Tissue-Specific Effects of Loss of Estrogen during Menopause and Aging

The roles of estrogens have been best studied in the breast, breast cancers, and in the female reproductive tract. However, estrogens have important functions in almost every tissue in the body. Recent clinical trials such as the Women’s Health Initiative have highlighted both the importance of estrogens and how little we know about the molecular mechanism of estrogens in these other tissues. In this review, we illustrate the diverse functions of estrogens in the bone, adipose tissue, skin, hair, brain, skeletal muscle and cardiovascular system, and how the loss of estrogens during aging affects these tissues. Early transcriptional targets of estrogen are reviewed in each tissue. We also describe the tissue-specific effects of selective estrogen receptor modulators (SERMs) used for the treatment of breast cancers and postmenopausal symptoms

BRCA1 Forms a Functional Complex with γ-H2AX as a Late Response to Genotoxic Stress

Following genotoxic stress, the histone H2AX becomes phosphorylated at serine 139 by the ATM/ATR family of kinases. The tumor suppressor BRCA1, also phosphorylated by ATM/ATR kinases, is one of several proteins that colocalize with phospho-H2AX (γ-H2AX) at sites of active DNA repair. Both the precise mechanism and the purpose of BRCA1 recruitment to sites of DNA damage are unknown. Here we show that BRCA1 and γ-H2AX form an acid-stable biochemical complex on chromatin after DNA damage. Maximal association of BRCA1 with γ-H2AX correlates with reduced global γ-H2AX levels on chromatin late in the repair process. Since BRCA1 is known to have E3 ubiquitin ligase activity in vitro, we examined H2AX for evidence of ubiquitination. We found that H2AX is ubiquitinated at lysines 119 and 119 in vivo and that blockage of 26S proteasome function stabilizes γ-H2AX levels within cells. When BRCA1 levels were reduced, ubiquitination of H2AX was also reduced, and the cells retained higher levels of phosphorylated H2AX. These results indicate that BRCA1 is recruited into stable complexes with γ-H2AX and that the complex is involved in attenuation of the γ-H2AX repair signal after DNA damage

Inflammation and changes in cytokine levels in neurological feline infectious peritonitis.

Feline infectious peritonitis (FIP) is a progressive, fatal, predominantly Arthus-type immune-mediated disease that is triggered when cats are infected with a mutant enteric coronavirus. The disease presents variably with multiple organ failure, seizures, generalized effusion, or shock. Neurological FIP is clinically and pathologically more homogeneous than systemic 'wet' or 'dry' FIP; thus, comparison of cytokine profiles from cats with neurological FIP, wet FIP, and non-FIP neurological disease may provide insight into some baseline characteristics relating to the immunopathogenesis of neurological FIP. This study characterizes inflammation and changes in cytokines in the brain tissue of FIP-affected cats. Cellular infiltrates in cats with FIP included lymphocytes, plasma cells, neutrophils, macrophages, and eosinophils. IL-1 beta, IL-6, IL-12, IL-18, TNF-alpha, macrophage inhibitory protein (MIP)-1 alpha, and RANTES showed no upregulation in the brains of control cats, moderate upregulation in neurological FIP cats, and very high upregulation in generalized FIP cats. Transcription of IFN-gamma appeared upregulated in cats with systemic FIP and slightly downregulated in neurological FIP. In most cytokines tested, variance was extremely high in generalized FIP and much less in neurological FIP. Principal components analysis was performed in order to find the least number of 'components' that would summarize the cytokine profiles in cats with neurological FIP. A large component of the variance (91.7%) was accounted for by levels of IL-6, MIP-1 alpha, and RANTES. These findings provide new insight into the immunopathogenesis of FIP and suggest targets for immune therapy of this disease

3',4'-Dihydroxyflavonol antioxidant attenuates aiastolic dysfunction and cardiac remodeling in streptozotocin-induced diabetic m(Ren2)27 rats

