (n=288 yr−1 including 76 primiparous replacement cows) assigned to either alfalfa-grass (AG, n=9 paddocks) or grass (G, n=9 paddocks) pastures until weaning. Post-weaning, pregnant cows (n=240 yr−1) were assigned to either extended-grazing (EG, n=120) of dormant regrowth of perennial pastures and swathed annual crops, or one of three diets fed in a drylot (DL): hay (HY, n=40), straw/barley (SB, n=40; 70% oat straw:30% steam-rolled barley grain DM), and silage/straw (SS, n=40; 40% barley silage:60% oat straw DM). Common diets were used for all treatment groups between the weaning and winter feeding period, as well as between the pre-calving and summer grazing period. Cow and calf body weight (BW) gains were higher (P&lt;0.05) for AG than G pasture until the third production year and the advantage diminished as the carrying capacity declined. The latter may be attributed to a lack of spring/summer moisture. Further, G pastures required more nitrogen fertilizer to achieve the same level of bioperformance as that of AG pastures in years 4 and 5. Cows in the EG treatment maintained BW better than those in the DL treatment (especially those cows receiving the SS diet) except in year 5 (P&lt;0.05) in which drought resulted in lower body weights for cows in the EG treatment. On all treatments, cows maintained BCS that supported reproductive function; however, fertility to TAI was lowest (P&lt;0.05) in years 4 and 5. Cows in the DL group had a 1.8 times greater risk of being culled before turnout and as a result lower (P&lt;0.05) rates of calf survival to weaning. In conclusion, AG pastures and EG are important alternatives to further develop for cow-calf production in western Canada.