FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis

The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21-/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1α or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21-/- and control mice. However, in FGF21-/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis.     

Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.     

ER,PR, and Her2 immunocytochemistry on cell‐transferred cytologic smears of primary and metastatic breast carcinomas: A Comparison Study With Formalin‐Fixed Cell Blocks and Surgical Biopsies

The use of formalin‐fixed cell blocks (CBs) for detection of ER, PR, and Her2 status of primary and metastatic breast carcinomas sampled by fine‐needle aspiration (FNA) has been extensively used in clinical practice; however, CBs sometimes lack adequate cellularity even when direct smears are cellular. The aim of this study is to assess the reliability of ER, PR, and Her2 status as demonstrated by immunocytochemical staining (ICC) on alcohol‐fixed direct smears using the cell transfer (CT) technique. FNA cases diagnosed as primary or metastatic breast carcinoma in which the status of ER, PR, and Her2 had been determined either on CB or concurrent biopsy were identified over a period of 18 months. ICC for ER, PR, and Her2 was performed on alcohol‐fixed direct smears using the CT technique. Results were compared with those reported for the corresponding formalin‐fixed tissue. A total of 47 FNA specimens from 46 patients were included in this study. ICC results were excluded from analysis if the CT smear contained fewer than 50 cells. Correlation between the ICC performed on the CT smears and the corresponding CB or biopsy revealed a sensitivity rate for ER, PR, and Her2 of 95%, 90%, and 88%, respectively with a specificity of 100% for all three markers. ICC performed on the FNA smears using the CT technique is a reliable method for assessment of the ER, PR, and Her2 status of breast carcinomas, especially when the direct smears are highly cellular and the CB lacks adequate cellularity. Diagn. Cytopathol. 2013. © 2012 Wiley Periodicals, Inc.     

Correlation of blood pressure readings from 6-hour intervals with the daytime period of 24-hour ambulatory blood pressure monitoring in pediatric patients

J Clin Hypertens (Greenwich). 2012; 14:396–400. ©2012 Wiley Periodicals, Inc.Shorter‐interval (6‐hour) ambulatory blood pressure monitoring (ABPM) has been shown to correlate well with 24‐hour ABPM in adults, but this has not been studied in children. The authors selected 131 patients aged 9 to 18 who underwent 24‐ABPM from 2000–2008. Six‐hour intervals beginning at different start times were compared with the daytime and 24‐hour period, with subset analysis for normotensive and hypertensive patients. Concordance correlation coefficients (CCCs) were used to assess for agreement. Among normotensive patients, the mean difference between daytime and 6‐hour intervals ranged from −0.1 mm Hg to 0.0 mm Hg for diastolic blood pressure (DBP) and −1.1 mm Hg to 0.6 mm Hg for systolic blood pressure (SBP) with CCCs of 0.88 to 0.93 for DBP and 0.93 to 0.96 for SBP. For hypertensive patients, mean difference ranged from −0.6 to 1.3 mm Hg for DBP and −0.8 to 1.1 mm Hg for SBP with CCCs of 0.89 to 0.98 for DBP and 0.86 to 0.95 for SBP. Shorter‐interval monitoring correlates significantly with full daytime monitoring in children, allowing for assessment of blood pressure with improved convenience.

Hypertension is one of the leading health care problems in the United States. The incidence of hypertension in children prior to the past decade was 1% to 3%. Recent reports confirm an increase in the average blood pressure (BP) in children with a prevalence of hypertension as high as 4.5% in school‐aged children. ¹ Currently, studies evaluating end organ structures demonstrate hypertension as a risk factor for development of left ventricular hypertrophy ² and carotid artery intimal‐medial thickness. ³ Clinic BP (CBP) is the standard for measuring BP in the office; however, ambulatory BP monitoring (ABPM) is becoming the preferred standard for evaluation of children with suspected hypertension. The indications for use of an ABPM device continue to grow and prompted the American Heart Association (AHA) in 2008 to publish a scientific statement providing guidelines on the use and the interpretation of ABPM in the pediatric population. ⁴ One indication for ABPM includes identifying children at greater risk for end organ damage. The ABPM results are a stronger predictor of hypertension‐associated target organ damage compared with CBP. ⁵ , ⁶ , ⁷ The 2008 AHA scientific statement outlines utilization of 24‐hour ABPM. Many families may find 24‐hour monitoring too burdensome or too costly. As such, one option is to order a shorter interval of monitoring. To date, nothing in the literature has provided evidence on the efficacy of shorter intervals of monitoring for the diagnosis of hypertension among children. Several studies have evaluated shorter intervals among the adult population. Ernst and colleagues ⁸ found that 6‐hour monitoring can approximate mean 24‐hour BP results; however, it does not provide information about circadian variations. Graves and colleagues ⁹ report 6‐hour monitoring as comparable to accurate office measurements without the limitations of poor reproducibility and observer bias. Two older studies ¹⁰ , ¹¹ concluded that 3 or 4 readings per hour during a shorter interval correlated with mean daytime pressures by 24‐hour ABPM.Given the option of 6‐hour ABPM at our institution and the recommendations for the use of 24‐hour monitoring, the evaluation of the concordance between the shorter and longer intervals could provide guidance for clinicians as well as increase power of future research studies on ABPM in children. The aim of this study was to determine whether mean and median systolic BP (SBP) and diastolic BP (DBP) from a 6‐hour daytime interval correlate with statistical significance with the mean and median daytime and 24‐hour SBP and DBP among pediatric patients who have undergone 24‐ABPM.     

Return to work after coronary artery bypass surgery. A 10-year follow-up study

Multislice Computed Tomography Coronary Angiography (CTCA) has emerged as a promising non-invasive modality for the detection of coronary artery stenosis. Image quality is still limited when compared to conventional coronary angiography. However, CTCA has been demonstrated to be highly reliable to rule out coronary artery stenosis. Technological improvements and the combination of CTCA with other non-invasive modalities are expected to further increase diagnostic accuracy. Although CTCA has clearly left the research environment, the precise role of CTCA in the diagnostic work-up of coronary artery disease needs further research.     

Evaluation of Training Program for the Maternal and Child Health Workforce at Tulane University

Objectives Despite significant investments in Maternal and Child Health (MCH), the United States still lags behind other countries in key MCH indicators. A well-trained workforce is needed to improve MCH. The Division of MCH Workforce Development of HRSA’s Maternal and Child Health Bureau provides funding to schools of Public Health to support Centers of Excellence in MCH, which is focused on preparing the next generation of MCH leaders through specialized training and mentorship. One such center, the Tulane Center of Excellence in MCH (CEMCH), is housed at the Tulane University School of Public Health and Tropical Medicine. This study evaluated the perceived effectiveness and acceptability of the CEMCH leadership training program. Methods A mixed-methods approach was used, consisting of semi-structured interviews and quantitative surveys which were analyzed through inductive methods based in grounded theory and non-parametric methods respectively. Results Results indicated an overall high level of program satisfaction by all stakeholders. Mentorship and personal attention emerged as an important benefit for both former and current Scholars. The opportunity to gain real-world understanding of MCH work through program activities was an added benefit, although these activities also presented the most challenges. Community stakeholders generally did not view the program as providing immediate organizational benefit, but recognized the distal benefit of contributing to a well-trained MCH workforce. Conclusions for Practice These results will be used to inform other MCH training programs and strengthen Tulane’s CEMCH. A well-trained MCH workforce is essential to improving MCH, and high-quality training its foundation.