Background Diabetic cardiomyopathy (DCM) is an increasingly recognized cause of chronic heart failure amongst diabetic patients. Both increased reactive oxygen species (ROS) generation and impaired ROS scavenging have been implicated in the pathogenesis of hyperglycemia-induced left ventricular dysfunction, cardiac fibrosis, apoptosis and hypertrophy. We hypothesized that 3',4'-dihydroxyflavonol (DiOHF), a small highly lipid soluble synthetic flavonol, may prevent DCM by scavenging ROS, thus preventing ROS-induced cardiac damage. Methodology/Principal Findings Six week old homozygous Ren-2 rats were randomized to receive either streptozotocin or citrate buffer, then further randomized to receive either DiOHF (1 mg/kg/day) by oral gavage or vehicle for six weeks. Cardiac function was assessed via echocardiography and left ventricular cardiac catheterization before the animals were sacrificed and hearts removed for histological and molecular analyses. Diabetic Ren-2 rats showed evidence of diastolic dysfunction with prolonged deceleration time, reduced E/A ratio, and increased slope of end-diastolic pressure volume relationship (EDPVR) in association with marked interstitial fibrosis and oxidative stress (all P<0.05 vs control Ren-2). Treatment with DiOHF prevented the development of diastolic dysfunction and was associated with reduced oxidative stress and interstitial fibrosis (all P<0.05 vs untreated diabetic Ren-2 rats). In contrast, few changes were seen in non-diabetic treated animals compared to untreated counterparts. Conclusions Inhibition of ROS production and action by DiOHF improved diastolic function and reduced myocyte hypertrophy as well as collagen deposition. These findings suggest the potential clinical utility of antioxidative compounds such as flavonols in the prevention of diabetes-associated cardiac dysfunction

Medical Students in Microscopic Anatomy and Pathology Laboratories: Design of an E-Learning Histology and Histopathology Atlas

Computer-assisted learning, also known as e-learning, has been successfully implemented to educate students in anatomical knowledge as well as transferable skills, such as critical analysis, teamwork, leadership and communication. E-learning allows students to self-teach material at their own paces and provides a platform for team-based laboratory approaches. Several institutions have already integrated histology and physiology in team based laboratory approaches, but integration of histology and pathology instruction has been done to a lesser extent. Our aim was to develop an e-learning atlas that integrates microanatomy and pathology laboratory for an interdisciplinary pre-clinical medical curriculum. A multidisciplinary team of teaching faculty and students developed an online atlas (microanatomyatlas.com) that includes a library of histology and histopathology images. Traditional laboratory manual instructions and study objectives were added onto the digital interface and made interactive by linking it to specific labeled images to allow for self- testing. Online clinical case studies involving a disease entity in a specific organ system were incorporated, which allows students to toggle between the normal as well as the pathological slides involving the disease as they apply their clinical reasoning skills to arrive at the correct diagnosis. We are collecting data on the number and frequency of students using the atlas. We are also administering a detailed survey to assess student satisfaction and learning. To assess the impact of this new teaching tool, a comparative study of two years of student performance and course evaluations between students who used the online atlas and students who did not use the online atlas in the pre-clinical medical curriculum will be conducted. Our preliminary data so far shows that student feedback has been positive and an e-learning atlas integrating microanatomy and pathology laboratory may be an essential tool that guides the studies and enhances the performance of students in an interdisciplinary pre-clinical medical curriculum. DISCLOSURES/ACKNOWLEDGEMENTS: American Educational Institute, University and Campus Management (AEIUCM) developed, designed, and maintains the online portal

Medical Students in Microscopic Anatomy and Pathology Laboratories: Design of an E-Learning Histology and Histopathology Atlas as an Evolving Response to Interdisciplinary Pre-Clinical Curricular Needs

E-learning, also known as computer-assisted learning, successfully bridges anatomical knowledge and transferrable skills, such as critical analysis, teamwork, leadership and communication. Several institutions have already integrated histology and physiology in team based laboratory approaches, but integration of histology and pathology instruction has been done to a lesser extent. Our aim was to develop an e-learning atlas that integrates microanatomy and pathology laboratory for an interdisciplinary pre-clinical medical curriculum. A multidisciplinary team of teaching faculty and students developed an online atlas (microanatomyatlas.com) that includes a library of histology and histopathology images. Traditional laboratory manual instructions and study objectives were added onto the digital interface and made interactive by linking it to specific labeled images to allow for self-testing. Online clinical case studies involving a disease entity in a specific organ system were incorporated, which allows students to toggle between the normal as well as the pathological slides involving this disease as they apply their clinical reasoning skills to arrive at the correct diagnosis. Data is being collected on the number and frequency of students using the atlas. Also, a detailed survey to assess student satisfaction and learning will be administered. To assess the impact of this new teaching tool, a comparative study of two years of student performance and course evaluations between students who used the online atlas and students who did not use the online atlas in the pre-clinical medical curriculum will be conducted. Our preliminary data so far shows that student feedback has been positive and an e-learning atlas integrating microanatomy and pathology laboratory may be an essential tool that guides the studies and enhances the performance of students in an interdisciplinary pre-clinical medical curriculum. Disclosures/Acknowledgements: American Educational Institute, University and Campus Management (AEIUCM) developed, designed, and maintains the online portal

Predictors and associations with outcomes of length of hospital stay in patients with acute heart failure: results from VERITAS

Background: The length of hospital stay (LOS) is important in patients admitted for acute heart failure (AHF) because it prolongs an unpleasant experience for the patients and adds substantially to health care costs. Methods and Results: We examined the association between LOS and baseline characteristics, 10-day post-discharge HF readmission, and 90-day post-discharge mortality in 1347 patients with AHF enrolled in the VERITAS program. Longer LOS was associated with greater HF severity and disease burden at baseline; however, most of the variability of LOS could not be explained by these factors. LOS was associated with a higher HF risk of both HF readmission (odds ratio for 1-day increase: 1.08; 95% confidence interval [CI] 1.01–1.16; P = .019) and 90-day mortality (hazard ratio for 1-day increase: 1.05; 95% CI 1.02–1.07; P < .001), although these associations are partially explained by concurrent end-organ damage and worsening heart failure during the first days of admission. Conclusions: In patients who have been admitted for AHF, longer length of hospital stay is associated with a higher rate of short-term mortality. Clinical Trial Registration: VERITAS-1 and -2: Clinicaltrials.gov identifiers NCT00525707 and NCT00524433

ВЛИЯНИЕ ВИДА ДВИЖЕНИЯ ЗЕРНОВОГО ВОРОХА В ГОРИЗОНТАЛЬНОМ ЦИЛИНДРИЧЕСКОМ РЕШЕТЕ НА ИНТЕНСИВНОСТЬ ПРОЦЕССА СЕПАРАЦИИ

The new technique is proposed to estimate the process of grain heap separation in a horizontal cylinder sieve that allows to determine the separation coefficient and detect small admixtures completely in dynamics, admixtures are detected after each 5–10 simultaneously for each of the 12 sites in the sieve surface. The experimental data obtained from this technique allow to have the following questions answered. How much time does it take for the grain to be in the working part in order to obtain the completeness assigned for admixture detecting? In which part of the sieve surface can admixture be detected? What is the way the grain heap movement mode in the sieve influences the intensity of the separation process? The paper provides the experimental data on identifying the completeness of admixtures detection and the coefficient of the separation process intensity for the cylinder sieve following the rolling, shuttle-rolling, mixed and new grain portion movement mode, designed by the authors, in different cultivars and with different levels of its being filled with grain [1]. The experiments showed that the most intensive separation process runs when grain heap movement by portions mode in the cylinder sieve where the coefficient of sieve surface utilization constitutes over 0.75, but the cinematic mode of the sieve is within 1.5–2.Предложена новая методика оценки процесса сепарации зернового вороха в горизонталь- ном цилиндрическом решете, позволяющая определить коэффициент сепарации и  полноту выделения мелких примесей в динамике через каждые 5–10 с одновременно для каждого из 12 участков поверхности решета. Результаты экспериментальных исследований, проведенных по данной методике, позволяют получить ответы на следующие вопросы. Сколько времени зерно должно находиться в рабочем органе, чтобы получить заданную полноту выделения примесей? На какой части поверхности решета выделяются примеси? Как влияет режим движения зернового вороха в  решете на интенсивность процесса сепарации? В  статье приведены результаты опытов по определению полноты выделения примесей и коэффициента интенсивности процесса сепарации для цилиндрического решета на перекатном, челночно-перекатном, смешанном и новом, открытом авторами, порционном режиме движения зернового вороха на различных культурах с разной степенью его заполнения зерном. Опыты показали, что наиболее интенсивно процесс сепарации идет при порционном режиме движения зернового вороха в цилиндрическом решете, при котором коэффициент использования поверхности решета составляет более 0,75, а кинематический режим решета находится в пределах 1,5–2